CN114478497B - Arylalkyl acid GLP-1 receptor agonists and uses thereof - Google Patents

Abstract

The present invention provides a series of arylalkylacid GLP-1 receptor agonist compounds, their preparation and pharmaceutical use, which are useful for the treatment or prevention of GLP-1 mediated and related diseases.

Description

Arylalkyl acid 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 and a preparation method thereof, and application of the compound in preparing a medicament for treating or preventing GLP-1 mediated diseases and related diseases.

Background

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

The main drugs currently available for the treatment of type II diabetes are the following: insulin secretagogues, metformin, alpha-glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and the like, wherein insulin and GLP-1 receptor agonists are one of the most effective diabetes treatment drugs, insulin preparations are still the most worldwide diabetes drugs, about 30-40% of type 2 diabetics finally need insulin, GLP-1 preparations mainly comprise exenatide, liraglutide, cable Ma Lutai and the like, and are suitable for type 2 diabetics which cannot sufficiently control blood sugar by combined application of metformin, sulfonylurea and the like. However, at present, insulin preparations and GLP-1 preparations are basically polypeptide medicaments and injection preparations, and even oral administration of the somalunin has a plurality of limitations in medication, so that further development of small molecule agonist medicaments 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 without risk of hypoglycemia. GLP-1 can increase the amount of insulin produced by beta cells and improve the responsiveness of beta cells to glucose. GLP-1 can delay gastric emptying and reduce food intake, thereby having the effect of reducing weight. In addition, GLP-1 also has unique effects of benefiting heart and cerebral vessels. GLP-1 receptor agonists are located in the transitional phase between oral hypoglycemic agents and insulin for use in clinical applications and can be used in combination with other drugs, being the fastest growing hypoglycemic agent in the past five years and the most growing potential in the future.

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

GLP-1 receptor agonists are currently most commercially available in the form of injection administration as a very potential drug. The development of oral small molecule GLP-1 receptor agonists can improve patient compliance and is a development trend of future GLP-1 receptor agonists. The development progress of the currently known GLP-1 receptor agonist small molecules is as follows:

Document WO2009111700A2 discloses a series of oxadiazepine GLP-1 receptor agonist compounds; WO2010114824A1 discloses a series of GLP-1 receptor agonist compounds of substituted azo anthracene 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 ] imidazole 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 and the like which are similar to the present application. There are several similar patent applications for GLP-1 receptor agonist compounds to the compounds disclosed in WO2018109607A1, such as WO2020103815A1, WO2020207474A1, WO2021018023A1, etc.

Disclosure of Invention

The present application provides a series of compounds of formula I:

and the pharmaceutically acceptable salts thereof,

wherein:

-representing the presence or absence of a bond;

Y ₁ 、Y ₂ and Y ₃ Each independently selected from carbon or nitrogen;

R ₁ independently selected from hydrogen, oxo, halogen, -CN, -R ₂ 、-NH ₂ 、-NH-R ₂ 、-CO-R ₂ 、-CO-NH-R ₂ Wherein R is ₁ And R is ₂ Optionally selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and R _x Is substituted one or more times with substituents of (2);

R ₂ independently selected from-C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _1～6 Alkoxy, C _3～8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, wherein R ₂ Optionally selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and R _y Is substituted one or more times with substituents of (2);

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, sulfonylamino, -OH, -C _3～8 Cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-8 membered heteroaryl, wherein R ₃ Optionally, where valence permits, are independently selected from R _y Is substituted one or more times with substituents of (2);

R ₅ independently selected from hydrogen, halogen, hydroxy, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy, -C _1～3 Cycloalkyl group, which isWherein said R is ₅ The alkyl, alkoxy and cycloalkyl in (a) can be optionally substituted by halogen atoms for 1-3 times or by hydroxy groups for 1 time under the condition of valence allowed;

R ₆ selected from-R _z 、-O-R _z 、-S-R _z 、-C _1～3 Alkyl, -C _1～3 Alkylene group-R _z 、-C _0～3 alkylene-amino-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 、-C _0～3 alkylene-sulfonamide-R _z Wherein said R is ₆ Optionally substituted 1 to 3 times by halogen atoms or 1 time by cyano groups, under the conditions of valence permitting;

R ₇ selected from-C (R) _y ) _n -, wherein the-C (R _y ) _n R in _y May be attached to C in the form of a backbone and/or a branch; wherein n is an integer selected from 0,1 or 2; when n is 2, two R _y Can be further cyclized into 3-8 carbocycle or heterocycle;

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

R _y independently selected from hydrogen, halogen, oxo, -C _1～3 Alkoxy, cyano, hydroxy, amino, carboxy, amido, sulfonyl, sulfonamide, -C _1～6 Alkyl, -C _2～6 Alkenyl, -C _2～6 Alkynyl, -C _3～6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein R is _y Alkyl, alkenyl, alkynyl, amino, amido, alkoxy, cycloalkyl, heterocyclyl, heteroaryl groups optionally being substituted by C under conditions of valency permitting _1～3 Alkyl, C _1～3 Haloalkyl, halogen, cyano, oxo, C _1～3 Alkoxy is substituted for 1 to 3 times;

R _z independently selected from hydrogen, C _1～3 Alkyl, C _1～3 Alkoxy, C _3～6 Cycloalkyl, 3-6 membered heterocyclic group, aryl, 5-6 membered hetero-ringAryl, wherein R is _z Optionally under valence-allowed conditions by C _1～3 Alkyl, C _1～3 Haloalkyl, C _1～3 Cyanoalkyl, halogen, cyano, oxo, C _1～3 Alkoxy and 3-6 membered heterocyclic groups are substituted 1-3 times.

As a specific embodiment, Y ₁ Selected from N or CH.

As a specific embodiment, Y ₂ Selected from N, CH or C.

As a specific embodiment, Y ₃ Selected from N or CH.

As a specific embodiment, said R ₂ Is selected from halogen, -CN, -C _1～3 Alkyl, -C _1～3 Alkoxy or C _3～6 Cycloalkyl, wherein R is ₂ The alkyl, alkoxy and cycloalkyl groups of (2) may optionally be substituted 1 to 3 times by halogen atoms, as the valences allow.

As a specific embodiment, said R ₂ Is 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. Cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl.

As a specific embodiment, 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.

As a specific embodiment, said R ₅ Can be selected from-F, -Cl, -CN, -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ 、-CH ₂ OH, isopropyl or cyclopropyl.

As a specific embodiment of the process for the preparation of a composition,the R is ₇ Of (2) C (R) _y ) _n R in _y May be attached to C in the form of a backbone and/or a branch; when R is _y In the form of a main chain attached to R ₇ When C is on, R _y Exists in the corresponding subunit form; when R is _y Attached in branched form to R ₇ When C is on, R _y In the form of the corresponding saturated radicals.

As a specific embodiment, said R ₇ is-C (Ry) R in n _y In the case of methyl, the linkage in the form of a main chain to C means thatStructural association (i.e. R at this time ₇ is-CH ₂ -) said branched form of the bond to C means that the bond is in the form of +.>Structural association (i.e. R at this time ₇ is-CH ₃ )。

As a specific embodiment, said R ₇ Can be further selected from-CH ₂ -、-CH ₂ CH ₂ -、-CF ₂ -、-CHF-、-CH(CH ₃ )-、-CF(CH ₃ )-、-CH(CH ₂ F) -, cyclopropylene, cyclobutylene.

As a specific embodiment, said R ₇ When n in (2), 2R _y Can be further cyclized into 3-membered or 4-membered carbocycle.

