CN114907351A

CN114907351A - Tricyclic GLP-1 receptor agonists and uses thereof

Info

Publication number: CN114907351A
Application number: CN202210100884.2A
Authority: CN
Inventors: 翟文强; 张智敏; 王哲; 王前; 潘豪; 夏炎; 刘东舟
Original assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Current assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Priority date: 2021-02-07
Filing date: 2022-01-27
Publication date: 2022-08-16

Abstract

The invention provides a series of tricyclic GLP-1 receptor agonist compounds, a preparation method and pharmaceutical application thereof, wherein the compounds can be used for preparing medicines for treating or preventing GLP-1 mediated diseases and related diseases.

Description

Tricyclic GLP-1 receptor agonists and uses thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a GLP-1 receptor agonist compound, a preparation method thereof and application of the compound in preparing medicines for treating or preventing GLP-1 mediated diseases and related diseases.

Background

Diabetes mellitus is a chronic complex disease mainly comprising disturbance of glucose metabolism caused by absolute or relative insufficiency of insulin or reduction of sensitivity of target cells to insulin, and is classified into type I diabetes mellitus and type II diabetes mellitus. Among them, type II diabetes is adult-onset diabetes, and is an endocrine disease mainly manifested by chronic elevation of blood glucose due to insulin resistance and/or insulin secretion deficiency. Type II diabetes patients account for more than 90% of diabetes patients.

The following classes of drugs are currently available for the treatment of type II diabetes: insulin secretagogues, metformin, alpha-glycosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and similar drugs and the like, wherein the insulin and the GLP-1 receptor agonists are one of the most effective diabetes treatment drugs, the insulin preparations are still the diabetes drugs with the most global use amount, about 30-40% of type 2 diabetes patients finally need to use the insulin, and the GLP-1 preparations mainly comprise exenatide, liraglutide, somaglutacotide and the like, and are suitable for type 2 diabetics who cannot control blood sugar fully by combined application of metformin, sulfonylureas and the like. However, the insulin preparation and the GLP-1 preparation are basically polypeptide drugs and injection preparations, and even oral administration of the somaglutide has a plurality of limitations on the medication, so that the development of small molecule agonist drugs of GLP-1 receptor is still necessary.

GLP-1 stimulates insulin secretion in a glucose-dependent manner and inhibits glucagon secretion in a glucose-dependent manner, thus presenting no risk of hypoglycemia. GLP-1 can increase the amount of insulin produced by beta cells and improve the responsiveness of the beta cells to glucose. GLP-1 can delay gastric emptying and reduce food intake, thereby having weight reducing effect. In addition, GLP-1 has unique effect of benefiting heart and cerebral vessels. The GLP-1 receptor agonist is positioned to be used in a transition stage between oral hypoglycemic drugs and insulin in clinical application, can be combined with other drugs, becomes the hypoglycemic drug which is the fastest growing in the past five years and has the highest growth potential in the future.

Other conditions associated with type II diabetes include diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-associated uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity, hypertension.

GLP-1 receptor agonist is used as a drug with great potential, and most of the drugs are currently in the form of injection administration. Development of oral small molecule GLP-1 receptor agonists can improve patient compliance, and is a development trend of GLP-1 receptor agonists in the future. The development of the small molecules of the GLP-1 receptor agonist known at present progresses as follows:

document WO2009111700a2 discloses a series of xanthenes GLP-1 receptor agonist compounds; WO2010114824a1 discloses a series of GLP-1 receptor agonist compounds of substituted azoanthracene derivatives; WO2017078352a1 discloses a series of GLP-1 receptor agonist compounds of cyclohexene derivatives; KR1020180101671A discloses a series of GLP-1 receptor agonist compounds of heteroaryl substituted pyridine [1,2-a ] imidazoles derivatives; WO2018056453a1 discloses a series of GLP-1 receptor agonist compounds of pyrazolopyridine derivatives; and WO2018109607a1 discloses a series of GLP-1 receptor agonist compounds similar to the present application, among others.

Disclosure of Invention

The invention provides a series of compounds shown as a formula I-2,

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

W ₂ is selected from CH ₂ 、CR _y ；

Z ₁ And Z ₄ Each independently selected from CH or N;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

R ₁ independently selected from hydrogen, oxo, halogen, -CN, -R ₈ 、-CO-R ₈ 、-CO-NH-R ₈ Wherein R is ₁ And R ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl in (1) can be optionally substitutedOptionally independently selected from R _x The substituent group is substituted for 1 to 3 times;

R ₂ is selected from-R _z 、-C _1～3 alkylene-R _z 、-C _0～3 alkylene-amino-R _z 、-S-R _z 、-C _0～3 alkylene-carbonyl-R _z 、-C _0～3 alkylene-amido-R _z 、-C _0～3 alkylene-sulfonyl-R _z 、-C _0～3 alkylene-phosphoryl-R _z Wherein said R is ₂ The alkyl, amino, amido and sulfonyl in the (A) can be optionally substituted by halogen for 1-3 times or R _w Substitution is carried out for 0-1 times;

R ₃ independently selected from hydrogen, oxo, halogen, -CN, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy, amino, amido, sulfonyl, sulfonamido, -OH, -C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 10-membered aryl, 5-to 8-membered heteroaryl, wherein R is ₃ Optionally independently selected from R under the allowed valence conditions _y The substituent(s) is substituted 1 to 3 times;

R ₄ independently selected from hydrogen, halogen, -C _1～3 Alkyl, -C _1～3 Haloalkyl, -C _1～3 Alkoxy, cyano, hydroxy, amino, amido, sulfonyl, sulfonamido;

R ₅ independently selected from hydrogen, halogen, hydroxy, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy, -C _3～6 Cycloalkyl, wherein said R ₅ The alkyl, alkoxy and cycloalkyl in (1) can be optionally substituted by halogen, hydroxy, -NR under the condition of valence allowing _z 、-CN、-C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 The cycloalkyl is substituted for 1 to 3 times;

R ₆ selected from-COOH, -CH ₂ COOH、-CH ₂ CH ₂ COOH、-CH(CH ₃ ) COOH, wherein said R ₆ Optionally substituted by halogen for 1-3 times under the condition of valence allowance;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 8-membered aryl, 5-to 8-membered heteroaryl, wherein R is ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl of (a) may optionally be independently selected from R _x The substituent(s) is substituted 1 to 3 times;

n is an integer selected from 0,1, 2 or 3;

m is an integer selected from 0,1 or 2;

o is an integer selected from 0,1, 2,3 or 4;

p is an integer selected from 0,1, 2,3 or 4;

when o is not 0 and p is not 0, any R ₄ And R ₅ Can be further cyclized into a 5-8 membered ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano, oxo or alkoxy for 1-3 times under the allowed condition of the compound;

R _w independently selected from-CN, -CH ₂ CN、-C _1～3 Alkyl, -OH, -C _1～3 Alkoxy, amido, sulfonyl, sulfonamido, -NH ₂ 、-NH-C _1～3 Alkyl, wherein R is _w The alkyl in (A) may optionally be substituted by C under the condition of valency permitting _1～3 Alkyl radical, C _1～3 Haloalkyl, halogen, cyano, C _1～3 Alkoxy is substituted for 1 to 3 times;

R _x independently selected from hydrogen, halogen, oxo, C _1～6 Alkoxy, cyano, hydroxy, carboxy, amino, amido, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R is _x The alkyl, the alkoxy, the cycloalkyl, the heterocyclic aryl and the heteroaryl can be optionally substituted by halogen for 1 to 3 times or optionally substituted by hydroxyl for 0 to 1 time under the condition of valence allowance;

R _y independently selected from hydrogen, halogen, oxo, -C _1～3 Alkoxy radicals, cyanogenRadical, hydroxyl, amino, carboxyl, acylamino, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _3～6 Cycloalkyl, 3-to 6-membered heterocyclic group, wherein R is _y The alkyl, the alkoxy, the cycloalkyl and the heterocyclic group can be optionally substituted by halogen for 1-3 times under the condition of valence allowance;

R _z independently selected from hydrogen, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl, 4-6 membered heterocycle, 5-6 membered aryl or 5-6 membered heteroaryl, wherein R _z Optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

As a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into a 5-8 membered ring; the 5-to 8-membered ring includes C _5～6 The compound is a carbocyclic ring, a 5-8-membered heterocyclic ring, a benzene ring and a 5-8-membered heteroaromatic ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano or alkoxy for 1-3 times under the condition allowed by the compound.

Further, the invention provides a compound of formula I-2 is R ₄ And R ₅ A tricyclic compound obtained by cyclization as shown in formulas I-2-A and I-2-B:

as a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized to form a 5-to 8-membered ring, wherein the 5-to 8-membered ring can be selected from

The resulting 5-to 8-membered ring may optionally be substituted with C under valency permitting conditions _1-3 Alkyl radical, C _1-3 Haloalkyl, halogen, cyano, oxo, C _1-3 Alkoxy is substituted 1-3 times.

As a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into a 5-8 membered ring, and the 5-8 membered ring is preferably:

As a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized to form a 5-8 membered ring, wherein the 5-8 membered ring can be selected from:

the resulting 5-to 8-membered ring may optionally be substituted with C when valency permits _1-3 Alkyl radical, C _1-3 Haloalkyl, halogen, cyano, oxo, C _1-3 Alkoxy is substituted 1-3 times.

As a specific embodiment, m is preferably 0 or 1;

as a specific embodiment, o is preferably 0,1 or 2;

further, the invention provides a series of compounds shown as a formula I-3,

further, the present invention provides a compound of formula I-3 is R ₄ And R ₅ A tricyclic compound obtained by cyclization as shown in formulas I-3-A and I-3-B:

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

R ₁ independently selected from hydrogen, oxo, halogen, -CN, -R ₈ 、-CO-R ₈ 、-CO-NH-R ₈ Wherein R is ₁ And R ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl of (a) may optionally be independently selected from R _x The substituent group is substituted for 1 to 3 times;

R ₂ is selected from-R _z 、-C _1～3 alkylene-R _z 、-C _0～3 alkylene-amino-R _z 、-S-R _z 、-C _0～3 alkylene-carbonyl-R _z 、-C _0～3 alkylene-amido-R _z 、-C _0～3 alkylene-sulfonyl-R _z 、-C _0～3 alkylene-phosphoryl-R _z Wherein said R is ₂ The alkyl, amino, amido and sulfonyl in the (A) can be optionally substituted by halogen for 1-3 times orFrom R _w Substitution is carried out for 0-1 time;

R ₅ selected from-F, -Cl, -CN, -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ OH、-OH、-CH ₂ OCH ₃ 、-OCH ₃ 、-CH ₂ CH ₂ OH、-CH ₂ CH ₂ OCH ₃ Isopropyl or cyclopropyl;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 8-membered aryl, 5-to 8-membered heteroaryl, wherein R is ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl of (A) may optionally be independently selected from R _x The substituent group is substituted for 1 to 3 times;

n is an integer selected from 0,1, 2 or 3;

p is an integer selected from 0,1, 2,3 or 4;

when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into a 5-8 membered ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano or alkoxy for 1-3 times under the permission of the compound;

R _w selected from-CN, -CH ₂ CN、-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -OH, -C _1～3 Alkoxy, amido, sulfonyl, sulfonamido, -NH ₂ 、-NH-C _1～3 Alkyl, wherein R is _w In which the alkyl group is allowed at valenceOptionally under the condition of (1) optionally consisting of C _1～3 Alkyl radical, C _1～3 Haloalkyl, halogen, cyano, C _1～3 Alkoxy is substituted for 1 to 3 times;

R _x selected from hydrogen, halogen, oxo, C _1～6 Alkoxy, cyano, hydroxy, carboxy, amino, amido, sulphonyl, sulphonamido, -C _1～6 Alkyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R is _x The alkyl, the alkoxy, the cycloalkyl, the heterocyclic aryl and the heteroaryl can be optionally substituted by halogen for 1-3 times under the condition of valence allowance;

R _y independently selected from hydrogen, halogen, oxo, -C _1～3 Alkoxy, cyano, hydroxy, amino, carboxyl, amido, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _3～6 Cycloalkyl, 3-to 6-membered heterocyclic group, wherein R is _y The alkyl, the alkoxy, the cycloalkyl and the heterocyclic group can be optionally substituted by halogen for 1-3 times under the condition of valence allowance;

As a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized to form a 5-to 8-membered ring,the 5-to 8-membered ring may be selected from

As a specific embodiment, n is selected from 1,2 or 3, preferably n ═ 2.

As a specific embodiment, p is selected from 0,1 or 2, preferably p ═ 1.

As a specific embodiment, R is ₁ Can be further independently selected from-F, -Cl, -CN, -OCH ₃ 、-OCH ₂ CH ₃ 、-CH ₃ 、-CH ₂ CH ₃ 、-COCH ₃ 、-CONH ₂ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CH ₂ F. -CO-cyclopropyl.

As a specific embodiment, R is ₃ Can be further selected from-F, -Cl, -CH ₃ 、-OCH ₃ 、-NH ₂ 、-OH、-CH ₂ CH ₃ 、-CH ₂ OH、-NHCH ₃ 、-COCH ₃ 、-SO ₂ CH ₃ 、-OCH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F. Isopropyl, cyclopropyl, fluorocyclopropyl.

As a specific embodiment, R is ₄ May further be selected from-CN, -CH ₃ 、-OH、-CH ₂ OH、-CH ₂ OCH ₃ 、-OCH ₃ 、-NH ₂ 、-NHCH ₃ 、-COCH ₃ 、-OCH ₂ CH ₃ 。

As a specific embodiment, R is ₆ Further preferred may be-COOH.

As a specific embodiment, R is ₈ Is selected from-CH ₂ CH ₃ 、-CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F. Isopropyl, cyclopropyl.

As a specific embodiment, R is _y Can be further selected from-F, -Cl, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, methoxy, amino, hydroxy, propyl, isopropyl, cyclopropyl, cyclobutyl.

As a specific embodiment, R is ₆ Is (R) of _y ) _n R in-COOH _y Can be connected to C in a main chain and/or a branched chain; when R is _y Linked to R in the form of a main chain ₆ At C, R is _y In the form of the corresponding subunit; when R is _y Is linked to R in a branched form ₆ At C, R is _y In the form of the corresponding saturated base.

As a specific embodiment, R is ₆ Is (R) of _y ) _n R in-COOH _y When methyl, the main chain form linked to C means

Are connected (i.e. when R is present) ₆ is-CH ₂ -) said being linked to C in branched form means

Are connected (i.e. when R is present) ₆ is-CH ₃ )。

As a specific embodiment, R is _z May further be selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy,

R _z optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

As a specific embodiment, Y ₁ Is CH or N, preferably Y ₁ Is N;

as a specific embodiment, W ₁ Is O or NH, preferably W ₁ Is O.

As a particular embodiment, -R ₂ is-R ₇ -R ₂ ', wherein R ₇ Selected from single bonds, -C _1～3 Alkylene, amino, amido, sulfonyl, sulfonamido.

As a specific embodiment, R is ₂ ' may be further selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy,

said R ₂ ' optionally with halogen under valency permitting conditionsSubstituted 1-3 times with an element or optionally C _1～3 Alkyl radical, C _1～3 Haloalkyl, cyano, C _1～3 Alkoxy is substituted 0 to 1 times.

As a particular embodiment, the present invention provides a series of compounds independently selected from one or any combination of the following:

and pharmaceutically acceptable salts thereof.

and pharmaceutically acceptable salts thereof.

Based on the foregoing, the present invention provides a series of compounds represented by formula I,

and pharmaceutically acceptable salts thereof, wherein

W ₁ Selected from O, S, CH ₂ 、NH；

W ₂ Is selected from CH ₂ 、CR _y ；

Z ₁ 、Z ₂ 、Z ₃ 、Z ₄ Each independently selected from CH, N or C;

the ring B is selected from an aromatic ring or a 5-to 6-membered heteroaromatic ring, the heteroaromatic ring being optionally substituted 1 to 3 times with an N atom;

the ring C is selected from an aromatic ring, a 4-8 membered heterocyclic ring, a 4-10 membered spirocyclic ring, a 4-10 membered bridged ring and a 5-7 membered heteroaromatic ring;

R ₂ is selected from-R _z 、-C _1～3 alkylene-R _z 、-C _0～3 alkylene-amino-R _z 、-O-R _z 、-S-R _z 、-C _0～3 alkylene-carbonyl-R _z 、-C _0～3 alkylene-amido-R _z 、-C _0～3 alkylene-sulfonyl-R _z 、-C _0～3 alkylene-phosphoryl-R _z Wherein said R is ₂ The alkyl, amino, amido and sulfonyl in the (A) can be optionally substituted by halogen for 1-3 times or R _w Substitution is carried out for 0-1 times;

R ₃ independently selected from hydrogen, oxo, halogen, -CN, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy, amino, amido, sulfonyl, sulfonamido, -OH, -C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 10-membered aryl, 5-to 8-membered heteroaryl, wherein R ₃ Optionally independently selected from R under the condition of valence permitting _y The substituent group is substituted for 1 to 3 times;

R ₅ independently selected from hydrogen, halogen, hydroxy, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 Cycloalkyl, wherein said R ₅ The alkyl, alkoxy and cycloalkyl in (1) can be optionally substituted by halogen, hydroxyl and-NR under the condition of valence allowing _z 、-CN、-C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 The cycloalkyl is substituted for 1 to 3 times;

R ₆ selected from-COOH or-C (R) _y ) _n -COOH, said-C (R) _y ) _n R in (A-C) _y Can be connected to C in a main chain and/or a branched chain; wherein n is an integer selected from 0,1 or 2; when n is 2, two R _y Can be further cyclized into a 3-to 8-membered carbocyclic or heterocyclic ring;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, phenyl, 5-to 8-membered heteroaryl, wherein R ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl of (a) may optionally be independently selected from R _x The substituent group is substituted for 1 to 3 times;

n is an integer selected from 0,1, 2 or 3;

m is an integer selected from 0,1 or 2;

o is an integer selected from 0,1, 2,3 or 4;

p is an integer selected from 0,1, 2,3 or 4;

when m is 2, two of R ₃ Can be further cyclized into a 3-to 8-membered carbocyclic or heterocyclic ring;

when m is 1 or 2, R ₁ And R ₃ Can be further cyclized into a 3-to 8-membered carbocycle or heterocycle;

R _z independently selected from hydrogen, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered aryl or 5-6 membered heteroaryl, wherein R _z Optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

As a specific embodiment, said ring B may be further selected from:

as a specific embodiment, said ring C may be further selected from:

further, the invention provides a series of compounds shown as a formula I-2,

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

W ₂ is selected from CH ₂ 、CR _y ；

Z ₁ And Z ₄ Each independently selected from CH or N;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

R ₂ is selected from-R _z 、-C _1～3 alkylene-R _z 、-C _0～3 alkylene-amino-R _z 、-S-R _z 、-O-R _z 、-C _0～3 alkylene-carbonyl-R _z 、-C _0～3 alkylene-amido-R _z 、-C _0～3 alkylene-sulfonyl-R _z 、-C _0～3 alkylene-phosphoryl-R _z Wherein said R is ₂ The alkyl, amino, amido and sulfonyl in the (A) can be optionally substituted by halogen for 1-3 times or R _w Substitution0-1 time;

R ₅ independently selected from hydrogen, halogen, hydroxy, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy, -C _3～6 Cycloalkyl, wherein said R ₅ The alkyl, alkoxy and cycloalkyl in (1) can be optionally substituted by halogen, hydroxyl and-NR under the condition of valence allowing _z 、-CN、-C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 Cycloalkyl is substituted for 1-3 times;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl;

n is an integer selected from 0,1, 2 or 3;

m is an integer selected from 0,1 or 2;

o is an integer selected from 0,1, 2,3 or 4;

p is an integer selected from 0,1, 2,3 or 4;

when o is not 0 and p is not 0, any R ₄ And R ₅ Can be further cyclized into 5-8 yuanThe formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano, oxo and alkoxy for 1-3 times under the condition allowed by the compound;

R _x independently selected from hydrogen, halogen, oxo, C _1～6 Alkoxy, cyano, hydroxy, carboxy, amino, amido, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R is _x The alkyl, alkoxy, cycloalkyl, heterocyclic aryl and heteroaryl can be optionally substituted by halogen for 1 to 3 times or optionally substituted by hydroxyl for 0 to 1 time under the condition of valence allowing;

R _z independently selected from hydrogen, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl, 4-to 6-membered heterocycle, 5-to 6-membered aryl or 5-to 6-membered heteroaryl, wherein R is _z Optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

As a kind ofIn a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into a 5-8 membered ring; the 5-to 8-membered ring includes C _5～6 The compound is a carbocyclic ring, a 5-8-membered heterocyclic ring, a benzene ring and a 5-8-membered heteroaromatic ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano or alkoxy for 1-3 times under the condition allowed by the compound.

