WO2024212742A1 - Glp-1r agonist, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a GLP-1R agonist, a preparation method therefor and a use thereof. In particular, the present invention relates to a GLP-1R agonist having the structure represented by formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use thereof as a GLP-1R agonist, and a use thereof in the treatment and/or prevention of GLP-1R-related diseases. The substituents in formula (I) are as defined in the description.

Description

A GLP-1R agonist, its preparation method and application Technical Field

The present invention belongs to the field of drug synthesis, and specifically relates to a GLP-1R agonist, a preparation method and application thereof.

Background Art

Diabetes is a chronic disease characterized by high blood sugar due to insufficient insulin secretion (relative or absolute) or insulin dysfunction in the human body. According to the ninth edition of the World Diabetes Atlas recently issued by the International Diabetes Federation (IDF), about 463 million adults (20 to 79 years old) suffered from diabetes in 2019, and it is estimated that the number of diabetes patients will reach 578 million by 2030. If this trend continues, there will be 700 million diabetics in the world in 2045. Long-term poor blood sugar control can also lead to a large number of complications, such as cardiovascular disease, kidney disease, etc. Therefore, diabetes has become the most serious disease facing the world in the 21st century.

Glucagon-like peptide-1 receptor (GLP-1R) is one of the proven effective drug targets for the treatment of type II diabetes. GLP-1R belongs to the G protein-coupled receptor B family and has seven transmembrane domains. Its natural agonist ligand is glucagon-like peptide-1 (GLP-1). When the GLP-1 receptor is activated, it can further activate downstream signaling pathways such as PKA, PI3K, and MAPK, and play a role in promoting insulin release and reducing glucagon release, thereby lowering blood sugar levels. Under physiological conditions, endogenous GLP-1 (7-36) amide is the main active form of GLP-1. However, after entering the blood circulation, it is quickly enzymatically hydrolyzed into inactive GLP-1 (9-36), and its half-life in the body is very short, only 1 to 2 minutes. Therefore, natural GLP-1 is not suitable for long-term treatment of diabetes. To this end, scientists have been working hard to transform natural GLP-1 into a drug for the treatment of diabetes. At present, achievements have been made in both aspects. On the one hand, by reducing the degradation of GLP-1 in the body, the hypoglycemic effect is achieved, such as DPP4 enzyme inhibitors. On the other hand, it is expected to find a class of longer-acting GLP-1 analogs that can increase the concentration and duration of action of GLP-1 (analogs) in the body. Since 2005, when the world's first GLP-1 analog Exenatide/BYETTA/Exenatide drug was approved by the FDA for the adjuvant treatment of type 2 diabetes, the competition in the GLP-1RA track has begun. Now, many GLP-1RAs have been approved for marketing. Such as: Novo Nordisk's liraglutide, Eli Lilly's dulaglutide, and the recently launched semaglutide. Based on these drugs, in 2022, Eli Lilly launched Tirzepatide, a GIPR/GLP-1R dual agonist, which has shown a very superior weight loss effect in clinical practice. Except for Tirzepatide, most of the drugs of this type on the market are obtained by structural modification of natural GLP 1. For example, liraglutide, exenatide, smiglutide, etc. are all peptides. These drugs bring good clinical benefits to patients with type 2 diabetes. In addition to lowering blood sugar, they also have advantages such as weight loss and reducing cardiovascular risks. The latest research also suggests that this type of drug has great potential in Alzheimer's disease and other aspects. However, the disadvantages of these drugs are also quite obvious. Frequent and multiple injections lead to challenges in patient compliance. In addition, the complex production process of peptides and the high cost also limit their widespread use. Thirdly, due to chronic diseases, most of them have complications and require combined medication, which often limits the use of such drugs. Most small molecule drugs can overcome these shortcomings.

Therefore, the development of small molecule GLP-1R agonists will improve the shortcomings of this type of drugs from the perspective of improving patient compliance, convenience of medication, and reducing drug side effects. It has broad clinical market prospects in blood sugar control, weight loss, and neurological diseases.

Summary of the invention

The purpose of the present invention is to provide a GLP-1R agonist, and its preparation method and application can be widely used in the preparation of drugs for treating and/or preventing GLP-1R-related diseases, thereby hopefully developing a new generation of GLP-1R agonists.

The first aspect of the present invention provides a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

in,

L is -CR _6a R _7a -O-, -(CR _6a R _7a ) _n - or -O-CR _6b R _7b -;

X is CR ₈ or N, Y is CR ₉ or N;

_Z1 is _CR10a or N, _Z2 is _CR10b or N, and _Z3 is _CR10c or N;

Z ₄ is CR _10d or N;

Ring A is selected from the following structures:

each _Ra is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, _C1-4 alkyl, halogen _- substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C1-4 alkylthio, halogen-substituted _C1-4 alkylthio, deuterium _- substituted C1-4 alkylthio, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy, _-C0-4 alkyl- _{SF5 and -NR14R15} ;

Each m is independently 0, 1, 2, 3, 4, 5 or 6;

R ₁ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _1-4 alkylthio, halogen-substituted C _1-4 alkylthio, deuterium-substituted C _1-4 alkylthio, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ;

_R2 and _R3 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _{C3-6 cycloalkoxy, -C0-4 alkyl} - _SF5 and _-NR14R15 , or, _R2 and _R3 together with the directly attached carbon atom form a carbonyl, a _C3-8 cycloalkyl or a 3-8 membered heterocyclyl _;

_R4 is selected from hydrogen, deuterium, _C1-4 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl and hydroxyl, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C6-8 aryl, _5-8 membered heteroaryl, =O, =S, _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , -OR12, -C(O) _OR12 , -C(O) _SR12 , _-SC (O) _R13 , -C(O) _R13 , -OC(O _{)R13 ,} -P(O)( _R13 ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ ;

R ₅ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ;

each R _6a and R _7a is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ , or, R _6a and R _7a together with the directly attached carbon atom form _a carbonyl, a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl;

R _6b and R _7b are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ , or, R _6b and R _7b together with the directly attached carbon atom form a carbonyl, a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl;

R ₈ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ;

Alternatively, R _6a and R ₈ or R ₅ together with the part to which they are directly connected form the following structure:

R ₉ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ;

R _10a , R _10b , R _10c and R _10d are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _{1-4 alkoxy, deuterium-substituted C 1-4 alkoxy} , C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ , and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3-6 cycloalkyl, C 3-6} cycloalkyloxy, 3-6 membered heterocyclyl, the aryl group is substituted with a substituent selected from the group consisting of C _6-8 aryl, 5-8 membered heteroaryl, ═O, ═S, —SF ₅ , —OS(O) ₂ R ₁₁ , —S(O) _r R ₁₁ , —OR ₁₂ , —C(O)OR ₁₂ , —C(O)SR ₁₂ , —SC(O)R ₁₃ , —C(O)R ₁₃ , —OC(O)R ₁₃ , —P(O)(R ₁₃ ) ₂ , —NR ₁₄ R ₁₅ , —C(O)NR ₁₄ R ₁₅ and —N(R ₁₄ )-C(O)R ₁₃ ;

each R ₁₁ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl and -NR ₁₄ R ₁₅ , which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, =O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ;

each R ₁₂ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl and 5-8 membered heteroaryl, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C 3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ;

each R ₁₃ is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C 2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ , the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ;

Each of R ₁₄ and R ₁₅ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-4 alkanoyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =0, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4 alkynyl} , halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C 1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C substituted by a _{C 6-8} aryl, C _6-8 aryloxy, 5-8 membered heteroaryl _, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl substituent;

Alternatively, R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-8 membered heteroaryl is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino _, di-C _1-4 alkylamino and C _1-4 alkanoyl;

n is 1, 2 or 3;

Provided that, when ring A is selected from hour,

1) L is -O-CR _6b R _7b -; or,

2) L is -CH(CF ₃ )-O-; or,

3) R ₁ is C _1-4 alkylthio, halogen-substituted C _1-4 alkylthio or deuterium-substituted C _1-4 alkylthio; or,

4) R _6a and R ₈ or R ₅ together with the part directly connected thereto form the following structure:

or,

5) R _6a and R ₈ together with the part to which they are directly connected form and R ₁ is cyano; or,

6) _R2 and _R3 together with the directly attached carbon atom form a carbonyl group, a _C3-8 cycloalkyl group or a 3-8 membered heterocyclic group; or,

7) At least one _Ra is not hydrogen.

As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, _R4 is selected from hydrogen, deuterium, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, C3-6 cycloalkyl-substituted _C1-4 alkyl, _3-6 membered heterocyclyl-substituted _C1-4 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl and hydroxyl;

R _10a , R _10b , R _10c and R _10d are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ;

wherein R ₁₄ and R ₁₅ are as defined in the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following structure (IIa):

Wherein, X is CH or N;

R _6b , R _7b are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ;

Ring A, R ₁ and R ₉ are as defined for the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following structure (IIb):

Wherein, X is CH or N; Ring A, R ₁ , and R ₉ are as defined in the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following structure:

wherein each R _7a is independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; Ring A, R ₁ , R _7a , R ₉ are as defined for the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following structure (IId):

wherein R _1a is selected from C _1-4 alkyl, halogen-substituted C _1-4 alkyl and deuterium-substituted C _1-4 alkyl;

R ₅ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; L, X, Ring A, R ₁ and R ₉ are as defined for the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the following structure (IIe):

Wherein, ring A is selected from the following structures:

R _6a , R _7a are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; X, R ₁ , R ₉ , _Ra and m are as defined for the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, ring A in the compound of formula (I) is selected from

each _Ra is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, _C1-4 alkyl, halogen- _{substituted C1-4} alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C1-4 alkylthio, halogen-substituted C1-4 alkylthio, deuterium-substituted _C1-4 alkylthio, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy and _-C0-4 alkyl- _SF5 ; each m is independently 0, 1, 2, 3 _, 4, 5 or 6.

As a further preferred embodiment, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable In the salt, R ₁ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideuteriomethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteriomethylthio, dideuteriomethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ;

R ₉ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ .

As the most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:

The second aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt of a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

The third aspect of the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt of a stereoisomer thereof in the preparation of a medicament for treating and/or preventing a GLP-1R-mediated disease.