As a specific embodiment, said R _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, said R _z Can be selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, R _z optionally halogen, cyano, C, where valence permits _1～3 Alkyl, C _1～3 Alkoxy, C _3～6 Cycloalkyl and 3-6 membered heterocyclic groups are substituted 1-3 times.

As a specific embodiment, the invention provides a compound of formula I, having the sub-formula shown in formula I-2:

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

and pharmaceutically acceptable salts thereof.

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

and pharmaceutically acceptable salts thereof.

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

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 dosage form.

The compounds and pharmaceutically acceptable salts thereof provided by the present invention can be formed into solid dosage forms such as capsules, tablets, pills, troches, dragees, granules, powders, ointments, creams, drops and the like; the compounds and pharmaceutically acceptable salts thereof provided herein may 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 in the pharmaceutical formulation art.

Pharmaceutically acceptable salts described herein include acid addition salts and base salts.

Pharmaceutically acceptable salts of the present invention can exist in unsolvated and solvated forms.

The invention also provides the use of a compound of formula I and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment and/or metabolism related disorders including GLP-1 mediated disorders and related disorders, 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 includes, 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 present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and pharmaceutically acceptable salts thereof, wherein the disease is GLP-1 mediated 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 includes, 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 compound shown in 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 pharmaceutically acceptable salt thereof in preparing GLP-1 receptor agonist related drugs.

In some embodiments of the invention, the GLP-1 receptor agonist related drugs are for use in the treatment of type II diabetes, type I diabetes and obesity.

The compounds described in the present invention are named according to chemical structural formulas, and if the names of the compounds do not match the chemical structural formulas when the same compounds are represented, the chemical structural formulas are used as references.

In the present invention, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are different from the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is intended.

The compounds provided herein and pharmaceutically acceptable salts thereof may exist in chiral form, i.e., in the S or R configuration. The compounds provided herein and pharmaceutically acceptable salts thereof may exist in an achiral form. The expression compounds of the invention, when exemplified in one configuration, also means that the structure of another configuration or achiral form thereof is disclosed.

The compounds of the present invention include stereoisomers of the compounds. Stereoisomers according to the present invention are enantiomers which occur when asymmetric carbon atoms are present in a compound of formula I; when the compound has a carbon-carbon double bond or a cyclic structure, a cis-trans isomer is produced; tautomers can occur when compounds exist as ketones or oximes. As a specific embodiment, stereoisomers described herein include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.

The compounds of the 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, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

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

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

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.

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

Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond->The stereogenic centre is shown in absolute configuration, but is not defined in particular as a wedge-shaped solid key +.>Or a wedge-shaped dotted key +.>By wave lines->Representing a wedge solid key +.>Or wedge-shaped dotted bondOr by wave lines->Representing a straight solid line key->Or straight dotted bond->

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

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that 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 of the drug and the like compared with the non-deuterated drug. 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 context of the present invention means 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 salt" of the present invention refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have a particular substituent found in the present invention and a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure 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 organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of 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 both.

The term "optional" or "optionally" of the 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" in the present invention means that any one or more hydrogen atoms on a particular atom are substituted with substituents, and may include deuterium and variants of hydrogen, provided that the valence 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 the aromatic group. The term "optionally substituted" means that it may or may not be substituted. The kind and number of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

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

When any variable (e.g., R) occurs more than once 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 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

When the number of one linking group is 0, such as- (CRR) ₀ -it is meant that the linking group is a single bond.

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

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

When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.

Where a bond of a substituent may be cross-linked to two or more atoms of a ring, such substituent may be bonded to any atom of the ring, e.g. a building block It means that the substituent R may be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.

When the exemplified linking groups do not indicate itThe connection direction, which is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group in which the linking rings A and B are linked in the same direction as the reading order from left to right>It is also possible to connect the ring A and the ring B in the opposite direction to the reading order from left to right>Combinations of such 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 bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bond Straight dotted line key->Or wave line->And (3) representing. For example-OCH ₃ The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group; />The straight-dashed bonds in (a) represent the two ends of the nitrogen atom in the group and other groupsAre connected; />The wavy line means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection modes, even though H atom is drawn on-N-, areStill include->The group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "5-7 membered ring" refers to a "ring" of 5-7 atoms arranged around a ring.

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

The term "C" in the present invention _1～6 Alkyl "is of the type havingStraight or branched alkyl groups of 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-, including, but 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 adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 10 membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including a benzo 3-8 membered cycloalkyl, a benzo 3-8 membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen, sulfur atoms; or further comprises a ternary nitrogen-containing fused ring containing a benzene ring.

The term "heteroaryl" according to the 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.

Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituent is 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, carboxyl or carboxylate.

The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" in the present invention are used interchangeably unless otherwise specified. The term "5-6 membered heteroaryl" means a monocyclic group of 5 to 6 ring atoms having a conjugated pi electron system, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O) _p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl, etc.

The term "alkoxy" according to the present invention refers to-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, cyclopentoxy, cyclohexyloxy. The 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, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

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 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and which 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, thiacyclohexenyl, oxacyclohexenyl, thiaoxacyclohexenyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, and the like.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl.

The term "C" according to the invention _3～8 Cycloalkyl "means a monovalent group derived from the removal of any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, i.e., a cycloalkyl of 3 to 8 carbons. Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two groups together form C _3～8 In the case of cycloalkane rings, the resulting groups may be divalent, such as cyclopropane-1, 1-diyl, cyclobutane-1, 1-diyl, cyclopentane-1, 1-diyl, cyclohexane-1, 1-diyl, cycloheptane-1, 1-diyl and cyclooctane-1, 1-diyl. Furthermore, the cycloalkyl, carbocycle, cyclic hydrocarbon in cycloalkyl may be cross-linked rings.

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 set forth below, embodiments formed by combining them with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The following examples are presented to illustrate the method and core concepts of the present invention and, as such, to those skilled in the art, any possible variations or alterations may be made without departing from the spirit of the present invention. The experimental method without specific conditions noted in the embodiments of the present invention is generally conventional conditions or conditions suggested by the manufacturer of the raw materials or goods; reagents of unspecified origin are typically conventional reagents commercially available.

Experiment 1-identification and characterization of Compounds

The 1HNMR spectra of the present invention were obtained by measurement using a Bruker instrument (400 MHz) and chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

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

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Experiment 2-in vitro Activity experiment (1) test instrument and reagent

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(2) GLP-1R kit

GLP-1R mediated agonist activity is determined by a cell-based functional assay 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 direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

The standard curve of native or unlabeled cAMP produced by the cells competes with d 2-labeled cAMP red acceptor for binding to the europium donor monoclonal anti-cAMP cryptate, and the specific signal is inversely proportional to the concentration of cAMP in the standard or experimental sample.

The human GLP-1R coding sequence (NCBI reference sequence 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 observation of GFP expression under a fluorescent microscope.

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

293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% pen-3Trep (Sangom Biotech Cat #E607011-0100) ] and in a humidified and 5% CO2 incubator at 37 ℃.

(4) cAMP level test method

Each test compound (in DMSO) was diluted 1:5 in distilled water at various concentrations in a stimulus buffer, 500. Mu.M 3-isobutyl-1-methylxanthene (IBMX; meilunit biocat #M5226) 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 (Corning 3824) using a multichannel pipette. The final DMSO concentration in the assay buffer mixture was 1%.

Cells were collected 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 μl of the cell suspension samples were counted on counter STAR IC1000 to determine cell viability and cell count per mL. The remaining cell suspension was then conditioned with stimulation buffer to deliver 2000 viable cells per well using a multichannel pipette. 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 with 5% CO2 for 30 min at 37 ℃.

