Nitrogen-containing macrocycle derivative regulator, preparation method therefor, and use thereof

Abstract

The present invention relates to a nitrogen-containing macrocycle derivative regulator, a preparation method therefor, and a use thereof. In particular, the present invention relates to a compound represented by general formula (A), a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof as a regulator in the preparation of a drug for treating metabolic diseases and related diseases, each substituent in general formula (A) being as defined in the description.

Description

A nitrogen-containing macrocyclic compound derivative modifier, its preparation method and application Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a nitrogen-containing macrocyclic compound derivative modifier, its preparation method, and its application. Background Technology

[0002] Diabetes mellitus is a common endocrine and metabolic disease caused by metabolic disorders resulting from various factors, leading to damage to multiple systems and organs. It has a high incidence rate, with approximately 425 million people living with diabetes worldwide. In China, the incidence rate is about 10%, with type 2 diabetes accounting for 90% of cases. Moreover, the prevalence is increasing, and the age of onset is becoming increasingly younger.

[0003] Currently, there are many types of drugs available for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and α-glucosidase inhibitors, among which GLP-1 receptor agonists have attracted the most attention.

[0004] GLP-1 is a peptide hormone secreted by L cells in the human intestine. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, neurons in the central nervous system, and peripheral nervous system. Activation of GLP-1 receptors promotes insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays gastric emptying. Clinical evidence shows that compared to other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effects and are less likely to cause side effects such as hypoglycemia. Furthermore, they offer additional cardiovascular benefits and can reduce food intake and delay gastric emptying, which is beneficial for weight control.

[0005] Currently available GLP-1 receptor agonists are all peptide drugs, most of which require subcutaneous administration, leading to poor patient compliance. Furthermore, the bioavailability of orally administered peptides is very low. Therefore, there is a significant clinical need to develop oral small-molecule GLP-1 receptor agonists.

[0006] Currently, no small molecule GLP-1 receptor agonists have been approved. Three small molecule GLP-1 receptor agonists have entered clinical trials: PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv, all currently in Phase I / II clinical trials. PF-06882961, in particular, has demonstrated significant blood glucose and weight-reducing effects in early clinical trials, with a safety profile similar to peptide GLP-1 receptor agonists. It is expected to provide more treatment options for patients with diabetes, obesity, and NASH in the future.

[0007] There is a significant clinical need for GLP-1 receptor agonists. Lower-cost, better-compliant oral small-molecule GLP-1 receptor agonists have the potential to treat a variety of metabolic diseases and possess a broad market prospect. Summary of the Invention

[0008] The object of this invention is to provide a compound of general formula (A) or (A'), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] X1 or X2 is selected from C or N;

[0011] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents of a 5-10 heteroaryl group are substituted;

[0012] Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -NR a6 S(O)2R b6 One or more substituents in it are replaced;

[0013] Ring N is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0014] R 11 Existence or non-existence;

[0015] When R 11 When it exists, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0016] or,

[0017] R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R15 and R 12 Each carbon atom is independently linked to form a 0-20 member carbon chain, which may contain 0-10 heteroatoms; when the carbon chain is 0 members, it contains at least one heteroatom.

[0018] The condition is R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 At least one of them is linked to form a 0-20 quinary carbon chain, optionally containing 0-10 heteroatoms; wherein when the carbon chain is 0 quinary, it contains at least one heteroatom;

[0019] n1-n9 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0020] m1-m7 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0021] In a further preferred embodiment of the invention, the compound of general formula (A) or (A'):

[0022] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0023] Preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15Each of the groups is independently selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl, or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl, or oxetane is optionally further substituted by one or more substituents selected from halogen, methoxy, or deuterated methyl.

[0024] In a further preferred embodiment of the invention, the compound of general formula (A) or (A'):

[0025] Ring M is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl; optionally further halogenated, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0026] Preferably, ring M is selected from C 3-8 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S; optionally further substituted with one or more substituents selected from methyl, hydroxyl or oxo;

[0027] More preferably, ring M is selected from Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo;

[0028] More preferably, for Optionally, it may be further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo.

[0029] In a further preferred embodiment of the invention, the compound of general formula (A) or (A'):

[0030] Ring N is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 quinone heteroaryl;

[0031] Preferably, ring N is selected from C 3-6 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S;

[0032] More preferably, cycloN is selected from cyclopropyl or

[0033] In a further preferred embodiment of the invention, the compound of general formula (A) or (A'):

[0034] R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0035] Preferably, R 11 The molecule is selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl, or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl, or oxetane is optionally further substituted with one or more substituents selected from halogen, methoxy, or deuterated methyl.

[0036] In a further preferred embodiment of the invention, the compound of general formula (A) or (A'):

[0037] R4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 Each carbon atom is independently linked to form a 1-15 member carbon chain, which may contain 0-6 heteroatoms selected from S, O or N; when the carbon chain is 0 members, it contains at least one heteroatom.

[0038] Preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 They connect independently to form -O- and -(CH2). n1 -、-(O) m1 -(CH2) n2 -(O) m2 -(CH2) n3 -(O) m3 -(CH2)n4 -(O) m4 -(CH2) n5 -or-(CH2) n6 -(O) m5 -(CH2) n7 -(O) m6 -(CH2) n8 -(O) m7 -(CH2) n9 -;

[0039] More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 They can be independently linked together to form 11-membered carbon chains containing 1 heteroatom, 12-membered carbon chains containing 2 heteroatoms, 10-membered carbon chains containing 2 heteroatoms, 9-membered carbon chains containing 2 heteroatoms, 8-membered carbon chains containing 4 heteroatoms, 12-membered carbon chains containing 3 heteroatoms, 9-membered carbon chains containing 3 heteroatoms, 8-membered carbon chains containing 3 heteroatoms, 3-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 1 heteroatom, 1-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 2 heteroatoms, 4-membered carbon chains containing 2 heteroatoms, or 6-membered carbon chains containing 3 heteroatoms.

[0040] More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 Each and each independently connected to form

[0041] The object of this invention is to provide a compound of general formula (I) or (I'), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0042] in,

[0043] X1 or X2 is selected from C or N;

[0044] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0045] Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -NR a6 S(O)2R b6 One or more substituents in it are replaced;

[0046] R 11 Existence or non-existence;

[0047] When R 11 When it exists, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0048] or,

[0049] R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each carbon atom is independently linked to form a 0-20 member carbon chain, which may contain 0-10 heteroatoms; when the carbon chain is 0 members, it contains at least one heteroatom.

[0050] The condition is R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R2 and R 10 R 2 and R 11 Or R 2 and R 12 At least one of them is linked to form a 0-20 quinary carbon chain, optionally containing 0-10 heteroatoms; wherein when the carbon chain is 0 quinary, it contains at least one heteroatom;

[0051] n1-n9 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0052] m1-m7 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0053] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is:

[0054] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0055] Preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each of the following is independently selected from fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl or oxetane is optionally further substituted by one or more substituents selected from halogen, methoxy or deuterated methyl.

[0056] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is:

[0057] Ring M is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl; optionally further halogenated, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0058] Preferably, ring M is selected from C 3-8 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S; optionally further substituted with one or more substituents selected from methyl, hydroxyl or oxo;

[0059] More preferably, ring M is selected from Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo;

[0060] More preferably, for Optionally, it may be further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo.

[0061] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is:

[0062] R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0063] Preferably, R 11The molecule is selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl, or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl, or oxetane is optionally further substituted with one or more substituents selected from halogen, methoxy, or deuterated methyl.

[0064] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is:

[0065] R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each carbon atom is independently linked to form a 1-15 member carbon chain, which may contain 0-6 heteroatoms selected from S, O or N; when the carbon chain is 0 members, it contains at least one heteroatom.

[0066] Preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 They connect independently to form -O- and -(CH2). n1 -、-(O) m1 -(CH2) n2 -(O) m2 -(CH2) n3 -(O) m3 -(CH2) n4 -(O) m4 -(CH2) n5 -or-(CH2)n6 -(O) m5 -(CH2) n7 -(O) m6 -(CH2) n8 -(O) m7 -(CH2) n9 -;

[0067] More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 They can be independently linked together to form 11-membered carbon chains containing 1 heteroatom, 12-membered carbon chains containing 1 heteroatom, 8-membered carbon chains containing 4 heteroatoms, 10-membered carbon chains containing 2 heteroatoms, 8-membered carbon chains containing 3 heteroatoms, 1-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 2 heteroatoms, 4-membered carbon chains containing 2 heteroatoms, or 6-membered carbon chains containing 3 heteroatoms.

[0068] More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each and each independently connected to form

[0069] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is:

[0070] More preferably, R 4 and R 5R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 They can be independently linked together to form 11-membered carbon chains containing 1 heteroatom, 12-membered carbon chains containing 2 heteroatoms, 10-membered carbon chains containing 2 heteroatoms, 9-membered carbon chains containing 2 heteroatoms, 8-membered carbon chains containing 4 heteroatoms, 12-membered carbon chains containing 3 heteroatoms, 9-membered carbon chains containing 3 heteroatoms, 8-membered carbon chains containing 3 heteroatoms, 3-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 1 heteroatom, 1-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 2 heteroatoms, 4-membered carbon chains containing 2 heteroatoms, or 6-membered carbon chains containing 3 heteroatoms.

[0071] More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each and each independently connected to form

[0072] In a further preferred embodiment of the present invention, the compound of general formula (I) or (I') is further shown as of general formula (I-1), (I-2), (I'-1), or (I'-2):

[0073] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is further shown as of general formula (II) or (II'):

[0074] in,

[0075] X1, X2, X3, X4, X5, X6, X7, X8, or X9 may or may not exist;

[0076] The condition is that X1, X2, X3, X4, X5, X6, X7, X8, or X9 cannot all be absent at the same time;

[0077] When X1, X2, X3, X4, X5, X6, X7, X8, or X9 exists, each of X1, X2, X3, X4, X5, X6, X7, X8, or X9 is independently selected from (CH2). q1 Or O;

[0078] q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0079] Ring M, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 13 The definition is as stated in general formula (I) or (I').