As a specific embodiment, the present invention provides a compound of formula I comprising a compound of the formula:

wherein Z is independently selected from carbon or nitrogen.

as a specific embodiment, m is preferably 0 or 1;

as a specific embodiment, o is preferably 0,1 or 2;

further, the invention provides a series of compounds shown as a formula I-3,

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

R ₂ is selected from-R _z 、-C _1～3 alkylene-R _z 、-C _0～3 alkylene-amino-R _z 、-S-R _z 、-O-R _z 、-C _0～3 alkylene-carbonyl-R _z 、-C _0～3 alkylene-amido-R _z 、-C _0～3 alkylene-sulfonyl-R _z 、-C _0～3 alkylene-phosphoryl-R _z Wherein said R is ₂ The alkyl, amino, amido and sulfonyl in the (A) can be optionally substituted by halogen for 1-3 times or R _w Substitution is carried out for 0-1 times;

R ₄ independently selected from hydrogen, halogen, -C _1～3 Alkyl, -C _1～3 Haloalkyl, -C _1～3 Alkoxy, cyano, hydroxy, amino, amidoSulfonyl, sulfonamido;

R ₅ selected from-F, -Cl, -CN, -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ OH, isopropyl or cyclopropyl;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-8 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl;

n is an integer selected from 0,1, 2 or 3;

p is an integer selected from 0,1, 2,3 or 4;

when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into 5-8 membered rings, and the formed rings can be optionally substituted by alkyl, haloalkyl, halogen, cyano-group and alkoxy for 1-3 times under the condition of permission of the compound;

R _w selected from-CN, -CH ₂ CN、-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -OH, -C _1～3 Alkoxy, amido, sulfonyl, sulfonamido, -NH ₂ 、-NH-C _1～3 Alkyl, wherein said R _w The alkyl in (A) may optionally be substituted by C under the condition of valency permitting _1～3 Alkyl radical, C _1～3 Haloalkyl, halogen, cyano, C _1～3 Alkoxy is substituted for 1 to 3 times;

R _x selected from hydrogen, halogen, oxo, C _1～6 Alkoxy, cyano, hydroxy, carboxy, amino, amido, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R _x In which alkyl, alkoxy, cycloalkyl, heterocyclylaryl and heteroaryl are combinedOptionally substituted 1-3 times by halogen under the condition of allowed valence;

R _z independently selected from hydrogen, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl, 4-6 membered heterocycle, 5-6 membered aryl or 5-6 membered heteroaryl, wherein R _z Optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 The cycloalkyl and the 3-6 membered heterocyclic group are substituted for 1-3 times;

as a specific embodiment, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into 5-8 membered rings; the 5-to 8-membered ring includes C _5～6 The compound is a carbocyclic ring, a 5-8-membered heterocyclic ring, a benzene ring and a 5-8-membered heteroaromatic ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano or alkoxy for 1-3 times under the condition allowed by the compound.

As a specific embodiment, n is selected from 1,2 or 3, preferably n ═ 2.

As a specific embodiment, p is selected from 0,1 or 2, preferably p ═ 1.

As a specific embodiment, R is ₁ Can be further independently selected from-F, -Cl, -CN, -OCH ₃ 、-OCH ₂ CH ₃ 、-CH ₃ 、-CH ₂ CH ₃ 、-COCH ₃ 、-CONH ₂ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CH ₂ F。

As a specific embodiment, R is ₃ Can be further selected from-F and-Cl、-CH ₃ 、-OCH ₃ 、-NH ₂ 、-OH、-CH ₂ CH ₃ 、-CH ₂ OH、-NHCH ₃ 、-COCH ₃ 、-SO ₂ CH ₃ 、-OCH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F. Isopropyl, cyclopropyl, fluorocyclopropyl.

As a specific embodiment, R ₆ Is (R) — C (R) _y ) _n R in-COOH _y Can be connected to C in a main chain and/or a branched chain; when R is _y Linked to R in the form of a main chain ₆ At C, R is _y In the form of the corresponding subunit; when R is _y Is connected to R in a branched form ₆ At C, R is _y In the form of the corresponding saturated base.

Are connected (i.e. when R is present) ₆ is-CH ₂ -) said branched linkage to C means

Are connected (i.e. when R is present) ₆ is-CH ₃ )。

As a specific embodiment, Y ₁ Is CH or N, preferably Y ₁ Is N;

as a specific embodiment, W ₁ Is O or NH, preferably W ₁ Is O.

said R ₂ ' optionally substituted 1-3 times by halogen or optionally C under the condition of valence allowing _1～3 Alkyl radical, C _1～3 Haloalkyl, cyano, C _1～3 Alkoxy is substituted 0 to 1 times.

As a specific embodiment, the present invention provides a series of compounds independently selected from one or any combination of the following:

and pharmaceutically acceptable salts thereof.

and pharmaceutically acceptable salts thereof.

The compounds provided herein and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in therapy.

The invention provides a pharmaceutical composition which contains a compound shown as a formula I and pharmaceutically acceptable salts thereof, and one or more than two other therapeutic active ingredients.

The invention also provides a pharmaceutical preparation which contains the compound shown in the formula I and pharmaceutically acceptable salts thereof, and one or more than two medicinal carriers; the pharmaceutical preparation is any clinically acceptable preparation formulation.

The compounds provided by the invention and pharmaceutically acceptable salts thereof can be prepared into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated agents, granules, powders, ointments, creams, drops and the like; the compounds and pharmaceutically acceptable salts thereof provided herein can be in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays and the like.

The pharmaceutically acceptable carrier and/or pharmaceutically acceptable diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent used in the art of pharmaceutical formulation.

The pharmaceutically acceptable salts include acid salt and alkali salt.

The compounds provided by the invention and pharmaceutically acceptable salts thereof can exist in chiral form, namely S configuration or R configuration. The compounds provided by the invention and pharmaceutically acceptable salts thereof may exist in achiral form. The compounds described herein, when structures are exemplified in one of their configurations, also indicate that the structures are disclosed in another configuration or achiral form.

The compounds of the present invention include stereoisomers of the compounds. The stereoisomer of the invention refers to the enantiomer generated when asymmetric carbon atoms exist in the compound; when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers can be generated; tautomers can occur when a compound is in the presence of a ketone or oxime; as a specific embodiment, stereoisomers of the present invention include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometrical isomers, epimers and mixtures thereof.

The pharmaceutically acceptable salts of the present invention can exist in unsolvated as well as solvated forms.

The invention also provides a compound shown as a formula I and a pharmaceutically acceptable salt thereof, and application of the compound in preparing a medicament for treating and/or metabolizing related diseases comprises GLP-1 mediated diseases and related diseases, including but not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, and the like; wherein, the diabetes mellitus comprises but is not limited to T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes and the like.

The invention also provides a method for treating diseases, which comprises the step of administering a therapeutically effective amount of the compound shown as the formula I and pharmaceutically acceptable salts thereof to a patient in need thereof, wherein the diseases are GLP-1 mediated diseases and related diseases; such diseases include, but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, and the like; wherein, the diabetes comprises but is not limited to T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes, etc.

The compound shown as the formula I and the pharmaceutically acceptable salt thereof have excellent GLP-1 receptor agonistic activity, and can treat and/or prevent GLP-1 mediated diseases and related diseases.

The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing GLP-1 receptor agonist-related medicaments.

In some embodiments of the invention, the GLP-1 receptor agonist-related medicament is for the treatment of type II diabetes, type I diabetes and obesity.

The compound expressed by the invention is named according to a chemical structural formula, and if the name of the compound does not accord with the chemical structural formula when the compound is expressed by the same compound, the chemical structural formula is taken as the standard.

In the present invention, unless otherwise defined, scientific and technical terms used herein have the meanings that are commonly understood by those of skill in the art, however, in order to better understand the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided by the present invention are different from the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided by the present invention shall control.

The compounds of the present invention include stereoisomers of the compounds. The stereoisomer of the invention refers to an enantiomer generated when asymmetric carbon atoms exist in the compound shown as the formula I; when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers can be generated; tautomers can occur when a compound exists as a ketone or oxime. As a specific embodiment, stereoisomers of the present invention include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometrical isomers, epimers and mixtures thereof.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.

Unless otherwise indicated, "(+)" means dextrorotation, "(-) -means levorotation," (±) "means racemization.

Using solid wedge keys, unless otherwise indicated

And wedge dotted bond

Showing the absolute configuration of a solid centre, by means of straight solid keys

And straight dotted line bond

Indicating that the solid center is of absolute configuration, but not specifically determined to be a wedge-shaped solid key

Or wedge-shaped dotted line key

By means of wavy lines

Indicating solid-line wedge-shaped keys

Or wedge dotted bond

Or by wavy lines

Indicating straight solid-line keys

Or straight dotted line bond

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amine group) or an acidic functional group (e.g., carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C) ³ H) Iodine-125 ( ¹²⁵ I) Or C-14( ¹⁴ C) In that respect For example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "pharmaceutically acceptable" in the present invention is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" of the present invention refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have certain substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid, either in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including such acids as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.

The terms "optional" or "optionally" of the present invention mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituted" as used herein means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., ═ O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the kind and number of substituents may be arbitrary on the basis that they can be chemically achieved.

The term "optionally substituted" in the present invention means both "substituted" and "unsubstituted".

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, e.g. - (CRR) ₀ -, represents that the linking group is a single bond.

When the number of a substituent is 0, it means that the substituent is absent, such as-A- (R) ₀ Indicating that the structure is actually-a.

When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z.

When a substituent's bond can be cross-linked to two or more atoms on a ring, such substituent can be bonded to any atom on the ring, e.g., a building block

Means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When no atom through which a substituent is attached to a substituted group is indicated in the listed substituents, such substituents may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be attached to a substituted group through any one of carbon atoms on the pyridine ring.

When the listed linking groups do not indicate their direction of attachment, the direction of attachment is arbitrary, for example,

wherein the linking group L is-M-W-, in which case-M-W-can be formed by connecting the ring A and the ring B in the same direction as the reading sequence from left to right

The ring A and the ring B may be connected in the reverse direction of the reading sequence from left to right

Combinations of the linking groups, substituents, and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group may be attached to other groups by chemical bonds. When the chemical bond is not positioned and H atoms exist in the connectable sites, the number of the H atoms of the connectable sites is correspondingly reduced along with the number of the connected chemical bonds to become a group with corresponding valence number. The chemical bond linking said site to other groups may be a direct solid bond

Straight dotted line key

Or wavy lines

And (4) showing. For example-OCH ₃ The straight solid line bond in (a) represents a bond to another group via an oxygen atom in the group;

the straight dotted bond in (1) represents the linkage to the other group through both ends of the nitrogen atom in the group;

the wavy line in (a) indicates that the phenyl group is bonded to other groups through the carbon atoms at the 1-and 2-positions in the phenyl group;

means that any of the available attachment sites on the piperidinyl group can be attached to another group via 1 bond, including at least

These 4 linkages, even though the-N-atom is depicted as H, are

Still comprise

This attachment is a group whose H at the site is reduced by 1 to the corresponding monovalent piperidinyl group, except when 1 bond is attached.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring members, e.g., "5-7 membered ring" means a "ring" around which 5-7 atoms are arranged.

The term "halogen atom" in the present invention means a fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Halogen atoms preferred as substituents of the aryl group of the present invention are fluorine atoms and chlorine atoms. Halogen atoms preferred as substituents of the alkyl group of the present invention are fluorine atoms and chlorine atoms. C having halogen atom as substituent _1-6 Alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3, 3-trifluoropropyl, 2, 3-dichloropropyl, 1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4, 4-pentafluorobutyl, 4, 4-dichlorobutyl, 5-iodopentyl, 5-difluoropentyl, 6-chlorohexyl, and 6,6, 6-trifluorohexyl.

The term "C" in the present invention _1～6 Alkyl "is a straight or branched chain alkyl group having 1 to 6 carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

The term "C" in the present invention _1～6 Alkoxy "means a group C _1-6 alkyl-O-includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, and 2-ethylbutoxy.

The term "aryl" in the present invention refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing an adjacent pair of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered rings, such as phenyl and naphthyl, more preferably phenyl. The aryl ring can be fused on a heteroaryl ring, a heterocyclic ring or a cycloalkyl ring and comprises a benzo 3-8 membered cycloalkyl group and a benzo 3-8 membered heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

The term "heteroaryl" in the present invention 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 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:

heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" of the present invention may be used interchangeably. The term "5-6 membered heteroaryl" denotes a monocyclic group consisting of 5 to 6 ring atoms with a conjugated pi-electron system, of which 1,2,3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O)) _p And p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-and 6-membered heteroaryl groups. Examples of such 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, and 4H-1,2, 4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), Thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furyl (including 2-furyl, 3-furyl, and the like), thienyl (including 2-thienyl, 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like).

The term "alkoxy" in the context of the present invention means-O- (alkyl) and-O- (unsubstituted cycloalkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogens.

The term "3-to 8-membered heterocyclic group" in the present invention means a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and it may be fully saturated or partially unsaturated. The ring may be a 3 to 8 membered monocyclic, bicyclic or spiro ring. Including, but not limited to, oxetanyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thiacyclohexyl, oxacyclohexyl, thiaoxacyclohexyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, and the like.

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

the term "C" according to the invention _3～8 The cycloalkyl group "means a monovalent group obtained by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, that is, a cycloalkyl group of 3 to 8 carbons. Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two radicals together form C _3～8 With cycloalkanes, the resulting radicals may be divalent, for example cyclopropane-1, 1-diyl, cyclobutane-1, 1-diyl, cyclopentane-1, 1-diyl, cyclohexane-1, 1-diyl, cycloheptane-1, 1-diyl and cyclooctane-1, 1-diylAnd (4) a base. In addition, the cycloalkane ring, carbocycle, and cyclic hydrocarbon in the cycloalkyl group may be cross-linked rings.

The term "fused ring" of the present invention refers to a 5 to 20 membered all carbon polycyclic group wherein 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 double bonds, but none of the rings has a completely conjugated pi-electron system. The fused ring is preferably 6 to 14-membered, more preferably 7 to 10-membered. Fused rings may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl, depending on the number of constituent rings. Which include but are not limited to:

the carbon atoms in the fused ring may optionally be replaced by heteroatoms of O, S, N, i.e., also including "fused heterocycles".

The term "fused heterocycle" in accordance with this invention refers to a 5 to 20 membered polycyclic heterocyclic group wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _t (wherein t is an integer from 0 to 2) and the remaining ring atoms are carbon. The fused heterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. The fused heterocyclic group may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/3-membered, 5-membered/4-membered or 5-membered/5-membered bicyclic fused heterocyclic group, depending on the number of constituent rings. Fused heterocycles include, but are not limited to:

the term "bridged ring" in the present invention refers to a 5 to 20 membered all carbon polycyclic group wherein any two rings share two carbon atoms not directly attached, which bridged ring may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. The bridge ring is preferably 6 to 14 membered, more preferably 7 to 10 membered. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Bridge rings include, but are not limited to:

the carbon atoms in the bridged ring may optionally be replaced by heteroatoms of O, S, N, i.e., also including "bridged heterocycles".

The term "bridged heterocyclic ring" according to the present invention refers to a 5-to 14-membered polycyclic heterocyclic group, any two rings sharing two atoms not directly attached, which bridged heterocyclic ring may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. The bridged heterocyclic ring is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, bridged heterocycles may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocycles, more preferably bicyclic or tricyclic bridged heterocycles. Bridged heterocycles include, but are not limited to:

the term "spirocyclic" in the present invention refers to a 5 to 20 membered polycyclic group wherein a single ring shares a carbon atom (called spiro atom) between them, which spirocyclic may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. The spiro ring is preferably 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Which include but are not limited to:

the carbon atoms in the spiro ring may optionally be replaced by heteroatoms of O, S, N, i.e. also including "spiro heterocycles".

The term "spiroheterocycle" in accordance with the present invention refers to a 5 to 20 membered polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between the monocyclic rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Spiroheterocycles may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. The spiroheterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Which include but are not limited to:

the compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The following examples are provided to understand the method and core idea of the present invention, and it will be apparent to those skilled in the art that any possible changes or substitutions may be made without departing from the spirit of the present invention. The experimental method of the present invention, in which no specific condition is specified, is usually a conventional condition or a condition suggested by a manufacturer of raw materials or goods; the reagent of which the source is not indicated is usually a conventional reagent commercially available.

Experiment 1-Compound identification and characterization

According to the invention ¹ The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used. ¹ Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.

The mass spectrum of the invention is obtained by LC/MS measurement, and the ionization mode can be ESI or APCI.

The experimental results are as follows:

compound 1

¹ H NMR(400MHz,CD ₃ OD)δ＝8.32(s,1H),7.97(d,J＝7.6Hz,1H),7.75–7.61(m,2H),7.59–7.48(m,2H),7.29(dd,J＝8.4,1.7Hz,1H),6.28(dd,J＝8.4,2.0Hz,1H),5.54–5.36(m,2H),5.28–5.17(m,1H),4.71–4.61(m,3H),4.44(dt,J＝9.1,5.9Hz,1H),4.33–4.21(m,1H),4.07(d,J＝13.7Hz,1H),4.02–3.80(m,2H),3.37(d,J＝11.3Hz,1H),3.25(d,J＝6.3Hz,3H),3.04–2.69(m,3H),2.51(dd,J＝17.8,9.7Hz,1H),2.38–2.13(m,2H).