As a preferred embodiment, the GLP-1R mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from prediabetes, idiopathic T1 D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, hepatocellular carcinoma, hepatocellular carcinoma, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, congestive heart disease, failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, thrombosis, transient ischemic attack, poor glucose metabolism, impaired fasting glucose condition, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, irritable bowel syndrome, or polycystic ovary syndrome.

As a further preferred embodiment, the GLP-1R mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from T2DM, colitis, insulin resistance, cirrhosis, cardiovascular disease or addiction disease.

As a further preferred embodiment, the GLP-1R-mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from T1D, renal disease, hypertension, stroke, angina pectoris, vascular restenosis or inflammatory bowel disease.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventors of the present application have developed for the first time a compound having the following structure (I): The GLP-1R agonists of the present invention can be widely used in the preparation of drugs for treating and/or preventing diseases related to GLP-1R, and are expected to be developed into a new generation of GLP-1R agonists. On this basis, the present invention is completed.

Detailed Description: Unless stated to the contrary or specifically indicated, the following terms used in the specification and claims have the following meanings.

“Alkyl” refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched alkyl group having 1 to 6 carbon atoms or 1 to 3 carbon atoms, including but not limited to 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 or various branched chain isomers thereof, etc. The "C _1-6 alkyl group" refers to a straight chain alkyl group and a branched chain alkyl group including 1 to 6 carbon atoms, and the "C _1-3 alkyl group" refers to a straight chain alkyl group and a branched chain alkyl group including 1 to 3 carbon atoms.

The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, _cyano , nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , -C(O) _SR12 , -SC(O _{)R13 ,} -C( _O ) _R13 , -OC(O) _R13 , -P(O)(R The group consisting of _{-R 14} )-C(O)R ₁₃ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, and the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably a cycloalkyl group including 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, for example, "C _3-12 cycloalkyl" refers to a cycloalkyl group including 3 to 12 carbon atoms, "C _3-10 cycloalkyl" refers to a cycloalkyl group including 3 to 10 carbon atoms, "C _3-8 cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms, and "C _3-6 cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms, wherein:

Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings and bridged rings. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl groups according to the number of spiro atoms shared between the rings. Spiroalkyl groups include but are not limited to:

"Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and fused cycloalkyl includes but is not limited to:

"Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Bridged cycloalkyl includes but is not limited to:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, _cyano , nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, = _{S, -SF5, -OS(O)2R11, -S(O)rR11, -OR12 , -C (} O) _OR12 , -C(O) _SR12 , -SC(O) _R13 , -C( _O ) _R13 , -OC(O) _R13 The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl are selected from N, O, N·O or S(O) _r (wherein r is an integer 0, 1, 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, the heterocyclyl includes 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl" refers to a heterocyclyl containing 3 to 6 ring atoms, "3-8 membered heterocyclyl" refers to a heterocyclyl containing 3 to 8 ring atoms, and "4-8 membered heterocyclyl" refers to a heterocyclyl containing 4 to 8 ring atoms. The heterocyclic group of the present invention is a "4-10 membered heterocyclic group" which refers to a heterocyclic group containing 4 to 10 ring atoms, a "5-8 membered heterocyclic group" which refers to a heterocyclic group containing 5 to 8 ring atoms, and a "3-12 membered heterocyclic group" which refers to a heterocyclic group containing 3 to 12 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called spiro atom) is shared between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O) _r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into single spiro heterocyclic groups, double spiro heterocyclic groups or multi-spiro heterocyclic groups according to the number of spiro atoms shared between rings. Spiro heterocyclic groups include but are not limited to:

"Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O) _r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

"Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N atoms or S(O) _r (which Where r is an integer (0, 1, 2) of heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups include but are not limited to:

The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, including but not limited to:

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, _cyano , nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclic group _{, C6-10} aryl, 5-10 membered heteroaryl, =O, =S, -SF5, -OS(O) _2R11 , -S(O _{)rR11, -OR12 , -C} (O) _OR12 , -C(O) _SR12 , -SC(O) _R13 , -C(O) _R13 , -OC(O) _R13 The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) group, a polycyclic (i.e., a ring with adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably an all-carbon aromatic group containing 6-10 or 6-8 carbons, for example, "C _6-10 aryl" refers to an all-carbon aromatic group containing 6-10 carbons, including but not limited to phenyl and naphthyl, and "C _6-8 aryl" refers to an all-carbon aromatic group containing 6-8 carbons. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

"Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, -SF5, -OS(O) _2R11 , -S(O) _{rR11 , -OR12 ,} -C(O) _OR12 , -C(O) _SR12 , -SC(O _{)R13, -C(O)R13 , -OC} (O) _R13 , -P(O)(R The group consisting of _{-R 14} )-C(O)R ₁₃ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N atoms and S(O)r (wherein r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. 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, including but not limited to:

"Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, = _S , -SF5, -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _{OR12 ,} -C(O) _SR12 , -SC(O) _R13 , -C(O) _R13 , _-OC (O) _R13 The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight chain or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, " _C2-10 alkenyl" refers to a straight chain or branched alkenyl group containing 2-10 carbon atoms, and " _C2-4 alkenyl" refers to a straight chain or branched alkenyl group containing 2-4 carbon atoms. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

"Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , _-C (O) _SR12 , -SC(O) _R13 , -C(O _{)R13 ,} -OC(O) _R13 The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C _2-10 alkynyl" refers to a straight chain or branched alkynyl group containing 2-10 carbon atoms, and "C _2-4 alkynyl" refers to a straight chain or branched alkynyl group containing 2-4 carbon atoms. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

"Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , _-C (O) _SR12 , -SC(O) _R13 , -C(O) _R13 , -OC(O) _R13 , _- The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Alkoxy" refers to -O-alkyl, wherein alkyl is as defined above, for example, " _C1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbon atoms, " _C1-4 alkoxy" refers to an alkyloxy group containing 1-4 carbon atoms, and " _C1-2 alkoxy" refers to an alkyloxy group containing 1-2 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

"Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _{C2-10 alkynyl} , _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, -SF5, -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , -C(O) _SR12 , -SC(O) _R13 , _-C (O) _R13 , _-OC (O) _R13 The group consisting of -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above, for example, "C _3-12 cycloalkyloxy" refers to a cycloalkyloxy containing 3-12 carbons, "C _3-6 cycloalkyloxy" refers to a cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium _- substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl _, =O, =S, -SF5, -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , _-C (O) _OR12 , -C(O _{)SR12, -SC(O)R13 , -C} (O) _R13 , -OC(O)R The group consisting of _{-R 14} , -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Heterocyclyloxy" or "heterocyclyloxy" refers to an -O-heterocyclyl group wherein heterocyclyl is as defined above and includes, but is not limited to, azetidinyloxy, oxetanyloxy, azopentyloxy, nitrogen, oxhexyloxy, and the like.

"Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium _- substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, =O, =S, -SF5, -OS(O) _2R11 , _-S (O) _rR11 , _-OR12 , -C(O) _OR12 , -C(O _{)SR12, -SC(O)R13 , -C} (O) _R13 , -OC(O) _R The group consisting of _{-R 14} , -P(O)(R ₁₃ ) ₂ , -NR ₁₄ R ₁₅ , -C(O)NR ₁₄ R ₁₅ and -N(R ₁₄ )-C(O)R ₁₃ is substituted.

"Halogen-substituted C _1-10 alkoxy" refers to an alkoxy group of 1-10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"Deuterium-substituted C _1-10 alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

"Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether; "EtOAc" or "EA" refers to ethyl acetate; "DMF" refers to dimethylformamide; "THF" refers to tetrahydrofuran; "MeOH" refers to methanol; "Pd ₂ dba ₃ " refers to tris(dibenzylideneacetone)dipalladium; "Cs ₂ CO ₃ " refers to cesium carbonate; "Burgess reagent" refers to Burgess reagent, the chemical name of which is N-(tri- "(Boc) ₂ O" refers to di-tert-butyl dicarbonate; "DIAD" refers to diisopropyl azodicarboxylate; "Pd(dppf)Cl ₂ " refers to (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride; "LiAlH ₄ " refers to lithium aluminum hydride; "TMSCF ₃ " refers to trimethylsilyl trifluoromethyl; "LDA" refers to lithium diisopropylamide; "BINAP" refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;"Cs ₂ CO ₃ " refers to cesium carbonate; "KHMDS" refers to potassium hexamethyldisilazide; "Ru ₃ (CO) ₁₂ " refers to triruthenium dodecacarbonyl; "NaBH ₄ " refers to sodium borohydride; "SOCl ₂ " refers to thionyl chloride; "DCM" refers to dichloromethane; "TMSCl" refers to trimethylsilyl chloride; "BrCH ₂ CH ₂ Br" refers to 1,2-dibromoethane; "t-BuOLi" refers to tert-butyllithium; "NIS" refers to N-iodosuccinimide; "PdG2precatalyst" refers to chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II);"Cy2NMe" refers to N,N-dihexylmethylamine; and "Zn(CN) ₂ " refers to zinc cyanide.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more "hydrogen atoms" in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the valence bond theory in chemistry, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin).

"Stereoisomers", whose English name is stereoisomer, refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configurational isomers, which are divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical properties due to the lack of anti-axis symmetry in the molecule are called optical isomers, which are divided into R and S configurations. In the present invention, the term "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

"Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). Sure.

NMR measurements were performed using a Bruker AVⅢ 400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) and HPLC were performed using Agilent 1200 HPLC/6100 SQ System mass spectrometer.

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

Preparation of intermediates

Intermediate A: Preparation of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Step 1: Synthesis of methyl (S)-4-nitro-3-((oxadiazine-2-ylmethyl)amino)benzoate

(S)-2-oxadiazine-1-ylmethylamine (1.04 g, 12 mmol) and methyl 3-fluoro-4-nitrobenzoate (2.0 g, 10.0 mmol) were dissolved in tetrahydrofuran (100 mL), potassium carbonate (2.07 g, 15.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours, filtered and concentrated to obtain a crude product, which was separated by column chromatography (PE/EA=2/1) to obtain methyl (S)-4-nitro-3-((2-oxadiazine-1-ylmethyl)amino)benzoate (2.12 g, yield: 79%). LCMS: m/z 265.2 [M+H] ⁺ .