[0080] In a further preferred embodiment of the invention, the compound of general formula (II) or (II') is further shown as of general formula (II-1) or (II'-1):

[0081] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is further shown as of general formula (III) or (III'):

[0082] in,

[0083] L1, L2, L3, L4, L5, or L6 may or may not exist;

[0084] The condition is that L1, L2, L3, L4, L5, or L6 cannot all be absent at the same time;

[0085] When L1, L2, L3, L4, L5, or L6 exists, each of L1, L2, L3, L4, L5, or L6 is independently selected from (CH2). q2 Or O;

[0086] q2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0087] Ring M, R 2 R 3 R 4 R 5 R 7 R 8 R 9 R 10 R 11 R 12 R 13 The definition is as stated in general formula (I) or (I').

[0088] In a further preferred embodiment of the invention, the compound of general formula (III) or (III') is further shown as of general formula (III-1) or (III'-1):

[0089] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is further shown as of general formula (IV) or (IV'):

[0090] in,

[0091] M1, M2, M3, M4, M5, or M6 may or may not exist;

[0092] The condition is that M1, M2, M3, M4, M5, or M6 cannot all be absent at the same time;

[0093] When M1, M2, M3, M4, M5, or M6 are present, each of M1, M2, M3, M4, M5, or M6 is independently selected from (CH2). q3 Or O;

[0094] q3 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0095] Ring M, R 1 R 2 R 3 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 The definition is as stated in general formula (I) or (I').

[0096] In a further preferred embodiment of the invention, the compound of general formula (IV) or (IV') is further shown as of general formula (IV-1) or (IV'-1):

[0097] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is further shown as of general formula (V) or (V'):

[0098] in,

[0099] N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 Existence or non-existence;

[0100] The condition is N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 They cannot both be absent at the same time;

[0101] When N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 When present, N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 Each is independently selected from (CH2). q4 Or O;

[0102] q4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0103] Ring M, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 The definition is as stated in general formula (I) or (I').

[0104] In a further preferred embodiment of the invention, the compound of general formula (V) or (V') is further shown as of general formula (V-1) or (V'-1):

[0105] In a further preferred embodiment of the invention, the compound of general formula (I) or (I') is further shown as of general formula (VI) or (VI'):

[0106] in,

[0107] Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 Existence or non-existence;

[0108] The condition is Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y10 They cannot both be absent at the same time;

[0109] When Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 When present, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 Each is independently selected from (CH2). q5 Or O;

[0110] q5 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0111] Ring M, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 The definition is as stated in general formula (I) or (I').

[0112] In a further preferred embodiment of the invention, the compound of general formula (VI) or (VI') is further shown as of general formula (VI-1) or (VI'-1):

[0113] In a further preferred embodiment of the invention, the compound of general formula (A) or (A') is further shown as of general formula (VII) or (VII'):

[0114] in,

[0115] O1, O2, O3, O4, O5, O6, O7, O8, or O9 may or may not exist;

[0116] The condition is that O1, O2, O3, O4, O5, O6, O7, O8, or O9 cannot be absent simultaneously;

[0117] When O1, O2, O3, O4, O5, O6, O7, O8, or O9 are present, each of O1, O2, O3, O4, O5, O6, O7, O8, or O9 is independently selected from (CH2). q6 Or O;

[0118] q6 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0119] Ring M, R 2 R 3 R4 R 5 R 6 R 7 R 8 R 9 R 11 R 13 The definition is as stated in general formula (A) or (A').

[0120] In a further preferred embodiment of the invention, the compound of general formula (VII) or (VII') is further shown as of general formula (VII-1) or (VII'-1):

[0121] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0122] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0123] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0124] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0125] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its prodrug, its stereoisomer or its pharmaceutically acceptable salt is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0126] In some embodiments of the invention, the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof may be administered by any convenient method, such as by oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0127] In some embodiments of the invention, the compound, its prodrug, its stereoisomer, or its pharmaceutically acceptable salt may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0128] The present invention further relates to the use of any of the general formula compounds shown, their prodrugs, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of GLP-1 receptor agonist drugs.

[0129] The present invention further relates to the use of compounds of the general formula, their prodrugs, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating metabolic-related diseases, wherein the diseases are selected from diabetes, obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.

[0130] The present invention further relates to a method of preparing a medicament for treating metabolic diseases and related diseases using compounds of the general formula, prodrugs thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0131] The present invention also relates to a method for treating, preventing, and / or treating metabolic-related diseases, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0132] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to GLP-1 receptor modulators.

[0133] The present invention also relates to a method for treating metabolic disease-related diseases in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0134] Detailed description of the invention

[0135] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0136] The term "carbon chain" refers to a long chain formed by carbon atoms connected by single, double, or triple bonds, optionally containing heteroatoms, preferably N, O, or S; where 0-20 members refer to the length of the carbon chain, i.e., the number of carbon atoms in the molecule. Non-limiting examples include methane (CH4) as a monovalent carbon chain, ethane (C2H6) as a binary carbon chain, and -CH2CH2OCH2- as a ternary carbon chain containing one heteroatom. It is an 11-membered carbon chain containing one heteroatom.

[0137] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0138] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0139] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0140] The term "alkenyl" refers to an alkenyl group in which one hydrogen atom is further substituted, for example, "vinylene" refers to -CH2=CH2-, and "propenylene" refers to -CH2-=CH2-CH2-, etc. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0141] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0142] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0143] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0144] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0145] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0146] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; even more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, aziridine, oxacyclobutane, oxacyclohexane, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, etc.; preferably pyrrolidinyl, aziridine, oxacyclobutane, tetrahydrofuranyl, pyrazolyl, morpholinyl, etc. Piperazinyl and pyranyl; furthermore, pyrrolyl, azirrocyclobutyl, oxetaneyl, oxetanehexyl, piperidinyl, Piperazinyl and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0147] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0148] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0149] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0150] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0151] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0152] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0153] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0154] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0155] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0156] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0157] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0158] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0159] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0160] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms. The alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0161] "Alkyne" refers to (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms. The alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0162] The term "ethynyl" refers to a group where one hydrogen atom of the alkynyl group is further substituted; for example, "ethynyl" refers to -C≡C- and "propenyl" refers to -C≡C-CH2-. The ethynyl group (containing three or more carbon atoms) can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0163] "Fused ring group" refers to a polycyclic group formed by two or more carbon rings or heterocycles sharing a common ring edge. Fused ring groups include fused ring alkyl, fused ring heteroaryl, fused ring aryl, and fused ring heteroaryl. The fused ring alkyl refers to a polycyclic group formed by a cycloalkyl group and a heterocyclic group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring heterocyclic group refers to a polycyclic group formed by a heterocyclic group and a cycloalkyl group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring aryl group refers to a polycyclic group formed by an aryl group and a cycloalkyl group, heterocyclic group, or heteroaryl group sharing a common ring edge; the fused ring heteroaryl group refers to a polycyclic group formed by a heteroaryl group and a cycloalkyl group, heterocyclic group, or heterol group sharing a common ring edge. For example:

[0164] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0165] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0166] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0167] "Hydroxy" refers to the -OH group.

[0168] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0169] "Amino" refers to -NH2.

[0170] “Cyano” refers to -CN.

[0171] "Nitro" refers to -NO2.

[0172] "Carboxyl group" refers to -C(O)OH.

[0173] "THF" refers to tetrahydrofuran.

[0174] “EtOAc” refers to ethyl acetate.

[0175] “MeOH” refers to methanol.

[0176] "DMF" refers to N,N-dimethylformamide.

[0177] "DIPEA" refers to diisopropylethylamine.

[0178] "TFA" refers to trifluoroacetic acid.

[0179] “MeCN” refers to Yi Qing.

[0180] “DMA” stands for N,N-dimethylacetamide.

[0181] “Et2O” refers to diethyl ether.

[0182] “DCE” refers to 1,2-dichloroethane.

[0183] "DIPEA" refers to N,N-diisopropylethylamine.

[0184] “NBS” refers to N-bromosuccinimide.

[0185] “NIS” refers to N-iodosuccinimide.

[0186] “Cbz-Cl” refers to benzyl chloroformate.

[0187] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0188] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0189] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0190] "KHMDS" refers to potassium hexamethyldisilamide.

[0191] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0192] “MeLi” refers to methyl lithium.

[0193] “n-BuLi” refers to n-butyllithium.

[0194] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0195] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0196] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0197] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0198] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0199] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0200] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0201] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0202] Example 1

[0203] (2 4 S,5 1 R,5 2 S,Z)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluorine-1 5 ,2 4 -dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropionylheptadecane-3-one

[0204] first step

[0205] (4-Fluoro-3-methyl-5-vinylphenyl)tert-butyl carbamate

[0206] In a 100 mL reaction flask, 5-bromo-2-fluoro-1-methyl-3-vinylbenzene (5 g, 23.25 mmol), tert-butyl carbamate (5.45 g, 46.50 mmol), Pd2dba3 (1.06 g, 1.16 mmol), Cs2CO3 (15.15 g, 46.50 mmol), and XantPhos (1.35 g, 2.32 mmol) were dissolved in dioxane (50 mL). The reaction mixture was then protected with nitrogen and stirred at 110 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (50 mL). The mixture was extracted with dichloromethane (50 mL × 2), and the combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (4-fluoro-3-methyl-5-vinylphenyl) tert-butyl carbamate (4.5 g, yellow solid), yield: 77.0%.

[0207] MS m / z(ESI): 252.1 [M+1].

[0208] Step 2

[0209] 4-Fluoro-3-methyl-5-vinylaniline

[0210] In a 100 mL reaction flask, tert-butyl (4.5 g, 17.91 mmol) of (4-fluoro-3-methyl-5-vinylphenyl)carbamate was dissolved in 25 mL of dichloromethane. Then, 25 mL of hydrochloric acid-methanol solution (100 mmol, 4 M) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. The reaction was stopped, and the solution was concentrated to give the title product, 4-fluoro-3-methyl-5-vinylaniline (2.6 g, yellow solid), in 96.0% yield.

[0211] MS m / z(ESI): 152.0 [M+1].

[0212] Step 3

[0213] (4-Fluoro-3-methyl-5-vinylphenyl)hydrazine

[0214] In a 250 mL reaction flask, 2.6 g (17.20 mmol) of 4-fluoro-3-methyl-5-vinylaniline was dissolved in 30 mL (3 M) hydrochloric acid. Then, a solution of sodium nitrite (1.42 g, 20.64 mmol) in 25 mL of water was added dropwise over 30 minutes. The mixture was then stirred at 0 °C for 30 minutes. A solution of stannous chloride (9.78 g, 51.59 mmol) in 50 mL (3 M) hydrochloric acid was added dropwise over 1 hour. After the addition was complete, the reaction mixture was protected with nitrogen and stirred at 0 °C for 1 hour. The reaction was stopped, and the pH was neutralized to 8 with saturated NaOH. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product (4-fluoro-3-methyl-5-vinylphenyl)hydrazine (2.1 g, yellow solid), yield: 73.4%.