Compound 2

¹ H-NMR(400MHz,MeOD)δ8.17(s,1H),7.94(d,J＝8.5Hz,1H),7.57(dddd,J＝8.9,8.0,6.6,5.3Hz,4H),6.94(dd,J＝8.3,0.7Hz,1H),6.07(dd,J＝8.3,1.7Hz,1H),5.38(s,2H),5.27(dd,J＝7.0,3.3Hz,1H),4.81(d,J＝6.6Hz,1H),4.75–4.58(m,2H),4.51–4.40(m,1H),4.37–4.28(m,1H),4.19–3.77(m,4H),3.34(d,J＝11.7Hz,1H),3.03–2.69(m,4H),2.52(dd,J＝17.0,10.1Hz,1H),2.32–2.20(m,1H),2.00(dt,J＝16.1,10.8Hz,1H).

Compound 2-P1&2-P2

¹ H-NMR(400MHz,MeOD)δ8.18(s,1H),7.94(d,J＝8.5Hz,1H),7.67–7.51(m,4H),6.94(d,J＝8.3Hz,1H),6.07(d,J＝8.3Hz,1H),5.38(s,2H),5.30–5.22(m,1H),4.92–4.86(m,2H),4.65(ddd,J＝21.8,14.6,5.2Hz,2H),4.47(dt,J＝9.1,6.0Hz,1H),4.34(d,J＝12.8Hz,1H),4.14–4.02(m,2H),3.93–3.80(m,2H),2.97(d,J＝11.4Hz,1H),2.86–2.75(m,3H),2.57–2.48(m,1H),2.29(dd,J＝11.6,8.7Hz,1H),1.98(t,J＝10.8Hz,1H). ¹ H-NMR(400MHz,MeOD)δ8.41(s,1H),8.31(s,1H),7.98(d,J＝8.5Hz,1H),7.64(dd,J＝16.5,8.1Hz,2H),7.57–7.42(m,2H),6.94(d,J＝8.3Hz,1H),6.08(d,J＝8.3Hz,1H),5.31(dd,J＝45.6,3.9Hz,3H),4.81(s,1H),4.76–4.58(m,2H),4.44(dt,J＝9.1,5.9Hz,1H),4.31(d,J＝12.5Hz,1H),4.15(dd,J＝10.9,2.9Hz,1H),3.92(ddd,J＝19.0,15.7,10.9Hz,3H),3.49–3.34(m,1H),2.99–2.67(m,4H),2.56–2.44(m,1H),2.33–2.18(m,1H),2.04(t,J＝10.8Hz,1H).

Compound 3-P1&3-P2

¹ H NMR(400MHz,MeOD)δ8.08(s,1H),7.85(d,J＝8.5Hz,1H),7.49(d,J＝8.4Hz,1H),7.33(t,J＝8.2Hz,1H),7.12–6.99(m,2H),6.82(d,J＝8.3Hz,1H),5.92(d,J＝8.3Hz,1H),5.25–5.13(m,3H),4.72(d,J＝6.6Hz,1H),4.62(dd,J＝15.3,2.8Hz,1H),4.52(d,J＝6.0Hz,1H),4.38–4.25(m,2H),4.05(dd,J＝10.9,2.8Hz,1H),3.89(s,2H),3.76(dd,J＝10.8,8.2Hz,1H),3.27(d,J＝2.5Hz,1H),2.80(d,J＝11.0Hz,2H),2.69(dd,J＝9.1,2.9Hz,2H),2.42(s,1H),2.17(d,J＝2.9Hz,1H),1.93(t,J＝10.8Hz,1H)

¹ H NMR(400MHz,CDCl3)δ8.25(s,1H),8.07(d,J＝8.4Hz,1H),7.84(d,J＝8.5Hz,1H),7.40(t,J＝8.0Hz,1H),7.14–7.04(m,2H),6.93(d,J＝8.3Hz,1H),6.06(d,J＝8.3Hz,1H),5.28(dd,J＝21.6,13.2Hz,3H),4.78(dd,J＝15.1,6.1Hz,1H),4.69–4.59(m,2H),4.48–4.39(m,2H), 4.13-3.99 (m,3H), 3.91-3.82 (m,1H),3.37(s,1H),3.01(d, J ═ 10.3Hz,1H), 2.87-2.70 (m,3H),2.46(dd, J ═ 21.9,10.8Hz,2H),2.06(t, J ═ 10.8Hz,1H) compound 4-P1&4-P2

¹ H NMR(400MHz,MeOD)δ8.20(s,1H),7.95(dd,J＝8.4,1.4Hz,1H),7.65–7.52(m,4H),7.38(d,J＝8.0Hz,1H),6.29(d,J＝7.9Hz,1H),5.45(s,2H),5.28(td,J＝6.9,4.1Hz,1H),4.83(s,1H),4.71(dd,J＝15.3,2.9Hz,1H),4.64(dd,J＝13.1,2.8Hz,2H),4.56–4.41(m,2H),3.93(dt,J＝13.1,12.0Hz,3H),3.81(dd,J＝12.9,2.8Hz,1H),3.71(dd,J＝12.9,6.3Hz,1H),3.48–3.41(m,1H),3.23(t,J＝10.7Hz,1H),2.81–2.73(m,3H),2.56–2.46(m,1H),2.36(dd,J＝11.0,8.4Hz,1H),2.23(t,J＝10.5Hz,1H).

¹ H NMR(400MHz,MeOD)δ8.30(s,1H),7.96(d,J＝8.0Hz,1H),7.67–7.52(m,4H),7.38(d,J＝8.0Hz,1H),6.30(d,J＝7.9Hz,1H),5.46(s,2H),5.25(d,J＝4.8Hz,1H),4.74–4.68(m,1H),4.63(t,J＝9.0Hz,2H),4.56–4.43(m,2H),4.01(d,J＝13.7Hz,1H),3.89(t,J＝11.9Hz,2H),3.79(dd,J＝12.9,2.8Hz,1H),3.72–3.63(m,1H),3.41(s,1H),3.24(s,2H),2.82(t,J＝11.4Hz,2H),2.69(d,J＝10.6Hz,1H),2.53(s,1H),2.40(s,1H),2.21(t,J＝10.4Hz,1H).

Compound 5-P1&5-P2

¹ H NMR(400MHz,MeOD)δ8.27(s,1H),7.96(d,J＝8.0Hz,1H),7.67–7.60(m,2H),7.59–7.46(m,2H),7.11(d,J＝8.3Hz,1H),6.23(d,J＝8.3Hz,1H),5.38(s,2H),5.32–5.24(m,1H),4.75(dd,J＝15.4,2.8Hz,2H),4.66–4.59(m,1H),4.44(dd,J＝5.9,3.2Hz,1H),4.16–4.02(m,2H),3.96(s,2H),3.72(d,J＝13.1Hz,1H),3.56(s,1H),3.24(s,1H),2.74(d,J＝10.7Hz,3H),2.44(d,J＝2.5Hz,2H),2.24(d,J＝9.5Hz,1H),2.08–1.97(m,1H),1.93(s,1H).

¹ H NMR(400MHz,MeOD)δ8.30(s,1H),7.96(d,J＝8.4Hz,1H),7.67–7.60(m,2H),7.55(t,J＝8.4Hz,2H),7.11(d,J＝8.3Hz,1H),6.23(d,J＝8.3Hz,1H),5.39(s,2H),5.30–5.23(m,1H),4.75–4.55(m,3H),4.49(dd,J＝6.0,3.2Hz,1H),4.13–4.01(m,3H),3.87(d,J＝13.6Hz,1H),3.73(d,J＝13.1Hz,1H),3.54(s,1H),3.26(s,1H),2.84–2.75(m,2H),2.67(d,J＝9.4Hz,1H),2.50(d,J＝25.1Hz,2H),2.22(d,J＝11.0Hz,1H),2.07–1.96(m,1H),1.93(s,1H).

Compound 6

¹ H NMR(400MHz,MeOD)δ8.17(s,1H),7.95(dd,J＝8.4,1.5Hz,1H),7.69–7.52(m,5H),6.75(d,J＝8.2Hz,1H),5.54(s,2H),5.26(d,J＝4.2Hz,2H),4.70(dd,J＝15.4,3.1Hz,1H),4.61(dd,J＝13.7,7.8Hz,1H),4.45(dt,J＝9.1,5.9Hz,1H),4.35(s,2H),4.10(dd,J＝34.7,13.6Hz,2H),3.87(s,2H),3.48(d,J＝1.7Hz,1H),3.24–3.23(m,1H),2.85–2.71(m,5H),2.53(d,J＝8.8Hz,1H).

Compound 7

¹ H NMR(400MHz,CDCl ₃ )δ8.19(q,J＝8.2Hz,2H),7.61(t,J＝7.5Hz,1H),7.52(d,J＝8.3Hz,1H),7.44(d,J＝7.8Hz,1H),7.37(d,J＝9.1Hz,1H),6.71(d,J＝8.2Hz,1H),5.51(s,2H),5.25(s,1H),4.93–4.85(m,1H),4.79(d,J＝12.9Hz,1H),4.61(d,J＝7.1Hz,1H),4.35(s,3H),4.20(s,2H),3.87(s,2H),3.28(s,2H),2.84(d,J＝5.4Hz,2H),2.74(s,3H),2.46(s,1H).

Compound 8

¹ H NMR(400MHz,CDCl ₃ )δ8.19(s,1H),8.04(d,J＝8.3Hz,1H),7.81(d,J＝8.3Hz,1H),7.61(t,J＝7.0Hz,1H),7.51(d,J＝7.8Hz,1H),7.40(d,J＝7.7Hz,1H),7.33(d,J＝9.5Hz,1H),6.70(d,J＝8.1Hz,1H),5.51(s,2H),5.21(s,1H),4.78–4.59(m,3H),4.36(d,J＝12.7Hz,3H),4.15(s,2H),3.88(s,2H),3.28(s,2H),2.85(s,2H),2.77(s,2H),2.73–2.67(m,1H),2.45(s,1H).

Compound 9-A &9-B

¹ H NMR(400MHz,MeOD)δ8.20(s,1H),7.95(dd,J＝8.4,1.3Hz,1H),7.68–7.50(m,4H),7.33(d,J＝8.4Hz,1H),6.69(d,J＝8.4Hz,1H),5.49(dd,J＝34.7,13.8Hz,2H),5.22(tt,J＝7.0,3.5Hz,1H),4.82–4.72(m,3H),4.63(ddd,J＝15.7,14.8,5.5Hz,2H),4.44(dt,J＝9.1,6.0Hz,1H),4.09(d,J＝13.7Hz,1H),3.97(d,J＝13.7Hz,1H),3.45(td,J＝9.9,4.0Hz,1H),3.07(dd,J＝10.0,4.6Hz,2H),2.74(ddd,J＝16.2,8.8,5.7Hz,1H),2.58–2.44(m,3H),2.35(t,J＝10.8Hz,1H),2.20(t,J＝10.2Hz,1H),1.37(dd,J＝12.3,3.2Hz,1H).

¹ H NMR(400MHz,MeOD)δ8.24(s,1H),7.96(dd,J＝8.5,1.4Hz,1H),7.65(dd,J＝13.5,8.1Hz,2H),7.58–7.50(m,2H),7.34(d,J＝8.4Hz,1H),6.69(d,J＝8.4Hz,1H),5.48(dd,J＝32.6,13.7Hz,2H),5.22(dt,J＝7.2,4.3Hz,1H),4.79(d,J＝3.6Hz,2H),4.76–4.56(m,3H),4.43(dt,J＝9.2,6.0Hz,1H),4.03(q,J＝13.7Hz,2H),3.48(td,J＝10.0,4.1Hz,1H),3.16(dd,J＝9.9,3.7Hz,1H),2.97(d,J＝11.5Hz,1H),2.80–2.71(m,1H),2.50(ddd,J＝18.8,12.2,6.2Hz,3H),2.28(dt,J＝20.2,10.0Hz,2H),1.40–1.30(m,1H).

Compound 10

¹ H NMR(400MHz,CD ₃ OD_SPE)δ8.17(d,J＝0.8Hz,1H),7.95(dd,J＝8.4,1.5Hz,1H),7.59(d,J＝8.5Hz,2H),7.47(t,J＝8.1Hz,1H),7.26–7.10(m,2H),6.69(d,J＝8.2Hz,1H),5.42(s,2H),5.26(qd,J＝7.1,2.9Hz,1H),4.88(d,J＝7.1Hz,1H),4.70(dd,J＝15.3,3.0Hz,1H),4.63–4.56(m,1H),4.45(dt,J＝9.1,6.0Hz,1H),4.34(s,2H),4.10(dd,J＝37.2,13.6Hz,2H),3.86(s,2H),3.23(t,J＝10.8Hz,2H),2.85–2.70(m,5H),2.57–2.47(m,1H).

Compound 11

Compounds 12A &12-B

1H NMR(400MHz,MeOD)δ8.17(s,1H),7.93(d,J＝8.4Hz,1H),7.68(t,J＝7.5Hz,1H),7.61–7.52(m,3H),7.41(d,J＝8.3Hz,1H),6.63(d,J＝8.2Hz,1H),5.56–5.44(m,2H),5.24(dt,J＝6.9,4.7Hz,1H),5.00–4.90(m,1H),4.74–4.60(m,4H),4.52–4.32(m,2H),4.13–3.86(m,2H),3.76(d,J＝13.5Hz,1H),3.21(s,1H),2.96–2.75(m,2H),2.74–2.26(m,6H),1.65(d,J＝9.3Hz,1H).

1H NMR(400MHz,MeOD)δ8.16(s,1H),7.94(dd,J＝8.4,1.2Hz,1H),7.68(t,J＝7.4Hz,1H),7.62–7.50(m,3H),7.41(d,J＝8.3Hz,1H),6.63(d,J＝8.2Hz,1H),5.55–5.42(m,2H),5.26(d,J＝7.0Hz,1H),4.90(s,1H),4.67(ddd,J＝21.1,16.6,10.3Hz,4H),4.44–4.25(m,2H),4.02–3.78(m,3H),3.21(s,1H),2.93(s,1H),2.85–2.73(m,1H),2.62–2.27(m,6H),1.66(d,J＝9.3Hz,1H).

Compound 13-A &13-B

¹ H NMR(400MHz,CD ₃ OD_SPE)δ8.22(s,1H),7.94(d,J＝8.4Hz,1H),7.61(t,J＝8.4Hz,2H),7.44–7.27(m,3H),6.92–6.56(m,2H),5.53–5.39(m,2H),5.25(d,J＝4.4Hz,1H),4.56(s,5H),4.42–4.28(m,2H),3.98–3.83(m,3H),3.26(s,1H),2.94(s,1H),2.78(dt,J＝16.5,8.1Hz,1H),2.65–2.25(m,7H).

¹ H NMR(400MHz,MeOD)δ8.16(s,1H),7.93(dd,J＝8.4,1.2Hz,1H),7.65–7.52(m,2H),7.44–7.27(m,3H),6.93–6.58(m,2H),5.47(q,J＝13.2Hz,2H),5.25(d,J＝4.9Hz,1H),4.49(ddd,J＝42.8,42.1,36.9Hz,7H),4.08–3.89(m,2H),3.76(d,J＝13.5Hz,1H),3.24(s,1H),2.97–2.15(m,9H).

Compound 14-A &14-B

¹ H NMR(400MHz,MeOD)δ8.19(s,1H),7.93(d,J＝8.4Hz,1H),7.68(t,J＝7.6Hz,1H),7.60–7.53(m,3H),7.41(d,J＝8.3Hz,1H),6.63(d,J＝8.2Hz,1H),5.50(s,2H),4.63(s,4H),4.36(d,J＝30.1Hz,2H),4.23–4.14(m,1H),4.12–4.02(m,1H),3.95(dd,J＝12.3,4.4Hz,1H),3.79(dt,J＝22.5,11.2Hz,2H),3.21(d,J＝8.9Hz,1H),2.87(s,1H),2.61(s,1H),2.45–2.27(m,4H),0.93–0.71(m,4H).

¹ H NMR(400MHz,MeOD)δ8.19(s,1H),7.93(d,J＝8.4Hz,1H),7.69(t,J＝7.6Hz,1H),7.60–7.52(m,3H),7.41(d,J＝8.2Hz,1H),6.63(d,J＝8.2Hz,1H),5.56–5.42(m,2H),4.62(d,J＝12.4Hz,5H),4.33(s,1H),4.19(d,J＝3.2Hz,1H),4.06(d,J＝3.2Hz,1H),3.88(ddd,J＝46.0,22.4,9.0Hz,3H),3.21(d,J＝9.4Hz,1H),2.87(s,1H),2.58(d,J＝26.9Hz,1H),2.45–2.27(m,4H),0.98–0.67(m,4H).

Compound 15-A &15-B

¹ H NMR(400MHz,CD ₃ OD_SPE)δ8.15(s,1H),7.93(dd,J＝8.4,1.2Hz,1H),7.70(t,J＝7.5Hz,1H),7.56(d,J＝8.4Hz,1H),7.50–7.39(m,3H),6.63(d,J＝8.2Hz,1H),5.55–5.44(m,2H),5.26(dd,J＝6.9,2.7Hz,1H),4.68(ddd,J＝29.4,15.1,7.2Hz,6H),4.38(ddd,J＝28.7,16.0,8.4Hz,2H),4.01–3.78(m,3H),3.23(d,J＝10.1Hz,1H),2.94(s,1H),2.82–2.73(m,1H),2.63–2.28(m,6H).

¹ H NMR(400MHz,MeOD)δ8.16(s,1H),7.93(d,J＝8.5Hz,1H),7.71(t,J＝7.3Hz,1H),7.56(d,J＝8.4Hz,1H),7.52–7.39(m,3H),6.64(d,J＝8.2Hz,1H),5.57–5.45(m,2H),5.24(d,J＝5.3Hz,1H),4.72–4.61(m,5H),4.54–4.33(m,3H),4.06–3.91(m,2H),3.76(d,J＝13.5Hz,1H),3.23(s,1H),2.95–2.77(m,2H),2.68(s,1H),2.59–2.41(m,2H),2.34(d,J＝8.1Hz,3H).

Compound 16

Compound 17-A &17-B

Experiment 2-in vitro Activity experiment

(1) Test instrument and reagent

(2) GLP-1R kit

GLP-1R-mediated agonist activity is determined by cell-based functional assays using a homogeneous time-resolved fluorescence (i.e., HTRF) cAMP detection kit that measures cAMP levels in cells. The method is a competitive immunoassay. It enables the direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

The native cAMP or unlabeled cAMP standard curve produced by the cells competes with the d2 labeled cAMP red receptor for binding to the monoclonal anti-cAMP crypt europium donor, with a specific signal inversely proportional to the concentration of cAMP in the standard or experimental sample.

The human GLP-1R coding sequence (NCBI reference NP-002053.3) was subcloned into pEGFP-N1(tsingke) and cell lines stably expressing the receptor were isolated and GLP-1R expression density was confirmed by observing GFP expression under a fluorescent microscope.

(3) GLP-1R-GFP-293A cell culture

293AGFP-GLP-1R cells in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat #900-108), 1% Pen-3Trep (SangomBiotech Cat # E607011-0100)]Cultured in medium and humidified at 37 ℃ with 5% CO ₂ Culturing in an incubator.

(4) cAMP level test method

Each test compound (in DMSO) was diluted 1:5 in distilled water at different concentrations in stimulation buffer, and 500. mu.M 3-isobutyl-1-methylxanthene (IBMX; Meilunbiocat # MB5226) was added to obtain a 2X compound working solution, and then 5. mu.L of the compound was added to a white 384-well assay plate (Corning3824) using a multichannel pipette. The final DMSO concentration in the assay buffer mixture was 1% o.

