WO2022228490A1

WO2022228490A1 - Polycyclic derivative modulator, and preparation method therefor and use thereof

Info

Publication number: WO2022228490A1
Application number: PCT/CN2022/089714
Authority: WO
Inventors: 苏熠东; 毛枭峰; 陈晓坡; 代国法; 俞文胜
Original assignee: 上海翰森生物医药科技有限公司; 江苏豪森药业集团有限公司
Priority date: 2021-04-30
Filing date: 2022-04-28
Publication date: 2022-11-03
Also published as: CN117177970A; TW202304440A

Abstract

Disclosed are a polycyclic derivative modulator, and a preparation method therefor and the use thereof. Specifically, disclosed are a compound as represented by general formula (I-D), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof as a modulator in the preparation of a drug for treating metabolic diseases and related diseases. Each of the substituents in general formula (I-D) is the same as defined in the description.

Description

Polycyclic derivative regulator, its preparation method and application

technical field

The invention belongs to the field of medicine and biological medicine, and particularly relates to a polycyclic derivative regulator and a preparation method and application thereof.

Background technique

Diabetes mellitus (diabetes mellitus) is a common endocrine and metabolic disease, which is caused by metabolic disorders caused by various reasons, resulting in multi-system and multi-organ damage. The incidence of diabetes is high. There are about 425 million diabetic patients in the world. The incidence of diabetes in China is about 10%, of which type II diabetes accounts for 90%, and the prevalence is still increasing, and the age of onset is getting younger.

At present, there are many types of drugs on the market for the treatment of type II diabetes, including insulin, biguanides, glucagon-like peptide-1 (glucagon-likepeptide 1, GLP-1) receptor agonists, dipeptidyl peptidase (DPP) -IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, α-glucosidase inhibitors, etc., among which GLP-1 receptor agonists are the most concerned.

GLP-1 is a peptide hormone secreted by human intestinal L cells, and its receptors are distributed in islet cells, various gastrointestinal cells, neurons of the central nervous system and peripheral nervous system. After activation, it has physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, suppressing appetite and delaying gastric emptying. Clinical evidence shows that compared with other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effect and are less prone to side effects such as hypoglycemia. It also has additional cardiovascular benefits, as well as reduced food intake and delayed gastric emptying for weight control.

The GLP-1 receptor agonists currently on the market are all polypeptide drugs, most of which require subcutaneous administration, and the patient's compliance is poor, and the bioavailability of oral polypeptides is very low. Therefore, there is a great clinical need to develop oral small-molecule GLP-1 receptor agonists.

At present, no small molecule GLP-1 receptor agonist has been approved, and 3 small molecule GLP-1 receptor agonists have entered the clinical research stage, such as PF-06882961 and PF-07081532 developed by Pifzer, and PF-07081532 developed by vTv. TTP273 is currently in phase I/II clinical research. Among them, PF-06882961 has demonstrated significant hypoglycemic and weight-reducing effects in early clinical trials, and its safety is similar to that of polypeptide GLP-1 receptor agonists. It is expected to bring more benefits to patients with diabetes, obesity and NASH in the future. treatment options.

There is a huge clinical need for GLP-1 receptor agonists. Oral small-molecule GLP-1 receptor agonists with lower cost and better compliance have the potential to treat a variety of metabolic diseases and have broad market prospects.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound represented by general formula (I-D), its stereoisomer or its pharmaceutically acceptable salt:

in:

Ring B is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl,

Preferred are C _5-8 cycloalkyl groups, 5-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C _6-10 aryl groups or 5-membered C 6-10 aryl groups containing 1-3 N, O or S atoms 10-membered heteroaryl,

more preferred

optionally can be further substituted;

Ring C is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl,

more preferred

optionally can be further substituted;

M ₂ is O, S, N, (CH ₂ ) _n11 O, (CH ₂ ) _n11 S, (CH ₂ ) _n11 NH or (CH ₂ ) _n11 , optionally further substituted;

M ₃ is O, S, N, (CH ₂ ) _n12 O, (CH ₂ ) _n12 S, (CH ₂ ) _n12 NH or (CH ₂ ) _n12 , optionally further substituted;

M4 is _CRm , O, S, _N , C, ( _CH ) _n13 , ( _CH2 ) _n13O , (CH2) _n13S , ( _CH2 ) _n13NH or ( _CH2 ) _n13 , optionally is further superseded;

M ₅ is O, S, N, C, (CH) _n14 , (CH ₂ ) _n14 O, (CH ₂ ) _n14 S, (CH ₂ ) _n14 NH or (CH ₂ ) _n14 , optionally further substituted ;

R ¹ are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkane base, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 halogenated alkyl group, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered hetero Cyclic, C _6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C _1-6 alkyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, substituted by one or more substituents in C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R ¹ are linked to form C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, _C1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

R ² is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkane base, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 halogenated alkyl group, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered hetero Cyclic, C _6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C _1-6 alkyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, substituted by one or more substituents in C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R ² are linked to form C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, nitro group, hydroxyl, cyano, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heterocyclyl substituted with one or more substituents in the aryl group;

R ³ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1- 6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 halogenated alkyl group , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2- Substituted by one or more substituents in ₆ -alkynyl, C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl and 5-10-membered heteroaryl;

R _m or R ⁷ are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _{1- 6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, _C1-6 Alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted by one or more substituents,

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _{1 -3} hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl, the amino, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy and C _2-4 alkenyl, optionally further deuterium, fluorine, chlorine, hydroxy , substituted by one or more substituents in cyano, carboxyl, methyl and ethyl;

Alternatively, any two R ⁷ are linked to form C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, _C1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

Preferably, any two R ⁷ are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

R ⁸ is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, optionally further substituted with one or more substituents,

Preferred are C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl or 5-10 membered heteroaryl, optionally further substituted by one or Multiple substituent substitutions,

more preferred

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.

In one embodiment of the present invention, the

selected from

In one embodiment of the present invention, the

selected from

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (I-C):

in:

more preferred

optionally can be further substituted;

M4 is O, S, N, C, ( _CH ) _n13 , ( _CH2 ) _n13O , (CH2) _n13S , (CH2) _n13NH , ( _CH ) _n13NH or ( _CH2 _)n13 _, any optionally can be further substituted;

_M5 is O, S, N, C, ( _CH ) _n14 , ( _CH2 ) _n14O , (CH2) _n14S , (CH2) _n14NH , ( _CH ) _n14NH or ( _CH2 ) _n14 , any optionally can be further substituted;

R ⁷ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1- 6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 halogenated alkyl group , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2- 6} -alkynyl, C _3-8 cycloalkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl substituted with one or more substituents,

R ⁸ is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by one or more substituents;

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, the compound of general formula (I-C):

Ring B is selected from

M ₂ is selected from O; M ₃ is selected from (CH ₂ ) _n12 or (CH ₂ ) _n12 O; M ₄ is selected from N or (CH) _n13 ; M ₅ is selected from (CH) _n14 ; R ¹ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy, preferably, R ¹ is selected from hydrogen, deuterium, fluorine, chlorine, C _1-3 alkoxy;

Or, R ² is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, oxo, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkyne group, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _3-6 cycloalkyl, Preferably, R ² is selected from hydrogen, deuterium, fluorine;

Or, R ³ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl, said amino, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy and C _2-4 alkenyl, optionally further is substituted by one or more substituents in deuterium, fluorine, chlorine, hydroxyl, cyano, carboxyl, methyl and ethyl, preferably, ^R is selected from hydrogen, deuterium, fluorine;

R ⁷ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _{1- 3} haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl, preferably, R ⁷ is selected from hydrogen, deuterium, fluorine or carboxyl;

R ⁸ is selected from

x is 2;

y is 0, 1 or 2;

z is 0 or 2;

r is 1 or 2;

n12 is 1 or 2;

n13 is 1 or 2; and

n14 is 1 or 2.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IV-1):

in:

Preferably C _5-8 cycloalkyl or 5-10 membered nitrogen-containing heterocyclic group,

more preferred

M ₂ is O, S, N, CH ₂ , (CH ₂ ) _n11 O, (CH ₂ ) _n11 S, (CH ₂ ) _n11 NH or (CH ₂ ) _n11 ;

M3 is O, _S , N, _CH2 , (CH2) _n12O , ( _CH2 ) _n12S , ( _CH2 ) _n12NH or ( _CH2 ) _n12 ;

M ₄ is O, S, N, C, CH, CH ₂ , (CH ₂ ) _n13 O, (CH ₂ ) _n13 S, (CH ₂ ) _n13 NH or (CH ₂ ) _n13 ;

M ₅ is O, S, N, C, CH, CH ₂ , (CH ₂ ) _n14 O, (CH ₂ ) _n14 S, (CH ₂ ) _n14 NH or (CH ₂ ) _n14 ;

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, for the compound of general formula (IV-1), wherein:

M ₂ is O, S, N, CH ₂ , CH ₂ O, CH ₂ S, CH ₂ NH or (CH ₂ ) ₂ ;

Or, M ₃ is O, S, N, CH ₂ , CH ₂ O, CH ₂ S, CH ₂ NH or (CH ₂ ) ₂ ;

Or, M ₄ is O, S, N, C or CH;

Alternatively, M ₅ is O, S, N or (CH) ₂ .

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IV-2) or (IV-3):

in:

Preferably C _5-8 cycloalkyl, 5-10 membered nitrogen-containing heterocyclic group, C _6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms,

more preferred

M ₂ is O, S, N, (CH ₂ ) _n11 O, (CH ₂ ) _n11 S, (CH ₂ ) _n11 NH or (CH ₂ ) _n11 ;

M3 is O, _S , N, (CH2) _n12O , ( _CH2 ) _n12S , ( _CH2 ) _n12NH or ( _CH2 ) _n12 ;

M ₄ is CR _m , O, S, N, C, (CH) _n13 , (CH ₂ ) _n13 O, (CH ₂ ) _n13 S, (CH ₂ ) _n13 NH, (CH) _n13 N or (CH ₂ ) _n13 ;

_M5 is O, S, N, C, ( _CH ) _n14 , ( _CH2 ) _n14O , (CH2) _n14S , (CH2) _n14NH , ( _CH ) _n14N or ( _CH2 ) _n14 ;

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention,

R ¹ is selected from hydrogen, deuterium, chlorine, fluorine, cyano or methoxy, preferably fluorine or chlorine;

Ring B is selected from

Or, M ₂ is selected from O, S, N, CH ₂ , CH ₂ O, CH ₂ S, CH ₂ NH or (CH ₂ ) ₂ , preferably O;

Or, M ₃ is selected from O, S, N, CH ₂ , CH ₂ O, CH ₂ S, CH ₂ NH or (CH ₂ ) ₂ , preferably CH ₂ O;

Or, M ₄ is selected from O, S, N, C or CH, preferably N or CH;

Or, M ₅ is selected from O, S, N or (CH) ₂ , preferably (CH) ₂ ;

Alternatively, x is 2, 3, 4 or 5, preferably 2.

In a further preferred embodiment of the present invention,

M ₂ is O, S, CH ₂ or (CH ₂ ) ₂ ;

M ₃ is O, S, CH ₂ , or CH ₂ O.

In a further preferred embodiment of the present invention,

M ₂ is O;

M ₃ is CH ₂ O.

In a further preferred embodiment of the present invention,

M ₂ is O, S, CH ₂ or (CH ₂ ) ₂ ;

M ₃ is O, S, CH ₂ , or CH ₂ O;

_M4 is N, C or CH;

M ₅ is N or (CH) ₂ .

In a further preferred embodiment of the present invention,

M ₂ is O;

M ₃ is CH ₂ O;

_M4 is N, C or CH;

M ₅ is N or (CH) ₂ .

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IV-2-A) or (IV-3-A):

in,

R ² , R ³ , L ₂ or Ring B are as defined above;

Ring B is preferably

more preferably

M ₄ is selected from N or CR _m ;

R _m is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl , C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl;

L ₂ is selected from a bond or CH ₂ , preferably a bond.

In a further preferred embodiment of the present invention, the compound of general formula (IV-2-A) or (IV-3-A) is further as described in general formula (IV-2-A') or (IV-3-A' ) as shown:

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (V):

in:

Ring B is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably C _5-8 cycloalkyl or 5-10 membered nitrogen-containing heterocyclic group;

more preferred

R ¹ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1 -6} hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycle base, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyl Alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 Substituted by one or more substituents in cycloalkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R ¹ are linked to form C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, _C1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents;

Preferably, any two R ¹ are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

R ² is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1 -6} hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycle base, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyl Alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C _1-6 alkyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 Substituted by one or more substituents in cycloalkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy;

R ⁴ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered Heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C _1-6 alkyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, substituted by one or more substituents in C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl base, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl, said amino, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy and C _2-4 alkenyl, optionally further substituted by deuterium, fluorine, chlorine, hydroxyl, cyano, substituted with one or more substituents of carboxyl, methyl and ethyl;

Alternatively, any two R ⁴ are linked to form C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, _C1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents;

Preferably, any two ^R4 are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

R ⁶ is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered Heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C _1-6 alkyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, substituted by one or more substituents in C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _6-10 -membered aryl and 5-10-membered heteroaryl;

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl group, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl, said amino, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy and C _2-4 alkenyl, optionally further substituted by deuterium, fluorine, chlorine, hydroxyl, cyano, substituted with one or more substituents of carboxyl, methyl and ethyl;

x is 0, 1, 2, 3, 4 or 5;

y is 0, 1, 2, 3 or 4;

z is 0, 1, 2, 3, 4, 5 or 6;

j is 0, 1, 2, 3, 4, 5 or 6

n11 is 0, 1, 2, or 3; and

n12 is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IV-1-A) or (IV-1-B):

in,

M4 is selected from N or _CR7 ^;

R ⁷ is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl , C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl;

M ₅ is selected from NH, O or S;

L ₂ is selected from a bond or CH ₂ .

In a further preferred embodiment of the present invention, for compounds of general formula (IV-1), (IV-2), (V), (IV-1-A) or (IV-1-B), wherein:

Ring B is selected from

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IV-1-C), (IV-1-D) or (IV-1-E):

in,

M ₄ are each independently selected from N, CRm or S;

M ₅ is each independently selected from (CH) ₂ , O, S, N or C;

M ₆ is selected from N or C;

_{M7 is} selected from O, S, N or _CH2 ;

Rm is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy or C _2-4 alkenyl;

L ₂ is selected from a bond or CH ₂ .

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (VIII):

W ₁ and W ₂ are each independently selected from N or CH;

more preferred

M ₃ is O, S, N, (CH ₂ ) _n12 O, (CH ₂ ) _n12 S, (CH ₂ ) _n12 NH or (CH ₂ ) _n12 ;

M ₄ is O, S, N, C, (CH ₂ ) _n13 O, (CH ₂ ) _n13 S, (CH) _n13 N or (CH) _n13 ;

M ₅ is O, S, N, C, (CH ₂ ) _n14 O, (CH ₂ ) _n14 S, (CH) _n14 N or (CH) _n14 ;

R ⁸ is selected from C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, optionally further substituted with one or more substituents.

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (VIII-1):

M ₄ is selected from N or CR _m ;

M ₅ is selected from (CH) ₂ or S;

Ring B is selected from

preferably

R ¹ is selected from chlorine or cyano;

R ² is selected from C _1-6 alkyl, preferably methyl;

^R is selected from hydrogen or deuterium;

R ⁸ is selected from

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (VIII-2):

The definitions of R ¹ , W ₁ , W ₂ , R ² , R ³ , R ⁸ , x, and y are as described above.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds of the general formula shown, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier, diluent or excipient.

The present invention further provides the compound represented by the general formula (M-1) or (M-2), its stereoisomer or its pharmaceutically acceptable salt:

The M ₄ , R ¹ , and x are as described above;

R _1' is selected from halogen, preferably fluorine, chlorine, bromine, more preferably chlorine;

R _2' is selected from C _1-6 alkyl, preferably methyl or ethyl;

R _3' is selected from hydrogen or amino protecting group, preferably hydrogen, (trimethylsilyl)ethoxymethyl, methoxymethyl ether, allyloxycarbonyl, trifluoroacetyl, 2,4-dimethyl Oxybenzyl, nitrobenzenesulfonyl, trityl, watmethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl , more preferably hydrogen or tert-butoxycarbonyl.

The present invention further provides the preparation method of the aforementioned compound of general formula (I-D) or its stereoisomer and its pharmaceutically acceptable salt, comprising the following steps:

The general formula (M-4) is reacted with the general formula (M-5) to obtain the general formula (I-D) after deprotection;

The R ¹ , R ² , R ³ , R ⁷ , R ⁸ , M ₂ , M ₃ , M ₄ , M ₅ , ring B, ring C, x, y, z, R _3' , R _1' as before said.

The present invention further provides a method for preparing the compound of general formula (IV-3-A) as described below or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

The general formula (M-1) is reacted with the general formula (M-6) to obtain the general formula (IV-3-A) after deprotection;

The L ₂ , R ² , R ³ , M ₄ , ring B, y, z, R _3' , R _2' , R _1' are as described above.

In one embodiment, the present invention provides a preparation method of the aforementioned compound or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the following steps:

The R _1' , R _2' , R _3' , M ₄ , R ⁸ , R ¹ , and x are as described above;

Further preferably in one embodiment, R _1' is chlorine;

R _2' is selected from methyl or ethyl;

R _3' is selected from hydrogen or tert-butoxycarbonyl;

M ₄ is selected from CH or N;

R ¹ is selected from hydrogen, deuterium, chlorine, fluorine, cyano or methoxy;

R ⁸ is selected from

x is 2, 3, 4 or 5.

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

The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of metabolic-related diseases, wherein the disease is selected from diabetes , obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.

The present invention further relates to a compound represented by the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of metabolic diseases and related diseases.

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

The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, conditions associated with GLP-1 receptor modulators.

The present invention also relates to a method of treating a metabolic disease-related disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, Hydrate or derivative.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms , most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 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 Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means _-CH2- , "ethylene" means -( _CH2 ) _2- , "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ - and the like.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.

The term "alkenylene" refers to an alkenyl group where one of the hydrogen atoms is further substituted, eg "vinylene" refers to _-CH2 =CH2-, "propenylene" refers to _-CH2- = _CH2 - _CH ₂ - etc. Alkenylene may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms; further preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydro Imidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably rolidine base, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidine, morpholinyl,

Piperazinyl and pyranyl; more preferably rolidinyl, azetidinyl, oxetanyl, oxanyl, piperidinyl,

Piperazinyl and pyranyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclo-linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), the remaining rings Atom is carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, such as phenyl and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10-membered, more preferably 5-8 membered, most preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazole base, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably An alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.

"Alkenyl" refers to an alkenyl group, also known as an alkenyl group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group of 2 to 6 carbon atoms, most preferably an alkyl group of 2 to 3 carbon atoms . The alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group of 2 to 6 carbon atoms, and most preferably an alkyl group of 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkynylene" refers to an alkynyl group where one hydrogen atom is further substituted, eg "ethynylene" refers to -C≡C-, "propenylene" refers to -C≡C _- CH2-, and the like. The alkynylene group (containing more than three carbon atoms) can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocycloalkylthio.

"Fused ring group" refers to a polycyclic group formed by two or more carbocyclic or heterocyclic rings sharing a ring edge, and the fused ring group includes fused ring alkyl, fused ring heteroaryl, fused ring aryl and fused ring Cyclic heteroaryl group, wherein the fused cycloalkyl group refers to a polycyclic group formed by sharing a ring edge with a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the fused ring heterocyclic group refers to a heterocyclic group. A polycyclic group formed by a ring group and a cycloalkyl group, an aryl group, and a heteroaryl group sharing a ring edge; the fused-ring aryl group refers to an aryl group, a cycloalkyl group, a heterocyclic group, and a heteroaryl group sharing a ring. The polycyclic group formed by the side of the ring; the fused ring heteroaryl group refers to the polycyclic group formed by the shared ring side of the heteroaryl group, the cycloalkyl group, the heterocyclic group and the hetero group; for example:

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carboxyl" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" means acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd2(dba ₎₃ _" refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" etc. all express the same Meaning, that means X can be any one or more of A, B, and C.

The hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. 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 case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.

Detailed ways

The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

Example

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methylsilane (TMS).

An Agilent 1200 Infinity Series mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ~ 0.20mm, and the specifications used for TLC 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 commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all the 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.

Intermediate Im-1((S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester) synthesis

The first step: (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

3-Fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile (2 g, 10.0 mmol) in a 50 mL reaction flask, K ₂ CO ₃ (2.8 g, 20 mmol) was dissolved in tetrahydrofuran (30 mL), then (S)-oxetan-2-ylmethanamine (880 mg, 10.0 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction was stopped, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL×2), the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was subjected to column chromatography Isolation and purification gave (S)-4-nitro-3-((oxbutan-2-ylmethyl)amino)benzoic acid methyl ester (2.0 g, 75%).

MS m/z(ESI): 267.0[M+H] ⁺ .

The second step: (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

(S)-4-Nitro-3-((oxbutan-2-ylmethyl)amino)benzoic acid methyl ester (3 g, 13.0 mmol) was dissolved in methanol (30 mL), then 10% Pd/ C (300 mg). The reaction was stirred under hydrogen atmosphere for 3 hours. The reaction solution was filtered, the organic phase was dried and then spin-dried to obtain (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.6g, yield: 100%) .

MS m/z(ESI): 237.1[M+H] ⁺ .

The third step (S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

In a 50 mL reaction flask, combine (S)-4-nitro-3-((oxbutan-2-ylmethyl)amino)benzoic acid methyl ester (2 g, 8.5 mmol), p-toluenesulfonic acid (86 mg, 0.5 mmol) was dissolved in tetrahydrofuran (100 mL), then 2-chloro-1,1,1-trimethoxyethane (1.3 g, 8.5 mmol) was added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (Im-1) (1.3 g, 52%).

MS m/z(ESI): 295.0[M+H] ⁺ .

Intermediate Im-2((S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-d]pyridine-5-carboxylic acid methyl ester) Synthesis

The first step: (S)-5-nitro-6-((oxbutan-2-ylmethyl)amino) 2-picolinate methyl ester

Using methyl 6-chloro-5-nitro-2-picolinate as raw material, with reference to step 1 of intermediate Im-1, obtain (S)-5-nitro-6-((oxabutane-2-ylmethyl) yl)amino)methyl 2-picolinate.

MS m/z(ESI): 268.1[M+H] ⁺ .

The second step: (S)-5-amino-6-((oxbutan-2-ylmethyl)amino) 2-picolinate methyl ester.

With (S)-5-nitro-6-((oxbutan-2-ylmethyl)amino) methyl 2-picolinate as raw material, with reference to step 2 of intermediate Im-1, obtain (S)-5 -amino-6-((oxbutan-2-ylmethyl)amino)2-picolinate methyl ester.

MS m/z(ESI): 238.1[M+H] ⁺ .

The third step ((S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-d]pyridine-5-carboxylic acid methyl ester

Methyl (S)-5-amino-6-((oxbutan-2-ylmethyl)amino)2-picolinate (0.34 g, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, then A solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise, stirred at room temperature for 30 minutes, then heated to 60° C., reacted for 2 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then washed with saturated sodium bicarbonate solution (15 mL×3), washed with saturated brine (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain ((S)-Methyl 2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-d]pyridine-5-carboxylate (Im-2)( Yellow oil, 0.40 g, 94%), the crude product was used directly in the next step.

MS m/z(ESI): 296.1,298.1[M+H] ⁺ .

Intermediate Im-3(S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Synthesis of Ethyl Ester

The first step: 3,5-difluoro-4-nitrobenzoic acid ethyl ester

In a 100 mL reaction flask, 3,5-difluoro-4-nitrobenzoic acid (4 g, 19.69 mmol) was dissolved in 20 mL of ethanol, and 1 mL of concentrated sulfuric acid was added dropwise thereto. The reaction solution was stirred in an oil bath at 80°C for 4 hours. After the reaction was completed, the reaction solvent was evaporated, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with saturated sodium chloride (20 mL × 2), anhydrous sodium sulfate Dry, filter, and concentrate to give crude ethyl 3,5-difluoro-4-nitrobenzoate (4.0 g, 88% yield).

1H NMR(400MHz, CDCl3)δ7.77(d,2H),4.45(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H).

The second step: (S)-ethyl 3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

In a 100 mL reaction flask, ethyl 3,5-difluoro-4-nitrobenzoate (3.5 g, 15.14 mmol) was dissolved in DMF (40 mL), to which was added K2CO3 (3.14 g, 22.71 mmol) and (S) -Oxetan-2-ylmethanamine (1.58 g, 18.17 mmol). The reaction system was stirred at 20°C for 16 hours. Water (20 mL) was added to it to quench the reaction, extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was isolated and purified by column chromatography to give (S)-ethyl 3-fluoro-4-nitro-5-((oxbutan-2-ylmethyl)amino)benzoate (4.2 g, 93% yield).

1H NMR(400MHz, CDCl3)δ7.36(s,1H),7.06(d,J=11.5,1H),5.20-5.07(m,1H),4.80-4.69(m,1H),4.66-4.55(m ,1H),4.40(q,J=7.2Hz,2H),3.56(s,2H),2.85–2.67(m,1H),2.66–2.51(m,1H),1.41(t,J=7.2Hz, 3H).

The third step: (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)ethyl benzoate

(S)-ethyl 3-fluoro-4-nitro-5-((oxbutan-2-ylmethyl)amino)benzoate (4.20 g, 14.13 mmol) was dissolved in MeOH (100 mL), to which was added Pd/C (500 mg, 10% purity) was added. After the hydrogen was pumped three times, the reaction system was stirred at 20° C. for 3 hours in a hydrogen atmosphere. After the completion of the reaction, diatomaceous earth was filtered, and the organic phase was spin-dried to obtain the crude product. The crude product was purified by column (PE/EtOAc=2:1, Rf=0.2), and finally 3.5 g of colorless oily liquid (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl) was obtained (yl)amino)ethyl benzoate (3.5 g, 13.05 mmol, 92.34% yield). MS m/z(ESI): 269.1[M+H] ⁺ .

1H NMR (400MHz, CDCl3) δ 7.31 (dd, J=10.6, 1.6Hz, 1H), 7.20 (t, J=1.4Hz, 1H), 5.09 (dt, J=6.9, 3.4Hz, 1H), 4.74 (ddd, J=8.5, 7.4, 6.0Hz, 1H), 4.61 (dt, J=9.2, 6.0Hz, 1H), 4.33 (q, J=7.2Hz, 2H), 3.54–3.28 (m, 2H), 2.75(ddd,J=10.4,5.6,2.4Hz,1H),2.57(ddt,J=9.2,7.0,2.0Hz,1H),1.37(t,J=7.2Hz,3H).

The fourth step (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

Ethyl (S)-4-amino-3-fluoro-5-((oxbutan-2-ylmethyl)amino)benzoate (3.5 g, 13.05 mmol) was dissolved in MeCN (50 mL), to which was added Add p-toluenesulfonic acid (673.96 mg, 3.91 mmol) and 2-chloro-1,1,1-trimethoxyethane (3.03 g, 19.57 mmol). The reaction system was stirred at 60°C for 4 hours. After the completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified by column to obtain light yellow solid (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate Ethyl acid (3.0 g, 9.18 mmol, 70.38% yield).

MS m/z(ESI): 327.0[M+H] ⁺ .

1H NMR(400MHz, CDCl3)δ7.95(s,1H),7.70(d,J=10.7Hz,1H),5.21(d,J=7.0Hz,1H),5.05(s,2H),4.71–4.51 (m, 3H), 4.47–4.29 (m, 3H), 2.78 (m, 1H), 2.51–2.35 (m, 1H), 1.43 (t, J=7.2Hz, 3H).

Synthesis of Intermediate Im-4 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

The first step: 2-(1-(aminomethyl)cyclopropyl)acetonitrile

2-(1-(Bromomethyl)cyclopropyl)acetonitrile (4.0 g, 23.12 mmol) was dissolved in NH3/i-PrOH (30 mL), and the reaction system was heated under microwave at 60°C for 6 hours. After completion of the reaction, concentrate to obtain crude 2-(1-(aminomethyl)cyclopropyl)acetonitrile (2.5g, crude). The crude product was directly used in the next reaction.

The second step: 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

Take 3-fluoro-4-nitrobenzoic acid ethyl ester as raw material, with reference to the synthesis of intermediate Im-3, finally obtain product 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

MS m/z(ESI): 332.11[M+H] ⁺ .

Synthesis of Intermediate Im-5 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

The first step 1-(fluoromethyl)cyclopropane-1-carboxylate ethyl ester

Ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (7 g, 48.55 mmol) was dissolved in DCM (100 mL), to which was added DAST (8.61 g, 53.41 mmol) at -78°C. The reaction system was naturally warmed to room temperature and stirred for 16 hours. After completion of the reaction, 50 mL of water was added thereto, extracted with dichloromethane (50 mL×2), washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain crude 1-(fluoromethyl)cyclopropane -1-Carboxylic acid ethyl ester (6.5 g, 44.47 mmol, 91.59% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.52 (dd, J=48.2, 1.5 Hz, 2H), 4.17 (q, J=3.6, 2H), 1.41-1.33 (m, 2H), 1.26 (t, J =7.2,3H),1.05–0.95(m,2H).

Step 2: 1-(Fluoromethyl)cyclopropylmethanol

Ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (6.5 g, 44.47 mmol) was dissolved in THF (60 mL), to which was added LiAlH4 (2.53 g, 66.71 mmol) in an ice-water bath. The reaction system was naturally warmed to room temperature and stirred for 16 hours. After the reaction was completed, 15 g of sodium sulfate decahydrate was added to quench the reaction, filtered and concentrated to obtain crude 1-(fluoromethyl)cyclopropylmethanol (3.5 g, 33.61 mmol, 75.59% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.36 (d, J=48.8 Hz, 2H), 3.58 (s, 2H), 0.60 (m, 4H).

The third step: (1-(fluoromethyl) cyclopropyl) methyl methanesulfonate

1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL), and methanesulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and trimethylsulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) were added dropwise thereto in an ice water bath. Ethylamine (2.53 g, 24.97 mmol, 3.48 mL). The reaction system was stirred at 20°C. After the reaction was completed, saturated NaHCO (10 mL) was added dropwise to quench the reaction, extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oily crude product (1-(Fluoromethyl)cyclopropyl)methylmethanesulfonate (2.0 g, 87% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.32 (d, J=48.5 Hz, 2H), 4.19 (s, 2H), 3.05 (s, 3H), 0.81–0.72 (m, 4H).

The fourth step: (1-(fluoromethyl) cyclopropyl) methylamine

(1-(Fluoromethyl)cyclopropyl)methylmethanesulfonate (1.0 g, 5.49 mmol) was dissolved in NH ₃ /i-PrOH (10 mL), and the reaction system was heated under microwave at 60° C. for 6 hours . After completion of the reaction, concentrate to obtain crude (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, crude). The crude product was directly used in the next reaction.

The fifth step: 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoic acid ethyl ester

Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), to which was added (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, 5.82 mmol) ) and K2CO3 (1.61 g, 11.64 mmol). The reaction system was stirred at 20°C for four hours. After the reaction was completed, water (10 mL) was added to it to dilute, extracted with ethyl acetate (20 mL×2), washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column (Petroleum ether: Ethyl acetate=5:1, UV=254nm, Rf=0.50), and finally a pale yellow solid 3-((((1-(fluoromethyl)cyclopropyl)methyl)amino) was obtained -4-Nitrobenzoic acid ethyl ester (1.2 g, 4.05 mmol, 69.59% yield).

MS m/z(ESI): 297.1[M+H] ⁺ .

1H NMR(400MHz, CDCl3)δ8.22(d,J=8.8Hz,1H),7.56(s,1H),7.25(d,J=7.6Hz,1H),4.41(q,J=3.2,2.8Hz ,2H),4.30(d,J＝38.0Hz,2H),3.42(d,J＝4.0Hz,2H),1.41(t,J＝7.2Hz,3H),0.76(m,4H).

The sixth step: 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)ethyl benzoate

Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, 4.05 mmol) was dissolved in MeOH (30 mL), to which was added Pd /C (200 mg, 10% purity). After the reaction system was purged with hydrogen three times, it was stirred at 20° C. for 2 hours. After the reaction, filtered through celite, and the filtrate was concentrated to obtain a crude product of ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol). , 92.72% yield).

MS m/z(ESI): 267.1[M+H] ⁺ .

Step 7: Ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol) was dissolved in MeCN (30 mL), to which was added p-toluene Sulfonic acid (193.99 mg, 1.13 mmol) and 2-chloro-1,1,1-trimethoxyethane (1.16 g, 7.51 mmol). The reaction system was stirred in an oil bath at 60°C for 4 hours. After completion of the reaction, concentrate to obtain crude product. The crude product was purified by column (Petroleum ether: Ethyl acetate=2:1, Rf=0.50) to obtain 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H- Ethyl benzo[d]imidazole-6-carboxylate (700 mg, 2.16 mmol, 57.40% yield).

MS m/z(ESI): 325.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 4.97 (s, 2H), 4.47 (s, 2H), 4.44 (q, J=7.6Hz, 2H), 4.03 (d, J=48.4Hz, 2H), 1.43 (t, J=7.2Hz, 3H), 0.92–0.82 (m, 4H) .

Intermediate Im-6 Ethyl 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Synthesis of Esters

Taking 6-chloro-5-nitropyridinecarboxylic acid ethyl ester as raw material, with reference to the synthesis of intermediate Im-5, the product 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl) is obtained Methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate ethyl ester

MS m/z(ESI): 326.10[M+H] ⁺ .

Synthesis of Intermediate Im-7 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

The first step: 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

2-Chloro-1-(4-chloro-2-fluorophenyl)ethan-1-one (2 g, 9.66 mmol) and 3-bromo-2-iodophenol (3.18 g, 10.63 mmol) were dissolved in acetone ( 50 mL), potassium carbonate (4.01 g, 28.98 mmol) was added under nitrogen protection. The mixture was stirred at 60°C for 3 hours. The mixture was cooled, dissolved in ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 100:0 to 95:5) to give the desired product 2-(3-bromo-2-iodophenoxy)-1-(4-chloro) -2-Fluorophenyl)ethan-1-one (3 g, 6.39 mmol, yield: 66.15%) as a white solid.

1H NMR(400MHz, CDCl3)δ7.94(t,J=8.0Hz,1H),7.35-7.27(m,2H),7.26-7.18(m,1H),7.18-7.11(m,1H),6.59( dd,J=8.3,1.3Hz,1H),5.23(d,J=3.3Hz,2H).

Step 2: 2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol

2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (0.5 g, 1.07 mmol) was dissolved in methanol (8 mL), Under ice-water bath cooling and nitrogen protection, sodium borohydride (60.44 mg, 1.60 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was evaporated to dryness, the mixture was dissolved in ethyl acetate (20 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol (0.48g, 1.02mmol,) was obtained, which was directly used in the following step.

The third step: 8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin

2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-ol (0.38 g, 805.96 μmol), cesium carbonate (525.19 mg, 1.61 mmol) and 1,10-phenanthroline (43.57 mg, 241.79 μmol) were dissolved in dimethyl sulfoxide (20 mL), and cuprous iodide (23.02 mg, 120.89 μmol) was added under nitrogen protection. The mixture was stirred at 110°C for 16 hours. The reaction solution was cooled, saturated brine (15 mL) was added to quench the reaction, extracted with ethyl acetate (25 mL×2), the organic phase was washed with saturated brine (30 mL×6), the organic phase was dried over anhydrous sodium sulfate, and chromatographed on flash silica gel Plate purification (petroleum ether:ethyl acetate=10:1) to obtain the target product 8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1, 4] Dioxin (80 mg, 232.85 μmol, yield: 28.89%).

1H NMR(400MHz, CDCl3)δ7.56-7.47(m,1H),7.25-7.21(m,1H),7.18-7.12(m,2H),6.93-6.85(m,1H),6.81-6.71(m , 1H), 5.52–5.43 (m, 1H), 4.49–4.40 (m, 1H), 3.99–3.89 (m, 1H).

Step 4: 4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6- Dihydropyridine-1(2H)-carboxylate tert-butyl ester

8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (80 mg, 232.85 μmol), 4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (108.00 mg, 349.27μmol) and sodium carbonate (74.04mg, 698.54μmol) were dissolved in 1'4-dioxane (5mL) and water (1.5mL), under nitrogen protection, 1,1'-bisdiphenylphosphine was added Ferrocene palladium dichloride (17.04 mg, 23.28 μmol). The mixture was stirred at 85°C for 3 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (25 mL), the mixture was separated, the organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography ( Petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin In-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (27 mg, 60.55 μmol, yield: 26.00%).

MS m/z(ESI): 446.2[M+H] ⁺ .

Step 5: 4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- tert-butyl carboxylate

4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine -1(2H)-Carboxylic acid tert-butyl ester (32 mg, 71.76 μmol) was dissolved in methanol (5 mL), and Wilkinson’s catalyst (13.28 mg, 14.35 μmol) was added under nitrogen protection. The mixture was stirred at 50°C for 16 hours under a hydrogen (1 atm) atmosphere. The reaction solution was evaporated to dryness, and the crude product was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(4-chloro-2-fluorophenyl)-2,3-di Hydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester (15 mg, 33.49 μmol, yield: 46.66%).

MS m/z(ESI): 448.2[M+H] ⁺ .

Step 6: 4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert-butyl The base ester (15 mg, 33.49 μmol) was dissolved in 25% TFA/DCM (15 mL), and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous solution of sodium bicarbonate was added to adjust the pH to 7-8. The organic phase is dried and then spin-dried to give 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine pyridine (11.6 mg, 100%).

MS m/z(ESI): 348.1[M+H] ⁺ .

Intermediate Im-7A(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Synthesis of Piperidine

The first step: (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine tert-Butyl pyridine-1-carboxylate, (R)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin In-5-yl)piperidine-1-carboxylate tert-butyl ester

4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert-butyl The product (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidine-1-carboxylate tert-butyl ester, (R)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4 ]dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester

Preparative-SFC conditions

Instrument:SFC-150(Waters)Column:OJ 20*250mm,10um(Daicel)Column temperature:35℃ Mobile phase:CO2/MEOH(0.2％Methanol Ammonia)＝85/15 Flow rate:100g/min Back pressure:100bar Detection wavelength: 214nm Cycle time: 4min Sample solution: 2300mg dissolved in 100ml Methanol and Dichloromethane Injection volume: 2ml

t _S = 1.182

_tR = 1.448

Step 2: (S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine pyridine

(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- Carboxylic acid tert-butyl ester (15 mg, 33.49 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve, and sodium bicarbonate aqueous solution was added to adjust the pH to 7-8, the organic phase is dried and then spin-dried to obtain (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di oxin-5-yl)piperidine (11.6 mg, 100%).

MS m/z(ESI): 348.1[M+H] ⁺ .

Intermediate Im-7B(R)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Synthesis of Piperidine

(R)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- Carboxylic acid tert-butyl ester (15 mg, 33.49 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve, and sodium bicarbonate aqueous solution was added to adjust the pH to 7-8, the organic phase is dried and then spin-dried to obtain (R)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di oxin-5-yl)piperidine (11.6 mg, 100%).

MS m/z(ESI): 348.1[M+H] ⁺ .

Synthesis of Intermediate Im-8 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

The first step: 2-(3-bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethan-1-one

2,2',4'-Trichloroacetophenone (5.0 g, 22.37 mmol) and 3-bromo-2-iodophenol (6.7 g, 22.37 mmol) were dissolved in acetone (50 mL), under nitrogen protection, added Potassium carbonate (6.2 g, 45.0 mmol). The mixture was stirred at 60°C for 3 hours. The mixture was cooled, dissolved in ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 95:5) to give the desired product 2-(3-bromo-2-iodophenoxy)-1-(2,4 -Dichlorophenyl)ethan-1-one (7 g, 14.4 mmol, yield: 64.3%).

MS m/z(ESI): 484.8[M+H] ⁺ .

Step 2: 2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-ol

2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethan-1-one (7 g, 14.4 mmol) was dissolved in methanol (60 mL) under ice Under water bath cooling and nitrogen protection, sodium borohydride (600 mg, 15.8 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was evaporated to dryness, the mixture was dissolved in ethyl acetate (20 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product 2-(3-bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-ol (7 g, 14.0 mmol, ) was obtained, which was directly used in the next step.

¹ H NMR (400MHz, Chloroform-d) δ 7.70 (d, J=8.4Hz, 1H), 7.36-7.23 (m, 3H), 7.16 (t, J=8.1Hz, 1H), 6.71 (dd, J =8.3,1.3Hz,1H),5.51(dd,J=8.0,2.8Hz,1H),4.34(dd,J=9.4,2.8Hz,1H),3.94–3.83(m,1H).

The third step: 8-bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin

2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-ol (7 g, 14.0 mmol), cesium carbonate (9.1 g, 28 mmol) and 1,10-O-phenanthroline (1.0 g, 2.8 mmol) was dissolved in dimethyl sulfoxide (50 mL), and cuprous iodide (266 mg, 1.4 mmol) was added under nitrogen protection. The mixture was stirred at 110°C for 16 hours. The reaction solution was cooled, saturated brine (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×2), the organic phase was washed with saturated brine (30 mL×6), the organic phase was dried over anhydrous sodium sulfate, and chromatographed on flash silica gel Plate purification (petroleum ether:ethyl acetate=10:1) to obtain the target product 8-bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4 ] Dioxin (1.5 g, 4.1 mol, yield: 29%).

The fourth step: 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-di Hydropyridine-1(2H)-carboxylate tert-butyl ester

8-Bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (1.5 g, 4.1 mmol), 4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.3g, 4.1 mmol) and sodium carbonate (870 mg, 8.2 mmol) were dissolved in 1'4-dioxane (20 mL) and water (3 mL), under nitrogen protection, 1,1'-bisdiphenylphosphinoferrocene was added Palladium dichloride (160 mg, 0.2 mmol). The mixture was stirred at 85°C for 3 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (25 mL), the mixture was separated, the organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography ( Petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 3.45 mmol, yield: 83%).

MS m/z(ESI): 462.1[M+H] ⁺ .

The fifth step: 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxyl tert-butyl acid

4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine- 1(2H)-tert-butyl carboxylate (1.6 g, 3.45 mmol) was dissolved in methanol (15 mL), and Wilkinson's catalyst (925 mg, 1 mmol) was added under nitrogen protection. The mixture was stirred at 50°C for 16 hours under a hydrogen (1 atm) atmosphere. The reaction solution was evaporated to dryness, and the crude product was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(2,4-dichlorophenyl)-2,3-dihydrogen Benzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester (800 mg, 1.72 mmol, yield: 49.7%).

MS m/z(ESI): 464.1[M+H] ⁺ .

Step 6: 4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert-butyl The ester (200 mg, 430 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. After drying, spin to dryness to obtain 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (156mg , 100%).

MS m/z(ESI): 364.0[M+H] ⁺ .

Intermediate Im-8A(S)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Synthesis of pyridine

The first step: (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine - 1-Carboxylic acid tert-butyl ester, (R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidine-1-carboxylate tert-butyl ester

4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert-butyl The product (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) is obtained after ester separation tert-Butyl piperidine-1-carboxylate, (R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin In-5-yl)piperidine-1-carboxylate tert-butyl ester

Preparative-SFC conditions

Instrument:SFC-150(Waters)Column:AD 20*250mm,10um(Daicel)Column temperature:35℃ Mobile phase:CO2/MeOH[0.2%NH3(7M in MeOH)]＝80/20 Flow rate:110g/min Back pressure: 100bar Detection wavelength: 214nm Cycle time: 2.7min Sample solution: 1000mg dissolved in 70ml MeOH Injection volume: 1.4ml

t _S = 1.00

_tR = 0.86

Step 2: (S)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine

(S)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate Acid tert-butyl ester (200 mg, 430 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous sodium bicarbonate solution was added to adjust the pH to 7- 8. The organic phase is dried and then spin-dried to obtain (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidine (156 mg, 100%).

MS m/z(ESI): 364.0[M+H] ⁺ .

Intermediate Im-8B(R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Synthesis of pyridine

(R)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate Acid tert-butyl ester (200 mg, 430 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous sodium bicarbonate solution was added to adjust the pH to 7- 8. The organic phase is dried and then spin-dried to obtain (R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidine (156 mg, 100%).

MS m/z(ESI): 364.0[M+H] ⁺ .

Example 1

(S)-2-((4-(6-(1-(4-Cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate tert-butyl ester

2,6-Dichloropyridine (4.6 g, 30.9 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6 - tert-butyl dihydropyridine-1(2H)-carboxylate (4.8 g, 15.5 mmol) and K ₂ CO ₃ (4.2 g, 31 mmol) were dissolved in dioxane (100 mL) and water (20 mL), Then Pd(dppf) _Cl2.CH2Cl2 ₍ 1.3 _g , 1.6 mmol) was added under _N2 protection. The reaction was stirred at 90°C overnight. Water was added, followed by extraction with ethyl acetate. The organic phase was dried, spin-dried, filtered and dried. The crude product was purified by column chromatography to give tert-butyl 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (3.2 g, Yield: 69%).

MS m/z(ESI): 295.1[M+H] ⁺ .

The second step: tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate

6-Chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate tert-butyl ester (3.2 g, 10.8 mmol) was dissolved in methanol (30 mL) , then _PtO2 (227 mg, 1.0 mmol) was added. The reaction was stirred under hydrogen atmosphere for 3 hours. The reaction solution was filtered, and the organic phase was dried and then spin-dried. The crude product was purified by column chromatography to give tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (1.3 g, yield: 40%).

MS m/z(ESI): 297.1[M+H] ⁺ .

The third step: 1-(4-bromo-2-fluorophenyl) cyclopropan-1-ol

4-(6-Chloropyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (2.3 g, 10.0 mmol), tetraisopropyl titanate (4.2 g, 15.0 mmol) in tetrahydrofuran (50 mL) , the reaction solution was protected with nitrogen, added at 0°C and then added dropwise with ethylmagnesium bromide Grignard reagent (3mol/L 10mL, 30.0mmol). The reaction was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried, spin-dried, filtered and dried. The crude product was purified by column chromatography to give 1-(4-bromo-2-fluorophenyl)cyclopropan-1-ol (1.4 g, yield: 61%).

MS m/z(ESI): 230.9[M+H] ⁺ .

The fourth step: tert-butyl 4-(6-(1-(4-bromo-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate

4-(6-Chloropyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (1.3 g, 4.3 mmol) was dissolved in dry THF (50 mL), 1-(4-bromo-2-fluoro) was added Phenyl)cyclopropan-1-ol (1.0 g, 4.3 mmol). Potassium tert-butoxide (1.1 g, 5.7 mmol) was added portionwise. After the addition was complete, the reaction solution was stirred at room temperature overnight. Aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain 4-(6-(1-(4-bromo-2-fluoro). Phenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (1.6 g, yield: 74%).

MS m/z(ESI): 491.1[M+H] ⁺ .