Step 2: Synthesis of methyl (S)-4-amino-3-((oxadiazine-2-ylmethyl)amino)benzoate

Methyl (S)-4-nitro-3-((oxadiazine-2-ylmethyl)amino)benzoate (2.12 g, 8 mmol) was dissolved in methanol (50 mL), and Pd/C (200 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (1 atm), filtered, and concentrated to give methyl (S)-4-amino-3-((oxadiazine-2-ylmethyl)amino)benzoate (1.84 g, yield: 96%), LCMS: m/z 237.1 [M+H] ⁺ .

Step 3: Synthesis of methyl (S)-2-(chloromethyl)-1-(oxadiazole-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-amino-3-((oxadiazine-2-ylmethyl)amino)benzoate (1.84 g, 7.8 mmol) was dissolved in acetonitrile (200 mL), 2-chloro-1,1,1-trimethoxyethane (1.26 g, 8.2 mmol) and p-toluenesulfonic acid pyridinium salt (741 mg, 3.9 mmol) were added, heated to 60°C, and stirred for 1 hour. After concentration, methyl (S)-2-(chloromethyl)-1-(oxadiazine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (950 mg, yield: 41%) was obtained by direct column chromatography separation. LCMS: m/z 295.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (s, 1H), 8.02 (dd, J＝8.5, 1.4Hz, 1H), 7.81 (d, J＝8.5Hz, 1H), 5.22 (ddd, J＝ 9.4,7.2,2.6Hz,1H),5.05(s,2H),4.68–4.58(m,2H),4.54(dd,J＝15.6,2.6Hz,1H),4.34(dt,J＝9.2,6.0Hz ,1H),3.96(s,3H),2.82–2.71(m,1H),2.50–2.36(m,1H).

Intermediate B1 Preparation of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Step 1: Synthesis of tert-butyl 5-hydroxy-5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

2-Bromo-6-methoxypyridine (500mg, 2.66mmol) was dissolved in tetrahydrofuran (10mL), cooled to -78°C, and butyl lithium (1.17mL, 2.9mmol) was added dropwise. After half an hour, a solution of tert-butyl 5-carbonyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (3eq) in tetrahydrofuran (5mL) was added dropwise, and stirred at room temperature for 2 hours. Water was added to quench, and ethyl acetate was extracted (30mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE/EA=2/1) was used to obtain tert-butyl 5-hydroxy-5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (723mg, yield: 85%). LCMS: m/z 265.1[M+H-56] ⁺ .

Step 2: Synthesis of tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate

Tert-butyl 5-hydroxy-5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (430 mg, 1.34 mmol) was dissolved in tetrahydrofuran (20 mL), and burgess reagent (947 mg, 4.03 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated and separated by column chromatography (PE/EA=1/1) to obtain crude tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (300 mg). LCMS: m/z 302.9[M+H] ⁺ .

Step 3: Synthesis of tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (300 mg, 0.99 mmol) was dissolved in methanol (20 mL), palladium carbon (30 mg) was added, hydrogen was replaced, stirred and reacted under hydrogen atmosphere (1 atmosphere) for 3 hours, filtered, and concentrated to obtain crude tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (290 mg). LCMS: m/z 304.9 [M+H] ⁺ .

Step 4: Synthesis of 6-(2-azabicyclo[2.2.1]heptane-5-yl)pyridine-2-ol

Tert-butyl 5-(6-methoxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (290 mg, 0.99 mmol) was dissolved in acetonitrile (20 mL), and trimethylsilyl chloride (330 mg, 3.04 mmol) and sodium iodide (460 mg, 3.04 mmol) were added. The mixture was heated to 60°C and stirred for 3 hours. The mixture was filtered and concentrated to give a crude product of 6-(2-azabicyclo[2.2.1]heptane-5-yl)pyridine-2-ol (600 mg). LCMS: m/z 190.9 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl 5-(6-hydroxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 6-(2-Azabicyclo[2.2.1]heptane-5-yl)pyridin-2-ol (600 mg) was dissolved in dichloromethane (20 mL), and triethylamine (2 mL) and (Boc) ₂ O (2 mL) were added. The mixture was stirred at room temperature for 3 hours, concentrated, and separated by column chromatography (PE/EA=1/1) to obtain tert-butyl 5-(6-hydroxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (200 mg, crude). LCMS: m/z 291.2 [M+H] ⁺ .

Step 6: Synthesis of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Tert-butyl 5-(6-hydroxypyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (241 mg, crude) was dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (283 mg, 1.08 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (137 mg, 0.91 mmol) were added. The mixture was stirred at room temperature for 0.3 hours, DIAD (188 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and directly separated by column chromatography (PE/EA=1/1) to obtain tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (70 mg). LCMS: m/z 368.2[M+H-56] ⁺ .

Intermediate B2: Preparation of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)piperidine-1-carboxylate

Step 1: Synthesis of 1'-(tert-butyl)6-methyl 3',6'-dihydro-[2,4'-bipyridine]-1',6(2'H)-dicarboxylate

Methyl 6-bromomethyl pyridinate (220 mg, 1.02 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (470 mg, 1.52 mmol) were dissolved in 1,4-dioxane/H ₂ O (5:1), and potassium carbonate (420 mg, 3.04 mmol) and Pd(dppf)Cl ₂ were added. (78 mg, 0.11 mmol), heated to 90 ° C, stirred in microwave for 1 hour, cooled to room temperature, quenched with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EtOAc/PE=10:1) to obtain 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[2,4'-bipyridine]-1',6(2'H)-dicarboxylate (310 mg, yield: 96%), LCMS: m/z 319.2[M+H] ⁺ .

Step 2: Synthesis of methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)methyl pyridine ester

1'-(tert-butyl) 6-methyl 3',6'-dihydro-[2,4'-bipyridine]-1',6(2'H)-dicarboxylate (310 mg, 0.97 mmol) was dissolved in MeOH (10.0 mL), Pd/C (10%, 120 mg) was added, and the mixture was heated to 40°C under a hydrogen atmosphere (1 atm), stirred and reacted for 2 hours, filtered and concentrated, and the crude product was separated by column chromatography (PE/EA=8:1) to obtain methyl 6-(1-(tert-butyloxycarbonyl)piperidin-4-yl)methylpyridine ester (267 mg, 0.83 mmol). LCMS: m/z 321.2[M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)piperidine-1-carboxylate

Methyl 6-(1-(tert-butyloxycarbonyl)piperidin-4-yl)methyl pyridine ester (267 mg, 0.83 mmol) was dissolved in tetrahydrofuran (8.0 mL), cooled to 0°C, and LiAlH ₄ (49 mg, 2.24 mmol) was added. The mixture was stirred for 1 hour, and then quenched with aqueous sodium sulfate solution. The mixture was filtered and the crude product was separated by column chromatography (PE/EA=4:1) to obtain tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)piperidine-1-carboxylate (186 mg, yield: 82%). LCMS: m/z 293.1[M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)piperidine-1-carboxylate

Tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)piperidine-1-carboxylate (186 mg, 0.64 mmol) and 3-fluoro-4-hydroxybenzonitrile (0.96 mmol) were dissolved in tetrahydrofuran (8.0 mL), triphenylphosphine (360 mg, 1.91 mmol) and DIAD (386 mg, 1.91 mmol) were added, stirred at room temperature for 2 hours, quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)piperidine-1-carboxylate (681 mg), which was directly used in the next step. LCMS: m/z 412.1[M+H] ⁺ .

Intermediate B3: Synthesis of tert-butyl 4-(6-(1-(4-cyano-2-fluorophenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)piperidine-1-carboxylate

Step 1: Synthesis of 3-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile

3-Fluoro-4-formylbenzonitrile (300 mg, 2.03 mmol) and TMSCF ₃ (346 mg, 2.43 mmol) were dissolved in DMF (5.0 mL) and tetrabutylammonium fluoride (68 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, 1.0 M HCl (2.0 mL) was added and stirred for 3 hours, water (30 mL) was added for dilution, and ethyl acetate (3*30 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography to obtain 3-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (340 mg, yield: 77%).

¹ H NMR (400MHz, Chloroform-d) δ7.84–7.78 (m, 1H), 7.56 (dd, J＝8.0, 1.6Hz, 1H), 7.42 (dd, J＝9.2, 1.6Hz, 1H), 5.48 (q,J=6.4Hz,1H).

Step 2: Synthesis of 4-(tert-butyl)1-methyl1-(6-chloropyridin-2-yl)cyclohexane-1,4-dicarboxylate

1-(tert-Butyl) 4-methylpiperidine-1,4-dicarboxylate (1.0 g, 4.1 mmol) was dissolved in tetrahydrofuran (4.0 mL), cooled to -78 °C, LDA (2 M in tetrahydrofuran, 4.47 mL) was added, stirred for 2 hours, 2,6-dichloropyridine (547 mg, 3.70 mmol) in tetrahydrofuran (4 mL) was added, stirred at room temperature overnight, quenched with water, extracted with ethyl acetate (3*30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, The crude product was separated by column chromatography to obtain 4-(tert-butyl) 1-methyl 1-(6-chloropyridin-2-yl) cyclohexane-1,4-dicarboxylate (1.01 g, yield: 77%), LCMS: m/z 299.0 [M+H] ⁺ .

Step 3: Synthesis of 1-(tert-butoxycarbonyl)-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid

4-(tert-butyl) 1-methyl 1-(6-chloropyridin-2-yl) cyclohexane-1,4-dicarboxylate (1.01 g, 2.88 mmol) was dissolved in methanol (4.0 mL), sodium hydroxide (4.0 M, 1.5 mL) was added, heated to 50°C, the reaction was stirred for 1 hour, diluted with water, pH was adjusted to 4, extracted with dichloromethane (30 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1-(tert-butyloxycarbonyl)-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid. (831 mg, yield: 85%), LCMS: m/z 285.0 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate

1-(tert-Butyloxycarbonyl)-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid (831 mg, 2.44 mmol) was dissolved in dichloroethane (12.0 mL), heated under reflux overnight, extracted with dichloromethane (30 mL*3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography to obtain tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (700 mg, yield: 97%). LCMS: m/z 241.0 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl 4-(6-(1-(4-cyano-2-fluorophenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)piperidine-1-carboxylate

Tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (84 mg, 0.36 mmol) were dissolved in toluene (5 mL), and Pd ₂ dba ₃ (30 mg, 0.04 mmol), BINAP (20 mg, 0.07 mmol) and Cs ₂ CO ₃ (272 mg, 0.90 mmol) were added. Under _N2 atmosphere, reflux overnight, concentrate to dryness, and the crude product is directly separated by column chromatography (PE/EtOAc=60/40) to obtain tert-butyl 4-(6-(1-(4-cyano-2-fluorophenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)piperidine-1-carboxylate (118 mg, yield 73%), LC/MS: m/z 424.1 [M+H-56] ⁺ .