Cells were harvested from T25 tissue culture flasks and centrifuged at 1000rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1ml of stimulation buffer. 20 μ L cell suspension samples were counted on a counter STARIC1000 to determine cell viability and cell counts per ml. The remaining cell suspension was then conditioned with stimulation buffer to use multiple channelsThe pipette delivers 2000 viable cells per well. mu.L of the cell suspension was added to each well of the assay plate already containing the compound. The plates were sealed and incubated at 37 ℃ with 5% CO ₂ Incubate for 30 minutes.

After 30 min incubation, 5 μ L d2 labeled cAMP and 5 μ L anti-cAMP cryptate (both diluted 1:20 in cell lysis buffer) were added to each well of the assay plate. The plates were then incubated at room temperature and after 60 minutes the absorbance at 340 nm/emission at 615nm and 665nm was excited by reading the change in HTRF signal with a Tecan Spark plate reader. Raw data were converted to nM cAMP by interpolation from the cAMP standard curve and percent effect was determined relative to the saturation concentration of the full agonist GLP-17-37 (400nM) contained on each plate. EC (EC) ₅₀ The assay was performed from an agonist dose-response curve, which was analyzed using a curve fitting program using a 4-parameter logistic dose-response equation.

This experiment demonstrates that the compounds of the invention activate GLP-1R signaling via the cAMP pathway and thus act as GLP-1R agonists. Test data are in terms of geometric mean (EC) based on the number of repetitions listed ₅₀ s) presents the results in the form of.

(5) Results of the experiment

Experiment 3-inhibition assay of hERG Potassium channel

1. Experimental materials: stable cell line HEK-hERG, line: HEK 293, source: military medical academy of sciences;

2. electrophysiological solution

Extracellular fluid (mM): N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid (HEPES)10, NaCl 145, KCl 4, CaCl ₂ 2、MgCl ₂ 1. Adjusting the pH of the Glucose 10 to 7.3-7.4 by using sodium hydroxide; the osmotic pressure is adjusted to 290-310 mOsm; filtering, and storing at 4 ℃.

Electrode internal solution (mM): KCl 120, KOH 31.25, CaCl ₂ 5.374、MgCl ₂ 1.75 ethylene glycol-bis (. beta. -aminoethylether) -N, N, N ', N' -tetraacetic acid (EGTA)10, HEPES 10, Na ₂ -ATP 4, adjusted to pH 7.2-7.3 with potassium hydroxide; the osmotic pressure is adjusted to 290-310 mOsm; filtering, packaging, and storing at-20 deg.C.

3. Positive control compound:

positive control: amitriptyline (Amitriptyline hydrochloride) or Terfenadine (Terfenadine)

The source is as follows: Sigma-Aldrich

4. Preparation of the drug delivery formulation

Preparing a solvent control: adding a certain volume of DMSO into the extracellular fluid to ensure that the volume of DMSO is equal to that of the final test solution (if the test solution contains different DMSO contents, the maximum DMSO content is taken as the standard) so as to eliminate the interference of DMSO on the self-current of the cells. Preparing a test article: the stock solution of 10mM stock solution is prepared into DMSO stock solution with required concentration (generally 1000/3 times of the actual administration concentration) according to a proportion, and finally the stock solution is diluted into the administration concentration required by the experiment by using extracellular fluid.

Preparing a positive control solution: weighing a proper amount of positive control, placing the positive control in a proper container, adding a certain volume of DMSO, fully stirring or oscillating to completely dissolve the positive control to prepare a 10mM stock solution, then preparing the stock solution with the required concentration according to a proportion, and finally diluting the stock solution with an extracellular fluid to obtain the administration concentration required by an experiment.

Before the working concentration solution is used, whether precipitation exists or not is checked, if precipitation exists, stock solution is diluted, the final concentration of DMSO in the extracellular fluid is increased, and the final concentration of DMSO in the extracellular fluid does not exceed 0.5%. Continuous perfusion from low concentration to high concentration is adopted in the experiment. After the experiment is finished, the residual administration solution of the test sample and the positive control sample is treated by waste liquid.

5. Experimental protocol

Cell preparation:

after the HEK-293-hERG cells are subcultured to an appropriate state, the cells are washed by PBS (or DPBS), digested and separated by Tryple solution, resuspended by using a culture medium and stored in a centrifuge tube, centrifuged, the supernatant is discarded, the cells are resuspended by using an extracellular fluid for standby, and the cells are stored at 2-8 ℃. Before patch clamp recording, cells were dropped into culture dishes to ensure that the cells had a certain density and were in a single isolation state.

Concentration setting:

test article/positive control article	Concentration (μ M)
		Compounds of the invention	1、10
Amitriptyline or terfenadine	1

Electrophysiological experiments:

whole cell patch clamp technology was used to record hERG currents. The cell suspension was added to a small petri dish and placed on the stage of an inverted microscope. After the cells adhere to the wall, the cells are perfused by using extracellular fluid, and the recommended flow rate is 1-2 mL/min. The glass microelectrode is drawn by a microelectrode drawing instrument in two steps, and the water resistance value of the glass microelectrode is 2-5 MOmega after filling the liquid in the electrode.

After establishing the whole-cell recording mode, the clamp potential was maintained at-80 mV. Depolarization voltage was given to +60mV for 850ms, then repolarization was maintained to-50 mV for 1275ms to elicit hERG tail current. Such a set of pulse programs was repeated every 15 seconds throughout the experiment.

After the current is stabilized, extracellular continuous perfusion administration from low concentration to high concentration is adopted. Starting from low concentration, the perfusion is continued until the drug effect is stable, and then the perfusion of the next concentration is performed. The test will test the blocking effect of each test sample and positive control on the hERG tail current (N is more than or equal to 2); the specific actual concentration may be adjusted according to the actual solubility and effect and is not considered a protocol deviation.

Pharmacodynamic stability is defined as: the change in current value of the last 5 stimulation bars for each concentration administration phase was either less than 10% of the mean (when the current was 200pA or greater) or less than 30% of the mean (when the current was less than 200 pA) and if not, the concentration data would not be taken.

6. Data analysis

In data processing, the peak value of the tail current and its baseline are corrected when the blocking effect on hERG is judged. The effect of each compound at different concentrations is expressed in terms of the Inhibition Rate (IR) of the wake. SD in% IR for all cells at each concentration ≦ 15 as an acceptance criterion (except for aberrant data).

IR 100% × (tail current peak before dosing-tail current peak after dosing)/tail current peak before dosing.

7. The experimental results are as follows:

8. conclusion of the experiment

The compounds of the invention do not exhibit hERG inhibitory activity.

Experiment 4-hepatic microsome metabolic stability

1. Experiment design: and (3) measuring the concentration: 1 mu M; control compound: testosterone; the culture conditions are as follows: incubating at 37 ℃ for 0,5,15,30,45 minutes; the determination method comprises the following steps: LC-MS/MS; the calculation method comprises the following steps: t is _1/2 ＝0693/K (K is ln [ concentration ]]Rate constant relative to incubation time plot), Cl _int ＝(0.693/T _1/2 ) X (1/(microsomal protein concentration (0.5mg/mL))) x scale factor.

2. The experimental method comprises the following steps: 1. pre-heating 0.1M K-buffer, 5nM MgCl ₂ The pH value is 7.4; 2. test and reference compounds, 500 μ M addition solution: add 5. mu.L of 10mM stock solution to 95. mu.LACN, 1.5. mu.M spiking solution in microsomes (0.75 mg/mL): 1.5. mu.L of 500. mu.M addition solution and 18.75. mu.L of 20Mg/mL liver microsomes were added to 479.75. mu.L of K/Mg buffer; 3.3 XNADPH stock (6mM, 5mg/mL) is NADPH dissolved in buffer; 4. dispense 30 μ L of 1.5 μ M addition solution containing 0.75mg/mL microsome solution onto assay plates designated for different time points (0, 5,15,30,45 minutes); 5. at 0min, 150 μ L of IS-containing ACN was added to the wells of the plate, followed by 15 μ L of ADPH stock solution (6mM, step 3); 6. all other plates were preincubated at 37 ℃ for 5 minutes; 7. add 15 μ l of adph stock solution to the plate to start the reaction and time; 8. at 5min, 15 min, 30 min and 45 min, 150 μ L of ACN containing IS was added to the wells of the respective plates to terminate the reaction; 9. after quenching, the plate was shaken on a shaker for 10 minutes (600 rpm/min) and then centrifuged at 6000rpm for 15 minutes; 10. from each well, 80 μ L of supernatant was transferred to a 96-well sample plate containing 140 μ L of water for LC/MS analysis.

3. The analysis method comprises the following steps:

the detection method comprises the following steps: LC-MS/MS-11(8050), internal standard: tolbutamide, wherein MS conditions comprise testosterone and positive ion ESI of a compound to be detected; ESI (tolbutamide anion); mobile phase: mobile phase a was 0.1% FA in water and mobile phase B was 0.1% FA in ACN; column and specification: ACQUITY UPLC HSS T31.8um 2.1 x 50 mm.

LC conditions:

4. experimental results (human microsomes):

compound numbering	LMS(t _1/2 min)
		2	41.82
2P-1	148.12
		2P-2	23.18
3P-1	16.21
		4P-1	37.81
5P-1	94.3
		6	68.21
7	180.00
		8	82.73
9	399.45
		9-B	338.86
10	25.70
		11	39.85
12	100.74
		16	56.64

5. And (4) experimental conclusion: the compound of the invention has good stability of liver microsome

Experiment 5-Caco-2 cell transport experiment

1. Experimental materials:

caco-2 cells, passage 77; HBSS, Lot G210713; ACN + IS (tolbutamide 200 ng/ml);

2. cell culture:

caco-2 was seeded at 2X 105 cells/cm 2 onto polyethylene film (PET) in 96-well Falcon plates until a confluent cell monolayer was formed for 21-28 days. The medium was changed every 3-4 days.

3. The experimental scheme is as follows:

test compounds were diluted to a concentration of 10uM with a 10mM stock of transport buffer (HBSS without BSA) and applied to the apical or basolateral side of the cell monolayer. At 37 ℃ and 5% CO ₂ And 95% relative humidity for 120 minutes, and the test compounds from A to B direction or B to A direction of penetration. And the efflux ratio of each compound was determined. The test and reference compounds were quantified by LC-MS/MS analysis based on the peak area ratio of analyte/IS.

4. And (3) experimental determination:

the apparent permeability coefficient Papp (cm/s) is calculated using the following equation:

papp ═ (dCr/dt) xVr/(axc 0), where dCr/dt is the cumulative concentration of compound in the receptor compartment as a function of time (S), Vr is the volume of solution in the receiver compartment (0.1 mL top, 0.25mL bottom), a is the surface area for transport, i.e. 0.0804cm2 is the area of the monolayer, C0 is the initial concentration in the donor compartment;

the outflow ratio was calculated using the following formula:

EffluxRatio＝Papp(BA)/Papp(AB)；

percent recovery is calculated by the equation:

％Recovery＝100×[(Vr×Cr)+(Vd×Cd)]/(Vd×C0)

％Total recovery＝100×[(Vr×Cr)+(Vd×Cd)+(Vc×Cc)]/(Vd×C0)，

where Vd is the volume in the donor chamber (0.1 mL topside, 0.25mL outside the substrate), Cd and Cr are the final concentration of the transport compound in the donor and acceptor chambers, respectively, Cc is the concentration of the compound in the cell lysate solution, and Vc is the volume of the insert well (0.1 mL in this experiment).

LC/MS conditions:

the detection method comprises the following steps: LC-MS/MS-20(TQ-6500+) & LC-MS/MS-11(8050), internal standard: metrafluyl urea, wherein MS conditions are atenolol, propranolol and cation ESI of the compound, digoxin anion ESI; mobile phase: mobile phase a was 0.1% FA in water and mobile phase B was 0.1% FA in ACN; column and specification: ACQUITYUPLC HSS T31.8um 2.1 x 50 mm.

LC conditions:

6. the experimental results are as follows:

compound numbering	AtoB/BtoA/Efflux ratio
		4-P1	1.54/9.36/6.08
6	0.98/11.05/11.27

7. And (4) experimental conclusion:

the compound of the invention has good absorption in intestinal tract.

Preparation examples

The intermediate reaction mass used in the preparation was prepared by the preparation method described in reference to WO2018109607a 1.

The intermediate, methyl 1-int-2, (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate, was prepared as follows:

(1) preparation of Compounds 1-2C

To a stirred solution of t-BuOK (170g, 1520mmol, 2.5 equiv.) in t-BuOH (500mL) at 60 ℃ under an argon atmosphere, Me was added portionwise ₃ SO ⁺ I ^- (335g, 1520mmol, 2.5 equiv.) to the mixture was added dropwise (S) -2- ((benzyloxy) methyl) oxirane 1-1C (100g, 610mmol, 1.00 equiv.) over 30 minutes. The resulting mixture was stirred at 60 ℃ for a further 13 hours. The mixture was cooled to room temperature, then filtered and the filter cake was washed with EtOAc (3X 200 mL). The combined organic layers were washed with brine (200mL) and Na ₂ SO ₄ Drying and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography eluting with PE/EtOAc (10:1) to give (S) -2- ((benzyloxy) methyl) oxetane as 1-2C (50.0g, 46% yield).

¹ H NMR(400MHz,CDCl3)δ＝7.39–7.26(m,5H),5.04–4.90(m,1H),4.73–4.50(m,4H),3.64(qd,J＝11.0,4.3Hz,2H),2.72–2.45(m,2H).

(2) Preparation of Compounds 1-3C

A solution of (S) -2- ((benzyloxy) methyl) oxetane 1-2C (50g, 280.9mmol, 1.0 equiv.) and Pd/C (20g, wet) in THF (200mL) was dissolved in H ₂ (4MPa) at 50 ℃ for 16 hours. The mixture was cooled to room temperature, then filtered and the filter cake was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give (S) -oxetan-2-ylmethanol as 1-3C (28g, crude product), which was used directly in the next step.

(3) Preparation of Compounds 1-4C

To a solution of (S) -oxetan-2-ylcarbinol 1-3C (28g, 317.8mmol, 1eq) in THF (200mL) at 25 deg.C were added TsCl (66.6g, 349.6mmol, 1.1eq) and TEA (48.2g, 476.7mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. By H ₂ The mixture was diluted with O (100mL) and extracted with DCM (100 mL. times.3). The combined organic layers were washed with Na ₂ SO ₄ Dry, filter and concentrate to give a residue which is purified by column chromatography on silica gel eluting with (EA/PE ═ 0-10%) to give (S) -oxetan-2-ylmethyl 4-methylbenzenesulfonate as 1-4C (56g, 72.7% yield) as a colorless oil.

¹ H NMR(400MHz,CDCl3)δ＝7.85–7.79(m,2H),7.35(dd,J＝8.6,0.6Hz,2H),5.00–4.83(m,1H),4.68–4.38(m,2H),4.16(d,J＝4.0Hz,2H),2.78–2.64(m,1H),2.58(d,J＝9.0Hz,1H),2.45(s,3H).

(4) Preparation of Compounds 1-5C

To a solution of (S) -oxetan-2-ylmethyl-4-methylbenzenesulfonate 1-4C (56g, 231mmol, 1eq) in DMF (200mL) was added NaN ₃ (22.5g, 346.7mmol, 1.5 eq). The mixture was stirred at 60 ℃ for 12 hours. By H ₂ The mixture was diluted O (100mL) and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with Na ₂ SO ₄ Dried, filtered and concentrated to give (S) -2- (azidomethyl) oxetane as 1-5C (20g, crude product) which was used directly in the next step.

(5) Preparation of Compounds 1-6C

A solution of (S) -2- (azidomethyl) oxetane 1-5C (20g, crude) and Pd/C (8g) in THF (100mL) was dissolved in H ₂ (15Psi) stirred at 25 ℃ for 16 h. The resulting mixture was filtered and the filter cake was washed with THF (3X 100 mL). The filtrate was directly concentrated to give (S) -oxetan-2-ylmethylamine as 1-6C (3.8g, crude).

¹ H NMR(400MHz,DMSO)δ＝4.60(dq,J＝6.5,5.2Hz,1H),4.52–4.43(m,1H),4.40–4.30(m,1H),2.67(t,J＝5.5Hz,2H),2.57–2.51(m,1H),2.38(ddt,J＝10.8,9.0,7.0Hz,2H).

(6) Preparation of Compounds 1-7C

To a solution of (S) -oxetan-2-ylmethylamine 1-6C (3.8g, 43.6mmol, 1eq) in THF (80mL) at 25 deg.C was added methyl 3-fluoro-4-nitrobenzoate 1-6D (8.69g, 43.6mmol, 1.0eq) and TEA (8.83g, 87.2mmol, 2 eq). The mixture was stirred at 40 ℃ for 6 hours. The mixture was concentrated to give a residue which was purified by silica gel column chromatography eluting with (EtOAc/petroleum ether ═ 0-80%) to give methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate as 1-7C (6.2g, 53.4% yield).

¹ H NMR(400MHz,CDCl3)δ＝8.36(s,1H),8.23(d,J＝8.9Hz,1H),7.63(d,J＝1.4Hz,1H),7.26(dd,J＝8.8,1.7Hz,1H),5.16(tt,J＝7.4,4.5Hz,1H),4.81–4.55(m,2H),3.94(s,3H),3.71–3.55(m,2H),2.84–2.72(m,1H),2.70–2.52(m,1H).

(7) Preparation of Compounds 1-8C

A solution of methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate 1-7C (6.2g, 23.3mmol, 1.0eq) and Pd/C (1.0g, wet) in MeOH (100mL) at 25 ℃ in H ₂ (1atm) for 12 hours. The mixture was filtered and the filter cake was washed with MeOH (3X 20 mL). The filtrate was directly concentrated to give methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate as 1-8C (5.2g, 94.5% yield). LCMS r.t. -. 1.201min, [ M +1] ⁺ 237.1, purity: 89.7 percent.

(8) Preparation of Compound 1-int-2

To a solution of methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate 1-8C (1.0g, 4.23mmol, 1eq) in THF (20mL) was added 2-chloro-1, 1, 1-trimethoxyethane 1-8D (0.98g, 6.35mmol, 1.5eq) and TsOH. H ₂ O (0.08g, 0.423mmol, 0.1 eq). The mixture was stirred at 50 ℃ for 8 hours. The mixture was diluted with saturated sodium bicarbonate solution. NaHCO 2 ₃ (20mL) and extracted with EtOAc (10 mL. times.3). The combined organic layers were washed with Na ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography using (EtOAc/petroleum ether ═ 0)-80%) to give (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d)]Imidazole-6-carboxylic acid methyl ester as 1-int-2(1.1g, 88% yield).

¹ H NMR(400MHz,CDCl3)δ8.12(d,J＝0.9Hz,1H),8.01(dd,J＝8.5,1.5Hz,1H),7.79(d,J＝8.5Hz,1H),5.21(ddd,J＝9.6,7.3,2.7Hz,1H),5.03(s,2H),4.69–4.45(m,3H),4.34(d,J＝9.2Hz,1H),3.96(s,3H),2.76(dtd,J＝11.5,8.1,6.0Hz,1H),2.42(ddt,J＝11.5,9.2,7.3Hz,1H).