The fifth step: tert-butyl 4-(6-(1-(4-cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate

4-(6-(1-(4-Bromo-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (1.6g , 3.2 mmol), CuCN (570 mg, 6.4 mmol) was dissolved in N-methylpyrrolidone (10 mL), and under nitrogen protection, the reaction was stirred at 140° C. for 8 hours. The reaction was stopped, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL×2), the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was subjected to column chromatography Separation and purification gave tert-butyl 4-(6-(1-(4-cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate (1.0 g, 70 %).

MS m/z(ESI): 438.2[M+H] ⁺ .

Step 6: 3-Fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile

4-(6-(1-(4-Cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (1 g, 2.3 mmol) was dissolved in 25% TFA/DCM (15 mL), stirred at room temperature for 3 hours, the reaction solution was spin-dried, then dissolved in dichloromethane, added with aqueous sodium bicarbonate solution, adjusted to pH 7-8, the organic phase was dried and spin-dried to obtain 3- Fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile (770 mg, 100%).

MS m/z(ESI): 338.1[M+H] ⁺ .

The seventh step: (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

MS m/z(ESI): 267.0[M+H] ⁺ .

The eighth step: (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

MS m/z(ESI): 237.1[M+H] ⁺ .

The ninth step (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

In a 50 mL reaction flask, combine (S)-4-nitro-3-((oxbutan-2-ylmethyl)amino)benzoic acid methyl ester (2 g, 8.5 mmol), p-toluenesulfonic acid (86 mg, 0.5 mmol) was dissolved in tetrahydrofuran (100 mL), then 2-chloro-1,1,1-trimethoxyethane (1.3 g, 8.5 mmol) was added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (1.3 g, 52%).

MS m/z(ESI): 295.0[M+H] ⁺ .

Step 10: (S)-2-((4-(6-(1-(4-cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

3-Fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile (500 mg, 1.7 mmol) was dissolved in acetonitrile (25 mL), (S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (572 mg, 1.7 mmol) was added separately and potassium carbonate (470 mg, 3.4 mmol), stirred at 50 ° C for 4 hours, added water, and then added ethyl acetate for extraction, the organic phase was dried and then spin-dried, and the crude product was purified by column chromatography to obtain (S)-2-( (4-(6-(1-(4-Cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (600 mg, 59%).

MS m/z(ESI): 596.2[M+H] ⁺ .

Step 11: (S)-2-((4-(6-(1-(4-cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(6-(1-(4-Cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.17 mmol) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added ), stirred overnight at 40°C, added 1 mol/L HCl, adjusted pH to 5-6, added ethyl acetate, extracted, the organic phase was dried and revolved to dryness, and the crude product was purified by prep-HPLC to obtain (S)-2-( (4-(6-(1-(4-Cyano-2-fluorophenyl)cyclopropoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (25 mg, 25%).

MS m/z(ESI): 582.2[M+H] ⁺ .

Example 2

(S)-2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)cyclopropyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: iodide 1-ethyl-1-methyl-4-carbonylpiperidine-1-cation

To the solution of N-methyl-4-piperidone (13.8 mL, 120 mmol) and 2-butanone (80 mL) was added dropwise iodoethane (10.6 mL, 132 mmol), and then stirred at room temperature for 4 days, a solid was precipitated, Filtration, drying the filter cake to obtain the product 1-ethyl-1-methyl-4-carbonylpiperidine-1-positive iodide (27.8g, yield: 86%)

MS m/z(ESI): 143.1[M+H] ⁺ .

The second step: methyl 1-(4-carbonylpiperidin-1-yl)cyclopropane-1-carboxylate

An aqueous solution (7 mL) of 1-ethyl-1-methyl-4-carbonylpiperidine-1-cation iodide (3 g, 11.15 mmol) was added dropwise to methyl 1-aminocyclopropanecarboxylate hydrochloride (1.1 g, 7.4 mmol), potassium carbonate (100 mg, 0.74 mmol) and methanol (20 mL) solution, then refluxed for one hour, cooled, added water (50 mL), then extracted with dichloromethane (50 mL×3), combined the organic phases and used Washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain methyl 1-(4-carbonylpiperidin-1-yl)cyclopropane-1- as a pale yellow oil. Carboxylic acid ester (2 g, yield: 91%).

MS m/z(ESI): 198.1[M+H] ⁺ .

The third step: methyl 1-(4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridin-1(2H)-yl)cyclopropane-1-carboxylate

To -78°C methyl 1-(4-carbonylpiperidin-1-yl)cyclopropane-1-carboxylate (1.5 g, 7.61 mmol) in tetrahydrofuran (20 mL) was added dropwise bistrimethylsilylamine Lithium (11.42 mmol, 1M), stirred at -78°C for 1 hour, added N-phenylbis(trifluoromethanesulfonyl)imide (3.26 g, 9.13 mmol) in tetrahydrofuran (10 mL), slowly warmed to room temperature and stirred For 12 hours, add saturated ammonium chloride solution to quench, then extract with dichloromethane, combine the organic phases and wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain methyl 1- (4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridin-1(2H)-yl)cyclopropane-1-carboxylate (1.3 g, yield: 52% ).

MS m/z(ESI): 330.1[M+H] ⁺ .

The fourth step: methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1 (2H)-yl)cyclopropane-1-carboxylate

Methyl 1-(4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridin-1(2H)-yl)cyclopropane-1-carboxylate (1 g, 3.03 mmmol), pinacol diboronate (926 mg, 3.6 mmol), potassium acetate (594 mg, 6.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex The mixture of compound (123 mg, 0.15 mmol) and dioxane (15 mL) was replaced with nitrogen three times, then stirred at 80 °C for 12 hours under nitrogen protection, cooled, filtered, the filtrate was added with water, then extracted with dichloromethane, and the organic phases were combined. Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolane-2-yl)-3,6-dihydropyridin-1(2H)-yl)cyclopropane-1-carboxylate (800 mg, yield: 86%).

MS m/z(ESI): 308.2[M+H] ⁺ .

The fifth step: methyl 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1' (2'H)-yl)cyclopropane-1-carboxylate

With 4-(((6-chloropyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile and methyl 1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-yl)cyclopropane-1-carboxylate is the raw material Reference Example 1 The first step is to obtain the product methyl 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H) -yl) cyclopropane-1-carboxylate.

MS m/z(ESI): 408.2[M+H] ⁺ .

The sixth step: 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1'(2 'H)-yl)cyclopropane-1-carboxylic acid

With methyl 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1'(2' H)-base) cyclopropane-1-carboxylate as raw material Reference Example 1 eleventh step to obtain product 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3', 6'-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)cyclopropane-1-carboxylic acid.

MS m/z(ESI): 394.2[M+H] ⁺ .

The seventh step: 1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)cyclopropane-1-carboxylic acid

With 1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H) - base) cyclopropane-1-carboxylic acid is the raw material Reference Example 1 The second step obtains the product 1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl ) piperidin-1-yl)cyclopropane-1-carboxylic acid.

MS m/z(ESI): 396.2[M+H] ⁺ .

The eighth step: methyl (S)-4-amino-3-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidine -1-yl)-N-(oxbutan-2-ylmethyl)cyclopropane-1-carbon weedamido<oxalamido>)benzoate

1-(6-((4-cyano-2-fluorobenzyl)oxo)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H) -yl)cyclopropane-1-carboxylic acid (500mg, 1.27mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ( 625mg, 1.65mmol), triethylamine (257mg, 2.54mmol), methyl(S)-4-amino-3-((oxbutan-2-ylmethyl)amino)benzoate (360mg, 1.5mmol) ), a mixture of N,N-dimethylformamide (8 mL) was stirred at room temperature for 12 hours, quenched with water, then extracted with dichloromethane, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, Filtration, concentration, and column chromatography gave methyl(S)-4-amino-3-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridine- 2-yl)piperidin-1-yl)-N-(oxbutan-2-ylmethyl)cyclopropane-1-carbon weedamido<oxalamido>)benzoate (450mg, yield : 58%).

MS m/z(ESI): 614.3[M+H] ⁺ .

The ninth step: (S)-2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl) ring Propyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl(S)-4-amino-3-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidine-1- yl)-N-(oxbutan-2-ylmethyl)cyclopropane-1-carbon weedamido<oxalamido>)benzoate (450 mg, 0.73 mmol) and glacial acetic acid (10 mL) Stir at 60°C for 10 hours, cool, add water, then extract with dichloromethane, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain (S)-2 -(1-(4-(6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)cyclopropyl)-1-(oxobutane) Cyclo-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 596.3[M+H] ⁺ .

Step 10: (S)-2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)ring Propyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl(S)-2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)cyclopropane Base)-1-(oxabutane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 The eleventh step to obtain the product (S)-2-(1 -(4-(6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)cyclopropyl)-1-(oxetan-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 582.2[M+H] ⁺ .

Example 3

(S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxo)thiazol-4-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2-aminothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Using 2-amino-4-bromothiazole as raw material Reference Example 1 The first step to obtain the product tert-butyl 4-(2-aminothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxyl acid ester.

MS m/z(ESI): 282.1[M+H] ⁺ .

The second step: tert-butyl 4-(2-bromothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Dissolve tert-butyl 4-(2-aminothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.6 mmol) in 20 mL of acetonitrile, add copper bromide (1.2 g, 5.3 mmol), tert-butyl nitrite (545 mg, 5.3 mmol) was added at 0°C, and the mixture was stirred at room temperature overnight. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give tert-butyl 4-(2-bromothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (870 mg, 70%).

MS m/z(ESI): 345.0[M+H] ⁺ .

The third step: 3-fluoro-4-(((4-(piperidin-4-yl)thiazol-2-yl)oxo)methyl)benzonitrile

Using tert-butyl 4-(2-bromothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 4-cyano-2-fluorobenzyl alcohol as raw materials Reference Example 1 In the second step, the fourth step and the sixth step, the product 3-fluoro-4-((((4-(piperidin-4-yl)thiazol-2-yl)oxo)methyl)benzonitrile is obtained.

MS m/z(ESI): 318.1[M+H] ⁺ .

The fourth step: (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxo)thiazol-4-yl)piperidin-1-yl)methyl) -1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

with 3-fluoro-4-(((4-(piperidin-4-yl)thiazol-2-yl)oxo)methyl)benzonitrile and methyl(S)-4-amino-3-(( Oxabutane-2-ylmethyl) amino) benzoate is the raw material Reference Example 1 The ninth step and the tenth step obtain the product (S)-2-((4-(2-((4-cyano-2 -Fluorobenzyl)oxo)thiazol-4-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6 -carboxylic acid.

MS m/z(ESI): 562.2[M+H] ⁺ .

Example 4

2-((6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptan-3-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 6-(6-chloropyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane- 3-Carboxylic acid ester (5 g, 15.5 mmol) was dissolved in dioxane (100 mL), 2,6-dichloropyridine (4.6 g, 30.9 mmol) and water (20 mL) _were added respectively, and Pd ( dppf)Cl ₂ .CH ₂ Cl ₂ (1.3 g, 1.6 mmol), stirred at 90° C. overnight, added water, and then added ethyl acetate for extraction, the organic phase was dried and then spin-dried, and the crude product was purified by column chromatography to obtain tertiary -Butyl 6-(6-chloropyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate.

MS m/z(ESI): 309.2[M+H] ⁺ .

Step 2: tert-butyl 6-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane- 3-carboxylate

tert-Butyl 6-(6-chloropyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (3 g, 9.7 mmol) was dissolved in dry THF (50 mL) , added (4-chloro-2-fluorophenyl) methanol (1.9 g, 11.7 mmol), added potassium tert-butoxide (2.2 g, 11.4 mmol) in batches, after the addition, the reaction solution was stirred at room temperature overnight, and chlorinated Aqueous ammonium solution was used to quench the reaction, and then ethyl acetate was added for extraction. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain tert-butyl 6-(6-((4-chloro-2-fluorobenzyl) yl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate.

MS m/z(ESI): 433.2[M+H] ⁺ .

The third step: 6-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane

tert-Butyl 6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylic acid The ester (2 g, 4.6 mmol) was dissolved in 25% TFA/DCM (50 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. After drying, spin to dryness to give 6-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane.

MS m/z(ESI): 333.2[M+H] ⁺ .

Step 4: 2-((6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane- 3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane (0.5 g, 1.5 mmol) was dissolved in Acetonitrile (25mL) was added with (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (443mg) respectively , 1.5 mmol) and potassium carbonate (1 g, 7.5 mmol), stirred at 50 ° C for 4 hours, added water, then added ethyl acetate for extraction, the organic phase was dried and then spin-dried, and the crude product was purified by column chromatography to obtain 2-( (6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptan-3-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester.

MS m/z(ESI): 591.2[M+H] ⁺ .

Step 5: 2-((6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane- 3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((6-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptan-3-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (200 mg, 0.34 mmol) was dissolved in THF (10 mL) ), add 2mol/L LiOH (2mL), stir overnight at 40°C, add 1mol/L HCl, adjust pH to 5-6, add ethyl acetate, extract, dry the organic phase and spin dry, and the crude product is purified by prep-HPLC , to give 2-((6-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 577.2[M+H] ⁺ .

Example 5

2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)-1-(( (S)-Oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid

The first step: (E)-3-(3-fluoro-4-nitrophenyl) acrylic acid methyl ester

In a 50 mL reaction flask, methyl 2-(diethoxyphosphoryl) acetate (3.73 g, 17.7 mmol) was dissolved in tetrahydrofuran (100 mL), and then NaH (780 mg, 19.5 mmol, 60% purity) was added at 0°C. , the reaction solution was stirred at 0° C. for 1 hour, then 3-fluoro-4-nitrobenzaldehyde (3.0 g, 17.7 mmol) was added, and the reaction was continued at room temperature for 12 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried. The crude product was purified by column chromatography to give (E)-methyl 3-(3-fluoro-4-nitrophenyl)acryloyl acid (2.4 g, yield: 61%).

MS m/z(ESI): 226.0[M+H] ⁺ .

The second step: 2-(3-fluoro-4-nitrophenyl) cyclopropane-1-carboxylic acid methyl ester

Trimethylsulfoxide (2.3 g, 10.6 mmol) was dissolved in DMSO (30 mL) in a 50 mL reaction flask under nitrogen protection, and then NaH (400 mg, 10 mmol, 60% purity) was added in batches, and the reaction solution was heated at 25 Stir at °C for 1 hour, then cool to 0 °C, and then add dropwise a solution of (E)-3-(3-fluoro-4-nitrophenyl)acryloyl acid methyl ester (2.4 g, 10.6 mmol) in DMSO, After the dropwise addition, the reaction was continued at 0°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried. The crude product was purified by column chromatography to give methyl 2-(3-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate (2.0 g, yield: 78%).

MS m/z(ESI): 240.0[M+H] ⁺ .

The third step: 2-(4-nitro-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylic acid methyl ester

Using 2-(3-fluoro-4-nitrophenyl) cyclopropane-1-carboxylate methyl ester as raw material Reference Example 1 The seventh step obtains the product 2-(4-nitro-3-((((S )-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylic acid methyl ester.

MS m/z(ESI): 307.1[M+H] ⁺ .

The fourth step: 2-(4-amino-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylic acid methyl ester

Using methyl 2-(4-nitro-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylate as raw material Reference Example 1 Section 1 The product 2-(4-amino-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylic acid methyl ester is obtained in eight steps.

MS m/z(ESI): 277.1[M+H] ⁺ .

The fifth step: 2-(2-(chloromethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane -1-Carboxylic acid methyl ester

Using 2-(4-amino-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)cyclopropane-1-carboxylate methyl ester as raw material Reference Example 1 Ninth The product 2-(2-(chloromethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane- 1-Carboxylic acid methyl ester.

MS m/z(ESI): 335.1[M+H] ⁺ .

Step 6: 2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)- Methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylate

2-(2-(Chloromethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1- Carboxylic acid methyl ester is the raw material Reference Example 1 The tenth step obtains the product 2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxy methyl acid.

MS m/z(ESI): 610.2[M+H] ⁺ .

Step 7: 2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid

2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)-1-( ((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylate methyl ester is the raw material Reference Example 1 The eleventh step obtains the product 2-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)-1-(( (S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid.

MS m/z(ESI): 596.2[M+H] ⁺ .

Example 6

(S)-1-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid

The first step: 1-(3-fluoro-4-nitrophenyl) cyclopropane-1-carboxylic acid methyl ester

Under nitrogen protection, methyl 2-(3-fluoro-4-nitrophenyl)acetate (3 g, 14 mmol) was dissolved in tetrahydrofuran (100 mL) in a 50 mL reaction flask, and then NaH (1.8 g, 47.6 g) was added in portions. mmol, 60% purity), the reaction solution was stirred at 25 ° C for 1 hour, and then a solution of 1,2-dibromoethane (2.4 g, 10.6 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued at 0 ° C after the dropwise addition for 1 Hour. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried. The crude product was purified by column chromatography to give 1-(3-fluoro-4-nitrophenyl)cyclopropane-1-carboxylic acid methyl ester (1.6 g, yield: 52%).

MS m/z(ESI): 240.0[M+H] ⁺ .

The second step: (S)-1-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid

Using 1-(3-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate methyl ester as raw material, (S)-2-(chloromethyl)-1-(oxetane-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester was replaced with 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxo ) methyl) benzonitrile reference example 1 eighth to eleventh steps to obtain product (S)-1-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo) )pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1- carboxylic acid.

MS m/z(ESI): 596.2[M+H] ⁺ .

Example 7

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydro Pyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester

With 3-bromobenzene-1,2-diol and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropenan-2-yl)-3,6-diol Hydropyridine-1(2H)-carboxylate tert-butyl ester is the raw material Reference Example 1 The first step obtains the product 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)- tert-butyl carboxylate.

MS m/z(ESI): 292.1[M+H] ⁺ .

Step 2: 4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-dihydro Pyridine-1(2H)-carboxylate tert-butyl ester

In a 50 mL reaction flask, 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (3 g, 10.3 mmol), 1-(4- Chloro-2-fluorophenyl)ethan-1-one (1.8 g, 10.3 mmol) and p-toluenesulfonic acid (0.1 g) were dissolved in toluene (30 mL), and the reaction solution was stirred at 110° C. for 6 hours. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (3.2 g, 69%).

MS m/z(ESI): 446.1[M+H] ⁺ .

The third step: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,2,3, 6-Tetrahydropyridine

4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid tert-butyl ester is the raw material Reference Example 1 The sixth step obtains the product 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ] Dioxazol-4-yl)-1,2,3,6-tetrahydropyridine.

MS m/z(ESI): 346.0[M+H] ⁺ .

The fourth step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,2,3,6-tetra Hydropyridine is the raw material Reference Example 1 The tenth step obtains the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate.

MS m/z(ESI): 604.1[M+H] ⁺ .

The fifth step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-di Hydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is Raw material reference example 1 Eleventh step to obtain product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 590.1[M+H] ⁺ .

Example 8

(S)-2-(7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl )-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: ethyl 7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-7-azaspiro[3.5]nonane-2-carboxylic acid ester

Combine 3-fluoro-4-(((6-fluoropyridin-2-yl)oxo)methyl)benzonitrile (600 mg, 2.43 mmol), potassium carbonate (1 g, 7.31 mmol), ethyl 7-aza A mixture of spiro[3.5]nonane-2-carboxylate (622 mg, 3.15 mmol) and dimethyl sulfoxide (10 mL) was stirred at 120 °C for 12 h, cooled, water was added, then extracted with dichloromethane, the organic phases were combined Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain ethyl 7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridine- 2-yl)-7-azaspiro[3.5]nonane-2-carboxylate (400 mg, yield: 39%)

MS m/z(ESI): 424.2[M+H] ⁺ .

The second step: (S)-2-(7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-7-azaspiro[3.5]nonane -2-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using ethyl 7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-7-azaspiro[3.5]nonane-2-carboxylate as raw material Reference Example 2 Sixth, eight, nine, ten, step to obtain product (S)-2-(7-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl) -7-Azaspiro[3.5]nonan-2-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 582.2[M+H] ⁺ .

Example 9

2-(5-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[2.3]hexane-1-yl)-1-( ((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 5-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[2.3]hexane-1-carboxylate

Using 2-((4-chloro-2-fluorobenzyl)oxo)-6-fluoropyridine and methyl 5-azaspiro[2.3]hexane-1-carboxylate as raw materials Reference Example 8 First The product is methyl 5-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[2.3]hexane-1-carboxylate.

MS m/z(ESI): 377.1[M+H] ⁺ .

Step 2: 2-(5-(6-((4-Chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[2.3]hexane-1-yl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Taking methyl 5-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[2.3]hexane-1-carboxylate as raw material for reference Example 2 sixth, eight, nine, ten steps to obtain product 2-(5-(6-((4-chloro-2-fluorobenzyl)oxo)pyridin-2-yl)-5-azaspiro[ 2.3] Hexan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 549.2[M+H] ⁺ .

Example 10

2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5]octane- 1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2-acetoxyethylene) piperidine-1-carboxylate

To tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate (5.80 g, 25.5 mmol), pyridine (4.13 mL, 51.0 mmol) in dichloromethane (100 mL) was added dropwise ethyl acetate Acid anhydride (4.82 mL, 51.0 mmol), stirred at room temperature for 2 hours, added water (50 mL), extracted with dichloromethane (50 mL×3), combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, Filtration, concentration, and column chromatography gave tert-butyl 4-(2-acetoxyethylene)piperidine-1-carboxylate (6 g, yield: 87%) as a pale yellow oil.

MS m/z(ESI): 270.2[M+H] ⁺ .

The second step: tert-butyl 2-(acetoxymethyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate

To tert-butyl 4-(2-acetoxyethylene)piperidine-1-carboxylate (3.23 g, 12.0 mmol) in tetrahydrofuran (30 mL) was added sodium iodide (0.899 g, 6.00 mmol) and (Trifluoromethyl)trimethylsilane (4.43 mL, 30.0 mmol), stirred at 90°C for 2 hours, cooled, added water, then extracted with ethyl acetate, combined organic phases were washed with saturated sodium chloride solution, anhydrous sulfuric acid Dry over sodium, filter, concentrate, and separate by column chromatography to give tert-butyl 2-(acetoxymethyl)-1,1-difluoro-6-azaspiro[2.5]octane-6 as a pale yellow oil - Carboxylic acid ester (1.9 g, yield: 50%).

MS m/z(ESI): 320.2[M+H] ⁺ .

The third step: tert-butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate

tert-butyl 2-(acetoxymethyl)-1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (568 mg, 1.8 mmol), methanol (8 mL), A mixture of potassium carbonate (730 mg, 5.3 mmol) was stirred at room temperature for 2 hours, water was added, and then extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography. , tert-butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (400 mg, yield: 80%) was obtained as pale yellow oil .

MS m/z(ESI): 278.2[M+H] ⁺ .

The fourth step: 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid

To a solution of tert-butyl 1,1-difluoro-2-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (400 mg, 1.45 mmol) in acetonitrile (10 mL) was added N-methylmorpholine-N-oxide (1.94g, 14mmol) and tetrapropylammonium perruthenate (51mg, 0.14mmol), then stirred at room temperature for 2 hours, and quenched by adding dilute hydrochloric acid (1mol/L), Diluted with ethyl acetate, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 6-(tert-butoxycarbonyl)-2,2- Difluoro-6-azaspiro[2.5]octane-1-carboxylic acid (320 mg, crude).

MS m/z(ESI): 292.1[M+H] ⁺ .

The fifth step: methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-yl)-1-(((S) -Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

with 6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid and methyl(S)-4-amino-3-((oxa Butane-2-ylmethyl) amino) benzoate is raw material Reference Example 2 eighth, nine steps to obtain product methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro-6 - Azaspiro[2.5]octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 492.2[M+H] ⁺ .

The sixth step: methyl 2-(2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylate

With methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-1-(((S)-oxabutane Cyclo-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 The sixth step obtains the product methyl 2-(2,2-difluoro-6-aza Spiro[2.5]octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 392.2[M+H] ⁺ .

The seventh step: methyl 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro [2.5]Octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl 2-(2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-1-(((S)-oxetan-2-yl)methyl)-1H -Benzo[d]imidazole-6-carboxylate and 3-fluoro-4-(((6-fluoropyridin-2-yl)oxo)methyl)benzonitrile as raw materials Reference Example 8 Obtained in the first step Product methyl 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5] Octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 618.2[M+H] ⁺ .

The eighth step: 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5 ]Octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5] Octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 Eleventh Step obtained product 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5] Octan-1-yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 604.2[M+H] ⁺ .

Example 11

2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5]octane- 1-yl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-3-(((S) -Oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octane-1-carboxylic acid and methyl(S)-5-amino-6-((oxa Butcyclo-2-ylmethyl)amino)picolinate is the raw material Reference Example 2 Eighth, the ninth step obtains the product methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro -6-Azaspiro[2.5]octan-1-yl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine- 5-carboxylate.

MS m/z(ESI): 493.2[M+H] ⁺ .

The second step: 2-(6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5 ]octan-1-yl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

With methyl 2-(6-(tert-butoxycarbonyl)-2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-3-(((S)-oxabutane Cyclo-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as the raw material Reference Example 10 The sixth, seventh and eighth steps to obtain the product 2-(6-(6-(( 4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,2-difluoro-6-azaspiro[2.5]octan-1-yl)-3-((( S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 605.2[M+H] ⁺ .

Example 12

(S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl)-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate methyl ester

2-(1-(tert-Butoxycarbonyl)piperidin-4-ylidene)acetic acid (3 g, 12.4 mmol) was dissolved in DMF (50 mL), HATU (7.1 g, 18.6 mmol) and DIEA (4.8 g, 37.3 mmol). After stirring at room temperature for 10 minutes, methyl (S)-4-amino-3-((oxbutan-2-ylmethyl)amino)benzoate (2.9 g, 12.4 mmol) was dissolved in DMF (10 mL) and added to the reaction , continue stirring overnight, add water, then add ethyl acetate for extraction, the organic phase is dried and then spin-dried, and the crude product is purified by column chromatography to obtain (S)-2-((1-(tert-butoxycarbonyl) Piperidine-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 442.2[M+H] ⁺ .

The second step: (S)-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

With (S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] imidazole-6-carboxylic acid methyl ester is raw material Reference Example 4 the third step obtains product (S)-1-(oxetan-2-ylmethyl)-2-(piperidine-4-ylidene methyl) yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 342.2[M+H] ⁺ .

The third step: (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

3-Fluoro-4-(((6-fluoropyridin-2-yl)oxo)methyl)benzonitrile (1 g, 4.1 mmol) was dissolved in DMSO (30 mL), (S)-1-(oxobutane) was added Cyclo-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1.4 g, 4.1 mmol) and potassium carbonate (1.7 g, 12.2 mmol), stirred at 90 °C overnight, added water, and then added ethyl acetate for extraction, the organic phase was dried and then spin-dried, and the crude product was purified by column chromatography to obtain (S)-2-((1-(6- ((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H -Methyl benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 568.2[M+H] ⁺ .

The fourth step: (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl )-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is the raw material Reference Example 4 the fifth step obtains the product (S)-2-((1-( 6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 13

(S)-2-((1-(6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2-ethoxy-1-fluoro-2-carbonyl ethylene) piperidine-1-carboxylate

tert-Butyl 4-carbonylpiperidine-1-carboxylate (2g, 10.0mmol) was dissolved in ethanol (30mL), and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (2.2g) was added separately. , 9.0 mmol) and potassium carbonate (1.4 g, 10.0 mmol), stirred at room temperature for 6 hours, the reaction solution was filtered and spin-dried, and the crude product was purified by column chromatography to obtain tert-butyl 4-(2-ethoxy-1 -Fluoro-2-carbonylethylidene)piperidine-1-carboxylate.

MS m/z(ESI): 288.2[M+H] ⁺ .

The second step: ethyl 2-fluoro-2-(piperidin-4-ylidene)acetate

Using tert-butyl 4-(2-ethoxy-1-fluoro-2-carbonyl ethylene) piperidine-1-carboxylate as raw material Reference Example 4 The third step obtains the product 2-fluoro-2- (Piperidin-4-ylidene)ethyl acetate.

MS m/z(ESI): 188.2[M+H] ⁺ .

The third step: ethyl 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2-fluoroacetate

Using ethyl 2-fluoro-2-(piperidin-4-ylidene)acetate and 3-fluoro-4-(((6-fluoropyridin-2-yl)oxo)methyl)benzonitrile as raw materials for reference Example 12 The third step obtains the product 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2- Ethyl Fluoroacetate.

MS m/z(ESI): 414.2[M+H] ⁺ .

The fourth step: 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2-fluoroacetic acid

Using ethyl 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2-fluoroacetate as raw material for reference The fifth step of embodiment 4 obtains product 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2- Fluoroacetic acid.

MS m/z(ESI): 386.2[M+H] ⁺ .

The fifth step: (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethane yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

with 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)-2-fluoroacetic acid and (S)- 4-amino-3-((oxetan-2-ylmethyl)amino) benzoic acid methyl ester is raw material Reference Example 12 The first step obtains product (S)-2-((1-(6-(( 4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethyl)-1-(oxetan-2-ylmethyl)-1H- Methyl benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 586.2[M+H] ⁺ .

The sixth step: (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethane yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethyl)- 1-(Oxabutane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is the raw material Reference Example 4 The fifth step obtains the product (S)-2-(((1- (6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)fluoromethyl)-1-(oxetan-2-ylmethyl) yl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 572.2[M+H] ⁺ .

Example 14

(S)-2-(1-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)ethyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(1-ethoxy-1-carbonylpropane-2-ylidene) piperidine-1-carboxylate

Using tert-butyl 4-carbonyl piperidine-1-carboxylate and 2-(diethoxyphosphoryl) ethyl propionate as raw materials Reference Example 13 The first step to obtain the product tert-butyl 4-(1 -Ethoxy-1-carbonylpropane-2-ylidene)piperidine-1-carboxylate.

MS m/z(ESI): 284.2[M+H] ⁺ .

Step 2: Ethyl 2-(Piperidin-4-ylidene)propionate

Using tert-butyl 4-(1-ethoxy-1-carbonylpropane-2-ylidene) piperidine-1-carboxylate as raw material Reference Example 4 The third step obtains the product 2-(piperidine-4 - subunit) ethyl propionate.

MS m/z(ESI): 184.2[M+H] ⁺ .

The third step: ethyl 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propanoate

Using ethyl 2-(piperidin-4-ylidene)propanoate and 3-fluoro-4-(((6-fluoropyridin-2-yl)oxo)methyl)benzonitrile as raw materials Reference Example 12 In the third step, the product 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propionic acid ethyl ester was obtained.

MS m/z(ESI): 410.2[M+H] ⁺ .

The fourth step: 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propionic acid

Using ethyl 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propanoate as raw material Reference Example 4 The fifth step obtains the product 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propionic acid.

MS m/z(ESI): 382.2[M+H] ⁺ .

The fifth step: (S)-2-(1-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene) Ethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

with 2-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)propionic acid and (S)-4-amino -3-((oxetan-2-ylmethyl)amino) benzoic acid methyl ester is the raw material Reference Example 12 The first step obtains the product (S)-2-(1-(1-(6-((4 -Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)ethyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Methyl imidazole-6-carboxylate.

MS m/z(ESI): 582.2[M+H] ⁺ .

The sixth step: (S)-2-(1-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene) Ethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

with (S)-2-(1-(1-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)ethyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is the raw material Reference Example 4 The fifth step obtains the product (S)-2-(1- (1-(6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-4-ylidene)ethyl)-1-(oxetan-2- (methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 568.2[M+H] ⁺ .

Example 15

(S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptane-2- yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

Dissolve 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 4.7 mmol) in 20 mL of toluene, add triphenylphosphine (2.5 g, 9.4 mmol), imidazole ( 952 mg, 14 mmol) and iodine (1.8 g, 7 mmol), the reaction solution was stirred under reflux for 1 h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 85%).

MS m/z(ESI): 324.0[M+H] ⁺ .

The second step: 4-(((6-bromopyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile

Using 4-cyano-2-fluorobenzyl alcohol and 2,6-dibromopyridine as raw materials, the fourth step of reference example 1 obtains the product 4-(((6-bromopyridin-2-yl)oxo)methyl)-3 - Fluorobenzonitrile.

MS m/z(ESI): 306.9[M+H] ⁺ .

The third step: 3-fluoro-4-(((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboropenan-2-yl)pyridin-2-yl) oxo)methyl)benzonitrile

4-(((6-Bromopyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile (1.2 g, 3.9 mmol) was dissolved in 20 mL of dioxane, and [1,1' -bis(diphenylphosphino)ferrocene]palladium dichloride (290mg, 0.4mmol), 1,1'-bis(diphenylphosphino)ferrocene (221mg, 0.4mmol), KOAc (1.2g) , 12 mmol) and pinacol diboronate (1.2 g, 4.8 mmol) were stirred overnight at 80°C under nitrogen protection. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 3-fluoro-4-((((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2 -yl)oxo)methyl)benzonitrile (1.2 g, 90%).

The fourth step: tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptane-2- Carboxylate

with 3-fluoro-4-(((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxo) Methyl) benzonitrile is the raw material Reference Example 1 The first step obtains the product tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2 - Azaspiro[3.3]heptane-2-carboxylate.

MS m/z(ESI): 424.2[M+H] ⁺ .

The fifth step: (S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptane Alk-2-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate For raw material reference example 1 the sixth step, tenth step and eleventh step obtain product (S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridine -2-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6- carboxylic acid.

MS m/z(ESI): 568.2[M+H] ⁺ .

Example 16

(S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane -2-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane -2-carboxylate

To 4-(((6-bromopyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile (1 g, 3.3 mmol), 2,6-diazaspiro[3.3]heptane-2 - A mixture solution of tert-butyl formate (971 mg, 4.9 mmol), cesium carbonate (3.2 g, 9.9 mmol) and toluene (30 mL) was added tris(dibenzylideneacetone)dipalladium (302 mg, 0.33 mmol) and 4,5 -Bisdiphenylphosphine-9,9-dimethylxanthene (380mg, 0.66mmol), stirred at 80°C for 12 hours after nitrogen replacement, cooled and filtered after the reaction, the filtrate was concentrated to dryness under reduced pressure, and the crude product column layer separation and purification to obtain tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane -2-Carboxylic acid ester (840 mg, 60% yield).

MS m/z(ESI): 425.2[M+H] ⁺ .

The second step: (S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,6-diazaspiro[ 3.3]Heptan-2-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

tert-butyl 6-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- Carboxylate is the raw material Reference Example 1 The sixth step, the tenth step and the eleventh step obtain the product (S)-2-((6-(6-((4-cyano-2-fluorobenzyl)oxygen substituted)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 569.2[M+H] ⁺ .

Example 17

(S)-2-(2-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl )-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl (S)-2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-yl)-1-(oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl(S)-4-amino-3-((oxbutan-2-ylmethyl)amino)benzoate and 2-BOC-2-azaspiro[3.3]heptane-6-carboxylic acid Reference Example 14 as the raw material in the fifth step to obtain the product methyl (S)-2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-yl)-1-(oxa Butcyclo-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 442.2[M+H] ⁺ .

The second step: methyl (S)-2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-yl)-1-(oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl (S)-2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate is the raw material for the sixth step of reference example 1, the first step of example 16 obtains the product methyl (S)-2-(2-(tert-butoxycarbonyl) -2-Azaspiro[3.3]heptan-6-yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 568.2[M+H] ⁺ .

The third step: (S)-2-(2-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptane -6-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl (S)-2-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-(oxetan-2-ylmethyl) -1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 The eleventh step to obtain the product (S)-2-(2-(6-((4-cyano-2-fluorobenzyl) yl)oxo)pyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-Carboxylic acid.

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 18

3-Fluoro-4-(((6-(1-((6-(S-methylsulfoimidoyl)-1-(((S)-oxetan-2-yl)methyl)-1H -Benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxo)methyl)benzonitrile

The first step: (3-fluoro-4-nitrophenyl)(methyl)sulfane

(3-Fluoro-4-bromophenyl)(methyl)sulfane (5 g, 22.6 mmol) was dissolved in DMSO (50 mL), followed by copper trifluoromethanesulfonate (1.8 g, 5 mmol) and potassium nitrite (3.8 g, 45.2 mmol), stirred at 130 °C for 24 h under nitrogen protection. The reaction was stopped, cooled to room temperature, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give (3-fluoro-4-nitrophenyl)(imino)(methyl) )-λ ⁶ -sulfanone.

MS m/z(ESI): 188.0[M+H] ⁺ .

The second step: (3-fluoro-4-nitrophenyl)(imino)(methyl)-λ ⁶ -sulfanone

(3-Fluoro-4-nitrophenyl)(methyl)sulfane (2 g, 10.6 mmol) was dissolved in methanol (30 mL), followed by the addition of ammonium carbamate (2.4 g, 31.8 mmol) and iodobenzene diacetate (6.8 g, 21.2 mmol) and stirred at room temperature for 1 hour. The reaction was stopped, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-fluoro-4-nitrophenyl)(imino)(methyl)-λ ⁶ -sulfane ketone.

MS m/z(ESI): 219.0[M+H] ⁺ .

The third step: imino(methyl)(4-nitro-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)-λ ⁶ -sulfanone

With (3-fluoro-4-nitrophenyl) (imino) (methyl)-λ ⁶ -sulfanone as raw material Reference Example 1 the seventh step obtains the product imino (methyl) (4-nitro- 3-((((S)-oxetan-2-yl)methyl)amino)phenyl) ^-λ6 -sulfanone.

MS m/z(ESI): 286.0[M+H] ⁺ .

The fourth step: (4-amino-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)(imino)(methyl)-λ ⁶ -sulfanone

Using imino(methyl)(4-nitro-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)-λ ⁶ -sulfanone as raw material Reference Example 1 The eighth step obtains product (4-amino-3-(((((S)-oxetan-2-yl)methyl)amino)phenyl)(imino)(methyl)-λ ⁶ -sulfanone .

MS m/z(ESI): 256.1[M+H] ⁺ .

The fifth step: (2-(chloromethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)(imino) (Methyl)-λ ⁶ -sulfanone

Reference example using (4-amino-3-((((S)-oxetan-2-yl)methyl)amino)phenyl)(imino)(methyl)-λ ⁶ -sulfanone as raw material 1 The ninth step gets the product (2-(chloromethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)(sub amino)(methyl) ^-λ6 -sulfanone.

MS m/z(ESI): 314.0[M+H] ⁺ .

The sixth step: 3-Fluoro-4-(((6-(1-((6-(S-methylsulfoimidoyl)-1-(((S)-oxetan-2-yl)methane yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxo)methyl)benzonitrile

with (2-(chloromethyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)(imino)(methyl )-λ ⁶ -sulfanone is the raw material reference example 1 the tenth step obtains the product 3-fluoro-4-(((6-(1-((6-(S-methylsulfoimidoyl)-1-( ((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxo)methyl base) benzonitrile.

MS m/z(ESI): 589.2[M+H] ⁺ .

Example 19

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperazine-1-carbonyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl (S)-2-(hydroxymethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Taking methyl (S)-4-amino-3-((oxetan-2-ylmethyl) amino) benzoate as raw material Reference Example 13 the fifth step obtains product methyl (S)-2-(hydroxyl methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 277.1[M+H] ⁺ .

The second step: (S)-6-(carbomethoxy<methoxycarbonyl>)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylic acid

Methyl (S)-2-(hydroxymethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (300 mg, 1.08 mmol) It was placed in a 50 mL flask, sodium carbonate (125 mg, 1.2 mmol) and 5 mL of water were added, and after boiling, potassium permanganate (158 mg, 1.8 mmol) in boiling water (5 mL) was added, and the reaction solution was refluxed for 4 h. Filter while hot, cool the filtrate to room temperature, adjust the pH to 2, separate out a solid, and filter to obtain the product (S)-6-(carboxycarbonyl<methoxycarbonyl>)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-2-carboxylic acid (250 mg).

MS m/z(ESI): 291.1[M+H] ⁺ .

The third step: 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxo)methyl)benzonitrile

Reference Example 16 The first step and In the sixth step of Example 1, the product 3-fluoro-4-((((6-(piperazin-1-yl)pyridin-2-yl)oxo)methyl)benzonitrile was obtained.

MS m/z(ESI): 313.1[M+H] ⁺ .

The fourth step: (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperazine-1-carbonyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxo)methyl)benzonitrile and (S)-6-(carbomethoxy<methoxycarbonyl) >)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-2-carboxylic acid as raw material Reference Example 12 The first step and the eleventh step of Example 1 obtain the product (S) -2-(4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperazine-1-carbonyl)-1-(oxetan-2-yl) methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 571.2[M+H] ⁺ .

Example 20

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate

1-(4-Chloro-2-fluorophenyl)ethan-1-one (5 g, 29.0 mmol) was dissolved in dry toluene (50 mL), and methyl 2,3-dihydroxypropionate (3.5 g, 29.0mmol) and 4-methylbenzenesulfonic acid (500mg, _2.9mmol ), the reaction was refluxed and stirred overnight, excess NaHCO solution was added to it, then ethyl acetate was added for extraction, the organic phase was dried and then spin-dried, and the crude product passed through the column layer Analytical purification gave 2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylic acid methyl ester.

MS m/z(ESI): 275.2[M+H] ⁺ .

The second step: 2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylic acid

Take 2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate methyl ester as raw material Reference Example 4 The fifth step obtains product 2-(4 -Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylic acid.

MS m/z(ESI): 261.2[M+H] ⁺ .

The third step: (S)-2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene Methyl [d]imidazole-6-carboxylate

With (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and tert-butylpiperazine- 1-Carboxylic acid ester is the raw material Reference Example 4 The fourth step obtains the product (S)-2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-1-(oxabutane) Cyclo-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 445.2[M+H] ⁺ .

The fourth step: (S)-1-(oxetan-2-ylmethyl)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

With (S)-2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylate methyl ester is raw material Reference Example 4 the third step obtains product (S)-1-(oxetan-2-ylmethyl)-2-(piperazin-1-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate methyl ester.

MS m/z(ESI): 345.2[M+H] ⁺ .

The fifth step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

With (S)-1-(oxetan-2-ylmethyl)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester and 2- (4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylic acid as raw material Reference Example 12 The first step to obtain the product 2-((4-(2- (4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl)methyl)-1-(((S)-oxa Butcyclo-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 587.2[M+H] ⁺ .

Step 6: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester is the raw material Reference Example 4 The fifth step obtains the product 2-( (4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carbonyl)piperazin-1-yl)methyl)-1-( ((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 573.2[M+H] ⁺ .

Example 21

2-((4-((2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol

Using 1-(4-chloro-2-fluorophenyl)ethan-1-one and glycerol as raw materials Reference Example 20 The first step to obtain the product (2-(4-chloro-2-fluorophenyl)-2- Methyl-1,3-dioxolan-4-yl)methanol.

MS m/z(ESI): 247.2[M+H] ⁺ .

The second step: (2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate

(2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol (3 g, 12.2 mmol) was dissolved in dichloromethane (50 mL), respectively TsCl (2.8 g, 14.6 mmol) and DIEA (4.7 g, 36.5 mmol) were added, stirred overnight at room temperature, added with water, and then extracted with dichloromethane. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain (2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate.

MS m/z(ESI): 401.2[M+H] ⁺ .

Step 3: 2-((4-((2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

With (2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate and (S)-1 -(Oxetan-2-ylmethyl)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is the raw material Reference Example 4 The fourth step The product 2-((4-((2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester.

MS m/z(ESI): 573.2[M+H] ⁺ .

Step 4: 2-((4-((2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazin-1-yl ) methyl)-1-(((S)-oxabutane-2-yl) methyl)-1H-benzo[d] imidazole-6-carboxylic acid methyl ester is the raw material Reference Example 4 fifth step to obtain Product 2-((4-((2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl)piperazin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 559.2[M+H] ⁺ .

Example 22

(S)-2-((4-(3-((4-Chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2-(tert-butoxycarbonyl)hydrazineidene)piperidine-1-carboxylate

A mixture of tert-butyl 4-carbonylpiperidine-1-carboxylate (3 g, 15.07 mmol), tert-butylcarbazate (2.6 g, 19.6 mmol) and methanol (30 mL) was stirred at room temperature for 12 hours, water was added , then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain tert-butyl 4-(2-(tert-butoxy) Carbonyl)hydrazineidene)piperidine-1-carboxylate (3.2 g, crude).

MS m/z(ESI): 314.2[M+H] ⁺ .

Step 2: Ethyl 4-(2-(tert-butoxycarbonyl)hydrazino)piperidine-1-carboxylate

Combine tert-butyl 4-(2-(tert-butoxycarbonyl)hydrazineidene)piperidine-1-carboxylate (3 g, 10.52 mmol), sodium cyanoborohydride (1.3 g, 21.04 mmol) and The mixture of methanol (30 mL) was stirred at room temperature for 12 hours, water was added, and then extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain ethyl acetate 4-(2-(tert-Butoxycarbonyl)hydrazino)piperidine-1-carboxylate (2.6 g, crude).

MS m/z(ESI): 288.2[M+H] ⁺ .

The third step: ethyl 4-hydrazinopiperidine-1-carboxylate

Using ethyl 4-(2-(tert-butoxycarbonyl)hydrazino)piperidine-1-carboxylate as raw material Reference Example 1 The sixth step obtains the product ethyl 4-hydrazinopiperidine-1-carboxylic acid ester.

MS m/z(ESI): 188.1[M+H] ⁺ .

The fourth step: ethyl 4-(5-hydroxy-1H-pyrazol-1-yl) piperidine-1-carboxylate

Ethyl 4-hydrazinopiperidine-1-carboxylate (1.5 g, 8.02 mmol), methyl-3-methoxyacrylate (1.4 g, 12.03 mmol), sodium hydroxide (642 mg, 16.04 A solution of mmol) in water (15 mL) was stirred at 40 °C for 5 hours, quenched by cooling with dilute hydrochloric acid (1 M), diluted with ethyl acetate, and then extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution. Dry over sodium sulfate, filter, and concentrate to give ethyl 4-(5-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate (900 mg, crude).

MS m/z(ESI): 240.1[M+H] ⁺ .

The fifth step: ethyl 4-(3-((4-chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Reference examples using ethyl 4-(5-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate and (4-chloro-2-fluorobenzyl)methanesulfonate ethyl as raw materials 4 In the fourth step, the product 4-(3-((4-chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidine-1-carboxylate is obtained.

MS m/z(ESI): 382.1[M+H] ⁺ .

The sixth step: 4-(3-((4-chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidine

An aqueous solution (10 mL) of ethyl 4-(5-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.3 mmol), sodium hydroxide (520 mg, 13 mmol) at 90° C. Stirred for 10 hours, cooled, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4-(3-((4-chloro-2-fluorobenzene Methyl)oxo)-1H-pyrazol-1-yl)piperidine (310 mg, crude).

MS m/z(ESI): 310.1[M+H] ⁺ .