[0215] MS m / z(ESI): 167.0 [M+1].

[0216] Step 4

[0217] (S)-3-amino-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0218] In a 100 mL reaction flask, (2S)-3-cyano-2-methyl-4-carbonylpiperidin-1-carboxylic acid tert-butyl ester (3.01 g, 12.64 mmol) was dissolved in EtOH (25 mL), and (4-fluoro-3-methyl-5-vinylphenyl)hydrazine (2.1 g, 12.64 mmol) and water (1.14 g, 63.18 mmol) were added. The reaction mixture was then protected with nitrogen and stirred at 80 °C for 2 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (20 mL). The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (S)-3-amino-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.8 g, yellow solid), yield: 57.3%.

[0219] MS m / z(ESI): 387.2 [M+1].

[0220] Step 5

[0221] (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0222] In a 100 mL reaction flask, (S)-3-amino-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.8 g, 7.25 mmol) was added to a pyridine (25 mL) solution, followed by the slow addition of 2-isocyano-1,1-dimethoxyethane (1.9 g, 14.49 mmol). The mixture was stirred at room temperature for 3 hours, followed by the addition of diethylamine (1.06 g, 14.49 mmol), and the mixture was stirred at room temperature for 5 minutes. Water (50 mL) was then added, and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture, now in suspension, was filtered, and the resulting solid was washed with water (20 mL) and dried under reduced pressure to give (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.5 g, yellow solid), yield: 66.6%.

[0223] MS m / z(ESI): 518.2 [M+1].

[0224] Step 6

[0225] (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0226] In a 100 mL reaction flask, (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.5 g, 4.83 mmol) was dissolved in tetrahydrofuran (25 mL), followed by the addition of trifluoromethanesulfonic acid (1.09 g, 7.24 mmol). The reaction solution was then reacted at 60 °C for 2 h. Subsequently, di-tert-butyl dicarbonate (1.58 g, 7.24 mmol) and triethylamine (1.46 g, 14.49 mmol) were added, and the reaction was continued at 25 °C for 2 h. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.6 g, yellow solid), yield: 73.0%.

[0227] MS m / z(ESI): 454.2 [M+1].

[0228] Step 7

[0229] (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0230] In a 50 mL reaction flask, (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.6 g, 3.53 mmol) and 5-bromo-4-fluoro-1-methyl-1H-indazole (808.09 mg) were added. 3.53 mmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (50.18 mg, 352.80 μmol), potassium carbonate (975.16 mg, 7.06 mmol), and cuprous iodide (67.19 mg, 352.80 μmol) were dissolved in N-methylpyrrolidone (25 mL), and the reaction mixture was protected with nitrogen and stirred at 130 °C for 5 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.2 g, yellow solid), yield: 58.2%.

[0231] MS m / z(ESI): 584.2 [M+1].

[0232] Step 8

[0233] (S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0234] In a 50 mL reaction flask, (S)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (100 mg, 171.33 μmol) was dissolved in dichloromethane (5 mL), and then GRUBBS II (14.54 mg, 17.13 μmol) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, yellow solid), yield: 50.4%.

[0235] MS m / z(ESI): 694.3 [M+1].

[0236] Step 9

[0237] (S)-1-(2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0238] In a 50 mL reaction flask, (S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, 86.22 μmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid methanol solution (1 mL, 4 mmol, 4 M) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. The reaction was stopped, and the reaction solution was concentrated to give the title product (S)-1-(2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, yellow solid), yield: 97.3%.

[0239] MS m / z(ESI): 594.3 [M+1].

[0240] Step 10

[0241] (S)-4-(allyloxy)-1,3,2-dioxathiapentane-2,2-dioxide

[0242] (R)-1-(allyloxy)ethane-1,2-diol (1.15 g, 9.79 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection and cooling in an ice-water bath, thionyl chloride (1.40 g, 11.75 mmol, 853.39 μL) was added. The mixture was stirred at 60 °C for 1 hour. The reaction solution was evaporated to dryness to obtain the crude product. The crude product was dissolved in acetonitrile (15 mL) and water (15 mL). Under ice-water bath cooling and nitrogen protection, sodium periodate (4.19 g, 19.58 mmol) was added, followed by ruthenium trichloride (101.55 mg, 489.57 μmol). The mixture was stirred at 25 °C for 3 hours. The reaction solution was quenched with saturated brine (30 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product (S)-4-(allyloxy)-1,3,2-dioxathiapentane 2,2-dioxide (1.6 g). The crude product was used directly in the next step.

[0243] MS m / z(ESI): 181.0 [M+1].

[0244] Step 11

[0245] 1-((1R,2S)-2-(allyloxy)-1-cyanocyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester

[0246] Ethyl (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (1 g, 2.94 mmol) and (S)-4-(allyloxy)-1,3,2-dioxathiapentane 2,2-dioxide (1.59 g, 8.81 mmol) were dissolved in tetrahydrofuran (25 mL), and the mixture was cooled to 0 °C. Under a nitrogen atmosphere, a THF solution of potassium bis(trimethylsilyl)amide (8.81 mL, 8.81 mmol, 1 M) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2.5 h, then formic acid (3 mL) was added, and the mixture was extracted with a mixture of ethyl acetate (40 mL). The organic layer was washed three times with water, twice with a saturated aqueous solution of sodium bicarbonate, and once with brine, and then dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to give ethyl 1-((1R,2S)-2-(allyloxy)-1-cyanocyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (900 mg, yellow solid), yield: 72.5%.

[0247] MS m / z(ESI): 423.2 [M+1].

[0248] Step Twelve

[0249] 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester

[0250] To a solution of ethyl 1-((1R,2S)-2-(allyloxy)-1-cyanocyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (900 mg, 2.13 mmol) in dimethyl sulfoxide (DMSO) (10 mL), 50% aqueous hydroxylamine (1.41 g, 21.3 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL) and brine (50 mL), then dried over magnesium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DMSO (10 mL). Then, carbonyl diimidazole (689.71 mg, 4.26 mmol) and 1,8-diazabicycloundec-7-ene (811.43 mg, 5.33 mmol) were added, and the resulting mixture was stirred at room temperature for 0.5 hours. Formic acid was added to the mixture, and it was then purified by reversed-phase chromatography (acetonitrile / water, 0.1% formic acid) to give ethyl 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (850 mg, yellow solid), yield: 82.8%.

[0251] MS m / z(ESI): 482.2 [M+1].

[0252] Step Thirteen

[0253] 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0254] Add 2M aqueous sodium hydroxide solution (4.16 mL, 8.32 mmol) to a DMSO solution of ethyl 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (850 mg, 1.77 mmol) and stir the mixture at room temperature for 1.5 hours. Formic acid was added to the mixture, followed by purification by reversed-phase chromatography (acetonitrile / water, 0.1% formic acid) to give 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (600 mg, yellow solid), yield: 74.9%.

[0255] MS m / z(ESI): 454.1 [M+1].

[0256] Step Fourteen

[0257] 3-((1R,2S)-2-(allyloxy)-1-(2-((S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0258] To 1-((1R,2S)-2-(allyloxy)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (50 mg, 110.25 μmol), (S)-1-(2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-4, HATU (41.92 mg, 110.25 μmol) and DIEA (28.50 mg, 220.50 μmol) were added to a DMF (3 mL) solution of 5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (65.69 mg, 110.25 μmol) and stirred at room temperature for 16 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 3-((1R,2S)-2-(allyloxy)-1-(2-((S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl) 4-Methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (70 mg, yellow solid), yield: 61.5%.

[0259] MS m / z(ESI): 1029.5 [M+1].

[0260] Step 15

[0261] (2 3 Z,2 4 S,5 1 R,5 2 S)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluoro-15,24-dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,25 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1 H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4

[0262] (2,1)-Indole-1(1,3)-Benzene-5(1,2)-Cyclopropanecycloheptadecane-7,16-dien-3-one

[0263] In a 50 mL reaction flask, 70 mg (67.88 μmol) of 3-((1R,2S)-2-(allyloxy)-1-(2-((S)-2-(3-(dec-1,9-dien-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one was dissolved in dichloromethane (5 mL), and then GRUBBS was added. II (11.52 mg, 13.57 μmol), the reaction solution was protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, quenched with an aqueous solution (10 mL), extracted with dichloromethane (10 mL × 2), the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was prepared by prep-HPLC to give the title product (2). 3 Z,2 4 S,5 1 R,5 2 S)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluoro-15,24-dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-7,16-dien-3-one (25 mg, white solid), yield: 36.7%.

[0264] MS m / z(ESI): 1001.4 [M+1].

[0265] Step Sixteen

[0266] (2 4 S,5 1 R,5 2 S,Z)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluorine-1 5 ,2 4 -dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1 H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropionylheptadecane-3-one

[0267] In a 50 mL reaction flask, add (2 3 Z,2 4 S,5 1 R,5 2 S)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluoro-15,24-dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-7,16-dien-3-one (25 mg, 24.97 μmol) was dissolved in ethyl acetate (5 mL), and then 10 mg of 5% palladium on carbon (55% water) was added. The reaction mixture was then protected with hydrogen and stirred at 25 °C for 1 hour. The reaction was stopped, filtered, and the residue was prepared by prep-HPLC to give the title product (2 4 S,5 1 R,5 2 S,Z)-4 5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1 4 -Fluorine-1 5 ,2 4 -dimethyl-2 3 -(3-(1-Methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5 1 -(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1 H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2.1)-indole-1(1,3)-benzene-5(1,2)-cyclopropionylheptadecane-3-one (9 mg, white solid), yield: 35.8%.

[0268] MS m / z(ESI): 1005.5 [M+1].

[0269] Example 2

[0270] 3-((24S,51S,52S)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-23-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-3-carbonyl-2 4 ,2 5 ,2 6 ,2 7 -Tetrahydro-2 2 H,4 1H-2(2,5)-pyrazolo[4,3-c]pyridin-4(2,1)-indole-1(1,3)-benzyl-5(1,2)-cyclopropanacycloheptadecaphane-51-yl)-1,2,4-oxadiazol-5(4H)-one

[0271] The product was obtained by referring to the synthesis method of Example 1.