After 30 minutes incubation, 5 μ l d2 labeled cAMP and 5 μ l of 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 change in HTRF signal was read with a Tecan Spark plate reader, exciting absorbance at 340 nm/emission 615nm and 665 nm. 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 (400 nM) contained on each plate. EC50 determinations were made from agonist dose-response curves analyzed using a curve fitting procedure using a 4-parameter logistic dose-response equation.

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

(5) Experimental results

Numbering of compounds	EC 50 (nM)	E max (％)
			1	13.34	114.42
3	17.45	56.33
			4	962	34.05
5	>1000	14.25
			6	141.2	61.47
7	73.69	88.10

Experiment 3- (human) liver microsomal metabolic stability

1. Experiment design: measuring the concentration: 1. Mu.M; control compound: testosterone; culture conditions: incubation was carried out for 0,5,15,30,45 min at 37 ℃; the measuring method comprises the following steps: LC-MS/MS; the calculation method comprises the following steps: t (T) _1/2 =0.693/K (K is ln [ concentration ]]Rate constant relative to incubation time), cl _int ＝(0.693/T _1/2 ) X (1/(microsomal protein concentration (0.5 mg/mL))) x scale factor.

Wherein the following table is a scale factor for the prediction of intrinsic clearance in human microsomes:

2. the experimental method comprises the following steps: (1) Preheating 0.1M K-buffer,5nM MgCl ₂ Ph=7.4; (2) Experimental solutions of test compound and reference compound, 500 μm additive solution: mu.L of 10 mM stock solution was added to 95. Mu.L of ACN, 1.5. Mu.M of 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) A stock solution of 3 XNADPH (6 mM,5 mg/mL) was prepared by subjecting NADPHDissolving in buffer solution; (4) mu.L of 1.5. Mu.M additive solution containing 0.75mg/mL microsome solution was dispensed onto assay plates designated for different time points (0, 5,15,30,45 minutes); (5) At 0 min, 150. Mu.L of IS-containing ACN was added to the wells of the plate, followed by 15. Mu.L of NADPH stock solution (6 mM, step 3); (6) all other plates were pre-incubated for 5 minutes at 37 ℃; (7) Add 15. Mu.L of NADPH stock solution to the plates to start the reaction and timing; (8) At 5,15,30 and 45 minutes, 150 μl of IS-containing ACN was added to the wells of the corresponding plate 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) 80. Mu.L of supernatant was transferred from each well to a 96-well sample plate containing 140. Mu.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, MS conditions are testosterone and positive ions ESI of the compound to be tested; tolbutamide 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: ACQUITY UPLC HSS T3 um 1.8.2.1.50 mm.

LC conditions:

4. experimental results (human microsome)

Numbering of compounds	LMS(t 1/2 min)
		1	18.15

5. Conclusion of experiment: the compound of the invention has good liver microsome stability

Preparation example

The intermediate reaction mass used in the preparation was prepared as described in reference to WO2018109607 A1.

Example 1

(S) -2- ((4- (6- ((4-acetyl-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid (Compound 1)

(1) Preparation of Compound 1-1

To a stirred solution of ethyl 2- (4-aminophenyl) acetate (2 g,5.580mmol,1.00 eq.) in AcOH (60 mL,0.500mmol,1.00 eq.) at 0deg.C was added HNO dropwise ₃ (1 mL,0.005mmol,0.50 eq.) the resulting mixture was stirred overnight at 60℃and the mixture was acidified to pH=5 with EA and H ₂ O extraction of the resulting mixture. The combined organic layers were washed with EA, dried over Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The organic phase was purified using a reverse phase column to give ethyl 2- (4-amino-3-nitrophenyl) acetate.

(2) Preparation of Compounds 1-2

To ethyl 2- (4-amino-3-nitrophenyl) acetate (338.00 mg,1.507mmol,1.00 eq.), fe (420.92 mg,7.537mmol,5.00 eq.) and Yb (OTf) ₃ (9.35 mg,0.015mmol,0.01 eq.) in AcOH (3.41 mL,56.732mmol,39.44 eq.) was added 2-chloro-1, 1-trimethyl with stirringOxyethane (1165.20 mg,7.537mmol,5.00 eq.). Nitrogen was purged 3 times. The resulting mixture was stirred at 60℃for 0.5H with DCM and H ₂ O extraction of the resulting mixture. The combined organic layers were washed with DCM and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The organic phase was purified using a reverse phase column to give 2- [2- (chloromethyl) -1H-1, 3-benzimidazol-5-yl]Ethyl acetate.

(3) Preparation of Compounds 1-3

To stirred 2- [2- (chloromethyl) -3H-1, 3-benzimidazol-5-yl at room temperature]Et is added to a solution of ethyl acetate (245.00 mg,0.970mmol,1.00 eq.) in DMF (3.00 mL) ₃ N (392.43 mg,3.878mmol,4 eq.) and 3-fluoro-4- ([ [6- (piperidin-4-yl) pyridin-2-yl)]Oxy group]Methyl) benzonitrile (362.25 mg,1.163mmol,1.20 eq). The resulting mixture was stirred overnight at 50 ℃ and the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% fa), gradient 0% to 100% in 10 min; detector, UV254nm. Thus obtaining 2- [2- [ (4- [6- [ (4-cyano-2-fluorophenyl) methoxy) ]Pyridin-2-yl]Piperidin-1-yl) methyl]-3H-1, 3-benzimidazol-5-yl]Ethyl acetate (130 mg, 25.41%), LC-MS (ES, M/z) [ M+1]] ⁺ ＝528.3。

(4) Preparation of Compounds 1-4

At room temperature, to 2- [2- [ (4- [6- [ (4-cyano-2-fluorophenyl) methoxy ] phenyl)]Pyridin-2-yl]Piperidin-1-yl) methyl]-3H-1, 3-benzimidazol-5-yl]To a stirred solution of ethyl acetate (100.00 mg,0.190mmol,1.00 eq.) in DMF (1.00 mL) was added K ₂ CO ₃ (52.39 mg,0.379mmol,2.00 eq.) and 4-methylbenzenesulfonic acid- (2S) -oxetan-2-ylmethyl ester (68.88 mg,0.284mmol,1.50 eq.). The resulting mixture was stirred at 100deg.CThe residue was purified by reverse phase flash chromatography overnight under the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% fa), gradient 0% to 100% in 10 min; detector, UV254nm. Thus obtaining 2- [2- [ (4- [6- [ (4-cyano-2-fluorophenyl) methoxy)]Pyridin-2-yl]Piperidin-1-yl) methyl]-1- [ (2S) -oxetan-2-ylmethyl]-1, 3-benzimidazol-5-yl]Ethyl acetate (70 mg, 61.79%).

(5) Preparation of Compound 1

To a stirred solution of ethyl 2- [2- [ (4- [6- [ (4-cyano-2-fluorophenyl) methoxy ] pyridin-2-yl ] piperidin-1-yl) methyl ] -1- [ (2S) -oxetan-2-ylmethyl ] -1, 3-benzimidazol-5-yl ] acetate (70.00 mg,0.117mmol,1.00 eq.) in ACN (1.00 mL,19.025mmol,162.44 eq.) was added sodium hydroxide (0.12 mL,0.240mmol,2.05 eq.) and triaza-bicyclodecene (0.23 mL,0.234mmol,2.00 eq.) in portions at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen overnight. The crude product was purified by reverse phase column chromatography (column, C18 silica gel; mobile phase, aqueous FA gradient from 10% to 90% in 10 min; detector, UV254 nm) to give [2- [ (4- [6- [ (4-cyano-2-fluorophenyl) methoxy ] pyridin-2-yl ] piperidin-1-yl) methyl ] -1[ (2S) -oxetan-2-ylmethyl ] -1, 3-benzodiazol-5-yl ] acetic acid (5.4 mg, 8%), LC-MS (ES, M/z): [ m+1] = 570.35.