The seventh step: (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidin-1-yl) Methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

4-(3-((4-Chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidine and (S)-2-(chloromethyl)-1-( Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester is the raw material Reference Example 1 Tenth, eleventh step to obtain product (S)-2-((4- (3-((4-Chloro-2-fluorobenzyl)oxo)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-(oxetan-2-yl methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 23

(S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[1.1.1] Pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentyl-1-yl)carbamate

Methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (2 g, 8.2 mmol) was dissolved in tetrahydrofuran (30 mL), then lithium tetrahydroaluminum was added at 0°C (380mg, 10.0mmol), stirred for 2 hours under this condition, stopped the reaction, added NaOH (2M, 1.2mL) to quench the reaction, a solid was precipitated, filtered, the liquid phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentyl-1-yl)carbamate (1.6 g, 90% yield) was obtained.

MS m/z(ESI): 214.1[M+H] ⁺ .

The second step: (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methylmethanesulfonate

(3-Hydroxymethyl)bicyclo[1.1.1]pentyl-1-yl)carbamate tert-butyl ester (1.6g, 7.5mmol) was dissolved in dichloromethane (20mL), triethylamine (1.5g) was added at room temperature , 15 mmol) and methanesulfonyl chloride (860 mg, 7.5 mmol), and stirred at room temperature for 12 hours. The reaction was stopped, water was added to quench the reaction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1 - base) methyl methanesulfonate was directly used in the next reaction.

MS m/z(ESI): 292.1[M+H] ⁺ .

The third step: tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pent-1-yl)carbamate

(3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methylmethanesulfonate (1 g, 3.5 mmol) was dissolved in DMF (20 mL) and added at room temperature Potassium cyanide (230 mg, 3.5 mmol), stirred at 70 ° C for 12 hours, stopped the reaction, added water to quench the reaction, extracted with EA, washed with saturated sodium chloride three times, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The obtained tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pent-1-yl)carbamate was used directly in the next reaction.

MS m/z(ESI): 223.1[M+H] ⁺ .

The fourth step: 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid

(3-(Cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester (600 mg, 2.7 mmol) was dissolved in dichloromethane (20 mL), and diisobutyl hydrogenation was added at minus 78 °C Aluminum (1.1 g, 8.1 mmol) was stirred for 2 hours, the reaction was stopped, ammonium chloride solution was added to quench the reaction, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(3-(((tert- Butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid.

MS m/z(ESI): 242.1[M+H] ⁺ .

The fifth step: (S)-2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxabutane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

with 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid and (S)-4-amino-3-((oxetan-2 Methyl-ylmethyl)amino)benzoate as the raw material Reference Example 12 The first step to obtain the product (S)-2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane Alk-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 442.2[M+H] ⁺ .

The sixth step: (S)-2-((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene Methyl [d]imidazole-6-carboxylate

With (S)-2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxabutan-2-yl Methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester is the raw material Reference Example 1 The sixth step obtains the product (S)-2-((3-aminobicyclo[1.1.1]pentane- 1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 342.2[M+H] ⁺ .

Step 7: (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)amino)bicyclo[1.1.1] Pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

With (S)-2-((3-aminobicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylate methyl ester is the raw material Reference Example 12 The third step obtains the product (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo )pyridin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole- 6-Carboxylic acid methyl ester.

MS m/z(ESI): 568.2[M+H] ⁺ .

The eighth step: (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[ 1.1.1]Pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

(S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)amino)bicyclo[1.1.1]pentane-1 -yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (200 mg, 0.35 mmol) was dissolved in methanol (5 mL), Formaldehyde aqueous solution (1 g, 37% aqueous solution) and acetic acid (0.5 mL) were added at room temperature, and after stirring at room temperature for 2 hours, sodium cyanoborohydride (150 mg, 1.7 mmol) was added, and the reaction was continued for 2 hours. The reaction was stopped, and sodium carbonate aqueous solution was added. The reaction was quenched, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give (S)-2-((3-((6-((4-cyano- 2-Fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl)-1-(oxetan-2-yl) methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 582.2[M+H] ⁺ .

The ninth step: (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[ 1.1.1]Pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[1.1.1 ]Pentan-1-yl)methyl)-1-(oxabutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester is the raw material Reference Example 1 The eleventh step The product (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)(methyl)amino)bicyclo[1.1. 1]Pentan-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 568.2[M+H] ⁺ .

Example 24

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxo)thiazol-2-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-(((2-aminothiazol-4-yl)oxo)methyl)-3-fluorobenzonitrile

Using 2-amino-4-bromothiazole and 3-fluoro-4-(hydroxymethyl)benzonitrile as raw materials, the fourth step of reference example 1 obtains the product 4-(((2-aminothiazol-4-yl)oxo ) methyl)-3-fluorobenzonitrile.

MS m/z(ESI): 250.0[M+H] ⁺ .

The second step: 4-(((2-bromothiazol-4-yl)oxo)methyl)-3-fluorobenzonitrile

Using 4-(((2-aminothiazol-4-yl)oxo)methyl)-3-fluorobenzonitrile as raw material Reference Example 24 second step to obtain product 4-(((2-aminothiazole-4- yl)oxo)methyl)-3-fluorobenzonitrile.

MS m/z(ESI): 312.9[M+H] ⁺ .

The third step: 3-fluoro-4-(((2-(piperidin-4-yl)thiazol-4-yl)oxo)methyl)benzonitrile

Taking 4-(((2-aminothiazol-4-yl)oxo)methyl)-3-fluorobenzonitrile as raw material Reference Example 1 The first step, the second step and the sixth step obtain the product 3-fluoro- 4-(((2-(piperidin-4-yl)thiazol-4-yl)oxo)methyl)benzonitrile.

MS m/z(ESI): 318.1[M+H] ⁺ .

The fourth step: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxo)thiazol-2-yl)piperidin-1-yl)methyl) -1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

with 3-fluoro-4-(((2-(piperidin-4-yl)thiazol-4-yl)oxo)methyl)benzonitrile and methyl(S)-4-amino-3-(( Oxabutane-2-ylmethyl)amino)benzoate is the raw material and the product (S)-2-((4-(2-((4-cyano) is obtained from the tenth step of reference example 1 and the eleventh step of example 1 yl-2-fluorobenzyl)oxo)thiazol-4-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 562.2[M+H] ⁺ .

Example 25

1-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid

The first step: 1-(3-fluorophenyl)cyclopropane-1-carbonitrile

Dissolve 2-(3-fluorophenyl)acetonitrile (5 g, 37 mmol) in DMF (50 mL), add 60% NaH (5.9 g, 148 mmol) at 0 °C, stir at room temperature for 1 hour, cool to 0 °C, add 1 , 2-dibromoethane (34.6 g, 185 mmol), and the reaction was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography. to give 1-(3-fluorophenyl)cyclopropane-1-carbonitrile (4 g, 67%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.29 (m, 1H), 7.11-7.09 (m, 1H), 7.01-6.96 (m, 2H), 1.81-1.70 (m, 2H), 1.47-1.36 (m,2H).

The second step: methyl 1-(3-fluorophenyl) cyclopropane-1-carboxylate

1-(3-Fluorophenyl)cyclopropane-1-carbonitrile (3 g, 18.6 mmol) was dissolved in methanol (10 mL), concentrated sulfuric acid (2 mL) was added at 0°C, and the reaction was stirred at 60°C overnight. Cooled to room temperature, spin-dried, added to ice water (30 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, the crude product was passed through Purification by column chromatography gave methyl 1-(3-fluorophenyl)cyclopropane-1-carboxylate (3 g, 83%).

MS m/z(ESI): 195.2[M+H] ⁺ .

The third step: methyl 1-(3-fluoro-4-nitrophenyl) cyclopropane-1-carboxylate

Methyl 1-(3-fluorophenyl)cyclopropane-1-carboxylate (3 g, 15.4 mmol) was dissolved in concentrated sulfuric acid (20 mL), fuming nitric acid (4 mL) was added at 0 °C, and the reaction was carried out at 0 °C Stir for 1 hour. The reaction solution was poured into ice water (30 mL), stirred for half an hour, filtered, and the solid was collected and spin-dried. The crude product was purified by column chromatography to obtain methyl 1-(3-fluoro-4-nitrophenyl)cyclopropane -1-Carboxylic acid ester (1 g, 27%).

The fourth step: methyl (S)-1-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)cyclopropane-1-carboxylate

Taking methyl 1-(3-fluoro-4-nitrophenyl) cyclopropane-1-carboxylate as raw material, the seventh step of reference example 1 obtained the product methyl (S)-1-(4-nitro- 3-((oxbutan-2-ylmethyl)amino)phenyl)cyclopropane-1-carboxylate.

MS m/z(ESI): 307.2[M+H] ⁺ .

The fifth step: methyl (S)-1-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)cyclopropane-1-carboxylate

Reference Example 1 Eighth The product is methyl (S)-1-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)cyclopropane-1-carboxylate.

MS m/z(ESI): 277.2[M+H] ⁺ .

The sixth step: methyl (S)-1-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane -1-Carboxylic acid ester

Using methyl (S)-1-(4-amino-3-((oxbutan-2-ylmethyl)amino)phenyl)cyclopropane-1-carboxylate as raw material Reference Example 1 The ninth step The product methyl (S)-1-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1 was obtained - Carboxylic acid esters.

MS m/z(ESI): 335.2[M+H] ⁺ .

The seventh step: methyl 1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1 - Carboxylate

With methyl (S)-1-(2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1- Carboxylate is the raw material Reference Example 1 The tenth step obtains the product methyl 1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d] Imidazol-6-yl)cyclopropane-1-carboxylate.

MS m/z(ESI): 646.2[M+H] ⁺ .

Step 8: 1-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxy acid

with methyl 1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)cyclopropane-1-carboxylic acid Ester as raw material Reference Example 1 The eleventh step obtains the product 1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6 - base) cyclopropane-1-carboxylic acid.

MS m/z(ESI): 632.2[M+H] ⁺ .

Example 26

2-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-methylpropionic acid

The first step: 2-(3-fluorophenyl)-2-methylpropionitrile

Dissolve 2-(3-fluorophenyl)acetonitrile (5 g, 37 mmol) in DMF (50 mL), add 60% NaH (5.9 g, 148 mmol) at 0 °C, stir at room temperature for 1 hour, cool to 0 °C, add iodine Methane (15.8 g, 110 mmol) and the reaction was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography. to give 2-(3-fluorophenyl)-2-methylpropionitrile (3 g, 48%).

MS m/z(ESI): 164.2[M+H] ⁺ .

The second step: methyl 2-(3-fluorophenyl)-2-methyl propionate

2-(3-Fluorophenyl)-2-methylpropionitrile (3 g, 18.4 mmol) was dissolved in methanol (10 mL), concentrated sulfuric acid (2 mL) was added at 0°C, and the reaction was stirred at 60°C overnight. Cooled to room temperature, spin-dried, added to ice water (30 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, the crude product was passed through Purification by column chromatography gave methyl 2-(3-fluorophenyl)-2-methylpropionate (3.2 g, 89%).

MS m/z(ESI): 197.2[M+H] ⁺ .

The third step: methyl 2-(3-fluoro-4-nitrophenyl)-2-methyl propionate

Methyl 2-(3-fluorophenyl)-2-methylpropionate (3.2 g, 16.3 mmol) was dissolved in concentrated sulfuric acid (20 mL), fuming nitric acid (4 mL) was added at 0 °C, and the reaction was carried out at 0 °C under stirring for 1 hour. The reaction solution was poured into ice water (30 mL), stirred for half an hour, filtered, and the solid was collected and spin-dried. The crude product was purified by column chromatography to obtain methyl 2-(3-fluoro-4-nitrophenyl)-2 - Methylpropionate (0.8 g, 20%).

The fourth step: methyl (S)-2-methyl-2-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)propionate

Taking methyl 2-(3-fluoro-4-nitrophenyl)-2-methyl propionate as raw material, the seventh step of reference example 1 obtained the product methyl (S)-2-methyl-2-( 4-Nitro-3-((oxbutan-2-ylmethyl)amino)phenyl)propanoate.

MS m/z(ESI): 309.2[M+H] ⁺ .

The fifth step: methyl (S)-2-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)-2-methylpropionate

Reference Example 1 Eighth The product is methyl (S)-2-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)-2-methylpropionate.

MS m/z(ESI): 279.2[M+H] ⁺ .

The sixth step: methyl (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-2 - Methylpropionate

Taking methyl (S)-2-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)-2-methyl propionate as raw material Reference Example 1 The ninth step The product methyl (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-2-methyl was obtained propionate.

MS m/z(ESI): 337.2[M+H] ⁺ .

The seventh step: methyl 2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-methyl propionate

With methyl (S)-2-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-2-methyl Propionate is the raw material Reference Example 1 The tenth step obtains the product methyl 2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d] imidazol-6-yl)-2-methylpropionate.

MS m/z(ESI): 648.2[M+H] ⁺ .

Step 8: 2-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-methylpropane acid

with methyl 2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-methylpropionic acid Ester is the raw material Reference Example 1 The eleventh step obtains the product 2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6 -yl)-2-methylpropionic acid.

MS m/z(ESI): 634.2[M+H] ⁺ .

Example 27

3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)propynoic acid

The first step: methyl 3-(3-fluoro-4-nitrophenyl) propiolate

4-Bromo-2-fluoro-1-nitrobenzene (1 g, 4.5 mmol), methyl propiolate (0.42 g, 5.0 mmol), PdCl ₂ (PPh ₃ ) ₂ (0.32 g, 0.45 mmol), CuI (0.26 g, 1.35 mmol), K ₂ CO ₃ (1.9 g, 13.5 mmol) was dissolved in DMF (30 mL), nitrogen was replaced, the reaction was stirred at 80° C. for 5 hours, cooled to room temperature, water (100 mL) was added, and ethyl acetate was added. Ester (30 mL x 2) was extracted, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain methyl 3-(3-fluoro-4). -Nitrophenyl)propiolate (0.6 g, 59%).

MS m/z(ESI): 224.2[M+H] ⁺ .

Step 2: Methyl (S)-3-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)propiolate

Taking methyl 3-(3-fluoro-4-nitrophenyl) propiolate as raw material, the seventh step of reference example 1 obtains the product methyl (S)-3-(4-nitro-3-(( Oxetan-2-ylmethyl)amino)phenyl)propiolate.

MS m/z(ESI): 291.2[M+H] ⁺ .

The third step: methyl (S)-3-(4-amino-3-((oxbutan-2-ylmethyl)amino)phenyl)propiolate

Methyl (S)-3-(4-nitro-3-((oxbutan-2-ylmethyl)amino)phenyl)propiolate (0.3 g, 1.0 mmol) was dissolved in ethanol (20 mL) ), saturated sodium bicarbonate solution (10 mL) and iron powder (0.58 g, 10 mmol) were added, and the reaction was stirred at 80° C. for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was extracted with dichloromethane (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain methyl (S)-3-(4-amino-3- ((oxbutan-2-ylmethyl)amino)phenyl)propiolate (0.2 g, yield: 74%).

MS m/z(ESI): 261.2[M+H] ⁺ .

The fourth step: methyl (S)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)propyne acid ester

Taking methyl (S)-3-(4-amino-3-((oxbutan-2-ylmethyl)amino)phenyl)propiolate as raw material Reference Example 1 The ninth step obtains the product methyl (S)-3-(2-(Chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)propynoate.

MS m/z(ESI): 319.2[M+H] ⁺ .

The fifth step: methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)propynoate

Take methyl (S)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)propiolate as The tenth step of raw material reference example 1 obtains the product methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6- base) propiolate.

MS m/z(ESI): 630.2[M+H] ⁺ .

Step 6: 3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)propynoic acid

with methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Iridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)propiolate as raw material reference Example 1 The eleventh step obtains the product 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)propane acetylenic acid.

MS m/z(ESI): 616.2[M+H] ⁺ .

Example 28

3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-5-yl)propynoic acid

The first step: (S)-5-bromo-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde

5-Bromo-1H-imidazole-2-carbaldehyde (2g, 11.5mmol), (S)-oxbutan-2-ylmethylmethanesulfonate (2.1g, 12.64mmol), cesium carbonate (7.47g, 23 mmol) and N,N-dimethylformamide (30 mL) were stirred at 100 degrees Celsius for 12 hours, cooled, added with water (50 mL), extracted with dichloromethane (50 mL×3), and the organic phases were combined with saturated sodium chloride. The solution (50 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain (S)-5-bromo-1-(oxetan-2-ylmethyl)-1H- Imidazole-2-carbaldehyde (1.8 g, yield: 64%).

MS m/z(ESI): 245[M+H] ⁺ .

Step 2: 1-((5-Bromo-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-(2-( 4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)piperidine

4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine (400 mg, 1.15 mmol), ( S)-5-bromo-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (337 mg, 1.38 mmol), sodium cyanoborohydride (290 mg, 4.6 mmol) and methanol (10 mL) ) mixture was stirred at room temperature for 12 hours, water (50 mL) was added, extracted with dichloromethane (50 mL×3), the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography , to give 1-((5-bromo-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-(2 -(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine (450 mg, yield: 68%).

MS m/z(ESI): 576.1[M+H] ⁺ .

The third step: methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-5-yl)propynoate

1-((5-Bromo-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-(2-(4-chloro) -2-Fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine (300 mg, 0.52 mmol), methyl propiolate (131 mg, 1.56 mmol) , cuprous iodide (10 mg, 0.052 mmol), bistriphenylphosphonium palladium dichloride (36 mg, 0.052 mmol), triethylamine (262 mg, 2.6 mmol) and N,N-dimethylformamide (10 mL) The mixture was stirred at 100 degrees Celsius for 12 hours, cooled, added with water (50 mL), extracted with dichloromethane (50 mL×3), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , and separated by column chromatography to obtain methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-5-yl)propyne acid ester (240 mg, yield: 80%).

MS m/z(ESI): 580.2[M+H] ⁺ .

The fourth step: 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propynoic acid

with methyl 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-5-yl)propynoate as raw material Reference Example 1 Eleventh Step obtained product 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine pyridin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-imidazol-5-yl)propynoic acid.

MS m/z(ESI): 566.2[M+H] ⁺ .

Example 29

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)sphaeric acid

With 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propynoic acid is the raw material Reference Example 1 The second step obtains the product ( E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)septoic acid.

MS m/z(ESI): 568.2[M+H] ⁺ .

Example 30

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydro Pyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-chloro-2-fluorophenyl)prop-2-yn-1-ol

4-Chloro-2-fluorobenzene(formaldehyde) (1.0 g, 6.3 mmol) was dissolved in 20 mL of THF, ethynylmagnesium bromide (14 mL, 7 mmol) was added at -78 °C, and the mixture was stirred at -78 °C to room temperature for 2 h. Ammonium chloride was added to quench the reaction, extracted with ethyl acetate (100 mL), and washed with saturated brine (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(4-chloro-2-fluorophenyl)prop-2-yn-1-ol (1.04 g, 90%).

MS m/z(ESI): 185.0[M+H] ⁺ .

Step 2: 1-(4-Chloro-2-fluorophenyl)prop-2-yn-1-one

1-(4-Chloro-2-fluorophenyl)prop-2-yn-1-ol (1.0 g, 5.4 mmol) was dissolved in 10 mL of DMSO, and 2-iodoylbenzoic acid (2.28 g, 8.1 mmol) was added , and stirred at room temperature for 5h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(4-chloro-2-fluorophenyl)prop-2-yn-1-one (840 mg, 85%).

MS m/z(ESI): 183.0[M+H] ⁺ .

Step 3: 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]bisoxazole

Using 1-(4-chloro-2-fluorophenyl)prop-2-yn-1-one as raw material, the second step of reference example 7 obtains the product 4-bromo-2-(4-chloro-2-fluorophenyl) )-2-ethynylbenzo[d][1,3]dioxazole.

MS m/z(ESI): 352.9[M+H] ⁺ .

The fourth step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]dioxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-bromo-2-(4-chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]dioxazole as raw material Reference Example 7 The first step, the third step, The fourth and fifth steps obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]dioxazole-4- yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid.

MS m/z(ESI): 600.1[M+H] ⁺ .

Example 31

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2,3-dihydroxyphenyl) piperidine-1-carboxylate

Dissolve tert-butyl 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 3.4 mmol) in 20 mL of methanol, add Pd/ C (100 mg, ) was stirred at room temperature under hydrogen atmosphere for 12 h. Filter and spin dry. The crude product was isolated by column chromatography to give tert-butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate (950 mg,).

MS m/z(ESI): 294.1[M+H] ⁺ .

Step 2: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-ethynylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using tert-butyl 4-(2,3-dihydroxyphenyl) piperidine-1-carboxylate as raw material, reference example 30 to obtain the product 2-((4-(2-(4-chloro-2-fluoro) Phenyl)-2-ethynylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 602.1[M+H] ⁺ .

Example 32

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-cyanobenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydro Pyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-chloro-2-fluorobenzoyl cyanation

4-Chloro-2-fluorobenzoyl chloride (1.0 g, 5.2 mmol) was dissolved in 20 mL of acetonitrile, cuprous cyanide (932 mg, 10.3 mmol) was added, and the mixture was stirred under reflux for 2 h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 4-chloro-2-fluorobenzoyl cyanide (400 mg,).

MS m/z(ESI): 184.0[M+H] ⁺ .

The second step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-cyanobenzo[d][1,3]bisoxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-chloro-2-fluorobenzoyl cyanation as raw material Reference Example 30 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-cyanobenzo[d ][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl) methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 601.1[M+H] ⁺ .

Example 33

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-cyanobenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-chloro-2-fluorobenzoyl cyanation as raw material Reference Example 31 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-cyanobenzo[d ][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 603.1[M+H] ⁺ .

Example 34

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2',3':4,5]benzo[1,2-d]imidazole- 6-Carboxylic acid

The first step: (2,5-difluoro-4-nitrophenyl)methanol

Under ice bath, 2,5-difluoro-4-nitrobenzoic acid (2.03 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), nitrogen was replaced, and then borane tetrahydrofuran solution (1.0 M, 20 mL) was added dropwise, The mixture was stirred under ice bath for 1 hour, then heated to 60°C and reacted overnight. Cooled to room temperature, the reaction solution was quenched with methanol, the reaction solution was diluted with ethyl acetate (50 mL), then washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. (2,5-Difluoro-4-nitrophenyl)methanol (1.10 g, 58%) was obtained.

MS m/z(ESI): 190.1[M+H] ⁺ .

Step 2: 2,5-Difluoro-4-nitrobenzaldehyde

Under ice bath, (2,5-difluoro-4-nitrophenyl)methanol (1.10 g, 5.82 mmol) was dissolved in dichloromethane (20 mL), then Dess-Martin oxidant (4.94 g, 11.64 mmol) was added ) and stirred at room temperature for three hours. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution, washed with saturated brine, and the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain 2,5-difluoro-4-nitrobenzaldehyde (0.87g, 80%).

MS m/z(ESI): 188.1[M+H] ⁺ .

The third step: methyl 5-fluoro-6-nitrobenzo[b]thiophene-2-carboxylate

Under nitrogen, 2,5-difluoro-4-nitrobenzaldehyde (0.87 g, 4.66 mmol) was dissolved in N,N-dimethylformamide (15 mL) followed by potassium carbonate (1.29 g, 9.32 mmol) , heated to 60°C and stirred for one hour. Then methyl 2-mercaptoacetate (0.50 g, 4.66 mmol) was added dropwise at 60°C, and the reaction was performed overnight. Cooled to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give methyl 5-fluoro-6nitrobenzo[b]thiophene-2-carboxylate (0.59 g, 50%).

MS m/z(ESI): 256.1[M+H] ⁺ .

The fourth step: methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2',3':4,5]benzo[ 1,2-d]imidazole-6-carboxylate

Using methyl 5-fluoro-6 nitrobenzo[b]thiophene-2-carboxylate as raw material, refer to steps 7, 8, and 9 of Example 1 to obtain methyl (S)-2-(chloromethyl) -1-(oxbutan-2-ylmethyl)-1H-thieno[2',3':4,5]benzo[1,2-d]imidazole-6-carboxylate

MS m/z(ESI): 351.1, 353.1 [M+H] ⁺ .

The fifth step: methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2',3':4,5]benzo[1, 2-d]imidazole-6-carboxylate

With methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2',3':4,5]benzo[1,2 -d]imidazole-6-carboxylate and 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidine is used as raw material, and the tenth step of reference example 1 obtains methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2',3': 4,5]Benzo[1,2-d]imidazole-6-carboxylate

MS m/z(ESI): 662.2, 664.2 [M+H] ⁺ .

Step 6: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2',3':4,5]benzo[1,2- d]Imidazole-6-carboxylic acid

With methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2',3':4,5]benzo[1,2-d ] Imidazole-6-carboxylate as raw material, the eleventh step of reference example 1 obtains 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] [1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2 ',3':4,5]benzo[1,2-d]imidazole-6-carboxylic acid.

MS m/z(ESI): 648.2, 650.2 [M+H] ⁺ .

Example 35

(S)-2-((4-(2-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin-6- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-bromo-6-(1-(4-chloro-2-fluorophenyl)-4-hydroxybutoxy)phenol

2-(4-Chloro-2-fluorophenyl)oxetane (1 g, 5.3 mmol) was dissolved in THF (15 mL), then 4-bromobenzo[d][1,3,2]dioxaborone was added Azol-2-ol (1.1 g, 5.3 mmol), stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 2-bromo-6-(1-(4-chloro-2-fluorophenyl)-4-hydroxybutoxy)phenol (300 mg).

MS m/z(ESI): 389.0[M+H] ⁺ .

Step 2: 6-Bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin

2-Bromo-6-(1-(4-chloro-2-fluorophenyl)-4-hydroxybutoxy)phenol (200 mg, 0.5 mmol) was dissolved in THF (15 mL) and triphenylphosphine ( 202 mg, 0.77 mmol) and diethyl azodicarboxylate (134 mg, 0.77 mmol), stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 6-bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin ( 100 mg).

MS m/z(ESI): 356.9[M+H] ⁺ .

The third step: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin Hept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 6-bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin as raw material Reference Example 1 obtained the product ( S)-2-((4-(2-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxen-6-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 36

(S)-2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]di Oxahept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-(4-chloro-2-fluorophenyl)-2-methyloxetane as raw material Reference Example 35 to obtain the product (S)-2-((4-(2-(4-chloro-2-fluoro) Phenyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxhept-6-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 620.2[M+H] ⁺ .

Example 37

(S)-2-((4-(4-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin-6- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Reference Example 35 to obtain the product (S)-2-((4-(4-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]di Oxahept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 38

(S)-2-((4-(4-(4-Chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]di Oxahept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Reference Example 36 to obtain the product (S)-2-((4-(4-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][ 1,4]Dioxhept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid .

MS m/z(ESI): 620.2[M+H] ⁺ .

Example 39

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxan-6-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 6-bromo-3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxin

Using (3-bromo-1,2-phenylene) dimethanol and 1-(4-chloro-2-fluorophenyl) ethane-1-one as raw materials Reference Example 7 The second step obtained the product 6-bromo- 3-(4-Chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxin.

MS m/z(ESI): 370.9[M+H] ⁺ .

Step 2: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane- 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

6-Bromo-3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxin and 4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester is the raw material Reference Example 1 The first step is to obtain the product tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane -6-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

MS m/z(ESI): 474.2[M+H] ⁺ .

The third step: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane- 6-yl)piperidine-1-carboxylate

With tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxan-6-yl )-3,6-dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 1 The second step obtains the product tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3 -Methyl-1,5-dihydrobenzo[e][1,3]dioxhept-6-yl)piperidine-1-carboxylate.

MS m/z(ESI): 476.2[M+H] ⁺ .

Step 4: 4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxhept-6-yl) piperidine

With tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxan-6-yl ) piperidine-1-carboxylate is the raw material Reference Example 1 the sixth step obtains the product 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[ e][1,3]Dioxhept-6-yl)piperidine.

MS m/z(ESI): 376.2[M+H] ⁺ .

The fifth step: methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxin Hept-6-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ester

with 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxan-6-yl)piperidine and (S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester is the raw material Reference Example 1 The tenth step The product methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane- 6-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 634.2[M+H] ⁺ .

Step 6: 2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane- 6-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3]dioxane-6 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material In the eleventh step of reference example 1, the product 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-1,5-dihydrobenzo[e][1,3 ]Dioxhept-6-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid.

MS m/z(ESI): 620.2[M+H] ⁺ .

Example 40

2-((((E)-3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)allyl yl)(methyl)amino)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl(E)-(3-(2,3-dihydroxyphenyl)allyl)(methyl)carbamate

3-Bromobenzene-1,2-diol (1 g, 5.3 mmol), tert-butylallyl(methyl)carbamate (1 g, 5.9 mmol), PPh ₃ (81 mg, 0.5 mmol), Pd(OAc) ₂ (112 mg, 0.5 mmol), K ₂ CO ₃ (1.5 g, 10.6 mmol) were dissolved in DMF (30 mL) and water (15 mL), nitrogen was replaced, the reaction was stirred at 120° C. for 18 hours, cooled to room temperature, Water (100 mL) was added, extracted with ethyl acetate (30 mL x 2), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain tertiary -Butyl(E)-(3-(2,3-dihydroxyphenyl)allyl)(methyl)carbamate (0.5 g, 34%).

MS m/z(ESI): 280.2[M+H] ⁺ .

The second step: tert-butyl (E)-(3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)allyl)(methyl)carbamate

Using tert-butyl (E)-(3-(2,3-dihydroxyphenyl) allyl) (methyl) carbamate as raw material Reference Example 7 second step to obtain product tert-butyl (E )-(3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)allyl)(methyl) carbamate.

MS m/z(ESI): 434.2[M+H] ⁺ .

The third step: (E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-N- Methylprop-2-en-1-amine

tert-butyl(E)-(3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)ene Propyl) (methyl) carbamate is raw material Reference Example 1 the sixth step obtains product (E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d ][1,3]Dioxazol-4-yl)-N-methylprop-2-en-1-amine.

MS m/z(ESI): 334.2[M+H] ⁺ .

The fourth step: methyl 2-((((E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)allyl)(methyl)amino)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid ester

With (E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-N-methylpropane -2-en-1-amine as raw material Reference Example 1 The tenth step to obtain the product methyl 2-((((E)-3-(2-(4-chloro-2-fluorophenyl)-2-methyl Benzo[d][1,3]bisoxazol-4-yl)allyl)(methyl)amino)methyl)-1-(((S)-oxbutan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 592.1[M+H] ⁺ .

The fifth step: 2-((((E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)allyl)(methyl)amino)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((((E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )allyl)(methyl)amino)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate is The eleventh step of raw material reference example 1 obtains the product 2-((((E)-3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)allyl)(methyl)amino)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid.

MS m/z(ESI): 578.1[M+H] ⁺ .

Example 41

(S,E)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methylene)pyrrolidin-1-yl) Methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 3-fluoro-4-(((6-methylpyridin-2-yl)oxo)methyl)benzonitrile

2-Fluoro-4-cyanobenzyl alcohol (1.51 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were dissolved in 1-methylpyrrolidin-2-one (20 mL) at room temperature, followed by the addition of 2-fluoro -6-methylpyridine (1.11 g, 10 mmol), heated to 100°C, and reacted for 4 hours. Cooled to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 3-fluoro-4-(((6-methylpyridin-2-yl)oxo)methyl)benzonitrile (1.94 g, 80%).

MS m/z(ESI): 243.1[M+H] ⁺ .

The second step: 4-(((6-(bromomethyl)pyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile

3-Fluoro-4-(((6-methylpyridin-2-yl)oxo)methyl)benzonitrile (1.94 g, 8 mmol) was dissolved in carbon tetrachloride (20 mL) at room temperature, then added Benzoyl peroxide (0.19 g, 0.8 mmol) and N-bromosuccinimide (1.42 g, 8 mmol) were heated to reflux for one hour. Cooled to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 4-(((6-(bromomethyl)pyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile (1.28 g, 50%).

MS m/z(ESI): 321.1, 323.1 [M+H] ⁺ .

The third step: ((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methyl)triphenylphosphonium bromide

4-(((6-(Bromomethyl)pyridin-2-yl)oxo)methyl)-3-fluorobenzonitrile (1.28 g, 4 mmol) was dissolved in toluene (15 mL) at room temperature, then added Triphenylphosphorus (1.15 g, 4.4 mmol) was heated to reflux for three hours. Cool to room temperature and spin to dry to obtain ((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methyl)triphenylphosphonium bromide. The crude product is directly used for in the next step (2.40 g).

MS m/z(ESI): 504.2[M+H] ⁺ .

The fourth step: tert-butyl (E)-3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methylene)pyrrolidine-1- Carboxylate

Under an ice bath, ((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methyl)triphenylphosphonium bromide (2.40 g) was dissolved in anhydrous tetrahydrofuran. (15mL), replace nitrogen, then add sodium hydrogen (60%, 0.32g, 8mmol), stir under ice bath for 30 minutes, then add tert-butyl 3-carbonylpyrrolidine-1-carboxylate (1.11g, 6mmol) , and stirred at room temperature for one hour. The reaction solution was quenched with saturated ammonium chloride solution (15 mL), the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give tert-butyl(E)-3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methylene)pyrrole Alkane-1-carboxylate (0.82 g, 50%).

MS m/z(ESI): 410.2[M+H] ⁺ .

Step 5: (S,E)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methylene)pyrrolidine- 1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Take tert-butyl(E)-3-((6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)methylene)pyrrolidine-1-carboxylate as Raw material, reference Example 1 sixth step, tenth step, eleventh step to obtain (S, E)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxygen substituted)pyridin-2-yl)methylene)pyrrolidin-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid .

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 42

2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydro Pyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 292.1[M+H] ⁺ .

Step 2: 4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydro Pyridine-1(2H)-carboxylate tert-butyl ester

In a 50 mL reaction flask, 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (3 g, 10.3 mmol), 5-acetylthiophene -2-carbonitrile (1.56 g, 10.3 mmol) and p-toluenesulfonic acid (0.1 g) were dissolved in toluene (30 mL), and the reaction solution was condensed and refluxed in a water separator at 110° C. and stirred for 6 hours. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain 4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (2.6 g, 59%).

MS m/z(ESI): 425.1[M+H] ⁺ .

The third step: 5-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3]dioxazol-2-yl)thiophene -2-carbonitrile

4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-dihydropyridine-1 (2H)-tert-butyl carboxylate as raw material Reference Example 1 The sixth step obtained the product 5-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d ][1,3]Dioxazol-2-yl)thiophene-2-carbonitrile.

MS m/z(ESI): 325.1[M+H] ⁺ .

The fourth step: 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

5-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3]dioxazol-2-yl)thiophene-2- Formonitrile is the raw material Reference Example 1 The tenth step obtains the product 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazole -4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate.

MS m/z(ESI): 583.1[M+H] ⁺ .

The fifth step: 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-di Hydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Reference Example 1 as the raw material in the eleventh step to obtain the product 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d ] Imidazole-6-carboxylic acid.

MS m/z(ESI): 569.1[M+H] ⁺ .

Example 43

2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]bisoxazol-2-yl)thiophene-2-carbonitrile

5-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3]dioxazol-2-yl)thiophene-2- Formonitrile is the raw material Reference Example 1 The second step obtains the product 5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]bisoxazol-2-yl)thiophene- 2-carbonitrile.

MS m/z(ESI): 327.1[M+H] ⁺ .

Step 2: 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

Using 5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]bisoxazol-2-yl)thiophene-2-carbonitrile as raw material The product is 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester.

MS m/z(ESI): 585.2[M+H] ⁺ .

Step 3: 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl ) methyl)-1-((((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester as raw material Reference Example 1 The eleventh step obtained Product 2-((4-(2-(5-cyanothiophen-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 571.1[M+H] ⁺ .

Example 44

2-((4-(6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 6-Acetyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate tert-butyl ester

With 1-(6-bromopyridin-2-yl)ethan-1-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl )-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester is the raw material Reference Example 1 The first step obtains the product 6-acetyl-3',6'-dihydro-[2,4' - Bipyridyl]-1'(2'H)-carboxylate tert-butyl ester.

MS m/z(ESI): 303.1[M+H] ⁺ .

Step 2: 6-(5-Chloro-2-methylbenzo[d][1,3]bisoxazol-2-yl)-3',6'-dihydro-[2,4'-bi Pyridine]-1'(2'H)-carboxylate tert-butyl ester

With 6-acetyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate tert-butyl ester and 4-chlorobenzene-1,2-di Alcohol is the raw material Reference Example 42 The second step obtains the product 6-(5-chloro-2-methylbenzo[d][1,3]bisoxazol-2-yl)-3',6'-dihydro- [2,4'-Bipyridine]-1'(2'H)-carboxylate tert-butyl ester.

MS m/z(ESI): 429.1[M+H] ⁺ .

The third step: 6-(5-chloro-2-methylbenzo[d][1,3]bisoxazol-2-yl)-1',2',3',6'-tetrahydro-2 ,4'-bipyridine

6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)-3',6'-dihydro-[2,4'-bipyridine]- 1'(2'H)-carboxylic acid tert-butyl ester is the raw material Reference Example 1 The sixth step obtains the product 6-(5-chloro-2-methylbenzo[d][1,3]dioxazole-2 - base)-1',2',3',6'-tetrahydro-2,4'-bipyridine.

MS m/z(ESI): 329.1[M+H] ⁺ .

Step 4: 2-(5-Chloro-2-methylbenzo[d][1,3]bisoxazol-2-yl)-6-(piperidin-4-yl)pyridine

6-(5-Chloro-2-methylbenzo[d][1,3]bisoxazol-2-yl)-1',2',3',6'-tetrahydro-2,4' - Bipyridine is the raw material Reference Example 1 The second step obtains the product 2-(5-chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)-6-(piperidine-4 - base) pyridine.

MS m/z(ESI): 331.1[M+H] ⁺ .

Step 5: 2-((4-(6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Using 2-(5-chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)-6-(piperidin-4-yl)pyridine as raw material Reference Example 1 The tenth step The product 2-((4-(6-(5-chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidin-1-yl was obtained )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 589.2[M+H] ⁺ .

Step 6: 2-((4-(6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidin-1-yl) Methyl)-1-((((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester as raw material Reference Example 1 The eleventh step was obtained Product 2-((4-(6-(5-Chloro-2-methylbenzo[d][1,3]dioxazol-2-yl)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 575.2[M+H] ⁺ .

Example 45

2-((4-(3-(5-Cyano-2-methylbenzo[d][1,3]dioxazol-2-yl)phenyl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-(3-acetylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester

With 1-(3-bromophenyl)ethan-1-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 , 6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester is the raw material Reference Example 1 The first step obtains the product 4-(3-acetylphenyl)-3,6-dihydropyridine-1(2H )-tert-butyl carboxylate.

MS m/z(ESI): 302.1[M+H] ⁺ .

Step 2: 4-(3-(5-cyano-2-methylbenzo[d][1,3]bisoxazol-2-yl)phenyl)-3,6-dihydropyridine-1 (2H)-tert-butyl carboxylate

Using 4-(3-acetylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 3,4-dihydroxybenzonitrile as raw materials, the second step of Reference Example 38 was obtained Product 4-(3-(5-Cyano-2-methylbenzo[d][1,3]dioxazol-2-yl)phenyl)-3,6-dihydropyridine-1(2H) - tert-butyl carboxylate.

MS m/z(ESI): 419.1[M+H] ⁺ .

The third step: 2-((4-(3-(5-cyano-2-methylbenzo[d][1,3]dioxazol-2-yl)phenyl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

4-(3-(5-cyano-2-methylbenzo[d][1,3]dioxazol-2-yl)phenyl)-3,6-dihydropyridine-1(2H) - tert-butyl carboxylate is the raw material Reference Example 44 The third to sixth steps obtain the product 2-((4-(3-(5-cyano-2-methylbenzo[d][1,3]dioxin azol-2-yl)phenyl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6 -carboxylic acid.

MS m/z(ESI): 565.2[M+H] ⁺ .

Example 46

2-((4-(2-((4-Chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-(4-chloro-2-fluorophenyl) but-3-yn-2-ol

Using 4-chloro-2-fluoro-1-iodobenzene and but-3-yn-2-ol as raw materials, the third step of reference example 28 obtained the product 4-(4-chloro-2-fluorophenyl) butan-3- Alkyn-2-ol.

MS m/z(ESI): 199.1[M+H] ⁺ .

The second step: 4-(4-chloro-2-fluorophenyl) but-3-yn-2-one

A mixture of 4-(4-chloro-2-fluorophenyl)but-3-yn-2-ol (600 mg, 3.0 mmol), manganese dioxide (522 mg, 6.0 mmol) and dichloromethane (10 mL) was added at room temperature Stir for 2 hours, filter, concentrate, and separate by column chromatography to give 4-(4-chloro-2-fluorophenyl)but-3-yn-2-one (400mg)

MS m/z(ESI): 197.0[M+H] ⁺ .

The third step: tert-butyl 4-(2-((4-chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-3,6-dihydropyridine-1(2H)-carboxylate

4-(4-Chloro-2-fluorophenyl)but-3-yn-2-one and tert-butyl 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1 (2H)-carboxylate as raw material Reference Example 7 The second step of the product was tert-butyl 4-(2-((4-chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d ][1,3]Dioxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

MS m/z(ESI): 470.2[M+H] ⁺ .

Step 4: 2-((4-(2-((4-Chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid

With tert-butyl 4-(2-((4-chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3 , 6-dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 7, the third, fourth and fifth steps obtain the product 2-((4-(2-((4-chloro-2-fluorophenyl)ethynyl) )-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-((((S )-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 614.2[M+H] ⁺ .

Example 47

2-((4-(2-((4-Chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using tert-butyl 4-(2,3-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate as raw material Reference Example 46 to obtain the product 2-((4-(2- ((4-Chloro-2-fluorophenyl)ethynyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1 -(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 616.2[M+H] ⁺ .

Example 48

(S)-2-((4-(2-(4-Chloro-2-fluorobenzyl)benzo[d]oxazol-4-yl)piperidin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(4-chloro-2-fluorophenyl)-N-(2,6-dibromophenyl)acetamide

At room temperature, 2-fluoro-4-chlorophenylacetic acid (1.88 g, 10 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of 2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate (4.56g, 12mmol) and N,N-diisopropylethylamine (2.58g, 20mmol), stirred at room temperature for 10 minutes, then added 2,6-Dibromoaniline (3.0 g, 12 mmol) was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 2-(4-chloro-2-fluorophenyl)-N-(2,6-dibromophenyl)acetamide (3.37 g, 80%).

MS m/z(ESI): 419.9, 421.9, 423.9[M+H] ⁺ .

Step 2: 4-Bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]oxazole

2-(4-Chloro-2-fluorophenyl)-N-(2,6-dibromophenyl)acetamide (1.68 g, 4 mmol) was dissolved in toluene (10 mL) at room temperature, followed by the addition of cesium carbonate ( 2.60g, 8mmol), 1,10-o-phenanthroline (0.08g, 0.4mmol) and cuprous iodide (0.04g, 0.2mmol), replace nitrogen, add reflux, and react overnight. Cool to room temperature, spin dry, the residue is dissolved in ethyl acetate (50 mL), washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 4-bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]oxazole (0.68 g, 50%)

MS m/z(ESI): 339.9,341.9[M+H] ⁺ .

The third step: (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)benzo[d]oxazol-4-yl)piperidin-1-yl)methyl )-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]oxazole as raw material, the first step, the second step, the sixth step, the tenth step, the reference example 1 Eleven steps to give (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)benzo[d]oxazol-4-yl)piperidin-1-yl)methan yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 589.2,591.2[M+H] ⁺ .

Example 49

(S)-2-((4-(2-(4-Chloro-2-fluorobenzyl)-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: N-(2-bromo-6-nitrophenyl)-2-(4-chloro-2-fluorophenyl)acetamide

At room temperature, 2-fluoro-4-chlorophenylacetic acid (1.88 g, 10 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of 2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate (4.56g, 12mmol) and N,N-diisopropylethylamine (2.58g, 20mmol), stirred at room temperature for 10 minutes, then added 2-Bromo-6-nitroaniline (2.60 g, 12 mmol) was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give N-(2-bromo-6-nitrophenyl)-2-(4-chloro-2-fluorophenyl)acetamide (3.10 g, 80%).

MS m/z(ESI): 386.9,388.9[M+H] ⁺ .

The second step: N-(2-amino-6-bromophenyl)-2-(4-chloro-2-fluorophenyl)acetamide

N-(2-Bromo-6-nitrophenyl)-2-(4-chloro-2-fluorophenyl)acetamide (3.10 g, 8 mmol) was dissolved in ethanol (40 mL) at room temperature, followed by the addition of iron powder (2.24 g, 40 mmol) and saturated aqueous ammonium chloride solution (20 mL), and refluxed for 2 hours. Cooled to room temperature, filtered through celite and washed with ethyl acetate. The organic phase was spin-dried, the residue was dissolved in ethyl acetate (50 mL), washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was isolated by column chromatography to give N-(2-amino-6-bromophenyl)-2-(4-chloro-2-fluorophenyl)acetamide (2.29 g, 80%).

MS m/z(ESI): 356.9,358.9[M+H] ⁺ .

The third step: 4-bromo-2-(4-chloro-2-fluorobenzyl)-1H-benzo[d]imidazole

At room temperature, N-(2-amino-6-bromophenyl)-2-(4-chloro-2-fluorophenyl)acetamide (2.29 g, 6.4 mmol) was dissolved in acetic acid (20 mL) and heated to reflux for 5 Hour. Cool to room temperature, spin to dry, the residue is dissolved in ethyl acetate (50 mL), the organic phase is washed with saturated sodium bicarbonate solution and saturated brine successively, the organic phase is dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was isolated by column chromatography to give 4-bromo-2-(4-chloro-2-fluorobenzyl)-1H-benzo[d]imidazole (1.74 g, 80%)

MS m/z(ESI): 338.9,340.9[M+H] ⁺ .

The fourth step: (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)-1H-benzo[d]imidazol-4-yl)piperidin-1-yl) Methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-bromo-2-(4-chloro-2-fluorobenzyl)-1H-benzo[d]imidazole as raw material, the first step, the second step, the sixth step and the tenth step in Reference Example 1 , the eleventh step to obtain (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)-1H-benzo[d]imidazol-4-yl)piperidine-1 -yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 588.2,590.2[M+H] ⁺ .

Example 50

(S)-2-((4-(2-(4-Chloro-2-fluorobenzyl)benzo[d]thiazol-4-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(4-chloro-2-fluorobenzyl)benzo[d]thiazole

At room temperature, 2-fluoro-4-chlorobenzoic acid (1.88 g, 10 mmol) was dissolved in toluene (20 mL), then phosphorus trichloride (1.65 g, 12 mmol) was added dropwise, heated to 60° C., and reacted for 30 minutes. Then, 2-mercaptoaniline (1.5 g, 12 mmol) was added dropwise, and the reaction was carried out for 3 hours. Cool to room temperature, spin to dry, the residue is dissolved in ethyl acetate (50 mL), the organic phase is washed with saturated sodium bicarbonate solution and saturated brine successively, the organic phase is dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was isolated by column chromatography to give 2-(4-chloro-2-fluorobenzyl)benzo[d]thiazole (1.94 g, 70%).