[0272] MS m / z(ESI): 1003.5 [M+1].

[0273] Example 3

[0274] (24S,51R,52S)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-23-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-6,9,12,15-tetraoxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0275] The product was obtained by referring to the synthesis method of Example 1.

[0276] MS m / z(ESI): 1011.5 [M+1].

[0277] Example 4

[0278] (24S,51R,52S)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-23-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-6,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0279] The product was obtained by referring to the synthesis method of Example 1.

[0280] MS m / z(ESI): 1007.5 [M+1].

[0281] Example 5

[0282] (24S,51S,52R)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-23-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-8,11,14-trioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacyclohexadecaphan-3-one

[0283] The product was obtained by referring to the synthesis method of Example 1.

[0284] MS m / z (ESI): 995.5 [M+1].

[0285] Example 6

[0286] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-fluoro-11-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyridino[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-9-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0287] Step 1: 9-Benzyl-3-fluoro-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-11-amine

[0288] 6-Amino-3-fluoro-2,4-dimethylphenol (1 g, 6.44 mmol), 4-acetyl-1-benzyl-2-methylpiperidine-3-carboxamide (1.77 g, 6.44 mmol), and p-toluenesulfonic acid monohydrate (61.29 mg, 322.23 μmol) were dissolved in toluene (200 mL). Under nitrogen protection, the mixture was stirred and refluxed at 110 °C for 24 hours, while water was separated using a water separator. The reaction solution was evaporated to dryness, and the residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 70:30) to give the target product 9-benzyl-3-fluoro-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-11-amine (150 mg, yield: 5.95%).

[0289] MS m / z(ESI): 392.2 [M+1].

[0290] Step 2: Tert-butyl(S)-11-amino-3-fluoro-2,4,10-trimethyl-7,8-dihydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-9(10H)-carboxylic acid ester

[0291] 9-Benzyl-3-fluoro-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-11-amine (150 mg, 383.16 μmol) and di-tert-butyl dicarbonate (83.62 mg, 383.16 μmol) were dissolved in methanol (10 mL), and 10% palladium (40.78 mg, water content 50% w / w) was added under nitrogen protection. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the crude product was obtained by liquid chromatography. The residue was purified by rapid silica gel chromatography (elution of petroleum ether: ethyl acetate = 100:0 to 70:30), and then chiral resolution was performed to obtain the target product tert-butyl(S)-11-amino-3-fluoro-2,4,10-trimethyl-7,8-dihydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-9(10H)-carboxylic acid ester (60 mg, yield: 39%).

[0292] MS m / z(ESI): 402.2 [M+1].

[0293] Step 3: (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(3-fluoro-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyridino[4',3':3,4]pyrrolo[1,2-d][1,4]oxazin-11-yl)-1,3-dihydro-2H-imidazol-2-one

[0294] The target product was obtained by referring to steps five, six, seven, and nine of Example 1.

[0295] MS m / z(ESI): 517.2 [M+1].

[0296] Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-fluoro-11-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,10-trimethyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrido[4',3':3,4]pyrrolo[1,2-d][1,4]oxazine-9-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0297] Using 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid as a starting material, the target product was obtained according to step fourteen of Example 1.

[0298] MS m / z(ESI): 910.4 [M+1].

[0299] Example 7

[0300] (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14,44-difluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5,8-dioxa-2(2,3)-pyrazolo[4,3-c]pyridina-4(5,6)-inzazoolo-3(1,3)-imidazozozol-1(1,3)-benzenacyclooctaphan-32-one

[0301] first step

[0302] 1-(allyloxy)-5-bromo-2-fluoro-3-methylbenzene

[0303] At room temperature, 5-bromo-2-fluoro-3-methylphenol (2.05 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added.

[0304] Dissolved in acetonitrile (25 mL), then allyl bromide (2.42 g, 20 mmol) was slowly added. The mixture was heated to 50 °C and reacted for 48 hours. After cooling to room temperature, the inorganic salts were filtered off. The residue was washed with petroleum ether (10 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine (15 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residues were separated by Flash column chromatography to obtain the target product (1.96 g), yield: 80%.

[0305] Step 2

[0306] tert-Butyl(S)-2-(3-(allyloxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]

[0307] Pyridine-5-carboxylic acid ester

[0308] Using 1-(allyloxy)-5-bromo-2-fluoro-3-methylbenzene as a raw material, referring to the first, second, third, fourth, fifth, sixth, and seventh steps of Example 1, tert-butyl(S)-2-(3-(allyloxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was obtained.

[0309] MS m / z(ESI): 648.3 [M+1].

[0310] Step 3

[0311] tert-Butyl(S)-2-(4-fluoro-3-methyl-5-(2-carbonylethoxy)phenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0312] Under ice bath conditions, tert-butyl(S)-2-(3-(allyloxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (0.65 g, 1 mmol) was dissolved in water (2 mL) and tetrahydrofuran (10 mL). Then, 2,6-dimethylpyridine (0.21 g, 2 mmol) and potassium iodate (37 mg, 0.1 mmol) were added, and the mixture was stirred at room temperature for one hour. Then, sodium periodate (0.856 g, 4 mmol) was added, and the mixture was stirred at room temperature for another hour. After the reaction was completed, the reaction solution was diluted with ethyl acetate (15 mL), and then saturated sodium sulfite aqueous solution (15 mL) was added. The mixture was stirred at room temperature for ten minutes, separated, and the organic phase was washed with saturated brine (10 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was used directly in the next step (0.65 g, crude product).

[0313] MS m / z (ESI): 650.3 [M+1].

[0314] Step 4

[0315] tert-Butyl(S)-2-(4-fluoro-3-(2-hydroxyethoxy)-5-methylphenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0316] Under ice bath conditions, tert-butyl(S)-2-(4-fluoro-3-methyl-5-(2-carbonylethoxy)phenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazole-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (0.65 g, 1 mmol) was dissolved in methanol (10 mL), and then sodium borohydride (76 mg, 2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (15 mL), and then the methanol was removed by rotary evaporation. The reaction solution was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography to obtain the target product (0.42 g), yield: 65%.

[0317] MS m / z (ESI): 652.3 [M+1].

[0318] Step 5

[0319] tert-Butyl(24S)-14,44-difluoro-15,24,41-trimethyl-32-carbonyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5,8-dioxa-2(2,3)-pyrazolo[4,3-c]pyridina-4(5,6)-inzazoolo-3(1,3)-imidazozoazole-1(1,3)-benzenacyclooctaphane-25-carboxylic acid ester

[0320] Under ice bath conditions, tert-butyl(S)-2-(4-fluoro-3-(2-hydroxyethoxy)-5-methylphenyl)-3-(3-(4-fluoro-6-hydroxy-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (0.42 g, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL), nitrogen gas was purged, and then the following were added sequentially: Triphenylphosphine (0.26 g, 0.98 mmol) and diisopropyl azodicarboxylate (0.20 g, 0.98 mmol) were stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with ethyl acetate (15 mL), and then washed successively with saturated sodium bicarbonate solution (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography to obtain the target product (0.12 g), yield: 30%.

[0321] MS m / z(ESI): 634.2 [M+1].

[0322] Step 6

[0323] (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14,44-difluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5,8-dioxa-2(2,3)-pyrazolo[4,3-c]pyridina-4(5,6)-inzazoolo-3(1,3)-imidazozozol-1(1,3)-benzenacyclooctaphan-32-one

[0324] Using tert-butyl(24S)-14,44-difluoro-15,24,41-trimethyl-32-carbonyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5,8-dioxa-2(2,3)-pyrazolo[4,3-c]pyridina-4(5,6)-inzazoolo-3(1,3)-imidazozoazole-1(1,3)-benzenacyclooctaphane-25-carboxylic acid ester as a starting material, the target product was obtained by referring to steps nine and fourteen of Example 1.

[0325] MS m / z(ESI): 927.3 [M+1].

[0326] Example 8

[0327] (1S,2S,4'S,Z)-5'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4'-fluoro-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,3',4',5'-tetramethylspiro[cyclopropane-1,5'-7,12-dioxa-6(3,5)-oxadiazola-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indoa-1(1,2)-benzenacyclododecaphan]-3'-one

[0328] Step 1: tert-Butyl(S)-3-amino-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0329] 3 g (8 mmol) of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in acetonitrile (30 mL), and liquid bromine (1.3 g (8 mmol)) was added at room temperature. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched by adding saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a pale yellow solid tert-butyl(S)-3-amino-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (1.8 g, yield: 50%).

[0330] MS m / z(ESI): 453.1 [M+1].

[0331] Step 2: Tert-butyl(S)-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0332] The target compound was obtained from tert-butyl(S)-3-amino-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester, following steps five, six, and seven of Example 1.

[0333] MS m / z (ESI): 668.2 [M+1].

[0334] Step 3: Tert-butyl(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-2-hydroxy-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0335] The following ingredients were added: tert-butyl(S)-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (600 mg, 0.9 mmol), potassium hydroxide (151 mg, 2.7 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (I A mixed solution of I (71 mg, 0.09 mmol), water (6 mL), and 1',4-dioxane (6 mL) was purged with nitrogen three times, stirred at 100 °C for 12 hours under nitrogen protection, cooled, and concentrated to dryness under reduced pressure to obtain a pale yellow solid tert-butyl(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-2-hydroxy-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (830 mg, crude product).

[0336] MS m / z (ESI): 606.3 [M+1].

[0337] Step 4: tert-Butyl(S)-2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0338] The target compound was obtained from tert-butyl(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-2-hydroxy-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester, referring to the first step of Example 7.

[0339] MS m / z(ESI): 646.3 [M+1].

[0340] Step 5: (S)-1-(2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0341] The target compound was obtained from tert-butyl(S)-2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester, following step 9 of Example 1.

[0342] MS m / z(ESI): 546.2 [M+1].

[0343] Step 6: 1-((1S,2S)-1-(5-chloro-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0344] Using 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide as the starting material, the target product was synthesized according to the method described in the reference [Tetrahedron Letters, 1995, vol.36, #25, pp.4471-4474].

[0345] MS m / z(ESI): 519.2 [M+1].