Intermediates B4-B7 are prepared by referring to all or part of the synthetic steps of intermediates B1-B3:

Intermediate B8: Preparation of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)piperidine-1-carboxylate

Step 1: Synthesis of 1,3-dibromo-2-(2-methoxyethyl)benzene

MeOCH ₂ PPh ₃ ⁺ Cl ^- (971 mg, 2.84 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78°C, KHMDS (1 M in tetrahydrofuran, 3.0 mL) was added, stirred for 1 hour, and a solution of 2,6-dibromobenzaldehyde (500 mg, 1.89 mmol) in tetrahydrofuran (10 mL) was added. The temperature was slowly raised to room temperature, stirred overnight, quenched with aqueous ammonium chloride solution (aq., 5 mL), diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (PE/EtOAc=98:2) to obtain 1,3-dibromo-2-(2-methoxyethyl)benzene (370 mg, yield: 67%).

¹ H NMR (400MHz, CDCl3) δ: 7.54 (d, J = 8.0Hz, 2H), 6.93 (d, J = 13.1Hz, 1H), 6.88 (t, J = 8.0Hz, 1H), 5.68 (d, J＝13.1Hz,1H),3.76(s,3H).

Step 2: Synthesis of 2-(2,6-dibromophenyl)acetaldehyde

1,3-Dibromo-2-(2-methoxyethyl)benzene (370 mg, 1.26 mmol) was dissolved in acetone (20 mL), HCl (5 mL, 2 M) was added, and refluxed for 4 hours. The mixture was extracted with ethyl acetate (10 mL*3), the organic phases were combined, washed with sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (PE/EtOAc=85:15) to obtain 2-(2,6-dibromophenyl)acetaldehyde (320 mg, yield: 91%).

¹ H NMR (400MHz, CDCl ₃ ) δ9.75 (t, J = 1.1 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 8.0 Hz, 1H), 4.22 (d ,J＝1.1Hz,2H).

Step 3: Synthesis of 4-(2-(2,6-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile

4-Bromo-3-fluorobenzonitrile (108 mg, 0.54 mmol) was dissolved in tetrahydrofuran (5.0 mL), cooled to -78 °C, butyl lithium (2.5 M in hexane, 0.2 mL, 0.5 mmol) was added dropwise, stirred for 20 minutes, 2-(2,6-dibromophenyl)acetaldehyde (100 mg, 0.36 mmol) was added, stirred for 30 minutes, returned to room temperature, quenched with aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (PE/EtOAc=65:35) to give 4-(2-(2,6-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile (52 mg, yield: 36%).

¹ H NMR (400MHz, CDCl3) δ7.75(t,J＝7.5Hz,1H),7.55(d,J＝8.0Hz,2H),7.51(dd,J＝8.1,1.6Hz,1H),7.31( dd,J＝9.6,1.5Hz,1H),6.99(t,J＝8.0Hz,1H),5.50(dd,J＝8.8,5.3Hz,1H),3.50(ddd,J＝19.1,13.8,7.1Hz ,2H).

Step 4: Synthesis of 4-(4-bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile

4-(2-(2,6-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile (50 mg, 0.125 mmol) was dissolved in toluene (2.0 mL), sodium hydride (6.4 mg, 0.16 mmol) was added, heated to 40°C, stirred for 15 minutes, returned to room temperature, cuprous chloride (1.0 mg, 0.02 mmol) and ethyl acetate (1.0 mg, 0.02 mmol) were added, refluxed for 24 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography (PE/EtOAc=85:15) to give 4-(4-bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (3 mg, yield: 58%).

¹ H NMR (400MHz, CDCl3) δ7.62 (t, J＝7.6Hz, 1H), 7.47 (dd, J＝8.0, 1.4Hz, 1H), 7.40 (dd, J＝9.6, 1.4Hz, 1H), 7.10–7.03(m,2H),6.89–6.81(m,1H),6.04(dd,J＝9.9,7.5Hz,1H),3.79(dd,J＝16.3,9.9Hz,1H),3.11(dd, J＝16.3,7.5Hz,1H).

Step 5: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

4-(4-Bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (25 mg, 0.078 mmol, 1.0 eq.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (49 mg, 0.16 mmol) were dissolved in 1,4-dioxane/water (3.0 mL/0.6 mL), and Pd(dppf)Cl ₂ (16 mg, 0.02 mmol, 20 mol%) and Na ₂ CO ₃ were added. (25 mg, 0.23 mmol), microwave heated to 90 ° C, reacted for 1 hour, cooled to room temperature, quenched with water, extracted with ethyl acetate (20 mL * 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was separated by column chromatography (PE / EtOAc = 80:20) to give tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (35 mg, yield: 55%).

¹ H NMR (400MHz, CDCl3) δ7.64 (t, J＝7.6Hz, 1H), 7.46 (dd, J＝8.0, 1.4Hz, 1H), 7.39 (dd, J＝9.6, 1.4Hz, 1H), 7.19(t,J＝7.9Hz,1H),6.84(dd,J＝9.9,7.9Hz,2H),δ6.02–5.95(m,1H),5.76(s,1H),4.07–4.01(m, 2H),3.81(dd,J＝15.8,9.8Hz,1H),3.59(t,J＝5.7Hz,2H),3.11(dd,J＝15.8,7.6Hz,1H),2.48–2.37(m,2H ),1.48(s,9H).

Step 6: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)piperidine-1-carboxylate

Tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (35 mg, 0.08 mmol) was dissolved in ethanol (5 mL), and Pd/C (4 mg, 10% wt) was added. The mixture was stirred for 2 hours under a hydrogen atmosphere (1 atm), filtered and concentrated, and separated by column chromatography (PE/EtOAc=90:10) to obtain Tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)piperidine-1-carboxylate (20 mg, yield: 57%). LC/MS: m/z 367.5 [M+H-tBu] ⁺ .

Intermediate B9: Preparation of tert-butyl 4-(2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate

Step 1: Synthesis of (4-ethynylphenyl)(trifluoromethyl)sulfane

4-((Trifluoromethyl)thio)benzaldehyde (5.00 g, 24.251 mmol) was dissolved in methanol (100 mL), potassium carbonate (5.03 g, 36.377 mmol) was added, cooled to 0°C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (Seyferth-Gilbert homologation, 6.99 g, 36.377 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate (200 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude (4-ethynylphenyl)(trifluoromethyl)sulfane (6.5 g).

Step 2: Synthesis of 4-bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole

(4-Ethynylphenyl)(trifluoromethyl)sulfane (6.50 g, 32.148 mmol) and 3-bromobenzene-1,2-diol (3.04 g, 16.074 mmol, dissolved in toluene (65 mL), added with Ru ₃ (CO) ₁₂ (0.21 g, 0.329 mmol), heated to 150°C in microwave, reacted for 4 hours, concentrated to dryness, and directly separated by column chromatography to obtain 4-bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole (1.00 g, yield: 16%).

Step 3: Synthesis of 4-bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole

4-Bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole (200 mg, 0.511 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (237 mg, 0.766 mmol) were dissolved in 1,4-dioxane (8 mL) and H ₂ O (2 mL), and cesium carbonate (333 mg, 1.022 mmol) and Pd(dppf)Cl ₂ (37 mg, 0.051 mmol) were added. ₂ atmosphere, heated to 90 ° C, stirred for 16 hours, cooled to room temperature, concentrated to dryness, and separated by column chromatography (PE/EA=5:1) to give 4-bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole (160 mg, yield: 63.41%).

Step 4: Synthesis of tert-butyl 4-(2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate

4-Bromo-2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazole (760 mg, 1.540 mmol) was dissolved in methanol (20 mL), Pd/C (10%, 100 mg) was added, and the mixture was stirred for 4 hours under a hydrogen atmosphere (1 atm). The mixture was filtered and concentrated, and column chromatography (PE/EA=5:1) was used to obtain tert-butyl 4-(2-methyl-2-(4-((trifluoromethyl)thio)phenyl)benzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate (630 mg, yield: 82.56%). LC-MS: m/z 496.6 [M+H] ⁺ .

Intermediate B10: Preparation of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate

Step 1: Synthesis of (2,3-dibromophenyl)methanol

To a solution of 2,3-dibromobenzaldehyde (500.0 mg, 1.9 mmol) in tetrahydrofuran (10 mL) was added NaBH ₄ (86.0 mg, 2.3 mmol). The reaction solution was stirred at 25°C for 1 hour. After the sampling point plate showed that the raw material was completely consumed, the reaction solution was poured into saturated brine (50 mL) and extracted with EA (50 mL*3). The combined organic phase was dried over Na ₂ SO ₄ and filtered. The filtrate was spin-dried and then monitored at 200 nm by a medium-low pressure rapid column machine to obtain (2,3-dibromophenyl)methanol (500.0 mg, 1.9 mmol, quantitative reaction).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.66 (ddt,J＝8.0,1.6,0.8Hz,1H),7.53(ddt,J＝7.7,1.8,1.0Hz,1H),7.36(t,J =7.8Hz, 1H), 5.60 (t, J = 5.7Hz, 1H), 4.53 (d, J = 5.6Hz, 2H).