MS m/z(ESI): 278.0, 280.0[M+H] ⁺ .

Step 2: 4-Bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]thiazole

2-(4-Chloro-2-fluorobenzyl)benzo[d]thiazole (1.94 g, 7 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, followed by the addition of N-bromo Succinimide (1.37 g, 7.7 mmol) was heated to 80°C and reacted for three hours. Cooled to room temperature, the reaction solution was dissolved in ethyl acetate (60 mL), the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was isolated by column chromatography to give 4-bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]thiazole (0.25 g, 10%).

MS m/z(ESI): 355.9,357.9[M+H] ⁺ .

The third step: (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)benzo[d]thiazol-4-yl)piperidin-1-yl)methyl) -1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-bromo-2-(4-chloro-2-fluorobenzyl)benzo[d]thiazole as raw material, the first step, the second step, the sixth step, the tenth step, the tenth step in Reference Example 1 In one step, (S)-2-((4-(2-(4-chloro-2-fluorobenzyl)benzo[d]thiazol-4-yl)piperidin-1-yl)methyl) -1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 605.2[M+H] ⁺ .

Example 51

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(2-bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

Using 2-bromo-1-(4-chloro-2-fluorophenyl) ethane-1-one and 3-bromobenzene-1,2-diphenol as raw materials Reference Example 1 tenth step to obtain product 2-(2 -Bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one.

MS m/z(ESI): 358.9[M+H] ⁺ .

Step 2: 2-(2-Bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

2-(2-Bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (5 g, 13.9 mmol) was dissolved in anhydrous THF, cooled to 0 °C , methylmagnesium bromide (7.0ml, 20.9mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 3 hours. Aqueous ammonium chloride solution was added slowly to quench the reaction, and then EA was added for extraction. The organic phase is dried and spun dry. The crude product was purified by column chromatography to give 2-(2-bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one.

MS m/z(ESI): 374.9[M+H] ⁺ .

The third step: 5-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin

Using 2-(2-bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl) ethane-1-one as raw material Reference Example 7 second step to obtain product 5-bromo-2 -(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin.

MS m/z(ESI): 356.9[M+H] ⁺ .

Step 4: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 5-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin as raw material Reference Example 1 First , two, six, ten and eleven steps to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][ 1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 52

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(3-bromo-2-methoxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

Using 2-bromo-1-(4-chloro-2-fluorophenyl) ethane-1-one and 3-bromo-2-methoxyphenol as raw materials Reference Example 1 The tenth step to obtain the product 2-(3- Bromo-2-methoxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one.

MS m/z(ESI): 372.9[M+H] ⁺ .

Step 2: 2-(3-Bromo-2-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one

2-(3-Bromo-2-methoxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (5 g, 13.4 mmol) was dissolved in dry DCM (100 ml) , cooled to -78°C. BBr3 (10.1 g, 40.2 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was warmed to 0°C and stirred for 4 hours. Water was added slowly to quench the reaction, and DCM was added for extraction. The organic phase is dried and spun dry. The crude product was purified by column chromatography to give 2-(3-bromo-2-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one.

MS m/z(ESI): 358.9[M+H] ⁺ .

The third step: 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin

Using 2-(2-bromo-6-hydroxyphenoxy)-1-(4-chloro-2-fluorophenyl) ethane-1-one as raw material Reference Example 7 second step to obtain product 8-bromo-2 -(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin.

MS m/z(ESI): 356.9[M+H] ⁺ .

Step 4: 2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin as raw material Reference Example 1 First , two, six, ten and eleven steps to obtain the product 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][ 1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 53

2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1,1-dihydroxy -1,2,5-Thiadiazopenten-2-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid

The first step: tert-butyl (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxo-4-yl)carbamate

At room temperature, 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (3.44 g, 10 mmol), tert-butylamino Formate (1.40 g, 12 mmol), tris(dibenzylideneacetone)dipalladium (0.91 g, 1 mmol), sodium tert-butoxide (1.92 g, 20 mmol) and 4,5-bis(diphenylphosphine) -9,9-Dimethylxanthene (1.16 g, 2 mmol) was dissolved in toluene (40 mL), replaced with N ₂ , heated to 100° C., and reacted overnight. Cool to room temperature, filter, wash the solid with ethyl acetate, collect the reaction solution and spin dry. The residue was dissolved in ethyl acetate (100 mL), then washed with saturated brine (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by column chromatography to obtain tert-butyl (2). -(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxo-4-yl)carbamate (2.28 g, 60%).

MS m/z(ESI): 380.1[M+H] ⁺ .

Step 2: 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-amine

At room temperature, tert-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxo-4-yl)carbamate (2.28 g , 6 mmol) was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Spin to dry, the residue was dissolved in ethyl acetate (60 mL), the organic phase was washed with saturated sodium bicarbonate solution and saturated brine successively, the organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried. The crude product 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-amine (1.51 g, 90%) was obtained.

MS m/z(ESI): 280.1[M+H] ⁺ .

The third step: 2-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,2,5- Thidiazopentidine 1,1-Dioxide

Under ice bath, 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-amine (1.51 g, 5.4 mmol) was dissolved in dioxane Chloromethane (20 mL), then triethylamine (1.09 g, 10.8 mmol) was added dropwise, then (2-chloroethyl)sulfamoyl chloride (1.92 g, 10.8 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with dichloromethane (20 mL), the organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, and the organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried. The residue was dissolved in dimethylsulfoxide (20 mL), then potassium carbonate (1.49 g, 10.8 mmol) was added, and the mixture was stirred at room temperature overnight. Filter, wash the solid with ethyl acetate, spin dry the ethyl acetate. The dimethyl sulfoxide solution was purified by reverse phase chromatography and lyophilized to give 2-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)-1,2,5-thidiazopentidine 1,1-dioxide (0.21 g, 5%).

MS m/z(ESI): 385.1,387.1[M+H] ⁺ .

The fourth step: methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)- 1,1-Dihydroxy-1,2,5-thidiazopentan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H- Benzo[d]imidazole-6-carboxylate

Under ice bath, 2-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,2,5 - Thiadiazopentidine 1,1-dioxide (0.21g, 0.54mmol) was dissolved in N,N-dimethylformamide (5mL), then sodium hydrogen (60%, 43.2mg, 1.08mmol) was added, Stir under ice bath for 20 minutes, then add methyl(S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid The ester (0.19 g, 0.65 mmol) was stirred at room temperature overnight, the reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was isolated by column chromatography to give methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)-1,1-dihydroxy-1,2,5-thidiazopentan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylate (0.17 g, 50%).

MS m/z(ESI): 643.1,645.1[M+H] ⁺ .

The fifth step: 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1, 1-Dihydroxy-1,2,5-thidiazopenten-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo [d]Imidazole-6-carboxylic acid

With methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,1 -Dihydroxy-1,2,5-thidiazopenten-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Imidazole-6-carboxylate is the raw material, and the eleventh step of Reference Example 1 obtains 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] ][1,3]Dioxazol-4-yl)-1,1-dihydroxy-1,2,5-thidiazopenten-2-yl)methyl)-1-(((S) -oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 629.1,631.1[M+H] ⁺ .

Example 54

2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1,1-dihydroxy -1,2,5-Thiadiazol-2(5H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid

MS m/z(ESI): 627.1[M+H] ⁺ .

Example 55

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2-carbonyl-2, 3-Dihydro-1H-imidazol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,3-dihydro -2H-imidazol-2-one

4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (0.69 g, 2 mmol) was dissolved in dioxane at room temperature Ring (10mL), then potassium carbonate (0.83g, 6mmol), cuprous iodide (1.91g, 10mmol), N1,N2-dimethylethane-1,2-diamine (1.06g, 12mmol), 1,3-Dihydro-2H-imidazol-2-one (0.69 g, 8 mmol), replaced with nitrogen, microwaved at 150°C, and reacted for 90 minutes. Cooled to room temperature, the reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1, 3-Dihydro-2H-imidazol-2-one (0.14 g, 20%).

MS m/z(ESI): 347.1,349.1[M+H] ⁺ .

Step 2: 2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2- Carbonyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid

1-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1,3-dihydro-2H- Using imidazol-2-one as raw material, referring to the fourth step of Example 53 and the eleventh step of Example 1, 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methyl) was obtained Benzo[d][1,3]Dioxazol-4-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-1-(((S)- Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 591.1,593.1[M+H] ⁺ .

Example 56

2-((2-((4-Cyano-2-fluorobenzyl)oxo)-3-fluoro-6a,7,9,10-tetrahydropyranazido[1,2-d] Pyrido[3,2-b][1,4]oxazin-8(6H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 3-(hydroxymethyl)-4-(3,5,6-trifluoropyridin-2-yl)piperazine-1-carboxylate

Taking 2,3,5,6-tetrafluoropyridine and tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate as raw materials, the seventh step of Reference Example 1 obtained the product tert-butyl 3-( Hydroxymethyl)-4-(3,5,6-trifluoropyridin-2-yl)piperazine-1-carboxylate.

MS m/z(ESI): 348.1[M+H] ⁺ .

The second step: tert-butyl 2,3-difluoro-6a,7,9,10-tetrahydropyranazino[1,2-d]pyrido[3,2-b][1,4 ]oxazine-8(6H)-carboxylate

tert-Butyl 3-(hydroxymethyl)-4-(3,5,6-trifluoropyridin-2-yl)piperazine-1-carboxylate (500 mg, 1.4 mmol) was dissolved in 20 mL of THF, NaH (56 mg, 1.4 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to obtain tert-butyl 2,3-difluoro-6a,7,9,10-tetrahydropyranazido[1,2-d]pyrido[3,2-b][ 1,4]oxazine-8(6H)-carboxylate.

MS m/z(ESI): 328.1[M+H] ⁺ .

The third step: 2-((2-((4-cyano-2-fluorobenzyl)oxo)-3-fluoro-6a,7,9,10-tetrahydropyranazido[1, 2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid

tert-butyl 2,3-difluoro-6a,7,9,10-tetrahydropyrandiazo[1,2-d]pyrido[3,2-b][1,4]oxazine -8(6H)-carboxylate is the raw material Reference Example 1 The fifth step, the sixth step, the tenth step and the eleventh step obtain the product 2-((2-((4-cyano-2-fluorobenzene Methyl)oxo)-3-fluoro-6a,7,9,10-tetrahydropyrandiazo[1,2-d]pyrido[3,2-b][1,4]oxazine- 8(6H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 603.2[M+H] ⁺ .

Example 57

3-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine-6-carboxylic acid

The first step: methyl (S)-4-hydroxy-3-((oxetan-2-ylmethyl)amino)benzoate

Taking methyl 3-chloro-4-hydroxybenzoate and (S)-oxetan-2-yl methylamine as raw materials, the seventh step of reference example 1 obtains the product methyl (S)-4-hydroxy-3-( (oxbutan-2-ylmethyl)amino)benzoate.

MS m/z(ESI): 238.2[M+H] ⁺ .

The second step: methyl (S)-3-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxazine-6-carboxyl acid ester

Using methyl (S)-4-hydroxy-3-((oxbutan-2-ylmethyl)amino)benzoate and 1,3-dibromopropan-2-one as raw materials Reference Example 1 The tenth step The product methyl (S)-3-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxazine-6-carboxylate was obtained .

MS m/z(ESI): 354.2[M+H] ⁺ .

Step 3: 3-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine-6-carboxylic acid

Take methyl (S)-3-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxazine-6-carboxylate as Raw material reference example 1 Tenth and eleventh step to obtain product 3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine -6-Carboxylic acid.

MS m/z(ESI): 607.2[M+H] ⁺ .

Example 58

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine-6-carboxylic acid

The first step: methyl (S)-4-iodo-3-((oxetan-2-ylmethyl)amino)benzoate

Taking methyl 3-chloro-4-iodobenzoate and (S)-oxabutane-2-yl methylamine as raw materials, the seventh step of reference example 1 obtains the product methyl (S)-4-iodo-3-( (oxbutan-2-ylmethyl)amino)benzoate.

MS m/z(ESI): 348.2[M+H] ⁺ .

The second step: methyl (S)-3-((3-bromo-2-carbonylpropyl)(oxetan-2-ylmethyl)amino)-4-iodobenzoate

Using methyl (S)-4-iodo-3-((oxbutan-2-ylmethyl)amino)benzoate and 1,3-dibromopropan-2-one as raw materials Reference Example 1 The tenth step The product methyl (S)-3-((3-bromo-2-carbonylpropyl)(oxetan-2-ylmethyl)amino)-4-iodobenzoate was obtained.

MS m/z(ESI): 481.9[M+H] ⁺ .

The third step: methyl (S)-2-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxazine-6-carboxyl acid ester

Methyl (S)-3-((3-bromo-2-carbonylpropyl)(oxetan-2-ylmethyl)amino)-4-iodobenzoate (2 g, 4.2 mmol) was dissolved in DMSO ( 50 ml), KOH (466 mg, 8.3 mmol) was added. The reaction was stirred at 120°C overnight. Water was added, followed by EA extraction. The organic phase is dried and spun dry. The crude product was purified by column chromatography to give methyl (S)-2-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxa oxazine-6-carboxylate.

MS m/z(ESI): 354.2[M+H] ⁺ .

Step 4: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine-6-carboxylic acid

Take methyl (S)-2-(bromomethyl)-4-(oxetan-2-ylmethyl)-4H-benzo[b][1,4]oxazine-6-carboxylate as Raw material reference example 1 Tenth and eleventh steps to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-benzo[b][1,4]oxazine -6-Carboxylic acid.

MS m/z(ESI): 607.2[M+H] ⁺ .

Example 59

(S)-2-((4-(6-(6-Cyano-1,1-dimethyl-3-carbonylisoindol-2-yl)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(6-bromopyridin-2-yl)-3,3-dimethyl-1-carbonylisoindoline-5-carbonitrile

3,3-Dimethyl-1-carbonylisoindole-5-carbonitrile (1 g, 5.4 mmol) was dissolved in 20 mL of 1,4-dioxane, and 2,6-dibromopyridine ( 1.5 g, 6.4 mmol), CuI (205 mg, 1.1 mmol), (1S,2S)-cyclohexane-1,2 _- diamine (125 mg, 1.1 mmol) and _K3PO4 (2.2 g, 10.8 mmol), Stir at reflux for 4h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 2-(6-bromopyridin-2-yl)-3,3-dimethyl-1-carbonylisoindole-5-carbonitrile (370 mg).

MS m/z(ESI): 342.0[M+H] ⁺ .

The second step: (S)-2-((4-(6-(6-cyano-1,1-dimethyl-3-carbonylisoindol-2-yl)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-(6-bromopyridin-2-yl)-3,3-dimethyl-1-carbonylisoindoline-5-carbonitrile as raw material Reference Example 1 to obtain the product (S)-2-( (4-(6-(6-Cyano-1,1-dimethyl-3-carbonylisoindol-2-yl)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 591.2[M+H] ⁺ .

Example 60

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3,6-diazepine Heterobicyclo[3.1.1]heptan-6-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6- carboxylic acid

4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole and tert-butyl 3,6-diazabicyclo [3.1.1] Heptane-6-carboxylate as raw material Reference Example 16 to obtain the product 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d ][1,3]Dioxazol-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-(((S)-oxetan Cyclo-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 605.2[M+H] ⁺ .

Example 61

2-((4-(2-(benzo[d]oxazol-5-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(benzo[d]oxazol-5-yl)ethan-1-one

1-(3-Amino-4-hydroxyphenyl)ethan-1-one (1 g, 6.6 mmol) was dissolved in 10 mL of triethyl orthoformate, and stirred at 150° C. for 4 h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(benzo[d]oxazol-5-yl)ethan-1-one (300 mg).

MS m/z(ESI): 162.0[M+H] ⁺ .

Step 2: 2-((4-(2-(benzo[d]oxazol-5-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(benzo[d]oxazol-5-yl)ethan-1-one as raw material Reference Example 31 to obtain the product 2-((4-(2-(benzo[d]oxazole-5- yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 581.2[M+H] ⁺ .

Example 62

2-((4-(2-Methyl-2-(quinolin-6-yl)benzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: N-methoxy-N-methylquinoline-6-carboxamide

Quinoline-6-carboxylic acid (1 g, 5.7 mmol) was dissolved in 20 mL of DMF, dimethylhydroxylamine hydrochloride (850 mg, 8.7 mmol), HATU (3.3 g, 8.7 mmol) and TEA (1.7 g, 17.1 mmol) were added ) and stirred at room temperature for 12h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give N-methoxy-N-methylquinoline-6-carboxamide (1 g).

MS m/z(ESI): 217.0[M+H] ⁺ .

Step 2: 1-(quinolin-6-yl)ethane-1-one

Dissolve N-methoxy-N-methylquinoline-6-carboxamide (500 mg, 2.3 mmol) in 20 mL of THF, add methylmagnesium bromide (3.4 mL, 3.4 mmol) at 0 °C, and stir at room temperature for 12 h . Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(quinolin-6-yl)ethan-1-one (350 mg).

MS m/z(ESI): 172.0[M+H] ⁺ .

The third step: 2-((4-(2-methyl-2-(quinolin-6-yl)benzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(quinolin-6-yl) ethane-1-one as raw material Reference Example 31 to obtain the product 2-((4-(2-methyl-2-(quinolin-6-yl)benzo[ d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo [d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 591.2[M+H] ⁺ .

Example 63

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-(trifluoromethyl)benzo[d][1,3]dioxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one

Dissolve 4-chloro-2-fluoro-1-iodobenzene (1 g, 3.9 mmol) in 20 mL of THF, add n-butyllithium (3 mL, 4.7 mmol, 1.6 M) at -78 °C, stir at -78 °C for 0.5 h . Ethyl trifluoroacetate (664 mg, 4.6 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 5 h. Water was added to quench, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was isolated by column chromatography to give 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one (530 mg).

MS m/z(ESI): 226.9[M+H] ⁺ .

Step 2: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-(trifluoromethyl)benzo[d][1,3]dioxazol-4-yl )-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid

Using 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one as raw material Reference Example 30 to obtain the product 2-((4-(2-(4-chloro -2-Fluorophenyl)-2-(trifluoromethyl)benzo[d][1,3]dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 644.1[M+H] ⁺ .

Example 64

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-(trifluoromethyl)benzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one as raw material, reference example 31 was used to obtain the product 2-((4-(2-(4-chloro -2-Fluorophenyl)-2-(trifluoromethyl)benzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-1-(((( S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 646.1[M+H] ⁺ .

Example 65

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-cyclopropylbenzo[d][1,3]bisoxazol-4-yl)-3,6-di Hydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (4-chloro-2-fluorophenyl) (cyclopropyl) ketone as raw material Reference Example 30 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2- Cyclopropylbenzo[d][1,3]bisoxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxa Butcyclo-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 616.2[M+H] ⁺ .

Example 66

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-cyclopropylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (4-chloro-2-fluorophenyl) (cyclopropyl) ketone as raw material Reference Example 30 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2- Cyclopropylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 618.2[M+H] ⁺ .

Example 67

2-((4-(5'-Chloro-2',3'-dihydrospiro[benzo[d][1,3]dioxazolo-2,1'-indene]-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 5-chloro-2,3-dihydro-1H-inden-1-one as raw material Reference Example 30 to obtain the product 2-((4-(5'-chloro-2',3'-dihydrospiro[benzene [d][1,3]Dioxazolo-2,1'-inden]-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 586.2[M+H] ⁺ .

Example 68

2-((4-(2-(4,4-Dimethylcyclohexyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(4,4-dimethylcyclohexyl)ethan-1-one as raw material Reference Example 30 to obtain the product 2-((4-(2-(4,4-dimethylcyclohexyl)-2 -Methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 574.3[M+H] ⁺ .

Example 69

2-((4-(Dispiro[benzo[d][1,3]bisoxazole-2,1'-cyclobutane-2',1"-cyclohexane]-4-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using spiro[3.5]nonan-1-one as raw material, the product 2-((4-(dispiro[benzo[d][1,3]bisoxazole-2,1'-cyclobutane) was obtained in Reference Example 30 Alkyl-2',1"-cyclohexane]-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 558.2[M+H] ⁺ .

Example 70

(S)-2-((4-(3-((4-cyano-2-fluorophenoxy)methyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 3-fluoro-4-hydroxybenzonitrile and 1-bromo-3-(bromomethyl)benzene as raw materials Reference Example 1 obtains the product (S)-2-((4-(3-((4-cyano (2-fluorophenoxy)methyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 553.2[M+H] ⁺ .

Example 71

(S)-2-((4-(2-(4-Chloro-2-fluorophenyl)benzo[d]oxazol-7-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-chloro-2-fluorobenzoic acid as raw material Reference Example 48 to obtain the product (S)-2-((4-(2-(4-chloro-2-fluorophenyl)benzo[d]oxazole- 7-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 575.2[M+H] ⁺ .

Example 72

2-((((2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)ethynyl)(methyl)amino )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one

Using tert-butylethynyl (methyl) carbamate as raw material Reference Example 28 The third step to obtain the product 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane -1-keto.

MS m/z(ESI): 418.1[M+H] ⁺ .

Step 2: 2-((((2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)ethynyl)( Methyl)amino)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethane-1-one as raw material, the sixth step, tenth step and eleventh step of reference example 1 obtained product 2 -((((2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)ethynyl)(methyl)amino) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 562.1[M+H] ⁺ .

Example 73

(S,E)-3-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxabutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)septic acid

The first step: (E)-ethyl 3-(3-fluoro-4-nitrophenyl) acryloyl acid

With 4-bromo-2-fluoro-1-nitrobenzene and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acryloyl acetate Base ester as raw material Reference Example 1 The product (E)-ethyl 3-(3-fluoro-4-nitrophenyl) acryloyl acid was obtained in the first step.

The second step: (S,E)-3-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)sphalic acid

Taking (E)-3-(3-fluoro-4-nitrophenyl) acrylic acid ethyl ester as raw material Reference Example 1, the seventh to eleventh steps to obtain the product (S,E)-3-(2-( (4-(6-((4-Cyano-2-fluorobenzyl)oxo)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-yl Methyl)-1H-benzo[d]imidazol-6-yl)septic acid.

MS m/z(ESI): 582.2[M+H] ⁺ .

Example 74

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)sphalic acid

The first step: methyl (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxin oxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl) Acrylate

With methyl (S,E)-3-(2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)acryloic acid Ester and 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine as raw materials Reference Example 1 Section 1 Ten steps to get the product methyl (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxin oxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl) Acrylates.

MS m/z(ESI): 632.2[M+H] ⁺ .

Step 2: (E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)fatamide acid

With methyl(E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)acryloic acid Ester is the raw material Reference Example 1 The eleventh step obtains the product (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] [1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d ] imidazol-6-yl) sputum acid.

MS m/z(ESI): 618.2[M+H] ⁺ .

Example 75

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)fatamide acid

Using 2,3-difluoro-4-bromonitrobenzene as raw material Reference Example 74 to obtain product (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)- 2-Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetane-2 -yl)methyl)-1H-benzo[d]imidazol-6-yl)sphaltic acid.

MS m/z(ESI): 636.2[M+H] ⁺ .

Example 76

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-cyanopyridine fatty acid

The first step: methyl (E)-2-cyano-3-(3-fluoro-4-nitrophenyl) acrylate

4-Bromo-2-fluoro-1-nitrobenzene (1 g, 4.5 mmol), methyl 2-cyanoacrylate (0.55 g, 5.0 mmol), Pd(OAc) ₂ (0.1 g, 0.45 mmol) ), PPh ₃ (0.23 g, 0.9 mmol), Et ₃ N (1.3 g, 13.5 mmol) were dissolved in DMF (30 mL), nitrogen was replaced, the reaction was stirred at 80° C. for 5 hours, cooled to room temperature, and water (100 mL) was added, Extract with ethyl acetate (30 mL x 2), wash the organic phase with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, spin dry, the crude product is purified by column chromatography to obtain methyl (E)-2 -Cyano-3-(3-fluoro-4-nitrophenyl) acrylate (0.45 g, 40%).

MS m/z(ESI): 251.0[M+H] ⁺ .

Step 2: (E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2 -Cyanoseptic acid

Using methyl (E)-2-cyano-3-(3-fluoro-4-nitrophenyl) acrylate as raw material Reference Example 27 The second step to the sixth step obtains the product (E)-3 -(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-cyanosphalic acid.

MS m/z(ESI): 643.2[M+H] ⁺ .

Example 77

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-methylsulfonyl fatty acid

Using methyl methacrylate as a raw material, Reference Example 76 was used to obtain the product (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo [d] Imidazol-6-yl)-2-methylseptic acid.

MS m/z(ESI): 632.2[M+H] ⁺ .

Example 78

(Z)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)-2-fluoropyrazine acid

Using methyl 2-fluoroacryloyl ester as raw material Reference Example 76 to obtain the product (Z)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl Benzo[d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H - Benzo[d]imidazol-6-yl)-2-fluoroseptaic acid.

MS m/z(ESI): 636.2[M+H] ⁺ .

Example 79

(E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)fatamide acid

The first step: (S)-6-chloro-3-nitro-N-(oxetan-2-ylmethyl)pyridin-2-amine

Taking 2,6-dichloro-3-nitropyridine as raw material, the seventh step of Reference Example 1 obtains the product (S)-6-chloro-3-nitro-N-(oxabutane-2-ylmethyl) Pyridin-2-amine.

MS m/z(ESI): 244.2[M+H] ⁺ .

Step 2: Methyl (S,E)-3-(5-nitro-6-((oxetan-2-ylmethyl)amino)pyridin-2-yl)acryloate

Combine (S)-6-chloro-3-nitro-N-(oxbutan-2-ylmethyl)pyridin-2-amine (1.0 g, 4.1 mmol), methyl acrylate (0.42 g, 4.9 mmol) and sodium acetate (1.0 g, 12.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), Pd(PPh ₃ ) ₂ Cl ₂ (0.58 g, 0.82 mmol) was added under N2 protection, and the reaction was Stir overnight at 140°C. Water (50 mL) was added and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain methyl (S,E)-3-(5-nitro-6-((oxetan-2-yl) Methyl)amino)pyridin-2-yl)acrylate (0.6 g, yield: 50%).

MS m/z(ESI): 294.1[M+H] ⁺ .

The third step: methyl (S,E)-3-(5-amino-6-((oxetan-2-ylmethyl)amino)pyridin-2-yl)acryloate

Methyl (S,E)-3-(5-nitro-6-((oxetan-2-ylmethyl)amino)pyridin-2-yl)acryloate (0.5 g, 1.7 mmol) Dissolved in ethanol (10 mL), saturated aqueous ammonium chloride solution (10 mL), iron powder (0.95 g, 17 mmol) were added, and the reaction was stirred at 60° C. for 2 hours. Filter, add water (20 mL), and extract with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain methyl (S,E)-3-(5-nitro-6-((oxetan-2-yl) Methyl)amino)pyridin-2-yl)acrylate (0.4 g, yield: 89%).

MS m/z(ESI): 264.1[M+H] ⁺ .

The fourth step: methyl (S,E)-3-(2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine- 5-yl) acrylate

Using methyl (S,E)-3-(5-nitro-6-((oxetan-2-ylmethyl)amino)pyridin-2-yl)acryloate as raw material Reference Example 1 Section 1 Nine-step product methyl (S, E)-3-(2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine- 5-yl) acrylate.

MS m/z(ESI): 322.2[M+H] ⁺ .

The fifth step: methyl (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxin oxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine- 5-yl) acrylate

With methyl(S,E)-3-(2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl ) Acryloyl ester is the raw material Reference Example 1 tenth step obtains the product methyl (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl) Benzo[d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H - Imidazo[4,5-b]pyridin-5-yl)acryloate.

MS m/z(ESI): 633.2[M+H] ⁺ .

Step 6: (E)-3-(2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- base) salicylic acid

With methyl(E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl ) Acryloyl ester is the raw material Reference Example 1 The eleventh step obtains the product (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzene [d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H- Imidazo[4,5-b]pyridin-5-yl)fatolic acid.

MS m/z(ESI): 619.2[M+H] ⁺ .

Example 80

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2,5-dihydro -1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5 -Dihydro-1H-pyrrole-1-carboxylate

4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (0.180 g, 0.52 mmol), 3-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate tert-butyl ester (154.65 mg, 0.52 mmol ), sodium carbonate (111.06mg, 1.05mmol), Pd(dppf)Cl ₂ (38.33mg, 0.052mmol) was dissolved in water (2mL) and 1'4-dioxane (6mL), replaced with nitrogen, heated to 100 ℃, the reaction was carried out for 14 hours. After cooling to room temperature, LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL), filtered through celite, washed with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine (10 mL×3), and the organic phase was dried with anhydrous sodium sulfate , filtered, spin-dried, and the residue was separated by preparative thin layer chromatography (PE:EA=10:1) to give tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzene [d][1,3]Dioxazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate as a colorless oil (130 mg, 57%).

MS m/z(ESI): 432.1,434.1[M+H] ⁺ .

Step 2: 3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5-dihydro -1H-pyrrole

Under ice bath, tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2, 5-Dihydro-1H-pyrrole-1-carboxylate (130 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. Spin dry to give 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5-dihydro -1H-pyrrole trifluoroacetate (130 mg, black oil), the crude product was used directly in the next step.

MS m/z(ESI): 332.1,334.1[M+H] ⁺ .

The third step: methyl 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)- 2,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- Carboxylate

3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5-dihydro -1H-pyrrole trifluoroacetate (130 mg, 0.30 mmol) was dissolved in acetonitrile (10 mL), then potassium carbonate (124.97 mg, 0.90 mmol) was added, followed by methyl 2-(chloromethyl)-3-[ [rac-(2S)-oxbutan-2-yl]methyl]benzimidazole-5-carboxylate (88.84 mg, 0.3 mmol), heated to 60° C., reacted for 2 hours, and cooled to room temperature. LCMS indicated the end of the reaction. The reaction solution was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry, and the residue was separated by preparative thin layer chromatography (EA:PE =2:1) to give methyl 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid ester as a colorless oil (41 mg, 23%).

MS m/z(ESI): 590.2,592.2[M+H] ⁺ .

The fourth step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2, 5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

At room temperature, methyl 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)- 2,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- The carboxylate (41 mg, 0.07 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), then an aqueous solution (0.5 mL) of sodium hydroxide (28 mg, 0.7 mmol) was added, heated to 30 °C, reacted for 14 hours, and cooled to At room temperature, LCMS indicated that the reaction was complete. Spin to dry, the residue was dissolved in ethyl acetate (20 mL), and the pH value was adjusted to 6-7 with dilute hydrochloric acid (1N) under ice bath, and the solution was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was separated by preparative high performance liquid phase. Lyophilization yields 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5 -Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Formate salt (12.5 mg, 27.5%, white solid).

MS m/z(ESI): 576.2,578.2[M+H] ⁺ .

Example 81

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)pyrrolidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)pyrrolidine-1 - Carboxylate

At room temperature, tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,5 -Dihydro-1H-pyrrole-1-carboxylate (0.50g, 1.16mmol) was dissolved in methanol (6mL), then Wilkinson's catalyst (50mg) was added, hydrogen was replaced, heated to 50°C, and reacted for 14 hours. After cooling to room temperature, LCMS indicated that the reaction was complete. Filter through celite, wash the celite with ethyl acetate, combine the organic phases, spin dry, and separate the residue by silica gel column chromatography (PE:EA=10:1) to obtain tert-butyl 3-(2-(4- Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)pyrrolidine-1-carboxylate (0.30 g, yellow solid, 60%).

MS m/z(ESI): 434.2,436.2[M+H] ⁺ .

Step 2: 2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)pyrrolidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)pyrrolidine-1-carboxylic acid Ester is the raw material, the second step, the third step and the fourth step of Reference Example 80 obtain 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] [1,3]Dioxazol-4-yl)pyrrolidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d ] Imidazole-6-carboxylic acid.

MS m/z(ESI): 578.2,580.2[M+H] ⁺ .

Example 82

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1H-pyrrole-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1H-pyrrole -1-Carboxylic acid ester

With 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole and tert-butyl 3-(4,4,5, Using 5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrrole-1-carboxylate as a raw material, the first step of Reference Example 80 was used to obtain tert-butyl 3-(2-( 4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1H-pyrrole-1-carboxylate.

MS m/z(ESI): 430.1,432.1[M+H] ⁺ .

Step 2: 3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1H-pyrrole

At room temperature, tert-butyl 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1H-pyrrole -1-Carboxylic acid ester (0.06 g, 0.14 mmol) was dissolved in hexafluoroisopropanol (3 mL), microwaved at 80° C. for 2 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. Spin dry and the residue is separated by preparative thin layer chromatography (EA:PE=3:1) to give 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1] ,3]Dioxazol-4-yl)-1H-pyrrole (0.012 g, yellow oil, 26%).

MS m/z(ESI): 330.1,332.1[M+H] ⁺ .

The third step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-1H- Pyrrol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-1H-pyrrole as raw material, reference example 80 The third step, the fourth step, to obtain 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)-1H-pyrrol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 574.2,576.2[M+H] ⁺ .

Example 83

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2,5-dihydro -1H-pyrrol-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: methyl 6-chloro-5-nitromethyl pyridine ester

Under ice bath, 6-chloro-5-nitro-pyridine-2-carboxylic acid (0.52 g, 2.57 mmol) was dissolved in dichloromethane (8 mL), then oxalyl chloride (651.70 mg, 5.13 mmol) was added, and then dropwise DMF (0.2 mL) was added, and the mixture was stirred under an ice bath for 1.5 hours, then methanol (2 mL) was added, and the mixture was stirred at room temperature for one hour. LCMS indicated the end of the reaction, the reaction solution was diluted with dichloromethane, then washed with saturated sodium bicarbonate solution (15mL×3), washed with saturated brine (15mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried , the residue was used directly in the next step (0.54 g, yellow solid, 97%).

MS m/z(ESI): 217.0, 219.0[M+H] ⁺ .

The second step: methyl (S)-5-amino-6-((oxbutan-2-ylmethyl)amino)picolinate

Using methyl 6-chloro-5-nitro-pyridine-2-carboxylate as a raw material, referring to the seventh step of Example 1, the eighth step obtains methyl 6-chloro-5-nitromethylpyridine ester.

MS m/z(ESI): 238.1[M+H] ⁺ .

The third step: methyl (S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

Methyl (S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate at room temperature (0.34 g, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL), then a solution of (2-chloroacetyl) 2-chloroacetate (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise, stirred at room temperature for 30 minutes, and then Heated to 60°C, reacted for 2 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then washed with saturated sodium bicarbonate solution (15 mL × 3), and washed with saturated brine (15 mL × 3). The organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The residue was used directly in the next step (0.40 g, yellow oil, 94%)

MS m/z(ESI): 296.1,298.1[M+H] ⁺ .

The fourth step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2, 5-Dihydro-1H-pyrrol-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine- 5-Carboxylic acid

With methyl (S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

As the raw material, refer to the third step and the fourth step of Example 80 to obtain 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H -Imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 577.2,579.2[M+H] ⁺ .

Example 84

2-((3-(2-(4-Cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2,5-di Hydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((3-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2 ,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid

Using 4-bromo-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole as raw material, the first step of reference example 80, the second Step, third step, fourth step, get 2-((3-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 567.2[M+H] ⁺ .

Example 85

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)oxo)acetic acid

The first step: ethyl 2-(3-fluoro-4-nitro-phenoxy)acetate

3-Fluoro-4-nitro-phenol (1 g, 6.37 mmol), ethyl 2-bromoacetate (1.06 g, 6.37 mmol) and DMF (10 mL) were added to a 100 mL flask, and K2CO3 (1.76 g) was added at 25°C , 12.73 mmol), and then the reaction solution was reacted at 80 °C for 2 h. TLC showed that a new spot was formed. After the reaction solution was concentrated, it was passed through a column with PE/EA=5/1 to obtain ethyl 2-(3-fluoro-4-nitro-phenoxy)acetate (1.1 g, 4.52 mmol). , 71.06% yield).

Step 2: 2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)oxo)acetic acid

Using ethyl 2-(3-fluoro-4-nitro-phenoxy)acetate as the raw material, the seventh to eleventh steps of Reference Example 1 were used and 3-fluoro-4-(1-((6-(piperidine- 4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile was replaced by 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]Dioxazol-4-yl)piperidine to give the product 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d] imidazol-6-yl)oxo)acetic acid.

MS m/z(ESI): 622.2[M+H] ⁺ .

Example 86

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)oxo)propionic acid

Using 3-fluoro-4-nitro-phenol as raw material Reference Example 85, the product 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo [d] Imidazol-6-yl)oxo)propionic acid.

MS m/z(ESI): 636.2[M+H] ⁺ .

Example 87

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6-yl)oxo)-2-fluoroacetic acid

Using 3-fluoro-4-nitro-phenol as raw material Reference Example 85, the product 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo [d] Imidazol-6-yl)oxo)-2-fluoroacetic acid.

MS m/z(ESI): 640.1[M+H] ⁺ .

Example 88

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)oxo)acetic acid

The first step: 5-chloro-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

Using 2,6-dichloro-3-nitropyridine as the raw material, the seventh to tenth steps of Reference Example 1 and 3-fluoro-4-(1-((6-(piperidin-4-yl)pyridine-2 -yl)oxo)cyclopropyl)benzonitrile to 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidine gives the product 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5 -yl)oxo)acetic acid.

MS m/z(ESI): 583.1[M+H] ⁺ .

Step 2: 2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)oxy Substitute) ethyl acetate

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)oxo)acetic acid ( 100 mg, 0.17 mmol), 2-hydroxyacetate ethyl ester (35 mg, 0.14 mmol) and DMF (2 mL) were added to a 10 mL flask, K ₂ CO ₃ (47 mg, 0.34 mmol) was added at 25° C., and then the reaction solution was The reaction was carried out at 80°C for 2h. TLC showed that a new spot was formed. After the reaction solution was concentrated, the product was purified by column chromatography to obtain 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzoyl) [d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazole Ethyl [4,5-b]pyridin-5-yl)oxo)acetate (60 mg, 0.09 mmol, 53.7% yield).

MS m/z(ESI): 651.2[M+H] ⁺ .

The third step: 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)oxy Substitute) acetic acid

2-((2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)oxo)acetic acid Ethyl ester is the raw material Reference Example 1 The eleventh step obtains the product 2-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5 -b]peridin-5-yl)oxo)acetic acid.

MS m/z(ESI): 623.2[M+H] ⁺ .

Example 89

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(2-methoxyethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: the preparation of 4,5-dibromo-2-methyl-1H-imidazole

2-Methyl-lH-imidazole (3 g, 36.54 mmol) was dissolved in DMF (10 mL) and potassium bicarbonate (9.21 g, 109.62 mmol) was added. Bromine (5.62 mL, 109.62 mmol) was added dropwise to the reaction system under an ice bath. After the dropwise addition was completed, the reaction was carried out at 100° C. for 3 hours. The reaction solution was quenched with aqueous sodium sulfite solution, and extracted with ethyl acetate (30 mL×2). The organic phases were combined and washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain the product 4,5-dibromo-2-methyl-1H-imidazole (5 g, yield rate: 57%).

MS m/z(ESI): 238.7[M+H] ⁺ .

The second step: preparation of 4,5-dibromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole

To a solution of 4,5-dibromo-2-methyl-1H-imidazole (1 g, 4.17 mmol) in DMF (20 mL) was added sodium hydride (200 mg, 5 mmol). After the reaction for 0.5 hours, 1-bromo-2-methoxyethane (637 mg, 4.59 mmol) was added, and the reaction was continued for 3 hours. Aqueous ammonium chloride solution (5 mL) was added to quench the reaction, the reaction solution was poured into water (60 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 4,5-dibromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole (1 g, yield: 80%).

MS m/z(ESI): 296.8[M+H] ⁺ .

The third step: the preparation of 4-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole-5-carbaldehyde

4,5-Dibromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole (300 mg, 1.01 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyl was added dropwise at -78°C Lithium (2.5M, 0.44 mL, 1.11 mmol). After reacting at -78°C for 0.5 hours, DMF (147 mg, 2.01 mmol) was added, the reaction was continued for 0.5 hours, and the temperature was raised to room temperature for another 2 hours. The reaction was quenched by adding aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 4-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole-5- Formaldehyde (240 mg, yield: 96%).

MS m/z(ESI): 246.8[M+H] ⁺ .

The fourth step: preparation of ethyl 1-(2-methoxyethyl)-2-methyl-1H-thieno[2,3-d]imidazole-5-carboxylate

4-Bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole-5-carbaldehyde (100 mg, 0.4 mmol) and methyl 2-mercaptoacetate were dissolved in ethanol (5 mL) and added Sodium ethoxide solution (0.5 mL) was reacted at 75°C for 16 hours. The reaction was quenched by adding water (1 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA=5:1-1:1) to give the product methyl 1-(2-methoxyethyl)-2-methyl-1H-thieno[2,3-d ] Imidazole-5-carboxylate (90 mg, yield: 83%).

MS m/z(ESI): 268.9[M+H] ⁺ .

The fifth step: preparation of ethyl 2-(bromomethyl)-1-(2-methoxyethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

Ethyl 1-(2-methoxyethyl)-2-methyl-1H-thieno[2,3-d]imidazole-5-carboxylate (60 mg, 0.22 mmol) was dissolved in carbon tetrachloride (3 mL), N-bromosuccinimide (44 mg, 0.25 mmol) and azobisisobutyronitrile (7.3 mg, 0.045 mmol) were added, and the mixture was reacted at 75° C. for 16 hours. After the reaction was cooled to room temperature, it was filtered and spin-dried to obtain the crude product (60 mg, yield: 77%), which was directly used in the next reaction.

MS m/z(ESI): 346.8[M+H] ⁺ .

Step 6: Ethyl 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Preparation of pyridin-1-yl)methyl)-1-(2-methoxyethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

Refer to the tenth step of Example 1.

MS m/z(ESI): 613.9[M+H] ⁺ .

Step Seven: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- Preparation of 1-yl)methyl)-1-(2-methoxyethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Refer to the eleventh step of Example 1.

MS m/z(ESI): 585.8[M+H] ⁺ .

Example 90

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: preparation of 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Refer to Example 89 for the second step.

MS m/z(ESI): 370.9[M+H] ⁺ .

The second step: preparation of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde

Refer to Example 89 for the third step.

MS m/z(ESI): 318.8[M+H] ⁺ .

Step 3: Ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid Preparation of esters

Refer to the fourth step of Example 89.

MS m/z(ESI): 340.8[M+H] ⁺ .

Step 4: Ethyl 2-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5 - Preparation of carboxylate

Refer to the fifth step of Example 89.

MS m/z(ESI): 418.8[M+H] ⁺ .

The fifth step: ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate preparation

Refer to the tenth step of Example 1.

MS m/z(ESI): 685.8[M+H] ⁺ .

Step 6: Ethyl 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Preparation of pyridin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

The compound ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (200mg , 0.29 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 6 hours. After concentration under reduced pressure, aqueous sodium bicarbonate solution (5 mL) was added, followed by extraction with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl) Benzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (150mg, Yield: 93%).

MS m/z(ESI): 555.8[M+H] ⁺ .

Step 7: Ethyl 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

The compound ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (150 mg, 0.27 mmol) was dissolved in DMF (3 mL), (S)-oxetane-2- Methyl methanesulfonate (54 mg, 0.32 mmol) and cesium carbonate (264 mg, 0.81 mmol) were reacted at 75° C. for 16 hours. Water (10 mL) was added and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared with prep-TLC (DCM:MeOH=10:1) to give the product (100 mg, yield: 65%).

MS m/z(ESI): 625.8[M+H] ⁺ .

Step 8: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Refer to the eleventh step of Example 1.

MS m/z(ESI): 597.8[M+H] ⁺ .

Example 91

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

Refer to Example 90.

MS m/z(ESI): 597.8[M+H] ⁺ .

Example 90-1 and Example 91-1

2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- Preparation of 1-carboxylate

tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-di Hydropyridine-1(2H)-carboxylate (10 g, 22.4 mmol) was dissolved in methanol (100 mL), palladium on carbon (2 g) was added, and the reaction was carried out at room temperature for 16 hours under hydrogen conditions. After filtration, it was concentrated under reduced pressure to obtain the product tert-butyl (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidine-1-carboxylate (10 g, yield: 99%).

MS m/z(ESI): 448.2[M+H] ⁺ .

The second step: tert-butyl (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl ) Preparation of piperidine-1-carboxylate

tert-Butyl 4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylic acid The ester (10 g, 22.4 mmol) was resolved by chirality (column conditions: AD; IPA [1% _NH3 (7M in MeOH)]) to give tert-butyl(R)-4-(2-(4-chloro- 2-Fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate (4.5g, rt: 0.902min) and tert-butyl (S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate acid ester (4g, rt: 1.387min).

The third step: (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine preparation

tert-Butyl(S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-Carboxylic acid ester (4 g, 8.9 mmol) was dissolved in ethyl acetate (50 mL), p-toluenesulfonic acid (1.7 g, 9.8 mmol) was added, and the reaction was carried out at 60° C. for 16 hours. Concentration under reduced pressure gave the product (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine p-toluenesulfonate (4.8g)

MS m/z(ESI): 347.8[M+H] ⁺ .

The fourth step: ethyl (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

(S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-p-toluenesulfonic acid salt and ethyl 2-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate Acid ester as raw material Reference Example 90 to obtain the product ethyl (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate.

MS m/z(ESI): 556.1[M+H] ⁺ .

The fifth step: ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxy acid ester and ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid Preparation of esters

The compound ethyl (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (110 mg, 0.2 mmol) was dissolved in DMF (5 mL), (S)-oxabutine was added Cyclo-2-ylmethylmethanesulfonate (66 mg, 0.4 mmol) and cesium carbonate (193 mg, 0.6 mmol) were reacted at 60° C. for 16 hours. Water (10 mL) was added and extracted with ethyl acetate (10 mL*2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared by prep-HPLC to obtain a mixed product, which was then resolved by chirality (column condition: AD-H; n-hexane:ethanol:ethylenediamine=70:30:0.1) to obtain the product ethyl 2-((4-( (S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl) -1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (40 mg, yield: 44%, rt: 6.607min) and ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxy Acid ester (20 mg, yield: 22%, rt: 8.727 min)

MS m/z(ESI): 625.8[M+H] ⁺ .

Step 6: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid and 2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- Preparation of 1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate and Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Iridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylate as raw material Reference Example Example 1 Eleventh step to obtain the product 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d ]imidazole-5-carboxylic acid and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazol-5 -carboxylic acid.

90-1: MS m/z(ESI): 597.8[M+H] ⁺ .

91-1: MS m/z(ESI): 597.8[M+H] ⁺ .

Example 92

2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Reference Example 90

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 92-1

2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid and 2-( (4-(2-(4-Cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl Preparation of )-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Ethyl 2- (Bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate as raw material for reference Example 90 to give 2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid and 2-(( 4-(2-(4-Cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl) - Mixtures of 1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acids.

MS m/z(ESI): 617.2[M+H] ⁺ .