Example 2 preparation of intermediates

The preparation method of the intermediate Int-2, (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester is as follows:

(1) Preparation of Compounds 1-2C

Me was added in portions to a stirred solution of t-BuOK (170 g,1520mmol,2.5 eq.) in t-BuOH (500 mL) under an argon atmosphere at 60 ℃ ₃ SO ⁺ I ^- (335 g, 460 mmol,2.5 eq.) to the mixture was added dropwise (S) -2- ((benzyloxy) methyl) oxirane 1-1C (100 g,610mmol,1.00 eq.) after 30 minutes. The resulting mixture was stirred at 60℃for a further 13 hours. The mixture was cooled to room temperature and then filtered, and the filter cake was washed with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), and with 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 (50.0 g,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 (50 g,280.9mmol,1.0 eq.) and Pd/C (20 g, wet) in THF (200 mL) was dissolved in H ₂ (4 MPa) 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-yl methanol as 1-3C (28 g, crude product) which was used directly in the next step.

(3) Preparation of Compounds 1-4C

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

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 (56 g,231mmol,1 eq) in DMF (200 mL) was added NaN ₃ (22.5 g,346.7mmol,1.5 eq). The mixture was stirred at 60℃for 12 hours. By H ₂ The mixture was diluted with O (100 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic layers were treated with Na ₂ SO ₄ Drying, filtration and concentration gave (S) -2- (azidomethyl) oxetane as 1-5C (20 g, 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 (20 g, crude product) and Pd/C (8 g) in THF (100 mL) in H ₂ (15 Psi) at 25℃for 16 hours. The resulting mixture was filtered and the filter cake was washed with THF (3X 100 mL). The filtrate was concentrated directly to give (S) -oxetan-2-ylmethylamine as 1-6C (3.8 g, 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 (3.8 g,43.6mmol,1 eq) in THF (80 mL) was added methyl 3-fluoro-4-nitrobenzoate 1-6D (8.69 g,43.6mmol,1.0 eq) and TEA (8.83 g,87.2mmol,2 eq) at 25 ℃. The mixture was stirred at 40℃for 6 hours. The mixture was concentrated to give a residue which was purified by column chromatography on silica gel eluting with (EtOAc/petroleum ether=0-80%) to give methyl (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoate as 1-7C (6.2 g,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 (S) -4-nitro-3- ((oxetan-2-ylmethyl) amino) benzoic acid methyl ester 1-7C (6.2 g,23.3mmol,1.0 eq) and Pd/C (1.0 g, wet) in MeOH (100 mL) at 25℃under H ₂ (1 atm) for 12 hours. The mixture was filtered and the filter cake was washed with MeOH (3X 20 mL). The filtrate was concentrated directly to give methyl (S) -4-amino-3- ((oxetan-2-ylmethyl) amino) benzoate as 1-8C (5.2 g,94.5% yield).

LCMS:r.t.＝1.201min,[M+1] ⁺ =237.1, purity: 89.7%.

(8) Preparation of Compound Int-2

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

(1) Preparation of Compound i-2A

To a mixture of 6-chloropyridin-2-ol i-1A (30.00 g,231.58 mmol) in DMF (200 mL) was added NaH at 0deg.C. The reaction mixture was reacted with Ar at 0 DEG C ₂ Stirring is carried out for half an hour. BnBr (43.57 g,254.74 mmol) was then added to the solution, followed by reaction with Ar at room temperature ₂ Stirred together for one hour. After completion of the reaction as determined by TLC, the reaction mixture was diluted with water (200 mL), with ethyl acetate Ethyl acetate (100 mL x 3) extraction. The combined organic layers were washed with saturated NaCl, with anhydrous Na ₂ SO ₄ Dried and filtered through a filter. The filtrate was concentrated to give a residue which was purified by column chromatography on silica gel eluting with (PE/ea=0-20%) to give 2- (benzyloxy) -6-chloropyridine as i-2A (25 g, 47.18%).

¹ H NMR(400MHz,CDCl ₃ )δ7.54–7.44(m,3H),7.40–7.30(m,3H),6.91(dd,J＝7.5,0.6Hz,1H),6.70(dd,J＝8.2,0.6Hz,1H),5.36(s,2H).

(2) Preparation of Compound i-4A

To tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate i-3A (35.19 g,113.81 mmol), 6-chloropyridin-2-ol i-2A (25.00 g,113.81 mmol) and Cs ₂ CO ₃ (55.62 g,170.71 mmol) in dioxane (200 mL) was added Pd (dppf) Cl ₂ (8.25 g,11.38 mmol). At N ₂ The reaction mixture was stirred at 100℃for 16 hours under an atmosphere. After completion of the reaction by LCMS, the mixture was concentrated to give a residue, which was purified by silica gel column chromatography eluting with (EA/pe=0-10%) to give 6- (benzyloxy) -3',6' -dihydro- [2,4' -bipyridine]-1 '(2' H) -carboxylic acid tert-butyl ester i-4A (47.00 g, 59.9%).

LCMS:r.t.＝2.368min,[M+1] ⁺ =367, purity: 75.78%.

(3) Preparation of Compound Int-3

To 6- (benzyloxy) -3',6' -dihydro- [2,4' -bipyridine]To a mixture of tert-butyl-1 '(2' H) -carboxylate i-4A (23 g,62.76 mmol) in THF (200 mL) was added Pd/C (4 g, wet). The mixture was reacted with H at room temperature ₂ Stir overnight. The reaction mixture was filtered through celite and the filter cake was purified with EA (50 mL. Times.3) washing. The combined filtrates were concentrated to give a residue, which was purified by silica gel column chromatography eluting with (MeOH/dcm=0-5%) to give tert-butyl 4- (6-hydroxypyridin-2-yl) piperidine-1-carboxylate as Int-3 (9.2 g, 53%).

LCMS:r.t.＝0.94min,[M-55] ⁺ =223, purity: 60%.

¹ H NMR(400MHz,CDCl ₃ )δ11.32(s,1H),7.38(dd,J＝9.1,6.9Hz,1H),6.42(d,J＝8.5Hz,1H),6.03(d,J＝6.8Hz,1H),4.25(s,2H),2.83(s,2H),2.61(dd,J＝13.8,10.5Hz,1H),1.92(d,J＝12.0Hz,2H),1.48(s,9H),1.25(s,2H).

Example 3

2- (2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) acetic acid (Compound 3)

(1) Preparation of Compound 3-1

To methyl 2- (4-nitro-3- ((oxetan-2-ylmethyl) amino) phenyl) acetate (270 mg,0.96 mmol) and NH ₄ In EtOH solution of Cl (216 mg,3.85 mmol): at room temperature to H ₂ To O (1:1, 2mL/2 mL) was added Fe powder (216 mg,3.85 mmol). The reaction mixture was stirred at 65℃for 2 hours. The reaction mixture was filtered through celite, and the mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with brine (10 mL), and dried over Na ₂ SO ₄ And (5) drying. The solvent was evaporated to dryness to give the product 3-1 (192 mg, crude) as a residual solid. LC-MS (ES, M/z) [ M+1 ]] ⁺ ＝251.1， ¹ H NMR(400MHz,CDCl ₃ )δ6.66(d,J＝8.2Hz,1H),6.60(d,J＝6.1Hz,2H),5.09(td,J＝10.9,6.7Hz,1H),4.73(dd,J＝14.2,7.6Hz,1H),4.60(dt,J＝9.0,6.0Hz,1H),3.67(s,3H),3.52(s,2H),3.39(dd,J＝12.8,6.2Hz,1H),3.32(dd,J＝12.8,3.8Hz,1H),2.73(ddd,J＝16.1,12.7,8.1Hz,1H),2.58(dt,J＝11.0,7.3Hz,1H).