Step 2: Synthesis of 1,2-dibromo-3-(chloromethyl)benzene

DMF (0.1 mL) and SOCl ₂ (1 mL) were added to a solution of (2,3-dibromophenyl)methanol (500.0 mg, 1.9 mmol) in DCM (10 mL). The reaction solution was stirred at 25°C for 4 hours. Samples were taken and sent to LCMS (200 nm) to show that the starting material was completely consumed. The reaction solution was poured into water (50 mL) and adjusted to pH = 7 with Na ₂ CO _3. The mixed solution was extracted with EA (50 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over Na ₂ SO _4, and filtered. The filtrate was spin-dried and then monitored by a medium-low pressure rapid column machine at 200 nm to obtain 1,2-dibromo-3-(chloromethyl)benzene (500.0 mg, yield: 92.5%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.78 (dd, J＝8.0, 1.5Hz, 1H), 7.63 (dd, J＝7.7, 1.6Hz, 1H), 7.36 (t, J＝7.8Hz, 1H),4.89(s,2H).

Step 3: Synthesis of 4-(2-(2,3-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile

Tetrahydrofuran (3 mL) was added to a mixture of zinc powder (150.0 mg, 2.3 mmol) and LiCl (98.0 mg, 2.3 mmol). After the mixture was purged of N ₂ , TMSCl (0.1 mL) and BrCH ₂ CH ₂ Br (0.1 mL) were added, and the reaction was stirred at 25 °C for 10 min. A solution of 1,2-dibromo-3-(chloromethyl)benzene (500.0 mg, 1.7 mmol) in tetrahydrofuran (2 mL) was added to the reaction system. The reaction was heated to 50 °C and reacted under N ₂ protection for 2 hours (until the zinc powder was almost completely consumed). After the reaction was allowed to stand for 5 min, the supernatant was added to a solution of 3-fluoro-4-formylbenzonitrile (253.5 mg, 1.7 mmol) in tetrahydrofuran (1 mL). The reaction was reacted overnight under N ₂ protection at room temperature. Samples were taken and sent to LCMS (200 nm) to show that the starting material was completely consumed. The reaction solution was poured into saturated brine (50 mL) and washed with EA (50mL*3) extraction. The combined organic phase was dried over Na ₂ SO ₄ and then filtered. The filtrate was spin-dried and then passed through the column using a medium-low pressure rapid column machine under 200nm monitoring to obtain 4-(2-(2,3-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile (220.0mg, yield: 32.4%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.81–7.68(m,3H),7.63(dd,J＝6.9,2.6Hz,1H),7.24–7.07(m,2H),5.80(d,J =5.1Hz,1H),5.21(dt,J＝7.4,5.6Hz,1H),3.14(dd,J＝6.8,3.3Hz,2H).

Step 4: Synthesis of 4-(7-bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile

To a mixture of t-BuOLi (984.7 mg, 12.3 mmol) and dioxane (30 mL) was added a solution of 4-(2-(2,3-dibromophenyl)-1-hydroxyethyl)-3-fluorobenzonitrile (1.6 g, 4.1 mmol) in tetrahydrofuran (30 mL). The reaction solution was stirred at 25 °C under N ₂ protection for 15 min. CuI (78.1 mg, 0.4 mmol) was added to the reaction system. The reaction was heated to 120 °C and reacted at this temperature under N ₂ protection for 16 hours. Samples were taken and sent to LCMS (200 nm) to show that the starting material was completely consumed. The reaction solution was poured into saturated brine (200 mL) and extracted with EA (200 mL*3). The combined organic phase was dried over Na ₂ SO ₄ and filtered. The filtrate was spin-dried and then passed through the column using a medium-low pressure rapid columnizer under monitoring at 200 nm to obtain 4-(7-bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (1.2 g, yield: 92.0%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13 (dd, J＝10.4, 1.6Hz, 1H), 7.94 (dd, J＝8.0, 1.6Hz, 1H), 7.78 (t, J＝7.7Hz, 1H),7.57(dd,J＝8.0,1.1Hz,1H),7.43(dq,J＝7.3,1.2Hz,1H),7.12–6.97(m,1H),6.37(dd,J＝10.0,7.1Hz ,1H),4.19–3.98(m,1H),3.47(ddd,J＝16.2,7.2,1.2Hz,1H).

Step 5: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Pd(dppf)Cl 2 (278.0 mg, 0.4 mmol) was added to a mixture of 4-(7-bromo-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (1.2 g, 3.8 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 4.2 mmol), cesium carbonate (3.7 g, 11.4 mmol), 1,4-dioxane (15 mL) and H ₂ O (1.5 _mL ). The reaction solution was stirred at 100°C under N ₂ protection for 18 hours. The sample was sent to LCMS (200 nm) to show that the starting material was completely consumed and the molecular weight of the product was detected. The reaction solution was poured into saturated brine (200 mL) and extracted with EA (200 mL*3). The combined organic phase was dried over Na ₂ SO ₄ and filtered. The filtrate was spin-dried and rapidly column-purified at medium and low pressure to obtain tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, yield: 87.6%). LCMS: m/z 365 [M-56+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.94 (dd, J＝10.3, 1.6Hz, 1H), 7.74 (dd, J＝7.9, 1.6Hz, 1H), 7.60 (t, J＝7.7Hz, 1H),7.20–7.09(m,2H),6.91(t,J＝7.6Hz,1H),6.32(s,1H),6.10(dd,J＝9.9,7.5Hz,1H),4.01(d,J ＝11.1Hz,2H),3.76(dd,J＝15.9,9.9Hz,1H),3.62–3.43(m,2H),3.13(dd,J＝15.9,7.5Hz,1H),2.60–2.51(m, 2H),1.43(s,9H).

Step 6: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (650.0 mg, 1.5 mmol) in EA (15 mL) was added 5% Pd/C (65.0 mg). The reaction solution was replaced with H ₂ and stirred at 25°C under hydrogen (1 atmosphere) for 2 hours. Samples were taken and sent to LCMS for reaction. The reaction mixture was filtered through diatomaceous earth. The filtrate was dried by spin drying and then separated by rapid column separation under medium and low pressure to obtain tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (230.0 mg, yield: 36.3%). LCMS: m/z 367 [M-56+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.94(dd,J＝10.3,1.6Hz,1H),7.75(dd,J＝7.9,1.6Hz,1H),7.59(t,J＝7.7Hz,1H),7.17–6.94(m,2H),6.86(t,J＝7.5Hz,1H),6.07(dd,J＝10.0,7.3Hz,1H),4 .06(s,2H),3.76(dd,J＝15.9,10.0Hz,1H),3.11(dd,J＝15.8,7.3Hz,1H),2.94–2.69(m,3H),1.77(d,J＝12.8Hz,2H),1.70–1.52(m,2H),1.40(s,9H).

Intermediates B11 to B12 are prepared by referring to all or part of the synthetic steps of intermediates B8 to B10:

Intermediate B13: Preparation of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chroman-5-yl)piperidine-1-carboxylate

Step 1: Synthesis of 4-acetyl-3-fluorobenzonitrile

4-Bromo-3-fluorobenzonitrile (2.0 g, 10.0 mmol) and tributyl(1-ethoxyvinyl)stannane (4.3 g, 12.0 mmol) were dissolved in 1,4-dioxane (20.0 mL), Pd(PPh ₃ ) ₄ (231 mg, 0.2 mmol) was added, heated to 110° C. under nitrogen atmosphere, stirred for 2 hours, cooled to room temperature, quenched with water, extracted with dichloromethane (3*50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA＝20:1) to obtain 4-acetyl-3-fluorobenzonitrile (1.0 g, yield: 61%).

¹ H NMR (400MHz, CDCl ₃ -d ₁ ) δ7.97 (t, J = 8.1, 1H), 7.54 (dd, J = 8.1Hz, 1.4Hz, 1H), 7.48 (dd, J = 10.1Hz, 1.4 Hz,1H).

Step 2: Synthesis of (E)-4-(3-(2-bromo-6-(methoxymethoxy)phenyl)acryloyl)-3-fluorobenzonitrile

4-Acetyl-3-fluorobenzonitrile (400 mg, 2.45 mmol) and 2-bromo-6-(methoxymethoxy)benzaldehyde (600 mg, 2.45 mmol) were dissolved in ethanol (25.0 mL), potassium hydroxide (412.4 mg, 7.35 mmol) was added, and the mixture was stirred at room temperature for half an hour, filtered, and concentrated to give (E)-4-(3-(2-bromo-6-(methoxymethoxy)phenyl)acryloyl)-3-fluorobenzonitrile (557 mg, yield: 58%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.09 (dd, J = 10.4, 1.2 Hz, 1H), 7.97–7.91 (m, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.88– 7.83(m,1H),7.70(dd,J＝16.0,2.4Hz,1H),7.41(dd,J＝7.9,1.1Hz,1H),7.34(t,J＝8.1Hz,1H),7.26(d ,J＝8.0Hz,1H),5.39(s,2H),3.41(s,3H).

Step 3: Synthesis of (E)-4-(3-(2-bromo-6-(methoxymethoxy)phenyl)-1-hydroxyallyl)-3-fluorobenzonitrile

(E)-4-(3-(2-bromo-6-(methoxymethoxy)phenyl)acryloyl)-3-fluorobenzonitrile (550mg, 1.41mmol) was dissolved in methanol (15.0mL), sodium borohydride (267mg, 7.05mmol) was added, stirred at room temperature for half an hour, quenched with water, extracted with dichloromethane (3*20mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (E)-4-(3-(2-bromo-6-(methoxymethoxy)phenyl)-1-hydroxyallyl)-3-fluorobenzonitrile (553mg, yield: 100%). LC-MS: m/z 346.0[M-45] ⁺ .

Step 4: Synthesis of 4-(5-bromo-2H-chromen-2-yl)-3-fluorobenzonitrile

(E)-4-(3-(2-Bromo-6-(methoxymethoxy)phenyl)-1-hydroxyallyl)-3-fluorobenzonitrile (553 mg, 1.41 mmol) was dissolved in a solution of HCl in dioxane (25.0 mL, 4 M), stirred for 12 hours, concentrated, and the crude product was separated by column chromatography (PE:EA=10:1) to give 4-(5-bromo-2H-chromen-2-yl)-3-fluorobenzonitrile (215 mg, yield: 46%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.96 (d, J = 10.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.21 (d,J＝8.0Hz,1H),7.11(t,J＝8.1Hz,1H),6.90–6.82(m,2H),6.38(d,J＝2.2Hz,1H),6.11(dd,J＝ 10.0,3.8Hz,1H).