Step 2: Ethyl 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5- Carboxylate, ethyl 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazol-5- Carboxylate, ethyl 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5- Carboxylic acid ester and ethyl 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazol-5- Preparation of carboxylate

2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid and 2-((4-( 2-(4-Cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1- A mixture of (((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acids was resolved chiral (chiral column: OD-H ; mobile phase: Hexane:EtOH=70:30) to obtain products P1 (rt=4.043min), P2 (rt=4.277min), P3 (rt=5.353min) and P4 (rt=7.037min).

P1: MS m/z(ESI): 617.2[M+H] ⁺ .

1H NMR(400MHz, Chloroform-d)δ7.77-7.67(m,2H),7.47-7.38(m,2H),6.82-6.75(m,1H),6.74-6.66(m,2H),5.23-5.16 (m, 1H), 4.68–4.60 (m, 1H), 4.60–4.49 (m, 2H), 4.36 (q, J=7.2Hz, 2H), 3.93–3.76 (m, 2H), 3.10–2.89 (m ,2H),2.79–2.66(m,2H),2.52–2.41(m,1H),2.37–2.24(m,2H),2.07(s,3H),1.92–1.69(m,5H),1.38(t ,J=7.2Hz,3H).

P2: MS m/z(ESI): 617.2[M+H] ⁺ .

P3: MS m/z(ESI): 617.2[M+H] ⁺ .

P4: MS m/z(ESI): 617.2[M+H] ⁺ .

The third step: 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid preparation

Using P1 as the raw material, the eleventh step of the reference example 1 obtains the product 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2, 3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 92-2

2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid preparation

Taking P3 in Example 92-1 as the raw material and referring to the eleventh step of Example 1, the product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methyl was obtained Benzo[d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H - Thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 93

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylic acid

The first step: the preparation of ethyl 3-bromo-4-carbonylcyclohexane-1-carboxylate:

N-bromosuccinimide (5.23 g, 29.4 mmol) was added to a solution of ethyl 4-carbonylcyclohexane-1-carboxylate (5 g, 29.4 mmol) in toluene (150 mL), and the reaction solution was stirred at room temperature After 5 minutes, p-toluenesulfonic acid monohydrate (0.59 g, 2.94 mmol) was added, and the reaction solution was heated to reflux for 2 hours. The reaction solution was evaporated to dryness, dissolved in ethyl acetate (150 mL), washed with saturated brine (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain ethyl 3-bromo-4-carbonylcyclohexane-1- The carboxylate (7 g, yield: 96%) was used directly in the next step.

The second step: Preparation of ethyl 2-(diethoxymethyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylate:

Ethyl 3-bromo-4-carbonylcyclohexane-1-carboxylate (1.7 g, 5.45 mmol) and 2,2-diethoxyacetylamidine hydrochloride (994.69 mg, 5.45 mmol) were dissolved in acetonitrile (30 mL), potassium carbonate (2.26 g, 16.34 mmol) was added. The mixture was stirred at 120°C for 16 hours. The latter mixture was stirred at 70°C for 16 hours. The reaction solution was cooled to room temperature, saturated brine (30 mL) was added, the mixture was extracted with ethyl acetate (25 mL×3), the organic phase was combined with saturated brine (25 mL×2), washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using (petroleum ether:ethyl acetate=100:0 to 00:100 elution) and then (dichloromethane:methanol=100:0 to 90:10 elution) to give the product Ethyl 2-(diethoxymethyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylate (0.4 g, yield: 20%).

MS m/z(ESI): 297.2[M+H] ⁺ .

The third step: ethyl 2-(diethoxymethyl)-1-(((S)-oxetan-2-yl)methyl)-4,5,6,7-tetrahydro-1H- Preparation of benzo[d]imidazole-6-carboxylate:

Under nitrogen blanket and ice bath, sodium hydrogen (135 mg, 3.37 mmol) was added to ethyl 2-(diethoxymethyl)-4,5,6,7-tetrahydro-1H-benzo[d] In a solution of imidazole-6-carboxylate (0.4 g, 1.35 mmol) in N,N-dimethylformamide (8 mL), the reaction solution was stirred under nitrogen protection and ice bath for 10 minutes, and then (S)-oxa was added. Butan-2-ylmethylmethanesulfonate (336 mg, 2.02 mmol), and the reaction solution was stirred at room temperature overnight. The reaction was quenched with brine (25 mL) under an ice bath. It was extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL×8), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was separated by high pressure liquid chromatography to obtain the product ethyl 2-(diethoxymethyl)-1-(((S)-oxetan-2-yl)methyl)-4,5,6,7- Tetrahydro-1H-benzo[d]imidazole-6-carboxylate (50 mg, yield: 10%).

MS m/z(ESI): 367.2[M+H] ⁺ .

Step 4: Ethyl 2-formyl-1-(((S)-oxbutan-2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole - Preparation of 6-carboxylate:

p-Toluenesulfonic acid monohydrate (2.6 mg, 0.013 mmol) was added to ethyl 2-(diethoxymethyl)-1-(((S)-oxetan-2-yl)methyl)- In a solution of 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.13 mmol) in acetone (8 mL), the reaction solution was stirred at room temperature for 30 minutes. After that, ethyl acetate (50 mL) was added, washed with saturated brine (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain ethyl 2-formyl-1-(((S)-oxetane- 2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylate (36 mg, yield: 90%), used directly in the next step.

MS m/z(ESI): 293.1[M+H] ⁺ .

The fifth step: ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole- Preparation of 6-carboxylate:

Sodium borohydride acetate (78 mg, 0.37 mmol) was added to ethyl 2-formyl-1-(((S)-oxbutan-2-yl)methyl)-4,5,6,7-tetrahydro -1H-Benzo[d]imidazole-6-carboxylate (36 mg, 0.12 mmol) and 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1 ,3] Dioxazol-4-yl)piperidine (56 mg, 0.16 mmol) in 1,2-dichloroethane (10 mL) solution, the reaction solution was stirred at room temperature overnight. The reaction was quenched with saturated brine (50 mL), the organic phase was separated, the organic phase was washed with saturated brine (50 mL×3), the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was separated by thin-layer silica gel chromatography (dichloromethane:methanol=20:1) to give the product ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzene) [d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-4, 5,6,7-Tetrahydro-1H-benzo[d]imidazole-6-carboxylate (43 mg, yield: 56%).

MS m/z(ESI): 624.3[M+H] ⁺ .

Step 6: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6- Preparation of Carboxylic Acids:

In the eleventh step of reference example 1, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 was obtained -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4,5,6,7-tetrahydro-1H-benzo[ d] Imidazole-6-carboxylic acid (16 mg, yield: 39%).

MS m/z(ESI): 596.2[M+H] ⁺ .

Example 94

2-((6-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3-azabicyclo [3.1.0]Hexan-3-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4-carbaldehyde

To -78 degrees Celsius 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (500 mg, 1.46 mmol) in tetrahydrofuran (8 mL ) was added dropwise n-butyllithium (1.75mmol, 1.1mL, 1.6M), -78 was stirred for 1 hour, N,N-dimethylformamide (160mg, 2.19mmol) in tetrahydrofuran (2mL) solution was added dropwise, slowly The temperature was raised to room temperature, stirred for 12 hours, quenched by adding saturated ammonium chloride solution, and then extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain Light yellow oil 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4-carbaldehyde (350 mg, yield: 82%).

MS m/z(ESI): 293.0[M+H] ⁺ .

Step 2: (E)-((2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)methylene) Hydrazine

Using 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4-carbaldehyde as raw material Reference Example 22 The first step to obtain product (E)- ((2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)methylene)hydrazine.

MS m/z(ESI): 307.1[M+H] ⁺ .

The third step: methyl 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)- 2,4-Dicarbonyl-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H - Benzo[d]imidazole-6-carboxylate

To (E)-((2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)methylene)hydrazine (350 mg , 1.14 mmol) in dioxane (5 mL) solution was added manganese dioxide (300 mg, 3.43 mmol), stirred at room temperature for 1 hour, then filtered, to the filtrate was added methyl (S)-2-((2,5 -Dicarbonyl-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Ester (405 mg, 1.14 mmol), then stirred at 100 °C for 12 h, concentrated, and separated by column chromatography to give methyl 2-((6-(2-(4-chloro-2-fluorophenyl) as a pale yellow oil -2-Methylbenzo[d][1,3]bisoxazol-4-yl)-2,4-dicarbonyl-3-azabicyclo[3.1.0]hexane-3-yl)methan yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, yield: 12%).

MS m/z(ESI): 632.1[M+H] ⁺ .

The fourth step: methyl 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)- 3-Azabicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole -6-carboxylate

to methyl 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2,4 -Dicarbonyl-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo [d] Imidazole-6-carboxylate (90 mg, 0.14 mmol) in tetrahydrofuran (4 mL) was added dropwise borane tetrahydrofuran (0.57 mmol, 0.57 mL, 1 M), then refluxed for 5 hours, cooled, and quenched with methanol, Water (30 mL) was added, then extracted with dichloromethane (30 mL×3), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a pale yellow oily methyl 2- ((6-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3-azabicyclo[3.1 .0]Hexan-3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (50mg , Yield: 59%).

MS m/z(ESI): 604.2[M+H] ⁺ .

The fifth step: 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3- Azabicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid

With methyl 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-3-nitrogen Heterobicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6- Carboxylate is the raw material Reference Example 1 The eleventh step obtains the product 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]di oxazol-4-yl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)- 1H-Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 590.2[M+H] ⁺ .

Example 95

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid

Using methyl 4-fluoro-3-nitrobenzoate as raw material Reference Example 30 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d ][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[ d] Imidazole-5-carboxylic acid.

MS m/z(ESI): 592.2[M+H] ⁺ .

Example 96

2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)thiophen-2-yl)methan yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl (S)-2-((5-bromothiophen-2-yl)methyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole- 6-carboxylate

Using 2-(5-bromothiophen-2-yl)acetic acid, methyl(S)-4-amino-3-((oxbutan-2-ylmethyl)amino)benzoate as raw material Reference Example 2 Section 2 The eighth step and the ninth step obtain the product methyl (S)-2-((5-bromothiophen-2-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Imidazole-6-carboxylate.

MS m/z(ESI): 421.0[M+H] ⁺ .

The second step: methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)thiophene -2-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl (S)-2-((5-bromothiophen-2-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate acid ester, 2-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane is the raw material Reference Example 1 The first step is to obtain the product methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2 -Methylbenzo[d][1,3]bisoxazol-4-yl)thiophen-2-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl) -1H-Benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 605.1[M+H] ⁺ .

The third step: 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)thiophene-2 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)thiophene-2- Base) methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 The eleventh step obtained Product 2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)thiophen-2-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 591.1[M+H] ⁺ .

Example 97

2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)thiophen-3-yl)methan yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-(5-chlorothiophen-3-yl)acetic acid as raw material, the first, second and third steps of Reference Example 96 obtained the product 2-((5-(2-(4-chloro-2-fluorophenyl)-2 -Methylbenzo[d][1,3]bisoxazol-4-yl)thiophen-3-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl) -1H-Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 591.1[M+H] ⁺ .

Example 98

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-4-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-Chloro-2-fluorophenyl)-2-(2,6-dibromophenyl)ethane-1-ol

Using 1-bromo-4-chloro-2-fluorobenzene and 2-(2,6-dibromophenyl)acetaldehyde as raw materials Reference Example 94 The first step to obtain 1-(4-chloro-2-fluorophenyl) )-2-(2,6-dibromophenyl)ethane-1-ol.

MS m/z(ESI): 408.8[M+H] ⁺ .

The second step: 1-(4-Chloro-2-fluorophenyl)-2-(2,6-dibromophenyl)ethan-1-one

Using 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenyl)ethane-1-ol as raw material Reference Example 34 The second step obtained 1-(4-chloro- 2-Fluorophenyl)-2-(2,6-dibromophenyl)ethan-1-one.

MS m/z(ESI): 406.8[M+H] ⁺ .

The third step: 2-(4-chloro-2-fluorophenyl)-1-(2,6-dibromophenyl)propan-2-ol

Using 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenyl) ethane-1-one as raw material Reference Example 30 The first step was to obtain 2-(4-chloro- 2-Fluorophenyl)-1-(2,6-dibromophenyl)propan-2-ol.

MS m/z(ESI): 422.8[M+H] ⁺ .

The fourth step: 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran

Using 2-(4-chloro-2-fluorophenyl)-1-(2,6-dibromophenyl)propan-2-ol as raw material Reference Example 53 The first step to obtain 4-bromo-2-(4 -Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran.

MS m/z(ESI): 341.0[M+H] ⁺ .

The fifth step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran as raw material Reference Example 1 First, Second, Six, Ten, Eleven Step to get 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-4-yl)piperidin-1-yl)methan yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 590.2[M+H] ⁺ .

Example 99

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-Chloro-2-fluorophenyl)-2-(2,3-dichlorophenyl)ethane-1-ol

Using 1-bromo-4-chloro-2-fluorobenzene and 2-(2,6-dichlorophenyl)acetaldehyde as raw materials Reference Example 94 The first step to obtain 1-(4-chloro-2-fluorophenyl) )-2-(2,3-dichlorophenyl)ethane-1-ol.

MS m/z(ESI): 319.0[M+H] ⁺ .

The second step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(4-chloro-2-fluorophenyl)-2-(2,3-dichlorophenyl) ethane-1-ol as raw material Reference Example 98 The second, third, fourth and fifth steps to obtain product 2 -((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 590.2[M+H] ⁺ .

Example 100

2-((4-(2-(4-Chloro-2-fluorophenyl)-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin -6-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 3-bromo-2-(methylamino)phenol as raw material Reference Example 37 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-5-methyl-2,3 ,4,5-Tetrahydrobenzo[b][1,4]oxazepin-6-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 619.2[M+H] ⁺ .

Example 101

2-((4-(3-(4-Chloro-2-fluorophenyl)-3,5-dimethyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxa azepin-6-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6- carboxylic acid

MS m/z(ESI): 633.2[M+H] ⁺ .

Example 102

2-((4-(2-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-2,3-dihydrobenzo[d]thiazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 3-bromo-2-(methylamino)benzenethiol as raw material Reference Example 7 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dimethylene yl-2,3-dihydrobenzo[d]thiazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)- 1H-Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 621.2[M+H] ⁺ .

Example 103

2-((4-(2-(Benzo[b]thiophen-5-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-(benzo[b]thiophen-5-yl)ethan-1-one as the raw material, the product 2-((4-(2-(benzo[b]thiophen-5-yl) was obtained in reference example 7 from the reference example 7. -2-Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl) methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 596.2[M+H] ⁺ .

Example 104

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-4-cyano-2 ,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid

The first step: tert-butyl 3-cyano-4-carbonylpyrrolidine-1-carboxylate

Under ice bath, tert-butyl 3-cyano-4-hydroxypyrrolidine-1-carboxylate (2.12 g, 10 mmol) was dissolved in dichloromethane (25 mL), and Dess-Martin reagent (6.36 g, 10 mmol) was added. 15 mmol), replaced with nitrogen, and stirred at room temperature overnight. The reaction solution was quenched with saturated sodium thiosulfate solution, the reaction solution was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was washed with silica gel Column chromatography (PE:EA=10:1-2:3) gave tert-butyl 3-cyano-4-carbonylpyrrolidine-1-carboxylate (1.47 g, 70%).

MS m/z(ESI): 211.1[M+H] ⁺ .

The second step: tert-butyl 3-cyano-4-(((trifluoromethyl)sulfonyl)oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate

At -78°C, tert-butyl 3-cyano-4-carbonylpyrrolidine-1-carboxylate (1.47 g, 7 mmol) was dissolved in tetrahydrofuran (20 mL), nitrogen was replaced, and then hexamethyldisilazane was added dropwise The n-hexane solution of lithium amide (0.9M, 9mL, 8.1mmol), after the dropwise addition, was stirred at -78°C for 20 minutes, and then 1,1,1-trifluoro-N-phenyl-N-( A solution of trifluoromethanesulfonyl)methanesulfonamide (2.88g, 8mmol) in tetrahydrofuran (30mL), stirred at -78°C, warmed to room temperature and stirred overnight, the reaction solution was quenched with water (100mL), separated, and the organic phase was Dry over anhydrous sodium sulfate, filter, spin dry, and separate the crude product by column chromatography (PE:EA=10:1) to obtain tert-butyl 3-cyano-4-(((trifluoromethyl)sulfonyl )oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.84 g, 35%).

MS m/z(ESI): 343.1[M+H] ⁺ .

The third step: tert-butyl 3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2,5-di Hydrogen-1H-pyrrole-1-carboxylate

At room temperature, tert-butyl 3-cyano-4-(((trifluoromethyl)sulfonyl)oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.84 g, 2.45 g mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.75g, 2.94mmol), potassium acetate (0.44g, 4.5mmol), Pd(dppf)Cl ₂ (183mg, 0.25mmol), dppf (137mg, 0.25mmol) were dissolved in dioxane (10mL), replaced with nitrogen, heated to 80 ℃, react overnight. Cool to room temperature, filter with celite, wash with ethyl acetate, combine the organic phases, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, spin dry, the crude product is directly used for Next step.

MS m/z(ESI): 321.2[M+H] ⁺ .

The fourth step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-4- Cyano-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid

Taking the mixture of the third step above as a raw material, the first step, the second step, the third step, and the fourth step of Reference Example 80 obtain 2-((3-(2-(4-chloro-2-fluorophenyl )-2-methylbenzo[d][1,3]dioxazol-4-yl)-4-cyano-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1 -(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 601.2,603.2[M+H] ⁺ .

Example 105

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-4-fluoro-2, 5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-4- Fluoro-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid

Using tert-butyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate as a raw material, the first step, the second step, the third step, and the fourth step in Reference Example 104 obtain 2-((3-(2 -(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-4-fluoro-2,5-dihydro-1H-pyrrole -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 594.2,596.2[M+H] ⁺ .

Example 106

2-((3-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-4-methyl-2 ,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid

The first step: 2-((3-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-4- Methyl-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid

Using tert-butyl 3-methyl-4-hydroxypyrrolidine-1-carboxylate as raw material, Reference Example 104 The first step, the second step, the third step, and the fourth step obtain 2-((3-( 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-4-methyl-2,5-dihydro-1H -pyrrol-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 590.2,592.2[M+H] ⁺ .

Example 107

2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

with 3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)benzonitrile and ethyl 2-( Bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate as raw material Reference Example 90 to product 2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 107-1

2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid preparation

Taking P2 in Example 92-1 as the raw material and referring to the eleventh step of Example 1, the product 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methyl was obtained Benzo[d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H - Thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 107-2

2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-thieno[2,3-d]imidazole-5-carboxylic acid preparation

Taking P4 in Example 92-1 as the raw material and referring to the eleventh step of Example 1, the product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2-methyl was obtained Benzo[d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H - Thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 588.8[M+H] ⁺ .

Example 108

2-(((2S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2- Methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: tert-butyl(2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-2-methylpiperazine-1-carboxylate preparation

To 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole (1 g, 2.91 mmol), tert-butyl (S) A mixture solution of -2-methylpiperazine-1-carboxylate (612.07 mg, 3.06 mmol) and cesium carbonate (2.84 g, 8.73 mmol) and toluene (30 mL) was added tris(dibenzylideneacetone)dipalladium ( 266.53 mg, 291.06 μmol) and 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (271.63 mg, 582.11 μmol). After nitrogen replacement, the reaction was carried out at 80 ° C for 12 hours. After the reaction was completed, it was cooled and filtered, and the filtrate was concentrated under reduced pressure to dryness. The crude product was separated and purified by column chromatography (PE:EA=10:1-5:1) to obtain tert-butyl (2S). )-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2-methylpiperazine-1 - Carboxylic acid ester (820 mg, yield: 61%).

MS m/z(ESI): 463.1[M+H] ⁺ .

The second step: (3S)-1-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3- Preparation of methylpiperazine

tert-Butyl(2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2 -Methylpiperazine-1-carboxylate (820 mg, 1.77 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the reaction was carried out at room temperature for 3 hours. After the solvent was removed, ethyl acetate (10 mL) was added, washed with saturated sodium bicarbonate solution (5 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (3S)-1-(2 -(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3-methylpiperazine (600 mg, yield: 93.36% ).

MS m/z(ESI): 363.1[M+H] ⁺ .

Steps 3 to 6: 2-(((2S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3- Preparation of d]imidazole-5-carboxylic acid

Reference Example 90 to obtain the product 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d] Imidazole-5-carboxylic acid.

MS m/z(ESI): 612.8[M+H] ⁺ .

Example 109

2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl )methyl)-6-methyl-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 1-(4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethane-1 - Preparation of ketones

4,5-Dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1 g, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL) , n-butyllithium (1.6M, 1.86mL, 2.97mmol) was added dropwise at -78°C, and the reaction was carried out for 15 minutes. The reaction was added dropwise to a solution (10 mL) of acetyl chloride (223 mg, 2.84 mmol) in tetrahydrofuran cooled to -78°C, and the reaction was carried out at -78°C for 30 minutes and then warmed to room temperature for 1 hour. The reaction was quenched by the addition of ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried, spin-dried, and purified by column chromatography to obtain the product 1-(4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Imidazol-5-yl)ethan-1-one (100 mg, yield: 11%).

MS m/z(ESI): 333.2[M+H] ⁺ .

Step 2: Ethyl 2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5 - Preparation of carboxylate

Methyl 2-mercaptoacetate (64 mg, 0.6 mmol) was dissolved in ethanol (5 mL), sodium ethoxide (20%, 204 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 1 hour. 1-(4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethan-1-one ( 100 mg, 0.3 mmol) dissolved in ethanol (5 mL) was added to the reaction solution and reacted at 75°C for 16 hours. After the solvent was spun off, water was added and extracted with ethyl acetate. The organic phase was dried, spin-dried, and purified by column chromatography to obtain the product ethyl 2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno [2,3-d]imidazole-5-carboxylate (60 mg, yield: 56%).

MS m/z(ESI): 355.2[M+H] ⁺ .

Steps 3 to 7:

Ethyl 2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid Ester as raw material, referring to the fourth to eighth steps of Example 90, the product 2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1, 3] Dioxazol-4-yl)piperidin-1-yl)methyl)-6-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-thieno [2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 612.2[M+H] ⁺ .

Example 110

2-(((2S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2- Methylpiperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: tert-butyl(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate and tert-Butyl(S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate

At -78°C, tert-butyl (S)-2-methyl-4-carbonylpiperidine-1-carboxylate (4.0 g, 19.18 mmol) was dissolved in tetrahydrofuran (40 mL), nitrogen was replaced, and six A n-hexane solution of lithium methyldisilazide (1.0 M, 28.77 mL, 28.77 mmol) was added dropwise, stirred at -78°C for 20 minutes, and then added dropwise with 1,1,1-trifluoro-N- A solution of phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (8.22 g, 23.01 mmol) in tetrahydrofuran (30 mL) was stirred at -78°C, and then warmed to room temperature and stirred overnight. The reaction solution was quenched with saturated ammonium chloride quenched (100 mL), separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and spun dry, and the crude product was separated by column chromatography (PE:EA=10:1) to obtain tert-butyl (S)-2-methyl. yl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl(S)-6-methyl-4 - Mixture of (((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate (4.5 g, 68%, red oil).

¹ H NMR (400M, CDCl ₃ ) δ 5.78-5.75(m, 0.3H), 5.74-5.71(m, 0.7H), 4.80-4.56(br, 1H), 4.46-4.35(m, 0.3H), 4.33-4.16(m, 0.7H), 3.66-3.22(m, 0.3H), 3.06-2.92(m, 0.7H), 2.93-2.78(m, 0.3H), 2.61-2.56(m, 0.7H), 2.23-2.18(m, 0.7H), 2.09-2.05(m, 0.3H), 1.48(s, 6.3H), 1.45(s, 2.7H), 1.23(d, J=6.8Hz, 2.1H), 1.17 (d, J=6.8Hz, 0.9H).

The second step: tert-butyl (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3 ,6-dihydropyridine-1(2H)-carboxylate and tert-butyl(S)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

At room temperature, tert-butyl(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate and A mixture of tert-butyl and (S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate ( 3.6g, 10.42mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.97g, 15.64mmol), potassium acetate (2.56g, 26.06mmol), Pd(dppf)Cl ₂ (0.76g, 1.04mmol), dissolved in dioxane (20mL), replaced with nitrogen, heated to 90°C, React overnight. After cooling to room temperature, the reaction solution was directly used in the next step without post-treatment.

The third step: tert-butyl (6S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl(2S)-4-(2-(4-chloro-2-fluorophenyl)-2 -Methylbenzo[d][1,3]bisoxazol-4-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate

At room temperature, the reaction solution obtained in step 2 was stirred at room temperature, and then 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]di Oxazole (2.15 g, 6.26 mmol), sodium carbonate (3.32 g, 31.28 mmol), Pd(dppf)Cl ₂ (0.76 g, 1.04 mmol), dioxane (10 mL) and water (6 mL), displacement nitrogen, Heated to 90°C, reacted for 14 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then filtered with celite, washed with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine (15 mL×2), and the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, spin dry, and purify the residue by flash chromatography on silica gel (petroleum ether:ethyl acetate = 85:15 to 50:50) to give the desired product as a colorless oil (0.7 g, 14.6 %, two-step total yield).

MS m/z(ESI): 460.2,462.2[M+H] ⁺ .

The fourth step: tert-butyl (2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-2-methylpiperidine-1-carboxylate

At room temperature, tert-butyl(6S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl(2S)-4-(2-(4-chloro-2-fluorophenyl)-2 -Methylbenzo[d][1,3]bisoxazol-4-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate mixture (0.70 g, 1.52 mmol) was dissolved in methanol, then Wilkinson's catalyst (0.07 g, 0.076 mmol) was added, hydrogen was replaced, heated to 50° C., reacted for 14 hours, and cooled to room temperature. LCMS indicated the end of the reaction, spin to dryness, and the residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 95:5 to 80:20 elution) to give tert-butyl(2S)-4-(2-(4- Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2-methylpiperidine-1-carboxylate (0.35 g, 50% , colorless oil).

MS m/z(ESI): 462.2,464.2[M+H]+.

The fifth step: 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-2-Methylpiperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole- 5-Carboxylic acid

with tert-butyl(2S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2 -Methylpiperidine-1-carboxylate is a raw material, and the sixth step, tenth step, embodiment ninety-sixth, seventh step and embodiment one eleventh step are obtained in turn with reference to the 11th step of Example 1 to obtain 2-( ((2S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2-methylpiperidine pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 612.2,614.2[M+H] ⁺ .

Example 111

5-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

The first step: 2-methyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Using 2-methyl-5-nitro-1H-imidazole as raw material Reference Example 90 The first step to obtain the product 2-methyl-5-nitro-1-((2-(trimethylsilyl)ethoxy) yl)methyl)-1H-imidazole.

MS m/z(ESI): 258.1[M+H] ⁺ .

Step 2: 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine

Using 2-methyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as raw material Reference Example 1 The eighth step to obtain the product 2-methyl -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine.

MS m/z(ESI): 228.1[M+H] ⁺ .

The third step: 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine

2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine (3 g, 21.9 mmol) was dissolved in CH2Cl2 (50 mL) and added Ethyl 2-chloro-2-carbonyl acetate (3.6 g, 26.3 mmol) and DIPEA (8.4 g, 65.7 mmol) were stirred at room temperature for 3 h. Water was added, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 2-methyl-1-(((2-(trimethyl) silyl)ethoxy)methyl)-1H-imidazol-5-amine (3 g, yield: 42%).

MS m/z(ESI): 328.1[M+H] ⁺ .

Step 4: Ethyl 2-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)amino)-2- Thioacetate

2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine (1 g, 3 mmol) was dissolved in toluene (20 mL), and laurel was added. Sen's reagent (860 mg, 2.1 mmol), stirred at 130 °C for 12 h under nitrogen protection. Water was added, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain ethyl 2-((2-methyl-1-( (2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)amino)-2-thioacetate (700 mg, yield: 68%).

MS m/z(ESI): 344.1[M+H] ⁺ .

Step 5: Ethyl 5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid ester

Ethyl 2-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)amino)-2-thioethyl The acid ester (100 mg, 0.29 mmol) was dissolved in CH ₂ Cl ₂ (5 mL), NBS (77 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature for 3 h. Concentration and column chromatography gave ethyl 5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-imidazo[4,5-d]thiazole- 2-Carboxylic acid ester (10 mg, yield: 10%).

MS m/z(ESI): 342.1[M+H] ⁺ .

Step 6: Ethyl 5-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylate

Reference Example 90 The fourth step to the seventh step obtains the product ethyl 5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3] Dioxazol-4-yl)piperidin-1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d] Thiazole-2-carboxylate.

MS m/z(ESI): 627.1[M+H] ⁺ .

Step Seven: 5-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

In the eleventh step of reference example 1, the product 5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 was obtained -yl)piperidin-1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxy acid.

MS m/z(ESI): 599.1[M+H] ⁺ .

Example 111-1

5-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

Reference Example 90-1 The fourth step to the sixth step obtains the product 55-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4, 5-d]thiazole-2-carboxylic acid.

MS m/z(ESI): 599.1[M+H] ⁺ .

Example 112

5-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl) Methyl)-6-(((S)-oxbutan-2-yl)methyl)-6H-imidazo[4,5-d]thiazole-2-carboxylic acid

Example 111 Hydrolysis of the by-product of the thiazoimidazole alkylation reaction in the ninth step to obtain the product 5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] [1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-6-(((S)-oxbutan-2-yl)methyl)-6H-imidazo[4 ,5-d]thiazole-2-carboxylic acid.

MS m/z(ESI): 599.1[M+H] ⁺ .

Example 112-1

5-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-6-(((S)-oxbutan-2-yl)methyl)-6H-imidazo[4,5-d]thiazole-2-carboxylic acid

Reference Example 111-1 Obtained the product 5-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-6-(((S)-oxetan-2-yl)methyl)-6H-imidazo[4,5-d]thiazole-2 - Carboxylic acid.

MS m/z(ESI): 599.1[M+H] ⁺ .

Example 113

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin

Using 2-bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one as raw material Reference Example 52 The first, second and third steps to obtain the product 8-bromo-2-(4-chloro-2 -Fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin.

Step 2: Methyl (S)-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

Using 6-chloro-5-nitro-pyridine-2-carboxylic acid as raw material Reference Example 83 The first, second and third steps to obtain the product methyl (S)-2-(chloromethyl)-3-(oxetane) -2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate.

MS m/z(ESI): 296.1,298.1[M+1] ⁺ .

Step 3: 2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- carboxylic acid

With 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin and methyl(S)-2 -(Chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as raw material Reference Example 1 First, Second, Six , ten and eleven steps to obtain the product 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b] Pyridine-5-carboxylic acid.

MS m/z(ESI): 607.2[M+H] ⁺ .

Example 114

2-((4-(3-(4-Cyano-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-(2-bromoacetyl)-3-fluorobenzonitrile as raw material Reference Example 52 to obtain the product 2-((4-(3-(4-cyano-2-fluorophenyl)-3-methyl -2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 597.2[M+H] ⁺ .

Example 115

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1-( ((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methylchroman-4-one

1-(3-Bromo-2-hydroxyphenyl)ethane-1-one (2 g, 9.3 mmol), 1-(4-chloro-2-fluorophenyl)ethane-1- The ketone (1.61 g, 9.3 mmol) was dissolved in acetonitrile (30 mL), then tetrahydropyrrole (963 mg, 9.3 mmol) was added, followed by stirring at 70 degrees Celsius for 24 hours. Cooled, quenched with water, extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by column chromatography to obtain 8-bromo-2-(4-chloro-2 -Fluorophenyl)-2-methylchroman-4-one (300 mg, yield: 8%).

MS m/z(ESI): 369.0[M+H] ⁺ .

The second step: methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Take 8-bromo-2-(4-chloro-2-fluorophenyl)-2-methylchroman-4-one as raw material Reference Example 1 First, two, six, ten steps to obtain product methyl 2-( (4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1-(((S )-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 632.2[M+H] ⁺ .

The third step: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate is the raw material Reference Example 1 The eleventh step obtains the product 2-((4 -(2-(4-Chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1-(((S)- Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 618.2[M+H] ⁺ .

Example 116

2-((4-(2-(4-Chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Add methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-4-carbonylchroman-8-yl)piperidin-1-yl successively into the 50mL three-necked flask )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.16 mmol) and dry dichloromethane (5 mL), diethylaminosulfur trifluoride (52 mg, 0.32 mmol) was slowly added dropwise under an ice bath at 0°C under nitrogen protection. The reaction solution was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by column chromatography to obtain methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (28 mg, yield: 27%).

MS m/z(ESI): 654.2[M+H] ⁺ .

Step 2: 2-((4-(2-(4-Chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidin-1-yl)methan Base)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 Eleventh step to obtain product 2- ((4-(2-(4-Chloro-2-fluorophenyl)-4,4-difluoro-2-methylchroman-8-yl)piperidin-1-yl)methyl)-1- (((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 640.2[M+H] ⁺ .

Example 117

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: ethyl 2-bromo-2-(4-chloro-2-fluorophenyl) acetate

Ethyl 2-(4-chloro-2-fluoro-phenyl)acetate (4 g, 18 mmol) was dissolved in carbon tetrachloride (50 mL) and 1-bromopyrrolidine-2,5-dione (3.6 g, 20.0 mmol) and benzoyl peroxide (0.9 g, 3.7 mmol) and stirred at 80°C for 1 hour. The solvent was spin-dried, water (30 mL) was added, the aqueous phase was extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain ethyl 2-Bromo-2-(4-chloro-2-fluorophenyl)acetate (5 g, yield: 91%), colorless liquid.

The second step: ethyl 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl) acetate

Ethyl 2-bromo-2-(4-chloro-2-fluorophenyl)acetate (5 g, 17 mmol) and 2-bromophenol (3.2 g, 18.6 mmol) were dissolved in acetonitrile (100 mL) and potassium carbonate was added (7.0 g, 50 mmol) and the reaction was stirred at 70 °C for 5 hours. Water (100 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain ethyl 2-(2-bromobenzene) oxy)-2-(4-chloro-2-fluorophenyl)acetate (5.5 g, yield: 84%), colorless gum.

MS m/z(ESI): 387.1, 389.1 [M+H] ⁺ .

The third step: ethyl 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl) propionate

Ethyl 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl)acetate (1 g, 2.6 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0 °C, and hydrogenated Sodium (125 mg, 3.1 mmol) and the reaction was stirred at this temperature for half an hour. Iodomethane (0.44 g, 3.1 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 18 hours. Water (30 mL) was added to the reaction, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain ethyl 2-(2-bromophenoxy yl)-2-(4-chloro-2-fluorophenyl)propanoate (0.6 g, yield: 57%), colorless gum.

MS m/z(ESI): 401.2, 403.2 [M+H] ⁺ .

The fourth step: 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl)propionic acid

Ethyl 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl)propionate (0.6 g, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), water (5 mL), lithium hydroxide (0.36 g, 15 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was spin-dried, water (10 mL) was added, the pH was adjusted to ~2 with dilute hydrochloric acid, the aqueous phase was extracted with ethyl acetate (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was subjected to column chromatography Isolation gave 2-(2-bromophenoxy)-2-(4-chloro-2-fluorophenyl)propionic acid (0.5 g, yield: 89%) as a pale yellow solid.

MS m/z(ESI): 373.2, 375.2 [M+H] ⁺ .

The fifth step: 7-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzofuran-3(2H)-one

2-(2-Bromophenoxy)-2-(4-chloro-2-fluorophenyl)propanoic acid (0.5 g, 1.34 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 °C, added with trichloromethane fluoromethanesulfonic acid (10 mL) and the reaction was stirred at room temperature overnight. Water (30 mL) was added to the reaction, the aqueous phase was extracted with dichloromethane (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain 7-bromo-2-(4-chloro- -2-Fluorophenyl)-2-methylbenzofuran-3(2H)-one (0.3 g, yield: 64%), pale yellow solid.

MS m/z(ESI): 353.1, 355.1 [MH] ^- .

The sixth step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)-3 ,6-Dihydropyridine-1(2H)-carboxylate

Using 7-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzofuran-3(2H)-one as raw material Reference Example 1 The first step to obtain the product tert-butyl 4- (2-(4-Chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H )-carboxylate.

MS m/z(ESI): 458.2[M+H] ⁺ .

The seventh step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl) piperidine -1-Carboxylic acid ester

With tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)-3,6- Dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 1 The second step obtains the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3 - Carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate.

MS m/z(ESI): 460.2[M+H] ⁺ .

The eighth step: 2-(4-chloro-2-fluorophenyl)-2-methyl-7-(piperidin-4-yl)benzofuran-3(2H)-one

Take tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine-1- Carboxylic acid ester is the raw material Reference Example 1 The sixth step obtains the product 2-(4-chloro-2-fluorophenyl)-2-methyl-7-(piperidin-4-yl)benzofuran-3(2H )-ketone.

MS m/z(ESI): 360.2[M+H] ⁺ .

The ninth step: methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Using 2-(4-chloro-2-fluorophenyl)-2-methyl-7-(piperidin-4-yl)benzofuran-3(2H)-one as raw material, the tenth step of Reference Example 1 was obtained. Product Methyl 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 618.2[M+H] ⁺ .

Step 10: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine- 1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 Tenth One-step product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 604.2[M+H] ⁺ .

Example 118

2-((4-(2-(4-Chloro-2-fluorophenyl)-3,3-difluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluoro-2-methyl-2,3-dihydrobenzofuran-7-yl ) piperidine-1-carboxylate

tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine-1- Carboxylic acid ester (0.1 g, 0.22 mmol) was dissolved in dichloromethane (10 mL), bis(2-methoxyethyl)aminosulfur trifluoride (0.25 g, 1.1 mmol) and a drop of methanol were added, and the reaction was carried out at 60 °C under stirring for 18 hours. Water (20 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain tert-butyl 4-(2-(4). -Chloro-2-fluorophenyl)-3,3-difluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.06g, yield : 57%), colorless gum.

MS m/z(ESI): 482.2[M+H] ⁺ .

The second step: 2-((4-(2-(4-chloro-2-fluorophenyl)-3,3-difluoro-2-methyl-2,3-dihydrobenzofuran-7-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine -1-Carboxylic acid ester as raw material Reference Example 117 Eighth to tenth steps to obtain product 2-((4-(2-(4-chloro-2-fluorophenyl)-3,3-difluoro-2 -Methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H - Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 626.2[M+H] ⁺ .

Example 119

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidine-1-carboxylate

tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-7-yl)piperidine-1- Carboxylic acid ester (0.1 g, 0.22 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, sodium bicarbonate (37 mg, 0.44 mmol), 3-chloro-benzoperoxyacid (76 mg, 0.44 mmol) were added , the reaction was stirred at room temperature for 18 hours. Water (30 mL) was added to the reaction, the aqueous phase was extracted with dichloromethane (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain tert-butyl 4-(3-( 4-Chloro-2-fluorophenyl)-3-methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate acid ester (55 mg, yield: 53%), colorless gum.

MS m/z(ESI): 476.2[M+H] ⁺ .

Step 2: 2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6- carboxylic acid

With tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4]dioxin -5-yl)piperidine-1-carboxylate as raw material Reference Example 117 The product 2-((4-(3-(4-chloro-2-fluorophenyl)-3 is obtained from the eighth step to the tenth step) -Methyl-2-carbonyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S) -oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 620.2[M+H] ⁺ .

Example 120

6-Chloro-2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: the preparation of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonitrile

4,5-Dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1 g, 2.7 mmol) was dissolved in tetrahydrofuran (15 mL) , n-butyllithium (1.6M, 1.9mL, 2.97mmol) was added dropwise at -78°C, and the reaction was carried out for 10 minutes. p-Toluenesulfonyl cyanide (514 mg, 2.84 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction system, and the reaction was carried out at -78° C. for 15 minutes and then raised to room temperature for 1 hour. The reaction was quenched by the addition of ammonium chloride solution (5 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried, spin-dried, and purified by column chromatography to obtain the product 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5 - Formonitrile (320 mg, yield: 37%).

MS m/z(ESI): 317.2[M+H] ⁺ .

Step 2: Ethyl 6-amino-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole- Preparation of 5-carboxylate

Methyl 2-mercaptoacetate (215 mg, 2 mmol) was dissolved in ethanol (10 mL), sodium ethoxide (20%, 688 mg, 2 mmol) was added, and the reaction was carried out at room temperature for 1 hour. 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonitrile (320 mg, 1 mmol) was dissolved in ethanol (10 mL) ) was added to the reaction solution and reacted at 75°C for 16 hours. After the solvent was removed, water (5 mL) was added, followed by extraction with ethyl acetate (10 mL). The organic phase was dried and then rotated to dryness, and purified by column chromatography to obtain the product ethyl 6-amino-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thiophene Di[2,3-d]imidazole-5-carboxylate (260 mg, yield: 72%).

MS m/z(ESI): 356.2[M+H] ⁺ .

Step 3: Ethyl 6-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole- Preparation of 5-carboxylate

Ethyl 6-amino-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The acid ester (260 mg, 0.56 mmol) was dissolved in acetonitrile (10 mL), and isoamyl nitrite (100 mg, 0.85 mmol) was added dropwise in an ice bath to react for 10 minutes. After adding copper chloride (151 mg, 1.13 mmol), the reaction was carried out for 20 minutes, and the temperature was raised to room temperature to continue the reaction for 2 hours. Water (10 mL) was added and extracted with ethyl acetate (10 mL). The organic phase was dried and then rotated to dryness, and purified by column chromatography to obtain the product ethyl 6-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thiophene Di[2,3-d]imidazole-5-carboxylate (130 mg, yield: 47%).

MS m/z(ESI): 375.1[M+H] ⁺ .

Steps 4 to 8:

Reference Example 90 gave the product 6-chloro-2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5- carboxylic acid.

MS m/z(ESI): 623.2,625.1[M+H] ⁺ .

Example 121

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Step 2: 2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol

¹ H NMR(400MHz, CDCl3)δ7.56-7.47(m,1H),7.25-7.21(m,1H),7.18-7.12(m,2H),6.93-6.85(m,1H),6.81-6.71( m, 1H), 5.52–5.43 (m, 1H), 4.49–4.40 (m, 1H), 3.99–3.89 (m, 1H).

The fourth step: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)- 3,6-Dihydropyridine-1(2H)-carboxylate

8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (80 mg, 232.85 μmol), 4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (108.00 mg, 349.27μmol) and sodium carbonate (74.04mg, 698.54μmol) were dissolved in 1'4-dioxane (5mL) and water (1.5mL), under nitrogen protection, 1,1'-bisdiphenylphosphine was added Ferrocene palladium dichloride (17.04 mg, 23.28 μmol). The mixture was stirred at 85°C for 3 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (25 mL), the mixture was separated, the organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography ( Petroleum ether:ethyl acetate=10:1) to obtain the target product tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1, 4] Dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27 mg, 60.55 μmol, yield: 26.00%).

MS m/z(ESI): 446.2[M+H] ⁺ .

The fifth step: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine pyridine-1-carboxylate

tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6 - Dihydropyridine-1(2H)-carboxylate (32 mg, 71.76 μmol) was dissolved in methanol (5 mL), and Wilkinson’s catalyst (13.28 mg, 14.35 μmol) was added under nitrogen protection. The mixture was stirred at 50°C for 16 hours under a hydrogen (1 atm) atmosphere. The reaction solution was evaporated to dryness, and the crude product was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2 ,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (15 mg, 33.49 μmol, yield: 46.66%).

MS m/z(ESI): 448.2[M+H] ⁺ .

Step 6: 2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 -Carboxylic acid ester as raw material Reference Example 1 Sixth, tenth and eleventh step to obtain the product 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b ][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 592.2[M+H] ⁺ .

Example 121-1

2-((4-((S)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Intermediate Im-7A (59 mg, 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (50 mg, 170 μmol) and potassium carbonate (65 mg, 340 μmol), stirred at 50° C. for 4 hours, added water, and then added ethyl acetate for extraction, the organic phase was dried and then revolved to dryness. The product was purified by column chromatography to give 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid methyl ester (60 mg, 58.3%).

MS m/z(ESI): 606.2[M+H] ⁺ .

Step 2: 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((S)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 99 μmol ) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, the organic phase was dried and then spin-dried. The product was purified by prep-HPLC to give 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid (30 mg, 51%).

MS m/z(ESI): 592.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.53-7.41 (m, 2H), 7.36(d, J=8.3Hz, 1H), 6.81–6.68 (m, 3H), 5.43–5.37 (m, 1H), 5.03–4.95 (m, 1H), 4.76–4.66 (m, 1H) ,4.61–4.52(m,1H),4.46–4.25(m,3H),4.08–3.99(m,1H),3.86(d,J=13.5Hz,1H),3.69(d,J=13.5Hz,1H) ), 2.93–2.87 (m, 1H), 2.82–2.74 (m, 2H), 2.66–2.55 (m, 1H), 2.38–2.27 (m, 1H), 2.18–2.03 (m, 2H), 1.74–1.62 (m,3H),1.57–1.43(m,1H).

Example 121-2

2-((4-((R)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Intermediate Im-7B (59 mg, 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (50 mg, 170 μmol) and potassium carbonate (65 mg, 340 μmol), stirred at 50 °C for 4 hours, added water, and then extracted with ethyl acetate. The product was purified by column chromatography to give 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid methyl ester (60 mg, 58.3%).

MS m/z(ESI): 606.2[M+H] ⁺ .

Step 2: 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((R)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 99 μmol ) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, the organic phase was dried and then spin-dried. The product was purified by prep-HPLC to give 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid (30 mg, 51%).

MS m/z(ESI): 592.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.55 (d, J=8.3Hz, 1H), 7.53-7.42 (m, 2H), 7.36 (d, J=8.3Hz, 1H), 6.81–6.68 (m, 3H), 5.40 (d, J=7.7Hz, 1H), 5.06–4.95 (m, 1H), 4.76–4.66 (m ,1H),4.61–4.52(m,1H),4.46–4.33(m,2H),4.33–4.24(m,1H),4.08–3.99(m,1H),3.84(d,J=13.6Hz,1H ), 3.71(d, J＝13.4Hz, 1H), 2.94-2.87(m,1H), 2.82-2.75(m,2H), 2.66-2.57(m,1H), 2.37-2.28(m,1H), 2.19–2.09 (m, 1H), 2.09–1.98 (m, 1H), 1.76–1.69 (m, 1H), 1.65–1.51 (m, 3H).

Example 122

2-((4-(3-(3-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-bromo-1-(3-chloro-2-fluorophenyl)ethan-1-one as raw material Reference Example 121 to obtain the product 2-((4-(3-(3-chloro-2-fluorophenyl) )-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 592.2[M+H] ⁺ .

Example 123

2-((4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl )methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-chloro-1-(2,4-dichlorophenyl)ethan-1-one as raw material Reference Example 121 to obtain the product 2-((4-(3-(2,4-dichlorophenyl) -2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 608.1[M+H] ^+.