(2) Preparation of Compound 3-2

To a solution of 3-1 (192 mg,0.76 mmol) in tetrahydrofuran (4 mL) was added 2-chloro-1, 1-trimethoxyethane (237 mg,1.53 mmol) followed by p-toluenesulfonic acid monohydrate (15 mg,0.076 mmol). The reaction mixture was heated at 45 ℃ for 16 hours, the resulting solution was extracted with ethyl acetate (10 ml x 3), the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, the solvent concentrated under reduced pressure, and the residue purified by flash column chromatography (silica gel, PE/ea=60-100% elution) to give product 3-2 (194 mg, yield 82%). LC-MS (ES, M/z) [ M+1 ] ] ⁺ ＝309.1， ¹ H NMR(400MHz,CDCl ₃ )δ7.72(d,J＝8.3Hz,1H),7.32(s,1H),7.20(dd,J＝8.3,1.3Hz,1H),5.20(ddd,J＝13.0,7.5,2.9Hz,1H),5.05–4.96(m,2H),4.64–4.47(m,3H),4.32(dt,J＝9.2,6.0Hz,1H),3.76(s,2H),3.70(s,3H),2.79–2.67(m,1H),2.42(m,7.2Hz,1H).

(3) Preparation of Compound 3-3

3-2 (44 mg,0.14 mmol), 3-fluoro-4- (((6- (piperidin-4-yl) pyridin-2-yl) oxy) methyl) benzonitrile 4-methylbenzenesulfonic acid (93 mg,0.14 mmol) and potassium carbonate (79 mg,0.57 mmol) in 1, 4-dioxane (4 ml) and CH ₃ The mixture in CN (2 ml) was stirred overnight at 60℃and then removed from the heat source, slowly diluted with water (10 ml). The resulting mixture was extracted with EtOAc (3X 10 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo silica gel chromatography (gradient: 0% to 10% MeOH/dichloromethane) to give 3-3 (47 mg, yield: 57%). LC-MS (ES, M/z) [ M+1 ]] ⁺ ＝584.1， ¹ H NMR(400MHz,DMSO)δ7.89(d,J＝10.2Hz,1H),7.70(d,J＝3.4Hz,2H),7.65(t,J＝7.8Hz,1H),7.53–7.48(m,2H),7.07(d,J＝7.4Hz,1H),6.88(d,J＝7.3Hz,1H),6.72(d,J＝8.2Hz,1H),5.47(s,2H),5.09(qd,J＝6.8,3.1Hz,1H),4.70(dd,J＝15.1,7.0Hz,1H),4.57(dd,J＝15.1,3.1Hz,1H),4.48(dd,J＝13.9,7.4Hz,1H),4.39(dt,J＝9.0,6.0Hz,1H),3.89(d,J＝13.4Hz,1H),3.76(s,2H),3.72(s,1H),3.61(s,3H),2.96(d,J＝10.7Hz,1H),2.84(d,J＝10.2Hz,1H),2.71–2.64(m,1H),2.58(dd,J＝13.2,9.7Hz,1H),2.43(dd,J＝16.9,8.2Hz,1H),2.24–2.08(m,2H),1.69(ddd,J＝24.2,18.3,7.6Hz,4H).

(4) Preparation of Compounds 3-4

A solution of 3-3 (233 mg,0.39 mmol) in 1NLiOH (2.0 mL) in THF (2 mL) was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure to give the crude product which was purified by HPLC (gradient: 10% MeCN/90% H) ₂ O，0.1％NH ₃ ·H ₂ O to 100% mecn) to give the product as compound 3 (89 mg, yield: 46%). LC-MS (ES, M/z) [ M+1 ]] ⁺ ＝570.1。

Example 4

2- (2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) propanoic acid (Compound 4)

(1) Preparation of Compound 4-2

4-1 (10 g,64.9 mmol) was added to CON.H ₂ SO ₄ (30 mL) and then CON.HNO was added at 0deg.C ₃ (4.3 mL,64.9 mmol). The mixture was stirred at 0℃for 1 hour. The reaction solution was stirred into ice water, filtered, and treated with H ₂ O (3X 20 mL) washes the filter cake. Collecting the filter cakeAnd dried in vacuo to give 7g of product 4-2. Yield: 54.2%. ¹ H NMR(400MHz,DMSO)δ12.56(s,1H),8.10(dd,J＝7.3,2.2Hz,1H),7.72(ddd,J＝8.5,4.4,2.3Hz,1H),7.54(dd,J＝11.4,8.6Hz,1H),3.76(s,2H).

(2) Preparation of Compound 4-3

4-2 (11 g,55.2 mmol) was added to MeOH (150 mL) followed by CON.H at 0deg.C ₂ SO ₄ (33 mL). The mixture was stirred at 80℃for 3 hours. Adding H ₂ O (300 mL), the reaction solution was extracted with EtOAc (3X 300 mL). The combined organic phases were washed with brine (300 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated, flash chromatography (SiO ₂ 10% EtOAc-hexane) afforded 8g of product 4-3. Yield: 68.3%. ¹ H NMR(400MHz,DMSO)δ8.12(dd,J＝7.3,2.2Hz,1H),7.74(ddd,J＝8.6,4.4,2.3Hz,1H),7.56(dd,J＝11.4,8.6Hz,1H),3.87(s,2H),3.65(s,3H).

(3) Preparation of Compounds 4-4

LiHMDS (1M in THF, 56.3mL,56.3 mmol) was added to a solution of 4-3 (8.0 g,37.5 mmol) in THF (150 mL) at-10deg.C. The mixture was stirred at-10℃for 10 min. Then CH is carried out ₃ A solution of I in THF (5.9 g,41.3 mmol) was added to the mixture. At N ₂ The mixture was stirred at room temperature for 5 hours under an atmosphere. The reaction solution was quenched with water (200 mL) and extracted with EtOAc (3X 200 mL). The combined organic phases were washed with brine (200 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated, flash chromatography (SiO ₂ 10% EtOAc-hexane) to yield 750mg of product 4-4. Yield: 8.8%. ¹ H NMR(400MHz,DMSO)δ8.00(dd,J＝7.2,2.4Hz,1H),7.68(ddd,J＝8.6,4.3,2.4Hz,1H),7.49(dd,J＝11.3,8.7Hz,1H),3.96(q,J＝7.2Hz,1H),3.53(s,3H),1.35(d,J＝7.2Hz,3H).

(4) Preparation of Compounds 4-5

To a solution of 4-4 (650 mg,2.8 mmol) in THF (15 mL) at room temperature was added TEA (870 mg,6.2 mmol). Oxetan-2-ylmethylamine (275 mg,3.1 mmol) was then added to the mixture. At N ₂ The mixture was stirred at 50℃for 16 hours. Adding H ₂ O (10 mL), the reaction solution was extracted with EtOAc (3X 10 mL). The combined organic phases were washed with brine (20 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated, flash chromatography (SiO ₂ EtOAc-hexanes) to give 350mg of product 4-5. Yield: 41.5%. ¹ H NMR(400MHz,DMSO)δ8.32(t,J＝5.7Hz,1H),7.98(d,J＝2.2Hz,1H),7.47(dd,J＝9.0,2.1Hz,1H),7.16(d,J＝9.0Hz,1H),5.04–4.91(m,1H),4.55(ddd,J＝8.4,7.4,5.9Hz,1H),4.44(dt,J＝9.1,6.0Hz,1H),3.81(q,J＝7.1Hz,1H),3.68–3.56(m,5H),2.73–2.59(m,1H),2.50–2.43(m,1H),1.38(d,J＝7.2Hz,3H).