[0346] Step 7: 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0347] Sodium hydroxide (96 mg, 2.4 mmol, 60%) was added to a 5 mL solution of allyl alcohol (67 mg, 1.2 mmol) in tetrahydrofuran at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, 1-((1S,2S)-1-(5-chloro-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (500 mg, 0.96 mmol) in THF was added dropwise. (5 mL) solution was added, stirred at 0 °C for 1.5 hours, quenched with water, extracted with EtOAc, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and then separated by column chromatography to give a pale yellow solid 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (320 mg, yield: 62%).

[0348] MS m / z(ESI): 541.3 [M+1].

[0349] Step 8: 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0350] A mixture of 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (320 mg, 0.59 mmol), ethylene glycol methyl ether (3 mL), and potassium hydroxide (330 mg, 5.9 mmol) was stirred at 100°C for 3 hours. Cool, adjust pH to 5 with dilute hydrochloric acid (HCl, 6M), extract with EtOAc, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a pale yellow solid 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (100 mg, crude product).

[0351] MS m / z(ESI): 452.2 [M+1].

[0352] Step 9: 1-((S)-5-(1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0353] The target compound was obtained from 1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid and (S)-1-(2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one, following step fourteen of Example 1.

[0354] MS m / z (ESI): 979.4 [M+1].

[0355] Step 10: (1S,2S,4'S,Z)-5'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4'-fluoro-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,3',4',5'-tetramethylspiro[cyclopropane-1,5'-7,12-dioxa-6(3,5)-oxadiazola-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,2)-benzenacyclododecaphan]-3'-one

[0356] The target compound was obtained from 1-((S)-5-(1-((1S,2S)-1-(5-(allyloxy)-1,2,4-oxadiazol-3-yl)-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(2-(allyloxy)-4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one, following steps 15 and 16 of Example 1.

[0357] MS m / z (ESI): 953.4 [M+1].

[0358] Example 9

[0359] (1S, 2S, 4'S, Z)-5'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4'-fluoro-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4',5'-trimethylspiro[cyclopropane-1,5'-9,12,15-trioxa-6(3,4)-oxadiazol-2(2,5-pyrazolo[4,3-c]pyridine-4(2,1-indole-1(1,3-benzocyclopentadecane)]-3',5'-dione

[0360] first step

[0361] (5-Bromo-2-fluoro-3-methylphenoxy)(tert-butyl)dimethylsilane

[0362] 5-Bromo-2-fluoro-3-methylphenol (300 mg, 1.46 mmol), imidazole (299 mg, 4.39 mmol), and TBSCl (331 mg, 2.19 mmol) were dispersed in DMF (10 mL) and reacted at room temperature for 4 hours with stirring. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (5-bromo-2-fluoro-3-methylphenoxy)(tert-butyl)dimethylsilane (402 mg, yield: 86.1%).

[0363] MS m / z(ESI): 319.1, 321.1[M+1].

[0364] Step 2

[0365] 3-((1S,2S)-1-(2-((S)-2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0366] Referring to the synthesis method of Example 1, the title product 3-((1S,2S)-1-(2-((S)-2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one was synthesized.

[0367] MS m / z(ESI): 999.4 [M+1].

[0368] Step 3

[0369] 3-((1S,2S)-1-(2-((S)-2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1,2,4-oxadiazol-5(4H)-one

[0370] 9b (100 mg, 100.1 μmol), 2-(2-(2-chloroethoxy)ethoxy)ethanol-1-ol (34 mg, 200.2 μmol), and potassium tert-butoxide (34 mg, 300.3 μmol) were dispersed in DMF (5 mL) and stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product 3-((1S,2S)-1-(2-((S)-2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazole-5-) -yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1,2,4-oxadiazol-5(4H)-one (64 mg, yield: 56.5%).

[0371] MS m / z(ESI): 1131.5 [M+1].

[0372] Step 4

[0373] 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-hydroxy-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1,2,4-oxadiazol-5(4H)-one

[0374] 9c (64 mg, 56.6 μmol) and TBAF (30 mg, 113.2 μmol) were dissolved in THF (5 mL), and the reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazole)). -5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-hydroxy-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1,2,4-oxadiazol-5(4H)-one (41 mg, yield: 71.3%).

[0375] MS m / z(ESI):1017.4[M+1].

[0376] Step 5

[0377] (1S, 2S, 4'S, Z)-5'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4'-fluoro-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4',5'-trimethylspiro[cyclopropane-1,5'-9,12,15-trioxa-6(3,4)-oxadiazol-2(2,5-pyrazolo[4,3-c]pyridine-4(2,1-indole-1(1,3-benzocyclopentadecane)]-3',5'-dione

[0378] Referring to the synthetic method in step 5 of Example 7, the title product (1S,2S,4'S,Z)-5'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4'-fluoro-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4',5'-trimethylspiro[cyclopropane-1,5'-9,12,15-trioxa-6(3,4)-oxadiazol-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3-benzocyclopentadecane)]-3',5'-dione was obtained.

[0379] MS m / z(ESI): 999.4 [M+1].

[0380] Example 10

[0381] (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptane-3-one

[0382] first step

[0383] (S,Z)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-(non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0384] Following the synthetic method of Example 1, the title product (S, Z)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-(non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one was obtained.

[0385] MS m / z(ESI): 598.3 [M+1]

[0386] Step 2

[0387] 3-((1S,2S)-2-((benzyloxy)methyl)-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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0388] 10a (500 mg, 0.836 mmol), 1-((1S, 2S)-2-((benzyloxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (433 mg, 0.836 mmol), HATU (477 mg, 1.25 mmol), and DIEA (432 mg, 3.34 mmol) were dissolved in DMF (10 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography to give the title product 3-((1S,2S)-2-((benzyloxy)methyl)-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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (649 mg, yield: 71%).

[0389] MS m / z (ESI): 1097.5 [M+1]

[0390] Step 3

[0391] 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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0392] 10b (400 mg, 0.365 mmol) was dissolved in trifluoroacetic acid (10 mL), and the mixture was stirred at 80 °C for 6 hours. The reaction solution was concentrated under reduced pressure to give a yellow oily crude product. The crude product was purified by silica gel column chromatography to give the title 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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (298 mg, yield: 81%).

[0393] MS m / z (ESI): 1007.5 [M+1]

[0394] Step 4

[0395] 3-((1S,2S)-2-((allyloxy)methyl)-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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0396] 10c (298 mg, 0.296 mmol), DIEA (191 mg, 1.48 mmol), and allyl bromide (72 mg, 0.592 mmol) were dissolved in dichloromethane (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography to give the title product 3-((1S,2S)-2-((allyloxy)methyl)-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-methyl-5-((Z)-non-1,8-dien-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (241 mg, yield: 78%).

[0397] MS m / z (ESI): 1047.5 [M+1]

[0398] Step 5

[0399] (23Z, 24S, 51S, 52S, 9E, 16Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-9,16-dien-3-one

[0400] Following the synthetic method of step 15 in Example 1, the title product ((23Z, 24S, 51S, 52S, 9E, 16Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15 ,24-Dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-9,16-dien-3-one.

[0401] MS m / z (ESI): 1019.5 [M+1]

[0402] Step 6

[0403] (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptane-3-one

[0404] Referring to the synthetic method in step sixteen of Example 1, the title product (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptane-3-one was obtained.

[0405] MS m / z(ESI): 1023.5 [M+1]

[0406] Example 11

[0407] (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptane-3-one

[0408] Following the synthetic method of Example 1, the title product (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptane-3-one was obtained.

[0409] MS m / z (ESI): 1025.5 [M+1]

[0410] Example 12

[0411] (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,12,17-trioxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-3-one

[0412] Following the synthetic method of Example 1, the title product (24S, 51S, 52S, Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,12,17-trioxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indola-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-3-one was obtained.

[0413] MS m / z(ESI): 1027.5 [M+1]

[0414] Example 13

[0415] (24S,51S,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0416] Step 1: 5-Bromo-1-cyclopropyl-4-fluoroindazole

[0417] 5-Bromo-4-fluoro-1H-indazole (200 mg, 0.93 mmol), cyclopropylboronic acid (160 mg, 1.86 mmol), copper acetate (169 mg, 0.93 mmol), 2,2'-bipyridine (146 mg, 0.93 mmol), and sodium carbonate (197 mg, 1.86 mmol) were dispersed in acetonitrile (6 mL). The reaction mixture was heated to 70 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product 5-bromo-1-cyclopropyl-4-fluoroindazole (204 mg, yield 86%).

[0418] MS m / z(ESI):255.0, 257.0[M+1].

[0419] Step 1: (24S,51S,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7-oxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0420] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 10.

[0421] MS m / z(ESI): 1049.5 [M+1].

[0422] Example 14

[0423] (24S,51S,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0424] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 11.

[0425] MS m / z(ESI): 1051.5 [M+1].

[0426] Example 15

[0427] (24S,51S,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,12,17-trioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0428] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 12.

[0429] MS m / z(ESI): 1053.5 [M+1].

[0430] Example 16

[0431] (24S,51R,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-6-oxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0432] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 11.

[0433] MS m / z(ESI): 1049.5 [M+1].

[0434] Example 17

[0435] 3-((24S,51S,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-3-carbonyl-24,25,26,27-tetrahydro-22H,41H-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphane-51-yl)-1,2,4-oxadiazol-5(4H)-one

[0436] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 2.

[0437] MS m / z(ESI): 1047.5 [M+1].

[0438] Example 18

[0439] (24S,51R,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-6,9,12,15-tetraoxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0440] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 3.

[0441] MS m / z(ESI): 1055.5 [M+1].

[0442] Example 19

[0443] (24S,51R,52S)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-6,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacycloheptadecaphan-3-one

[0444] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 4.

[0445] MS m / z(ESI): 1051.5 [M+1].

[0446] Example 20

[0447] (24S,51S,52R)-23-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-8,11,14-trioxa-2(2,5)-pyrazolo[4,3-c]pyridina-4(2,1)-indola-1(1,3)-benzena-5(1,2)-cyclopropanacyclohexadecaphan-3-one

[0448] The target product was obtained using 5-bromo-1-cyclopropyl-4-fluoroindazole as a starting material, referring to Example 5.

[0449] MS m / z(ESI): 1039.5 [M+1].

[0450] Example 21

[0451] (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcycloheptane-32-one

[0452] Referring to the synthesis method of Example 7, the title product (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcycloheptane-32-one was obtained.

[0453] MS m / z(ESI): 893.4 [M+1]

[0454] Example 22

[0455] (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcyclooctane-32-one

[0456] Following the synthetic method of Example 7, the title product (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-5-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcyclooctane-32-one was obtained.