Example 123-1

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Intermediate Im-8A (61.8 mg, 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Methyl imidazole-6-carboxylate (50 mg, 170 μmol) and potassium carbonate (65 mg, 340 μmol) were stirred at 50 °C for 4 hours, water was added, and then ethyl acetate was added for extraction. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to give 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid methyl ester (50 mg, 47.3%).

MS m/z(ESI): 622.1[M+H] ⁺ .

Step 2: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (50 mg, 80 μmol) Dissolve in THF (3mL), add 2mol/L LiOH (1mL), stir at 40°C overnight, add 1mol/L HCl, adjust pH to 5-6, add ethyl acetate, extract, dry the organic phase and spin dry, the crude product Purification by prep-HPLC to give 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ( 20 mg, 40.9%).

MS m/z(ESI): 608.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.19(s,1H),7.76-7.67(m,2H),7.59-7.46(m,3H),6.83-6.69(m,3H),5.38(dd , J=7.9, 2.4Hz, 1H), 5.06–4.95 (m, 1H), 4.77–4.67 (m, 1H), 4.61–4.52 (m, 1H), 4.46–4.35 (m, 2H), 4.35–4.25 (m, 1H), 4.01–3.91 (m, 1H), 3.86 (d, J=13.6Hz, 1H), 3.68 (d, J=13.5Hz, 1H), 2.95–2.87 (m, 1H), 2.82– 2.75 (m, 2H), 2.66–2.57 (m, 1H), 2.36–2.31 (m, 1H), 2.14–2.03 (m, 2H), 1.75–1.59 (m, 3H), 1.58–1.47 (m, 1H) ).

Example 123-2

2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Intermediate Im-8B (61.8 mg, 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Methyl imidazole-6-carboxylate (50 mg, 170 μmol) and potassium carbonate (65 mg, 340 μmol) were stirred at 50 °C for 4 hours, water was added, and then ethyl acetate was added for extraction. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to give 2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid methyl ester (50 mg, 47.3%).

MS m/z(ESI): 622.1[M+H] ⁺ .

Step 2: 2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (50 mg, 80 μmol) Dissolve in THF (3mL), add 2mol/L LiOH (1mL), stir at 40°C overnight, add 1mol/L HCl, adjust pH to 5-6, add ethyl acetate, extract, dry the organic phase and spin dry, the crude product Purification by prep-HPLC to give 2-((4-((R)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ( 20 mg, 40.9%).

MS m/z(ESI): 608.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.74(s,1H),8.27(s,1H),7.83-7.74(m,2H),7.65-7.53(m,3H),6.90-6.76(m ,3H),5.48–5.42(m,1H),5.10–5.04(m,1H),4.84–4.74(m,1H),4.68–4.60(m,1H),4.52–4.43(m,2H),4.40 –4.31(m,1H),4.08–3.99(m,1H),3.95–3.87(m,1H),3.82–3.76(m,1H),3.01–2.96(m,1H),2.91–2.83(m, 2H), 2.70–2.65 (m, 1H), 2.41–2.37 (m, 1H), 2.24–2.11 (m, 2H), 1.85–1.77 (m, 1H), 1.71–1.60 (m, 3H).

Example 124

2-((4-(3-(4-Cyclopropyl-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine- 1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-(4-cyclopropyl-2-fluorophenyl) ethane-1-one

1-(4-Bromo-2-fluoro-phenyl)ethanone (6g, 27.65mmol), potassium cyclopropanetrifluoroborate (4.09g, 27.65mmol), 1,1'-bis(diphenylphosphino) Ferrocene dichloride palladium(II) (2.34g, 1.38mmol), potassium carbonate (7.64g, 55.29mmol) and water (10mL), dioxane (50mL) were added to a 250mL flask, and then the reaction liquid was nitrogen The protection was reacted at 90°C for 6h. The reaction solution was added to ice water (20mL), extracted with EA (30mL*2), the organic phase was dried with anhydrous sodium sulfate, concentrated, and passed through the column with PE/EA=3/1 to obtain the product 1-(4-cyclopropane) yl-2-fluorophenyl)ethan-1-one (2 g, 11.22 mmol, 40.60% yield).

Step 2: 2-Chloro-1-(4-cyclopropyl-2-fluorophenyl)ethane-1-one

MS m/z(ESI): 179.0[M+H] ⁺ .

1-(4-Cyclopropyl-2-fluorophenyl)ethan-1-one (1 g, 5.61 mmol) and methanol (179 mg, 5.61 mmol) were dissolved in DCM (10 mL), cooled in an ice water bath and nitrogen Under protection, sulfonyl chloride (751 mg, 5.61 mmol) was added. The mixture was stirred under O compound for 2 hours. The pH of the reaction solution was adjusted to 6 with 10% aqueous sodium hydroxide solution, washed with saturated brine (50 mL brine), the organic phase was dried, and evaporated to dryness to obtain the product 2-chloro-1-(4-cyclopropyl-2-fluorobenzene) yl)ethan-1-one (1.06 g, 5.0 mmol, 89.0% yield), the crude product was used directly in the next step.

MS m/z(ESI): 213.0[M+H] ⁺ .

The third step: 2-((4-(3-(4-cyclopropyl-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-chloro-1-(4-cyclopropyl-2-fluorophenyl) ethane-1-one as raw material Reference Example 115 to obtain the product 2-((4-(3-(4-cyclopropyl- 2-Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)- Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 598.2[M+H] ⁺ .

Example 125

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

With tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 -Carboxylic acid ester is the raw material, referring to the sixth step, tenth step, and eleventh step of Example 1 to obtain 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3- Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl) -3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 593.2,595.2[M+H] ⁺ .

Example 125-1

2-((4-((S)-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-((S)-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- Methyl Carboxylate

2-(Chloromethyl)-3-[[rac-(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate methyl ester at room temperature (48.02 mg, 162.40 μmol), 4-[rac-(3S)-3-(4-chloro-2-fluoro-phenyl)-2,3-dihydro-1,4-benzodioxin-5 -yl]piperidine (75 mg, 162.40 μmol, TF) was dissolved in acetonitrile (12 mL), then potassium carbonate (67.33 mg, 487.19 μmol) was added, heated to 45° C., reacted for 14 hours, and cooled to room temperature. LCMS indicated that the reaction was over, diluted with ethyl acetate (20 mL), then washed with saturated brine (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was separated by preparative thin layer chromatography (PE : EA=1:1) to give 2-((4-((S)-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4 ]dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b ]Pyridine-5-carboxylate methyl ester as a colorless oil (70 mg, 71%).

MS m/z(ESI): 607.2,609.2[M+H] ⁺ .

Step 2: 2-((4-((S)-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- carboxylic acid

At room temperature, 2-((4-((S)-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- Methyl carboxylate (70 mg, 115.31 μmol) was dissolved in methanol (2 mL) and tetrahydrofuran (3 mL), then a solution of lithium hydroxide (27.61 mg, 1.15 mmol) in water (1 mL) was added, heated to 40° C., and reacted for 14 hours. Cooled to room temperature, LCMS indicated the end of the reaction. Spin to dry, the residue was dissolved in ethyl acetate (20 mL), under ice bath, the pH value was adjusted to 6-7 with aqueous formic acid, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate, Filter and spin dry. The residue was separated by preparative high performance liquid phase (prepared under neutral conditions). Lyophilization gave the target product as a white solid (22.1 mg, 29%).

MS m/z(ESI): 593.2,595.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.13 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.52 (d, J=8.0Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.86-6.77(m, 3H), 5.49-5.43(m, 1H), 5.18-5.11(m, 1H), 4.88-4.83 (m,1H), 4.73-4.69(m,1H), 4.51-4.42(m,2H), 4.40-4.34(m,1H), 4.13-4.08(m,1H), 3.99(d,J=13.6Hz ,1H),3.90(d,J＝13.6Hz,1H),2.99-2.84(m,3H),2.73-2.64(m,1H),2.46-2.42(m,1H),2.25-2.18(m,2H ),1.80-1.56(m,4H).

Example 125-2

2-((4-((R)-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-((R)-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5- carboxylic acid

Taking Im-2, Im-7B as raw materials, the tenth step of reference example one, the eleventh step obtains 2-((4-((R)-(3-(4-chloro-2-fluorophenyl)- 2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl )methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 593.2,595.2[M+H] ⁺ .

Example 126

2-((4-(3-(4-Cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-(2-chloroacetyl)-3-fluorobenzonitrile

4-Acetyl-3-fluorobenzonitrile (1 g, 6.13 mmol) and methanol (196 mg, 6.13 mmol) were dissolved in DCM (10 mL), and sulfonyl chloride (992 mg, 6.13 mmol) was added under ice-water bath cooling under nitrogen protection. mmol). The mixture was stirred under O compound for 2 hours. The pH of the reaction solution was adjusted to 6 with 10% aqueous sodium hydroxide solution, washed with saturated brine (50 mL brine), the organic phase was dried, and evaporated to dryness to obtain the product 4-(2-chloroacetyl)-3-fluorobenzonitrile ( 800 mg, 4.0 mmol, 66.0% yield), the crude product was used directly in the next step.

MS m/z(ESI): 198.0[M+H] ⁺ .

Step 2: 2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-(2-chloroacetyl)-3-fluorobenzonitrile as raw material Reference Example 115 to obtain the product 2-((4-(3-(4-cyano-2-fluorophenyl)-2,3 -Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 583.2[M+H] ⁺ .

Example 127

2-(((2S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)- 2-Methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: tert-butyl (2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)-2-methylpiperazine-1-carboxylate

8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (0.2 g, 0.58 mmol), tert. -Butyl 2-methylpiperazine-1-carboxylate (0.12g, 0.61mmol), Pd2(dba)3 (0.053g, 0.058mmol), Ruphos (0.054g, 0.116mmol), Cesium carbonate (0.56g , 1.74 mmol) was dissolved in toluene (5 mL), replaced with nitrogen, heated to 100° C., reacted for 14 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL), filtered through celite, washed with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine (10 mL×2), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, spin dry, and the residue is separated by preparative thin layer chromatography (PE:EA=1:1) to give tert-butyl(2S)-4-(3-(4-chloro-2-fluorophenyl) -2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazine-1-carboxylate (0.134 g, 50%, yellow oil).

MS m/z(ESI): 463.2,465.2[M+H] ⁺ .

Step 2: 2-(((2S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid

with tert-butyl(2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) -2-Methylpiperazine-1-carboxylate is the raw material, refer to the sixth step, tenth step, and eleventh step of Example 1 to obtain 2-(((2S)-4-(3-(4- Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazin-1-yl)methyl)-1 -(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 607.2,609.2[M+H] ⁺ .

Example 128

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-(fluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate acid

The first step: 1,3-dichloro-2-(4-chloro-2-fluorophenyl)propan-2-ol

1-Bromo-4-chloro-2-fluorobenzene (5 g, 23.87 mmol) was dissolved in tetrahydrofuran (100 mL), and under ice-water bath cooling and nitrogen protection, isopropyl Grignard reagent (2M, 17.90 mL, 35.81 mL) was added. mmol). The mixture was stirred at 0 °C for 0.5 hr. 1,3-Dichloropropan-2-one (4.55 g, 35.81 mmol) was then added. The mixture was stirred at 0 °C for 0.5 hr. The mixture was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed successively with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=100:0 to 60:40) to give the desired product 1,3-dichloro-2-(4-chloro-2-fluorophenyl)propane -2-ol (4.2 g, 16.31 mmol, yield: 68.32%).

Step 2: 2-(4-Chloro-2-fluorophenyl)-2-(chloromethyl)oxapropane

1,3-Dichloro-2-(4-chloro-2-fluorophenyl)propan-2-ol (4 g, 15.53 mmol) was dissolved in toluene (30 mL) and 20% potassium hydroxide was added under nitrogen Aqueous solution (8 mL). The mixture was stirred at 20°C for 3 hours. The mixture was separated and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=100:0 to 95:5) to give the desired product 2-(4-chloro-2-fluorophenyl)-2-(chloromethyl) Oxapropane (1.5 g, 6.79 mmol, yield: 43.69%).

The third step: (8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

2-(4-Chloro-2-fluorophenyl)-2-(chloromethyl)oxapropane (1.5 g, 6.79 mmol), 3-bromobenzene-1,2-diol (1.28 g, 6.79 mmol) ) was dissolved in toluene (30 mL), and sodium hydroxide (597.09 mg, 14.93 mmol) was added under nitrogen protection. The mixture was stirred at 20°C for 16 hours. The mixture was separated and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 90:10 eluting) to give the desired product (8-bromo-2-(4-chloro-2-fluorophenyl)-2, 3-Dihydrobenzo[b][1,4]dioxin-2-yl)methanol (0.6 g, 1.61 mmol, yield: 23.67%).

Step 4: 8-Bromo-2-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxin

(8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (0.6 g, 1.61 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (284.75 mg, 1.77 mmol) was added under ice-water bath cooling under nitrogen protection. The mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated brine (10 mL), extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL×2) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=100:0 to 95:5) to give the desired product 8-bromo-2-(4-chloro-2-fluorophenyl)-2-( Fluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxin (0.3 g, 798.74 μmol, yield: 49.73%).

The fifth step: 2-((4-(3-(4-chloro-2-fluorophenyl)-3-(fluoromethyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine -5-Carboxylic acid

8-Bromo-2-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxin and methyl (S )-2-(chloromethyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as raw material Reference Example 1 First, Two, six, ten and eleven steps give the product 2-((4-(3-(4-chloro-2-fluorophenyl)-3-(fluoromethyl)-2,3-dihydrobenzo[b ][1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[ 4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 625.2[M+H] ⁺ .

Example 129

2-((4-(2-(4-cyano-2-fluorophenyl)-3-fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: ethyl 2-bromo-2-(4-cyano-2-fluorophenyl) acetate

Using ethyl 2-(4-cyano-2-fluorophenyl) acetate as raw material Reference Example 117 The first step to obtain the product ethyl 2-bromo-2-(4-cyano-2-fluorophenyl) ) acetate.

The second step: ethyl 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl) acetate

Using ethyl 2-bromo-2-(4-cyano-2-fluorophenyl) acetate as raw material Reference Example 117 The second step obtained the product ethyl 2-(2-bromophenoxy)-2- (4-cyano-2-fluorophenyl)acetate.

MS m/z(ESI): 378.2, 380.2 [M+H] ⁺ .

The third step: ethyl 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl) propionate

Using ethyl 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl) acetate as raw material Reference Example 117 The third step obtains the product ethyl 2-(2-bromo) Phenoxy)-2-(4-cyano-2-fluorophenyl)propionate.

MS m/z(ESI): 392.2, 394.2 [M+H] ⁺ .

The fourth step: 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl)propionic acid

Using ethyl 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl) propionate as raw material Reference Example 117 The fourth step obtains the product 2-(2-bromophenoxy) yl)-2-(4-cyano-2-fluorophenyl)propionic acid.

MS m/z(ESI): 364.2, 366.2 [M+H] ⁺ .

The fifth step: 4-(7-bromo-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile

Using 2-(2-bromophenoxy)-2-(4-cyano-2-fluorophenyl)propionic acid as raw material Reference Example 117 the fifth step to obtain product 4-(7-bromo-2-methyl) -3-Carbonyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile.

MS m/z(ESI): 345.9[MH] ^- .

The sixth step: 4-(7-bromo-3-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile

4-(7-Bromo-2-methyl-3-carbonyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (0.5 g, 1.44 mmol) was dissolved in methanol (30 mL) ), cooled to 0°C, sodium borohydride (66 mg, 1.7 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction, the aqueous phase was extracted with EA (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain 4-(7-bromo-3-hydroxy-2 -Methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (0.45 g, yield: 90%), pale yellow solid.

MS m/z(ESI): 348.2, 350.2 [M+H] ⁺ .

The seventh step: 4-(7-bromo-3-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile

4-(7-Bromo-3-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (0.3 g, 0.9 mmol) was dissolved in anhydrous bismuth Chloromethane (10 mL) was replaced with nitrogen, cooled to -78°C, diethylamino-sulfur trifluoride (167 mg, 0.1 mmol) was added, and the reaction was stirred at this temperature for 1 hour. Saturated sodium bicarbonate (10 mL) was added to the reaction, the aqueous phase was extracted with dichloromethane (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain 4-(7-bromo- 3-Fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile (50 mg, yield: 16%), pale yellow solid.

MS m/z(ESI): 350.2, 352.2 [M+H] ⁺ .

The eighth step: 2-((4-(2-(4-cyano-2-fluorophenyl)-3-fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine Perid-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 4-(7-bromo-3-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)-3-fluorobenzonitrile as raw material Reference Example 117 Steps 6 to 10 Step to get the product 2-((4-(2-(4-cyano-2-fluorophenyl)-3-fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 599.2[M+H] ⁺ .

Example 130

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-(fluoromethyl)benzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (4-bromo-2-(4-chloro-2-fluorophenyl)benzo[d][1,3]bisoxazol-2-yl)methyl acetate

Using 2-(4-chloro-2-fluorophenyl)-2-carbonylethyl acetate, 3-bromobenzene-1,2-diphenol as raw material Reference Example 7 The second step (4-bromo-2- (4-Chloro-2-fluorophenyl)benzo[d][1,3]bisoxazol-2-yl)methyl acetate.

MS m/z(ESI): 401.0[M+H] ⁺ .

Step 2: tert-butyl 4-(2-(acetoxymethyl)-2-(4-chloro-2-fluorophenyl)benzo[d][1,3]dioxazole-4- base)-3,6-dihydropyridine-1(2H)-carboxylate

With (4-bromo-2-(4-chloro-2-fluorophenyl)benzo[d][1,3]bisoxazol-2-yl)methyl acetate, 4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester is the raw material Reference Example 1 Section 1 One-step product tert-butyl 4-(2-(acetoxymethyl)-2-(4-chloro-2-fluorophenyl)benzo[d][1,3]dioxazole-4- base)-3,6-dihydropyridine-1(2H)-carboxylate.

MS m/z(ESI): 504.1[M+H] ⁺ .

The third step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-(hydroxymethyl)benzo[d][1,3]dioxazol-4-yl) -3,6-Dihydropyridine-1(2H)-carboxylate

With tert-butyl 4-(2-(acetoxymethyl)-2-(4-chloro-2-fluorophenyl)benzo[d][1,3]dioxazol-4-yl)- 3,6-dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 10 The third step obtains the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-( Hydroxymethyl)benzo[d][1,3]bisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

MS m/z(ESI): 462.1[M+H] ⁺ .

The fourth step: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)benzo[d][1,3]dioxazol-4-yl) -3,6-Dihydropyridine-1(2H)-carboxylate

With tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-(hydroxymethyl)benzo[d][1,3]dioxazol-4-yl)-3, 6-dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 119 The first step obtains the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-(fluoromethyl) yl)benzo[d][1,3]bisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

MS m/z(ESI): 464.1[M+H] ⁺ .

Step 5: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-(fluoromethyl)benzo[d][1,3]bisoxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)benzo[d][1,3]dioxazol-4-yl)-3, 6-dihydropyridine-1(2H)-carboxylate is the raw material Reference Example 1 The second, six, ten, eleven steps to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl) )-2-(fluoromethyl)benzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane- 2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 610.2[M+H] ⁺ .

Example 131

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d ][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[ d]Imidazole-6-carboxylic acid

The first step: bicyclo[4.2.0]octa-1,3,5-triene-3,4-diol

3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-triene (2 g, 12.2 mmol) and dichloromethane (30 mL) were added to a 50 mL flask, and tribromide was added at 25°C Boronide (15.3 g, 60.9 mmol), and then the reaction solution was reacted at 25° C. for 2 h. The reaction solution was added to ice water (30 mL), extracted with dichloromethane (20 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through the column with PE/EA=3/1 to obtain the yellow solid bicyclo[4.2 .0] Octa-1,3,5-triene-3,4-diol (1.5 g, 11.0 mmol, yield: 90.45%).

MS m/z(ESI): 137.0[M+H] ⁺ .

Step 2: 2-Bromobicyclo[4.2.0]octa-1,3,5-triene-3,4-diol

Tert-butylamine (1.07g, 14.7mmol), liquid bromine (1.17g, 7.3mmol) and toluene (20mL) were added to a 50mL flask, cooled to -60°C and bicyclo[4.2.0]octa-1,3,5-tris En-3,4-diol (1.0 g, 7.3 mmol). Then the reaction solution was reacted at 25°C for 24h. The reaction solution was added to ice-water (20 mL), extracted with DCM (20 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through a column with PE/EA=3/1 to obtain the product as a yellow solid 2-bromobicyclo[ 4.2.0] Octa-1,3,5-triene-3,4-diol (800 mg, 3.72 mmol, yield: 50.65%).

MS m/z(ESI): 214.9[M+H] ⁺ .

The third step: 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2- d][1,3]Dioxazole

2-Bromobicyclo[4.2.0]octa-1,3,5-triene-3,4-diol (340 mg, 1.56 mmol), 1-(4-chloro-2-fluoro-phenyl)ethanone ( 268.61 mg, 1.56 mmol) and toluene (10 mL) were added to a 50 mL flask, p-toluenesulfonic acid (26.80 mg, 155.64 μmol) was added at 25 °C, and then the reaction solution was separated and reacted at 140 °C for 12 h. The reaction solution was concentrated and passed through the column with PE/EA=20/1 to obtain the product 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadiene. [4,5]benzo[1,2-d][1,3]dioxazole (265 mg, 728.91 μmol, 46.83% yield).

MS m/z(ESI): 368.9[M+H] ⁺ .

Step 4: 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d ][1,3]Dioxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d][1 ,3] Dioxazole (168.0 mg, 455.57 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroboran-2-yl)-3,6 - Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (80 mg, 258.73 μmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (13.21 mg, 16.17 μmol), potassium carbonate (44.70 mg, 323.41 μmol), dioxane (20 mL), and water (3 mL) were added to a 50 mL flask, and the reaction solution was reacted at 90° C. for 1 h under nitrogen protection. The reaction solution was filtered, concentrated, and passed through a column with PE/EA=20/1 to obtain the product 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadiene Do[4,5]benzo[1,2-d][1,3]bisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (137 mg, 291.88 μmol, yield 90.25%).

MS m/z(ESI): 472.1[M+H] ⁺ .

Step 5: 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d ][1,3]Dioxazol-4-yl)-1,2,3,6-tetrahydropyridine

4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d][1, 3] Dioxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (137 mg, 291.88 μmol) and dichloromethane (5 mL) were added to a 50 mL flask, at 25 Trifluoroacetic acid (332.81 mg, 2.92 mmol) was added at °C, and then the reaction solution was reacted at 25 °C for 1 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), washed with saturated aqueous sodium carbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the product as a yellow solid 4-(2-(4-chloro) -2-Fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d][1,3]dioxazol-4-yl )-1,2,3,6-tetrahydropyridine (120 mg, 290.00 μmol, 99.36% yield).

MS m/z(ESI): 372.0[M+H] ⁺ .

Step 6: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1 ,2-d][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetane- 2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

(S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (50 mg, 169.65 μmol), 4- (2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d][1,3] Dioxazol-4-yl)-1,2,3,6-tetrahydropyridine (62.0 mg, 169.65 μmol) and acetonitrile (3 mL) were added to a 50 mL flask, and potassium carbonate (70.34 mg, 508.94 mg) was added at 25°C μmol), and then the reaction solution was reacted at 60 °C for 1 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the product 2-((4-(2-(4-chloro-2-fluoro). phenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d][1,3]dioxazol-4-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl base ester (56 mg, 89.28 μmol, yield: 52.63%).

MS m/z(ESI): 630.2[M+H] ⁺ .

Step 7: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1 ,2-d][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetane- 2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d ][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (56 mg, 89.28 μmol) and methanol (5 mL) were added to a 50 mL flask, and sodium hydroxide (21.42 mg, 535.66 μmol) was added at 25°C ), and then the reaction solution was reacted at 25 °C for 12 h. After the reaction solution was concentrated, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[ 4,5]Benzo[1,2-d][1,3]bisoxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(( (S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (34 mg, 55.51 μmol, 62.17% yield).

MS m/z(ESI): 616.1[M+H] ⁺ .

Step 8: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1 ,2-d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H -Benzo[d]imidazole-6-carboxylic acid

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadieno[4,5]benzo[1,2-d ][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylic acid (18 mg, 30.39 μmol) and methanol (5 mL) were added to a 25 mL flask, and triphenylphosphine rhodium chloride (28.12 mg, 30.39 μmol), and then the reaction solution was replaced with hydrogen for 5 times and then reacted at 50° C. for 12 hours under a hydrogen atmosphere. The reaction solution was filtered, concentrated, and the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-5,6-dihydrocyclobutadiene was prepared by prep-hplc Do[4,5]benzo[1,2-d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetanes -2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (4.7 mg, 7.58 μmol, yield: 24.92%).

MS m/z(ESI): 618.1[M+H] ⁺ .

Example 132

2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-6-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

With (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine and ethyl 2 ,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate as raw material reference Example 90 to obtain the product 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-6-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole -5-Carboxylic acid.

MS m/z(ESI): 612.2[M+H] ⁺ .

Example 133

2-(((S)-4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole -5-Carboxylic acid

with (S)-4-(4-bromo-2-methylbenzo[d][1,3]dioxazol-2-yl)-3-fluorobenzonitrile and ethyl 2-(bromomethyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate as the raw material, refer to Example 108 to obtain the product 2-(((S)-4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4- yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole -5-Carboxylic acid.

MS m/z(ESI): 603.8[M+H] ⁺ .

Example 134

2-((4-(3-(4-Chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-1-((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene

4-Chloro-2-fluorobenzene(formaldehyde) (4g, 25.23mmol) and nitromethane (14mL) were dissolved in glacial acetic acid (50mL), ammonium acetate (5.83g, 75.68mmol) was added and stirred at 110°C 3 hours, cooled, the reaction solution was added to ice water, a solid was precipitated, filtered, and the filter cake was purified by column chromatography to obtain (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (2.5 g, yield: 49%).

MS m/z(ESI): 202.0[M+H] ⁺ .

Step 2: 5-Bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one

To (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (451.26 mg, 2.24 mmol), 2-bromo-6-hydroxybenzene (carbaldehyde) (300 mg, 1.49 mmol) , 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole bromide (37.63 mg, 149.24 μmol) was added to a solution of 4A molecular sieves (400 mg) in dichloromethane (10 mL), followed by stirring at room temperature 0.5 hours, then dropwise added 1,4-diazidobicyclo[2.2.2]octane (33.48mg, 298.48μmol), stirred at room temperature for 12 hours under nitrogen protection, stirred with silica gel and concentrated to dryness under reduced pressure, and then separated and purified by column chromatography , to obtain 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (90 mg, yield: 17%).

MS m/z(ESI): 355[M+H] ⁺ .

The third step: methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1- (((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Using 5-bromo-3-(4-chloro-2-fluorophenyl) chroman-4-one as raw material Reference Example 1 First, two, six, ten steps to obtain the product methyl 2-((4-(3 -(4-Chloro-2-fluorophenyl)-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 618.2[M+H] ⁺ .

The fourth step: methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1-(((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as the raw material Reference Example 116 The first step obtained the product methyl 2-((4-(3- (4-Chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 640.2[M+H] ⁺ .

The fifth step: 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-1 -(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-1- (((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate is the raw material Reference Example 1 The eleventh step obtains the product 2-((4-( 3-(4-Chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane- 2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 626.2[M+H] ⁺ .

Example 135

2-((4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1-( ((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 5-bromo-3-(4-chloro-2-fluorophenyl)-3-methylchroman-4-one

To a 0 degree Celsius solution of 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (500 mg, 1.41 mmol) in tetrahydrofuran (10 mL) was added sodium hydrogen (113 mg, 2.82 mmol, 60 %), stirred for 30 minutes, then dropwise added methyl iodide (300 mg, 2.12 mmol) and stirred at room temperature for 2 hours, quenched with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, Spin dry, and the crude product was separated and purified by column chromatography to obtain 5-bromo-3-(4-chloro-2-fluorophenyl)-3-methylchroman-4-one (160 mg, yield: 31%).

MS m/z(ESI): 369.0[M+H] ⁺ .

The second step: methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl yl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Using 5-bromo-3-(4-chloro-2-fluorophenyl)-3-methylchroman-4-one as raw material Reference Example 1 First, two, six, ten steps to obtain product methyl 2-( (4-(3-(4-Chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1-(((S )-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 632.2[M+H] ⁺ .

The third step: 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate is the raw material Reference Example 1 The eleventh step obtains the product 2-((4 -(3-(4-Chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)-1-(((S)- Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 618.2[M+H] ⁺ .

Example 136

2-((4-(3-(4-Chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidine-1- yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-4-carbonylchroman-5-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate is the raw material Reference Example 116 The first step is to obtain the product methyl 2-(( 4-(3-(4-Chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidin-1-yl)methyl)-1-(( (S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 654.2[M+H] ⁺ .

Step 2: 2-((4-(3-(4-Chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidin-1-yl) Methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidin-1-yl)methan Base)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 Eleventh step to obtain product 2- ((4-(3-(4-Chloro-2-fluorophenyl)-4,4-difluoro-3-methylchroman-5-yl)piperidin-1-yl)methyl)-1- (((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 640.2[M+H] ⁺ .

Example 137

2-((4-(2-(4-Chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperidin-1-yl)methyl)-1-((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one

Using 1-(3-bromo-2-hydroxyphenyl) ethane-1-one, 4-chloro-2-fluorobenzene (formaldehyde), potassium hydroxide as raw materials Reference Example 115 The first step to obtain the product 8-bromo -2-(4-Chloro-2-fluorophenyl)chroman-4-one.

The second step: methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1- (((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Using 8-bromo-2-(4-chloro-2-fluorophenyl) chroman-4-one as raw material Reference Example 1 First, two, six, ten steps to obtain the product methyl 2-((4-(2 -(4-Chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 618.2[M+H] ⁺ .

The third step: 2-((4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperidin-1-yl)methyl)-1 -(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidin-1-yl)methyl)-1-((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as the raw material Reference Example 116 The first and second steps of the product 2-((4-(2-( 4-Chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 626.2[M+H] ⁺ .

Example 138

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Taking intermediate Im-7A as raw material Reference Example 1 tenth, eleventh step to obtain product (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-di Hydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)- 1H-Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 615.2[M+H] ⁺ .

Example 139

(S)-1-((1-(Cyanomethyl)cyclopropyl)methyl)-2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydro Benzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Taking intermediate Im-8A as raw material Reference Example 1 tenth, eleventh step to obtain product (S)-1-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4- (3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1H - Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 631.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.76(s, 1H), 8.25(s, 1H), 7.81(dd, J=8.4, 1.6Hz, 1H), 7.76(d, J=2.0Hz, 1H), 7.65(d,J=8.4Hz,1H),7.62-7.55(m,2H),6.87-6.77(m,3H),5.45(dd,J=8.0,2.4Hz,1H),4.60(s,2H) ,4.46(dd,J＝11.6,2.4Hz,1H),4.03(dd,J＝11.6,8.0Hz,1H),3.84(s,2H),2.99-2.84(m,4H),2.66(s,2H) ),2.03-1.96(m,,1H),1.81-1.60(m,4H),0.79-0.63(m,4H).

Example 140

2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-6-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

First step: ethyl 6-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole- Preparation of 5-carboxylate

Ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (2 g , 5.87 mmol) was dissolved in tetrahydrofuran (40 mL), and n-butyllithium (2.5 M, 2.58 mL) was added dropwise at -78 °C. After reacting at -78°C for 3 hours, a solution of N-fluorobenzenesulfonimide (2.78 g, 8.81 mmol) in tetrahydrofuran (40 mL) was added. After continuing the reaction at -78°C for 1 hour, the reaction solution was raised to room temperature for 16 hours. Aqueous ammonium chloride solution (5 mL) was added to quench the reaction and extracted with ethyl acetate (30 mL*2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the product ethyl 6-fluoro-2-methyl-1-((2-(trimethyl) silyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (570 mg, yield: 27%).

MS m/z(ESI): 359.2[M+H] ⁺ .

Step 2: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-6-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole - Preparation of 5-carboxylate

Ethyl 6-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate Acid ester and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)piperidine as raw materials Reference Example 90 to obtain the product ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-6-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d ] Imidazole-5-carboxylate.

MS m/z(ESI): 644.2[M+H] ⁺ .

The third step: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-6-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5 - Preparation of carboxylic acids

In the eleventh step of reference example 1, the product 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]di Oxazol-4-yl)piperidin-1-yl)methyl)-6-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3 -d]imidazole-5-carboxylic acid.

MS m/z(ESI): 616.2[M+H] ⁺ .

Example 141

6-Chloro-2-((4-((S)-2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

First step: ethyl 6-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole- Preparation of 5-carboxylate

Ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (2 g , 5.87 mmol) was dissolved in tetrahydrofuran (40 mL), and n-butyllithium (2.5 M, 2.58 mL) was added dropwise at -78 °C. After reacting at -78°C for 3 hours, a solution of N-chlorosuccinimide (941 mg, 7.05 mmol) in tetrahydrofuran (40 mL) was added. After continuing the reaction at -78°C for 1 hour, the reaction solution was raised to room temperature for 16 hours. Aqueous ammonium chloride solution (5 mL) was added to quench the reaction and extracted with ethyl acetate (30 mL*2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the product ethyl 6-chloro-2-methyl-1-((2-(trimethyl) silyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (450 mg, yield: 20%).

MS m/z(ESI): 374.8[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ5.66(s, 2H), 4.37(q, J=7.1Hz, 2H), 3.68-3.60(m, 2H), 2.68(s, 3H), 1.39(t , J=7.1Hz, 3H), 0.91(t, J=8.0Hz, 2H), 0.03(s, 9H).

Step 2: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-6-chloro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole -5-carboxylate and ethyl 6-chloro-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1, 3] Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2,3- d] Preparation of imidazole-5-carboxylate

Ethyl 6-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate Acid ester and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)piperidine as raw materials Reference Example 90 to obtain the product ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-6-chloro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d ] Imidazole-5-carboxylate and ethyl 6-chloro-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][ 1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-thieno[2, 3-d]imidazole-5-carboxylate

The mixture was separated by chiral (chiral column: OD-H; mobile phase: Hexane:IPA=80:20) to obtain compounds 141-1 (rt=3.960min) and 141-2 (rt=5.317min) .

141-1: MS m/z(ESI): 659.8[M+H] ⁺ .

141-2: MS m/z(ESI): 659.8[M+H] ⁺ .

The third step: 6-chloro-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazole -4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5 - Preparation of carboxylic acids

Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-6-chloro-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5- Carboxylic acid ester is used as raw material to obtain product 141 in the eleventh step of reference example 1.

MS m/z(ESI): 632.1[M+H] ⁺ .

Example 142

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate ethyl ester

(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (70mg , 201.26 μmol) was dissolved in MeCN (10 mL), to which was added K ₂ CO ₃ (139.08 mg, 1.01 mmol) and 2-(chloromethyl)-3-[[1-(fluoromethyl)cyclopropyl] Methyl]benzimidazole-5-carboxylic acid ethyl ester (65.36 mg, 201.26 μmol). The reaction system was stirred at 50°C for 4 hours. After the reaction, add water (10 mL) to dilute, extract with ethyl acetate (20 mL×2), wash with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, and concentrate to obtain crude product. The crude product was subjected to Prep-TLC (PE/EtOAc=2:1, Rf=0.40) to obtain (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-di Hydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H - ethyl benzo[d]imidazole-6-carboxylate (120 mg, 188.05 μmol, 93.43% yield).

MS m/z(ESI): 636.2[M+H] ⁺ .

The second step (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (120 mg, 0.18 mmol ) was dissolved in MeOH (1 mL), to which was added LiOH (90.36 mg, 3.77 mmol), H ₂ O (1 mL) and THF (4 mL). The reaction system was stirred at room temperature of 20°C for 4 hours. After completion of the reaction, concentrated to obtain crude product. The crude product was purified by Prep-HPLC to give 3-[[1-(fluoromethyl)cyclopropyl]methyl]-2-[[4-[rac-(3S)-3-(4-chloro-2-fluoro -Phenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]-1-piperidinyl]methyl]benzimidazole-5-carboxylic acid (36 mg, 29.2% yield ).

MS m/z(ESI): 608.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.22(s,1H),7.81(d,J=8.4Hz,1H),7.64-7.50(m,3H),7.43(d,J=8.4Hz,1H), 6.87–6.77(m, 3H), 5.46(d, J=7.6Hz, 1H), 4.59(s, 2H), 4.43(d, J=11.2Hz, 1H), 4.20(s, 1H), 4.12-4.07 (m, 2H), 3.82 (s, 2H), 2.98–2.77 (m, 4H), 2.03–1.96 (m, 1H), 1.81–1.55 (m, 4H), 0.80–0.76 (m, 2H), 0.68 -0.64(m,2H).

Example 143

(S)-2-((4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step (S)-2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate ethyl ester

4-[rac-(3S)-3-(2,4-dichlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidine (40 mg, 109.81 μmol) was dissolved in MeCN (10 mL), to which was added K ₂ CO ₃ (75.88 mg, 549.05 μmol) and 2-(chloromethyl)-3-[[1-(fluoromethyl)cyclopropyl]methyl ] ethyl benzimidazole-5-carboxylate (35.66 mg, 109.81 μmol). The reaction system was stirred in an oil bath at 50°C for 4 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL×2), washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow solid crude product 3-[[ 1-(Fluoromethyl)cyclopropyl]methyl]-2-[[4-[rac-(3S)-3-(2,4-dichlorophenyl)-2,3-dihydro-1, 4-Benzodioxin-5-yl]-1-piperidinyl]methyl]benzimidazole-5-carboxylic acid ethyl ester (70 mg, crude). The crude product was directly used in the next reaction.

MS m/z(ESI): 652.2[M+H] ⁺ .

The second step (S)-2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

3-[[1-(Fluoromethyl)cyclopropyl]methyl]-2-[[4-[rac-(3S)-3-(2,4-dichlorophenyl)-2,3- Dihydro-1,4-benzodioxin-5-yl]-1-piperidinyl]methyl]benzimidazole-5-carboxylic acid ethyl ester (70 mg, crude) was dissolved in THF (4 mL), To this was added LiOH (51.38 mg, 2.15 mmol), _H2O (1 mL) and MeOH (1 mL). The reaction system was stirred at room temperature 20°C for 3 hours. After completion of the reaction, concentrate to obtain crude product. The crude product was purified by Prep-HPLC to give 3-[[1-(fluoromethyl)cyclopropyl]methyl]-2-[[4-[rac-(3S)-3-(2,4-dichlorobenzene base)-2,3-dihydro-1,4-benzodioxin-5-yl]-1-piperidinyl]methyl]benzimidazole-5-carboxylic acid (14 mg, 22.42 μmol, 20.90% yield).

MS m/z(ESI): 624.2[M+H] ⁺ .

1H NMR(400MHz, DMSO-d6)δ8.16(s,1H),7.81–7.77(m,1H),7.76(d,J=2.0Hz,1H),7.59(d,J=2.1Hz,1H) ,7.56(d,J＝8.7Hz,2H),6.85–6.78(m,3H),5.44(dd,J＝8.0,2.4Hz,1H),4.58(s,2H),4.46(dd,J＝11.6 ,2.4Hz,1H),4.21(s,1H),4.09(s,1H),4.05–3.98(m,1H),3.80(s,2H),2.97–2.80(m,4H),2.02–1.98( m, 1H), 1.78–1.60 (m, 4H), 0.80–0.75 (m, 2H), 0.69–0.65 (m, 2H).

Example 144

(S)-2-((4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Taking intermediate Im-8A as raw material Reference Example 1 tenth, eleventh step to obtain product (S)-2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydro Benzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 625.2[M+H] ⁺ .

Example 145

2-((4-((S)-3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-chloro-1-(4-chloro-2-methoxyphenyl)ethan-1-one

1-(4-Chloro-2-methoxyphenyl)ethan-1-one (6 g, 32.5 mmol) and methanol (1.04 g, 32.5 mmol), dichloromethane (50 mL) were added to a 100 mL flask under nitrogen Sulfonyl chloride (5.10 g, 37.7 mmol) was added at 0 °C under protection, and then the reaction solution was reacted at 0 °C for 2 h. After the reaction solution was concentrated, pass through the column with PE/EA=10/1 to obtain the product 2-chloro-1-(4-chloro-2-methoxyphenyl)ethane-1-one (6g, 27.3mmol, 84.6% yield) )

MS m/z(ESI): 218.9[M+H] ⁺ .

The second step: 2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-methoxyphenyl)ethane-1-one

2-Chloro-1-(4-chloro-2-methoxyphenyl)ethan-1-one (6 g, 27.3 mmol) and 3-bromo-2-iodophenol (8.1 g, 21.3 mmol) were dissolved in acetone (60 mL), under nitrogen protection, was added potassium carbonate (5.9 g, 42.6 mmol). The mixture was stirred at 60°C for 3 hours. The mixture was cooled, dissolved in ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 100:0 to 95:5) to give the desired product 2-(3-bromo-2-iodophenoxy)-1-(4-chloro) -2-Methoxyphenyl)ethan-1-one (9 g, 18.7 mmol, yield: 68.2%).

The third step: 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-methoxyphenyl)ethane-1-ol

2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-methoxyphenyl)ethan-1-one (9 g, 18.7 mmol) was dissolved in methanol (100 mL), Under ice-water bath cooling and nitrogen protection, sodium borohydride (708 mg, 18.7 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was evaporated to dryness, the mixture was dissolved in ethyl acetate (100 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product 2-(3-bromo-2-iodophenoxy)-1-(4-chloro-2-methoxyphenyl)ethane-1-ol (9g, 18.7mmol,) was obtained, which was directly used in the following step.

Step 4: 8-Bromo-2-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin

2-(3-Bromo-2-iodophenoxy)-1-(4-chloro-2-methoxyphenyl)ethane-1-ol (5 g, 10.3 mmol), cesium carbonate (6.7 g, 20.6 mmol) and 1,10-phenanthroline (560 mg, 2.0 mmol) were dissolved in dimethyl sulfoxide (50 mL), and cuprous iodide (190 mg, 1.0 mmol) was added under nitrogen protection. The mixture was stirred at 110°C for 16 hours. The reaction solution was cooled, saturated brine (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×2), the organic phase was washed with saturated brine (30 mL×6), the organic phase was dried over anhydrous sodium sulfate, and chromatographed on flash silica gel Plate purification (petroleum ether:ethyl acetate=10:1) to obtain the target product 8-bromo-2-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1 , 4] Dioxin (1.6 g, 4.5 mmol, yield: 43.5%).

Step 5: 4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6 -Dihydropyridine-1(2H)-carboxylate tert-butyl ester

8-Bromo-2-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin (1.6 g, 4.5 mmol), 4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboropenan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.4 g, 4.5 mmol) and sodium carbonate (954 mg, 9 mmol) were dissolved in 1'4-dioxane (20 mL) and water (3 mL), and under nitrogen protection, 1,1'-bis-diphenylphosphonicene was added Iron palladium chloride (170 mg, 230 μmol). The mixture was stirred at 85°C for 3 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (25 mL), the mixture was separated, the organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography ( Petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.8 g, 4.0 mmol, yield: 87.3%).

MS m/z(ESI): 458.1[M+H] ⁺ .

Step 6: 4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 - tert-butyl carboxylate

4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydro Pyridine-1(2H)-carboxylate tert-butyl ester (1.8 g, 4.0 mmol) was dissolved in methanol (20 mL), and Wilkinson's catalyst (1.85 g, 2 mmol) was added under nitrogen protection. The mixture was stirred at 50°C for 16 hours under a hydrogen (1 atm) atmosphere. The reaction solution was evaporated to dryness, and the crude product was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(4-chloro-2-methoxyphenyl)-2,3- Dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester (1.0 g, 2.17 mmol, yield: 55.3%).

MS m/z(ESI): 460.1[M+H] ⁺ .

Step 7: (S)-4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidine-1-carboxylate tert-butyl ester, (R)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester

4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylic acid tert. After the butyl ester is resolved, the product (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidine-1-carboxylate tert-butyl ester, (R)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][ 1,4]Dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester

The eighth step: (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) piperidine

(S)-4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 - tert-butyl carboxylate (200 mg, 434 μmol) was dissolved in 25% TFA/DCM (15 mL) and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve it, and an aqueous sodium bicarbonate solution was added to adjust the pH to 7-8, the organic phase is dried and then spin-dried to obtain (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidine (156 mg, 100%).

MS m/z(ESI): 360.1[M+H] ⁺ .

Step 9: 2-((4-((S)-3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

(S)-4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (61 mg , 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl was added respectively Acid methyl ester (50 mg, 170 μmol) and potassium carbonate (65 mg, 340 μmol) were stirred at 50° C. for 4 hours, water was added, and ethyl acetate was added for extraction. The organic phase was dried and spin-dried. The crude product was purified by column chromatography. 2-((4-((S)-3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl was obtained )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60mg , 57.2%).

MS m/z(ESI): 618.2[M+H] ⁺ .

Step 10: 2-((4-((S)-3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((S)-3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 97 μmol) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, the organic phase was dried and then spin-dried, The crude product was purified by prep-HPLC to give 2-((4-((S)-3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4 ]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6 - Carboxylic acid (30 mg, 51%).

MS m/z(ESI): 604.2[M+H] ⁺ .

Example 146

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(chloromethyl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Taking spiro[2.2]pentan-1-ylmethylamine as raw material and referring to the synthesis of intermediate Im-2, the product 2-(chloromethyl)-1-(spiro[2.2]pentan-1-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester

MS m/z(ESI): 305.1[M+H] ⁺ .

Step 2: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-(chloromethyl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester and intermediate Im-8A as raw materials Reference Example 121-1 to obtain the product 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin In-5-yl)piperidin-1-yl)methyl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 618.1[M+H] ⁺ .

Example 147

2-((4-((S)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Taking intermediate Im-7A as raw material Reference Example 1 tenth, eleventh step to obtain product 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-di Hydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 610.2[M+H] ⁺ .

1H NMR (400MHz, DMSO-d6)δ8.49-8.45(m,2H),7.59-7.54(m,1H),7.54-7.48(m,1H),7.48-7.41(m,1H),6.85-6.73 (m, 3H), 5.47 (d, J=7.7Hz, 1H), 5.11–5.03 (m, 1H), 4.78–4.69 (m, 1H), 4.60 (d, J=14.9Hz, 1H), 4.50– 4.41 (m, 2H), 4.39–4.33 (m, 1H), 4.13–4.07 (m, 1H), 3.90 (d, J=13.4Hz, 1H), 3.74 (d, J=13.3Hz, 1H), 3.01 –2.94(m,1H), 2.89–2.81(m,2H), 2.73–2.64(m,1H), 2.44–2.34(m,1H), 2.23–2.09(m,2H), 2.02–1.98(m, 1H), 1.83–1.67 (m, 2H), 1.63–1.51 (m, 1H).