(5) Preparation of Compounds 4-6

4-5 (350 mg,1.1 mmol) was added to EtOH (10 mL) and H2O (10 mL), followed by Fe (267 mg,4.7 mmol) and NH ₄ Cl (515 mg,9.5 mmol). At N ₂ The reaction solution was stirred under an atmosphere at 65℃for 3 hours. Adding H ₂ O (10 mL), the reaction solution was extracted with EtOAc (3X 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated. After filtration, the filtrate was concentrated to give 450mg of product 4-6. The product was used in the next step without further purification. LC-MS (ES, M/z) [ M+1 ]] ⁺ ＝265.2。

(6) Preparation of Compounds 4-7

To a solution of 4-6 (450 mg,1.1 mmol) in THF (10 mL) was added 2-chloro-1, 1-trimethoxyethane (406 mg,2.6 mmol) and TsOH H ₂ O (23 mg,0.1 mmol). At N ₂ The mixture was heated to 60 ℃ for 2 hours under an atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. Flash chromatography (SiO) ₂ 50% EtOAc-hexane) to afford 350mg of product 4-7. Yield: 91.1%. ¹ H NMR(400MHz,DMSO)δ8.94(s,1H),7.70(d,J＝8.3Hz,2H),7.51(dt,J＝21.1,5.5Hz,2H),7.40(d,J＝8.2Hz,2H),5.40(d,J＝4.5Hz,1H),4.68(q,J＝12.4Hz,2H),4.05–3.79(m,4H),3.07(ddd,J＝22.8,15.2,5.4Hz,2H),2.35(s,3H),1.28(t,J＝7.1Hz,3H),0.79(s,10H),-0.00(d,J＝2.8Hz,6H).

(7) Preparation of Compounds 4-8

To a solution of 4-7 (350 mg,1.0 mmol) in dioxane (10 mL) and MeCN (8 mL) was added 3-fluoro-4- (((6- (piperidin-4-yl) pyridin-2-yl) oxy) methyl) benzonitrile (340 mg,1.0 mmol) and K ₂ CO ₃ (300 mg,2.1 mmol). At N ₂ The mixture was heated to 65 ℃ for 16 hours under an atmosphere. Adding H ₂ O (20 mL), the reaction solution was extracted with EtOAc (3X 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na ₂ SO ₄ ) Filtration and concentration, purification by flash chromatography (SiO 2, 50% EtOAc-hexane) afforded 400mg of product 4-8. Yield: 61.6%. ¹ H NMR(400MHz,CDCl ₃ )δ7.59(s,1H),7.55(t,J＝7.5Hz,1H),7.48–7.42(m,1H),7.35(dd,J＝13.5,8.2Hz,2H),7.30(dd,J＝9.4,1.3Hz,1H),7.16(d,J＝8.3Hz,1H),6.68(d,J＝7.3Hz,1H),6.57(d,J＝8.1Hz,1H),5.43(s,2H),5.17–5.10(m,1H),4.62–4.50(m,3H),4.33(dt,J＝9.1,5.9Hz,1H),3.89–3.74(m,3H),3.58(s,3H),2.89(t,J＝12.2Hz,2H),2.69–2.59(m,1H),2.56–2.36(m,2H),2.22–2.12(m,2H),1.82–1.67(m,4H),1.48(d,J＝7.2Hz,3H).

(8) Preparation of Compound 4

To a solution of 4-8 (200 mg,0.3 mmol) in MeOH (1 mL) and THF (3 mL) was added 1MLiOH (5 mL). The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by preparative HPLC to give 54mg of compound 4.LC-MS (ES, M/z) [ M+1 ]] ⁺ ＝584.1。

Example 5

(S) -1- (2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) cyclopropane-1-carboxylic acid (Compound 5)

(1) Preparation of Compound 5-2

5-1 (5.0 g,25.8 mmol) was added to H ₂ SO ₄ (50 mL) and then HNO are added respectively ₃ (1.95 g,31.0 mmol). The reaction solution was stirred at room temperature for 2 hours, and was added dropwise to ice water. The mixture was extracted with EtOAc (3X 500 mL). By H ₂ The combined organic phases were washed with O (3X 500 mL) and brine (400 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated. Flash chromatography (SiO) ₂ 12% EtOAc-hexane) afforded 5-2 (4.65 g, 75.5%). LCMS (ESI) m/z 239.0[ M+H ]] ⁺ ， ¹ H NMR(400MHz,DMSO)δ8.09(dd,J＝7.2,2.3Hz,1H),7.82(ddd,J＝8.6,4.3,2.4Hz,1H),7.55(dd,J＝11.2,8.7Hz,1H),3.57(s,3H),1.54(q,J＝4.2Hz,2H),1.31(q,J＝4.2Hz,2H).

(2) Preparation of Compound 5-3

5-2 (1.45 g,6.1 mmol) and oxetan-2-ylmethylamine (1.1 g,12.2 mmol) were added to solvent MeCN (20 mL), et3N (3.1 g,30.5 mmol) was added and the reaction stirred at room temperature for 16 h, and the mixture was extracted with EtOAc (3X 50 mL). By H ₂ The combined organic phases were washed with O (3X 50 mL) and brine (40 mL), dried (Na ₂ SO ₄ ) Filtered and concentrated. Flash chromatography (SiO) ₂ Treatment with 10% EtOAc-hexane afforded 5-3 (375 mg, 20.2%). LCMS (ESI) m/z 306.0[ M+H] ⁺

(3) Preparation of Compounds 5-4

Mixture 5-3 (375 mg,1.23 mmol) and NH ₄ Cl (326 mg,6.15 mmol) was added to EtOH (10 mL) and H ₂ To O (2 mL) was then added Fe (690 mg,12.3 mmol). The reaction solution was filtered. The filtrate was extracted with ethyl acetate (3X 30 mL) and the combined organic phases were washed with brine (50 mL), dried (Na ₂ SO ₄ ) Filtration and concentration gave 5-4 (330 mg, 97.6%). LCMS (ESI) m/z 276.0[ M+H ]] ⁺

(4) Preparation of Compounds 5-5

5-4 (330 mg,1.24 mmol) was added to solvent THF (10 ml), trimethoxymethyl hypochlorite (234 mg,1.5 mmol) and 4-methylbenzenesulfonic acid (640 mg,3.72 mmol) were added. The reaction was stirred at 45℃for 16 h, quenched with ice water (30 ml) at 0℃and extracted with ethyl acetate (30 ml No. 3), combined with the organic phase and quenched with NaHCO ₃ (aqueous solution) and brine (30 ml) washing in Na ₂ SO ₄ The mixture was dried and concentrated to give 7-5 (265 mg, 66.3%). LCMS (ESI) m/z 334.0[ M+H] ⁺

(5) Preparation of Compounds 5-6

To a solution of 5-5 (265 mg,0.79 mmol) in dioxane/MeCN (2/1, 10 mL) was added 3-fluoro-4- (((6- (piperidin-4-yl) pyridin-2-yl) oxy) methyl) benzonitrile (300 mg,0.96 mmol), K ₂ CO ₃ (552 mg,4 mmol) and the mixture was stirred at 60℃for 16 h, after the reaction was completed, most of the solvent was removed under reduced pressure, the mixture was poured into water, extracted with EtOAc (3X 30 mL), washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, evaporation of the solvent and purification of the residue by flash column chromatography (silica gel, PE/ea=0% -20% > elution) gave 5-6 (440 mg, 91.1%). LCMS (ESI) m/z 609[ M+H ] ] ⁺