The intermediate methyl 1-int-3, 2- (chloromethyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate was prepared as follows:

(1) preparation of 3a-1

To a solution of methyl 3-fluoro-4-nitrobenzoate (2.0g, 10.05mmol) in DMF (30mL) at 80 deg.C under nitrogen was added (1- (aminomethyl) cyclopropyl) methanol (1.015g, 10.05mmol) and K ₂ CO ₃ (2.087g, 15.075mmol) were mixed for 16 h and the reaction was monitored by LCMS. The reaction mixture was poured into water (300mL), extracted with EtOAc (80mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (PE/EtOAc ═ 0-30%) to give 3a-1(2.5g, 89.2% yield).

LCMS:r.t.＝1.3min,[M+1] ⁺ 281, purity: 92 percent of

(2)3a-2 preparation

To a solution of 3a-1(2.5g, 8.6mmol) in 100mL MeOH under nitrogen at 25 deg.C was added Pd/C (1.25g) and stirred for 2 h. LCMS monitor reaction. The reaction mixture was filtered and the filtrate was concentrated to give crude product 3a-2(1.7g, 76.2% yield) which was used in the next step without purification.

LCMS:r.t.＝0.8min,[M+1] ⁺ 251, purity: 92 percent of

(3)3a-3 preparation

To a solution of 3a-2(1.7g, 6.8mmol) in 30mL THF at 50 deg.C were added 2-chloro-1, 1, 1-trimethoxyethane (3.142g, 20.4mmol)) and TsOH (129.2mg, 0.68mmol) with stirring and mixed for 16 h. LCMS monitor reaction. By adding saturated NaHCO ₃ The reaction mixture was quenched with aqueous solution (50mL), extracted with EtOAc (30mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (EA/PE ═ 10-51%) to give 3a-3(1.5g, 71% yield).

LCMS:r.t.＝1.5min,[M+1] ⁺ 309, purity: 90 percent

(4) Preparation of 1-int-3

Under a nitrogen atmosphere, stir at-65 ℃ for 3 hours, add to a solution of 3a-3(500mg, 1.62mmol) in 15mL DAST/THF. LCMS monitor reaction. The reaction mixture was concentrated to a crude product, which was further purified by pre-HPLC to give 1-int-3(400mg, 79.52% yield). LCMS r.t. -. 1.708min, [ M +1] ⁺ 311, purity: 90 percent of

The chiral presfc method is as follows:

the system comprises the following steps: waters SFC 150

Column: main Reprosil Chiral-MIC (

IC)

Column size: 250 x 25mm 10m

The mobile phase A is supercritical CO ₂ The mobile phase B is MEOH (+ -0.1% 7.0mol/l ammonia water in MEOH), A: B ═ 50:50

Wavelength: 214nm

Flow rate: 120ml/min

Column temperature: at normal temperature

Back pressure: 100bar

Injection amount: 4mL

Cycle time: for 10min

The sample preparation method comprises the following steps: the sample was dissolved in about 20ml of mooh.

Example 1

2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (compound 1)

(1) Preparation of Compounds 1-2

To a solution of 2, 6-dichloro-3-nitropyridine (i.e., 1-1) (1g, 5.2mmol, 1eq) in THF (20mL) at 25 ℃,1- (tert-butyl) 3-methylpiperazine-1, 3-dicarboxylate and (i.e., 1A) (1.3g, 5.2mmol, 1.0eq) and TEA (0.786g, 7.77mmol, 1.5eq) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and a residue was obtained which was purified by column chromatography on silica gel eluting with (PE/EA ═ 0-50%) to give 1- (tert-butyl) 3-methyl-4- (6-chloro-3-nitropyridin-2-yl) piperazine-1, 3-dicarboxylate as compound 1-2(1.7g, 81.7% yield).

LCMS r.t. ═ 2.953min, [ M-55] + ═ 345.0, purity: 90 percent.

(2) Preparation of Compounds 1-3

To a solution of 4- (6-chloro-3-nitropyridin-2-yl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester (i.e., 1-2) (1.6g, 4mmol, 1eq) in HOAc (20mL) was added Zn (2.6g, 40mmol, 10eq) at 25 ℃. The mixture was stirred at 60 ℃ for 2 hours. The mixture was diluted with NH3.H2O (30mL) and extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (20mL) and Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 2-chloro-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester was compound 1-3(0.8g, 59.2% yield).

LCMS r.t. ═ 1.549min, [ M-55] + ═ 283.0, purity: 81.3 percent.

(3) Preparation of Compounds 1-4

To 2-chloro-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] at 0 deg.C]Pyrido [3,2-e]To a solution of pyrazine-8-carboxylic acid tert-butyl ester (i.e., 1-3) (1.5g, 4.44mmol) in 20ml of DMF was added NaH (60%, 266.6mg, 6.66mmol), and the mixture was stirred at room temperature under nitrogen for 15 minutes. CH was then added to the reaction mixture at room temperature ₃ I (755.7mg, 5.33mmol) over 30 min. The reaction mixture was poured into water (50mL) and extracted with EtOAc (80 mL. times.3). The combined organic layers were washed with brine (20mL), Na ₂ SO ₄ Drying, concentrating under reduced pressure to obtain residue, purifying with silica gel column chromatography, eluting with (PE/EA 0-30%) to obtain 2-chloro-5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester as compound 1-4(1.44g, 92.2% yield).

LCMS r.t. ═ 2.083min, [ M-55] + ═ 297.2, purity 90.8%.

(4) Preparation of Compounds 1-5

To 2-chloro-5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] at 110 ℃ under nitrogen atmosphere]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester (i.e., 1-4) (1.44g, 4.1mmol) in 10mL dioxane/H ₂ To a solution of O (5:1) were added KOH (688.8mg, 12.3mmol), t-BuXPhos (348mg, 0.82mmol) and Pd ₂ (dba) ₃ (187mg, 0.2mmol) were mixed and stirred for 16 h. The mixture was adjusted to pH 5 with HCl (1N) and extracted with EtOAc (80mL × 3). The combined organic layers were washed with brine (20mL) and Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 2-hydroxy-5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester as compound 1-5(0.73g, 53% yield).

LCMS r.t. ═ 1.643min, [ M-55] + ═ 279.0, purity: 82.7 percent.

(5) Preparation of Compounds 1-6

To 2-hydroxy-5-methyl-6-oxo-5, 6,6A,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] at 0 deg.C]Pyrido [3,2-e]To a solution of pyrazine-8-carboxylic acid tert-butyl ester (i.e., 1-5) (0.3g, 0.9mmol, 1eq) in DMF (10mL) was added NaH (60%, 0.043g, 1mmol, 1.2eq) followed by 4- (bromomethyl) -3-fluorobenzonitrile (i.e., 5A) (0.19g, 0.9mmol, 1 eq). The mixture was stirred at room temperature for 2 hours. By H ₂ The mixture was diluted O (10mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na ₂ SO ₄ Drying, filtering and concentrating to give a residue which is purified by silica gel column chromatography, eluting with (PE/EA ═ 0-80%) to give 2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] o]Pyrido [3,2-e ]]Pyrazine-8-carboxylate as compound 1-6(0.25g, 59.6% yield).

LCMS r.t. ═ 1.304min, [ M-55] + ═ 412.1, purity: 88.6 percent.

(6) Preparation of Compounds 1-7

A solution of tert-butyl 2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6A,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (i.e., 1-6) (0.25g, 0.53mmol, 1eq) in HCl/EtOAc (10mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 3-fluoro-4- (((5-methyl-6-oxo-6, 6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-2-yl) oxy) methyl) benzonitrile hydrochloride as compound 1-7(0.15g, 76.5% yield).

LCMS r.t. ═ 1.128min, [ M +1] + ═ 368.1, purity: 54.5 percent.

(7) Preparation of Compounds 1-8

To 3-fluoro-4- (((5-methyl-6-oxo-6, 6a,7,8,9, 10-hexahydro-5H-pyrazino [1, 2-a)]Pyrido [3,2-e]Pyrazin-2-yl) oxy) methyl) benzonitrile hydrochloride (i.e., 1-7) (0.15g, 0.41mmol, 1eq) in CH ₃ CN (10mL) solution was added (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (i.e., 1-int-2) (0.12g, 0.41mmol, 1eq) and DIEA (0.26g, 2.04mmol, 5.0 eq). The mixture was stirred at 60 ℃ for 12 hours. The mixture was purified by silica gel column chromatography eluting with (PE/EA ═ 0-50%) to give 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1, 2-a)]Pyrido [3,2-e]Pyrazin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester as compound 1-8(0.2g, 78.4% yield).

LCMS r.t ═ 1.808min, [ M +1] + ═ 626.3, purity: 93.9 percent.

(8) Preparation of Compound 1

To 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] at 25 deg.C]Pyrido [3,2-e ]]Pyrazin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]To a solution of methyl imidazole-6-carboxylate (i.e., 1-8) (0.18g, 0.29mmol, 1eq) in THF (3mL) was added LiOH (0.035g, 1.44mmol, 5eq) in H ₂ Solution in O (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give a residue which was purified by pre-HPLC under basic conditions to give 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5-methyl-6-oxo-5, 6,6a,7,9, 10-hexahydro-8H-pyrazino [1, 2-a)]Pyrido [3,2-e]Pyrazin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid as compound 1(30.8mg, 16.02% yield).

LCMS r.t ═ 1.578min, MH + ═ 612.3, purity: 100 percent.

Example 2

2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 (Compound 2)

(1) Preparation of Compound 2-1

To a mixture of tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate SM (2g, 9.3mmol) and 2, 6-dichloro-3-fluoropyridine (1.53g, 9.3mmol) in 1, 4-dioxane (20mL) was added cesium carbonate (6.06g, 18.6mmol), Xantphos (1.04g, 1.8mmol) and Pd at 25 ℃ under a nitrogen atmosphere ₂ (dba) ₃ (820mg, 0.9 mmol). The mixture was stirred at 100 ℃ for 7 hours under a nitrogen atmosphere. LCMS monitor reaction. The reaction mixture was quenched with water and the mixture was extracted with EA, the combined organic layers were washed with brine (30mL), Na ₂ SO ₄ Dried and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with PE/EA (1:1) to give tert-butyl 4- (6-chloro-3-fluoropyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate as compound 2-1(2.2g, 60% yield).

LCMS:[M+1] ⁺ 346; purity: 91 percent.

(2) Preparation of Compound 2-2

To a solution of tert-butyl 4- (6-chloro-3-fluoropyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (i.e., 2-1) (1.4g, 4.05mmol) in DMSO (5mL) at 25 ℃, potassium tert-butoxide (545mg, 4.86mmol) was added. The mixture was stirred under nitrogen at 70 ℃ for 5 hours. LCMS monitor reaction. The mixture was diluted with MeOH (5mL) and the crude product was purified by pre-HPLC under basic conditions (ACN/water ═ 30-80%) to give 2-chloro-6 a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester as compound 2-2(450mg, 35% yield).

LCMS:[M+1] ⁺ 326; purity: 97 percent.

¹ H-NMR(400MHz,CDCl3)δ6.90(d,J＝8.0Hz,1H),6.57(d,J＝8.0Hz,1H),4.48(d,J＝12.3Hz,1H),4.31–4.00(m,3H),3.92(dd,J＝11.0,8.2Hz,1H),3.35(ddt,J＝11.3,8.1,3.2Hz,1H),3.05–2.50(m,3H),1.48(s,9H).

(3) Preparation of Compounds 2-3

At 25 ℃, 2-chloro-6 a,7,9, 10-tetrahydropyrazino [1,2-d ] is reacted]Pyrido [3,2-b][1,4]To a mixture of tert-butyl oxazine-8 (6H) -carboxylate (i.e., 2-2) (450mg, 1.38mmol) in 1, 4-dioxane (10mL) was added KOH (155mg, 2.76mmol), tBuXPhos (119mg, 0.28mmol) and Pd ₂ (dba) ₃ (128mg, 0.14 mmol). The mixture was stirred at 110 ℃ for 8 hours under a nitrogen atmosphere. LCMS monitor reaction. Quench the reaction mixture with water, extract the mixture with EA, wash the combined organic layers with brine (30mL), and Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography, eluting with DCM/MeOH (3:1) to give 2-hydroxy-6 a,7,9, 10-tetrahydropyrazino [1,2-d ]]Pyrido [3,2-b][1,4]Oxazine-8 (6H) -carboxylic acid tert-butyl ester as compound 2-3(200mg, 40% yield).

LCMS:[M+1] ⁺ 308; purity: 76 percent.

(4) Preparation of Compounds 2-4

At 0 ℃, 2-hydroxy-6 a,7,9, 10-tetrahydropyrazino [1,2-d ] is reacted]Pyrido [3,2-b ]][1,4]To a solution of oxazine-8 (6H) -carboxylic acid tert-butyl ester (i.e., 2-3) (70mg, 0.23mmol) in DMF (3mL) was added sodium hydride (19mg, 0.46 mmol). The mixture was stirred under a nitrogen atmosphere for 15 minutes, then 4- (bromomethyl) -3-fluorobenzonitrile (49mg, 0.23mmol) was added. The mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. LCMS monitor reaction. The reaction mixture was quenched with ice water, the mixture was extracted with EA, and the combined organic layers were washed with brine (30mL), Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography, eluting with PE/EA (20:1) to give 2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Oxazine-8 (6H)) Tert-butyl formate, compound 2-4(76mg, 75% yield).

LCMS:[M+1] ⁺ 441; purity: 83 percent.

(5) Preparation of Compounds 2-5

A solution of tert-butyl 2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylate (i.e., 2-4) (76mg, 0.04mmol) and HCl in EtOAc (4M, 1mL) was stirred at 25 ℃ under nitrogen for 3 hours. LCMS monitor reaction. The reaction mixture was concentrated under reduced pressure to give 3-fluoro-4- (((6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-2-yl) oxy) methyl) benzonitrile (60mg, crude, 102% yield) as the hydrochloride salt of compound 2-5.

LCMS:[M+1] ⁺ 341; purity: 62 percent.

(6) Preparation of Compounds 2 to 6

To 3-fluoro-4- (((6,6a,7,8,9, 10-hexahydropyrazino [1, 2-d) at 25 ℃]Pyrido [3,2-b][1,4]Oxazin-2-yl) oxy) methyl) benzonitrile (i.e., 2-5) (50mg, 0.15mmol) and DIEA (97mg, 0.75mmol) in ACN (5mL) was added (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (i.e., 1-int-2) (35mg, 0.12 mmol). The mixture was stirred at 60 ℃ for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was quenched with water and the mixture was extracted with EA, the combined organic layers were washed with brine (30mL), Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography, eluting with PE/EA (1:5) to give 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 acidEster, compound 2-6(30mg, 42% yield).

LCMS:[M+1] ⁺ 599; purity: 75 percent.

(7) Preparation of Compound 2

To 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1, 2-d) at 25 DEG C]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) methyl-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (i.e., 2-6) (30mg, 0.05mmol) in THF (5mL) and H ₂ To the O (1mL) mixture was added lithium hydroxide (7mg, 0.25 mmol). The mixture was stirred at 25 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was purified by pre-HPLC (0.05% NH ₃ ·H ₂ O/ACN: 20% -35%) to obtain 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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, compound 2(7.7mg, 28% yield).

LCMS:[M+1] ⁺ 585; purity: 96.21%

Preparation methods of compound 2-6-P1 and compound 2-6-P2

Methyl 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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-carboxylate 2-6(220mg, 0.37mmol) was further purified by the SFC method to give methyl 2- (((R) -2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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-carboxylate 2-6-P1(90mg, SFC r.t ═ 2.47min, yield 41%) and methyl 2- (((S-2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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-carboxylate 2-6-P2(80mg, SFC r.t ═ 3.34min, yield 36%).

Wherein, the SFC method comprises the following steps:

sample name: MT89_02-MC 20-1147-; the system comprises the following steps: waters SFC 150; column:

AD; column diameter: 250 x 25mm 10 m;

mobile phase A: supercritical CO ₂ B, carrying out the following steps of; mobile phase B: MeOH (. + -. 0.1%. + -. 7.0mol/l aqueous ammonia in MeOH); a, B: 50: 50; wavelength: 214 nm; flow rate: 100 ml/min; column temperature: room temperature; back pressure: 100 bar; injecting: 1 mL; cycle time: 5 min;

preparation of sample solution: the sample was dissolved in about 20mM LEOH/DCM (2: 1).

Process for the preparation of compounds 2-P1 and 2-P2

To methyl 2- (((R) -2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1, 2-d) at 25 deg.C]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) methyl-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate 2-6-P1(90mg, 0.15mmol) in THF (5mL) and H ₂ To the mixture in O (1mL) was added lithium hydroxide (18mg, 0.75 mmol). The mixture was stirred at 25 ℃ for 20 hours. The reaction was checked by LCMS and the mixture was purified by pre-HPLC (0.05% NH) ₃ .H ₂ O/ACN：20% -35%) to obtain 2- (((R) -2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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, compound 2-P1(43mg, 50%) as an off-white solid, was confirmed by the pure R-product as the same SFC result as R-.

LCMS:[M+1] ⁺ 585, purity: 98.5 percent

Preparation method of compound 2-P2

To methyl 2- (((S) -2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1, 2-d) at 25 deg.C]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) methyl-1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate 2-6-P2(80mg, 0.13mmol) in THF (5mL) and H ₂ To the mixture in O (1mL) was added lithium hydroxide (17mg, 0.70 mmol). The mixture was stirred at 25 ℃ for 3 hours. The reaction was checked by LCMS and the mixture was purified by pre-HPLC (0.05% NH ₃ .H ₂ O/ACN: 20% -35%) to obtain 2- (((S) -2- ((4-cyano-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 as compound 2-P2(16.7mg, 21%).

LCMS:[M+1] ⁺ 585, purity: 98.5 percent.

Example 3

2- (((R) -2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 and 2- (((S) -2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 (compounds 3-P1 and 3-P2)

(1) Preparation of Compound 3-2

To a solution of 2-3(250mg, 0.81mmol) in DMF (10mL) at 0 deg.C was added sodium hydride (65mg, 1.62 mmol). Then 1- (bromomethyl) -4-chloro-2-fluorobenzene (172mg, 0.81mmol) was added. In N ₂ The mixture was stirred at room temperature under an atmosphere for 3 hours. LCMS monitor reaction. The reaction mixture was quenched with ice water, the mixture was extracted with EA, and the combined organic layers were washed with brine (30mL) and Na ₂ SO ₄ Drying and concentrating under reduced pressure to give a residue which is purified by silica gel column chromatography, eluting with PE/EA (20:1) to give 2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Tert-butyl oxazine-8 (6H) -carboxylate, (230mg, 64%) was the product 3-2.

LCMS:r.t.＝3.94min,[M+1] ⁺ 450, purity: 93 percent.