Step 5: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2H-chromen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

4-(5-Bromo-2H-chromen-2-yl)-3-fluorobenzonitrile (215 mg, 0.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (242.0 mg, 0.78 mmol) and Pd(dppf)Cl ₂ (95mg, 0.13mmol), dissolved in dioxane (6.0mL) and water (2.0mL), added potassium carbonate (270mg, 1.95mmol), heated to 110℃ under nitrogen atmosphere, stirred for 2 hours, cooled to room temperature, quenched with water, extracted with dichloromethane (3*30mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (DCM:MeOH＝10:1) to obtain tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2H-chromen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (188.0mg, yield: 67%). LC-MS: m/z 377.0[M+H-56] ⁺ .

Step 6: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chroman-5-yl)piperidine-1-carboxylate

Tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2H-chromen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (83.0 mg, 0.19 mmol) was dissolved in ethyl acetate, palladium carbon (96 mg) was added, hydrogen was replaced, and the reaction was stirred under a hydrogen atmosphere (1 atmosphere) for 1 hour, filtered, concentrated, and separated by column chromatography (DCM:MeOH=20:1) to obtain tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chromen-5-yl)piperidine-1-carboxylate (45 mg, yield: 53%). LC-MS: m/z 381.2[M+H-56] ⁺ .

Intermediate B14: Preparation of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate

Step 1: Synthesis of 3-fluoro-4-(1-hydroxyallyl)benzonitrile

3-Fluoro-4-formylbenzonitrile (5 g, 33.53 mmol) was dissolved in tetrahydrofuran (170 mL), cooled to 0°C, and vinylmagnesium bromide (40 mL, 1.2 eq) was added dropwise. After the reaction was complete, aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (3*100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (EtOAc/PE=5:1) to give 3-fluoro-4-(1-hydroxyallyl)benzonitrile (2.1 g, yield: 35.4%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.66 (t, J＝7.5Hz, 1H), 7.49 (dd, J＝8.0, 1.4Hz, 1H), 7.34 (dd, J＝9.6, 1.5Hz, 1H) ,6.08–5.94(m,1H),5.56(d,J＝5.9Hz,1H),5.40(dd,J＝17.1,1.1Hz,1H),5.32–5.22(m,1H).

Step 2: Synthesis of tert-butyl 4-(5-bromo-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

4-Bromo-2-iodophenol (10 g, 33.44 mmol) was dissolved in dioxane (120 mL) and water (20 ml), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (12.4 g, 40.13 mmol), potassium carbonate (13.9 g, 10.33 mmol) and Pd(PPh ₃ ) ₄ (2.3 g, 2.01 mmol) were added in sequence. Under N ₂ protection, the mixture was heated to 110°C and stirred for 18 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (EtOAc/PE=1:4) to obtain tert-butyl 4-(5-bromo-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (7.4 g, yield: 74%). LCMS: m/z 297.8 [M+H-56] ⁺ .

Step 3: Synthesis of tert-butyl 4-(5-bromo-2-hydroxyphenyl)piperidine-1-carboxylate

Tert-butyl 4-(5-bromo-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 5.66 mmol) was dissolved in ethyl acetate (30 mL), and platinum dioxide (127 mg, 0.56 mmol) was added. The mixture was stirred for 72 hours under a hydrogen atmosphere (1 atm), filtered and concentrated, and separated by column chromatography (EtOAc/PE=1:5) to obtain tert-butyl 4-(5-bromo-2-hydroxyphenyl)piperidine-1-carboxylate (1.4 g, yield: 70%). LCMS: m/z 299.8[M+H-56] ⁺ .

Step 4: Synthesis of tert-butyl 4-(5-bromo-2-hydroxy-3-iodophenyl)piperidine-1-carboxylate

Tert-butyl 4-(5-bromo-2-hydroxyphenyl)piperidine-1-carboxylate (1.4 g, 3.94 mmol) was dissolved in DMF (20 mL), and NIS (1.06 g, 4.73 mmol) was added, heated to 50°C, stirred for 1 hour, cooled to room temperature, extracted with ethyl acetate (40 mL), washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and column purified. Chromatographic separation (EtOAc/PE=10:1) gave tert-butyl 4-(5-bromo-2-hydroxy-3-iodophenyl)piperidine-1-carboxylate (840 mg, yield 44%). LCMS: m/z 425.6 [M+H-56] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.62 (d, J = 2.4Hz, 1H), 7.21 (d, J = 2.4Hz, 1H), 5.39 (brs, 1H), 3.08-3.02 (m, 1H) ,2.84-2.78(m,2H),1.82-1.80(m,2H),1.56-1.52(m,2H),1.48(s,9H).

Step 5: Synthesis of tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-oxopropyl)-2-hydroxyphenyl)piperidine-1-carboxylate

Tert-butyl 4-(5-bromo-2-hydroxy-3-iodophenyl)piperidine-1-carboxylate (840 mg, 1.75 mmol), 3-fluoro-4-(1-hydroxyallyl)benzonitrile (309 mmol, 1.75 mmol), PdG2precatalyst (138 mg, 0.175 mmol) and Cy2NMe (512 mg, 2.62 mmol) were dissolved in toluene (30 mL), _N2 protected, heated to 100 ° C, reacted for 16 hours, cooled to room temperature, concentrated to dryness, and the crude product was separated by column chromatography (EtOAc/PE=2:5) to give tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-oxopropyl)-2-hydroxyphenyl)piperidine-1-carboxylate (440 mg, yield: 48%). LCMS: m/z 528.8[M-1] ^- .

Step 6: Synthesis of tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-hydroxypropyl)-2-hydroxyphenyl)piperidine-1-carboxylate

Tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-oxopropyl)-2-hydroxyphenyl)piperidine-1-carboxylate (440 mg, 0.83 mmol) was dissolved in methanol (15 mL), sodium borohydride (63 mg, 1.66 mmol) was added, stirred at room temperature for 2 hours, quenched with water (30 mL), extracted with ethyl acetate (40 mL), washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EtOAc/PE=1:1) to obtain tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-hydroxypropyl)-2-hydroxyphenyl)piperidine-1-carboxylate (400 mg, yield: 90%). LCMS: m/z 532.8[M-1] ^- .

Step 7: Synthesis of tert-butyl 4-(6-bromo-2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate

Tert-butyl 4-(5-bromo-3-(3-(4-cyano-2-fluorophenyl)-3-hydroxypropyl)-2-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 0.75 mmol) and triphenylphosphine (237 mg, 0.90 mmol) were dissolved in tetrahydrofuran (20 mL), and DIAD (182 mg, 0.90 mmol) was slowly added. After the reaction was completed, water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (30 mL), washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EtOAc/PE=1:1) to obtain tert-butyl 4-(6-bromo-2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate (240 mg, yield: 68%). LCMS: m/z 459.1[M+H-56] ⁺ .

Step 8: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate

Tert-butyl 4-(6-bromo-2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate (240 mg, 0.47 mmol) was dissolved in ethanol (10 mL), 10% Pd/C (30 mg) was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for 16 hours, filtered, concentrated, and the crude product was separated by column chromatography (EtOAc/PE=1:5) to give tert-butyl 4-(2-(4-cyano-2-fluorophenyl)chroman-8-yl)piperidine-1-carboxylate (88 mg, yield: 43%). LCMS: m/z 381.0 [M+H-56] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.30 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 3H), 7.04 (d,J＝7.2Hz,1H),6.94(d,J＝6.8Hz,1H),6.86-6.83(m,1H),5.42-5.41(m,1H),5.27-5.23(m, 1H),4.89-4.87(m,1H),4.73-4.61(m,2H),4.46-4.44(m,1H),4.08-3.93(m,2H),3.14-2.99(m,4H),2.81- 2.76(m,2H),2.53-2.49(m,1H),2.40-2.27(m,3H),2.01-1.74(m,5H).

Intermediate B15: Preparation of tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)piperidine-1-carboxylate

Step 1: Synthesis of ethyl 2-(4-bromo-2-fluorophenyl)-2-((6-chloro-3-nitropyridin-2-yl)oxy)acetate

Ethyl 2-(4-bromo-2-fluorophenyl)-2-hydroxyacetate (1.58 g, 5.70 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0°C, sodium hydride (1.5 eq) was added in batches, stirred for 15 minutes, and a tetrahydrofuran solution of 2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol) was added dropwise, stirred at room temperature for half an hour, quenched with ammonium chloride solution, extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA=65/35) to obtain ethyl 2-(4-bromo-2-fluorophenyl)-2-((6-chloro-3-nitropyridine-2-yl)oxy)acetate (1.8 g, yield: 73%). LCMS: m/z 454.8 [M+Na] ⁺ .

Step 2: Synthesis of 3-(4-bromo-2-fluorophenyl)-6-chloro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Ethyl 2-(4-bromo-2-fluorophenyl)-2-((6-chloro-3-nitropyridin-2-yl)oxy)acetate (1.8 g, 4.16 mmol) was dissolved in acetic acid (20 mL), iron powder (1.16 g, 20.8 mmol) was added, heated to 70°C, stirred for 12 hours, concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE/EA=65/35) to obtain 3-(4-bromo-2-fluorophenyl)-6-chloro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.1 g, yield: 73.9%). LCMS: m/z 356.9[M+H] ⁺ .

Step 3: Synthesis of 3-(4-bromo-2-fluorophenyl)-6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

3-(4-bromo-2-fluorophenyl)-6-chloro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (560mg, 1.57mmol) was dissolved in tetrahydrofuran (10mL), cooled to 0℃, BH ₃ in dimethylsulfane (3.1mL, 10M) was added dropwise, heated to 60℃, and the reaction was stirred for 12 hours. Cooled to 0℃, methanol (5mL) and water were added dropwise, stirred for half an hour, concentrated, extracted with ethyl acetate (30ml*2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA＝65/35) to obtain 3-(4-bromo-2-fluorophenyl)-6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (360mg, yield: 67%). LCMS: m/z 342.9 [M+H] ⁺ .