(6) Preparation of Compound 5

A solution of 5-6 (260 mg,0.43 mmol), liOH (51.6 mg,2.15 mmol) in THF (5 mL) and MeOH (5 mL) was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure to give the crude product which was purified by HPLC (gradient: 10% MeCN/90% H) ₂ O，0.1％NH ₃ ·H ₂ O to 100% mecn) to give the product as compound 5.LCMS (ESI) m/z 596[ M+H ]] ⁺

Example 6

2- (2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) acetic acid (Compound 6)

(1) Preparation of Compound 6-2

To DIPA (381 mg,8.23 mmol) at-30℃TTo a solution of HF (10 ml) was added n-BuLi (1.6M, 5.2ml,8.23 mmol) over 15 minutes. The mixture was cooled to-30℃and a solution of 6-1 (2 g,8.23 mmol) in THF (5 ml) was added over 25 minutes. After 10 minutes, a solution of 2, 6-dichloropyridine (1.2 g,8.23 mmol) in THF (5 ml) was added over 2 minutes. The mixture was warmed to 25 ℃ for 2.5 hours and the reaction mixture quenched with saturated aqueous ammonium chloride. NH (NH) ₄ Cl (50 ml) was extracted with EtOAc (3X 20 ml). The organic layer was concentrated under reduced pressure to give product 6-2 (2.7 g, yield: 92.8%). LCMS (ESI) m/z 299.1[ M+H ]] ⁺

(2) Preparation of Compound 6-3

To a solution of 6-2 (2.7 g,7.63 mmol) in MeOH (30 ml) was added 4M NaOH (5 ml,15.26 mmol) over 5 minutes. The mixture was stirred at 50 ℃ for 0.5 hours and the resulting mixture was concentrated under reduced pressure. Dissolved in water and pH adjusted to 4 with citric acid. Filtration and recrystallization from n-hexane gave the product 6-3 (2.5 g, yield: 96.2%). LCMS (ESI) m/z 285.1[ M+H ] ] ⁺

(3) Preparation of Compounds 6-4

A solution of 6-3 (2.5 g,7.4 mmol) in DCE (20 ml) was stirred at 85℃for 16 hours and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using PE: EA (10:1) gave 6-4 (1.4 g, yield: 64.2%). LCMS (ESI) m/z 241.1[ M+H ]] ⁺ ， ¹ H NMR(400MHz,CDCl ₃ )δ7.59(t,J＝7.8Hz,1H),7.17(d,J＝7.9Hz,1H),7.07(d,J＝7.6Hz,1H),4.40–4.12(m,2H),2.92–2.73(m,3H),1.92(d,J＝13.5Hz,2H),1.69(dd,J＝12.7,4.3Hz,2H),1.47(s,9H).

(4) Preparation of Compounds 6-5

To a solution of methyl 2- (4-fluoro-3-nitrophenyl) acetate (5.27 g,24.72 mmol) in MeCN (50 mL) under nitrogen were added oxetan-2-ylmethylamine (2.4 g,27.19 mmol) and TEA (5.5 g,54.38 mmol), and the mixture was stirred at 50℃for 16 hours, after completion of the reaction, the solvent was removed under reduced pressure. The mixture was then poured into water, extracted with EtOAc (3×300 mL), washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, evaporation of the solvent and purification of the residue by SGC gave product 6-5 (4.4 g, 64%). LCMS (ESI) m/z 281.0[ M+H ]] ⁺ ， ¹ H NMR(400MHz,DMSO)δ8.31(s,1H),8.00(d,J＝2.0Hz,1H),7.44(dd,J＝8.9,2.0Hz,1H),7.14(d,J＝8.9Hz,1H),4.94-5.01(m,1H),4.52-4.58(m,1H),4.41-4.47(m,1H),3.56-3.69(m,2H),3.61(s,3H),3.66(s,2H),2.75–2.60(m,1H),2.49–2.41(m,1H).

(5) Preparation of Compounds 6-6

To a solution of 6-5 (146 mg,0.52 mmol) in EtOH/H2O (2/1, 4.0 mL) was added Fe (116 mg,2.08 mmol), NH ₄ Cl (222 mg,4.16 mmol) and the mixture was stirred at 65℃for 1 h. After completion of the reaction, fe was filtered and the solvent was removed under reduced pressure, then extracted with EA and water, washed with brine, and dried over Na ₂ SO ₄ The crude product was purified by SGC, dried, filtered, and the solvent was distilled off to afford product 6-6 (113 mg, 87%). LCMS (ESI) m/z 251.0[ M+H ] ] ⁺ ， ¹ H NMR(400MHz,DMSO)δ6.45(s,1H),6.38(q,J＝8.0Hz,2H),4.94–4.84(m,1H),4.53(dd,J＝14.7,7.2Hz,3H),4.49–4.38(m,2H),3.56(d,J＝1.9Hz,3H),3.37(s,2H),3.24(dd,J＝18.8,9.2Hz,2H),2.69–2.58(m,1H),2.48–2.37(m,1H).

(6) Preparation of Compounds 6-7

To 6-6 (100 mg,0.40 mmol)To a solution of THF (4.0 mL) was added 2-chloro-1, 1-trimethoxyethane (136 mg,0.88 mmol) and p-toluenesulfonic acid monohydrate (8 mg,0.04 mmol), and the mixture was stirred at 45℃for 16 hours, after completion of the reaction, the solvent was removed under reduced pressure, extracted with EA and water, washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, evaporation of the solvent and purification of the crude product by SGC gave product 6-7 (87 mg, 71%).

(7) Preparation of Compounds 6-8

To a solution of 6-7 (24.0 g,80.9 mmol) in dioxane (240 mL) and water (50 mL) was added Pd ₂ (dba) ₃ (7.4 g,8.1 mmol), t-Buxphos (3.9 g,8.1 mmol), KOH (9.1 g,161.8 mmol) and the mixture was stirred at 105℃for 2 hours, after which the solvent was removed under reduced pressure, extracted with EA/H2O, washed with brine, and dried over Na ₂ SO ₄ Drying, filtration and evaporation of the solvent purified the crude product by SGC (DCM: meOH=20:1) to give 6-8 (22.0 g, yield: 97%). LCMS (ESI) m/z 223.0[ M+H ]] ⁺¹ ，H NMR(400MHz,DMSO)δ11.50(s,1H),7.42–7.23(m,1H),6.14(d,J＝8.9Hz,1H),5.98(s,1H),4.04(d,J＝12.3Hz,2H),2.84–2.52(m,3H),1.78(d,J＝12.3Hz,2H),1.52–1.43(m,2H),1.40(s,9H).

(8) Preparation of Compounds 6-9

To a solution of 6-8 (1.0 g,3.60 mmol) in anhydrous toluene (15 mL) under nitrogen was added 1- (bromomethyl) -4-chloro-2-fluorobenzene (965 mg,4.32 mmol), ag ₂ CO ₃ (1.1 g,3.96 mmol) was protected from light by a tin foil, and after the reaction was completed, the mixture was stirred at 110℃for 1 hour, filtered through EA and the solvent was removed under reduced pressure. Then extracted with EA and water, washed with brine, na ₂ SO ₄ Drying, filtering, distilling off the solvent, and purifying the crude product by SGCThe reaction mixture was converted to 6-9 (1.41 g, yield 93%). LCMS (ESI) m/z 421.0[ M+H ]] ⁺¹ ， ¹ H NMR(400MHz,DMSO)δ7.64(dd,J＝8.1,7.4Hz,1H),7.55(t,J＝8.2Hz,1H),7.44(dd,J＝10.0,2.0Hz,1H),7.29(dd,J＝8.2,1.8Hz,1H),6.87(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),5.36(s,2H),4.10–3.98(m,2H),2.90–2.70(m,3H),1.77(d,J＝10.8Hz,2H),1.55(qd,J＝12.5,4.2Hz,2H),1.42(s,9H).