[0457] MS m / z (ESI): 907.4 [M+1]

[0458] Example 23

[0459] (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-6-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcyclooctane-32-one

[0460] Referring to the synthesis method of Example 7, the title product (24S)-25-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-14-fluoro-15,24,41-trimethyl-24,25,26,27,32,33-hexahydro-22H,31H,41H-6-oxa-2(2,3)-pyrazolo[4,3-c]pyridine-4(5,6)-indazole-3(1,3)-imidazol-1(1,3)-phenylcyclooctane-32-one was obtained.

[0461] MS m / z (ESI): 907.4 [M+1]

[0462] Example 24

[0463] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-43-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0464] Step 1: 2-(tert-butyl)-1-ethyl-1-hydroxycyclopropane-1,2-dicarboxylic acid ester

[0465] The target product was obtained by referring to the synthesis method in step four of Example 9.

[0466] MS m / z(ESI): 231.1 [M+1].

[0467] Step 2: Tert-butyl-2-hydroxy-2-(hydroxymethyl)cyclopropane-1-carboxylic acid ester

[0468] Sodium borohydride (4.13 g, 108.7 mmol) was added to a solution of 2-(tert-butyl)-1-ethyl-1-hydroxycyclopropane-1,2-dicarboxylic acid ester (5 g, 21.74 mmol) in THF (30 mL) and MeOH (50 mL) at 0 °C. The mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride, and then extracted with DCM. The organic phase was washed with saturated brine, and the organic phases were combined and evaporated to dryness to obtain (4.2 g, crude product).

[0469] MS m / z(ESI): 189.1 [M+1].

[0470] Step 3: Tert-butyl 4,6-dioxa-5-thiaspiro[2,4]heptane-1-carboxylate 5,5-dioxa

[0471] The target product was obtained by referring to the synthesis method in step 10 of Example 1.

[0472] MS m / z(ESI): 251.1 [M+1].

[0473] Step 4: tert-butyl(4R)-4-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(methyl(phenyl)carbamoyl)-1H-indol-1-yl)-4-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[2.2]pentane-1-carboxylic acid ester

[0474] The target product was obtained by referring to the synthesis method of Example 1.

[0475] MS m / z(ESI): 613.3 [M+1].

[0476] Step 5: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1R)-4-(hydroxymethyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[2.2]pentan-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0477] MS m / z(ESI): 543.3 [M+1].

[0478] Step 6: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1R)-4-(hydroxymethyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[2.2]pentan-1-yl)-1H-indole-2-carboxylic acid

[0479] The target product was obtained by referring to the synthesis method in step 8 of Example 8.

[0480] MS m / z(ESI): 454.2 [M+1].

[0481] Step 7: Methyl 2-(((tert-butoxycarbonyl)((S)-1-cyanopropane-2-yl)amino)methyl)but-3-enoate

[0482] Using [(2S)-1-cyano-2-propyl] tert-butyl carbamate and methyl 2-(hydroxymethyl)but-3-enoate as raw materials, the target product was obtained by referring to the synthesis method in step 5 of Example 7.

[0483] MS m / z(ESI): 297.2 [M+1].

[0484] Step 8: tert-Butyl(2S)-3-cyano-2-methyl-4-carbonyl-5-vinylpiperidine-1-carboxylic acid ester

[0485] The mixture was stirred at 85°C for 12 hours in a solution of methyl 2-(((tert-butoxycarbonyl)((S)-1-cyanopropane-2-yl)amino)methyl)but-3-enoate (3 g, 10.1 mmol), potassium tert-butoxide (2.26 g, 20.2 mmol), and toluene (50 mL). After cooling, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and then separated by column chromatography to give the title product tert-butyl(2S)-3-cyano-2-methyl-4-carbonyl-5-vinylpiperidine-1-carboxylic acid ester (1.9 g, yield: 71.2%).

[0486] MS m / z(ESI): 265.2 [M+1].

[0487] Step 9: 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7-vinyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0488] The target product was obtained by referring to the synthesis method of Example 1.

[0489] MS m / z(ESI): 498.2 [M+1].

[0490] Step 10: 3-((1R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-7-vinyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one

[0491] The target product was obtained by referring to the synthesis method in step fourteen of Example 1.

[0492] MS m / z(ESI): 933.4 [M+1].

[0493] Step 11: 3-((1R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-7-(2-hydroxyethyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one

[0494] To 0 degrees Celsius 3-((1R)-1-(5-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-7-vinyl-4,5,6,7-tetrahydro-2H-pyrazolo[4, [3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one (800 mg, 0.86 mmol) was added dropwise to a THF (10 mL) solution of borane tetrahydrofuran complex (2.6 mL, 1 M), stirred at room temperature for 1 hour, and then sodium hydroxide solution (3.44 mL, 1 M) and superphosphate were added dropwise at 0 °C. Hydrogen peroxide (1 mL, 35%) was slowly heated to room temperature and stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain the target product 3-((1R)-1-(5-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-7-(2-hydroxyethyl)-4 -Methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one (500 mg, yield: 61.2%).

[0495] MS m / z (ESI): 951.4 [M+1].

[0496] Step 12: (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-43-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0497] To 3-((1R)-1-(5-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-7-(2-hydroxyethyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-ind In a solution of (100 mg, 0.11 mmol)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.11 mmol), triethylamine (11.11 mg, 0.11 mmol), and acetonitrile (50 mL), p-toluenesulfonyl chloride (21 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Potassium tert-butoxide (18 mg, 0.17 mmol) was then added, and the mixture was stirred at room temperature for 12 hours. Water was then added. Extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Preparative chromatography was performed to obtain a white solid (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-43-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-11-(5-carbonyl) -4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one (35 mg, yield: 34%), was then chirally isolated to give 24A, 24B, 24C, and 24D.

[0498] MS m / z(ESI): 933.4 [M+1].

[0499] Example 25

[0500] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-43-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-6-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,8(1,2)-dicyclopropanaoctaphan-3-one

[0501] Step 1: 3-((1R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-7-(hydroxymethyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-4-(hydroxymethyl)spiro[2.2]pentan-1-yl)-1,2,4-oxadiazol-5(4H)-one

[0502] The target product was obtained by referring to the synthesis method in steps three and four of Example 7.

[0503] MS m / z(ESI): 937.4 [M+1].

[0504] Step 2: (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-43-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-6-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,8(1,2)-dicyclopropanaoctaphan-3-one

[0505] The target product is obtained by referring to the method in step 12 of Example 24.

[0506] MS m / z(ESI): 919.4 [M+1].

[0507] Example 26

[0508] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-43-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0509] The target product was obtained by referring to the synthesis methods of Examples 1 and 24.

[0510] MS m / z (ESI): 951.4 [M+1].

[0511] Example 27

[0512] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-43-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-6-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,8(1,2)-dicyclopropanaoctaphan-3-one

[0513] The target product was obtained by referring to the synthesis methods of Examples 1 and 25.

[0514] MS m / z(ESI): 937.4 [M+1].

[0515] Example 28

[0516] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-43-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0517] Step 1: 5-Bromo-4-fluoro-1-(methyl-d3)-1H-indazole

[0518] 5-Bromo-4-fluoro-1H-indazole (3 g, 13.95 mmol) was dissolved in DMF (30 mL) under ice bath conditions, and nitrogen gas was added. Sodium hydroxide (837 mg, 20.93 mmol, 60%) was then added, and the mixture was stirred under ice bath conditions for 30 minutes. Deuterated iodomethane (2.43 g, 16.74 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride, and then extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by column chromatography (PE:EA 85:15–75:25 elution) to give a pale yellow solid 5-bromo-4-fluoro-1-(methyl-d3)-1H-indazole (1.8 g, yield: 55.6%).

[0519] MS m / z(ESI): 231.9 233.9 [M+1].

[0520] Step 2: (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-43-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0521] The target product was obtained by referring to the synthesis methods of Examples 1 and 24.

[0522] MS m / z (ESI): 954.4 [M+1].

[0523] Example 29

[0524] (11R,44S)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-43-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-6-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,8(1,2)-dicyclopropanaoctaphan-3-one

[0525] The target product was obtained by referring to the synthesis methods of Examples 1 and 25.

[0526] MS m / z(ESI): 940.4 [M+1].

[0527] Example 30

[0528] (11R,44S)-43-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-7-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,9(1,2)-dicyclopropananonaphan-3-one

[0529] The target product was obtained by referring to the synthesis methods of Examples 1 and 24.

[0530] MS m / z (ESI): 977.4 [M+1].

[0531] Example 31

[0532] (11R,44S)-43-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-25-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-42-(4-fluoro-3,5-dimethylphenyl)-44-methyl-11-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-44,45,46,47-tetrahydro-21H,42H-6-oxa-4(5,7)-pyrazolo[4,3-c]pyridina-2(1,2)-indola-1,8(1,2)-dicyclopropanaoctaphan-3-one

[0533] The target product was obtained by referring to the synthesis methods of Examples 1 and 25.

[0534] MS m / z (ESI): 963.4 [M+1].

[0535] Biological testing evaluation

[0536] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0537] I. Determination of the ability of the compounds of this invention to stimulate cAMP production in human GLP1 receptor-stabilized cell lines

[0538] 1. Experimental objective:

[0539] The purpose of this test case was to evaluate the ability of the compound to activate the human GLP-1 receptor on the cell surface. Activation of this receptor stimulated the production of AMP in ECs. 50 The activation ability of the compound on human GLP-1 receptor was characterized.

[0540] 2. Experimental reagents and instruments:

[0541] 2.1 Experimental Apparatus:

[0542] Microplate reader (BioTek Synergy H1);

[0543] Pipettes (Eppendorf & Rainin).

[0544] 2.2 Experimental Reagents:

[0545] DMEM / F12 medium was purchased from Gibco, catalog number 11330032;

[0546] Casein was purchased from Sigma, product number C3400;

[0547] The 384-well plate was purchased from Sigma, part number CLS4514;

[0548] IBMX was purchased from Sigma, part number I7018;

[0549] The Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio, part number 62AM4PEC.