Step 4: Synthesis of 4-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)-3-fluorobenzonitrile 3-(4-bromo-2-fluorophenyl)-6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (460 mg, 1.34 mmol) was dissolved in DMF (10 mL), and Zn(CN) ₂ (3.14 g, 26.8 mmol) and Pd(PPh ₃ ) ₄ (0.1 eq) were added. The mixture was heated at 100° C. in a microwave under a nitrogen atmosphere for 1.5 hours. Cool, extract with ethyl acetate (30 ml*2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE/EA=1/2) to obtain 4-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)-3-fluorobenzonitrile (250 mg, yield: 64%), LCMS: m/z 291.0 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

4-(6-Chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)-3-fluorobenzonitrile (550 mg, 1.90 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (880.6 mg, 2.85 mmol) and potassium phosphate (1.21 g, 5.70 mmol) were dissolved in dioxane: water (4:1, 5 mL), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (139.3 mg, 0.19 mmol) was added, and the mixture was heated to 100°C under nitrogen atmosphere for 4 hours. Filter, extract with ethyl acetate (30ml*2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE/EA=1/1) to obtain tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (450mg, yield: 54%). LCMS: m/z 437.2[M+H] ⁺ .

Step 6: Synthesis of tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)piperidine-1-carboxylate

Tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (480 mg, 1.1 mmol) was dissolved in methanol (10 mL), palladium carbon (96 mg) was added, hydrogen was replaced, and the reaction was stirred for 0.5 hours under a hydrogen atmosphere (1 atmosphere), filtered, concentrated, and separated by column chromatography (PE:EtOAc=2:3) to obtain tert-butyl 4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)piperidine-1-carboxylate (460 mg, yield: 95%). LCMS: m/z 439.2[M+H] ⁺ .

Preparation of Examples

Example 1 Preparation of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (10 mL), stirred at room temperature for 0.3 hours, concentrated, diluted with dichloromethane (20 mL), methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (52 mg, 0.18 mmol) and cesium carbonate (156 mg, 0.48 mmol) were added in sequence, stirred at room temperature for 1 hour, and concentrated. Methanol (3 mL) and water (10 mL) were added to dilute, lithium hydroxide (100 mg) was added, and the mixture was stirred at room temperature for 3 hours. The crude product was separated by column chromatography (dichloromethane/methanol=10/1), and 2-((5-(6-(( ₄ -cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg, yield: 32%) was obtained by column chromatography separation (acetonitrile/water (0.1% NH 4 OH)). LCMS: m/z 567.8 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ12.76 (s, 1H), 8.24 (s, 1H), 7.86 (d, J = 9.9 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J = 13.9 ,6.0Hz,3H),7.60(s,1H),7.01(d,J＝6.9Hz,1H),6.78(d,J＝8.0Hz,1H),5.58(s,2H) ,5.01(s,1H),4.72(dd,J＝15.1,7.2Hz,1H),4.64–4.54(m,1H),4.44(s,1H),4.30(d,J＝26.6Hz,1H), 4.02(s,1H),3.02(s,1H),2.67(d,J＝1.7Hz,2H),2.33(d,J＝1.8Hz,4H),1.83(s,3H).

Examples 2 to 15 were prepared by selecting appropriate intermediates and reagents according to the synthetic steps of Example 1:

Example 16 Preparation of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Step 1: Synthesis of methyl (S)-4-nitro-3-((oxadiazine-2-ylmethyl)amino)benzoate

Methyl 3-fluoro-4-nitrobenzoate (1.6 g, 8.0 mmol) was dissolved in THF (30 mL), K ₂ CO ₃ (1.7 g, 12.1 mmol) was added, and after stirring for ten minutes, (S)-oxabutane-2-ylmethylamine (875.0 mg, 10.0 mmol) was added, and the mixture was reacted at room temperature for 12 hours. After the reaction was complete as determined by LCMS, 300 mL of water was added, and then the mixture was extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Methyl (S)-4-nitro-3-((oxabutane-2-ylmethyl)amino)benzoate (2.0 g, yield: 93.4%) was obtained by column separation with PE/EA (85/15, v/v). LCMS: m/z 267.2 [M+1] ⁺ .

Step 2: Synthesis of methyl (S)-4-amino-3-((oxadiazine-2-ylmethyl)amino)benzoate

Dissolve methyl (S)-4-nitro-3-((oxadiazine-2-ylmethyl)amino)benzoate (2.0 g, 7.5 mmol) in MeOH (30 mL), add palladium carbon (400.0 mg), replace the system with a hydrogen balloon, and react at room temperature for 2-3 hours. After the reaction is complete as detected by LCMS, filter and remove the solvent by rotary evaporation to obtain methyl (S)-4-amino-3-((oxadiazine-2-ylmethyl)amino)benzoate (1.5 g, yield: 84.6%). LCMS: m/z 236.9[M+1] ⁺ .

Step 3: Synthesis of methyl (S)-4-(2-(4-bromophenyl)acetylamino)-3-((oxadiazole-2-ylmethyl)amino)benzoate

Methyl (S)-4-amino-3-((oxadiazole-2-ylmethyl)amino)benzoate (1.5 g, 6.3 mmol) was dissolved in DMF (12 mL), and 2-(4-bromophenyl)acetic acid (1.4 g, 6.5 mmol), HATU (3.7 g, 9.7 mmol), and DIEA (2.5 g, 19.4 mmol) were added, and stirred at room temperature overnight. After the reaction was complete by LCMS, 300 mL of water was added, and then extracted three times with EA. The organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Methyl (S)-4-(2-(4-bromophenyl)acetylamino)-3-((oxadiazole-2-ylmethyl)amino)benzoate (1.2 g, yield: 43.6%) was obtained by column chromatography with PE/EA (56/44, v/v). LCMS: m/z 434.8 [M+1] ⁺ .

Step 4: Synthesis of methyl (S)-2-(4-bromobenzyl)-1-(oxadiazole-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(4-bromophenyl)acetylamino)-3-((oxadiazole-2-ylmethyl)amino)benzoate (700.0 mg, 1.6 mmol) was added to AcOH (20 mL), heated in an oil bath at 60°C, and stirred for 12 hours. After the reaction was complete, LCMS detected that the AcOH was removed by vacuum distillation with an oil pump, and then 150 mL of water was added. The pH was adjusted to 5-6 with an aqueous sodium carbonate solution, and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Methyl (S)-2-(4-bromophenyl)acetylamino)-3-((oxadiazole-2-ylmethyl)amino)benzoate was separated by column with PE/EA (1/1, v/v). Benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (530.0 mg, yield: 79.0%). LCMS: m/z 415.3 [M+1] ⁺ .

Step 5: Synthesis of methyl (S)-1-(oxabutan-2-ylmethyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate

Dissolve methyl (S)-2-(4-bromobenzyl)-1-(oxadiazole-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (530.0 mg, 1.3 mmol) in dioxane (20 mL), add Pd(dppf)Cl ₂ (53.0 mg, 72.4 μmol), KOAc (151.0 mg, 1.5 mmol), and bisborane (390.0 mg, 1.5 mmol). Replace with nitrogen three times, heat in an oil bath at 90°C, and stir to react for 4-5 hours. After the reaction was complete, the solvent was removed by rotary evaporation, and then PE/EA (1/1, v/v) was used for column separation to obtain methyl (S)-1-(oxabutan-2-ylmethyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, yield: 20.2%). LCMS: m/z 462.7[M+1] ⁺ .

Step 6: Synthesis of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Weigh methyl (S)-1-(oxetan-2-ylmethyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.175 mmol), 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (87 mg, 0.189 mmol), Pd(dppf)Cl ₂ (13 mg, 0.018 mmol) and cesium carbonate (171 mg, 0.525 mmol) in a 5 ml microwave tube, replace the reaction system with nitrogen atmosphere, add 1,4-dioxane (1.2 mL) and water (0.2 mL). Stir the reaction at 90°C for 1 hour. LCMS monitoring shows that the reaction is complete and the main peak is the product. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and then dried under reduced pressure. The crude product was separated by silica gel column (petroleum ether: ethyl acetate = 1:1, Rf = 0.5, flash purification gradient: 0-50% ethyl acetate/petroleum ether within 15 min) to obtain methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzyl)-1-(((S)-oxadiazine-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (95 mg, yield: 90.6%). LCMS: m/z 599.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.10–8.06 (m, 1H), 8.01–7.95 (m, 1H), 7.79 (d, J = 8.5Hz, 1H), 7.71 (d, J = 8.2Hz, 2H),7.51(t,J＝8.2Hz,1H),7.34(d,J＝8.3Hz,2H),7.16–7.01(m,3H),6.89(t,J＝ 7.9Hz,1H),6.81(dd,J＝7.7,1.2Hz,1H),5.12–5.03(m,1H),4.65–4.46(m,3H),4.42–4.24(m,3H),3.94(s ,3H),2.70–2.59(m,1H),2.39–2.28(m,1H),2.08(s,3H).

Step 7: Synthesis of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzyl)-1-(((S)-oxadiazol-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.117 mmol) was dissolved in 1,4-dioxane (2 mL) and selenium dioxide (65 mg, 0.584 mmol) was added. The reaction was stirred at 60°C for 2 hours. The reaction was completed by LCMS monitoring, and the main peak was the product. The reaction solution was filtered and dried under reduced pressure. The crude product was separated by flash column chromatography to give methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (73 mg, yield: 99%). LCMS: m/z 613.4 [M+H] ⁺ .

Step 8: Synthesis of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxadiazole-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxadiazol-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.114 mmol) was dissolved in methanol (5 mL) and 1 M aqueous sodium hydroxide solution (1 mL) was added. The mixture was heated and stirred at 45°C for 7 hours. The reaction was completed after monitoring by LCMS. A 0.5 M aqueous hydrochloric acid solution was added to adjust the pH to 4-5 and the solution was concentrated under reduced pressure. The crude product was separated by reverse phase preparative separation to give 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)benzoyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg, yield: 43.9%). LCMS: m/z 599.3 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.49 (s, 1H), 8.39 (d, J = 8.2Hz, 2H), 8.13 (d, J = 1.4Hz, 1H), 8.00 (d, J = 8.6Hz ,1H),7.94(d,J＝8.3Hz,2H),7.52(t,J＝8.2Hz,1H),7.19–7.07(m,3H),6.94(t,J＝7.9Hz,1H),6 . 87(dd,J＝7.7,1.1Hz,1H),5.31–5.21(m,1H),5.05–4.90(m,2H),4.59(dd,J＝14.0,7.7Hz,1H),4.36(dt, J＝8.7,6.1Hz,1H),2.85–2.72(m,1H),2.51–2.37(m,1H),2.12(s,3H).