Example 148

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3- Deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-deutero-1-ol

2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethan-1-one (7 g, 14.4 mmol) was dissolved in methanol (60 mL) under ice Under water bath cooling and nitrogen protection, sodium borodeuteride (660 mg, 15.8 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was evaporated to dryness, the mixture was dissolved in ethyl acetate (20 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product 2-(3-bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-deutero-1-ol (7g, 14.4mmol,) was obtained, which was directly used in the next step.

¹ H NMR (400MHz, Chloroform-d) δ7.70 (d, J=8.4Hz, 1H), 7.36-7.23 (m, 3H), 7.16 (t, J=8.1Hz, 1H), 6.70 (dd, J =8.2,1.3Hz,1H),4.33(d,J=9.4Hz,1H),3.88(d,J=9.3Hz,1H).

Step 2: 8-Bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-deuterium

2-(3-Bromo-2-iodophenoxy)-1-(2,4-dichlorophenyl)ethane-1-deutero-1-ol (7 g, 14.0 mmol), cesium carbonate (9.1 g , 28 mmol) and 1,10-o-phenanthroline (1.0 g, 2.8 mmol) were dissolved in dimethyl sulfoxide (50 mL), and cuprous iodide (266 mg, 1.4 mmol) was added under nitrogen protection. The mixture was stirred at 110°C for 16 hours. The reaction solution was cooled, saturated brine (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×2), the organic phase was washed with saturated brine (30 mL×6), the organic phase was dried over anhydrous sodium sulfate, and chromatographed on flash silica gel Plate purification (petroleum ether:ethyl acetate=10:1) to obtain the target product 8-bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4 ] Dioxin-2-deuterium (1.5 g, 4.1 mol, yield: 29%).

The third step: 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)-3 ,6-Dihydropyridine-1(2H)-carboxylate tert-butyl ester

8-Bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-deuterium (1.5 g, 4.1 mmol), 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.3g, 4.1mmol) and sodium carbonate (870mg, 8.2mmol) were dissolved in 1'4-dioxane (20mL) and water (3mL), under nitrogen protection, 1,1'-bisdiphenyl was added Phosphinoferrocene palladium dichloride (160 mg, 0.2 mmol). The mixture was stirred at 85°C for 3 hours. The reaction solution was added with saturated brine (5 mL) to quench the reaction, extracted with ethyl acetate (25 mL), the mixture was separated, the organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, and purified by flash silica gel chromatography ( Petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl-3-deutero)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 3.45 mmol, yield: 83%).

MS m/z(ESI): 463.1[M+H] ⁺ .

The fourth step: 4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)piperidine -1-Carboxylic acid tert-butyl ester

4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)-3,6- Dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.6 g, 3.4 mmol) was dissolved in methanol (15 mL), and Wilkinson's catalyst (925 mg, 1 mmol) was added under nitrogen protection. The mixture was stirred at 50°C for 16 hours under a hydrogen (1 atm) atmosphere. The reaction solution was evaporated to dryness, and the crude product was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product 4-(3-(2,4-dichlorophenyl)-2,3-dihydrogen Benzo[b][1,4]dioxin-5-yl-3-deutero)piperidine-1-carboxylate tert-butyl ester (800 mg, 1.7 mmol, yield: 49%).

MS m/z(ESI): 465.1[M+H] ⁺ .

The fifth step: (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3- Deutero)piperidine-1-carboxylate tert-butyl ester, (R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl-3-deutero)piperidine-1-carboxylate tert-butyl ester

4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)piperidine-1-carboxylate The product (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl-3-deutero)piperidine-1-carboxylate tert-butyl ester, (R)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b ][1,4]Dioxin-5-yl-3-deutero)piperidine-1-carboxylate tert-butyl ester

Step 6: (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3- deuterium) piperidine

(S)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)piperidine -1-Carboxylic acid tert-butyl ester (200 mg, 430 μmol) was dissolved in 25% TFA/DCM (15 mL), and stirred at room temperature for 3 hours. After the reaction solution was spin-dried, dichloromethane was added to dissolve, and aqueous sodium bicarbonate solution was added to adjust pH to 7-8, the organic phase was dried and spun to give (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl-3-deutero)piperidine (156 mg, 430 μmol, yield: 100%).

MS m/z(ESI): 365.0[M+H] ⁺ .

Step 7: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl-3-deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

(S)-4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-deuterium)piperidine (61 mg, 170 μmol) was dissolved in acetonitrile (25 mL), and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 was added separately -Carboxylic acid methyl ester (50mg, 170μmol) and potassium carbonate (65mg, 340μmol), stirred at 50 ° C for 4 hours, added water, then added ethyl acetate for extraction, the organic phase was dried and spin-dried, and the crude product was subjected to column chromatography Purification to give 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl -3-Deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl base ester (50 mg, 47.3%).

MS m/z(ESI): 623.1[M+H] ⁺ .

Step 8: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl-3-deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3- Deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 50 mg, 80 μmol) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, and the organic phase was dried and spun. The dry, crude product was purified by prep-HPLC to give 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4 ]dioxin-5-yl-3-deutero)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d ] Imidazole-6-carboxylic acid (20 mg, 40.9%).

MS m/z(ESI): 609.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.26(s,1H), 7.83-7.73(m,2H), 7.66-7.53(m,3H), 6.89-6.76(m,3H), 5.13-5.02 (m, 1H), 4.83–4.73 (m, 1H), 4.68–4.59 (m, 1H), 4.53–4.42 (m, 2H), 4.42–4.32 (m, 1H), 4.06–3.99 (m, 1H) ,3.93(d,J＝13.5Hz,1H),3.76(d,J＝13.5Hz,1H),3.02-2.94(m,1H),2.89-2.82(m,2H),2.75-2.62(m,1H) ), 2.47–2.34 (m, 1H), 2.22–2.10 (m, 2H), 1.82–1.69 (m, 3H), 1.65–1.51 (m, 1H).

Example 149

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3 -d)Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (S)-4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3- d) Piperidine

Using 2-chloro-1-(4-chloro-2-fluorophenyl) ethane-1-one as a raw material, the first to sixth steps of Reference Example 148 obtained the product (S)-4-(3-(4 -Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-d)piperidine

MS m/z(ESI): 349.1[M+H] ⁺ .

The second step: (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl-3-d)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3-d)piperidine The pyridine (50 mg, 143 μmol) was dissolved in acetonitrile (5 mL), the intermediate Im-5 (46.5 mg, 143 μmol) and potassium carbonate (39.5 mg, 286 μmol) were added respectively, stirred at 50 ° C for 4 hours, water was added, and then ethyl acetate was added. Ester extraction, the organic phase was dried and spun to dryness, and the crude product was purified by column chromatography to give (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydro) Benzo[b][1,4]dioxin-5-yl-3-d)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (50 mg, 54.7%).

MS m/z(ESI): 637.2[M+H] ⁺ .

The third step: (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl-3-d)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl-3 -d)Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester ( 50 mg, 78.5 μmol) was dissolved in THF (3 mL), 2 mol/L LiOH (1 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, and the organic phase was dried. Spin dry and the crude product is purified by prep-HPLC to give (S)-2-(((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1] ,4]dioxin-5-yl-3-d)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid (25 mg, 52.3%).

MS m/z(ESI): 609.2[M+H] ⁺ .

Example 150

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 2-(chloromethyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Taking 2-methylamine oxazole hydrochloride as raw material, the seventh step, the eighth step, and the ninth step of reference example 1 obtain methyl 2-(chloromethyl)-1-(oxazol-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate

MS m/z(ESI): 306.1[M+H] ⁺ .

The second step: (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and methyl Base 2-(chloromethyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate as raw material Reference Example 1 The tenth step, the eleventh step (S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) is obtained Piperidin-1-yl)methyl)-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 603.2[M+H] ⁺ .

Example 151

2-((4-((S)-3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 3-((4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate

Taking 2-aminocyclopentanol as raw material, referring to the seventh step of Example 1, methyl 3-((4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate was obtained

MS m/z(ESI): 283.1[M+H] ⁺ .

The second step: methyl 4-nitro-3-((4-carbonyltetrahydrofuran-3-yl)amino)benzoate

Taking methyl 3-((4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate as raw material, referring to the second step of Example 30 to obtain methyl 4-nitro-3-((4-carbonyl Tetrahydrofuran-3-yl)amino)benzoate

MS m/z(ESI): 281.1[M+H] ⁺ .

The third step: methyl 3-((4,4-difluorotetrahydrofuran-3-yl)amino)-4-nitrobenzoate

Using methyl 4-nitro-3-((4-carbonyltetrahydrofuran-3-yl)amino)benzoate as raw material, refer to Example 116 in the first step to obtain methyl 3-((4,4-difluorotetrahydrofuran- 3-yl)amino)-4-nitrobenzoate

MS m/z(ESI): 303.0[M+H] ⁺ .

The fourth step: methyl 2-(chloromethyl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate

Taking methyl 3-((4,4-difluorotetrahydrofuran-3-yl) amino)-4-nitrobenzoate as raw material, referring to the eighth step of Example 1, the ninth step obtains methyl 2-(chloromethyl) yl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate

MS m/z(ESI): 331.0[M+H] ⁺ .

The fifth step: 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and methyl Base 2-(chloromethyl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate as the raw material, refer to the tenth step of Example 1, the first step Eleven steps to give 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-(4,4-difluorotetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylic acid

MS m/z(ESI): 628.2[M+H] ⁺ .

Example 152

(S)-1-((2-oxabicyclo[2.1.1]hexane-1-yl)methyl)-2-((4-(3-(4-chloro-2-fluorophenyl) -2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (3-methylenecyclobutyl)methanol

Dissolve 3-methylenecyclobutane-1-carboxylic acid (10 g, 89 mmol) in tetrahydrofuran (100 mL), cool to 0 °C, add lithium tetrahydroaluminum (3.95 g, 107 mmol) in batches, and stir the reaction at room temperature for 5 Hour. Water (4 mL), 15% aqueous sodium hydroxide solution (4 mL), and water (12 mL) were sequentially added, stirred for half an hour, filtered, the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain (3 -methylenecyclobutyl)methanol (6 g, yield: 69%), colorless liquid.

Step 2: 1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexane

(3-methylenecyclobutyl)methanol (6g, 61mmol) was dissolved in methyl tert-butyl ether (60mL) and water (30mL), sodium bicarbonate (10.3g, 122mmol) and elemental iodine (31g, 122 mmol) and the reaction was stirred at room temperature for 18 hours. Saturated aqueous sodium thiosulfate solution (300 mL) was added to quench the reaction, the aqueous phase was extracted with methyl tert-butyl ether (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was separated by column chromatography , to obtain 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (11 g, yield: 81%) as a yellow liquid.

The third step: (2-oxabicyclo[2.1.1]hexane-1-yl)methyl acetate

Dissolve 1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (11 g, 49 mmol) in dimethyl sulfoxide (100 mL), add potassium acetate (7.2 g, 73.5 mmol), and react Stir at 90°C for 18 hours. Water (300 mL) was added, the aqueous phase was extracted with methyl tert-butyl ether (100 mL×3), the organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain (2 -oxabicyclo[2.1.1]hexane-1-yl)methyl acetate (6 g, yield: 79%), yellow liquid.

The fourth step: (2-oxabicyclo[2.1.1]hexane-1-yl)methanol

(2-oxabicyclo[2.1.1]hexane-1-yl)methyl acetate (6 g, 39 mmol) was dissolved in ethanol (60 mL), replaced with nitrogen, cooled to 0 °C, and sodium ethoxide was added in portions (4 g, 58.5 mmol) and the reaction was stirred at room temperature for 18 hours. Ammonium chloride (2 g, 39 mmol) was added and stirred at room temperature for 2 hours. Filtration, the filter cake was washed with methyl tert-butyl ether (50 mL x 3), spin-dried, and the crude product was separated by column chromatography to obtain (2-oxabicyclo[2.1.1]hexane-1-yl)methanol ( 3.1 g, yield: 70%), pale yellow liquid.

The fifth step: (2-oxabicyclo[2.1.1]hexane-1-yl)methyl 4-methylbenzenesulfonate

(2-oxabicyclo[2.1.1]hexane-1-yl)methanol (3.1 g, 27 mmol) was dissolved in dichloromethane (30 mL), triethylamine (5.5 g, 54 mmol) and 4-dichloromethane were added Methylaminopyridine (170 mg, 1.4 mmol) was cooled to 0°C, p-toluenesulfonyl chloride (5.1 g, 27 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction solution was washed with water (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain (2-oxabicyclo[2.1.1]hexane-1-yl)methyl 4-methyl Benzenesulfonate (7.2 g, yield: 100% crude), yellow solid.

Step 6: 1-(azidomethyl)-2-oxabicyclo[2.1.1]hexane

(2-oxabicyclo[2.1.1]hexane-1-yl)methyl 4-methylbenzenesulfonate (7.2 g, 27 mmol) was dissolved in dimethyl sulfoxide (70 mL) and azide was added Sodium (2.67 g, 41 mmol), the reaction was stirred at 85 °C for 18 hours. Water (70 mL) was added, the aqueous phase was extracted with methyl tert-butyl ether (50 mL×6), the organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and most of the solvent was removed, Methanol was added to give a methanol solution of 1-(azidomethyl)-2-oxabicyclo[2.1.1]hexane (3.7 g, yield: 100% crude).

The seventh step: (2-oxabicyclo[2.1.1]hexane-1-yl)methanamine

Dissolve 1-(azidomethyl)-2-oxabicyclo[2.1.1]hexane (3.7 g, 27 mmol) in methanol (40 mL), add palladium on carbon (2.0 g), replace hydrogen, and react at room temperature under stirring for 18 hours. The reaction solution was filtered, and the filtrate was spin-dried to obtain (2-oxabicyclo[2.1.1]hexane-1-yl)methanamine (1.3 g, yield: 43%) as a colorless gum.

The eighth step: (S)-1-((2-oxabicyclo[2.1.1]hexane-1-yl)methyl)-2-((4-(3-(4-chloro-2- Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid

Using (2-oxabicyclo[2.1.1]hexane-1-yl)methanamine as raw material, the product (S)-1-((2-oxadi Cyclo[2.1.1]hexane-1-yl)methyl)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][ 1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 618.2[M+H] ⁺ .

Example 153

2-((4-(2-(2,4-Dichlorophenyl)-4,4-difluorochroman-8-yl)piperidin-1-yl)methyl)-3-((((S )-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Substitute 4-chloro-2-chlorobenzene (formaldehyde) with 4-chloro-2-fluorobenzene (formaldehyde) Reference Example 137 to obtain the product 2-((4-(2-(2,4-dichlorophenyl) )-4,4-Difluorochroman-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo [4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 643.2[M+H] ⁺ .

Example 154

2-((4-(4-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxan-6-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Step 1: 4-Bromobenzo[d][1,3,2]dioxaborazol-2-ol

3-Bromobenzene-1,2-diphenol (10 g, 53 mmol) and boric acid (3.3 g, 53 mmol) were dissolved in toluene (150 mL), an oil-water separator was added, and the reaction was stirred at 140° C. for 5 hours. The solvent was spun dry to give 4-bromobenzo[d][1,3,2]dioxaborazol-2-ol (11.3 g, yield: 100% crude) as a white solid.

Step 2: 2-(4-Chloro-2-fluorophenyl)oxapropane

Trimethylsulfoxide (16.5 g, 76 mmol) was dissolved in dimethylsulfoxide (100 mL), sodium hydrogen (3 g, 76 mmol) was added, and the reaction was stirred at room temperature for 1 hour. A solution of 4-chloro-2-fluorobenzene(formaldehyde) (10 g, 63 mmol) in dimethyl sulfoxide (20 mL) was added and the reaction was stirred at room temperature for 18 hours. Water (300 mL) was added to quench the reaction, the aqueous phase was extracted with EA (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain 2-(4-chloro-2 -Fluorophenyl)oxapropane (4g, yield: 23%), pale yellow liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12-7.08 (m, 3H), 4.13-4.09 (m, 1H), 3.18-3.16 (m, 1H), 2.76-2.74 (m, 1H).

The third step: 2-(4-chloro-2-fluorophenyl) oxetane

Potassium tert-butoxide (4.5 g, 40 mmol) was dissolved in tert-butanol (50 mL), nitrogen was replaced, trimethylsulfoxide (8.8 g, 40 mmol) was added, and the reaction was stirred at 60° C. for 1 hour. 2-(4-Chloro-2-fluorophenyl)oxapropane (3.5 g, 20 mmol) was added and the reaction was stirred at 80°C for 4 hours. Water (200 mL) was added to quench the reaction, the aqueous phase was extracted with EA (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography to obtain 2-(4-chloro-2 -Fluorophenyl)oxetane (1.5 g, yield: 39%), colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62-7.58 (m, 1H), 7.21-7.19 (m, 1H), 7.07-7.04 (m, 1H), 6.01-5.97 (m, 1H), 4.86-4.81 (m, 1H), 4.70–4.64 (m, 1H), 3.11–3.07 (m, 1H), 2.64–2.59 (m, 1H).

The fourth step: 3-bromo-2-(1-(4-chloro-2-fluorophenyl)-3-hydroxypropoxy)phenol

4-Bromobenzo[d][1,3,2]dioxaborazol-2-ol (2.3 g, 10.7 mmol) was dissolved in tetrahydrofuran (30 mL), and 2-(4-chloro-2-fluorobenzene was added) oxetane (1.0 g, 5.4 mmol) in tetrahydrofuran (10 mL), and the reaction was stirred at room temperature for 2 hours. The solvent was spin-dried, and the crude product was separated by column chromatography to obtain 3-bromo-2-(1-(4-chloro-2-fluorophenyl)-3-hydroxypropoxy)phenol (1.4 g, yield: 69%) ), a colorless gum.

Step 5: 9-Bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin

3-Bromo-2-(1-(4-chloro-2-fluorophenyl)-3-hydroxypropoxy)phenol (1.2 g, 3.2 mmol) was dissolved in tetrahydrofuran (20 mL), and triphenylphosphine ( 1.7 g, 6.4 mmol), replaced with nitrogen, cooled to 0° C., added diisopropyl azodicarboxylate (1.0 g, 4.8 mmol), and the reaction was stirred at room temperature for 18 hours. The solvent was spin-dried, and the crude product was separated by column chromatography to obtain 9-bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]di Oxyheptine (0.5 g, yield: 43%), colorless gum.

Step 6: 2-((4-(4-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin-6- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 9-bromo-2-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxin as raw material Reference Example 1 First , two, six, ten, eleven steps to obtain the product 2-((4-(4-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1, 4] Dioxhept-6-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 155

2-((4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl )methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Taking Im-2 and Im-8 as raw materials, the tenth step of reference example one, the eleventh step obtains 2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydrogen Benzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H -Imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 609.2,611.2[M+H] ⁺ .

Example 155-1

2-((4-((S)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-((S)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

2-(Chloromethyl)-3-[[rac-(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate methyl ester at room temperature (63.07mg, 213.26μmol), 4-[rac-(3S)-3-(2,4-dichlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl ] Piperidine (102 mg, 213.26 μmol, TF) was dissolved in acetonitrile (10 mL), then potassium carbonate (88.42 mg, 639.78 μmol) was added, heated to 45° C., reacted for 14 hours, and cooled to room temperature. LCMS indicated the end of the reaction, the reaction solution was diluted with ethyl acetate (20 mL), then washed with saturated brine (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and rotated to dryness, and the residue was separated by preparative thin layer chromatography (PE:EA=1:1) to give 2-((4-((S)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1, 4] Dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5- b] Methyl pyridine-5-carboxylate as a colorless oil (100 mg, 75.2%).

MS m/z(ESI): 623.2,625.2[M+H] ⁺ .

Step 2: 2-((4-((S)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate acid

At room temperature, 2-((4-((S)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl ester (100 mg, 160.38 μmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL), then a solution of lithium hydroxide (38.49 mg, 1.60 mmol) in water (1 mL) was added, heated to 40° C., reacted for 14 hours, and cooled to At room temperature, LCMS indicated the end of the reaction. Spin to dryness, and the residue was dissolved in ethyl acetate (20 mL). Under ice bath, the pH value was adjusted to 6-7 with aqueous formic acid, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate and filtered. Spin dry. The residue was separated by preparative HPLC (neutral conditions). Lyophilization gave the desired product as a white solid (30 mg, 29.8%).

MS m/z(ESI): 609.2,611.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.09 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.60-7.55 (m, 2H), 6.88-6.79(m, 3H), 5.47-5.43(m, 1H), 5.19-5.11(m, 1H), 4.87-4.81(m, 1H), 4.71-4.68(m, 1H), 4.51- 4.45(m, 2H), 4.39-4.31(m, 1H), 4.06-3.96(m, 2H), 3.89-3.86(m, 1H), 2.97-2.83(m, 3H), 2.71-2.63(m, 1H ), 2.48-2.43(m, 1H), 2.23-2.17(m, 2H), 1.81-1.58(m, 4H).

Example 155-2

2-((4-((R)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: 2-((4-((R)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

2-(Chloromethyl)-3-[[rac-(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate methyl ester at room temperature (63.07mg, 213.26μmol), 4-[rac-(3R)-3-(2,4-dichlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl ] Piperidine (102 mg, 213.26 μmol, TF) was dissolved in acetonitrile (10 mL), then potassium carbonate (88.42 mg, 639.78 μmol) was added, heated to 45° C., reacted for 14 hours, and cooled to room temperature. LCMS indicated that the reaction was over, diluted with ethyl acetate (20 mL), then washed with saturated brine (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was separated by preparative thin layer chromatography (PE : EA=1:1) to give 2-((4-((R)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b] Methyl pyridine-5-carboxylate was a colorless oil (100 mg, 75.2%).

MS m/z(ESI): 623.2,625.2[M+H] ⁺ .

Step 2: 2-((4-((R)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate acid

At room temperature, 2-((4-((R)-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl ester (100 mg, 160.38 μmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL), then a solution of lithium hydroxide (38.49 mg, 1.60 mmol) in water (1 mL) was added, heated to 40° C., reacted for 14 hours, and cooled to At room temperature, LCMS indicated the end of the reaction. Spin dry, and the residue was dissolved in ethyl acetate (20 mL). Under ice bath, the pH value was adjusted to 6-7 with aqueous formic acid, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and Spin dry. The residue was separated by preparative HPLC (neutral conditions). Lyophilization gave the desired product as a white solid (30 mg, 29.8%).

MS m/z(ESI): 609.2,611.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.04(d, J=8.0Hz, 1H), 7.91(d, J=8.0Hz, 1H), 7.71(s, 1H), 7.54-7.49(m, 2H), 6.81-6.73(m, 3H), 5.41-5.36(d, 1H), 5.10-5.03(m, 1H), 4.79-4.75(m, 1H), 4.67-4.64(m, 1H), 4.38- 4.31(m, 2H), 4.30-4.25(m, 1H), 3.99-3.83(m, 3H), 2.90-2.79(m, 3H), 2.65-2.57(m, 1H), 2.45-2.40(m, 1H ),2.21-2.08(m,2H),1.75-1.51(m,4H).

Example 156

2-((4-((S)-3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-bromo-4-(difluoromethyl)-2-fluorobenzene

At room temperature, 4-bromo-3-fluorobenzaldehyde (5.0 g, 24.63 mmol) was dissolved in dichloromethane (70 mL), then N,N-diethylaminosulfur trifluoride (4.37 g, 27.09 g) was added dropwise. mmol) in dichloromethane (70 mL), stirred overnight at room temperature, TLC indicated the end of the reaction, the reaction solution was quenched with saturated ammonium chloride solution, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried, the residue Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate = 100:0 to 95:5) gave the title product as a colorless oil (4.2 g, 75.8%).

1H NMR(400M, CDCl3)δ7.65(t,J=7.6Hz,1H),7.31-7.29(m,1H),7.18(d,J=7.6Hz,1H),6.61(t,J=56Hz, 1H).

The second step: 4-(difluoromethyl)-1-(1-ethoxyvinyl)-2-fluorobenzene

At room temperature, tri-n-butyl(1-ethoxyvinyl)tin (7.30 g, 20.22 mmol), 1-bromo-4-(difluoromethyl)-2-fluorobenzene (3.5 g, 15.56 mmol) , tetrakis(triphenyl)phosphorus palladium (898.75 mg, 777.76 μmol) was dissolved in 1,4-dioxane (50 mL), replaced with nitrogen, heated to 90° C., and reacted for 14 hours. Cooled to room temperature, TLC indicated the end of the reaction, then added saturated potassium fluoride solution, stirred at room temperature for one hour, a solid was precipitated, filtered, the solid was washed with ethyl acetate, separated, and the organic phase was dried with anhydrous sodium sulfate, filtered, and spun. After drying, the residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=20:1) to give the title product as a colorless oil (1.2 g, 35.7%).

1H NMR(400M, CDCl3)δ7.70(t,J=7.6Hz,1H),7.26-7.21(m,2H),6.61(t,J=56Hz,1H),4.77(d,J=2.0Hz, 1H), 4.50 (br, 1H), 3.92 (q, J=6.8Hz, 2H), 1.41 (t, J=6.8Hz, 3H).

The third step: 4-(difluoromethyl)-2-fluoroacetophenone

At room temperature, 4-(difluoromethyl)-1-(1-ethoxyvinyl)-2-fluorobenzene (1.20 g, 5.55 mmol) was dissolved in tetrahydrofuran (20 mL), and then diluted hydrochloric acid (2N, 20mmol, 10mL), stirred at room temperature for 2 hours, TLC indicated the end of the reaction, the reaction solution was diluted with ethyl acetate (20mL), then washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried, and the residue was directly Used in the next step (0.95 g, 91%).

¹ H NMR(400M, CDCl3)δ7.96(t,J=7.6Hz,1H),7.36(d,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H),6.66(t, J=56Hz, 1H), 2.67(d, J=4.8Hz, 3H).

The fourth step: 2-chloro-1-(4-(difluoromethyl)-2-fluorophenyl)-ethan-1-one

Under ice bath, 4-(difluoromethyl)-2-fluoroacetophenone (0.95 g, 5.05 mmol) was dissolved in dichloromethane (50 mL), followed by methanol (161.58 mg, 5.05 mmol, 204.01 μL) and Sulfonyl chloride (1.09g, 8.08mmol) was stirred under ice bath for 2 hours, TLC indicated that the reaction was over, the reaction solution was adjusted to pH 6-7 with 10% aqueous sodium hydroxide solution, the reaction solution was diluted with dichloromethane, and then Washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry, and the residue was used directly in the next step (1.10 g, 97.8%).

Step 5: 2-((4-(3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Take 2-chloro-1-(4-(difluoromethyl)-2-fluorophenyl)-ethan-1-one as raw material, refer to intermediate Im-7 first step, second step, third step in turn Step, the fourth step, the fifth step, the sixth step, and the tenth step of embodiment one, obtain 2-((4-(3-(4-(difluoromethyl)-2-fluorophenyl)-2 ,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl) methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester.

MS m/z(ESI): 622.2[M+H] ⁺ .

Step 6: 2-((4-((S)-3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-6- Methyl Carboxylate

The target product was obtained by chiral resolution.

MS m/z(ESI): 622.2[M+H] ⁺ .

Step 7: 2-((4-((S)-3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazol-6- carboxylic acid

2-((4-((S)-3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl Ester is used as raw material, and 2-((4-((S)-3-(4-(difluoromethyl)-2-fluorophenyl)-2,3-dihydrobenzene) is obtained in the eleventh step of reference example 1 [b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 608.2[M+H] ⁺ .

Example 157

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-((1-(difluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (1-(difluoromethyl)cyclopropyl)methanamine as raw material Reference Example 1 from the seventh step to the tenth step to obtain the product 2-((4-(3-(4-chloro-2-fluorophenyl) )-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(difluoromethyl)ring Propyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 626.2[M+H] ⁺ .

Example 158

2-((4-((S)-3-(4-Chloro-2,6-difluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-chloro-1-(4-chloro-2,6-difluoro-phenyl)ethanone

1-(4-Chloro-2,6-difluoro-phenyl)ethanone (6g, 31.48mmol) and methanol (867.78mg, 31.48mmol, 1.10mL), dichloromethane (49.93mL) were added to a 100mL flask , sulfonyl chloride (5.10 g, 37.78 mmol) was added at 0 °C under nitrogen protection, and then the reaction solution was reacted at 0 °C for 2 h. After the reaction solution was concentrated, it was passed through a column with PE/EA=10/1 to obtain the product 2-chloro-1-(4-chloro-2,6-difluoro-phenyl)ethanone (6g, 26.66mmol, 84.69% yield) .

MS m/z(ESI): 224.9[M+H] ⁺ .

Step 2: 2-((4-((S)-3-(4-chloro-2,6-difluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin In-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 2-chloro-1-(4-chloro-2,6-difluoro-phenyl)ethanone as raw material, referring to Example 121 and Example 121-1, the product 2-((4-((S)-3 -(4-Chloro-2,6-difluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl) -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 610.1[M+H] ⁺ .

Example 159

Taking intermediate Im-8A as raw material Reference Example 1 tenth, eleventh step to obtain product (S)-2-((4-(3-(2,4-dichlorophenyl)-2,3-dihydro Benzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 626.2[M+H] ⁺ .

Example 160

2-(4-(3-(2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,5-difluoro Benzyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(4-bromo-2,5-difluorophenyl)acetic acid

Using ethyl 2-(4-bromo-2,5-difluorophenyl) acetate as raw material, the eleventh step of reference example 1 obtains 2-(4-bromo-2,5-difluorophenyl) Acetic acid.

MS m/z(ESI): 250.9[M+H] ⁺ .

The second step: methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylate

Using 2-(4-bromo-2,5-difluorophenyl)acetic acid as raw material, referring to the eighth step of Example 2, the ninth step obtains methyl (S)-2-(4-bromo-2,5- Difluorobenzyl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 451.0[M+H] ⁺ .

The third step: 2-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolane

8-Bromo-2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (500 mg, 1.4 mmol), 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane)(530mg, 2.0mmol),Pd(dppf)Cl ₂ (50 mg, 0.07 mmol) and potassium acetate (410 mg, 4.2 mmol) were dissolved in dioxane (20 mL) and reacted at 90° C. for 3 h under nitrogen protection. It was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain 2-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin in-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (340 mg, 60%).

The fourth step: methyl 2-(4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)- 2,5-Difluorobenzyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

With 2-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane and methyl(S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxabutan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate is used as raw material, and the first step of reference example 1 obtains methyl 2-(4-(3-(2,4-dichlorophenyl)- 2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2,5-difluorobenzyl)-1-(((S)-oxetane-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 651.1[M+H] ⁺ .

The fifth step: 2-(4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2, 5-Difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With methyl 2-(4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,5 -Difluorobenzyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material, refer to Example 1 Eleven steps give 2-(4-(3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2, 5-Difluorobenzyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 637.1[M+H] ⁺ .

Example 161

1-((2,8-Dioxaspiro[4.5]decan-3-yl)methyl)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3 -Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (2,8-dioxaspiro[4.5]decane-3-yl)methanamine as raw material, referring to Example 146, 1-((2,8-dioxaspiro[4.5]decane-3- yl)methyl)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 676.2[M+H] ⁺ .

Example 162

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-((1-methoxycyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: methyl 2-(chloromethyl)-1-((1-methoxycyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Using (1-methoxycyclopropyl)methylamine as raw material, referring to intermediate Im-1, methyl 2-(chloromethyl)-1-((1-methoxycyclopropyl)methyl)- 1H-Benzo[d]imidazole-6-carboxylate.

MS m/z(ESI): 309.0[M+H] ⁺ .

Step 2: 2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-((1-methoxycyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using methyl 2-(chloromethyl)-1-((1-methoxycyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate as raw material, refer to Example 1 No. Ten steps, eleventh step to obtain 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-((1-methoxycyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 606.2[M+H] ⁺ .

Example 163

(Pivaloylindandioneoxy)methyl 5-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3 ]Dioxazol-4-yl)piperidin-1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d ]thiazole-2-carboxylate

5-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-4-(((S)-oxbutan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid (50 mg, 0.08 mmol), chloromethyl pivaloyl indionate (19 mg, 0.13 mmol) and triethylamine (24 mg, 0.24 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 3 h. Concentrated under reduced pressure, the crude product was purified by prep-HPLC to give (pivaloylindandioneoxy)methyl 5-((4-((S)-2-(4-chloro-2-fluorophenyl)- 2-Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-4-(((S)-oxetan-2-yl)methan yl)-4H-imidazo[4,5-d]thiazole-2-carboxylate (17 mg, 30%).

MS m/z(ESI): 713.2[M+H] ⁺ .

Example 164

(5-Methyl-2-carbonyl-1,3-dioxazol-4-yl)methyl(S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2 -Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl) -4H-imidazo[4,5-d]thiazole-2-carboxylate

The first step: (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

Using (1-(fluoromethyl)cyclopropyl)methanamine as raw material, referring to Example 111-1, (S)-5-((4-(2-(4-chloro-2-fluorophenyl)) was obtained -2-Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methan yl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid.

MS m/z(ESI): 615.1[M+H] ⁺ .

The second step: (5-methyl-2-carbonyl-1,3-dioxazol-4-yl)methyl (S)-5-((4-(2-(4-chloro-2-fluorobenzene) yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl) )methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylate

With (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine -1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid and 4-chloromethane Base-5-methyl-1,3-dioxol-2-one was used as raw material, referring to Example 163 to obtain (5-methyl-2-carbonyl-1,3-dioxazol-4-yl )methyl(S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylate.

MS m/z(ESI): 727.2[M+H] ⁺ .

Example 165

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-2-methyl-2 ,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate acid

The first step: tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate

Using tert-butyl 2-methyl-4-carbonylpyrrolidine-1-carboxylate as raw material, referring to Example 110, the first step was to obtain tert-butyl 2-methyl-4-(((trifluoromethyl )sulfonyl)oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate.

¹ H NMR (400M, CDCl3) δ 5.66 (d, J=14.4Hz, 1H), 4.67-4.53 (m, 1H), 4.33-4.15 (m, 2H), 1.49-1.47 (m, 9H), 1.38 -1.33(m,3H).

Step 2: 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)-2- Methyl-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-Carboxylic acid

Using tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-2,5-dihydro-1H-pyrrole-1-carboxylate as raw material, refer to Examples in turn 110 The second step, the third step and the sixth step of embodiment one, the tenth step, the eleventh step obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl Benzo[d][1,3]Dioxazol-4-yl)-2-methyl-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1-(((S) -oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 590.2,592.2[M+H] ⁺ .

Example 166

(S)-2-((4-(2-Chloro-11H-dibenzo[b,e][1,4]dioxhept-6-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 1-bromo-3-((5-chloro-2-iodobenzyl)oxo)-2-((4-methoxybenzyl)oxo)benzene

Using 5-chloro-2-iodobenzyl alcohol and 3-bromo-2-((4-methoxybenzyl)oxo)phenol as raw materials, the fifth step of Reference Example 154 obtained 1-bromo-3-((5 -Chloro-2-iodobenzyl)oxo)-2-((4-methoxybenzyl)oxo)benzene.

MS m/z(ESI): 558.9[M+H] ⁺ .

The second step: 2-bromo-6-((5-chloro-2-iodobenzyl)oxo)phenol

1-Bromo-3-((5-chloro-2-iodobenzyl)oxo)-2-((4-methoxybenzyl)oxo)benzene (500 mg, 0.9 mmol) was dissolved in DMF (10 mL) ), TFA (306 mg, 2.7 mmol) was added, and the reaction was carried out at room temperature for 1 h. Concentration under reduced pressure gave 2-bromo-6-((5-chloro-2-iodobenzyl)oxo)phenol (390 mg, 99%).

MS m/z(ESI): 438.8[M+H] ⁺ .

The third step: 6-bromo-2-chloro-11H-dibenzo[b,e][1,4]dioxin

Using 2-bromo-6-((5-chloro-2-iodobenzyl)oxo)phenol as a raw material, the third step of Reference Example 121 obtained 6-bromo-2-chloro-11H-dibenzo[b ,e][1,4]Dioxin.

The fourth step: (S)-2-((4-(2-chloro-11H-dibenzo[b,e][1,4]dioxhept-6-yl)piperidin-1-yl)methan yl)-1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 6-bromo-2-chloro-11H-dibenzo[b,e][1,4]dioxin as raw material, the fourth to sixth steps of Reference Example 121 were used to obtain (S)-2-( (4-(2-Chloro-11H-dibenzo[b,e][1,4]dioxhept-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 560.2[M+H] ⁺ .

Example 167

(S)-2-((4-(7-Chlorodibenzo[b,e][1,4]dioxin-1-yl)piperidin-1-yl)methyl)-1-(oxa Butane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Step 1: 1-Bromo-7-chlorodibenzo[b,e][1,4]dioxin

Using 4-chloro-2-iodophenol and 2-iodo-3-bromophenol as raw materials, the third step of Reference Example 121 obtained 1-bromo-7-chlorodibenzo[b,e][1,4]bis oxin.

Step 2: (S)-2-((4-(7-Chlorodibenzo[b,e][1,4]dioxin-1-yl)piperidin-1-yl)methyl)- 1-(oxbutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-bromo-7-chlorodibenzo[b,e][1,4]dioxin as a raw material, the fourth step to the sixth step of Reference Example 121 obtained (S)-2-((4-( 7-Chlorodibenzo[b,e][1,4]dioxin-1-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 546.1[M+H] ⁺ .

Example 168

2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5 -Fluoro-2-carbonylpyridin-1(2H)-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b] Pyridine-5-carboxylic acid

The first step: methyl (S)-2-((4-bromo-5-fluoro-2-carbonylpyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl) )-3H-imidazo[4,5-b]pyridine-5-carboxylate

Using 4-bromo-5-fluoropyridine-2(1H)-one as raw material Reference Example 1 tenth step to obtain the product methyl (S)-2-((4-bromo-5-fluoro-2-carbonylpyridine- 1(2H)-yl)methyl)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

MS m/z(ESI): 451.0[M+H] ⁺ .

The second step: (S)-(5-fluoro-1-((5-(carbomethoxy<methoxycarbonyl>)-3-(oxetan-2-ylmethyl)-3H-imidazo[4 ,5-b]pyridin-2-yl)methyl)-2-carbonyl-1,2-dihydropyridin-4-yl)boronic acid

Taking 4-bromo-5-fluoropyridine-2(1H)-one as raw material Reference Example 2 the fourth step obtains product (S)-(5-fluoro-1-((5-(carbomethoxy<methoxycarbonyl) >)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-carbonyl-1,2-dihydropyridine- 4-yl) boronic acid.

MS m/z(ESI): 417.1[M+H] ⁺ .

The third step: 2-((4-((S)-3-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)-5-fluoro-2-carbonylpyridin-1(2H)-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4, 5-b]pyridine-5-carboxylic acid

With (S)-(5-fluoro-1-((5-(carbomethoxy<methoxycarbonyl>)-3-(oxbutan-2-ylmethyl)-3H-imidazo[4,5- b] Pyridin-2-yl)methyl)-2-carbonyl-1,2-dihydropyridin-4-yl)boronic acid and (S)-8-bromo-2-(2,4-dichlorophenyl) -2,3-Dihydrobenzo[b][1,4]dioxin as raw material Reference Example 1 The tenth step, the eleventh step obtains the product 2-((4-((S)-3-( 2,4-Dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-fluoro-2-carbonylpyridin-1(2H)-yl )methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 637.1[M+H] ⁺ .

Example 169

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (1-(trifluoromethyl) cyclopropyl) methylamine as raw material Reference Example 1 from the seventh step to the tenth step to obtain the product 2-((4-(3-(4-chloro-2-fluorophenyl) )-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(trifluoromethyl)ring Propyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 644.2[M+H] ⁺ .

Example 170

2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-1-((1-methoxycyclobutyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using (1-methoxycyclobutyl)methanamine ester as raw material, 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzene was obtained in Reference Example 169 [b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-methoxycyclobutyl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 620.2[M+H] ⁺ .

Example 171

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester

(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (40mg , 115.01 μmol) was dissolved in MeCN (10 mL), to which was added K ₂ CO ₃ (79.47 mg, 575.03 μmol) and 2-(chloromethyl)-3-[[1-(fluoromethyl)cyclopropyl] Methyl]imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (35.85 mg, 115.01 μmol). The reaction system was stirred in an oil bath at 60°C for 4 hours. After the reaction is completed, after the reaction is completed, add water (10 mL) to dilute, extract with ethyl acetate (20 mL × 2), wash with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate to obtain crude product (S)- 2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester (70 mg, crude). The crude product was directly used in the next reaction.

MS m/z(ESI): 623.2[M+H] ⁺ .

The second step (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester ( 70 mg, crude) was dissolved in THF (4 mL), to which was added LiOH (53.81 mg, 2.25 mmol) and MeOH (1 mL). The reaction system was stirred at room temperature of 20°C for 4 hours. After completion of the reaction, concentrated to obtain crude product. The crude product was purified by Prep-HPLC to give (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]di Oxin-5-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine- 5-Carboxylic acid (18 mg, 29.55 μmol, 26.31% yield).

MS m/z(ESI): 609.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO)δ8.01(d,J=8.2Hz,1H),7.90(d,J=8.4Hz,1H),7.60-7.50(m,2H),7.42(d,J=8.4 ,2.0Hz,1H),6.88–6.76(m,3H),5.46(d,J=7.9,2.4Hz,1H),4.55(s,2H),4.47–4.40(m,1H),4.29(d, J=48.8Hz, 2H), 4.14–4.06 (m, 1H), 3.84 (s, 2H), 2.94 (d, J=11.1Hz, 2H), 2.89–2.80 (m, 1H), 2.28–2.12 (m ,2H),1.84–1.57(m,4H),1.14–1.03(m,2H),0.67–0.54(m,2H).

Example 172

(S)-2-((4-(3-(4-Cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (S)-4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidine-1-carboxylate tert-butyl ester

(S)-4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1- Carboxylic acid tert-butyl ester (80.00mg, 178.60μmol), zinc cyanide (62.92mg, 535.80μmol), zinc powder (11.68mg, 178.60μmol), 1,1′-bis(diphenylphosphino) dimethylene Iron (19.80mg, 35.72μmol), tris(dibenzylideneacetone)dipalladium (16.35mg, 17.86μmol) and NMP (5mL) were added to a 20mL microwave tube, then the reaction solution was reacted under nitrogen protection at 150°C in a microwave 8h. TLC showed a new spot, the reaction solution was quenched with water, extracted with EA (30 mL), the organic phase was concentrated, and the product (S)-4-(3-(4-cyano) was obtained after passing through the column with PE/EA=3/1 -2-Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate tert-butyl ester (45 mg, 102.62 μmol, 57.46 %yield).

MS m/z(ESI): 439.2[M+H] ⁺ .

Step 2: (S)-3-Fluoro-4-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl) benzonitrile

(S)-4-(3-(4-Cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1 - tert-butyl carboxylate (45 mg, 102.6 μmol) was dissolved in 25% TFA/DCM (15 mL), stirred at room temperature for 3 hours, the reaction solution was spin-dried, then dissolved in dichloromethane, and aqueous sodium bicarbonate solution was added to adjust pH To 7-8, the organic phase was dried and then spin-dried to give (S)-3-fluoro-4-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4] ] Dioxin-2-yl)benzonitrile (34.7 mg, 100%).

MS m/z(ESI): 339.1[M+H] ⁺ .

The third step: (S)-2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

(S)-3-Fluoro-4-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile ( 34.7 mg, 102 μmol) was dissolved in acetonitrile (5 mL), and ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d] was added separately Imidazole-6-carboxylate (33 mg, 102 μmol) and potassium carbonate (28 mg, 204 μmol) were stirred at 50°C for 4 hours, water was added, and ethyl acetate was added for extraction. The organic phase was dried and then spin-dried. The crude product was passed through the column layer. analytical purification to obtain (S)-2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (45 mg, 70.6%).

MS m/z(ESI): 627.2[M+H] ⁺ .

Fourth step: (S)-2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(3-(4-Cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate ethyl ester (45 mg, 71.8 μmol) was dissolved in THF (3 mL), 2 mol/L LiOH (0.3 mL) was added, stirred at 40°C overnight, 1 mol/L HCl was added, the pH was adjusted to 5-6, ethyl acetate was added, extracted, the organic phase was dried and then spin-dried , the crude product was purified by prep-HPLC to give (S)-2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1, 4] Dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6 - Carboxylic acid (11 mg, 25.5%).

MS m/z(ESI): 599.2[M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.31(d,J=1.5Hz,1H),7.96(dd,J=8.5,1.5Hz,1H),7.76-7.58(m,4H),6.90- 6.79 (m, 2H), 6.78–6.71 (m, 1H), 5.53 (dd, J=7.6, 2.4Hz, 1H), 4.68 (s, 2H), 4.48–4.41 (m, 1H), 4.21–4.12 ( m, 1H), 4.09–4.02 (m, 2H), 4.02–3.91 (m, 2H), 3.08–2.91 (m, 3H), 2.40–2.22 (m, 2H), 1.91–1.73 (m, 4H), 0.97–0.80 (m, 2H), 0.81–0.69 (m, 2H).

Example 173

(S)-2-((4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

with (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and Intermediate Im-5 is the synthesis product (S)-2-((4-(3-(4-chloro-2-methoxyphenyl)-2 of the 9th step and the 10th step of raw material reference example 145, 3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 620.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6)δ8.24(s,1H),7.87-7.75(m,1H),7.73-7.61(m,1H),7.37(d,J=8.2Hz,1H),7.20 (s, 1H), 7.13 (dd, J=8.1, 2.0Hz, 1H), 6.90– 6.73 (m, 3H), 5.41–5.30 (m, 1H), 4.64–4.51 (m, 2H), 4.44–4.33 (m, 1H), 4.24–4.16 (m, 1H), 4.13–4.04 (m, 1H), 3.97–3.80 (m, 6H), 2.98–2.82 (m, 3H), 2.26–2.10 (m, 2H) ,1.82–1.64(m,4H),0.83–0.76(m,2H),0.73–0.66(m,2H).

Example 174

(S)-2-((4-(3-(4-Chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

with (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and Intermediate Im-6 is the synthesis of raw material reference example 145 ninth step and tenth step to obtain product (S)-2-((4-(3-(4-chloro-2-methoxyphenyl)-2, 3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl )-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 621.2[M+H] ⁺ .

Example 175

(S)-2-((4-(3-(4-Fluoro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: (S)-4-(3-(4-fluoro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) piperidine

Using 1-(4-fluoro-2-methoxyphenyl)ethan-1-one as raw material, the product (S)-4-(3-(4- Fluoro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine.

MS m/z(ESI): 344.1[M+H] ⁺ .

Step 2: (S)-2-((4-(3-(4-Fluoro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-4-(3-(4-fluoro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and Intermediate Im-5 is the synthetic product (S)-2-((4-(3-(4-fluoro-2-methoxyphenyl)-2 of the 9th step and the 10th step of raw material reference example 145, 3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 604.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δ8.22 (d, J=1.5Hz, 1H), 7.80 (dd, J=8.4, 1.5Hz, 1H), 7.64 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.5, 6.8Hz, 1H), 7.03 (dd, J=11.3, 2.5Hz, 1H), 6.94–6.86 (m, 1H), 6.82–6.74 (m, 3H), 5.33 (dd, J=8.2, 2.3Hz, 1H), 4.60 (s, 2H), 4.40–4.33 (m, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 3.95–3.88 (m, 1H), 3.86 (s, 3H), 3.82 (s, 2H), 2.99–2.77 (m, 3H), 2.24–2.10 (m, 2H), 1.84–1.62 (m, 4H), 0.81–0.76 (m, 2H), 0.70 –0.66(m,2H).