[0550] 3. Experimental methods:

[0551] The frozen human GLP1 receptor stable cell line CHO-K1 / GLP-1R / CRE-luc was removed from the liquid nitrogen tank and rapidly thawed in a 37°C water bath. The cells were resuspended in DMEM / F12 medium, centrifuged, washed once, and resuspended in experimental buffer (DMEM / F12 medium containing 0.1% casein). The cell density was adjusted to 2500 cells / 5 μL / well in a 384-well plate. 2.5 μL of IBMX working solution (prepared in buffer, final concentration 0.5 mM) and 2.5 μL of serially diluted compound samples (starting at 1000 nM, 3-fold dilution, 11 concentrations) were added to each well. The plates were centrifuged at 1000 rpm for 1 min, vortexed for 30 seconds to mix, and incubated at room temperature for 30 min. The samples were then analyzed using the Cisbio cAMP-Gs Dynamic Kit, which analyzed cAMP-d2 and Anti-cAMP-Eu. 3+ Cryptate was diluted 20-fold with cAMP Lysis & Detection Buffer and mixed thoroughly. 5 μL of diluted cAMP-d2 solution was added to each well, followed by 5 μL of diluted Anti-cAMP-Eu3. + -Cryptate solution, vortex for 30 seconds to mix, and incubate at room temperature in the dark for 1 hour. HTRF signal readings were performed using a Biotek Synergy H1 microplate reader with excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[0552] 4. Experimental data processing methods:

[0553] The signal-to-weight ratio (665nm / 620nm*10,000) was calculated, and the signal-to-weight ratio was nonlinearly fitted to the sample concentration using a four-parameter equation in GraphPad Prism 6 to obtain the EC value. 50 value.

[0554] In some embodiments, the compounds of the present invention have shown good biological activity in experiments stimulating cAMP production in human GLP1 receptor stable cell lines. The EC50 of the compounds of the present invention stimulating cAMP production in hGLP1R stable cell lines is less than about 100 nM, preferably less than about 50 nM, further preferably less than about 10 nM, more preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM among the compounds listed in the present invention.

[0555] II. Effects of a single dose of the compound of this invention on intraperitoneal glucose tolerance in GLP-1R humanized mice

[0556] 1. Experimental objective:

[0557] The effect of a single dose of the compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance (ipGTT) experiment in GLP-1R humanized C57BL / 6 mice was evaluated.

[0558] 2. Experimental materials:

[0559] C57BL / 6_hGLP-1R, male, 5-8 weeks; clean bench; electronic balance; active blood glucose meter; glucose.

[0560] 3. Experimental procedures and data processing:

[0561] 3.1 The day before the experiment, animals were randomly divided into groups of 5 based on their body weight. All animals were fasted overnight without food and remained fasted for at least 16 hours until the administration of the drug.

[0562] 3.2 Prepare a 0.2 g / mL glucose solution using pure water, filter it through a 0.22 μm filter membrane, and set it aside for later use;

[0563] 3.3 On the day of the test, before administering the medication, the blood glucose level of each animal was measured sequentially using the tail clipping method and recorded as the baseline value;

[0564] Blood glucose testing method: Place the mouse in a restraint, disinfect the tail tip with an alcohol swab, then cut off a small part of the tail tip with scissors, discard the first drop of blood, and drop the second drop of blood onto the prepared blood glucose test strip to test the blood glucose value.

[0565] 3.4. Administer medication according to the animal's body weight and record the administration time for each animal. One hour after administration, measure the blood glucose level of each animal sequentially and record it as the 0-minute blood glucose level.

[0566] 3.5. Subsequently, based on the patient's weight on that day, immediately administer an intraperitoneal injection of pure water or glucose solution at a volume of 10 mL / kg and a glucose dose of 2 g / kg.

[0567] 3.6. After injection of pure water or glucose solution for 15, 30, 60, 90 and 120 minutes, the blood glucose level of each mouse was measured and the time and data were recorded.

[0568] 3.7 After the test, all animals resumed eating.

[0569] 3.8 Data Processing:

[0570] Plot the blood glucose (BG)-time curve and calculate the area under the blood glucose-time curve using the following formula:

[0571] AUC (mmol / L.hr)=(BG0+BG15)×0.25 / 2+(BG15+BG30)×0.25 / 2+(BG30+BG60)×0.5 / 2+(BG60+BG90)×0.5 / 2+(BG90+BG120)×0.5 / 2.

[0572] Note: BG0, BG15, BG30, BG60, BG90 and BG120 represent blood glucose levels before glucose administration (0 min), and 15, 30, 60, 90 and 120 min after glucose administration, respectively.

[0573] The blood glucose reduction rate at each time point and based on the average blood glucose value and blood glucose AUC is calculated using the following formula: Blood glucose reduction rate = (Blood glucose in the treatment group / AUC - Blood glucose in the model control group / AUC) / Blood glucose in the model control group / AUC × 100%.

[0574] The compounds in the embodiments of the present invention can effectively reduce blood glucose in mice, with a blood glucose reduction rate of more than 20%, preferably more than 40%, and more preferably more than 60%.

[0575] III. Effects of long-term administration of the compounds of this invention on body weight and food intake in GLP-1R humanized mice fed a high-fat diet

[0576] 1. Experimental objective:

[0577] The purpose of this test was to evaluate the effects of long-term administration of the compound on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0578] 2. Experimental reagents and instruments

[0579] C57BL / 6_hGLP-1R, male, 5-8 weeks old, purchased from Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[0580] 60% high-fat diet (HFD), purchased from Shanghai Bopai Biotechnology Co., Ltd. (D12492, Research Diet)

[0581] Clean bench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.)

[0582] Electronic balance (BSA2202S-CW, Sartorius)

[0583] 3. Experimental Methods

[0584] 3.1 On the day the high-fat diet was started, the C57BL / 6 mice were randomly divided into two groups according to their body weight. The first group was Blank, consisting of 7 mice, which were fed a normal control diet. The remaining animals were the model group, which were fed a high-fat diet. This continued until the end of the experiment.

[0585] 3.2 During week 8 of HFD feeding, the model group animals were randomly divided into groups of 7 animals each according to their body weight. The first group was the Vehicle group (Vehicle: 0.5% CMC-Na + 1% Tween 80), which was given the solvent. The remaining groups were the drug administration groups. The administration regimen was: oral administration of the corresponding compound for 14 days, once a day, at a dose of 10 mg / kg and a volume of 10 mL / kg. The Blank group continued to be fed a normal diet and did not receive any drug administration.

[0586] 3.3 The day of administration is defined as Day 0.

[0587] 3.4 Each time an animal is given an administration, it is weighed and the data is recorded. The animal is then given an oral administration of 10 mL / kg based on its body weight.

[0588] 3.5 Starting from day 0 of the experiment, the food intake of mice in each group was measured every three days. Specifically, the feed was changed after each administration of medication and the amount added and the amount remaining were recorded.

[0589] 3.6 Day 14, the final day, all mice were euthanized in the order of their groups, and their livers were dissected and weighed.

[0590] 4. Experimental Data Processing and Statistical Analysis

[0591] The body weight and body weight change rate of mice after drug administration were summarized and statistically analyzed. The body weight change rate was calculated as: (BWt - BW0) / BW0 × 100%. BWt represents the body weight of the mouse on day t of the experiment, and BW0 represents the body weight of the mouse on day 0 of the experiment.

[0592] Food intake calculation: (addition amount (g) - remaining amount (g)) / number of animals per cage. The cumulative food intake is the total daily food intake of each animal during the drug administration period.

[0593] The experimental data were analyzed and plotted using GraphPad Prism software. The t-test was used for comparison between two groups. The one-way ANOVA was used for comparison among three or more groups. A p value < 0.05 was defined as statistically significant difference.

[0594] Long-term administration of the compound of the embodiment of the present invention has a good effect on reducing body weight in GLP-1R humanized C57BL / 6 mice fed with high-fat diet, and the body weight loss rate is greater than 5%, and more preferably greater than 10%.

[0595] IV. Mouse Pharmacokinetic Evaluation Test

[0596] 1. Research Objective:

[0597] Using Balb / c mice as the test animals, study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral administration at a dose of 5 mg / kg and intravenous administration at a dose of 1 mg / kg.

[0598] 2. Experimental Protocol:

[0599] 2.1 Experimental Drugs:

[0600] The compound of the embodiment of the present invention, self-made.

[0601] 2.2 Experimental Animals:

[0602] There are 3 male Balb / c mice in each group, from Shanghai Bikai Laboratory Animal Co., Ltd., with the animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

[0603] 2.3 Formulation Prescription:

[0604] Drug preparation for oral administration: 10% PEG400 / 10% PG / 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10) buffer.

[0605] Measure 10 ml of PEG400, 10 ml of PG, and 80 ml (100 mM glycine, 64 mM NaOH, pH 10) and place them in a 100 ml volumetric flask. Vortex, mix, and sonicate to obtain a clear solution.

[0606] Weigh the compound of the embodiment and add it to a 4 mL glass bottle. Add this solution and sonicate for 10 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0607] Drug preparation for intravenous administration: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0608] Weigh out the compound from the examples, add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[0609] 2.4 Administration:

[0610] Three male Balb / c mice were administered oral medication (PO) after fasting overnight; the dose was 5 mg / kg, and the administration volume was 10 mL / kg.

[0611] Three male Balb / C mice were used. After fasting overnight, they were administered the drug intravenously at a dose of 1 mg / kg and a volume of 5 mL / kg.

[0612] 2.5 Sample Collection:

[0613] Blood collection: 0.04 mL of blood was collected from the orbital cavity of mice before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma. The plasma was stored at -80°C. Mice were fed 4 hours after administration.

[0614] 2.6 Sample preparation:

[0615] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0616] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000Qtrap.

[0617] 2.7 Liquid phase analysis:

[0618] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0619] ● Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[0620] ● Flow rate: 0.4 mL / min

[0621] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0622] 3. Experimental Results and Analysis

[0623] The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0624] Experimental results show that the compounds in the embodiments of the present invention exhibit good metabolic properties, with low exposure AUC and high maximum plasma concentration C. max They all performed well.

[0625] V. Pharmacokinetic Determination in SD Rats

[0626] 1. Research Objective:

[0627] Using SD rats as test animals, the pharmacokinetic behavior of the following compounds in rat plasma after oral administration at a dose of 50 mg / kg was studied.

[0628] 2. Test Plan

[0629] 2.1 Test Drugs:

[0630] Solvent formulation: 0.5% CMC-Na (1% Tween 80);

[0631] This invention is a self-made product.

[0632] 2.2 Experimental animals:

[0633] Three male SD rats were used in each group.