(2) Preparation of Compound 3-3

To a solution of 3-2(230mg, 0.53mmol) in EA (5mL) was added HCl (3 mL). In N ₂ The mixture was stirred at 25 ℃ for 3 hours under an atmosphere. LCMS monitor reaction. The reaction mixture was concentrated under reduced pressure to give 2- ((4-chloro-2-fluorobenzyl) oxy) -6,6a,7,8,9, 10-hexahydropyrazino [1, 2-d)]Pyrido [3,2-b ]][1,4]Oxazine (180mg, yield: 100%) as product 3-3 as HCl salt.

LCMS:r.t.＝2.4min,[M+1] ⁺ 350, purity: 85 percent.

(3) Preparation of Compounds 3-4

To a mixture of 3-3(180mg, 0.52mmol) and DIEA (340mg, 2.60mmol) in ACN (10mL) at 25 deg.C was added 1-int-2(155mg, 0.52 mmol). In N ₂ The mixture was stirred at 60 ℃ for 7 hours under an atmosphere. The reaction was checked by LCMS, the reaction mixture was quenched with water, the mixture was extracted with EA, the combined organic layers were washed with brine (30mL), Na ₂ SO ₄ Drying and concentrating under reduced pressure to obtain a residue, purifying by silica gel column chromatography, eluting with PE/EA (1:5) to obtain 2- ((2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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-carboxylate (220mg, 69%) as product 3-4. SFC shows a ratio of 1: 1.

(4) Resolution of Compounds 3-4

A sample of 3-4(220mg, 0.37mmol) was further purified by SFC method to give 3-4-P1(90mg, SFC r.t ═ 2.47min, yield: 41%) and 3-4-P2(80mg, SFC r.t ═ 3.34min, yield: 36%).

(5) Preparation of Compounds 3-P1 and 3-P2

To methyl 3-4-P1(90mg, 0.15mmol) in THF (5mL) and H at 25 deg.C ₂ To the mixture in O (1mL) was added lithium hydroxide (18mg, 0.75 mmol). The mixture was stirred at 25 ℃ for 20 hours. The reaction was monitored by LCMS and the mixture was purified by pre-HPLC (0.05% NH3. H2O/ACN: 20% -35%) to give 2- (((R) -2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 (18.5mg, 50%) as compound 3-P1.

LCMS:r.t.＝1.33min,[M+1] ⁺ 594, purity: 95 percent

To 3-4-P2(80mg, 0.13mmol) in THF (5mL) and H at 25 deg.C ₂ To the mixture in O (1mL) was added lithium hydroxide (17mg, 0.70 mmol). The mixture was stirred at 25 ℃ for 3 hours. Reaction completion was checked by LCMS and the mixture was purified by pre-HPLC (0.05% NH3. H2O/ACN: 20% -35%) to give 2- (((S) -2- ((4-chloro-2-fluorobenzyl) oxy) -6a,7,9, 10-tetrahydropyrazino [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 (15.6mg, 40%) as compound 3-P2.

LCMS:r.t.＝1.34min,[M+1] ⁺ 594, purity: 96 percent

Example 4

2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -7a,8,10, 11-tetrahydro-5H-pyrazino [2,1-c ] pyrido [2,3-e ] [1,4] oxazepin-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 4)

(1) Preparation of Compound 4-2

To a solution of 1- (tert-butyl) 3-methylpiperazine-1, 3-dicarboxylate 4-1(4.0g, 16.4mmol, 1eq) and methyl 2, 6-dichloronicotinate (3.38g, 16.4mmol, 1.0eq) in NMP (50mL) was added DIPEA (2.24g, 32.8mmol, 2.0 eq). In N ₂ The mixture was stirred at 120 ℃ for 12 hours under an atmosphere. LCMS monitor reaction. By H ₂ The mixture was diluted O (100mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with Na ₂ SO ₄ Dried, filtered and concentrated to give a residue,this was purified by silica gel column chromatography eluting with (EA/PE ═ 0-20%) to give 4- (6-chloro-3- (methoxycarbonyl) pyridin-2-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester 4-2(1.6g, 23.6% yield).

¹ H NMR(400MHz,CDCl3)δ7.96(t,J＝7.1Hz,1H),6.75(dd,J＝13.8,7.9Hz,1H),4.74(d,J＝16.5Hz,1H),4.48(d,J＝13.4Hz,1H),4.07–3.92(m,1H),3.88(s,3H),3.75(s,3H),3.60(dd,J＝19.9,9.7Hz,1H),3.48(d,J＝13.0Hz,1H),3.37(d,J＝11.4Hz,1H),3.15(s,1H),1.46(s,9H).

(2) Preparation of Compound 4-3

To a solution of 4-2(1.6g, 3.9mmol, 1.0eq) in THF (50mL) at 0 deg.C was added LiAlH ₄ (441.6mg, 11.616mmol, 3.0 eq). In N ₂ The mixture was then stirred at 0 ℃ for 10 minutes. LCMS monitor reaction. Slowly adding H to the mixture ₂ O (0.4mL), 15% NaOH solution (0.4mL) and EtOAc (50 mL). The organic layer was washed with brine, over Na ₂ SO ₄ Drying and concentration gave 4- (6-chloro-3- (hydroxymethyl) pyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester 4-3(640mg, 46.3% yield).

LCMS:r.t.＝1.64min,[M+1] ⁺ 358, purity: 80 percent

(3) Preparation of Compound 4-4

To a solution of 4-3(1.0g, 2.8mmol, 1.0eq) in toluene (150mL) was added camphorsulfonic acid (3.26g, 14mmol, 5.0 eq). The mixture was stirred at 110 ℃ for 2 hours. LCMS monitor reaction. The mixture was concentrated to give a residue, which was diluted with saturated aqueous sodium bicarbonate. NaHCO 2 ₃ (200mL) and extracted with DCM (150 mL. times.3). The organic layers were combined and washed with Na ₂ SO ₄ Drying, filtering, concentrating to obtain a residue, and subjecting the residue to silica gel column chromatographyPurification by chromatography eluting with (MeOH/DCM ═ 0-10%) afforded the product 4-4(366mg, 54.7% yield).

LCMS:r.t.＝0.62min,[M+1] ⁺ 240, purity: 99.7 percent

(4) Preparation of Compounds 4-5

To a solution of 4-4(330mg, 1.38mmol, 1.0eq) in DCM (15mL) was added Boc ₂ O (390mg, 1.78mmol, 1.3eq) and TEA (280mg, 2.76mmol, 2.0 eq). The mixture was stirred at 10 ℃ for 2 hours. LCMS monitor reaction. The mixture was concentrated to give a residue which was purified by silica gel column chromatography eluting with (EtOAc/PE ═ 0-10%) to give the product 4-5(360mg, 76.9% yield).

LCMS:r.t.＝2.059min,[M+1] ⁺ 340, purity: 99.7 percent

(5) Preparation of Compounds 4-6

To a solution of 4-5(290mg, 0.855mmol) in 20mL dioxane under nitrogen and stirring at 110 deg.C was added 3-fluoro-4- (hydroxymethyl) benzonitrile (259.03mg, 1.711mmol), Cs ₂ CO ₃ (557.8mg, 1.711mmol), Xantphos (98.94mg, 0.1711mmol) and Pd ₂ (dba) ₃ (78.3mg, 0.0855mmol) for 60 h. The reaction mixture was concentrated to the crude product and further purified by elution (0-20% EtOAC/PE) to give the product 4-6(347mg, 89.4% yield).

LCMS:r.t.＝2.13min,[M+1] ⁺ 455, purity: 95 percent

(6) Preparation of Compounds 4 to 7

To a solution of 4-6(347mg, 0.76mmol) in 6mL HCl/EA was stirred at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give crude 4-7(270mg, 99% yield) as a crude product, which was used in the next step without purification.

LCMS:r.t.＝1.12min,[M+1] ⁺ 335, purity: 99 percent

(7) Preparation of Compounds 4-8

DIEA (920mg, 0.71mmol) was added to a solution of 4-7(270mg, 0.78mmol) in 15mL of LCeCN for 10min with stirring at room temperature under nitrogen. Then, 1-int-2(209mg, 0.71mmol) was added to the reaction mixture at 60 ℃ for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated to the crude product and further purified by elution (EtOAc/PE 0-5%) to give the product 4-8(210mg, 60% yield).

LCMS:r.t.＝1.553min,[M+1] ⁺ 613, purity: 99 percent

(8) Preparation of Compound 4

To a solution of 4-8(200mg, 0.32mmol) in THF/H ₂ O (8mL) solution was stirred at room temperature for 16 h, LiOH (40mg, 1.63mmol) was added, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give compound 4(70mg, 75% yield).

LCMS:r.t.＝1.246min,[M+1] ⁺ 599, purity: 98 percent of

(9) Preparation (resolution) of Compounds 4-P1 and 4-P2

A sample of compound 4(70mg, 0.117mmol) was further purified by SFC method to give 4-P1(36.55mg, SFC r.t ═ 4.76 min, yield: 95%) and 4-P2(9mg, SFC r.t ═ 5.9 min, yield: 26%) as off-white solids.

Compound 4-P1: LCMS r.t. -. 1.246min, [ M +1] ⁺ 599, purity: 98 percent

Compound 4-P2: LCMS r.t. -. 1.274min, [ M + H] ⁺ 599, purity 98.7%.

Example 5

2- (((R) -2- ((4-cyano-2-fluorobenzyl) oxy) -6,7,7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-B ] [1,4] oxazepin-9-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid and 2- (((S) -2- ((4-cyano-2-fluorobenzyl) oxy) -6,7,7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-B ] [1,4] Oxazazepin-9-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 5-P1 and Compound 5-P2)

(1) Preparation of Compound 5-2

To a solution of tert-butyl 3- (2-hydroxyethyl) piperazine-1-carboxylate 5-1(4000mg, 17.4mmol) in 50mL of dioxane under nitrogen and with stirring at 110 deg.C were added 2, 6-dichloro-3-fluoropyridine (3.04g, 17.4mmol), Cs ₂ CO ₃ (12.6g, 38.64mmol), Xantphos (2.23g, 3.864mmol) and Pd ₂ (dba) ₃ (1.77g, 1.94mmol) for 16 h. LCMS monitor reaction. The reaction mixture was concentrated to the crude product, which was further purified by elution (MeOH/DCM ═ 0-5%) to give product 5-2(3.6g, 58% yield).

LCMS:r.t.＝1.17min,[M+H] ⁺ 360, purity: 90 percent of

(2) Preparation of Compound 5-3

To a solution of 5-2(3.6g, 8.89mmol) in 60mL of DMF at 1000 deg.C under nitrogen was added NaH (711.4mg, 17.78mmol)) for 4h and the reaction was monitored by LCMS. The reaction mixture was poured into water (300mL), extracted with EtOAc (100mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (EtOAc/PE ═ 0-25%) to give the product 5-3(200mg, 6.6% yield).

LCMS:r.t.＝2.148min,[M+H] ⁺ 340, purity: 95 percent

(3) Preparation of Compounds 5-4

To a solution of 5-3(110mg, 0.325mmol) of 10mL dioxane/H under nitrogen at 110 deg.C ₂ To the O solution were added KOH (54.61mg, 0.97mmol), t-Buxphos (27.56mg, 0.065mmol) and Pd ₂ (dba) ₃ (14.9mg, 0.016mmol) was stirred for 16 h and the reaction was monitored by LCMS. Concentrating processThe mixture was allowed to give the crude product, which was further purified by elution (EtOAc/PE 0-70%) to give the product 5-4(80mg, 65% yield).

LCMS:r.t.＝1.478min,[M+H] ⁺ 322, purity: 91 percent

(4) Preparation of Compounds 5-5

To a solution of 5-4(80mg, 0.249mmol) in 5mL DMF under nitrogen at room temperature with stirring was added NaH (15mg, 0.374mmol) for 15 min, followed by stirring under nitrogen at room temperature for 30 min, and 4- (bromomethyl) -3-fluorobenzonitrile (53.3mg, 0.249mmol) was added to the reaction mixture. LCMS monitor reaction. The reaction mixture was poured into water (50mL), extracted with EtOAc (30mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (PE/EA ═ 0-13%) to give the product 5-5(90mg, 76.9% yield).

LCMS:r.t.＝2.213min,[M+H] ⁺ 455, purity: 99 percent

(5) Preparation of Compounds 5-6

To a solution of 5-5(90mg, 0.198mmol) in 5mL HCl/EA was stirred at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give 5-6(70mg, 98%) as a crude product, which was used in the next step without purification.

LCMS:r.t.＝1.174min,[M+H] ⁺ 355, purity: 87 percent of

(6) Preparation of Compounds 5-7

After stirring at room temperature for 10min under nitrogen, DIEA (255.9mg, 1.98mmol) was added to a solution of 5-6(70mg, 0.198mmol) in 10mL of MeCN. 1-int-2(58.14mg, 0.198mmol) was then added to the reaction mixture at 60 ℃ for 16 h. LCMS monitor reaction. The reaction mixture was concentrated to the crude product and further purified by elution (EtOAc/PE ═ 0-5%) to give 5-7(80mg, 66% yield) as a white solid.

LCMS:r.t.＝1.513min,[M+H] ⁺ 613, purity: 88 percent

(7) Resolution and preparation of Compounds 5-P1 and 5-P2

To a solution of 5-7-P2(28mg, 0.045mmol) in THF/H ₂ To a solution in O (4mL) was added LiOH (5.5mg, 0.23mmol) while stirring at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to the crude product and further purified by preparative HPLC to give compound 5-P2(13.65mg, 69.6%).

LCMS:r.t.＝1.246min,[M+H] ⁺ 599, purity: 98 percent of

To a solution of 5-7-P1(28mg, 0.045mmol) in THF/H2O (4mL) was added LiOH (5.5mg, 0.23mmol) while stirring at room temperature for 16H, and the reaction was monitored by LCMS. The reaction mixture was concentrated to the crude product, which was further purified by preparative HPLC to give 5-P1(7.25mg, 26.6%) as a white solid.

LCMS:r.t.＝1.246min,[M+H] ⁺ 599, purity: 98 percent of

Example 6

(S) -2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydrooxa [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 6)

(1) Preparation of Compound 6-2

To a mixture of 2-chloro-6-hydroxynicotinic acid 6-1(5.0g, 29mmol) in MeOH (40mL) was added sulfuric acid (10 mL). The mixture was stirred at 80 ℃ for 16 hours. Reaction was checked by LCMS. Quench the reaction mixture with ice water, extract the mixture with EA, wash the combined organic layers with brine (50mL), and Na ₂ SO ₄ Dried and concentrated under reduced pressure to give methyl 2-chloro-6-hydroxynicotinate 6-2(4.5g, 83%).

LCMS:r.t.＝2.1min,[M+H] ⁺ 188, purity: 92 percent of

(2) Preparation of Compound 6-3

6-2(3.4g, 18.2mmol), PMB-Cl (3.4g, 21.2mmol) and K were added ₂ CO ₃ (3.76g, 27.3mmol) in DMF (50 ml). At 80 ℃ with Ar ₂ The mixture was stirred for 2 hours. The reaction was checked by LCMS. The reaction mixture was quenched by the addition of water. The aqueous phase was extracted with EtOAc (100 ml. times.3) and washed with brine (50 ml. times.2). The combined organic layers were washed with Na ₂ SO ₄ And (5) drying. Concentration and purification by elution (PE/EA ═ 0-20%) gave methyl 2-chloro-6- ((4-methoxybenzyl) oxy) nicotinate 6-3(2.9g, 52%).

LCMS:r.t.＝3.5min,[M+H] ⁺ 308, purity: 95 percent

(3) Preparation of Compound 6-4

6-3(2.9g, 9.4mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1, 3(2H) -dicarboxylic acid 1-4 methyl ester (4) were added.16g，11.3mmol)、C _s2 CO ₃ (6.16g, 18.8mmol) and Pd (dppf) Cl ₂ (0.69g, 0.94mmol) the mixture was reacted in 1, 4-dioxane (80 ml). With Ar at 110 ℃ ₂ The mixture was stirred for 16 hours. The reaction was checked by LCMS. Concentration and purification by elution (PE/EA ═ 0-20%) gave 1' - (tert-butyl) 3,3' -dimethyl-6- ((4-methoxybenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine]-1',3,3' (2' H) -tricarboxylic acid ester 6-4(2.5g, 53.2%).

LCMS:r.t.＝1.37min,[M+H] ⁺ 513, purity: 95 percent

(4) Preparation of Compounds 6-5

6-4(1.5g, 2.9mmol) was dissolved in anhydrous THF (15mL) and LiAlH was added portionwise at 0 deg.C ₄ (0.222g, 5.8 mmol). After 10min, the reaction was checked by LCMS. The reaction mixture was quenched with ice water (0.5 ml). The mixture was filtered and concentrated to give 3,5 '-bis (hydroxymethyl) -6- ((4-methoxybenzyl) oxy) -3',6 '-dihydro- [2,4' -bipyridine]-1'(2' H) -carboxylic acid tert-butyl ester 6-5(1.2g, 92%).

LCMS:r.t.＝1.95min,[M+H] ⁺ 457, purity: 88 percent

(5) Preparation of Compounds 6-6

A reaction mixture of 6-5a (1.1g, 2.4mmol), camphorsulfonic acid (3.24g, 9.6mmol) in TOL (20ml) was added. The mixture was heated at 110 ℃ for 1 hour. The reaction was checked by LCMS. Concentrated and purified by elution (MeOH/DCM ═ 0-20%) to give 5,7,8,9,10, 11-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridinyl-2-ol 6-6(0.4g, 76%).

LCMS:r.t.＝1.25min,[M+H] ⁺ 219, purity: 96 percent

(6) Preparation of Compound Int-5

Mixing 6-6(0.35g, 1.6mmol), (BOC) ₂ O (0.42g, 1.9mmol) and TEA in DCM (15 ml). The mixture was stirred at room temperature for 1 hour. The reaction was checked by LCMS. Concentrated and purified by elution (MeOH/DCM ═ 0-10%) to give 2-hydroxy-5, 8,10, 11-tetrahydroxepinotrienone [4,3-b:6,5-c']Bipyridine-9 (7H) -carboxylate Int-5(350mg, 70%).

LCMS:r.t.＝2.32min,[M+H] ⁺ 319, purity: 95 percent

¹ H NMR(400MHz,CDCl ₃ )δ12.63(s,1H),7.43(d,J＝9.2Hz,1H),6.49(d,J＝9.1Hz,1H),4.17(s,4H),3.80(s,2H),3.67(t,J＝5.5Hz,2H),2.72(s,2H),1.51(s,9H).

(7) Preparation of Compounds 6-7

Int-5(0.3g, 1.2mmol) was dissolved in anhydrous DMF (5mL) and NaH (45mg, 1.44mmol) was added portionwise at 0 deg.C, after 5min a solution of 4- (bromomethyl) -3-fluorobenzonitrile (0.202g, 1.2mmol) (5mL DMF) was added to the reaction via cannula. After 20 min, the reaction was checked by LCMS. The reaction mixture was quenched by the addition of water. The aqueous phase was extracted with EtOAc (20 ml. times.3) and washed with brine (20 ml. times.2). The combined organic layers were washed with Na ₂ SO ₄ And (5) drying. Concentration and purification by elution (PE/EA. RTM.0-20%) gave 2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c']Bipyridine-9 (7H) -carboxylate 6-7(0.35g, 83.3%).