Example 176

(S)-2-((4-(3-(4-cyano-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine- 1-Carboxylic acid tert-butyl ester is the raw material Reference Example 172 obtains the product (S)-2-((4-(3-(4-cyano-2-methoxyphenyl)-2,3-dihydrobenzene [b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzene and [d]imidazole-6-carboxylic acid.

MS m/z(ESI): 611.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.24(s, 1H), 7.81(d, J=8.5Hz, 1H), 7.65(d, J=8.5Hz, 1H), 7.61(s, 1H) ,7.58–7.50(m,2H),6.87–6.72(m,3H),5.50–5.40(m,1H),4.71–4.53(m,2H),4.47–4.35(m,1H),4.25–4.15( m, 1H), 4.15–4.04 (m, 1H), 4.02–3.89 (m, 4H), 3.88–3.77 (m, 2H), 3.14–2.76 (m, 3H), 2.34–2.09 (m, 2H), 1.94–1.77 (m, 1H), 1.76–1.54 (m, 3H), 0.91–0.74 (m, 2H), 0.74–0.61 (m, 2H).

Example 177

(S)-2-((4-(3-(4-cyano-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

With (S)-4-(3-(4-chloro-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine- 1-Carboxylic acid tert-butyl ester was used as the starting material in Reference Example 172 and 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d] Imidazole-6-carboxylate was replaced with 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine- Ethyl 5-carboxylate gives the product (S)-2-((4-(3-(4-cyano-2-methoxyphenyl)-2,3-dihydrobenzo[b][1, 4] Dioxin-5-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b ] Pyridine-5-carboxylic acid.

MS m/z(ESI): 612.2[M+H] ⁺ .

Example 178

(S)-2-((4-(3-(5-Chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 5-chloro-2-(oxapropan-2-yl)pyridine

To a solution of trimethyl sulfoxide (46.64 g, 211.93 mmol) in dimethyl sulfoxide (200 mL) was added potassium tert-butoxide (23.78 g, 211.93 mmol) in portions, then stirred at room temperature for 30 minutes, then 0 A solution of 5-chloropyridine-2-carbaldehyde (20 g, 141.29 mmol) in dimethyl sulfoxide (100 mL) was added at degrees Celsius, stirred at 0 degrees Celsius for 30 minutes, quenched with ice cubes, extracted with ethyl acetate (100 mL*3), organic The phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and then separated by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain 5-chloro-2-(oxopropane) as a pale yellow oily product Cyclo-2-yl)pyridine (9.3 g, yield: 42.3%)

MS m/z(ESI): 156.0[M+H] ⁺ .

Step 2: 2-(3-Bromo-2-iodophenoxy)-1-(5-chloropyridin-2-yl)ethane-1-ol

To a solution of 3-bromo-2-iodophenol (6 g, 20.07 mmol) in N,N-dimethyl-formamide (100 mL) at 0°C was added sodium hydrogen (1.04 g, 26.10 mmol, 60% purity), then Stir at 0 degrees Celsius for 0.5 h, then add dropwise a solution of 5-chloro-2-(oxapropan-2-yl)pyridine (4.68 g, 30.11 mmol) in N,N-dimethyl-formamide (30 mL) at 60 Stir at degrees Celsius for 12 hours, add water to quench the reaction, extract with dichloromethane (100 mL*3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, and then separate by column chromatography (petroleum ether: ethyl acetate) Ester = 10:1) to give 2-(3-bromo-2-iodophenoxy)-1-(5-chloropyridin-2-yl)ethane-1-ol (1.5 g, yield: 16.4%)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.57 (d, J=2.5Hz, 1H), 7.95 (dd, J=8.5, 2.5Hz, 1H), 7.71 (d, J=8.5Hz, 1H) ,7.35–7.21(m,2H),6.99(dd,J=7.4,2.1Hz,1H),5.94(d,J=4.9Hz,1H),5.00(q,J=4.5Hz,1H),4.35( dd,J＝10.1,3.9Hz,1H),4.27(dd,J＝10.1,5.6Hz,1H).

MS m/z(ESI): 454.0[M+H] ⁺ .

The third step: 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-5-chloropyridine

2-(3-Bromo-2-iodo-phenoxy)-1-(5-chloro-2-pyridyl)ethanol (1.5 g, 3.30 mmol), cuprous iodide (125.71 mg, 660.09 μmol), A mixture of 1,10-phenanthroline (297.04 mg, 1.65 mmol), cesium carbonate (3.22 g, 9.90 mmol), toluene (30 mL) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 120°C under nitrogen protection For 16 hours, the reaction was quenched by adding water, extracted with dichloromethane (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and then separated by column chromatography (petroleum ether: ethyl acetate= 10:1), 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-5-chloropyridine (500 mg, produced as a colorless oil) was obtained as a colorless oil. rate: 46.4%).

MS m/z(ESI): 326.0[M+H] ⁺ .

The fourth step: (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl) Pyridine

Using 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-5-chloropyridine as raw material Reference Example 145 Fifth, sixth, seventh, Eight steps to obtain the product (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl) Pyridine.

MS m/z(ESI): 331.1[M+H] ⁺ .

The fifth step: (S)-2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)pyridine and intermediate Body Im-5 is the raw material Reference Example 145 The ninth, tenth step obtains the product (S)-2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[ b][1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[ d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 591.2[M+H] ⁺ .

Example 179

(S)-2-((4-(3-(5-Chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

With (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)pyridine and intermediate Body Im-6 is the raw material Reference Example 145 The ninth, tenth step obtains the product (S)-2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[ b][1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[ 4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 592.2[M+H] ⁺ .

Example 180

2-((4-((S)-3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

With (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)pyridine and intermediate Body Im-2 is the raw material Reference Example 145 The ninth, tenth step obtains the product 2-((4-((S)-3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[ b][1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxbutan-2-yl)methyl)-3H-imidazo [4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 576.2[M+H] ⁺

Example 181

2-((4-((S)-3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine -1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

With (S)-5-chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)pyridine and intermediate Body Im-1 is the raw material Reference Example 145 The ninth, tenth step obtains the product 2-((4-((S)-3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[ b][1,4]Dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo [d] Imidazole-6-carboxylic acid.

MS m/z(ESI): 575.2[M+H] ⁺ .

Example 182

(S)-2-((4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine Perid-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

The first step: methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Synthesis of Esters

Using methyl 5-chloro-6-nitropicolinate as raw material, with reference to the synthesis of intermediate Im-5, the product methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropane) was obtained yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate.

MS m/z(ESI): 312.1[M+H] ⁺ .

The second step: (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5 -yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid preparation

With (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine and methyl Base 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate as raw material, refer to Example 171 yielded the product (S)-2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate acid.

MS m/z(ESI): 609.1[M+H] ⁺ .

Example 183

2-((4-((S)-3-(4-cyano-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-3-methoxy-4-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzene Formonitrile and Im-1 are raw materials, and the tenth step and eleventh step of Reference Example 1 obtain the product 2-((4-((S)-3-(4-cyano-2-methoxyphenyl)- 2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 595.2[M+H] ⁺ .

Example 184

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6 -Dihydropyridin-1(2H)-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step 1-(fluoromethyl)cyclopropane-1-carboxylate ethyl ester

Step 2: 1-(Fluoromethyl)cyclopropylmethanol

The third step: (1-(fluoromethyl) cyclopropyl) methyl methanesulfonate

1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL), and methanesulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and trimethylsulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) were added dropwise thereto in an ice water bath. Ethylamine (2.53 g, 24.97 mmol, 3.48 mL). The reaction system was stirred at 20°C. After the reaction was completed, saturated NaHCO (10 mL) was added dropwise to quench the reaction, extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oily crude product (1-(Fluoromethyl)cyclopropyl)methylmethanesulfonate (2.0 g, 88% yield).

The fourth step: (1-(fluoromethyl) cyclopropyl) methylamine

(1-(Fluoromethyl)cyclopropyl)methylmethanesulfonate (1.0 g, 5.49 mmol) was dissolved in NH ₃ /i-PrOH (10 mL), and the reaction system was heated under microwave at 60° C. for 6 hours . After completion of the reaction, concentrate to obtain crude (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, crude). The crude product was used directly in the next reaction.

Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), to which was added (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, 5.82 mmol) ) and K ₂ CO ₃ (1.61 g, 11.64 mmol). The reaction system was stirred at 20°C for four hours. After the reaction was completed, water (10 mL) was added to it to dilute, extracted with ethyl acetate (20 mL×2), washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column (Petroleum ether: Ethyl acetate=5:1, UV=254nm, Rf=0.50), and finally a pale yellow solid 3-((((1-(fluoromethyl)cyclopropyl)methyl)amino) was obtained -4-Nitrobenzoic acid ethyl ester (1.2 g, 4.05 mmol, 69.59% yield).

MS m/z(ESI): 297.1[M+H] ⁺ .

¹ H NMR(400MHz, CDCl3)δ8.22(d,J=8.8Hz,1H),7.56(s,1H),7.25(d,J=7.6Hz,1H),4.41(q,J=3.2,2.8 Hz, 2H), 4.30(d, J＝38.0Hz, 2H), 3.42(d, J＝4.0Hz, 2H), 1.41(t, J＝7.2Hz, 3H), 0.76(m, 4H).

Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, 4.05 mmol) was dissolved in MeOH (30 mL), to which was added Pd /C (200 mg, 10% purity). After the reaction system was purged with hydrogen three times, it was stirred at 20° C. for 2 hours. After the reaction, filtered through celite, and the filtrate was concentrated to obtain a crude product of ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol). , 92.7% yield).

MS m/z(ESI): 267.1[M+H] ⁺ .

The seventh step: 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

MS m/z(ESI): 325.1[M+H] ⁺ .

Step 8: 2-(4-Bromo-2-methyl-1,3-benzobisoxazol-2-yl)-5-chloro-pyridine

3-Bromobenzene-1,2-diol (5 g, 26.45 mmol), 5-chloro-2-ethynyl-pyridine (3.64 g, 26.45 mmol) and toluene (100 mL) were added to a 25 mL flask at 25°C Ru3CO12 (1.34g, 2.65mmol) was added, and then the reaction solution was reacted under nitrogen protection at 100°C for 12h. The reaction solution was filtered, concentrated, and passed through the column with PE/EA=20/1 to obtain the product 2-(4-bromo-2-methyl) yl,3-benzobisoxazol-2-yl)-5-chloro-pyridine (3 g, 9.19 mmol, 34.7% yield).

MS m/z(ESI): 325.9[M+H] ⁺ .

Step 9: 4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]-3,6-dihydro-2H-pyridine -1-Carboxylic acid tert-butyl ester

2-(4-Bromo-2-methyl-1,3-benzobisoxazol-2-yl)-5-chloro-pyridine (3g, 9.19mmol),4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.84g, 9.19mmol), 1, 1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (672.17 mg, 918.63 μmol), Cs2CO3 (8.98 g, 27.56 mmol) and 1'4-Dioxane (50 mL), H2O (10 mL) It was added to a 100 mL flask, and then the reaction solution was reacted at 90° C. for 4 h under nitrogen protection. LCMS showed that the reaction was successful. The reaction solution was filtered, concentrated, and passed through a column with PE/EA=3/1 to obtain the product 4-[2-(5-chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazole- 4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g, 7.46 mmol, 81.2% yield).

MS m/z(ESI): 429.1[M+H] ⁺ .

Step 10: (S)-4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]-3,6-dihydro -2H-Pyridine-1-carboxylate tert-butyl ester

4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate Acid tert-butyl ester (3.2g, 7.46mmol) was chiral resolved to give the product (S)-4-[2-(5-chloro-2-pyridyl)-2-methyl-1,3-benzo Dioxazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 3.50 mmol, 46.87% yield).

Step 11: (S)-5-Chloro-2-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3] Dioxazol-2-yl)pyridine

(S)-4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]-3,6-dihydro-2H-pyridine -1-Carboxylic acid tert-butyl ester (300 mg, 699.44 μmol) and DCM (10 mL) were added to a 100 mL flask, trifluoroacetic acid (1.59 g, 13.92 mmol) was added at 25 °C, and then the reaction solution was reacted at 25 °C 1h. The reaction solution was concentrated to obtain the product (S)-5-chloro-2-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3 ] Dioxazol-2-yl)pyridine (229 mg, 696.47 μmol, 99.57% yield) was used directly in the next reaction.

MS m/z(ESI): 329.1[M+H] ⁺ .

The twelfth step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-3,6-dihydropyridin-1(2H)-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6 -Ethyl formate

(S)-5-Chloro-2-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3]dioxazole-2 -yl)pyridine (229 mg, 696.47 μmol), 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Ethyl ester (226.2 mg, 696.47 μmol) and MeCN (10 mL) were added to a 100 mL flask, K2CO3 (288.27 mg, 2.09 mmol) was added at 25 °C, and the reaction solution was reacted at 25 °C for 24 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through the column with PE/EA=3/1 to obtain the product yellow solid (S)-2 -((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-dihydropyridine- 1(2H)-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (320 mg, 518.54 μmol, 74.45% yield).

MS m/z(ESI): 617.2[M+H] ⁺ .

Thirteenth step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl )-3,6-dihydropyridin-1(2H)-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6 - Formic acid

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6 -Dihydropyridin-1(2H)-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester ( 320 mg, 518.54 μmol) and MeOH (20 mL) were added to a 100 mL flask, sodium hydroxide (237.66 mg, 5.94 mmol) was added at 25 °C, and the reaction solution was reacted at 25 °C for 2 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and prepared by prep-hplc to obtain a white solid (S)-2-((4- (2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6-dihydropyridine-1(2H)- yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (170 mg, 288.59 μmol, 55.66% yield, 98.5% purity ).

MS m/z(ESI): 589.1[M+H] ⁺ .

Example 185

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 4-[2-(5-chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]piperidine-1-carboxylate tert-butyl ester

4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate Acid tert-butyl ester (3g, 6.99mmol) and MeOH (50mL) were added to a 25mL flask, PtO2 (1g, 4.40mmol) was added at 25°C, and then the reaction solution was replaced with hydrogen for 5 times and then reacted under a hydrogen atmosphere for 2 Hour. The reaction solution was filtered, concentrated, and passed through a column with PE/EA=3/1 to obtain the product 4-[2-(5-chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazole- 4-yl]piperidine-1-carboxylate tert-butyl ester (1.4 g, 3.25 mmol, 46.5% yield).

MS m/z(ESI): 431.1[M+H] ⁺ .

The second step: (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl)piperidine-1 - tert-butyl carboxylate

4-[2-(5-Chloro-2-pyridyl)-2-methyl-1,3-benzobisoxazol-4-yl]piperidine-1-carboxylate tert-butyl ester (1.4 g, 3.25mmol) was obtained by chiral resolution (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidine-1-carboxylate tert-butyl ester (450 mg, 1.04 mmol, 32.1% yield).

The third step: (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)pyridine

(S)-tertiary 4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylic acid Butyl ester (300 mg, 696.18 μmol) and DCM (10 mL) were added to a 100 mL flask, trifluoroacetic acid (1.59 g, 13.92 mmol) was added at 25 °C, and the reaction solution was reacted at 25 °C for 1 h. After the reaction solution was concentrated, the product (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl) was obtained Pyridine (230 mg, 99.87% yield) was used directly in the next reaction.

MS m/z(ESI): 331.1[M+H] ⁺ .

The fourth step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate ethyl ester

(S)-5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)pyridine (230 mg, 695.27 μmol ), 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (225.8 mg, 695.27 μmol) and MeCN (10 mL) were added to a 100 mL flask, K ₂ CO ₃ (288.27 mg, 2.09 mmol) was added at 25° C., and then the reaction solution was reacted at 25° C. for 24 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through the column with PE/EA=3/1 to obtain the product yellow solid (S)-2 -((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl )-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (350 mg, 81.3% yield).

MS m/z(ESI): 619.2[M+H] ⁺ .

The fifth step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (350 mg, 565.31 μmol) and MeOH ( 20 mL) was added to a 100 mL flask, sodium hydroxide (237.66 mg, 5.94 mmol) was added at 25 °C, and then the reaction solution was reacted at 25 °C for 2 h. The reaction solution was added to ice water (10 mL), extracted with DCM (10 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and prepared by prep-hplc to obtain a white solid (S)-2-((4- (2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-1-( (1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 210 mg, 62.9% yield, 98.0% purity).

MS m/z(ESI): 591.2[M+H] ⁺ .

Example 186

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)-3,6 -Dihydropyridin-1(2H)-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5- carboxylic acid

The first step: 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate ethyl ester

Using 6-chloro-5-nitropyridinecarboxylic acid ethyl ester as a raw material, the synthesis of the fifth to seventh steps of Reference Example 184 was used to obtain the product 2-(chloromethyl)-3-((1-(fluoromethyl) Cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ethyl ester.

MS m/z(ESI): 326.10[M+H] ⁺ .

The second step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl) -3,6-Dihydropyridin-1(2H)-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b] Pyridine-5-carboxylic acid

ethyl 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate and (S )-5-chloro-2-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d][1,3]dioxazol-2-yl ) pyridine is a raw material, and the synthesis of the twelfth to thirteenth steps of reference example 184 obtains the product (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methyl) Benzo[d][1,3]Dioxazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-((1-(fluoromethyl)cyclic Propyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

MS m/z(ESI): 590.1[M+H] ⁺ .

Example 187

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

ethyl 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate and (S )-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]bisoxazol-2-yl)pyridine as raw material, Reference Example 185 Synthesis of the fourth to fifth steps to obtain product (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bis oxazol-4-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine- 5-Carboxylic acid

MS m/z(ESI): 592.2[M+H] ⁺ .

Example 188

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

The first step: 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester

Taking 3-fluoro-4-nitrobenzoic acid ethyl ester and 2-(1-(aminomethyl) cyclopropyl) acetonitrile as raw materials, the synthesis of the fifth to seventh steps of Reference Example 1 finally obtains the product 2- (Chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester.

MS m/z(ESI): 332.1[M+H] ⁺ .

The second step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

ethyl 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate and (S)-5- Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]bisoxazol-2-yl)pyridine was used as the raw material, refer to Example 185 No. 4 to No. Five-step synthesis to obtain the product (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 598.2[M+H] ⁺ .

Example 189

(S)-2-((4-(2-(6-Cyanopyridin-3-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

The first step: (S)-4-(2-(6-cyanopyridin-3-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine- 1-Carboxylic acid tert-butyl ester

(S)-tertiary (S)-4-(2-(6-chloropyridin-3-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylic acid Butyl ester (200.00mg, 464.11μmol), zinc cyanide (108.99mg, 928.23μmol), zinc powder (30.34mg, 464.11μmol), 1,1′-bis(diphenylphosphino)ferrocene (51.00 mg, 92.00 μmol), tris(dibenzylideneacetone)dipalladium (84.24 mg, 92.00 μmol) and NMP (5 mL) were added to a 20 mL microwave tube, and then the reaction solution was reacted at 150 °C for 8 h under nitrogen protection. TLC showed a new spot, the reaction solution was quenched with water, extracted with EA (30 mL), the organic phase was concentrated, and the product (S)-4-(2-(6-cyano) was obtained after passing through the column with PE/EA=3/1 Pyridin-3-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate tert-butyl ester (110 mg, 56.23% yield).

MS m/z(ESI): 422.2[M+H] ⁺ .

Step 2: (S)-5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)cyanopyridine

with (S)-4-(2-(6-cyanopyridin-3-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1-carboxylate Acid tert-butyl ester is a raw material, and the synthesis of the third step of Reference Example 185 is used to obtain the product (S)-5-(2-methyl-4-(piperidin-4-yl)benzo[d][1, 3] Dioxazol-2-yl)cyanopyridine.

MS m/z(ESI): 322.1[M+H] ⁺ .

The third step: (S)-2-((4-(2-(6-cyanopyridin-3-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl )piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

ethyl 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate and (S )-5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)cyanopyridine as raw material, reference example 185 fourth To the synthesis of the fifth step, the product (S)-2-((4-(2-(6-cyanopyridin-3-yl)-2-methylbenzo[d][1,3]dioxin is obtained azol-4-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5 -carboxylic acid.

MS m/z(ESI): 583.2[M+H] ⁺ .

Example 190

(S)-1-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(2-(6-cyanopyridin-3-yl)-2-methylbenzene [d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

ethyl 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate and (S)-5- (2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxazol-2-yl)cyanopyridine is the raw material, the fourth to fifth steps of Reference Example 185 The synthesis of the product (S)-1-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(2-(6-cyanopyridin-3-yl)- 2-Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

MS m/z(ESI): 589.2[M+H] ⁺ .

Example 191

2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a solution of 4,5-dibromo-2-methyl-1H-imidazole (1 g, 4.17 mmol) in DMF (20 mL) was added sodium hydride (200 mg, 5 mmol). After 0.5 hours of reaction, 2-(trimethylsilyl)ethoxymethyl chloride (760 mg, 4.59 mmol) was added, and the reaction was continued for 3 hours. Aqueous ammonium chloride solution (30 mL) was added to quench the reaction, the reaction solution was poured into water (60 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethyl) oxy)methyl)-1H-imidazole (1.1 g, yield: 71%).

MS m/z(ESI): 371.0[M+H] ⁺ .

Step 2: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde

4,5-Dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (374 mg, 1.01 mmol) was dissolved in tetrahydrofuran (10 mL) , n-butyllithium (2.5M, 0.44 mL, 1.11 mmol) was added dropwise at -78°C. After reacting at -78°C for 0.5 hours, DMF (147 mg, 2.01 mmol) was added, the reaction was continued for 0.5 hours, and the reaction was raised to room temperature for 2 hours. The reaction was quenched by adding aqueous ammonium chloride (15 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl) yl)-1H-imidazole-5-carbaldehyde (260 mg, yield: 81%).

MS m/z(ESI): 319.0[M+H] ⁺ .

Step 3: Ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ester

4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbaldehyde (127 mg, 0.4 mmol) and 2-mercaptoacetic acid The methyl ester was dissolved in ethanol (5 mL), sodium ethoxide solution (0.5 mL) was added, and the reaction was carried out at 75° C. for 16 hours. The reaction was quenched by adding water (1 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA=5:1-1:1) to give the product ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-thieno[2,3-d]imidazole-5-carboxylate (80 mg, yield: 59%).

MS m/z(ESI): 341.1[M+H] ⁺ .

Step 4: Ethyl 2-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5 - Carboxylate

Ethyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (75 mg , 0.22 mmol) was dissolved in carbon tetrachloride (3 mL), N-bromosuccinimide (44 mg, 0.25 mmol) and azobisisobutyronitrile (7.3 mg, 0.045 mmol) were added, and the reaction was carried out at 75° C. 16 hours. After the reaction was cooled to room temperature, filtered and spin-dried to obtain ethyl 2-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2, 3-d]imidazole-5-carboxylate (60 mg, crude).

MS m/z(ESI): 419.0[M+H] ⁺ .

The fifth step: ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5- Carboxylate

Reference Example 185 Fourth step to obtain ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxin azol-4-yl)piperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d] Imidazole-5-carboxylate.

MS m/z(ESI): 669.2[M+H] ⁺ .

The sixth step: ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

Ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (194 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 6 hours. After concentration under reduced pressure, aqueous sodium bicarbonate solution (15 mL) was added, followed by extraction with ethyl acetate (20 mL×2). The organic phases were combined and washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2). -Methylbenzo[d][1,3]bisoxazol-4-yl)piperidin-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (145 mg, yield: 93%).

MS m/z(ESI): 539.1[M+H] ⁺ .

Step 7: Ethyl 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ester

Ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (145 mg, 0.27 mmol) was dissolved in DMF (3 mL) and (S)-oxetane- 2-ylmethylmethanesulfonate (54 mg, 0.32 mmol) and cesium carbonate (264 mg, 0.81 mmol) were reacted at 75° C. for 16 hours. Water (10 mL) was added and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared by prep-TLC (DCM:MeOH=10:1) to give the product ethyl 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[ d][1,3]Dioxazol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxbutan-2-yl)methyl)-1H-thieno [2,3-d]imidazole-5-carboxylate (80 mg, yield: 49%).

MS m/z(ESI): 609.2[M+H] ⁺ .

Step 8: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Reference Example 185 The fifth step obtained 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole- 4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazol-5- carboxylic acid.

MS m/z(ESI): 581.1[M+H] ⁺ .

Example 192

5-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

Using 2-methyl-5-nitro-1H-imidazole as raw material Reference Example 191 The first step to obtain the product 2-methyl-5-nitro-1-((2-(trimethylsilyl)ethoxylate) yl)methyl)-1H-imidazole.

MS m/z(ESI): 258.1[M+H] ⁺ .

Step 2: 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine

2-Methyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4 g, 15.56 mmol) was dissolved in methanol (100 mL), then 10% Pd/C (400 mg) was added. The reaction was stirred under a hydrogen atmosphere for 5 hours. The reaction solution was filtered, the organic phase was dried and then spin-dried to obtain 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine (3.2 g, crude product) ).

MS m/z(ESI): 228.1[M+H] ⁺ .

2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine (3 g, 21.9 mmol) was dissolved in DCM (50 mL) and added Ethyl 2-chloro-2-carbonyl acetate (3.6 g, 26.3 mmol) and DIPEA (8.4 g, 65.7 mmol) were stirred at room temperature for 3 h. Water was added, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 2-methyl-1-(((2-(trimethyl) silyl)ethoxy)methyl)-1H-imidazol-5-amine (3 g, yield: 42%).

MS m/z(ESI): 328.1[M+H] ⁺ .

2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine (1 g, 3 mmol) was dissolved in toluene (20 mL), and laurel was added. Sen's reagent (860 mg, 2.1 mmol), stirred at 130°C for 12 hours under nitrogen protection. Water was added, then extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain ethyl 2-((2-methyl-1-( (2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)amino)-2-thioacetate (700 mg, yield: 68%).

MS m/z(ESI): 344.1[M+H] ⁺ .

Ethyl 2-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)amino)-2-thioethyl The acid ester (100 mg, 0.29 mmol) was dissolved in DCM (5 mL), NBS (77 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature for 3 h. Concentration and column chromatography gave ethyl 5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-imidazo[4,5-d]thiazole- 2-carboxylate (10 mg, yield: 10%).

MS m/z(ESI): 342.1[M+H] ⁺ .

Step 6: 5-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]bisoxazol-4-yl) Piperidin-1-yl)methyl)-4-(((S)-oxetan-2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

Ethyl 5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylate and ( S)-oxbutan-2-yl methyl methanesulfonate as raw material Reference Example 191 The fourth to eighth steps obtain the product 5-((4-((S)-2-(5-chloropyridine- 2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl)-4-(((S)-oxetane- 2-yl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid.

MS m/z(ESI): 582.1[M+H] ⁺

Example 193

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

The first step: ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4- yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

Ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate and (1-(fluoromethyl)cyclopropyl)methylmethanesulfonate Reference Example 191 The seventh step is to obtain ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ester.

MS m/z(ESI): 625.2[M+H] ⁺ .

The second step: (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl) Piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Ethyl (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine Perid-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate as raw material reference Example 191 The eighth step to obtain (S)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazole-4 -yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid .

MS m/z(ESI): 597.2[M+H] ⁺ .

Example 194

(S)-5-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

Reference Example 192 Obtained (S)-5-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl )piperidin-1-yl)methyl)-4-((1-(fluoromethyl)cyclopropyl)methyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid

MS m/z(ESI): 598.2[M+H] ⁺ .

Example 195

(S)-2-((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidine-1 -yl)methyl)-1-((1-cyanocyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

Substitute (1-cyanocyclopropyl)methylmethanesulfonate for (S)-oxbutan-2-ylmethylmethanesulfonate Reference Example 191 The seventh and eighth steps to obtain (S)-2- ((4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxazol-4-yl)piperidin-1-yl)methyl) -1-((1-cyanocyclopropyl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid.

MS m/z(ESI): 590.2[M+H] ⁺ .

Biological Test Evaluation

The present invention is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Determination of the ability of the compounds of the present invention to stimulate the production of cAMP in human GLP1 receptor stably transfected cell lines

1. Experimental purpose:

The purpose of this test case was to test the ability of a compound to activate the human GLP-1 receptor on the cell surface. The _EC50 for stimulation of AMP production after agonism characterizes the compound's ability to activate the human GLP-1 receptor.

2. Experimental reagents and instruments:

2.1 Experimental equipment:

Microplate reader (BioTek Synergy H1);

Pipette (Eppendorf & Rainin).

2.2 Experimental reagents:

DMEM/F12 medium was purchased from Gibco, Cat. No. 11330032;

Casein was purchased from Sigma, catalog number C3400;

The 384-well plate was purchased from Sigma, catalog number CLS4514;

IBMX was purchased from Sigma, item number I7018;

Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio, catalog number 62AM4PEC.

3. Experimental method:

Take out the cryopreserved human GLP1 receptor stably transfected cell line CHO-K1/GLP-1R/CRE-luc from the liquid nitrogen tank, put it in a 37°C water bath and quickly thaw it, resuspend it in DMEM/F12 medium, and centrifuge it. Cells were washed once, resuspended in DMEM/F12 medium containing 0.1% casein, and the cell density was adjusted with experimental buffer. The cells were plated in a 384-well plate at a density of 2500 cells/5 μL/well, and then each well Add 2.5 μL of IBMX working solution prepared in buffer, the final concentration of IBMX is 0.5 mM, and 2.5 μL of serially diluted compound samples (1000nM initial, 3-fold dilution, 11 concentrations), centrifuge at 1000 rpm for 1 min, shake for 30 seconds to mix, Incubate at room temperature for 30 minutes. For detection using Cisbio cAMP-Gs Dynamic kit, cAMP-d2 and Anti-cAMP-Eu ³⁺ -Cryptate were diluted 20 times with cAMP Lysis&Detection Buffer respectively and mixed. Add 5 μL of diluted cAMP-d2 solution to each well, and then add 5 μL of diluted Anti-cAMP-Eu3 ⁺ -Cryptate solution, shake for 30 seconds to mix, and incubate at room temperature for 1 hour in the dark. Signal reading of HTRF was performed using a Biotek Synergy H1 microplate reader with excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

4. Experimental data processing method:

The signal ratio (665nm/620nm*10,000) was calculated and nonlinearly fitted to the sample concentration using a four-parameter equation in GraphPad Prism 6 to give the _EC50 value.

5. Experimental results:

Table 1

实施例Example	EC ₅₀(nM) _EC50 (nM)
90-190-1	0.870.87
9292	0.390.39
107107	0.540.54
108108	0.900.90
111111	0.300.30
121-1121-1	0.530.53
123123	0.650.65
123-1123-1	0.380.38
125-1125-1	0.240.24
133133	0.290.29
138138	0.180.18
139139	0.280.28
140140	0.520.52
141141	0.190.19
142142	0.130.13
143143	0.080.08
144144	0.470.47
147147	0.400.40

155-1155-1	0.550.55
171171	0.540.54
172172	0.270.27
173173	0.040.04
174174	0.190.19
175175	0.130.13
176176	0.090.09
187187	0.090.09

6. Experimental conclusion: According to the above scheme, the compounds of the examples of the present invention showed good biological activity in the experiment in which the human GLP1 receptor stably transfected cell line was stimulated to produce cAMP.

2. Determination of pharmacokinetics in Balb/C mice

1. Research purposes:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in the plasma of mice administered orally at a dose of 5 mg/kg.

2. Experimental protocol

2.1 Test drug:

Solvent formula: 0.5% CMC-Na (1% Tween 80);

The compound of the present invention is self-made.

2.2 Experimental animals:

Balb/C Mouse 18 (6/example), male, Shanghai Jisijie Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

2.3 Administration:

18 Balb/C mice, male; p.o. after overnight fasting, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.

2.4 Sample collection:

Before and after administration of mice, at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K ₂ test tube, and centrifuged at 6000 rpm at 4°C for 6 min to separate plasma. , and stored at -80°C.

2.5 Sample processing:

1) Add 160uL of acetonitrile to 40uL of plasma sample for precipitation, and centrifuge at 3500×g for 5-20 minutes after mixing.

2) Take 100 uL of the supernatant solution after treatment for LC/MS/MS analysis of the concentration of the compound to be tested.

2.6 Liquid phase analysis

●Liquid phase condition: Shimadzu LC-20AD pump

Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

Column: phenomenex Gemiu 5um C18 50×4.6mm

●Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile

●Flow rate: 0.8mL/min

●Elution time: 0-4.0 minutes, the eluent is as follows:

3. Test results and analysis

The main parameters of pharmacokinetics are calculated with WinNonlin8.2, and the results of the mice pharmacokinetics experiments are shown in the following table:

ParametersParameters	t _max(h) _tmax (h)	C _max(ng/mL) _Cmax (ng/mL)	AUC _0-t(ng/mLh) AUC _0-t (ng/mLh)	AUC _0-∞(ng/mLh) AUC _0-∞ (ng/mLh)	t _1/2(h) t _1/2 (h)	MRT _0-∞(h) MRT _0-∞ (h)
实施例121Example 121	0.50.5	10471047	28622862	29842984	1.71.7	2.52.5
实施例121-1Example 121-1	0.50.5	18301830	71627162	71677167	2.42.4	3.23.2
实施例123-1Example 123-1	1.01.0	23802380	1243912439	1246912469	2.82.8	4.24.2
实施例125-1Example 125-1	0.50.5	21072107	77057705	78917891	1.31.3	2.62.6
实施例142Example 142	0.50.5	18871887	70567056	71767176	2.92.9	3.83.8
实施例143Example 143	1.01.0	17331733	79417941	79667966	3.03.0	4.24.2
实施例171Example 171	1.01.0	34203420	2087120871	2104921049	3.53.5	4.94.9
实施例173Example 173	0.50.5	21102110	58525852	58715871	3.43.4	2.92.9
实施例174Example 174	1.01.0	29502950	1972119721	1980219802	3.13.1	4.74.7

4. Experimental conclusion: It can be seen from the results of the mouse pharmacokinetic experiment that the compounds of the examples of the present invention have good metabolic properties.

3. Effects of long-term administration of the compounds of the present invention on body weight and food intake of GLP-1R humanized mice fed with high-fat diet

1. Experimental purpose:

The purpose of this test was to evaluate the effect of chronic administration of compounds on body weight and food intake in high-fat diet-fed GLP-1R humanized C57BL/6 mice.

2. Experimental reagents and instruments

C57BL/6_hGLP-1R, male, 5-8 weeks old, was purchased from Biositu (Beijing) Pharmaceutical Technology Co., Ltd.

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

Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.

Electronic balance (BSA2202S-CW, Sartorius)

3. Experimental method

3.1 On the day when the high-fat diet started to be fed, the C57BL/6 mice were randomly divided into two groups according to their body weight. The first group was Blank, with 7 mice, fed with normal control diet, and the remaining animals were the modeling group, fed with high-fat diet, and continued until the experiment end.

3.2 In the 8th week of HFD feeding, animals in the modeling group were randomly divided into groups according to body weight, with 7 animals in each group. The first group was the Vehicle group (Vehicle: 0.5% CMC-Na+1% Tween 80), which was given the vehicle; the remaining groups were given the vehicle. Drug group; Dosing scheme: Oral administration of the corresponding compound, the dosing cycle is 14 days, once a day, the dosing dose is 10 mg/kg, and the dosing volume is 10 mL/kg. The Blank group continued to be fed with normal chow without any administration.

3.3 The day of administration was defined as Day 0.

3.4 At each administration, animals were weighed and data were recorded, and oral administration was performed according to body weight, and the administration volume was 10 mL/kg.

3.5 From the 0th day of the experiment, once every three days, the food intake of the mice in each group was measured, specifically, the feed was changed after each weighing and administration, and the addition and remaining amount were recorded.

3.6 On the end of Day 14, all mice were euthanized in sequence according to the grouping order, and the livers were dissected out and weighed.

4. Experimental data processing and statistical analysis

Summary and statistical analysis of body weight and body weight change rate of mice after administration. Calculation of body weight change rate: (BWt-BW0)/BW0×100%. BWt represents the body weight of mice on day t of the experiment, and BW0 represents the body weight of mice on day 0 of the experiment.

Calculation of food intake: (addition amount (g)-remaining amount (g))/number of animals per cage, the cumulative food intake is the sum of the daily food intake of each animal during the administration period.

Experimental data were analyzed and plotted using GraphPad Prism software. The comparison between the two groups was performed using the t-test method. One-way ANOVA was used for comparison among three or more groups. p<0.05 was defined as a statistically significant difference.

5. Experimental results

6. Experimental conclusion: According to the above experimental results, it can be seen that the long-term administration of the compounds of Examples 142 and 171 of the present invention has a good weight loss effect on the GLP-1R humanized C57BL/6 mice fed with high-fat diet.

Claims

A compound represented by general formula (I-D), its stereoisomer or its pharmaceutically acceptable salt:

in:

Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl,

Preferred are C 5-8 cycloalkyl groups, 5-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 aryl groups or 5-membered C 6-10 aryl groups containing 1-3 N, O or S atoms 10-membered heteroaryl,

more preferred

optionally can be further substituted;

Ring C is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl,

Preferred are C 5-8 cycloalkyl groups, 5-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 aryl groups or 5-membered C 6-10 aryl groups containing 1-3 N, O or S atoms 10-membered heteroaryl,

more preferred
optionally can be further substituted;

M 2 is O, S, N, (CH 2 ) n11 O, (CH 2 ) n11 S, (CH 2 ) n11 NH or (CH 2 ) n11 , optionally further substituted;

M 3 is O, S, N, (CH 2 ) n12 O, (CH 2 ) n12 S, (CH 2 ) n12 NH or (CH 2 ) n12 , optionally further substituted;

M 4 is CR m , O, S, N, C, (CH) n13 , (CH 2 ) n13 O, (CH 2 ) n13 S, (CH 2 ) n13 NH, (CH) n13 N or (CH 2 ) n13 , optionally further substituted;

M5 is O, S, N, C, ( CH ) n14 , ( CH2 ) n14O , (CH2) n14S , (CH2) n14NH , ( CH ) n14NH or ( CH2 ) n14 , any optionally can be further substituted;

R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 1 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

R 2 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 2 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, nitro group, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heterocyclyl substituted with one or more substituents in the aryl group;

R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- Substituted by one or more substituents in 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

R m or R 7 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Alkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted by one or more substituents,

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 2-4 alkenyl, optionally further deuterium, fluorine, chlorine, hydroxy , substituted by one or more substituents in cyano, carboxyl, methyl and ethyl;

Alternatively, any two R 7 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

Preferably, any two R 7 are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

R 8 is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally further substituted with one or more substituents,

Preferred are C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl or 5-10 membered heteroaryl, optionally further substituted by one or Multiple substituent substitutions,

more preferred

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.
The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that,

R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-8 alkyl, C 1-8 Deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl or 5-14-membered heteroaryl, said amino, C 1-8 alkyl, C 1-8 deuterated alkane base, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3- 12 -cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo , thio, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy One or more of C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl substituted by a substituent,

Preferred are hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl, C 6-10 aryl or 5-10-membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 -hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2- 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl or 5-10-membered heteroaryl substituted with one or more substituents;

More preferably hydrogen, deuterium, fluorine, chlorine, cyano or methoxy;

Alternatively, any two R 3 are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl, optionally further substituted by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, One of C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy or replaced by multiple substituents,

Preferably C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl or 5-10-membered heteroaryl, the C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl substituted with one or more substituents in the group consisting of C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that,

R 7 or R are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl, said amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 2-4 alkenyl, optionally further is substituted by one or more substituents in deuterium, fluorine, chlorine, hydroxyl, cyano, carboxyl, methyl and ethyl, preferably, R or R is independently selected from hydrogen, deuterium or carboxyl;

R 8 is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally further is substituted by one or more substituents, preferably, R 8 is selected from
The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, the compound is further represented by general formula (IV-2) or (IV-3):

in:

Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl,

Preferably C 5-8 cycloalkyl or 5-10 membered nitrogen-containing heterocyclic group,

more preferred

M 2 is O, S, N, (CH 2 ) n11 O, (CH 2 ) n11 S, (CH 2 ) n11 NH or (CH 2 ) n11 ;

M 3 is O, S, N, (CH 2 ) n12 O, (CH 2 ) n12 S, (CH 2 ) n12 NH or (CH 2 ) n12 ;

M 4 is O, S, N, C, (CH 2 ) n13 O, (CH 2 ) n13 S, (CH) n13 N or (CH) n13 ;

M 5 is O, S, N, C, (CH 2 ) n14 O, (CH 2 ) n14 S, (CH) n14 N or (CH) n14 ;

R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 1 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

R 2 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 2 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, nitro group, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heterocyclyl substituted with one or more substituents in the aryl group;

R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- Substituted by one or more substituents in 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

R 7 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 -membered aryl and 5-10-membered heteroaryl substituted with one or more substituents,

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 2-4 alkenyl, optionally further deuterium, fluorine, chlorine, hydroxy , substituted by one or more substituents in cyano, carboxyl, methyl and ethyl;

Alternatively, any two R 7 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

Preferably, any two R 7 are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.
The compound according to claim 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, the compound is further represented by the general formula (IV-1):
The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is further represented by the general formula (VIII):

W 1 and W 2 are each independently selected from N or CH;

Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl,

Preferably C 5-8 cycloalkyl or 5-10 membered nitrogen-containing heterocyclic group,

more preferred

M 2 is O, S, N, (CH 2 ) n11 O, (CH 2 ) n11 S, (CH 2 ) n11 NH or (CH 2 ) n11 ;

M 3 is O, S, N, (CH 2 ) n12 O, (CH 2 ) n12 S, (CH 2 ) n12 NH or (CH 2 ) n12 ;

M 4 is O, S, N, C, (CH 2 ) n13 O, (CH 2 ) n13 S, (CH) n13 N or (CH) n13 ;

M 5 is O, S, N, C, (CH 2 ) n14 O, (CH 2 ) n14 S, (CH) n14 N or (CH) n14 ;

R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 1 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

R 2 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Alternatively, any two R 2 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, nitro group, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heterocyclyl substituted with one or more substituents in the aryl group;

R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- Substituted by one or more substituents in 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl and 5-10-membered heteroaryl;

R 7 is each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- 6 -alkynyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 -membered aryl and 5-10-membered heteroaryl substituted with one or more substituents,

Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 2-4 alkenyl, optionally further deuterium, fluorine, chlorine, hydroxy , substituted by one or more substituents in cyano, carboxyl, methyl and ethyl;

Alternatively, any two R 7 are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further by halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents,

Preferably, any two R 7 are linked to form phenyl, thienyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydro thienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl ;

R 8 is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally further is substituted by one or more substituents,

Preferred are C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl or 5-10 membered heteroaryl, optionally further substituted by one or Multiple substituent substitutions,

more preferred

x is 0, 1, 2, 3, 4, or 5;

y is 0, 1, 2, 3, or 4;

z is 0, 1, 2, 3 or 4;

r is 0, 1, 2 or 3;

n11 is 0, 1, 2 or 3;

n12 is 0, 1, 2 or 3;

n13 is 0, 1, 2 or 3; and

n14 is 0, 1, 2 or 3.
The compound according to any one of claims 4-6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that,

R 1 is selected from hydrogen, deuterium, chlorine, fluorine, cyano or methoxy;

Ring B is selected from

M 2 is O, S, N, CH 2 , CH 2 O, CH 2 S, CH 2 NH or (CH 2 ) 2 ;

Or, M 3 is O, S, N, CH 2 , CH 2 O, CH 2 S, CH 2 NH or (CH 2 ) 2 ;

Or, M 4 is O, S, N, C or CH;

Or, M 5 is O, S, N or (CH) 2 ;

x is 1, 2, 3, 4 or 5.
The compound of claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein M 2 is O;

M 3 is CH 2 O.
The compound of claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein M 2 is O;

M 3 is CH 2 O;

M4 is N, C or CH;

M 5 is N or (CH) 2 .
The compound according to claim 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is further represented by the general formula (IV-2-A) or (IV-3-A) Show:

in,

M 4 is selected from N or CR m ;

R m is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl;

L 2 is selected from a bond or CH 2 , preferably a bond;

Ring B is selected from
preferably
The compound according to claim 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the compound is further according to the general formula (IV-2-A') or (IV-3-A' ) as shown:
The compound according to claim 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by the general formula (VIII-1):

W 1 and W 2 are each independently selected from N or CH;

M 4 is selected from N or CR m ;

M 5 is selected from (CH) 2 or S;

R m is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl;

Ring B is selected from
preferably

R 1 is selected from chlorine or cyano;

R 2 is selected from C 1-6 alkyl, preferably methyl;

R is selected from hydrogen or deuterium;

R 8 is selected from
The compound according to any one of claims 1-12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that,

R 1 is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxy alkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

Or, R 2 is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 3-6 cycloalkyl;

Or, R 3 is selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 Haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 2-4 alkenyl, the amino, C 1-3 alkyl, C 1-3 Deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 2-4 alkenyl, optionally further deuterium, Substituted with one or more substituents of fluorine, chlorine, hydroxyl, cyano, carboxyl, methyl and ethyl.
The compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
A compound represented by general formula (M-1) or (M-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

The M 4 , R 1 , and x are as described in any one of claims 1-14;

R 1' is selected from halogen, preferably fluorine, chlorine, bromine, more preferably chlorine;

R 2' is selected from C 1-6 alkyl, preferably methyl or ethyl;

R 3' is selected from hydrogen or amino protecting group, preferably hydrogen, (trimethylsilyl)ethoxymethyl, methoxymethyl ether, allyloxycarbonyl, trifluoroacetyl, 2,4-dimethyl Oxybenzyl, nitrobenzenesulfonyl, trityl, watmethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl , more preferably hydrogen or tert-butoxycarbonyl.
A method for preparing the compound of general formula (I-D) according to claim 1 or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that, comprising the following steps:

The general formula (M-4) is reacted with the general formula (M-5) to obtain the general formula (I-D) after deprotection;

The R 1 , R 2 , R 3 , R 7 , R 8 , M 2 , M 3 , M 4 , M 5 , ring B, ring C, x, y, and z are as described in claim 1;

The R 3' and R 1' are as described in claim 15.
A method for preparing the compound of general formula (IV-3-A) according to claim 10 or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that, comprising the following steps:

The general formula (M-1) is reacted with the general formula (M-6) to obtain the general formula (IV-3-A) after deprotection;

The L 2 , R 2 , R 3 , M 4 , ring B, y, z are as described in claim 11;

The R 3' , R 2' and R 1' are as described in claim 15.
A pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of claims 1 to 14, a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipient.
Use of the compound according to any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a GLP-1 receptor agonist medicine .
Use of the compound shown in claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicine for treating metabolic-related diseases; Said disease is selected from diabetes, obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.