[0634] 2.3 Administration:

[0635] Three male SD rats were administered the drug to each group. After fasting overnight, the rats were administered the drug PO at a dose of 50 mg / kg and a volume of 10 mL / kg.

[0636] 2.4 Sample Collection:

[0637] Before and after drug administration, 0.2 mL of blood was collected from the jugular vein of rats at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4℃ to separate the plasma, and stored at -80℃. The rats were fed 4 hours after drug administration.

[0638] 2.5 Sample preparation:

[0639] 1) Add 40uL of plasma sample to 160uL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5-20 minutes.

[0640] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[0641] 2.6 Liquid Chromatography Analysis

[0642] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0643] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0644] ● Column: phenomenex Gemiu 5um C18 50×4.6mm

[0645] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is methanol.

[0646] ● Flow rate: 1.0 mL / min

[0647] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0648] 3. Experimental Results and Analysis

[0649] The main pharmacokinetic parameters were calculated using WinNonlin 8.2.

[0650] The compounds in the embodiments of this invention exhibited favorable metabolic properties, with low exposure AUC and high peak plasma concentration C. max They all performed well.

Claims

A compound of general formula (A) or (A'), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof: in, X1 or X2 is selected from C or N; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents of a 5-10 heteroaryl group are substituted; Preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted; More preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 Or R 15 Each of the following is independently selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl or oxetane may optionally be further substituted by one or more substituents selected from halogen, methoxy or deuterated methyl. Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -NR a6 S(O)2R b6 One or more substituents in it are replaced; Preferably, ring M is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl; optionally further halogenated, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted; More preferably, ring M is selected from C 3-8 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S; optionally further substituted with one or more substituents selected from methyl, hydroxyl or oxo; More preferably, ring M is selected from Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo; More preferably, for Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo; Ring N is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Preferably, ring N is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 quinone heteroaryl; More preferably, the ring N is selected from C 3-6 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S; More preferably, cycloN is selected from cyclopropyl or R 11 Existence or non-existence; When R 11 When it exists, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted; Preferably, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-sulfoalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted; More preferably, R 11 The molecule is selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl or oxetane may optionally be further substituted with one or more substituents selected from halogen, methoxy or deuterated methyl. or, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 Each carbon atom is independently linked to form a 0-20 member carbon chain, which may contain 0-10 heteroatoms; when the carbon chain is 0 members, it contains at least one heteroatom. Preferred, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 Each carbon atom is independently linked to form a 1-15 member carbon chain, which may contain 0-6 heteroatoms selected from S, O or N; when the carbon chain is 0 members, it contains at least one heteroatom. More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 They connect independently to form -O- and -(CH2). n1 -、-(O) m1 -(CH2) n2 -(O) m2 -(CH2) n3 -(O) m3 -(CH2) n4 -(O) m4 -(CH2) n5 -or-(CH2) n6 -(O) m5 -(CH2) n7 -(O) m6 -(CH2) n8 -(O) m7 -(CH2) n9 -; More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 They can be independently linked together to form 11-membered carbon chains containing 1 heteroatom, 12-membered carbon chains containing 2 heteroatoms, 10-membered carbon chains containing 2 heteroatoms, 9-membered carbon chains containing 2 heteroatoms, 8-membered carbon chains containing 4 heteroatoms, 12-membered carbon chains containing 3 heteroatoms, 9-membered carbon chains containing 3 heteroatoms, 8-membered carbon chains containing 3 heteroatoms, 3-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 1 heteroatom, 1-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 2 heteroatoms, 4-membered carbon chains containing 2 heteroatoms, or 6-membered carbon chains containing 3 heteroatoms. More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 or R 15 and R 12 Each and each independently connected to form The condition is R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 R 2 and R 12 R 14 and R 10 R 15 and R 10 R 15 and R 10 Or R 15 and R 12 At least one of them is linked to form a 0-20 quinary carbon chain, optionally containing 0-10 heteroatoms; wherein when the carbon chain is 0 quinary, it contains at least one heteroatom; n1-n9 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1-m7 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, is characterized in that, The compound is further shown as in general formula (I) or (I'): in, X1 or X2 is selected from C or N; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents of a 5-10 heteroaryl group are substituted; Preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted; More preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Or R 13 Each of the following is independently selected from fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl or oxetane is optionally further substituted by one or more substituents selected from halogen, methoxy or deuterated methyl. Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or -NR a6 S(O)2R b6 One or more substituents in it are replaced; Preferably, ring M is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-8 heteroaryl; optionally further halogenated, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted; More preferably, ring M is selected from C 3-8 Cycloalkyl, containing 1-3 3-6 membered heterocyclic groups selected from N, O or S, or containing 1-3 5-6 membered heteroaryl groups selected from N, O or S; optionally further substituted with one or more substituents selected from methyl, hydroxyl or oxo; More preferably, ring M is selected from Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo; More preferably, for Optionally further substituted with one or more of the following substituents: methyl, hydroxyl, or oxo; R 11 Existence or non-existence; When R 11 When it exists, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted; Preferably, R 11 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6- 10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted; More preferably, R 11 The molecule is selected from hydrogen, fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl or oxetane, wherein the methyl, ethynyl, methylthio, amino, cyclopropyl or oxetane may optionally be further substituted with one or more substituents selected from halogen, methoxy or deuterated methyl. or, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each carbon atom is independently linked to form a 0-20 member carbon chain, which may contain 0-10 heteroatoms; when the carbon chain is 0 members, it contains at least one heteroatom. Preferred, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 Each carbon atom is independently linked to form a 1-15 member carbon chain, which may contain 0-6 heteroatoms selected from S, O or N; when the carbon chain is 0 members, it contains at least one heteroatom. More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 They connect independently to form -O- and -(CH2). n1 -、-(O) m1 -(CH2) n2 -(O) m2 -(CH2) n3 -(O) m3 -(CH2) n4 -(O) m4 -(CH2) n5 -or-(CH2) n6 -(O) m5 -(CH2) n7 -(O) m6 -(CH2) n8 -(O) m7 -(CH2) n9 -; More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 They can be independently linked together to form 11-membered carbon chains containing 1 heteroatom, 12-membered carbon chains containing 2 heteroatoms, 10-membered carbon chains containing 2 heteroatoms, 9-membered carbon chains containing 2 heteroatoms, 8-membered carbon chains containing 4 heteroatoms, 12-membered carbon chains containing 3 heteroatoms, 9-membered carbon chains containing 3 heteroatoms, 8-membered carbon chains containing 3 heteroatoms, 3-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 1 heteroatom, 1-membered carbon chains containing 1 heteroatom, 2-membered carbon chains containing 2 heteroatoms, 4-membered carbon chains containing 2 heteroatoms, or 6-membered carbon chains containing 3 heteroatoms. More preferably, R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 or R 2 and R 12 Each and each independently connected to form The condition is R 4 and R 5 R 1 and R 6 R 1 and R 10 R 1 and R 11 R 1 and R 12 R 2 and R 6 R 2 and R 10 R 2 and R 11 Or R 2 and R 12 At least one of them is linked to form a 0-20 quinary carbon chain, optionally containing 0-10 heteroatoms; wherein when the carbon chain is 0 quinary, it contains at least one heteroatom; n1-n9 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1-m7 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, is characterized in that, The compound is further shown as in general formula (II) or (II'): in, X1, X2, X3, X4, X5, X6, X7, X8, or X9 may or may not exist; The condition is that X1, X2, X3, X4, X5, X6, X7, X8, or X9 cannot all be absent at the same time; When X1, X2, X3, X4, X5, X6, X7, X8, or X9 exists, each of X1, X2, X3, X4, X5, X6, X7, X8, or X9 is independently selected from (CH2). q1 Or O; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Ring M, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 13 The definition is as described in claim 2. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, is characterized in that, The compound is further shown as in general formula (III) or (III'): in, L1, L2, L3, L4, L5, or L6 may or may not exist; The condition is that L1, L2, L3, L4, L5, or L6 cannot all be absent at the same time; When L1, L2, L3, L4, L5, or L6 exists, each of L1, L2, L3, L4, L5, or L6 is independently selected from (CH2). q2 Or O; q2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M, R 2 R 3 R 4 R 5 R 7 R 8 R 9 R 10 R 11 R 12 R 13 The definition is as described in claim 2. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, is characterized in that, The compound is further shown as in general formula (IV) or (IV'): in, M1, M2, M3, M4, M5, or M6 may or may not exist; The condition is that M1, M2, M3, M4, M5, or M6 cannot all be absent at the same time; When M1, M2, M3, M4, M5, or M6 are present, each of M1, M2, M3, M4, M5, or M6 is independently selected from (CH2). q3 Or O; q3 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M, R 1 R 2 R 3 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 The definition is as described in claim 2. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, is characterized in that, The compound is further shown as in general formula (V) or (V'): in, N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 Existence or non-existence; The condition is N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 They cannot both be absent at the same time; When N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 When present, N1, N2, N3, N4, N5, N6, N7, N8, N9 or N 10 Each is independently selected from (CH2). q4 Or O; q4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 The definition is as described in claim 2. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, is characterized in that, The compound is further shown as in general formula (VI) or (VI'): in, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 Existence or non-existence; The condition is Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 They cannot both be absent at the same time; When Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 When present, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9 or Y 10 Each is independently selected from (CH2). q5 Or O; q5 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 The definition is as described in claim 2. The compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, is characterized in that, The compound is further shown as in general formula (VII) or (VII'): in, O1, O2, O3, O4, O5, O6, O7, O8, or O9 may or may not exist; The condition is that O1, O2, O3, O4, O5, O6, O7, O8, or O9 cannot be absent simultaneously; When O1, O2, O3, O4, O5, O6, O7, O8, or O9 are present, each of O1, O2, O3, O4, O5, O6, O7, O8, or O9 is independently selected from (CH2). q6 Or O; q6 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 11 R 13 The definition is as described in claim 1. The compounds, their prodrugs, their stereoisomers, or their pharmaceutically acceptable salts according to claims 1-8, wherein, The structure of the compound is as follows: A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 9, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The use of the compound, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, or the pharmaceutical composition of claim 10 in the preparation of a GLP-1 receptor agonist drug. The use of the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 9, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating metabolic-related diseases; wherein the diseases are selected from diabetes, obesity, or non-alcoholic steatohepatitis-related diseases, or other related diseases caused by diabetes, obesity, or non-alcoholic steatohepatitis.

Images