The NMR data of some compounds prepared in the above examples are as follows:

Biological activity test

1. Reagents and consumables

2. Experimental Instruments

The stable cell lines used in the experiment were purchased by our company from Eurofins, cultured in our laboratory and stored in liquid nitrogen for a long time.

3. Experimental Methods

1. Compound treatment

100X compounds were transferred to the assay plate using a nanoliter sonic pipetting system.

2. Cell Treatment

(1) Take out the CHO-K1/GLP-1 stable cell line from the liquid nitrogen storage system, quickly thaw in a 37°C electric thermostatic water bath, transfer the cell suspension to a 15 mL centrifuge tube with a pipette, and add 10 mL of complete culture medium (DMEM/F12 culture medium + 10% fetal bovine serum + 500 μg/mL geneticin).

(2) After centrifugation at 1000 rpm for 4 minutes, discard the supernatant, resuspend the cell pellet with 5 mL of complete culture medium, transfer to a T75 culture flask, add 15 mL of culture medium, and culture in a 37°C, 5% CO ₂ incubator. After the cells are passaged once, they are used in this cell experiment.

(3) When the cell density reaches 80% to 90%, discard the culture medium and wash the cells with 5 mL of phosphate buffer.

(4) Remove the phosphate buffer, add 2 mL of pancreatic enzyme, and place in a 37°C carbon dioxide incubator for 2-5 min.

(5) Add 10 mL of culture medium to collect the cells, centrifuge at 1000 rpm for 4 minutes, and discard the supernatant.

(6) Count the cells using a cell counter and adjust the cell suspension to an appropriate density using Stimulation Buffer.

3. Reaction

(1) Transfer 10uL of cell solution to the assay plate.

(2) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 30 minutes.

(3) Add 5uL 4X Eu-cAMP tracer solution and 5uL 4X ULight ^™ -anti-cAMP solution from the cAMP detection kit to the plate.

(4) Centrifuge at 4,600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

(5) Read cAMP signal on a multifunctional microplate reader and process the data using GraphPad Prism.

IV. Experimental Results

The activity of the compound was detected using the Ultra Lance cAMP method. The test results are as follows:

It can be seen from the above experimental results that the compounds provided in the examples of the present invention have a strong agonistic effect on GLP-1R.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as references separately. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (15)

A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:
in, L is -CR _6a R _7a -O-, -(CR _6a R _7a ) _n - or -O-CR _6b R _7b -; X is CR ₈ or N, Y is CR ₉ or N; _Z1 is _CR10a or N, _Z2 is _CR10b or N, and _Z3 is _CR10c or N; Z ₄ is CR _10d or N; Ring A is selected from the following structures:
each _Ra is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, _C1-4 alkyl, halogen _- substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C1-4 alkylthio, halogen-substituted _C1-4 alkylthio, deuterium _- substituted C1-4 alkylthio, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy, _-C0-4 alkyl- _{SF5 and -NR14R15} ; Each m is independently 0, 1, 2, 3, 4, 5 or 6; R ₁ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _1-4 alkylthio, halogen-substituted C _1-4 alkylthio, deuterium-substituted C _1-4 alkylthio, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ; _R2 and _R3 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _{C3-6 cycloalkoxy, -C0-4 alkyl} - _SF5 and _-NR14R15 , or, _R2 and _R3 together with the directly attached carbon atom form a carbonyl, a _C3-8 cycloalkyl or a 3-8 membered heterocyclyl _{; R4} is selected from hydrogen, deuterium, _C1-4 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic group and hydroxyl, and the above groups are independently wherein the alkyl radical is optionally further substituted with one or more radicals selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, _5-8 membered heteroaryl, =O, =S, _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , -C(O) _SR12 , -SC(O) _{R13 ,} -C(O) _R13 , -OC( _O ) _R13 , -P(O)( _R13 ) ₂ , _-NR14R15 , -C(O) _NR14R15 and _-N ( _R14 )-C(O)R ₁₃ is substituted by a substituent; R ₅ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ; each R _6a and R _7a is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ , or, R _6a and R _7a together with the directly attached carbon atom form _a carbonyl, a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl; R _6b and R _7b are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ , or, R _6b and R _7b together with the directly attached carbon atom form a carbonyl, a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl; R ₈ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ; Alternatively, R _6a and R ₈ or R ₅ together with the part to which they are directly connected form the following structure:
R ₉ is selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _{1-4 alkyl, deuterium-substituted C 1-4 alkyl} , C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ; _R10a , _R10b , _R10c and _R10d are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy, _-C0-4 alkyl- _SF5 and _-NR14R15 , _and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, _cyano , _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, C3-6 cycloalkyloxy, 3-6 membered heterocyclyl, C _substituted by a substituent selected from the group consisting of _6-8 membered aryl, 5-8 membered heteroaryl, =O, = _S , _-SF5 , -OS(O) _2R11 , -S(O) _rR11 , _-OR12 , -C(O) _OR12 , -C(O) _SR12 , -SC(O) _R13 , -C(O) _R13 , -OC(O) _R13 , -P(O)( _R13 ) ₂ , _-NR14R15 , -C(O) _{NR14R15 and -N(R14 )} -C(O) _{R13 ;} Each R ₁₁ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl and -NR ₁₄ R ₁₅ , and the above groups are independently optionally further substituted by one or substituted by multiple substituents selected from deuterium, halogen, hydroxy, =O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ; each R ₁₂ is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl and 5-8 membered heteroaryl, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C 3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ; each R ₁₃ is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C 2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ , the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₄ R ₁₅ ; Each of R ₁₄ and R ₁₅ is independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-4 alkanoyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =0, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4 alkynyl} , halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C 1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C substituted by a _{C 6-8} aryl, C _6-8 aryloxy, 5-8 membered heteroaryl _, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino and C _1-4 alkanoyl substituent; Alternatively, R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-8 membered heteroaryl is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C _1-4 alkylamino _, di-C _1-4 alkylamino and C _1-4 alkanoyl; n is 1, 2 or 3; Provided that, when ring A is selected from hour, 1) L is -O-CR _6b R _7b -; or, 2) L is -CH(CF ₃ )-O-; or, 3) R ₁ is C _1-4 alkylthio, halogen-substituted C _1-4 alkylthio or deuterium-substituted C _1-4 alkylthio; or, 4) R _6a and R ₈ or R ₅ together with the part directly connected thereto form the following structure:
or, 5) R _6a and R ₈ together with the part to which they are directly connected form and R ₁ is cyano; or, 6) _R2 and _R3 together with the directly attached carbon atom form a carbonyl group, a _C3-8 cycloalkyl group or a 3-8 membered heterocyclic group; or, 7) At least one _Ra is not hydrogen. The compound of formula (I) as described in claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that _R4 is selected from hydrogen, deuterium, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C3-6 cycloalkyl-substituted _C1-4 alkyl, 3-6 membered heterocyclyl-substituted _C1-4 alkyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl and hydroxyl; R _10a , R _10b , R _10c and R _10d are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, -C _0-4 alkyl-SF ₅ and -NR ₁₄ R ₁₅ ; wherein R ₁₄ and R ₁₅ are as defined in claim 1. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt as described in claim 1, characterized in that the compound of formula (I) has the following structure (IIa):
Wherein, X is CH or N; R _6b , R _7b are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; Ring A, R ₁ and R ₉ are as defined in claim 1. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt as described in claim 1, characterized in that the compound of formula (I) has the following structure (IIb):
wherein X is CH or N; and ring A, R ₁ , and R ₉ are as defined in claim 1 . The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt as described in claim 1, characterized in that the compound of formula (I) has the following structure:
wherein each R _7a is independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; Ring A, R ₁ , R _7a , and R ₉ are as defined in claim 1. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt as described in claim 1, characterized in that the compound of formula (I) has the following structure (IId):
wherein R _1a is selected from C _1-4 alkyl, halogen-substituted C _1-4 alkyl and deuterium-substituted C _1-4 alkyl; R ₅ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; L, X, Ring A, R ₁ and R ₉ are as defined in claim 1. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt as described in claim 1, characterized in that the compound of formula (I) has the following structure (IIe):
Wherein, ring A is selected from the following structures:
R _6a , R _7a are each independently selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ . X, R ₁ , R ₉ , _Ra and m are as defined in claim 1. A compound of formula (I) as claimed in claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, It is characterized in that, in the compound of formula (I), ring A is selected from each _Ra is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, _C1-4 alkyl, halogen _- substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted C1-4 alkoxy, deuterium-substituted _C1-4 alkoxy, _C1-4 alkylthio, halogen-substituted _C1-4 alkylthio, deuterium _- substituted C1-4 alkylthio, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy and _-C0-4 alkyl- _SF5 ; Each m is independently 0, 1, 2, 3, 4, 5 or 6. The compound of formula (I) as claimed in claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that R ₁ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ ; R ₉ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylthio, ethylthio, isopropylthio, trifluoromethylthio, difluoromethylthio, trideuteromethylthio, dideuteromethylthio, vinyl, cyclopropyl, cyclobutyl, -SF ₅ and -NH ₂ . The compound of formula (I) as claimed in claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that it is selected from the following compounds:

A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, a pharmaceutically acceptable salt of a stereoisomer thereof, and one or more pharmaceutically acceptable carriers. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt of a stereoisomer thereof in the preparation of a medicament for treating and/or preventing GLP-1R-mediated diseases. The use as claimed in claim 12, characterized in that the GLP-1R-mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, hepatocellular carcinoma, hepatocellular carcinoma, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis. dysphagia, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, thrombosis, transient ischemic attack, poor glucose metabolism, impaired fasting glucose condition, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, irritable bowel syndrome, or polycystic ovary syndrome. The use according to claim 12, characterized in that the GLP-1R mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from T2DM, colitis, insulin resistance, cirrhosis, cardiovascular disease or addictive disease. The use according to claim 11, characterized in that the GLP-1R-mediated disease refers to cardiometabolic and related diseases, wherein the disease is selected from T1D, renal disease, hypertension, stroke, angina pectoris, vascular restenosis or inflammatory bowel disease.