(8) Preparation of Compounds 6-8

6-7(0.35g, 0.78mmol) was added in HCl/EA (20ml, 3M). The mixture was stirred at room temperature for 0.5 hour. The reaction was checked by LCMS. The mixture was concentrated to give 3-fluoro-4- (((5,7,8,9,10, 11-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridin-2-yl) oxy) methyl) benzonitrile 6-8(0.27g, 98%).

LCMS:r.t.＝2.21min,[M+H] ⁺ 351, purity: 95 percent

(9) Preparation of Compound 6-A

6-8(0.27g, 1.1mmol) DIEA (0.451g, 3.5mmol) in 20mL CH ₃ The reaction mixture in CN was stirred at room temperature for 10 minutes. 1-int-2(206.5g, 1.0mmol) was then added and heated at 65 ℃ for 15 hours. The reaction was checked by LCMS. Concentration and purification by elution (MeOH/DCM ═ 0-8%) gave the product as compound 6-a (250mg, 59%).

LCMS:r.t.＝2.51min,[M+H] ⁺ 610, purity: 95 percent

¹ H NMR(400MHz,CDCl ₃ )δ8.16(s,1H),7.99(dd,J＝8.5,1.3Hz,1H),7.77(d,J＝8.5Hz,1H),7.60(t,J＝7.5Hz,1H),7.51(d,J＝8.2Hz,1H),7.40(dd,J＝28.4,9.0Hz,2H),6.70(d,J＝8.2Hz,1H),5.51(s,2H),5.26–5.17(m,1H),4.76–4.58(m,3H),4.42–4.33(m,3H),4.18–4.09(m,2H),3.95(s,3H),3.88(s,2H),3.25(s,2H),2.81(t,J＝5.5Hz,2H),2.72(p,J＝8.2Hz,3H),2.45(dq,J＝11.2,7.3Hz,1H).

(10) Preparation of Compound 6

6-A (0.25g, 0.41mmol) was dissolved in THF (4mL) and aqueous lithium hydroxide (4mL) was added. The mixture was stirred at room temperature for 8 hours. The reaction was checked by LCMS. Concentration and HPLC (NH) ₃ ·H ₂ O) purification to give compound 6(0.13g, 53%). LCMS r.t. -. 1.225min, [ M + H] ⁺ 596, purity: 99 percent

(11) Preparation (resolution) of Compound 6-P1

Compound 6(22mg, 0.037mmol) was dissolved in H ₂ To O (2mL), NaOH (1.48mg, 0.037mmol) was then added. The mixture was stirred at room temperature for 2 minutes. Concentration afforded compound 6-P1(22.8mg, 100%).

LCMS:r.t.＝1.225min,[M+H] ⁺ 596, purity: 96 percent

Example 7

(S) -2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydrooxa [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (Compound 7)

(1) Preparation of Compound 7-A

A reaction mixture of 6-8(96mg, 0.27mmol), 1-int-2(80mg, 0.27mmol), N-diisopropylethylamine (175mg, 1.35mmol) in 5mL acetonitrile was stirred at 60 ℃ for 16 h. The reaction was monitored by TLC. The reaction mixture was evaporated to dryness and the residue was purified by SGC (EA/MeOH ═ 10:1) to give compound 7-a (100mg, 60%).

LCMS r.t. ═ 0.773min, [ M + H ] + ═ 611, purity: 97 percent

(2) Preparation of Compound 7

Lithium hydroxide (20mg, 0.81mmol) in 1mLH at 25 deg.C ₂ The O solution was added to a reaction mixture of compound 7-A (100mg, 0.16mmol) in 5mL tetrahydrofuran. The mixture was stirred at 25 ℃ for 3 hours. LCMS monitoring is complete. The reaction mixture was purified by pre-HPLC to give compound 7(22.45mg, 22%).

LCMS:r.t.＝1.211min,[M+H] ₊ 597, purity: 99 percent

Example 8

(S) -2- ((2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,8,10, 11-tetrahydrooxa [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 8)

(1) Preparation of Compounds 8-7

60% sodium hydride (19mg, 0.75mmol) was slowly added to Int-5(200mg, 0.62mmol) in 4mL of N, N-dimethylformamide at 0 ℃. The mixture was stirred at 0 ℃ for 15 minutes. Then, 1- (bromomethyl) -2-fluoro-4- (trifluoromethyl) benzene (162mg, 0.62mmol) was added to the mixture. The reaction was monitored by TLC. An ammonium chloride solution was then added to the mixture, and the mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness and the residue was purified by SGC (PE: EA ═ 5:1) to give compounds 8-7(150mg, 48%).

LCMS:r.t.＝1.12min,[M+H] ⁺ 495, purity: 95 percent

(2) Preparation of Compounds 8-8

8-7(150mg, 0.30mmol) was stirred in 6mL (3M) of hydrogen chloride in ethyl acetate at 25 ℃ for 2 h. The reaction was checked by TLC. The reaction mixture was evaporated to dryness to give the crude 8-8(120mg, 99%).

LCMS:r.t.＝0.764min,[M+H] ⁺ 395, purity: 51 percent

(3) Preparation of Compounds 8-9

A solution of 8-8(90mg, 0.30mmol), 1-int-2(120mg, 0.30mmol), N-diisopropylethylamine (197mg, 1.52mmol) in 5mL acetonitrile was stirred at 60 ℃ for 16 h. The reaction was checked by TLC. The reaction mixture was evaporated to dryness and the residue was purified with SGC (PE: EA ═ 1:1) to give compounds 8-9(60mg, 30%).

LCMS:r.t.＝1.73min,[M+H] ⁺ 653, purity: 91 percent

(4) Preparation of Compound 8

To a reaction mixture of 8-9(60mg, 0.09mmol) in 5mL tetrahydrofuran at 25 ℃. The reaction mixture was stirred at 25 ℃ for 16 hours. Reaction was checked by LCMS. The reaction mixture was purified by pre-HPLC to give (S) -2- ((2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,8,10, 11-tetrahydrooxa [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid as compound 8(8.3mg, 14%).

LCMS:r.t.＝0.887min,[M+H] ⁺ 639, purity: 99 percent

Example 9

2- (((6a,10a) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,6a,7,9,10,10 a-hexahydro-8H-pyrano [4,5-b:2,3-c' ] bipyridinyl-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 9)

(1) Preparation of Compounds 9-A and 9-B

To 2- (((6aR,10aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,6a,7,9,10,10 a-hexahydro-8H-pyrano [4,5-b:2,3-c ') at 25 deg.C']Bipyridin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]To a solution of imidazole-6-carboxylate (130mg,0.22mmol,1eq) in THF (4mL) was added LiOH (26mg,1.08mmol,5eq) in water (1mL), mixed for 16 h, and the reaction was monitored by LCMS. The reaction was concentrated, pre-HPLC purified and lyophilized to give 2- (((6aR,10aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,6a,7,9,10,10 a-hexahydro-8H-pyrano [4,5-b:2,3-c']Bipyridin-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (33.39mg, 26.3%). LCMS r.t ═ 1.232min, [ M + H-] ⁺ 584.2, purity: 100 percent

To a solution of 2- (((6aS,10aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,6a,7,9,10,10 a-hexahydro-8H-pyrano [4,5-b:2,3-c' ] bipyridinyl-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate (130mg,0.22mmol,1eq) in THF (4mL) at 25 ℃ was added LiOH (26mg,1.08mmol,5eq) in water (1mL), mixed for 16H and LCMS monitored the reaction. The reaction was concentrated, pre-HPLC purified and lyophilized to give 2- (((6aS,10aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,6a,7,9,10,10 a-hexahydro-8H-pyrano [4,5-b:2,3-c' ] bipyridinyl-8-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (49.99mg, 39.4%).

LCMS:r.t＝1.240min,[M+H] ⁺ 584.2, purity: 100 percent

Example 10

(S) -2- ((2- ((4-chloro-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 10)

(1) Preparation of Compounds 10-7

To a solution of Int-5(200mg, 0.63mmol, 1eq) in DMF (8mL) at 0, NaH (38mg, 1.57mmol, 1.5eq) was added for 30 min. 1- (bromomethyl) -4-chloro-2-fluorobenzene (140mg, 0.63mmol, 1.0eq) was added and stirred at 25 ℃ for 30 min. The reaction was monitored by TLC. The mixture was diluted with EtOAc (50mL) and washed with H ₂ O (70mL) and extracted with EtOAc (50 mL. times.2). The combined organic layers were washed with brine (50mL) and Na ₂ SO ₄ Dried and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography, eluting with (PE/EA ═ 0-20%) to give the product 10-7(230mg, 79.6% yield).

¹ H NMR(400MHz,CDCl ₃ )δ7.53(d,J＝8.3Hz,1H),7.43(t,J＝8.1Hz,1H),7.16–7.04(m,2H),6.69(d,J＝8.2Hz,1H),5.43(s,2H),4.34(s,2H),4.12(d,J＝2.9Hz,2H),3.88(s,2H),3.64(t,J＝5.4Hz,2H),2.76(s,2H),1.51(s,9H).

(2) Preparation of Compound 10-8

To a solution of 10-7(200mg, 0.43mmol, 1eq) in HCl/EA (6 mL). The reaction mixture was stirred at 25 ℃ for 1 hour. LCMS monitor reaction. The reaction mixture was concentrated under reduced pressure to give 10-8(160mg, crude product).

LCMS:r.t.＝1.921min,[M+H] ⁺ 361.1, purity: 95.2 percent

(3) Preparation of Compound 10-9

DIEA (286mg, 2.2mmol, 5eq) was added to a solution of 10-8(160mg, 0.44mmol, 1eq) and 1-int-2(130mg, 0.44mmol, 1eq) in MeCN (6 mL). The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with (MeOH/DCM ═ 0-10%) to give the product 10-9(150mg, 55% yield).

LCMS:r.t.＝1.553min,[M+H] ⁺ 619.4, purity: 94.7 percent

(4) Preparation of Compound 10

LiOH (29mg, 1.0mmol, 5eq) in THF (5mL) at 25 deg.C in 10-9(150mg, 0.2mmol, 1eq) was added ₂ O (1mL) solution. The mixture was stirred at room temperature for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated and purified by HPLC, freeze-dried to give (S) -2- ((2-, ((4-chloro-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid as compound 10(57.53mg, 39.2% yield).

LCMS:r.t.＝1.316min,[M+H] ⁺ 605.2, purity: 100 percent

Example 11

(S) -2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 11)

(1) Preparation of Compounds 11-7

Int-5(0.3g, 1.2mmol) was dissolved in anhydrous DMF (5mL) and NaH (45mg, 1.44mmol) was added portionwise at 0 deg.C, after 5min a solution of 4- (bromomethyl) -3-fluorobenzonitrile (0.202g, 1.2mmol) (5mL DMF) was added to the reaction via cannula. After 20 min, the reaction was checked by LCMS. The reaction mixture was quenched by the addition of water. The aqueous phase was extracted with EtOAc (20 ml. times.3) and washed with brine (20 ml. times.2). The combined organic layers were washed with Na ₂ SO ₄ And (5) drying. Concentration and purification by elution (PE/EA ═ 0-20%) gave the product 11-7(0.35g, 83.3%).

LCMS:r.t.＝2.21min,[M+H] ⁺ 477.5, purity: 95 percent

(2) Preparation of Compounds 11-8

11-7(0.35g, 0.78mmol) was added in HCl/EA (20ml, 3M). The mixture was stirred at room temperature for 0.5 hour. And detecting the reaction by LC-MS. The mixture was concentrated to give product 11-8(0.27g, 98%).

LCMS:r.t.＝1.21min,[M+H] ⁺ 376.2, purity: 92 percent of

(3) Preparation of Compounds 11-9

11-8(0.27g, 1.1mmol) DIEA (0.451g, 3.5mmol) in 20mL CH ₃ The reaction mixture in CN was stirred at room temperature for 10 minutes. 1-int-2(206.5g, 1.0mmol) was then added and heated at 65 ℃ for 15 hours. The reaction was detected by LC-MS. Concentration and purification by elution (MeOH/DCM ═ 0-8%) gave the product 11-9(250mg, 59%).

LCMS:r.t.＝2.51min,[M+H] ⁺ 635, purity: 95 percent

(4) Preparation of Compound 11

11-9(0.25g, 0.41mmol) was dissolved in THF (4mL), thenThen aqueous lithium hydroxide (4mL) was added. The mixture was stirred at room temperature for 8 hours. The reaction was detected by LC-MS. Concentrated and passed through preparative HPLC (NH) ₃ .H ₂ O) purification to give (S) -2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (0.13g, 53%).

LCMS:r.t.＝1.225min,[M+H] ⁺ 621, purity: 96 percent

Example 12

2- (((7a,11a) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-B:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 12)

(1) Preparation of Compounds 12-7

To 13-6(190mg, 594mmol) in 10mL DMF under nitrogen and stirring at 25 ℃ was added 4- (bromomethyl) -3-fluorobenzonitrile (127.1mg, 0.594mmol), NaH (35.60mg, 0.89mmol) for 0.5 h. LCMS monitor reaction. The reaction mixture was poured into water (30mL), extracted with DCM (20mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution of EtOAc/(PE ═ 0-47%) to give the product 12-7(260mg, yield: 70%),

LCMS:r.t.＝2.109min,[M+H] ⁺ 454, purity: 98 percent of

(2) Preparation of Compounds 12-8

To a solution of 12-7(260mg, 0.57mmol) in 6mL of HCl/EA was stirred at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give 12-8(200mg) as a crude product, which was used in the next step without purification.

LCMS:r.t.＝0.88min,[M+H] ⁺ 355, purity: 88 percent

(3) Preparation of Compounds 12-9

DIEA (736.7mg, 0.57mmol) was added to a solution of 12-8(200mg, 0.57mmol) in 15mL MeCN under nitrogen at room temperature with stirring for 10 min. Then, 1-int-2(166.6mg, 5.7mmol) was added to the reaction mixture at 60 ℃ for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated to a crude product, which was further purified by elution (PE/EtOAc ═ 0-5%) to give the product 12-9(200mg, yield: 57.8%).

LCMS:r.t.＝1.553min,[M+H] ⁺ 613, purity: 98 percent of

(4) Resolution of Compounds 12-9

12-9(180mg,0.327mmoL) was further purified by the SFC method to give 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxoheterocyclohepteno [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate (80mg, SFC r.t ═ 3.376mins, yield: 88%) and 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxoheterocyclohepteno [ 4], 3-b 6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate (80mg, SFC r.t ═ 3.926mins, yield: 88%).

(5) Preparation of Compounds 12-A and 12-B

To 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate (80mg, 0.131mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (15.7mg, 0.655mmol), stirred at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxoxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (50.6mg, yield: 65%).

LCMS:r.t.＝1.242min,[M+H] ⁺ 599, 100% pure

To 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate (80mg, 0.131mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (15.7mg, 0.655mmol), stirred at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product which was further purified by preparative HPLC to give 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- (((S) -2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (45.6mg, yield: 60%).

LCMS:r.t.＝1.226min,[M+H] ⁺ 599% pure 100%

Example 13

2- (((7aS,11aS) -2- ((4- (difluoromethyl) -2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid and

2- (((7aR,11aR) -2- ((4- (difluoromethyl) -2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-B:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 13A/B)

(1) Preparation of Compound 13-1

To a solution of methyl 2-chloro-6-methoxynicotinate (2g, 10mmol, 1.0eq) in dioxane (50mL) was added 1- (tert-butyl) 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1, 3(2H) -dicarboxylate (3.67g, 10mmol, 1.0eq), K ₂ CO ₃ (2.76g, 20mmol, 2.0eq) and Pd (dppf) Cl ₂ (731mg, 1mmol, 0.1 eq). At N ₂ The mixture was stirred at 90 ℃ for 16 hours under an atmosphere. LCMS monitor reaction. The mixture was directly concentrated to give a residue, which was purified by silica gel column chromatography, eluting with (EA/P ═ 0-30%) to give product 13-1(1.1g, 27.1% yield).

LCMS:r.t.＝2.025min,[M-55] ⁺ 407, purity: 92 percent

(2) Preparation of Compound 13-2

To a solution of 13-1(0.83g, 2mmol, 1.0eq) in THF (50mL) at 0 deg.C was added LiAlH ₄ (152mg, 4mmol, 2.0eq) and the mixture was then stirred at 20 ℃ for 10 min. LCMS monitor reaction. Slowly adding H to the mixture ₂ O (0.2mL), 15% NaOH solution (0.2mL) and EtOAc (50 mL). The organic layer was washed with brine, over Na ₂ SO ₄ Drying and concentration gave product 13-2(630mg, 90% yield).

LCMS:r.t.＝1.57min,[M+H] ⁺ 351.0, purity: 90 percent of

(3) Preparation of Compound 13-3

A solution of 13-2(300mg, 0.286mmol, 1.0eq) and Pd/C (100mg) in THF (15mL) was dissolved in H ₂ (15psi) at 20 ℃ for 14 hours. LCMS monitor reaction. The resulting mixture was filtered and the filter cake was washed with THF (3X 20 mL). The filtrate was directly concentrated to give a residue which was purified by column chromatography on silica gel eluting with (PE/EA ═ 0-50%) to give the product 13-3(118mg, 40% yield).

LCMS:r.t.＝1.60min,[M+H] ⁺ 353.2, purity: 95.9 percent

(4) Preparation of Compound 13-4

To a solution of 13-3(1.2g, 3.4mmol, 1.0eq) in toluene (80mL) was added camphorsulfonic acid (3.95g, 17mmol, 5.0 eq). The mixture was stirred at 110 ℃ for 2 hours. LCMS monitor reaction. The reaction mixture was directly concentrated to give a residue which was purified by silica gel column chromatography eluting with (MeOH/DCM ═ 0-10%) to give product 13-4(700mg, 87.9% yield).

LCMS:r.t.＝1.528min,[M+H] ⁺ 235.2, purity: 86.9 percent

(5) Preparation of Compound 13-5

A solution of 3-4(0.35g, 1.5mmol, 1.0eq) in HBr (10mL) was stirred at 120 ℃ for 6 h. LCMS monitor reaction. The reaction mixture was adjusted to PH 7 with NaOH (1N) and extracted with DCM (20mL × 3). The combined organic layers were washed with Na ₂ SO ₄ Drying, filtration and concentration gave 13-5(200mg, 60.6% yield).

LCMS:r.t.＝0.385min,[M+H] ⁺ 221.1, purity：87.18％

(6) Preparation of Compound 13-6

To a solution of 13-5(200mg, 0.91mmol, 1.0eq) in DCM (10mL) was added TEA (184.2mg, 1.82mmol, 2.0eq) and Boc ₂ O (238mg, 1.1mmol, 1.2 eq). The mixture was stirred at 25 ℃ for 2 hours. LCMS monitor reaction. The mixture was concentrated directly to give a residue which was purified by silica gel column chromatography eluting with (MeOH/DCM ═ 0-10%) to give the product 13-6(190mg, 65.5% yield). LCMS r.t. ═ 1.35min, [ M + H] ⁺ 343, purity: 93.8 percent

(7) Preparation of Compounds 13-7

To 13-6(190mg, 594mmol) in 10mL DMF were added 1- (bromomethyl) -4- (difluoromethyl) -2-fluorobenzene (127.1mg, 0.594mmol), NaH (35.60mg, 0.89mmol), and the mixture was stirred under nitrogen at 25 ℃ for 0.5 h. LCMS monitor reaction. The reaction mixture was poured into water (30mL), extracted with DCM (20mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (PE/EtOAc ═ 0-47%) to give product 13-7(260mg, yield: 70%).