(9) Preparation of Compounds 6-10

To a solution of 6-9 (1.41 g,3.35 mmol) in EtOAc (20 mL) was added 4-methylbenzenesulfonic acid (1.6 g,8.38 mmol), and the mixture was heated to 60℃and stirred for 1 hour, then cooled to room temperature and stirred overnight. After completion of the reaction, filtration with EA gave 6-10 (2.0 g, yield 90%). ¹ H NMR(400MHz,DMSO)δ7.64(t,J＝7.8Hz,1H),7.58(t,J＝8.2Hz,1H),7.53–7.39(m,1H),7.31(dd,J＝8.2,1.6Hz,1H),6.85(d,J＝7.3Hz,1H),6.68(d,J＝8.2Hz,1H),5.38(s,2H),3.08(d,J＝12.1Hz,2H),2.76–2.57(m,3H),2.29(s,1H),1.77(d,J＝11.0Hz,2H),1.62(qd,J＝12.4,3.9Hz,2H).

(10) Preparation of Compounds 6-11

To 6-10 (211 mg,0.68 mmol) and 2- (2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ]]To a solution of methyl imidazol-5-yl) acetate (Int 2) (452 mg,0.68 mmol) in dioxane/MeCN (2/1, 15 mL) was added K ₂ CO ₃ (376 mg,2.72 mmol) the mixture was stirred at 60℃for 16 hours, after the reaction was complete, extracted with EA and water, washed with brine, and dried over Na ₂ SO ₄ The above was dried, filtered, and the solvent was distilled off, and the crude product was purified by SGC to give 6-11 (375 mg, yield 93%). ¹ H NMR(400MHz,DMSO)δ7.67–7.59(m,1H),7.56(t,J＝8.0Hz,2H),7.46(dd,J＝9.4,2.6Hz,2H),7.29(dd,J＝8.3,2.1Hz,1H),7.11(dd,J＝8.3,1.5Hz,1H),6.87(d,J＝7.3Hz,1H),6.67(d,J＝8.2Hz,1H),5.37(s,2H),5.10(dd,J＝7.2,2.9Hz,1H),4.70(dd,J＝15.2,7.1Hz,1H),4.58(dd,J＝15.0,3.1Hz,1H),4.47(dd,J＝14.4,6.9Hz,1H),4.39(dt,J＝9.0,6.0Hz,1H),3.90(d,J＝13.4Hz,1H),3.79–3.69(m,3H),3.60(s,3H),2.98(d,J＝10.2Hz,1H),2.85(d,J＝11.7Hz,1H),2.75–2.53(m,2H),2.43(dd,J＝19.0,8.2Hz,1H),2.26–2.10(m,2H),1.84–1.60(m,4H).

(11) Preparation of Compound 6

To a solution of 6-11 (375 mg,0.63 mmol) in THF/MeOH (1/1, 8.0 mL) was added LiOH (3.2 mL,1.0M aqueous solution), the mixture was stirred at room temperature for 1h, after completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified by HPLC to give the title compound 6 (207 mg, yield 57%).

Example 7

2- (2- (((R) -4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) -2-methylpiperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) acetic acid (Compound 7)

(1) Preparation of Compound 7-2

NaH (1.0 g,42.9 mmol) was slowly added to a stirred solution of 2, 6-dichloropyridine (5.3 g,35.8 mmol) and 3-fluoro-4- (hydroxymethyl) benzonitrile (5.4 g,35.8 mmol) in anhydrous DMF (50 mL) at 0deg.C under nitrogen atmosphere, the mixture was stirred at the same temperature for 3 hours, after completion of the reaction, extracted with EA and water, the combined organic layers were washed with brine and Na ₂ SO ₄ Drying, filtering and evaporating the solvent, passing the crude product through SGC purification gave product 7-2 (2.1 g, 22% yield). LCMS (ESI) m/z 263.1[ M+H ]] ⁺

(2) Preparation of Compound 7-3

To a solution of 7-2 (300 mg,1.14 mmol) in anhydrous toluene (10 mL) under nitrogen was added tert-butyl (S) -2-methylpiperazine-1-carboxylate (571 mg,2.85 mmol), pd ₂ (dba) ₃ (55mg，0.06mmol)、BINAP(71mg，0.11mmol)、Cs ₂ CO ₃ (1.1 g,3.42 mmol) and the mixture was stirred at 100deg.C for 16 hours. Then extracted with EA and water and washed with brine, washed with Na ₂ SO ₄ The solvent was dried, filtered, and distilled off, and the crude product was purified by SGC to give product 7-3 (369 mg, yield 76%). LCMS (ESI) m/z 427.1[ M+H ] ] ⁺

(3) Preparation of Compound 7-4

To a solution of 7-3 (146 mg,0.34 mmol) in EA (4.0 mL) was added 4-methylbenzenesulfonic acid hydrate (323 mg,1.70 mmol), and the mixture was heated to 60℃and stirred for 1 hour, then cooled to room temperature and stirred overnight. After completion of the reaction, filtration with EA gave product 7-4 (135 mg, yield 59%). LCMS (ESI) m/z 327.1[ M+H ]] ⁺

(4) Preparation of Compounds 7-5

To a solution of 7-4 (200 mg,0.65 mmol) and 6-7 (436 mg,0.65 mmol) in dioxane/MeCN (2/1, 15 mL) was added K ₂ CO ₃ (319 mg,2.60 mmol) the mixture was stirred at 60℃for 16 hours, after which the solvent was removed under reduced pressure, extracted with EA and water, washed with brine, and Na ₂ SO ₄ The crude product was purified by SGC to give product 7-5 (282 mg, crude product). LCMS (ESI) m/z 599.2[ M+H ]] ⁺

(5) Preparation of Compound 7

To a solution of 7-5 (282 mg,0.47 mmol) in THF/MeOH (1/1, 8.0 mL) was added LiOH (2.4 mL,1.0M aqueous solution), the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the solvent was removed under reduced pressure, and the crude product was purified by HPLC to give compound 7 (42 mg, yield 15%). LCMS (ESI) m/z 585.4[ M+H ]] ⁺

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 have been described herein with reference to specific examples, the description of which is intended only to aid in the understanding of the method of the present invention and its central ideas. It should be noted that it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the principles of the invention, which also falls within the scope of the appended claims.

Claims (7)

1. The compound of the formula I-2,

and the pharmaceutically acceptable salts thereof,

wherein:

R ₁ independently selected from-F, -CN, -Cl, -CH ₃ ；

R ₅ Selected from-H, -F or-CH ₃ ；

R ₇ Selected from-CH ₂ -、-CH(CH ₃ )-、-CF ₂ -、-CH ₂ CH ₂ -or-CHF-;

Y ₂ is N or CH;

p is 2.

2. A compound of formula I-2 according to claim 1, which is independently selected from the following compounds:

and pharmaceutically acceptable salts thereof.

3. A compound of formula I-2 according to claim 1, which is independently selected from the following compounds:

and pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition comprising a compound of formula I-2 as defined in any one of claims 1 to 3 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

5. Use of a compound of formula I-2 according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of GLP-1 receptor agonist mediated or related diseases.

6. The use according to claim 5 for the manufacture of a medicament for the treatment of GLP-1 receptor agonist mediated diseases or related diseases, 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.

7. A process for the preparation of the GLP-1 receptor agonist compound (S) -2- ((4- (6- ((4-acetyl-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylic acid, which is prepared according to the following route,