LCMS:r.t.＝2.323min,[M-55] ⁺ 423, purity: 99.7 percent

(8) Preparation of Compounds 13-8

13-7(260mg, 0.57mmol) was stirred in 6mL HCl/EA at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give crude 13-8(200mg), which was used in the next step without purification.

LCMS:r.t.＝0.846min,[M+H] ⁺ 376, purity: 95 percent

(9) Preparation of Compounds 13-9

DIEA (736.7mg, 0.57mmol) was added to 13-8(200mg, 0.57mmol) in 15mL MeCN under nitrogen and stirred at room temperature for 10 min. Then, 1-int-2(166.6mg, 5.7mmol) was added to the reaction mixture at 60 ℃ and mixed for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated to a crude product, which was further purified by elution (PE/EtOAc ═ 0-5%) to give the product 13-9(180mg, yield: 50.3%).

LCMS:r.t.＝0.945min,[M+H] ⁺ 637, purity: 100 percent

(10) Resolution of Compound 13-9 (to give 13-9-P1 and 13-9-P2)

A sample of 13-9(180mg, 0.27mmol) was further purified by SFC method to give 13-9-P1(60mg, SFC r.t ═ 2.176 min, yield: 67%) and 13-9-P2(60mg, SFC r.t ═ 2.68 min, yield: 67%).

(11) Preparation of Compounds 13-A and 13-B

To the solution after 13-9 resolution (60mg, 0.09mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (20mg, 0.83mmol), stirred at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give 2- (((7aS,11aS) -2- ((4- (difluoromethyl) -2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Bipyridin-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]imidazole-6-AAcid as compound 13-A (12.1mg, yield: 21.2%), and 2- (((7aR,11aR) -2- ((4- (difluoromethyl) -2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Bipyridin-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid, compound 13-B (6.6mg, yield: 11.6%).

LCMS:r.t.＝1.27min,[M+H] ⁺ 623, purity: 100 percent

Example 14

2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 14)

(1) Preparation of Compounds 14-7

To 13-6(190mg, 594mmol) in 10mL DMF under nitrogen at 25 ℃ under stirring was added 4- (bromomethyl) -3-fluorobenzonitrile (127.1mg, 0.594mmol), NaH (35.60mg, 0.89mmol) for 0.5 h. LCMS monitor reaction. The reaction mixture was poured into water (30mL), extracted with DCM (20mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (EtOAc/PE ═ 0-47%) to give 2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -carboxylate 14-7(260mg, yield: 70%).

LCMS:r.t.＝2.109min,[M+H] ⁺ 454, purity: 98 percent of

(2) Preparation of Compounds 14-8

A solution of 14-7(260mg, 0.57mmol) in 6mL HCl/EA was stirred at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give the crude product 3-fluoro-4- (((5,7,7a,8,9,10,11,11 a-octahydrooxepino [4,3-b:6,5-c' ] bipyridin-2-yl) oxy) methyl) benzonitrile 14-8(200mg) which was used in the next step without purification.

LCMS:r.t.＝0.88min,[M+H] ⁺ 355, purity: 88 percent

(3) Preparation of Compounds 14-9

DIEA (736.7mg, 0.57mmol) was added to a solution of 14-8(200mg, 0.57mmol) in 15mL of MeCN under nitrogen at room temperature with stirring for 10 min. Then, 1-int-3(166.6mg, 5.7mmol) was added to the reaction mixture at 60 ℃ for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated to a crude product which was further purified by elution (EtOAc/PE ═ 0-5%) to give 2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate 14-9(200mg, yield: 57.8%).

LCMS:r.t.＝1.553min,[M+H] ⁺ 627, purity: 98 percent of

(4) Resolution of Compounds 14-9

Further analytical purification of 14-9 by SFC method gave 14-9-P1(80mg, SFC r.t ═ 3.376min, yield: 88%) and 14-9-P2(80mg, SFC r.t ═ 3.926min, yield: 88%).

(5) Preparation of Compounds 14-A and 14-B

To methyl 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Bipyridin-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate (80mg, 0.13mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (15.7mg, 0.655mmol) while stirring at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (26.7mg, yield: 35%).

LCMS:r.t.＝1.272min,[M+H] ⁺ 614.2, purity: 93.7 percent

To methyl 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d]Imidazole-6-carboxylate (80mg, 0.13mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (15.7mg, 0.655mmol) while stirring at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product which was further purified by preparative HPLC to give 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- ((1- (fluoromethyl) cyclopropyl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (26.5mg, yield: 34.7%).

LCMS:r.t.＝1.272min,[M+H] ⁺ 614.2, purity: 98.6 percent

Example 15

2- (((7aS,11aS) -2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c '] bipyridinyl-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid and 2- (((7aR,11aR) -2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- (7H) -yl) ((S) -Oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 15A &15B)

(1) Preparation of Compounds 15-7

To 13-6(190mg, 594mmol) in 10mL DMF under nitrogen at 25 ℃ with stirring was added 1- (bromomethyl) -2-fluoro-4- (trifluoromethyl) benzene (127.1mg, 0.594mmol), NaH (35.60mg, 0.89mmol) and mixed for 0.5 h. LCMS monitor reaction. The reaction mixture was poured into water (30mL), extracted with DCM (20mL × 3), washed with brine and dried, concentrated to give the crude product, which was further purified by elution (PE/EtOAc ═ 0-47%) to give 15-7(260mg, yield: 70%).

LCMS:r.t.＝2.442min,[M+H] ⁺ 441, purity: 99.7 percent

(2) Preparation of Compounds 15-8

To a solution of 15-7(260mg, 0.57mmol) in 6mL of HCl/EA was stirred at room temperature for 30 min. LCMS monitor reaction. The reaction mixture was concentrated to give crude 15-8(200mg), which was used in the next step without purification.

LCMS:r.t.＝0.88min,[M+H] ⁺ 396, purity: 98 percent of

(3) Preparation of Compounds 15-9

DIEA (736.7mg, 0.57mmol) was added to 15-8(200mg, 0.57mmol) in 15mL of MercN under nitrogen and stirred at room temperature for 10 min. Then, 1-int-2(166.6mg, 5.7mmol) was added to the reaction mixture at 60 ℃ for 16 hours. LCMS monitor reaction. The reaction mixture was concentrated to a crude product, which was further purified by elution (PE/EtOAc ═ 0-5%) to give 15-9(180mg, yield: 50.3%).

LCMS:r.t.＝0.968min,[M+H] ⁺ 655, purity: 98.5 percent

(4) Resolution of Compounds 15-9

Further purification of 15-9 by the SFC method afforded 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydrooxepino [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -1- ((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester (60mg, SFC r.t ═ 2.176 min, yield 67%) and 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a, methyl 8,10,11,11 a-hexahydrooxepino [4,3-b:6,5-c' ] bipyridinyl-9 (7H) -yl) methyl) -1- ((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate (60mg, SFC r.t ═ 2.68 min, yield 67%).

(5) Preparation of Compounds 15-A and 15-B

To 2- (((7aS,11aS) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydrooxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- ((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (60mg, 0.09mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (22mg, 0.92mmol), stirred at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give 2- (((7aS,11aS) -2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyDioxacyclohepta [4,3-b:6,5-c']Bipyridin-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (42.3mg, yield: 72.93%).

LCMS:r.t.＝1.383min,[M+H] ⁺ 641.2, purity: 95.6 percent

To 2- (((7aR,11aR) -2- ((4-cyano-2-fluorobenzyl) oxy) -5,7a,8,10,11,11 a-hexahydrooxepino [4,3-b:6,5-c']Dipyridin-9 (7H) -yl) methyl) -1- ((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid methyl ester (60mg, 0.09mmol) in THF/H ₂ To a solution in O (5mL) was added LiOH (22mg, 0.9mmol), stirred at room temperature for 16 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated to a crude product which was further purified by preparative HPLC to give 2- (((7aR,11aR) -2- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) -5,7a,8,10,11,11 a-hexahydroxyoxepino [4,3-b:6,5-c']Bipyridin-9 (7H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (44.87mg, yield: 75.6%).

LCMS:r.t.＝1.31min,[M+H] ⁺ 641.2, purity: 100 percent

Example 16

(S) -2- ((2- ((4-cyano-2-fluorobenzyl) oxy) -5,8,10, 11-tetrahydroxepin [4,3-b:6,5-c' ] bipyridin-9 (7H) -yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [4,5-b ] pyridine-5-carboxylic acid (Compound 16)

(1) Preparation of Compounds 16-7

Int-5(0.3g, 1.2mmol) was dissolved in anhydrous DMF (5mL) and NaH (45mg, 1.44mmol) was added portionwise at 0 deg.C, after 5min a solution of 4- (bromomethyl) -3-fluorobenzonitrile (0.202g, 1.2mmol) in DMF (5mL) was added to the reaction via cannula. After 20 minutesLCMS detection reaction. The reaction mixture was quenched by the addition of water. The aqueous phase was extracted with EtOAc (20 mL. times.3) and washed with brine. The combined organic layers were washed with Na ₂ SO ₄ And (5) drying. Concentration and purification by elution (PE/EA ═ 0-20%) gave the product 16-7(0.35g, 83.3% yield).

(2) Preparation of Compounds 16-8

16-7(0.35g, 0.78mmol) was added in HCl/EA (20mL, 3M). The mixture was stirred at room temperature for 0.5 hour. The reaction was checked by LCMS. The mixture was concentrated to give the product 16-8(0.27g, 98% yield).

LCMS:r.t.＝1.31min,[M+H] ⁺ 395, purity: 95 percent

(3) Preparation of Compounds 16-9

A reaction mixture of 16-8(96mg, 0.27mmol), 1-int-2(80mg, 0.27mmol), N-diisopropylethylamine (175mg, 1.35mmol) in 5mL acetonitrile was stirred at 60 ℃ for 16 h. The reaction mixture was evaporated to dryness and the residue was purified by SGC (EA/MeOH ═ 10:1) to give compound 16-9(100mg, 60%).

LCMS:r.t.＝0.773min,[M+H] ⁺ 653, purity: 93 percent

(4) Preparation of Compound 16

Lithium hydroxide (20mg, 0.81mmol) in 1mLH at 25 deg.C ₂ The O solution was added to a reaction mixture of 16-9(100mg, 0.16mmol) in 5mL tetrahydrofuran. The mixture was stirred at 25 ℃ for 3 hours. LCMS monitor reaction. The reaction mixture was purified by pre-HPLC to give compound 9(22.45mg, 22%).

LCMS:r.t.＝1.211min,[M+H] ⁺ 640, purity: 99 percent

The GLP-1 receptor agonist and the application thereof provided by the invention are described in detail. The principles and embodiments of the present invention are explained herein using specific examples, which are presented only to assist in understanding the method and its central concept. It should be noted that it would be apparent to those skilled in the art that various changes and modifications can be made in the invention without departing from the principles of the invention, and such changes and modifications are intended to be covered by the appended claims.

Claims

1. A compound of the formula I-2,

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

W ₂ is selected from CH ₂ 、CR _y ；

Z ₁ And Z ₄ Each independently selected from CH or N;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

R ₃ independently selected from hydrogen, oxo, halogen, -CN, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy, amino, amido, sulfonyl, sulfonamido, -OH, -C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 10-membered aryl, 5-to 8-membered heteroaryl, wherein R ₃ Optionally independently selected from R under the allowed valence conditions _y The substituent group is substituted for 1 to 3 times;

R ₅ independently selected from hydrogen, halogen, hydroxy, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy, -C _3～6 Cycloalkyl, wherein said R ₅ The alkyl, alkoxy and cycloalkyl in (1) can be optionally substituted by halogen, hydroxy, -NR under the condition of valence allowing _z 、-CN、-C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 Cycloalkyl is substituted for 1-3 times;

R ₈ is independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy radical, C _3～8 Cycloalkyl, 3-to 8-membered heterocyclic group, 6-to 8-membered aryl, 5-to 8-membered heteroaryl, wherein R is ₈ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl of (a) may optionally be independently selected from R _x By substitution ofThe substituent is substituted for 1 to 3 times;

n is an integer selected from 0,1, 2 or 3;

m is an integer selected from 0,1 or 2;

o is an integer selected from 0,1, 2,3 or 4;

p is an integer selected from 0,1, 2,3 or 4;

when o is not 0 and p is not 0, any R ₄ And R ₅ Can be further cyclized into 5-8 membered rings, and the formed rings can be optionally substituted by alkyl, haloalkyl, halogen, cyano, oxo and alkoxy for 1-3 times under the condition of permission of the compound;

R _w independently selected from-CN, -CH ₂ CN、-C _1～3 Alkyl, -OH, -C _1～3 Alkoxy, amido, sulfonyl, sulfonamido, -NH ₂ 、-NH-C _1～3 Alkyl, wherein said R _w The alkyl in (A) may optionally be substituted by C under the condition of valency permitting _1～3 Alkyl radical, C _1～3 Haloalkyl, halogen, cyano, C _1～3 Alkoxy is substituted for 1 to 3 times;

2. Compounds of formula I-2 according to claim 1, wherein R is when o is not 0 and p is not 0 ₄ And R ₅ Can be further cyclized into a 5-8 membered ring; the 5-to 8-membered ring includes C _5～6 The compound is a carbocyclic ring, a 5-8-membered heterocyclic ring, a benzene ring and a 5-8-membered heteroaromatic ring, and the formed ring can be optionally substituted by alkyl, haloalkyl, halogen, cyano or alkoxy for 1-3 times under the condition allowed by the compound.

3. The compound of formula I-2 according to claim 2, which is R ₄ And R ₅ A tricyclic compound obtained by cyclization as shown in formulas I-2-A and I-2-B:

4. a compound of formula I-2 according to claim 1, which is a compound of formula I-3:

and pharmaceutically acceptable salts thereof, wherein

Represents the presence or absence of a bond;

Y ₁ selected from CH or N;

Y ₂ selected from CH, N or C;

Y ₃ selected from CH or N;

n is an integer selected from 0,1, 2 or 3;

p is an integer selected from 0,1, 2,3 or 4;

R _w selected from-CN, -CH ₂ CN、-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -OH, -C _1～3 Alkoxy, amido, sulfonyl, sulfonamido, -NH ₂ 、-NH-C _1～3 Alkyl, wherein R is _w The alkyl in (A) may optionally be substituted by C under the condition of valency permitting _1～3 Alkyl radical, C _1～3 Haloalkyl, halogen, cyano, C _1～3 Alkoxy is substituted for 1 to 3 times;

R _x selected from hydrogen, halogen, oxo, C _1～6 Alkoxy, cyano, hydroxy, carboxy, amino, amido, sulfonyl, sulfonamido, -C _1～6 Alkyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R is _x The alkyl, the alkoxy, the cycloalkyl, the heterocyclic aryl and the heteroaryl can be optionally substituted by halogen for 1-3 times under the condition of valence allowance;

R _z independently selected from hydrogen, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl, 4-6 membered heterocycle, 5-6 membered aryl or 5-6 membered heteroaryl, wherein R _z Optionally under the condition of valence allowingWith halogen, cyano, C _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

5. A compound of formula I-3 according to claim 4, which is R ₄ And R ₅ A tricyclic compound shown in formula I-3-A obtained by cyclization:

6. a compound of formula I-2 according to claim 1, when o is not 0 and p is not 0, any adjacent R ₄ And R ₅ Can be further cyclized into 5-8 membered rings, and the 5-8 membered rings can be selected from:

the resulting 5-to 8-membered ring may optionally be substituted with C under valency permitting conditions _1-3 Alkyl radical, C _1-3 Haloalkyl, halogen, cyano, oxo, C _1-3 Alkoxy is substituted for 1 to 3 times;

and/or, the 5-8 membered ring is preferably:

and the formed 5-to 8-membered ring can be selected optionally under the condition of valence allowanceGround is composed of C _1-3 Alkyl radical, C _1-3 Haloalkyl, halogen, cyano, oxo, C _1-3 Alkoxy is substituted 1-3 times.

7. A compound of formula I-2 according to claim 1, wherein n is selected from 1,2 or 3, preferably n-2; and/or, said p is selected from 0,1 or 2, preferably p ═ 1; and/or, m is selected from 0 or 1; and/or, said o is selected from 0,1 or 2.

8. A compound of formula I-2 according to claim 1, wherein Y is ₁ Is CH or N, preferably Y ₁ Is N; and/or, W ₁ Is O or NH, preferably W ₁ Is O.

9. A compound of formula I-2 according to claim 1, wherein R is ₁ Further independently selected from-F, -Cl, -CN, -OCH ₃ 、-OCH ₂ CH ₃ 、-CH ₃ 、-CH ₂ CH ₃ 、-COCH ₃ 、-CONH ₂ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CH ₂ F. -CO-cyclopropyl;

and/or, said R ₃ Can be further selected from-F, -Cl, -CH ₃ 、-OCH ₃ 、-NH ₂ 、-OH、-CH ₂ CH ₃ 、-CH ₂ OH、-NHCH ₃ 、-COCH ₃ 、-SO ₂ CH ₃ 、-OCH ₂ CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F. Isopropyl, cyclopropyl, fluorocyclopropyl;

and/or, said R ₄ Selected from-CN, -CH ₃ 、-OH、-CH ₂ OH、-CH ₂ OCH ₃ 、-OCH ₃ 、-NH ₂ 、-NHCH ₃ 、-COCH ₃ 、-OCH ₂ CH ₃ ；

And/or, said R ₆ is-COOH;

and/or, said R ₈ Is selected from-CH ₂ CH ₃ 、-CH ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F. Isopropyl, cyclopropyl.

10. A compound of formula I-2 according to claim 1, wherein R is _y Can be further selected from-F, -Cl, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, methoxy, amino, hydroxy, propyl, isopropyl, cyclopropyl, cyclobutyl;

and/or, said R _z May further be selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy,

wherein R is _z Optionally with halogen, cyano, C, under valency permitting conditions _1～3 Alkyl radical, C _1～3 Alkoxy radical, C _3～6 Cycloalkyl and 3-6 membered heterocyclic group for 1-3 times.

11. A compound of formula I-2 according to claim 1, wherein, -R ₂ Is R ₇ -R ₂ ', wherein R ₇ Selected from single bonds, -C _1～3 Alkylene, amino, amido, sulfonyl, sulfonamido; wherein, R is ₂ ' may be further selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy,

r is as described ₂ ' optionally substituted 1-3 times by halogen or optionally C under the condition of valence allowing _1～3 Alkyl radical, C _1～3 Haloalkyl, cyano, C _1～3 Alkoxy is substituted 0 to 1 times.

12. The compound of formula I-2 according to claim 1, which can be:

and pharmaceutically acceptable salts thereof.

13. The compound of formula I-2 according to claim 1, which can be:

and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 13 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

15. Use of a compound of formula I according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a GLP-1 receptor agonist mediated disease or a related disorder.

16. A method for preventing and/or treating GLP-1 mediated diseases and related diseases comprising administering to a subject a therapeutically effective amount of a compound of formula I as described in any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein said GLP-1 mediated diseases and related diseases include, but are not limited to, diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia.