Benzimidazolone glp-1 receptor agonists and uses thereof

Abstract

A benzimidazolone GLP-1 receptor agonist compound, its pharmaceutical use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to GLP-1 receptor agonist compounds and their preparation methods, as well as the use of said compounds in the preparation of medicaments for treating or preventing GLP-1-mediated diseases and related diseases. Background Technology

[0002] Diabetes mellitus is a chronic, complex disease primarily characterized by disordered glucose metabolism, caused by absolute or relative insulin deficiency or decreased sensitivity of target cells to insulin. It is classified into type 1 and type 2 diabetes mellitus. Type 2 diabetes is adult-onset diabetes, an endocrine disorder primarily characterized by chronic hyperglycemia caused by insulin resistance and / or insulin secretion defects. Type 2 diabetes accounts for more than 90% of all diabetes cases. According to the global diabetes atlas, there were approximately 425 million people with diabetes worldwide in 2017, with China having the largest number at approximately 114.4 million. It is projected that by 2045, there will be 629 million people with diabetes globally. Clearly, diabetes is a very prevalent chronic disease worldwide.

[0003] Currently, the main classes of drugs available for treating type 2 diabetes include: 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 analogues. Among these, insulin and GLP-1 receptor agonists are among the most effective diabetes treatments. Insulin remains the most widely used diabetes medication globally, with approximately 30-40% of type 2 diabetes patients eventually requiring insulin. GLP-1 inhibitors, such as exenatide, liraglutide, and semaglutide, are suitable for type 2 diabetes patients whose blood sugar cannot be adequately controlled by combined use of metformin, sulfonylureas, and other antibiotics. However, current insulin and GLP-1 inhibitors are primarily peptide drugs and injectable formulations. Even oral semaglutide has several limitations in its use. Therefore, further development of small molecule GLP-1 receptor agonists is still necessary.

[0004] GLP-1 stimulates insulin secretion in a glucose-dependent manner and inhibits glucagon secretion in a glucose-dependent manner, thus posing no risk of hypoglycemia. GLP-1 increases the amount of insulin produced by β-cells, enhancing their responsiveness to glucose. GLP-1 can delay gastric emptying, reducing food intake and thus contributing to weight loss. Furthermore, GLP-1 offers unique cardiovascular benefits. In clinical applications, GLP-1 receptor agonists are positioned as a transitional drug between oral hypoglycemic agents and insulin, and can be used in combination with other medications. They have become the fastest-growing hypoglycemic drug in the past five years and are considered to have the greatest growth potential in the future.

[0005] Other conditions associated with type 2 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, and hypertension.

[0006] GLP-1 receptor agonists are highly promising drugs, but most currently available medications are administered via injection. Developing oral small-molecule GLP-1 receptor agonists could improve patient compliance and represents a future trend in GLP-1 receptor agonist development. The known progress in the development of small-molecule GLP-1 receptor agonists is as follows:

[0007] Documents WO2009111700A2 disclose a series of oxadiazathane GLP-1 receptor agonist compounds; WO2010114824A1 discloses a series of substituted azoanthracene derivative GLP-1 receptor agonist compounds; WO2017078352A1 discloses a series of cyclohexene derivative GLP-1 receptor agonist compounds; KR1020180101671A discloses a series of heteroaryl-substituted pyridine [1,2-a] pizimidazole derivative GLP-1 receptor agonist compounds; WO2018056453A1 discloses a series of pyrazolopyridine derivative GLP-1 receptor agonist compounds; and WO2018109607A1 discloses a series of GLP-1 receptor agonist compounds similar to those in this application. In relation to the compound disclosed in WO2018109607A1, there are several other patent applications for GLP-1 receptor agonist compounds that are similar to it, such as WO2020103815A1, WO2020207474A1, and WO2021018023A1. Summary of the Invention

[0008] This invention provides a series of compounds as shown in Formula I:

[0009]

[0010] and its pharmaceutically acceptable salts,

[0011] in:

[0012] X is selected from carbonyl, methyloxyphosphoryl, and sulfonyl groups;

[0013] W1 is selected from O, S, CR y NR z ;

[0014] W2 is selected from O, NH, CH2, and CR. y ;

[0015] Z1, Z2, Z3, and Z4 are each independently selected from C, CH, or N;

[0016] Ring A is selected from aromatic rings or 5- to 6-membered heteroaromatic rings;

[0017] Ring B is selected from aromatic rings or 5- to 6-membered heteroaromatic rings;

[0018] Ring C is selected from aromatic rings, 4-8 membered heterocyclic rings, 7-10 membered spirocyclic rings, 7-10 membered bridged rings, 7-10 membered fused rings and 5-7 membered heteroaromatic rings;

[0019] R1 is selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～8 Cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, -NH2, -NH-C 1～6 Alkyl, -N-(C 1～6 Alkyl)2、-NH-C 1～6 Alkoxy, -NH-C 1～6 Cycloalkoxy, -NH-C 2～6 alkenyl, -NH-C 2～6 Alkyne group, -NH-C 3～8 Cycloalkyl, -NH-3 to -8-membered heterocyclic, -NH-6 to -8-membered aryl, -NH-5 to -8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic, aryl, or heteroaryl group in R1 may optionally be selected independently from R x The substituents are substituted 1 to 3 times;

[0020] R2 is independently selected from hydrogen, oxo, halogen, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, -C 1～6 Cycloalkoxy, -CN, 3-8 membered heterocyclic, aryl, 5-8 membered heteroaryl, or -CO-R1, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, heterocyclic, aryl, or heteroaryl group in R2 may optionally be selected independently from R1. x The substituents are substituted 1 to 3 times;

[0021] R3 is independently selected from hydrogen, oxo, halogen, -CN, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, amino, amide, sulfonyl, sulfonamide, -OH, -C 3～8Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-8 membered heteroaryl, wherein R3 may be optionally selected independently from R, provided that the valence allows. y The substituents are substituted 1 to 3 times;

[0022] R4 is independently selected from hydrogen, halogen, and -C. 1～3 Alkyl, -C 1～3 Haloalkyl, -C 1～3 Alkoxy, cyano, hydroxyl, amino, amide, sulfonyl, sulfonamide;

[0023] R5 is independently selected from hydrogen, halogen, hydroxyl, -CN, and -C. 1～3 Alkyl, -C 1～3 Alkoxy, -C 1～3 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group in R5 may optionally be substituted 1 to 3 times with a halogen atom or 1 time with a hydroxyl group, provided that the valence allows.

[0024] R6 is selected from -R z -OR z -SR z -C 1～3 Alkyl, -C 1～3 Alkylene-R z -C 0～3 alkylene-amino-R z -C 0～3 alkylene-carbonyl-R z -C 0～3 alkylene-amide-R z -C 0～3 alkylene-sulfonyl-R z -C 0～3 alkylene-phosphoryl-R z -C 0～3 alkylene-sulfonamide-R z The alkyl, amino, sulfonyl, and sulfonamide groups in R6 may optionally be substituted 1 to 3 times by a halogen atom, or by R6, provided that the valence allows. w Replace 1 time;

[0025] n is an integer selected from 0, 1, 2 or 3;

[0026] m is an integer selected from 0, 1, or 2;

[0027] o is an integer selected from 0, 1, 2, 3 or 4;

[0028] p is an integer selected from 0, 1, 2, 3 or 4;

[0029] When m is 2, the two R3s can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

[0030] When n is 1 or 2 and m is 1 or 2, R2 and R3 can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

[0031] When p is greater than or equal to 2, any two R5s can be further cyclized with ring C to form 7-10 spirocyclic, fused, or bridged rings. The resulting spirocyclic, fused, and bridged rings can be optionally substituted 1 to 3 times with alkyl, haloalkyl, halogen, cyano, or alkoxy groups, provided that the valence allows.

[0032] When o is not 0 and p is not 0, any R4 and R5 can be further cyclically transformed into 5- to 8-membered rings. The resulting rings can be arbitrarily composed of C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0033] R w Independently selected from -CN, -CH2CN, -C 1～3 Alkyl, -OH, -C 1～3 Alkoxy, amide, sulfonyl, sulfonamide, -NH2, -NH-C 1～3 Alkyl, wherein the R w The alkyl group in the compound may optionally be converted from C1 to C2, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0034] R x Independently selected from hydrogen, halogen, oxo, C 1～6 Alkoxy, cyano, hydroxy, carboxyl, amino, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in the compound may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 The alkoxy group is substituted 1 to 3 times or optionally substituted once with a hydroxyl group;

[0035] R y Independently selected from hydrogen, halogen, oxo, -C 1～3 Alkoxy, cyano, hydroxy, amino, carboxyl, amide, sulfonyl, sulfonamide, -C1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, wherein R y Alkyl, alkenyl, alkynyl, amino, amide, alkoxy, cycloalkyl, heterocyclic, and heteroaryl groups may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0036] R z Independently selected from hydrogen, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl, wherein R z Subject to the allowable valence, C can be arbitrarily selected. 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Cyanoalkyl, halogen, cyano, oxo, C 1～3 The alkoxy group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0037] As one specific implementation scheme, ring A can be selected from:

[0038]

[0039] As a specific implementation scheme, ring A is preferably:

[0040] As one specific implementation scheme, ring B can be selected from:

[0041]

[0042] As a specific implementation scheme, ring B is preferably:

[0043] As one specific implementation scheme, the ring C can be selected from:

[0044]

[0045] As a specific implementation scheme, the ring C is preferably:

[0046] Furthermore, the present invention provides a series of compounds as shown in Formulas I-2.

[0047]

[0048] and its pharmaceutically acceptable salts,

[0049] in:

[0050] X is selected from carbonyl, methyloxyphosphoryl, and sulfonyl groups;

[0051] ------ indicates whether the key exists or does not exist;

[0052] W1 is selected from CH2, O, or NH;

[0053] Y1 is selected from CH or N;

[0054] Y2 is selected from CH, N, or C;

[0055] Y3 is selected from CH or N;

[0056] Z1, Z2, and Z3 are each independently selected from CH or N;

[0057] R1 is selected from -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～8 Cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, -NH2, -NH-C 1～6 Alkyl, -N-(C 1～6 Alkyl)2、-NH-C 1～6 Alkoxy, -NH-C 1～6 Cycloalkoxy, -NH-C 2～6 alkenyl, -NH-C 2～6 Alkyne group, -NH-C 3～8 Cycloalkyl, -NH-3 to -8-membered heterocyclic, -NH-6 to -8-membered aryl, -NH-5 to -8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic, aryl, or heteroaryl group in R1 may optionally be selected independently from R x The substituents are substituted 1 to 3 times;

[0058] R2 is independently selected from hydrogen, oxo, halogen, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, -C 1～6 Cycloalkoxy, -CN, 3-8 membered heterocyclic, aryl, 5-8 membered heteroaryl, or -CO-R1, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, heterocyclic, aryl, or heteroaryl group in R2 may optionally be selected independently from R1. x The substituents are substituted 1 to 3 times;

[0059] R4 is independently selected from hydrogen, halogen, and -C. 1～3 Alkyl, -C 1～3 Haloalkyl, -C 1～3 Alkoxy, cyano, hydroxyl, amino, amide, sulfonyl, sulfonamide;

[0060] R5 is independently selected from hydrogen, halogen, hydroxyl, -CN, and -C. 1～3 Alkyl, -C 1～3 Alkoxy, -C 1～3 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group in R5 may optionally be substituted by a halogen atom 1 to 3 times, provided that the valence allows;

[0061] R6 is selected from -R z -OR z -SR z -C 1～3 Alkyl, -C 1～3 Alkylene-R z -C 0～3 alkylene-amino-R z -C 0～3 alkylene-carbonyl-R z -C 0～3 alkylene-amide-R z -C 0～3 alkylene-sulfonyl-R z -C 0～3 alkylene-phosphoryl-R z -C 0～3 alkylene-sulfonamide-R z The alkyl, amino, sulfonyl, and sulfonamide groups in R6 may optionally be substituted 1 to 3 times by a halogen atom, or by R6, provided that the valence allows. w Replace 1 time;

[0062] n is an integer selected from 0, 1, 2 or 3;

[0063] o is an integer selected from 0, 1, 2, 3 or 4;

[0064] p is an integer selected from 0, 1, 2, 3 or 4;

[0065] When p is greater than or equal to 2, any two R5s can be further cyclized with ring C to form 7-10 spirocyclic, fused, or bridged rings. The resulting spirocyclic, fused, or bridged rings can be optionally substituted 1 to 3 times with alkyl, haloalkyl, cyanoalkyl, halogen, cyano, or alkoxy groups, provided that the valence allows.

[0066] When o is not 0 and p is not 0, any R4 and R5 can be further cyclically transformed into 5- to 8-membered rings. The resulting rings can be arbitrarily composed of C, provided that the valence allows.1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0067] R w Independently selected from -CN, -CH2CN, -C 1～3 Alkyl, -OH, -C 1～3 Alkoxy, amide, sulfonyl, sulfonamide, -NH2, -NH-C 1～3 Alkyl, wherein the R w The alkyl group in the compound may optionally be converted from C1 to C2, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0068] R x Independently selected from hydrogen, halogen, oxo, C 1～6 Alkoxy, cyano, hydroxy, carboxyl, amino, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0069] R y Independently selected from hydrogen, halogen, oxo, -C 1～3 Alkoxy, cyano, hydroxy, amino, carboxyl, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, wherein R y Alkyl, alkenyl, alkynyl, amino, amide, alkoxy, cycloalkyl, heterocyclic, and heteroaryl groups may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0070] R z Independently selected from hydrogen, C1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl, wherein R z Subject to the allowable valence, C can be arbitrarily selected. 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Cyanoalkyl, halogen, cyano, oxo, C 1～3 The alkoxy group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0071] As one specific implementation, X is selected from carbonyl, methylphosphoryl, or sulfonyl, preferably carbonyl.

[0072] As a specific implementation scheme, W1 is selected from O or NH, with O being the preferred choice.

[0073] As a specific implementation scheme, W2 is selected from CH2 or O, preferably CH2.

[0074] As a specific implementation scheme, Z1 and Z2 are each independently preferred to be CH.

[0075] As one specific embodiment, the compound of formula I described in this invention has the following sub-general formulas I-3 and I-3':

[0076]

[0077] As one specific implementation, R1 can be selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)CH3, piperidine, pyridine, pyrimidine, hexahydropyridine, pyrrole, pyrazole, and imidazole, wherein R1 can optionally be composed of halogen or C 1～3 Alkyl substitution 1 to 3 times.

[0078] As one specific implementation scheme, R2 can be selected from halogen, -CN, or -C. 1～3 Alkyl, -C 1～3 Alkoxy or C 3～6 Cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl groups in R2 may optionally be substituted 1 to 3 times by a halogen atom, provided that the valence allows.

[0079] As one specific implementation scheme, R2 can be selected from -F, -Cl, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -COCH3, -CONH2, -CF3, -CHF2, -CH2F, -CH2CH2F, cyclopropyl, cyclobutyl, -O-cyclopropyl, and -O-cyclobutyl.

[0080] As one specific implementation scheme, R3 can be selected from -F, -Cl, -CH3, -OCH3, -NH2, -OH, -CH2CH3, -CH2OH, -NHCH3, -COCH3, -SO2CH3, -OCH2CH3, -CF3, -CHF2, -CH2F, isopropyl, cyclopropyl, and fluorocyclopropyl.

[0081] As one specific implementation, R5 can be selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CF3, -CH2OH, isopropyl, or cyclopropyl.

[0082] As a specific implementation scheme, the R mentioned z Optional from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy R z Halogen, cyano, or C can be used arbitrarily, provided the oxidation state allows. 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 The cycloalkyl group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0083] As a specific implementation plan, n is 1 or 2.

[0084] As a specific implementation scheme, m is 0 or 1.

[0085] As a specific implementation scheme, o is 0 or 1.

[0086] As a specific implementation scheme, p is 0 or 1.

[0087] As one specific embodiment, the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] And its pharmaceutically acceptable salts.

[0094] The compounds provided by this invention and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in treatment.

[0095] The present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.

[0096] The present invention also provides a pharmaceutical preparation comprising a compound of formula I and a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers; the pharmaceutical preparation is any clinically acceptable dosage form.

[0097] The compounds and pharmaceutically acceptable salts provided by this invention can be formed into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated preparations, granules, powders, ointments, creams, drops, etc.; the compounds and pharmaceutically acceptable salts provided by this invention can be formed into liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, suspensions, solutions, sprays, etc.

[0098] The pharmaceutical carriers and / or pharmaceutical diluents used in the pharmaceutical compositions or pharmaceutical formulations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical formulations.

[0099] The pharmaceutically acceptable salts described in this invention include acid addition salts and base salts.

[0100] The pharmaceutically acceptable salts described in this invention can exist in both non-solventized and solvated forms.

[0101] The present invention also provides the use of compounds of Formula I and pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or metabolic-related diseases, wherein the metabolic-related diseases include 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, etc.; wherein the diabetes includes, but is not limited to, type 1 diabetes and / or type 2 diabetes mellitus (T1D) and / or type 2 diabetes mellitus (T2DM), idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes, etc.

[0102] The present invention also provides a method for treating a disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound as shown in Formula I and a pharmaceutically acceptable salt thereof, wherein the disease is a GLP-1 mediated disease or related disease; the disease includes, but is not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, etc.; wherein the diabetes includes, but is not limited to, type 1 diabetes and / or type 2 diabetes mellitus (T1D) and / or type 2 diabetes mellitus (T2DM), idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes, etc.

[0103] The compounds of Formula I and their pharmaceutically acceptable salts provided by this invention have excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1 mediated diseases and related diseases.

[0104] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of GLP-1 receptor agonist-related drugs.

[0105] In some embodiments of the present invention, the GLP-1 receptor agonist-related drugs are used to treat type II diabetes, type I diabetes, and obesity.

[0106] The compounds described in this invention are named according to their chemical structural formulas. If the name of the compound does not match the chemical structural formula when referring to the same compound, the chemical structural formula shall prevail.

[0107] Unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0108] The compounds and pharmaceutically acceptable salts provided by this invention may exist in chiral forms, i.e., S-configuration or R-configuration. The compounds and pharmaceutically acceptable salts provided by this invention may also exist in achiral forms. When the compounds described in this invention are illustrated with one configuration, it also indicates the disclosure of another configuration or achiral form.

[0109] The compounds described in this invention include stereoisomers of the compounds. The stereoisomers described in this invention refer to the following: when a compound as shown in Formula I contains an asymmetric carbon atom, it produces an enantiomer; when the compound contains a carbon-carbon double bond or a cyclic structure, it produces a cis-trans isomer; when the compound contains a ketone or oxime, it produces a tautomer. As a specific embodiment, the stereoisomers described in this invention include, but are not limited to: enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0110] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this 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 this invention.

[0111] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0112] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0113] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0114] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0115] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key This indicates that the center of the solid is an absolute configuration, but it is uncertain whether it is a wedge-shaped solid line key. or wedge-shaped dashed key Use wavy lines Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0116] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, 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 desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amine) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to form carbamates).

[0117] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0118] The term "pharmaceutically acceptable" in this invention means that, with respect to those compounds, materials, compositions and / or dosage forms, they are suitable for use in contact with human and animal tissues, within the limits of reliable medical judgment, without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0119] The term "pharmaceutically acceptable salt" in this invention refers to a salt of a compound of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When a compound of this invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When a compound of this invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0120] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0121] The term "optional" or "optionally" in this invention refers to an event or condition that may, but is not required, to occur as described below, and the description includes both cases where said event or condition occurs and cases where said event or condition does not occur.

[0122] The term "substituted" in this invention means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state 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 replaced. 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 type and number of substituents can be arbitrary on a chemically feasible basis.

[0123] The term "optionally replaced" in this invention refers to both "replaced" and "not replaced" scenarios.

[0124] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0125] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0126] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0127] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0128] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0129] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, a structural unit. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0130] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0131] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0132] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0133] In this invention, the term "halogen atom" refers to fluorine, chlorine, bromine, iodine, etc. Preferably, the halogen atom used as a substituent in the aryl group of this invention is a fluorine or chlorine atom. Preferably, the halogen atom used as a substituent in the alkyl group of this invention is a fluorine or chlorine atom. C having a halogen atom as a 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, 5,5-difluoropentyl, 6-chlorohexyl, and 6,6,6-trifluorohexyl.

[0134] The term "C" in this invention 1～6"Alkyl" refers to a straight-chain or branched 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, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0135] The term "C" in this invention 1～6 "Alkoxy" refers to the carbon group. 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, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, and 2-ethylbutoxy.

[0136] In this invention, the term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a three-membered nitrogen-containing fused ring containing a benzene ring.

[0137] The term "heteroaryl" in this invention refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0138]

[0139] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0140] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" in this invention are used interchangeably. The term "5-6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are 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 (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0141] The term "alkoxy" in this invention refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. 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, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester groups.

[0142] The term "halogenated alkyl" in this invention refers to an alkyl group that has been substituted with one or more halogens.

[0143] The term "3- to 8-membered heterocyclic group" in this invention refers to a non-aromatic cyclic group comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and may be fully saturated or partially unsaturated. The ring may be a 3- to 8-membered monocyclic, bicyclic, or spirocyclic group. Examples include, but are not limited to, oxacyclobutane, aziranebutane, piperazine, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, thiohexane, oxacyclohexane, thiazoxane, dihydroindolyl, isodihydroindolyl, tetrahydrodihydroindolyl, quininecycloyl, and azirzoyl.

[0144] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0145] The term "C" in this invention 3～8 "Cycloalkyl" refers to 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 with 3 to 8 carbons. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two groups together form a C12 group... 3～8 When cycloalkyl groups are formed, the resulting group can 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 cycloalkane ring, carbide ring, and cyclohydrocarbon in cycloalkyl groups can be cross-linked rings.

[0146] The term "fused ring" in this 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, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Fused rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, fused rings can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. These include, but are not limited to:

[0147] The carbon atom in a fused ring can be optionally replaced by a heteroatom of O, S, or N, which also includes "fused heterocycles".

[0148] The term "fused heterocycle" in 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 rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, and wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O).t (Where t is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. The fused heterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, the fused heterocycle can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycle groups, preferably bicyclic or tricyclic, more preferably 5-membered / 3-membered, 5-membered / 4-membered, or 5-membered / 5-membered bicyclic fused heterocycle groups. Fused heterocycles include, but are not limited to:

[0149] The term "bridged ring" in this invention refers to a 5- to 20-membered all-carbon polycyclic group, wherein any two rings share two non-directly connected carbon atoms. The bridged ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Bridged rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Bridged rings include, but are not limited to:

[0150]

[0151] The carbon atom in the bridged ring can be optionally replaced by heteroatoms of O, S, or N, which also includes "bridged heterocycles".

[0152] The term "bridged heterocycle" in this invention refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. The bridged heterocycle may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. The bridging heterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, bridging heterocycles can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocycles, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Bridging heterocycles include, but are not limited to:

[0153]

[0154] The term "spirocyclic" in this invention refers to a 5- to 20-membered polycyclic group, wherein the monocyclic rings share a carbon atom (called a spiro atom), and the spirocyclic ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spirocyclic rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Spirocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups according to the number of shared spiro atoms between the rings, preferably monospirocyclic alkyl groups and bispirocyclic alkyl groups. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic alkyl groups are included, but are not limited to:

[0155] The carbon atom in a spiroring can be optionally replaced by heteroatoms of O, S, or N, which also includes "spiroheterorings".

[0156] In this invention, the term "spiroheterocycle" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein the monocyclic rings share a common atom (called a spiro atom), and one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Spiroheterocyclic rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic rings are preferably 6 to 14-membered, more preferably 7 to 10-membered. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiroatoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups are preferred. These include, but are not limited to:

[0157] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Detailed Implementation

[0158] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are used to understand the method and core idea of ​​the present invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention. Experimental methods in the embodiments of the present invention that do not specify specific conditions are generally under conventional conditions or according to the conditions recommended by the raw material or product manufacturer; reagents whose source is not specified are generally commercially available conventional reagents.

[0159] Experiment 1 - Compound Identification and Characterization

[0160] The 1H NMR spectra of this invention were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. A tetramethylsilane internal standard (0.00 ppm) was used. 1H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If coupling constants are provided, their units are Hz.

[0161] The mass spectrometry of this invention is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] Experiment 2 - In vitro activity test

[0174] (1) Testing instruments and reagents

[0175] Reagents / Instruments supplier model cAMP-GSDYNAMIC kit CisBio 62AM4PEC DMEM CellMax CGN101.5 FBS Gemini 900-108 1% Pen-3trep Sangom biotech E607011-0100 IBMX Meilunbio MB5226 384-hole plate Corning 3824 Incubator Thermo 3111 microscope Jiangnan XD-202 Cell counter Counter Star Star IC1000 board reader Tecan Tecan Spark Fume Hood ESCO AC2-6S1

[0176] (2) GLP-1R kit

[0177] GLP-1R-mediated agonist activity was determined using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit via a cell-based functional assay that measures cAMP levels in cells. This method is a competitive immunoassay. It enables the direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

[0178] The standard curve of naturally produced cAMP or unlabeled cAMP produced by cells competes with the red cAMP receptor labeled with d2 for binding to the monoclonal anti-cAMP cavitary compound europium donor. The specific signal is inversely proportional to the concentration of cAMP in the standard or experimental sample.

[0179] 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. The expression density of GLP-1R was confirmed by observing GFP expression under a fluorescence microscope.

[0180] (3) GLP-1R-GFP-293A cell culture

[0181] 293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), and 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100) and in a humidified incubator at 37°C with 5% CO2.

[0182] (4) cAMP level testing method

[0183] Different concentrations of each analyte (in DMSO) were diluted 1:5 in distilled water with stimulation buffer. 500 μM of 3-isobutyl-1-methylxanthin (IBMX; Meilunbiocat#MB5226) was added to obtain a 2X working solution. Then, 5 μL 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‰.

[0184] Cells were collected from T25 tissue culture flasks and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 mL of stimulation buffer. A 20 μL sample of cell suspension was counted using a STAR IC1000 counter to determine cell viability and cell count per mL. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 live cells per well using a multichannel pipette. 5 μL of cell suspension was added to each well of an assay plate already containing the compound. The plate was sealed and incubated at 37°C with 5% CO2 for 30 minutes.

[0185] After a 30-minute incubation, 5 μl of d2-labeled cAMP and 5 μl of anti-cAMP cavitation compound (both diluted 1:20 in cell lysis buffer) were added to each well of the assay plate. The plate was then incubated at room temperature, and after 60 minutes, changes in the HTRF signal were read using a Tecan Spark plate reader, measuring absorbance at 340 nm excitation and 615 nm emission. The raw data were converted to nM cAMP by interpolation from the cAMP standard curve, and the percentage effect was determined relative to the saturation concentration of the full agonist GLP-17-37 (400 nM) contained on each plate. EC50 assays were performed from agonist dose-response curves, which were analyzed using a curve fitting procedure with a 4-parameter logical dose-response equation.

[0186] This experiment demonstrates that the compound of the present invention activates GLP-1R signaling via the cAMP pathway, thus acting as a GLP-1R agonist. Experimental data are presented as the geometric mean (EC50s) based on the number of repetitions listed.

[0187] (5) Experimental Results

[0188]

[0189]

[0190] Experiment 3 - Inhibition of hERG potassium ion channels

[0191] 1. Experimental materials: Stable cell line HEK-hERG, strain: HEK 293, source: Academy of Military Medical Sciences;

[0192]

[0193] 2. Electrophysiological solutions

[0194] Extracellular fluid (mM): 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 145 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 10 glucose. Adjust the pH to 7.3–7.4 with sodium hydroxide; adjust the osmotic pressure to 290–310 mOsm; filter and store at 4°C.

[0195] Electrode internal solution (mM): KCl 120, KOH 31.25, CaCl2 5.374, MgCl2 1.75, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 10, HEPES 10, Na2-ATP 4, pH adjusted to 7.2-7.3 with potassium hydroxide; osmotic pressure adjusted to 290-310 mOsm; filtered and dispensed, stored at -20℃.

[0196] 3. Positive control compound:

[0197] Positive control: Amitriptyline hydrochloride or terfenadine

[0198] Source: Sigma-Aldrich

[0199] 4. Preparation of drug delivery formulations

[0200] Solvent control preparation: Add a certain volume of DMSO to the extracellular fluid to make it contain the same amount of DMSO as the final test solution (if the test solution contains different amounts of DMSO, the maximum DMSO content shall prevail) to eliminate the interference of DMSO on the cell's own current.

[0201] Preparation of test sample: Prepare the above 10mM stock solution into DMSO stock solution of the required concentration according to the ratio (generally 1000 / 3 times the actual drug concentration). Finally, dilute the stock solution with extracellular fluid to the drug concentration required for the experiment.

[0202] Preparation of positive control solution: Weigh an appropriate amount of positive control sample and place it in a suitable container. Add a certain volume of DMSO and stir or shake thoroughly to dissolve it completely. Prepare a 10mM stock solution. Then prepare the stock solution of the required concentration according to the ratio. Finally, dilute the stock solution with extracellular fluid to the required drug concentration for the experiment.

[0203] Before using the working concentration solution, check for any precipitation. If precipitation occurs, dilute the stock solution to increase the final DMSO concentration in the extracellular fluid, but the final DMSO concentration in the extracellular fluid should not exceed 0.5%. Continuous perfusion from low to high concentrations is used in the experiment. After the experiment, any remaining test sample and positive control solutions are disposed of as waste.

[0204] 5. Experimental Design

[0205] Cell preparation:

[0206] After passage and culture HEK-293-hERG cells to a suitable state, wash the cells with PBS (or DPBS), digest and separate them with Tryple solution, resuspend the cells in culture medium, and store them in centrifuge tubes. After centrifugation, discard the supernatant, resuspend the cells in extracellular fluid, and store at 2-8°C. Before patch-clamp recording, add cells to a culture dish to ensure a certain cell density and that the cells are individually separated.

[0207] Concentration settings:

[0208] Test sample / positive control Concentration (μM) Compounds of the present invention 1、10 Amitriptyline or Terfenadine 1

[0209] Electrophysiological experiments:

[0210] hERG currents were recorded using whole-cell patch-clamp technique. Cell suspension was added to a small culture dish and placed on the stage of an inverted microscope. After cell attachment, the cells were perfused with extracellular fluid at a recommended flow rate of 1–2 mL / min. The glass microelectrode was fabricated in two steps using a microelectrode drawing instrument; after filling with electrode fluid, its water resistance was 2–5 MΩ.

[0211] After establishing the whole-cell recording mode, the clamping potential was maintained at -80 mV. A depolarization voltage of +60 mV was applied for 850 ms, followed by repolarization to -50 mV for 1275 ms to extract the hERG tail current. This pulse program was repeated every 15 seconds throughout the experiment.

[0212] After the current stabilizes, a continuous extracellular perfusion administration method is adopted, starting from low concentrations and gradually increasing to high concentrations. Perfusion is continued from a low concentration until the efficacy stabilizes, and then the next concentration is applied. This experiment will test the blocking effect of each test sample and the positive control on the hERG tail current (N≥2); the specific actual concentration can be adjusted according to the actual solubility and effect, and this is not considered a deviation from the protocol.

[0213] The definition of stable efficacy is: if the change in current value of the last 5 stimulation strips in each concentration administration phase is less than 10% of the mean (when the current is greater than or equal to 200 pA) or less than 30% of the mean (when the current is less than 200 pA), it can be considered stable. If it is unstable, the concentration data will not be used.

[0214] 6. Data Analysis

[0215] In data processing, when determining the blocking effect on hERG, the peak value of the tail current and its baseline were corrected. The effect of each compound at different concentrations was expressed as the tail current inhibition rate (IR). A SD ≤ 15 for the %IR at all cell concentrations was considered acceptable (except for outlier data).

[0216] IR = 100% × (peak tail current before administration - peak tail current after administration) / peak tail current before administration.

[0217] 7. Experimental Results

[0218]

[0219] 8. Experimental conclusion: The compounds of this invention did not show hERG inhibitory activity.

[0220] Experiment 4 - (Human) Liver Microsomal Metabolic Stability

[0221] 1. Experimental Design: Concentration to be measured: 1 μM; Control compound: Testosterone; Culture conditions: Incubated at 37℃ for 0, 5, 15, 30, and 45 minutes; Measurement method: LC-MS / MS; Calculation method: T 1 / 2 = 0.693 / K (K is the rate constant of ln[concentration] versus incubation time), Cl int =(0.693 / T) 1 / 2 )×(1 / (microsomal protein concentration (0.5mg / mL)))×proportional factor.

[0222] The following table shows the scaling factors for predicting intrinsic clearance in human microsomes:

[0223]

[0224] 2. Experimental methods: (1) Preheat 0.1M K-buffer, 5nM MgCl2, pH=7.4; (2) Experimental solutions for test compounds and reference compounds, 500μM additive solution: add 5μL of 10 mM stock solution to 95μL In ACN, the doping solution in 1.5 μM microsomes (0.75 mg / mL): 1.5 μL of 500 μM doping solution and 18.75 μL of 20 Mg / mL liver microsomes were added to 479.75 μL of K / Mg buffer; (3) 3× NADPH stock solution (6 mM, 5 mg / mL) was prepared by dissolving NADPH in buffer; (4) 30 μL of 1.5 μM doping solution containing 0.75 mg / mL microsomes was dispensed into the assay plates designated for different time points (0, 5, 15, 30, 45 minutes); (5) at 0 minutes, 150 μL of ACN containing IS was added to the well of the plate, followed by 15 μL of NADPH stock solution (6 mM, step 3); (6) all other plates were pre-incubated at 37°C for 5 minutes; (7) 15 μL of NADPH stock solution was added to the plate. (8) Start the reaction and start timing with NADPH stock solution; (9) At 5, 15, 30 and 45 minutes, add 150 μL of ACN containing IS to the wells of the corresponding plate to terminate the reaction; (10) After quenching, shake the plate on a shaker for 10 minutes (600 rpm / min) and then centrifuge at 6000 rpm for 15 minutes; (11) Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of water for LC / MS analysis.

[0225] 3. Analysis Methods:

[0226] Detection method: LC-MS / MS-11(8050), internal standard: tolbutamide, MS conditions: testosterone and analyte positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA in water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.

[0227] LC conditions:

[0228]

[0229] 4. Experimental Results (Human Microsomes)

[0230]

[0231]

[0232] 5. Experimental Conclusion: The compound of this invention exhibits good stability in liver microsomes.

[0233] Experiment 5 - Caco-2 cell transport experiment

[0234] 1. Experimental materials:

[0235] Caco-2 cells, passage 77; HBSS, Lot: G210713; ACN+IS (tolbutamide 200 ng / mL);

[0236] 2. Cell culture:

[0237] Caco-2 was distributed at a concentration of 2 × 10⁵ cells / cm². 2 Inoculate onto polyethylene (PET) membranes in 96-well Falcon plates until a confluent cell monolayer forms after 21–28 days. Change the culture medium every 3–4 days.

[0238] 3. Experimental Design:

[0239] The test compound was diluted to 10 μM with 10 mM stock solution in transport buffer (HBSS without BSA) and applied to the apical or basal side of a cell monolayer. Incubation was performed at 37°C and 5% CO2 for 120 min at 95% relative humidity. The permeation of the test compound from A to B or B to A was measured in duplicate. The elution ratio of each compound was also determined. Based on the analyte / IS peak area ratio, the test and reference compounds were quantified by LC-MS / MS analysis.

[0240] 4. Experimental measurements:

[0241] The apparent permeability coefficient Papp (cm / s) is calculated using the following equation:

[0242] Papp=(dCr / dt)x Vr / (A×C0),

[0243] Where dCr / dt is the cumulative concentration of the compound in the acceptor chamber, which is a function of time (s), Vr is the solution volume in the receiver chamber (0.1 mL on the top side and 0.25 mL on the bottom side), A is the surface area used for transport, i.e., 0.0804 cm2 is the area of ​​the monolayer, and C0 is the initial concentration in the donor chamber.

[0244] The outflow ratio is calculated using the following formula:

[0245] Outflow ratio = Papp(BA) / Papp(AB);

[0246] The recovery percentage is calculated using the following equation:

[0247] % recovery = 100 × [(Vr × Cr) + (Vd × Cd)] / (Vd × C0)

[0248] Total recovery % = 100 × [(Vr × Cr) + (Vd × Cd) + (Vc × Cc)] / (Vd × C0),

[0249] Where Vd is the volume in the donor chamber (0.1 mL on the top side and 0.25 mL on the bottom side), Cd and Cr are the final concentrations of the transported compounds in the donor and recipient 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).

[0250] 5. LC / MS conditions:

[0251] Detection methods: LC-MS / MS-20 (TQ-6500+) & LC-MS / MS-11 (8050), internal standard: tolbutamide, MS conditions: atenolol and propranolol and the cation ESI of the compounds, digoxin anion ESI; mobile phase: mobile phase A is 0.1% FA in water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.

[0252] LC conditions:

[0253]

[0254] 6. Experimental Results:

[0255] Compound numbering AB / BA / Outflow Ratio 7 2.76 / 21.65 / 7.85 12 1.10 / 20.91 / 18.97 20 1.60 / 11.12 / 6.96

[0256] 7. Experimental Conclusion:

[0257] The compounds of this invention are well absorbed in the intestine.

[0258] Preparation Examples

[0259] The intermediate reactants used in the preparation process were prepared according to the preparation method described in WO2018109607A1.

[0260] intermediate preparation method

[0261] The preparation method of intermediate Int-1,(4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorophenyl)(cyclopropyl)methyl ketone is as follows:

[0262]

[0263] Under nitrogen atmosphere, at room temperature and with stirring, NaH (463.2 mg, 11.58 mmol) was added to 30 mL of a DMF solution of 6-chloropyridin-2-ol (1.0 g, 7.72 mmol) for 30 min. Then, (4-(bromomethyl)-3-fluorophenyl)(cyclopropyl) methyl ketone (1.976 g, 7.72 mmol) was added to the reaction mixture at room temperature for 30 min. LC-MS analysis was performed. The reaction mixture was poured into water (20 mL), extracted with EtOAc (5 mL × 3), washed with brine, dried, and concentrated to give a crude product, which was further purified (PE / EtOAc = 0-47%) to give (4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorophenyl)(cyclopropyl) methyl ketone, Int-1 (1.4 g, 60.9% yield).

[0264] LCMS: rt = 2.03 min, [M+H] + =306

[0265] The preparation method of intermediate Int-2,(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester is as follows:

[0266]

[0267] (1) Preparation of compound 1-2C

[0268]

[0269] Me3SO4 was added in portions to a stirred solution of t-BuOK (170 g, 1520 mmol, 2.5 equivalents) in t-BuOH (500 mL) at 60 °C under an argon atmosphere. + I - (335 g, 1520 mmol, 2.5 equivalents), after 30 minutes, (S)-2-((benzyloxy)methyl)ethylene oxide 1-1C (100 g, 610 mmol, 1.00 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at 60 °C for another 13 hours.

[0270] The mixture was cooled to room temperature and then filtered. The filter cake was washed with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography by elution with PE / EtOAc (10:1) to give (S)-2-((benzyloxy)methyl)oxetine, 1-2C (50.0 g, 46% yield).

[0271] 1H 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).

[0272] (2) Preparation of compounds 1-3C

[0273]

[0274] A solution of (S)-2-((benzyloxy)methyl)oxetane 1-2C (50 g, 280.9 mmol, 1.0 equivalent) and Pd / C (20 g, wet) in THF (200 mL) was stirred at 50 °C for 16 hours under H2 (4 MPa). The mixture was cooled to room temperature and then filtered, with the filter cake washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give (S)-oxetane-2-ylmethanol, 1-3C (28 g, crude product), which was used directly in the next step.

[0275] (3) Preparation of compounds 1-4C

[0276]

[0277] At 25 °C, TsCl (66.6 g, 349.6 mmol, 1.1 eq) and TEA (48.2 g, 476.7 mmol, 1.5 eq) were added to a THF (200 mL) solution of (S)-oxetane-2-ylmethanol 1-3C (28 g, 317.8 mmol, 1 eq). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel, eluting with (EA / PE = 0-10%) to give (S)-oxetane-2-ylmethyl 4-methylbenzenesulfonate, 1-4C (56 g, 72.7% yield), as a colorless oil.

[0278] 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),4.6 8–4.38(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).

[0279] (4) Preparation of compounds 1-5C

[0280]

[0281] To a DMF (200 mL) solution of (S)-oxetane-2-ylmethyl-4-methylbenzenesulfonate 1-4C (56 g, 231 mmol, 1 eq), NaN3 (22.5 g, 346.7 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C for 12 hours. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give (S)-2-(azidomethyl)oxetane, 1-5C (20 g, crude product), which was used directly in the next step.

[0282] (5) Preparation of compounds 1-6C

[0283]

[0284] A solution of (S)-2-(azidomethyl)oxetane 1-5C (20 g, crude product) and Pd / C (8 g) in THF (100 mL) was stirred at 25 °C for 16 hours under H2 (15 Psi). The resulting mixture was filtered, and the filter cake was washed with THF (3 × 100 mL). The filtrate was directly concentrated to give (S)-oxetane-2-ylmethylamine, 1-6C (3.8 g, crude product).

[0285] 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).

[0286] (6) Preparation of compounds 1-7C

[0287]

[0288] At 25 °C, methyl 3-fluoro-4-nitrobenzoate 1-6D (8.69 g, 43.6 mmol, 1.0 eq) and TEA (8.83 g, 87.2 mmol, 2 eq) were added to a THF (80 mL) solution of (S)-oxetane-2-ylmethylamine 1-6C (3.8 g, 43.6 mmol, 1 eq). The mixture was stirred at 40 °C for 6 hours. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography by elution with (EtOAc / petroleum ether = 0-80%) to give methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate, 1-7C (6.2 g, 53.4% ​​yield).

[0289] 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), 5.1 6(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).

[0290] (7) Preparation of compounds 1-8C

[0291]

[0292] A solution of methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate 1-7C (6.2 g, 23.3 mmol, 1.0 eq) and Pd / C (1.0 g, wet) in MeOH (100 mL) was stirred at 25 °C under H2 (1 atm) for 12 hours. The mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was directly concentrated to give methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate 1-8C (5.2 g, 94.5% yield).

[0293] LCMS: rt = 1.201 min, [M+1] + =237.1, purity: 89.7%.

[0294] (8) Preparation of compound Int-2

[0295]

[0296] Add 2-chloro-1,1,1-trimethoxyethane 1-8D (0.98 g, 6.35 mmol, 1.5 eq) and TsOH·H₂O (0.08 g, 0.423 mmol, 0.1 eq) to a THF (20 mL) solution of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate 1-8C (1.0 g, 4.23 mmol, 1 eq). Stir the mixture at 50 °C for 8 hours. Dilute the mixture with saturated sodium bicarbonate solution. Extract with NaHCO₃ (20 mL) and EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain the residue, which was purified by silica gel column chromatography and eluted with (EtOAc / petroleum ether = 0-80%) to give (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, Int-2 (1.1 g, 88% yield).

[0297] 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).

[0298] The preparation method of the intermediate Int-3,4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester is as follows:

[0299]

[0300] (1) Preparation of compound i-2A

[0301]

[0302] NaH was added to a mixture of 6-chloropyridin-2-ol i-1A (30.00 g, 231.58 mmol) and DMF (200 mL) at 0 °C. The reaction mixture was stirred with Ar2 at 0 °C for half an hour. Then BnBr (43.57 g, 254.74 mmol) was added to the above solution, and the mixture was stirred with Ar2 at room temperature for one hour. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated NaCl, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with (PE / EA = 0-20%) to give 2-(benzyloxy)-6-chloropyridine, i-2A (25 g, 47.18%).

[0303] 1 H NMR (400MHz, CDCl3) 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).

[0304] (2) Preparation of compound i-4A

[0305]

[0306] Pd(dppf)Cl2 (8.25 g, 11.38 mmol) was added to a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate i-3A (35.19 g, 113.81 mmol), 6-chloropyridine-2-ol i-2A (25.00 g, 113.81 mmol), and Cs2CO3 (55.62 g, 170.71 mmol) in dioxane (200 mL). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was confirmed by LCMS, the mixture was concentrated to obtain the residue, which was purified by silica gel column chromatography and eluted with (EA / PE = 0-10%) to give tert-butyl 6-(benzyloxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid, i-4A (47.00 g, 59.9%).

[0307] LCMS: rt = 2.368 min, [M+1] + =367, purity: 75.78%.

[0308] (3) Preparation of compound Int-3

[0309]

[0310] Pd / C (4 g, wet) was added to a mixture of 6-(benzyloxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester i-4A (23 g, 62.76 mmol) in THF (200 mL). The mixture was stirred overnight with H2 at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (50 mL × 3). 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 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester, Int-3 (9.2 g, 53%).

[0311] LCMS: rt = 0.94 min, [M-55] + =223, purity: 60%.

[0312] 1 H NMR (400MHz, CDCl3) 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).

[0313] The preparation method of intermediate Int-5,4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid is as follows:

[0314] (1) Preparation of compound i-2

[0315]

[0316] At 0 °C, NaH (0.26 g, 6.5 mmol, 1.3 eq) was added to a DMF (20 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (1.4 g, 5.0 mmol, 1 eq). The mixture was stirred at 0 °C for 30 min. Then, methyl 4-(bromomethyl)-3-fluorobenzoate Int-1 (1.6 g, 6.5 mmol, 1.3 eq) was added to the above solution, and the mixture was stirred at 25 °C for 2 h. TLC showed complete consumption of the starting material and the discovery of new spots. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate i-2 (1.1 g, 50%).

[0317] 1 H NMR (400MHz, CDCl3) δ = 7.81 (dd, J = 8.0, 1.5Hz, 1H), 7.73 (dd, J = 10.4, 1.5Hz, 1H), 7.62–7.44 (m, 2H), 6.73 (d, J = 7.3Hz, 1H), 6.65 ( d,J=8.1Hz,1H),5.49(s,2H),4.20(s,1H),3.92(s,3H),2.77(d,J=43.3Hz,3H),2.05(s,1H),1.85(d,J=12.6Hz,2H),1.49(s,9H).

[0318] (2) Preparation of compound Int-5

[0319]

[0320] At 25 °C, LiOH (0.378 g, 15.7 mmol, 5.0 eq) in 10 mL of THF was added to a solution of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester i-2 (1.4 g, 3.15 mmol, 1 eq) in 10 mL of H2O. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with HCl (1 N). The reaction mixture was diluted with 100 mL of H2O and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid, Int-5 (0.47 g, 34.7% yield).

[0321] LCMS: rt=2.177min, [M+1]+=431.2, purity: 69.7%.

[0322] The preparation method of the intermediate Int-7,4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester is as follows:

[0323] (1) Preparation of compound Int-7

[0324]

[0325] A solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid Int-5 (0.470 g, 1.09 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (0.214 g, 2.18 mmol, 2.0 eq), DIEA (0.564 g, 4.37 mmol, 4.0 eq), and HATU (0.623 g, 1.64 mmol, 1.5 eq) in DMF (6 mL) was stirred at 25 °C for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O (80 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give tert-butyl 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate, Int-7 (0.440 g, 85.4% yield).

[0326] LCMS: rt=2.262min, [M+1]+=474.3, purity: 98%.

[0327] Preparation method of intermediate Int-2A,(S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[0328]

[0329] To a solution of methyl 6-chloro-5-nitropyridinecarboxylate 2A-1 (2.2 g, 10.34 mmol) in 20 mL of THF, (S)-oxetane-2-ylmethylamine (900 mg, 10.34 mmol) and TEA (2.0 g, 20 mmol) were added. The reaction mixture was stirred at 40 °C for 16 hours under nitrogen. The reaction mixture was concentrated to a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give methyl (S)-5-nitro-6-((oxetane-2-ylmethyl)amino)pyridinecarboxylate 2A-2 (1.2 g, 45%). Ethyl acetate was added to a 5 mL MeOH solution of the obtained 2A-2 (1.2 g, 4.49 mmol), and Pd / C (500 mg) was added. The mixture was stirred at room temperature for 16 hours under H2 atmosphere. The reaction mixture was further purified and concentrated by filtration to give crude (S)-5-amino-6-((oxetane-2-ylmethyl)amino)pyridinecarboxylate methyl ester 2A-3 (840 mg, 78.9%). 2-chloroacetic anhydride (667 mg, 3.9 mmol) was added to a solution of 2A-3 (840 mg, 3.54 mmol) in 10 mL of THF, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution, extracted with EA (40 mL × 3), washed with brine, and concentrated to give crude product. Further purification by column chromatography (PE / EA = 10-51%) yielded (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester, Int-2A (422 mg, 43%).

[0330] LCMS: rt = 1.694 min, [M+H] + =296, purity: 98%.

[0331] Example 1

[0332] (S)-2-((4-(6-((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 1)

[0333]

[0334] (1) Preparation of compound 1-1

[0335]

[0336] Butyl vinyl ether (1.25 mL) was added to a mixture of (4-bromo-2-fluorophenyl)methanol (500.00 mg, 2.439 mmol, 1.00 eq), Pd(OAc)₂ (10.95 mg, 0.049 mmol, 0.02 eq), DPPP (40.6 mg, 0.09 mmol, 0.04 eq), and K₂CO₃ (404.45 mg, 2.926 mmol, 1.20 equivalent) in DMF (5 mL) with stirring at room temperature. The flask was evacuated and rinsed three times with nitrogen. The final reaction mixture was irradiated with microwave at 120 °C for 2 hours, and the resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with sodium carbonate (aqueous solution) and brine, dried, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography to give 1-[3-fluoro-4-(hydroxymethyl)phenyl]acetone (104 mg, 25.36%) as a yellow solid.

[0337] (2) Preparation of compounds 1-2

[0338]

[0339] At room temperature, 1-[3-fluoro-4-(hydroxymethyl)phenyl]acetone (620.00 mg, 3.687 mmol, 1.00 eq), tert-butyl 4-(6-chloropyridin-2-yl)piperidin-1-carboxylate (1094.25 mg, 3.687 mmol, 1.00 eq), Pd2(dba)3 (168.80 mg, 0.184 mmol, 0.05 eq), BINAP (229.57 mg, 0.369 mmol, 0.1 eq), Cs2CO3 (2402.47 mg, 7.374 mmol, 2 eq), and dioxane (6 mL) were added to a sealed tube. The flask was evacuated and rinsed three times with nitrogen. The final reaction mixture was stirred overnight at 100 °C, and the resulting solution was extracted with ethyl acetate. The combined organic layers were washed with sodium carbonate (aqueous solution) and brine, dried, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography to give tert-butyl 4-[6-[(4-acetyl-2-fluorophenyl)methoxy]pyridin-2-yl]piperidine-1-carboxylate (85 mg, 5.38%) as a yellow solid.

[0340] (3) Preparation of compounds 1-3

[0341]

[0342] HCl (gas) in 1,4-dioxane (1.00 mL) was added to a stirred solution of tert-butyl 4-[6-[(4-acetyl-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-carboxylate (95.00 mg, 0.222 mmol, 1.00 eq) in dioxane (1.00 mL), and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification; LC-MS (ES, m / z): [M+1] = 329.2.

[0343] (4) Preparation of compounds 1-4

[0344]

[0345] Et3N (116.73 mg, 1.154 mmol, 4 eq) was added to a stirred DMF (1 mL) solution of 1-[3-fluoro-4-([[6-(piperidin-4-yl)pyridin-2-yl]oxy]methyl)phenyl]ethyl ketone (104.17 mg, 0.317 mmol, 1.10 eq) at room temperature, and the reaction mixture was stirred at room temperature for 15 minutes. Then, methyl 2-(chloromethyl)-3-[(2S)-oxetane-2-ylmethyl]-1,3-benzodiazole-5-carboxylic acid (85.00 mg, 0.288 mmol, 1.00 eq) was added to the mixture, and the mixture was stirred overnight at room temperature. The resulting solution was extracted with ethyl acetate. The combined organic layers were washed with sodium carbonate (aqueous solution) and brine, dried, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-[(4-[6-[(4-acetyl-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-yl)methyl]-3-[(2S)-oxecyclobutane-2-ylmethyl]-1,3-benzodiazole-5-carboxylic acid (120 mg, 70.93%), as a yellow solid, LC-MS (ES, m / z): [M+1] = 587.3.

[0346] (5) Preparation of compound 1

[0347]

[0348] At room temperature, TBD (1 M, in H₂O) (0.4 mL, 0.400 mmol, 2 eq) and LiOH (2 M, in H₂O) (0.2 mL, 0.400 mmol, 2 eq) were added to a stirred solution of methyl 2-[(4-[6-[(4-acetyl-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-yl) in 1.2 mL of ACN (0.2 mL). The reaction was then stirred overnight at room temperature. The pH of the solution was adjusted to 6–7 with 1 M HCl. The resulting solution was extracted with ethyl acetate. The combined organic layers were washed with sodium carbonate (aqueous solution) and brine, dried, and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: SunFirePrep C18 OBD column, 150 mm 5 μm 10 nm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18B to 46B over 10 min; UV detector, 220 nm; RT1: 7.90) to give 2-[(4-[6-[(4-acetyl-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-yl)methyl]-3-[(2S)-oxecyclobutane-2-ylmethyl]-1,3-benzodiazole-5-carboxylic acid (26.2 mg, 22.37%), as an off-white solid, LC-MS (ES, m / z): [M+1] = 573.

[0349] 1 H NMR (300MHz, chloroform-d) δ8.13(s,1H),8.03(d,J=8.7Hz,1H),7.81(d,J=8.5Hz,1H ),7.75–7.58(m,3H),7.57–7.49(m,1H),6.77(d,J=7.3Hz,1H),6.67(d,J=8.2 Hz,1H),5.52(s,2H),5.22(s,1H),4.87–4.55(m,3H),4.43(d,J=7.2Hz,1H),4 .10(s,2H),3.18(s,2H),2.73(s,2H),2.59(s,3H),2.46(s,3H),1.93(s,4H).

[0350] Example 2

[0351] (S)-2-((4-(6-((2-fluoro-4-(methanesulfonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 2)

[0352]

[0353] (1) Preparation of compound 2-2

[0354]

[0355] Under nitrogen atmosphere and at 0°C, 2-fluoro-4-(methanesulfonyl)benzaldehyde 2-1 (900 mg, 4.46 mmol) was added in portions to 10 mL of MeOH solution with stirring for 10 minutes, followed by the addition of NaBH4 (165 mg, 4.46 mmol). The reaction mixture was concentrated, and then water (50 mL) was added. Extraction was performed with EA (30 mL × 3). The combined organic layers were washed with brine, dried, and concentrated to a crude product, which was further purified by column chromatography (PE / EA = 0-30%) to give (2-fluoro-4-(methanesulfonyl)phenyl)methanol 2-2 (890 mg, 98%).

[0356] 1 H NMR (400MHz, CDCl3) δ7.74(s,2H),7.65–7.59(m,1H),4.87(d,J=5.9Hz,2H),3.06(s,3H),2.06(dd,J=11.2,5.2Hz,1H).

[0357] (2) Preparation of compounds 2-3

[0358]

[0359] Under nitrogen atmosphere and stirring at 100 °C, tert-butyl 4-(6-chloropyridin-2-yl)piperidin-1-carboxylate (814.74 mg, 2.745 mmol) in 5 mL of dioxane was added to (2-fluoro-4-(methanesulfonyl)phenyl)methanol 2-2 (560 mg, 2.745 mmol), Cs₂CO₃ (1788 mg, 0.488 mmol), Xantphos (158.8 mg, 0.274 mmol), and Pd₂(dba)₃ (125.7 mg, 0.137 mmol) for 32 hours. The reaction mixture was concentrated to a crude product, which was further purified by column chromatography (PE / EA = 0-30%) to give tert-butyl 4-(6-((2-fluoro-4-(methanesulfonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 2-3 (1.1 g, 89% yield).

[0360] LCMS: rt = 1.257 min, [M + Na] + =487.0, purity: 82%.

[0361] (3) Preparation of compounds 2-4

[0362]

[0363] At room temperature, tert-butyl 4-(6-((2-fluoro-4-(methylthio)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid ester 2-3 (250 mg, 0.538 mmol) was stirred in 5 mL of HCl / EA solution for 30 minutes, and the LC-MS was observed. The reaction mixture was concentrated to give the crude product 2-((2-fluoro-4-(methylsulfonyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine 2-4 (190 mg, 97% yield).

[0364] LCMS: rt = 0.79 min, [M+H] + =365, purity: 80%.

[0365] (4) Preparation of compounds 2-5

[0366]

[0367] Under nitrogen atmosphere, at room temperature and with stirring, DIEA (219.8 mg, 1.7 mmol) was added to a solution of 2-((2-fluoro-4-(methanesulfonyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine 2-4 (185 mg, 0.51 mmol) in 2 mL MeCN, and the reaction was allowed to proceed for 10 min. Then, at room temperature, (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (100 mg, 0.34 mmol) was added to the reaction mixture for 60 min. LC-MS was then observed. The reaction mixture was concentrated to a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give (S)-2-((4-(6-((2-fluoro-4-(methanesulfonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 2-5 (200 mg, 94% yield).

[0368] LCMS: rt = 1.04 min, [M+H] + =623, purity: 98%.

[0369] (2) Preparation of compound 2

[0370]

[0371] LiOH (36 mg, 0.8 mmol) was added to a THF / H2O (4 mL) solution of (S)-2-((4-(6-(((2-fluoro-4-(methanesulfonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 2-5 (200 mg, 0.16 mmol) and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with 1N HCl, and the crude product was concentrated. It was further purified by preparative HPLC to obtain (S)-2-((4-(6-((2-fluoro-4-(methanesulfonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, a white solid, which was compound 2 (44 mg, 22.6% yield).

[0372] LCMS: rt = 2.13 min, [M+H] + =608, purity: 98%.

[0373] 1 H NMR(400MHz,MeOD)δ8.33(s,1H),7.98(dd,J=8.5,1.3Hz,1H),7.78–7.66(m,4H),7.64–7.56(m,1H),6. 84(d,J=7.3Hz,1H),6.70(d,J=8.2Hz,1H),5.55(s,2H),5.27(dd,J=7.4,2.4Hz,1H),4.92–4.87(m,1H), 4.76–4.61(m,2H),4.47(dd,J=6.0,3.2Hz,1H),4.08(dd,J=41.5,14.0Hz,2H),3.15(d,J=11.8Hz,1H), 3.11–2.99(m,4H),2.80(d,J=6.0Hz,1H),2.68(s,1H),2.49(dd,J=36.2,4.9Hz,3H),1.95–1.75(m,4H).

[0374] Example 3

[0375] (S)-2-((4-(6-((4-carbamoyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 3)

[0376]

[0377] (1) Preparation of compound 3-2

[0378]

[0379] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester (2 g, 7.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.21 g, 8.6 mmol) was added in portions at 0 °C. After 30 minutes, a DMF solution of 4-(bromomethyl)-3-fluorobenzoate Int-3 (1.78 g, 7.2 mmol) was added to the above reaction mixture via a sleeve. After 2 hours, the reaction mixture was completely analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried with Na2SO4, concentrated, and purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 3-2 (2.02 g, 63%).

[0380] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[0381] (2) Preparation of compound 3-3

[0382]

[0383] To a solution of tert-butyl 4-(6-(((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 3-2 (300 mg, 0.675 mmol) in 12 mL of NH3 / MeOH, the mixture was stirred at 80 °C for 16 h in a 20 mL sealed tube. LC-MS was observed. The reaction mixture was concentrated to give a crude product, which was further purified by column chromatography (PE / EA = 0-45%) to give tert-butyl 4-(6-((4-aminoformyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 3-3 (287 mg, 97% yield).

[0384] 1 H NMR (400MHz, CDCl3) δ7.63–7.44(m,4H),6.83(s,1H),6.65(dd,J=10.7,7.7Hz,2H),5.49(s ,2H),4.12(dd,J=14.2,7.1Hz,2H),2.92–2.52(m,3H),1.65(d,J=28.1Hz,4H),1.53(s,9H).

[0385] (3) Preparation of compounds 3-4

[0386]

[0387] A solution of tert-butyl 4-(6-(((4-aminoformyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 3-3 (287 mg, 0.67 mmol) in HCl / EA (10 mL, 3 M) was stirred at room temperature for 1 hour. The reaction mixture was determined to be complete by LC-MS. The mixture was concentrated to give 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 3-4 (210 mg, 95% yield).

[0388] LCMS: rt = 1.76 min, [M+1] + =330, purity: 96%.

[0389] (4) Preparation of compounds 3-5

[0390]

[0391] A mixture of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 3-4 (0.168 g, 0.51 mmol) and DIEA (0.22 g, 0.3 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then, (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (0.1 g, 0.51 mmol) was added, and the mixture was heated at 65 °C for 15 h. LC-MS was used for detection. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-(((4-carbamoyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 3-5 (0.18 g, 90% yield).

[0392] LCMS: rt = 2.15 min, [M+1] + =588, purity: 97%.

[0393] (5) Preparation of compound 3

[0394]

[0395] Methyl (S)-2-((4-(6-(((4-carbamoyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 3-5 (0.18 g, 0.3 mmol) was dissolved in THF (4 mL), and then an aqueous lithium hydroxide solution (4 N, 4 mL) was added. The mixture was stirred at room temperature for 20 hours. The mixture was concentrated by LC-MS and purified by preparative HPLC under alkaline conditions to give (S)-2-((4-(6-(((4-carbamoyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 3 (0.095 g, 55% yield).

[0396] LCMS: rt = 2.02 min, [M+1] + =574, purity: 98%.

[0397] 1 H NMR: (400MHz, MeOD) δ8.22(s,1H),7.95(d,J=8.3Hz,1H),7.73–7.49(m,5H),6.81(d,J=7.2Hz,1H),6. 65(d,J=8.2Hz,1H),5.49(s,2H),5.28(d,J=4.9Hz,1H),4.91(d,J=6.7Hz,1H),4.78–4.68(m,1H),4.6 2(dd,J=13.9,7.6Hz,1H),4.48(dt,J=8.9,6.0Hz,1H),3.95(dd,J=46.5,13.6Hz,2H),2.99(dd,J=40. 8,11.1Hz,2H),2.79(dt,J=16.0,8.0Hz,1H),2.71–2.47(m,2H),2.43–2.17(m,2H),1.99–1.74(m,4H).

[0398] Example 4

[0399] (S)-2-((4-(6-((2-fluoro-4-(methylaminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 4)

[0400]

[0401] (1) Preparation of compound 4-2

[0402]

[0403] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester (2 g, 7.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.21 g, 8.6 mmol) was added in portions at 0 °C. After 30 minutes, a DMF solution of 4-(bromomethyl)-3-fluorobenzoate (1.78 g, 7.2 mmol) was added to the reaction mixture via a tube. After 2 hours, LC-MS analysis was performed, and the reaction mixture was quenched by the addition of water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried with Na2SO4, concentrated, and purified by column chromatography (PE / / EA = 0-20%) to give 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 4-2 (2.02 g, 63% yield).

[0404] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[0405] (2) Preparation of compound 4-3

[0406]

[0407] A solution of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 4-2 (300 mg, 0.675 mmol) in 12 mL of CH3NH2 / MeOH was stirred in a 20 mL sealed tube at 80 °C for 16 hours. The reaction mixture was concentrated to give a crude product, which was further purified by column chromatography (PE / EA = 0-45%) to give tert-butyl 4-(6-((2-fluoro-4-(methylaminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 4-3 (299 mg, 99% yield).

[0408] LCMS: rt = 2.07 min, [M+1] + =444, purity: 94.2%.

[0409] (3) Preparation of compound 4-4

[0410]

[0411] 4-(6-((2-fluoro-4-(methylcarbamoyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 4-3 (299 mg, 0.67 mmol) was added to HCl / EA (10 mL, 3 M). The mixture was stirred at room temperature for 1 hour. The reaction mixture was determined to be complete by LC-MS. The mixture was concentrated to give 3-fluoro-N-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 4-4 (164 mg, 97% yield).

[0412] LCMS: rt = 1.85 min, [M+1] + =345, purity: 97%.

[0413] (4) Preparation of compounds 4-5

[0414]

[0415] The reaction mixture of 3-fluoro-N-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 4-4 (0.164 g, 0.51 mmol), DIEA (0.22 g, 0.3 mmol), and 10 mL of CH3CN was stirred at room temperature for 10 minutes. Then, (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.1 g, 0.51 mmol) was added, and the mixture was heated at 65 °C for 15 hours. The reaction mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((2-fluoro-4-(methylaminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 4-5 (0.18 g, 90% yield) as a yellow oil.

[0416] LCMS: rt = 2.15 min, [M+1] + =602, purity: 97%.

[0417] (5) Preparation of compound 4

[0418]

[0419] Methyl (S)-2-((4-(6-((2-fluoro-4-(methylaminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 4-5 (0.18 g, 0.3 mmol) was dissolved in THF (4 mL), and then an aqueous solution of lithium hydroxide (4 N, 4 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was determined to be complete by LC-MS. The reaction mixture was directly concentrated and purified by preparative HPLC under alkaline conditions to give (S)-2-((4-(6-((2-fluoro-4-(methylaminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 4 (0.06 g, 34%).

[0420] LCMS: rt = 2.07 min, [M+1] + =588, purity: 97%.

[0421] 1 H NMR: (400MHz, MeOD) δ8.28(s,1H),7.96(d,J=8.4Hz,1H),7.67–7.51(m,5H),6.81(d,J=7.2Hz,1H),6.65 (d,J=8.2Hz,1H),5.48(s,2H),5.27(d,J=5.1Hz,1H),4.90(d,J=7.1Hz,1H),4.77–4.58(m,2H),4.47(dt, J=8.7,6.0Hz,1H),3.98(dd,J=48.4,13.7Hz,2H),3.07(d,J=10.8Hz,1H),2.95(d,J=10.9Hz,1H),2.88(s ,3H),2.79(dt,J=15.9,8.0Hz,1H),2.68–2.48(m,2H),2.40–2.24(m,2H),1.87(dd,J=22.5,18.6Hz,4H).

[0422] Example 5

[0423] (S)-2-((4-(6-((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 5)

[0424]

[0425] (1) Preparation of compound 5-1

[0426]

[0427] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (2 g, 7.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.21 g, 8.6 mmol) was added in portions at 0 °C. After 30 minutes, a solution of 4-(bromomethyl)-3-fluorobenzoate methyl ester (1.78 g, 7.2 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 2 hours, the reaction mixture was analyzed by LC-MS, and the reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 5-1 tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate (2.02 g, 63%).

[0428] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[0429] (2) Preparation of compound 5-2

[0430]

[0431] 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 5-1 (2.0 g, 4.5 mmol) was dissolved in THF (15 mL), and then an aqueous lithium hydroxide solution (15 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS, and the pH of the mixture was adjusted to 7-8 with dilute hydrochloric acid solution. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. Concentration gave 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 5-2 (1.7 g, 87.6%).

[0432] LCMS: rt = 2.85 min, [M+1] + =375, purity: 95%.

[0433] (3) Preparation of compound 5-3

[0434]

[0435] Add 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 5-2 (1.7 g, 3.95 mmol), N,O-dimethylhydroxylamine (0.765 g, 7.9 mmol), HATU (2.34 g, 5.93 mmol), and DIEA (2.04 g, 15.8 mmol) to a reaction mixture in DMF (25 mL). Stir the mixture at room temperature for 2 hours, analyze the reaction mixture by LC-MS, and quench the reaction mixture by adding water. Extract the aqueous phase with EtOAc (50 mL × 3) and wash with brine (50 mL × 2). Dry the combined organic layers with Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 5-3 (1.6 g, 85.6%) of 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0436] LCMS: rt = 2.42 min, [M+1] + =474, purity: 97%.

[0437] (4) Preparation of compound 5-4

[0438]

[0439] 4-(6-(((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 5-3 (0.4 g, 0.845 mmol) was dissolved in anhydrous THF (10 mL) with Ar2. CH3MgBr (1 M) (4 mL) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS and quenched by the addition of saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by Com-Flash to give 4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 5-4 (0.32 g, 88%).

[0440] LCMS: rt = 3.21 min, [M+1] + =429, purity: 98%.

[0441] (5) Preparation of compound 5-5

[0442]

[0443] Add 4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 5-4 (320 mg, 0.75 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 1 hour. Analyze the reaction mixture by LC-MS, and concentrate the mixture to give 1-(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 5-5 (230 mg, 95%).

[0444] LCMS: rt = 2.056 min, [M+1] + =329, purity: 98%.

[0445] (5) Preparation of compounds 5-6

[0446]

[0447] The reaction mixture of 1-(3-fluoro-4-((((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 5-5 (0.167 g, 0.51 mmol) and DIEA (0.22 g, 1.7 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.1 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture did not pass the test completely. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 5-6 (0.15 g, 75%).

[0448] LCMS: rt = 2.35 min, [M+1] + =588, purity: 93%.

[0449] (6) Preparation of compound 5

[0450]

[0451] Methyl (S)-2-((4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ester 5-6 (0.15 g, 0.26 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS, concentrated, and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, compound 5 (35.7 mg, 25.7%).

[0452] LCMS: rt = 2.25 min, [M+1] + =574, purity: 97%.

[0453] 1 H NMR(400MHz,MeOD)δ8.05(dd,J=20.4,8.3Hz,2H),7.78(dd,J=8.0,1.5Hz,1H),7.69(dd,J=10.8,1.5Hz,1H),7.65–7.55(m,2 H),6.83(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.51(s,2H),5.32(d,J=4.1Hz,1H),5.05(dd,J=14.8,6.6Hz,1H),4.91(dd,J =14.7,3.1Hz,1H),4.61(dd,J=13.9,7.9Hz,1H),4.44(dt,J=9.0,6.1Hz,1H),4.06(dd,J=47.6,13.8Hz,2H),3.04(dd,J=32. 6,11.2Hz,2H),2.85–2.70(m,1H),2.64(dd,J=10.0,5.5Hz,1H),2.55(d,J=5.4Hz,4H),2.42–2.28(m,2H),1.99–1.76(m,4H).

[0454] Example 6

[0455] (S)-2-((4-(6-((4-(dimethylphosphoryl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 6)

[0456]

[0457] (1) Preparation of compound 6-2

[0458]

[0459] NBS (792 mg, 4.45 mmol) and AIBN (69 mg, 0.42 mmol) were added to a solution of 2-fluoro-4-iodo-1-toluene 6-1 (1 g, 4.23 mmol) in CCl4 (10 mL), and the mixture was stirred at 85 °C under an Ar atmosphere for 5 hours. TLC showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with DCM, and the combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography, eluting with PE / EA (100:1) to give 1-(bromomethyl)-2-fluoro-4-iodobenzene 6-2 (780 mg, 58%).

[0460] LCMS:[M+H] + =315, purity: 80%.

[0461] (2) Preparation of compound 6-3

[0462]

[0463] To a DMF (10 mL) solution of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (400 mg, 1.27 mmol) cooled to 0 °C, NaH (78 mg, 1.94 mmol) was added. The mixture was stirred at 0 °C under N2 for 10 min, followed by the addition of 1-(bromomethyl)-2-fluoro-4-iodobenzene 6-2 (354 mg, 1.27 mmol). The mixture was stirred at room temperature for 3 h. TLC showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with EA (100 mL), and the combined organic layers were washed with brine (30 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography by elution with PE / EA (2:1) to give tert-butyl 4-(6-((2-fluoro-4-iodobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 6-3 (470 mg, 78%).

[0464] LCMS: MS(+23) = 535, purity: 85%.

[0465] (3) Preparation of compound 6-4

[0466]

[0467] To a solution of 4-(6-((2-fluoro-4-iodobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 6-3 (470 mg, 0.92 mmol) in 1,4-dioxane (3 mL), HCl (2 mL, 1 M) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was detected by LCMS. The mixture was concentrated under reduced pressure to give 2-((2-fluoro-4-iodobenzyl)oxy)-6-(piperidin-4-yl)pyridine 6-4 hydrochloride (400 mg, 105%).

[0468] LCMS:[M+H] + =413, purity: 95%.

[0469] (4) Preparation of compound 6-5

[0470]

[0471] DIEA (264 mg, 2.05 mmol) was added to a mixture of 2-((2-fluoro-4-iodobenzyl)oxy)-6-(piperidin-4-yl)pyridine 6-4 (274 mg, 0.61 mmol) in ACN (4 mL), and the mixture was stirred at room temperature for 5 minutes. Then (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (120 mg, 0.41 mmol) was added, and the mixture was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature, diluted with EA (100 mL), and the combined organic layers were washed with brine (30 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography. The residue was eluted with PE / EA (2:1) to give (S)-2-((4-(6-(((2-fluoro-4-iodobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 6-5 (150 mg, 56%).

[0472] LCMS:[M+1] + =671, purity: 84%.

[0473] (5) Preparation of compound 6-6

[0474]

[0475] Under N2, Pd2(dba)3 (18 mg, 0.02 mmol) and XantPhos (23 mg, 0.04 mmol) were added to a solution of (S)-2-((4-(6-(((2-fluoro-4-iodobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 6-5 (120 mg, 0.18 mmol), dimethylphosphine oxide (21 mg, 0.27 mmol), and triethylamine (45 mg, 0.53 mmol) in 4 mL of 1,4-dioxane. The mixture was then stirred at 110 °C under an Ar atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature and diluted with EtOAc (100 mL). The combined organic layers were washed with brine (30 mL), dried with Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC under alkaline conditions to give (S)-2-((4-(6-((4-(dimethylphosphoryl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl 6-6 (70 mg, 95%).

[0476] LCMS:[M+1] + =621, purity: 93%.

[0477] (6) Preparation of compound 6

[0478]

[0479] A solution of (S)-2-((4-(6-((4-(dimethylphosphoryl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 8-6 (70 mg, 0.12 mmol) in THF (4 mL) was added, followed by the addition of LiOH (9 mg, 0.36 mmol) in H2O (1 mL). The mixture was stirred at room temperature for 5 hours. The reaction was detected by LCMS. The mixture was purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((4-(dimethylphosphoryl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 6 (45 mg, 66%).

[0480] LCMS: MS(+H): 607, Purity: 100%.

[0481] 1H NMR (400MHz, DMSO) δ8.23(s,1H),7.87–7.74(m,1H),7.73–7.52(m,5H),6.88(d,J=7.3Hz,1H),6.69(d,J=8.2Hz,1H),5.4 4(s,2H),5.18–5.05(m,1H),4.79(dd,J=15.1,7.2Hz,1H),4.65(d,J=12.7Hz,1H),4.42(ddd,J=9.9,8.9,4.6Hz,2H),3.9 4(d,J=13.5Hz,1H),3.77(d,J=13.4Hz,1H),2.99(d,J=11.3Hz,1H),2.85(d,J=10.5Hz,1H),2.70(dd,J=17.6,7.0Hz,1H) ,2.58(d,J=11.6Hz,1H),2.45(d,J=11.1Hz,1H),2.33–2.12(m,2H),1.76(d,J=15.2Hz,4H),1.62(dt,J=13.5,2.8Hz,6H).

[0482] Example 7

[0483] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 7)

[0484]

[0485] (1) Preparation of compound 7-1

[0486]

[0487] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (2 g, 7.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.21 g, 8.6 mmol) was added in portions at 0 °C. After 30 minutes, a solution of 4-(bromomethyl)-3-fluorobenzoate methyl ester (1.78 g, 7.2 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 2 hours, the reaction mixture was analyzed by LC-MS, and the reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 7-1 (2.02 g, 63%).

[0488] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[0489] (2) Preparation of compound 7-2

[0490]

[0491] 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 7-1 (2.0 g, 4.5 mmol) was dissolved in THF (15 mL), and then an aqueous solution of lithium hydroxide (15 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The pH of the mixture was adjusted to 7-8 with dilute hydrochloric acid solution. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. Concentration gave 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 7-2 (1.7 g, 87.6%).

[0492] LCMS: rt = 2.85 min, [M+1] + =375, purity: 95%.

[0493] (3) Preparation of compound 7-3

[0494]

[0495] Add 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 7-2 (1.7 g, 3.95 mmol), N,O-dimethylhydroxylamine (0.765 g, 7.9 mmol), HATU (2.34 g, 5.93 mmol), and DIEA (2.04 g, 15.8 mmol) to a reaction mixture in DMF (25 mL). Stir the mixture at room temperature for 2 hours. Analyze the reaction mixture by LC-MS. Quench the reaction mixture by adding water. Extract the aqueous phase with EtOAc (50 mL × 3) and wash with brine (50 mL × 2). Dry the combined organic layers with Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid 7-3 (1.6 g, 85.6%).

[0496] LCMS: rt = 2.42 min, [M+1] + =474, purity: 97%.

[0497] (4) Preparation of compound 7-4

[0498]

[0499] 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 7-3 (0.4 g, 0.845 mmol) was dissolved in anhydrous THF (10 mL) with Ar2. Cyclopropylmagnesium bromide (1 M) (4 mL) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography to give 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 7-4 (0.35 g, 91%).

[0500] LCMS: rt = 2.18 min, [M+1] + =455, purity: 97%.

[0501] (5) Preparation of compound 7-5

[0502]

[0503] Add a solution of tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 7-4 (350 mg, 0.77 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 1 hour. Analyze the reaction mixture by LC-MS, and concentrate the mixture to give cyclopropyl(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone 7-5 (260 mg, 95%).

[0504] LCMS: rt = 2.22 min, [M+1] + =355, purity: 85%.

[0505] (6) Preparation of compound 7-6

[0506]

[0507] The reaction mixture of cyclopropyl (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl) ketone 7-5 (0.180 g, 0.51 mmol) and DIEA (0.22 g, 1.7 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.1 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The mixture was concentrated and purified by column chromatography (MeOH in DCM = 0-5%) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 7-6 (0.18 g, 86%).

[0508] LCMS: rt = 2.2 min, [M+1] + =613, purity: 90%.

[0509] (7) Preparation of compound 7

[0510]

[0511] Methyl (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 7-6 (0.18 g, 0.3 mmol) was dissolved in THF (3 mL), and then an aqueous solution of lithium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS, concentrated, and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 7 (93.3 mg, 52%).

[0512] LCMS: rt = 2.42 min, [M+1] + =509, purity: 99%.

[0513] 1 H NMR (400MHz, MeOD) δ8.26(s,1H),7.95(dd,J=8.5,1.3Hz,1H),7.83(dd,J=8.0,1.5Hz,1H),7.73(dd,J=10.8,1.5Hz,1H),7.60(dt ,J=15.7,8.5Hz,3H),6.82(d,J=7.3Hz,1H),6.67(d,J=8.1Hz,1H),5.57–5.47(m,2H),5.28(tt,J=7.2,3.6Hz,1H),4.91(dd,J=15. 3,7.1Hz,1H),4.74(dd,J=15.3,2.7Hz,1H),4.65–4.59(m,1H),4.48(dt,J=9.1,6.0Hz,1H),3.96(dd,J=48.0,13.7Hz,2H),3.04( d,J=10.9Hz,1H),2.93(d,J=11.2Hz,1H),2.85–2.47(m,4H),2.41–2.19(m,2H),1.86(dd,J=37.8,18.8Hz,4H),1.15–0.96(m,4H).

[0514] Example 8

[0515] (S)-2-((4-(6-((2-fluoro-4-nicotinanoylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 8)

[0516]

[0517] (1) Preparation of compound 8-3

[0518]

[0519] N-BuLi (0.7 mL, 1.69 mmol, 2 eq) was added to a THF (5 mL) solution of 3-bromopyridine 8-1A (0.4 g, 0.84 mmol, 1 eq) at -70 °C, and the mixture was stirred at -70 °C under N2 for 30 min. The above solution was added dropwise to a THF (15 mL) solution of 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-7 (267 mg, 1.69 mmol, 1 eq), and the mixture was stirred at -70 °C to -25 °C for 12 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried with Na2SO4, filtered and concentrated to obtain the residue, which was purified by silica gel column chromatography and eluted with (EA / PE = 0-20%) to give 8-3 tert-butyl 4-(6-((2-fluoro-4-nicotinylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate (200 mg, 60.7% yield), as a gray solid.

[0520] LCMS: rt = 1.475 min, [M+1] + =492.0, purity: 80%.

[0521] (3) Preparation of compound 8-4

[0522]

[0523] At 25 °C and Ar, tert-butyl 4-(6-(((2-fluoro-4-nicotinylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 8-3 (0.2 g, 0.41 mmol, 1 eq) was mixed in HCl / EA (4 mL). The mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(pyridin-3-yl)methyl ketone 8-4 (0.188 g, crude product), as the hydrochloride salt of 8-4.

[0524] LCMS: rt = 1.160 min, [M+1] + =392.3, purity: 71.8%.

[0525] (4) Preparation of compound 8-5

[0526]

[0527] At 25 °C, DIEA (0.277 g, 2.12 mmol, 5 eq) was added to a solution of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(pyridin-3-yl)methyl ketone 8-4 (0.168 g, 0.43 mmol, 1 eq) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.152 g, 0.52 mmol, 1.2 eq) in CH3CN (5 mL). The mixture was stirred at 60 °C under an Ar atmosphere for 16 hours. The mixture was concentrated to obtain a crude compound, which was purified by silica gel column chromatography by elution with PE / EtOAc (3:1) to give (S)-2-((4-(6-(((2-fluoro-4-nicotinylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 8-5 (0.1 g, 36.5%).

[0528] LCMS: rt = 1.293 min, [M+H] + =650.3, purity: 56.1%.

[0529] (5) Preparation of compound 8

[0530]

[0531] At 25 °C, LiOH (0.0019 g, 0.79 mmol, 5.0 eq) in 4 mL of H₂O (4 mL) was added to a solution of methyl (S)-2-((4-(6-(((2-fluoro-4-nicotinylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 8-5 (0.1 g, 0.16 mmol, 1 eq). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-(((2-fluoro-4-nicotinylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 8 (36 mg, 36.6%).

[0532] LCMS: rt = 1.342 min, [M+H] + =636.4, purity: 99.1%.

[0533] 1H NMR (400MHz, CD3OD_SPE) δ8.84(d,J=1.4Hz,1H),8.71(dd,J=4.9,1.6Hz,1H),8.20–8.11(m,2H),7.93(dd,J=8.4,1.4Hz,1H),7.68(t,J =7.6Hz,1H),7.60–7.50(m,5H),6.82(d,J=7.2Hz,1H),6.67(d,J=8.0Hz,1H),5.55(s,2H),5.27(dt,J=6.7,4.1Hz,1H),4.91(d,J=7.1H z,1H),4.72(dd,J=15.3,3.0Hz,1H),4.60(dd,J=13.8,7.9Hz,1H),4.45(dt,J=9.1,6.0Hz,1H),3.99(d,J=13.6Hz,1H),3.88(d,J=13.6 Hz,1H),2.97(dd,J=37.5,11.6Hz,2H),2.84–2.71(m,1H),2.65–2.46(m,2H),2.34–2.16(m,2H),1.84(ddd,J=22.4,16.9,10.2Hz,4H).

[0534] Example 9

[0535] (S)-2-((4-(6-((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 9)

[0536]

[0537] (1) Preparation of compound 9-2

[0538]

[0539] To 10 mL of a DMF solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (500 mg, 2.17 mmol), NaH (130 mg, 3.26 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 30 min. Then, compound 9-1 (500 mg, 2.17 mmol) was added to the reaction mixture at room temperature for 30 min. LC-MS was observed. The reaction mixture was poured into water (100 mL), extracted with EtOAc (50 mL × 3), washed with brine, dried over Na2SO4, and concentrated to give a crude product, which was further purified by vacuum distillation (EA / PE = 0-20%) to give methyl 6-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)nicotinic acid ester 9-2 (250 mg, 26.9%).

[0540] LCMS: rt = 2.15 min, [M-55] + =428, purity: 99%.

[0541] (2) Preparation of compound 9-3

[0542]

[0543] LiOH (70 mg, 2.9 mmol) was added to a solution of methyl 6-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)nicotinic acid 9-2 (250 mg, 0.58 mmol) in THF / H2O (4 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with 1N HCl, extracted with EA (10 mL × 3), washed with brine, dried over Na2SO4, and concentrated to give crude product 6-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)nicotinic acid 9-3 (210 mg, 87%), which could be used for the next reaction without further purification.

[0544] LCMS: rt = 1.94 min, [M+H] + =414.0, purity: 98%.

[0545] (3) Preparation of compound 9-4

[0546]

[0547] To a solution of 6-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)nicotinic acid 9-3 (210 mg, 0.5 mmol) in 5 mL of DMF, N,O-dimethylhydroxylamine (98 mg, 1.02 mmol), HATU (290 mg, 0.76 mmol), and DIEA (262 mg, 2.0 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water (30 mL), extracted with EA (20 mL × 3), washed with brine, dried over Na2SO4, and concentrated to give a crude product, which was further purified by vacuum distillation (EA / PE = 0-47%) to give 4-(6-((5-(methoxy(methyl)aminoformyl)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 9-4 (220 mg, 95%).

[0548] LCMS: rt = 2.05 min, [M+H] + =457, purity: 93%.

[0549] (4) Preparation of compound 9-5

[0550]

[0551] A solution of tert-butyl 4-(6-((5-(methoxy(methyl)aminoformyl)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylate 9-4 (250 mg, 0.55 mmol) in 10 mL of THF was stirred under nitrogen at room temperature for 30 min. CH3MgBr (3 mL) was added, and the reaction mixture was monitored by LCMS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give a crude product. This crude product was further purified by column chromatography (EA / PE = 0-22%) to give tert-butyl 4-(6-((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylate 9-5 (150 mg, 67%).

[0552] LCMS: rt = 2.09 min, [M+H] + =412, purity: 97%.

[0553] (5) Preparation of compound 9-6

[0554]

[0555] Add 5 mL of HCl / EtOAc solution of tert-butyl 4-(6-(((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylic acid 9-5 (150 mg, 0.34 mmol) to the solution and stir at room temperature for 40 minutes. Concentrate the reaction mixture to give crude product 1-(6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)ethane-1-one 9-6 (110 mg, 97%), which can be used directly in the next step without purification.

[0556] LCMS: rt = 1.005 min, [M+H] + =312.1, purity: 61%.

[0557] (6) Preparation of compounds 9-7

[0558]

[0559] Under nitrogen atmosphere and with stirring at room temperature, DIEA (155 mg, 1.2 mmol) was added to a solution of 1-(6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridin-3-yl)ethane-1-one 9-6 (110 mg, 0.35 mmol) in 10 mL MeCN for 10 minutes. Then, (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (70 mg, 0.22 mmol) was added to the reaction mixture at 60 °C for 16 hours. LCMS was observed. The reaction mixture was concentrated to give a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give (S)-2-((4-(6-(((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 9-7 (200 mg, 99%).

[0560] LCMS: rt = 1.5 min, [M+H] + =571, purity: 99%.

[0561] (7) Preparation of compound 9

[0562]

[0563] LiOH (44 mg, 1.84 mmol) was added to a THF / H2O (10 mL) solution of (S)-2-((4-(6-(((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 9-7 (210 mg, 0.33 mmol) and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with 1N HCl, concentrated, and the crude product was obtained. It was further purified by preparative HPLC under alkaline conditions to give (S)-2-((4-(6-(((5-acetylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 9 (12.7 mg, 6%).

[0564] LCMS: rt = 1.36 min, [M+H] + =556, purity: 95.6%.

[0565] 1 H NMR (400MHz, MeOD) δ9.07(d,J=2.0Hz,1H),8.31(dd,J=8.5,2.4Hz,2H),7.96(dd,J=8.5,1.5Hz,1H),7.62( dd,J=14.4,8.3Hz,3H),6.83(d,J=7.3Hz,1H),6.74(d,J=8.2Hz,1H),5.54(s,2H),5.26(dt,J=6.9,4.3Hz,1 H),4.89(d,J=7.1Hz,1H),4.77–4.59(m,2H),4.52–4.40(m,1H),4.01(d,J=13.7Hz,1H),3.90(d,J=13.7Hz ,1H),2.99(s,1H),2.95–2.72(m,2H),2.57(s,5H),2.29(dtd,J=15.0,11.0,3.8Hz,2H),1.83–1.64(m,4H).

[0566] Example 10

[0567] (S)-2-((4-(6-((4-acetyl-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 10)

[0568]

[0569] (1) Preparation of compound 10-2

[0570]

[0571] CBr4 (12.6 g, 38 mmol, 2 eq) and PPh3 (9.9 g, 10 mmol, 2 eq) were added to a solution of (4-bromo-2-methylphenyl)methanol 10⁻¹ (3.8 g, 19 mmol, 1 eq) in 40 mL of DCM. The mixture was stirred at 25 °C for 16 h. TLC showed complete consumption of the starting material. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography, eluting with PE, to give 4-bromo-1-(bromomethyl)-2-methylbenzene 10⁻² (4.04 g, 81.2%).

[0572] 1 H NMR (400MHz, CDCl3) δ7.34 (s, 2H), 7.16 (d, J = 8.1Hz, 1H), 4.45 (s, 2H), 2.38 (s, 3H).

[0573] (2) Preparation of compound 10-3

[0574]

[0575] NaH (0.083 g, 3.47 mmol, 1.3 eq) was added to a DMF (6 mL) solution of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (0.7 g, 2.67 mmol, 1.3 eq) and mixed for 1 hour at 0 °C. 4-bromo-1-(bromomethyl)-2-methylbenzene was added to the mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete consumption of the starting material. The mixture was diluted with EtOAc (100 mL), washed with H2O (150 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE to give 10-3 (1.0 g, 81.3%) of 4-(6-((4-bromo-2-methylbenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0576] 1H NMR (400MHz, CDCl3) δ7.50(dd,J=8.1,7.4Hz,1H),7.30(dd,J=17.9,15.5Hz,3H),6.72(d,J=7.2Hz,1H),6.59(d,J=8.1H z,1H),5.31(s,2H),4.15(s,2H),2.78(d,J=42.9Hz,3H),2.37(s,3H),1.88(d,J=12.0Hz,2H),1.66(s,2H),1.49(s,9H).

[0577] (3) Preparation of compound 10-4

[0578]

[0579] At 25 °C, Pd(PPh3)2Cl2 (0.045 g, 0.06 mmol, 0.05 eq) was added to a solution of 10-3 (0.59 g, 1.28 mmol, 1 eq) of 4-(6-((4-bromo-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 10-3 (1.28 g, 1 eq) and tributyl(1-ethoxyvinyl)stanane (0.486 g, 1.35 mmol, 1.05 eq) in DMF (8 mL). The mixture was stirred at 100 °C under an Ar atmosphere for 16 hours. TLC showed complete consumption of the starting material. A saturated aqueous solution of ammonium chloride and a KF solution were added and stirred at 25 °C for 1 hour. The mixture was diluted with EtOAc (80 mL), washed with H2O (150 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated under reduced pressure to give the residue. Then HCl (1 mol / L, 24 mL) was added and stirred at 25 °C for 1 hour. The combined organic layers were concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography by elution with PE / EtOAc (3:1) to give 10⁻⁴ (0.3 g, 55.5%) of 4-(6-((4-(1-ethoxyvinyl)-2-methylbenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester, a grayish-white oil.

[0580] 1H NMR (400MHz, CDCl3) δ7.84–7.71(m,2H),7.58–7.47(m,2H),6.73(d,J=7.2Hz ,1H),6.63(d,J=8.1Hz,1H),5.41(s,2H),4.22(s,1H),2.77(ddd,J=17.8,15. 4,9.8Hz,3H),2.60(s,3H),2.45(s,3H),1.87(d,J=12.5Hz,2H),1.71(dt,J= 12.7,8.7Hz,2H),1.49(d,J=6.3Hz,9H),0.90(ddd,J=13.5,10.9,8.3Hz,2H).

[0581] (4) Preparation of compound 10-5

[0582]

[0583] At 25 °C, under Ar, 10⁻⁴ (0.28 g, 0.66 mmol, 1 eq) of tert-butyl 4-(6-((4-acetyl-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid was added dropwise to a solution of HCl / EtOAc (6 mL). The mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give 10⁻⁵ (0.26 g, crude product) of 1-(3-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one as a 10⁻⁵ hydrochloride.

[0584] LCMS: rt = 1.130 min, [M+1] + =325.6, purity: 98.2%.

[0585] (5) Preparation of compound 10-6

[0586]

[0587] At 25 °C, DIEA (0.264 g, 2.05 mmol, 5 eq) was added to a solution of 1-(3-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 10⁻⁵ (0.2 g, 0.62 mmol, 1.5 eq) and methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.12 g, 0.41 mmol, 1 eq) in CH₃CN (6 mL). The mixture was stirred at 60 °C under an Ar atmosphere for 16 hours. The mixture was concentrated directly under reduced pressure to obtain a residue, which was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give (S)-2-((4-(6-(((4-acetyl-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 10-6 (0.230 g, 64.0%).

[0588] LCMS: rt = 1.294 min, [M+H] + =583.7, purity: 77.8%.

[0589] (6) Preparation of compound 10

[0590]

[0591] At 25 °C, a solution of LiOH (0.082 g, 3.44 mmol, 10 eq) in H₂O (3 mL) was added to a solution of (S)-2-((4-(6-((4-acetyl-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 10⁻⁶ (0.2 g, 0.34 mmol, 1 e q) in THF (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((4-acetyl-2-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 10 (76.2 mg, 38.9%).

[0592] LCMS: rt = 1.314 min, [M+H] + =569.1, purity: 100%.

[0593] 1H NMR(400MHz,MeOD)δ8.32(s,1H),7.97(dd,J=8.5,1.2Hz,1H),7.84–7.75(m,2H),7.68(d,J=8.5Hz,1H),7.5 8(t,J=7.8Hz,1H),7.52(d,J=7.9Hz,1H),6.83(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.44(s,2H),5.29–5 .21(m,1H),4.88(s,1H),4.84(d,J=7.2Hz,1H),4.74–4.42(m,3H),4.12(dd,J=38.7,14.1Hz,2H),3.16(dd, J=38.5,11.1Hz,2H),2.84–2.68(m,2H),2.55(s,3H),2.50(d,J=7.7Hz,2H),2.44(s,3H),1.97–1.84(m,4H).

[0594] Example 11

[0595] (S)-2-((4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 11)

[0596]

[0597] (1) Preparation of compound 11-1

[0598]

[0599] HCl (10 mL) was added to a MeOH (50 mL) solution of 4-methyl-3-(trifluoromethyl)benzoic acid (4 g, 19.6 mmol), and the mixture was stirred at 80 °C under an Ar atmosphere for 5 hours. The mixture was then cooled to room temperature. The mixture was concentrated under vacuum. The mixture was diluted with EA (200 mL), washed with brine (100 mL), and the organic layer was dried over Na2SO4. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography by elution with PE / EA (20:1) to give a colorless oily methyl 4-methyl-3-(trifluoromethyl)benzoate 11-1 (3.1 g, 74%).

[0600] LCMS: MS(+H): 219, Purity: 98%.

[0601] 1H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.08 (d, J = 7.9Hz, 1H), 7.37 (d, J = 7.9Hz, 1H), 3.93 (s, 3H), 2.54 (s, 3H).

[0602] (2) Preparation of compound 11-2

[0603]

[0604] NBS (856 mg, 4.81 mmol) and AIBN (75 mg, 0.46 mmol) were added to a solution of methyl 4-methyl-3-(trifluoromethyl)benzoate 11-1 (1 g, 4.58 mmol) in CCl4 (10 mL). The mixture was stirred at 85 °C under an Ar atmosphere for 5 hours. The mixture was cooled to room temperature and diluted with DCM. The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography by elution with PE / EA (30:1) to give methyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate 11-2 (700 mg, 53%).

[0605] LCMS: MS(+H): 296, Purity: 90%.

[0606] (3) Preparation of compound 11-3

[0607]

[0608] To a DMF (4 mL) solution of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (400 mg, 1.52 mmol) cooled to 0 °C, NaH (85 mg, 2.12 mmol) was added. The mixture was stirred at 0 °C under an Ar atmosphere for 10 minutes, and then methyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate 11-2 (350 mg, 1.52 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was cooled to room temperature, diluted with EA (200 mL), and the combined organic layers were washed with brine (100 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EA (2:1) to give tert-butyl 4-(6-((4-(methoxycarbonyl)-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 11-3 (320 mg, 82%).

[0609] LCMS: MS(+H): 495, Purity: 82%.

[0610] (4) Preparation of compound 11-4

[0611]

[0612] A solution of tert-butyl 4-(6-((4-(methoxycarbonyl)-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 11-3 (280 mg, 0.55 mmol) in THF (4 mL) was added to a solution of LiOH (26 mg, 1.10 mmol) in water (1 mL), and the mixture was stirred at room temperature for 2 hours. The combined aqueous layers were extracted with EA (40 mL) to remove neutral impurities. The aqueous phase was acidified with HCl (1 M) to pH 5 and extracted with EA (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethyl)benzoic acid 11-4 (200 mg, 76%).

[0613] LCMS: MS(+H): 481, Purity: 76%.

[0614] (5) Preparation of compound 11-5

[0615]

[0616] To a DMF (4 mL) solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethyl)benzoic acid 11-4 (200 mg, 0.41 mmol) and HATU (239 mg, 0.63 mmol), N,O-dimethylhydroxylamine (39 mg, 0.63 mmol) and DIEA (271 mg, 2.1 mmol) were added, and the mixture was stirred for 5 hours at room temperature under an Ar atmosphere. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give tert-butyl 4-(6-((4-(methoxy(methyl)aminoformyl)-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 11-5 (230 mg, 90%).

[0617] LCMS: MS(+H): 524, Purity: 90%.

[0618] (6) Preparation of compound 11-6

[0619]

[0620] To an anhydrous THF solution of tert-butyl 4-(6-((4-(methoxy(methyl)aminoformyl)-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 11-5 (230 mg, 0.44 mmol), CH3MgBr (1 M) (2.2 mL) was added through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3), washed with brine (30 mL × 2), and the combined organic layers were dried over Na2SO4, concentrated, and purified under reduced pressure to give tert-butyl 4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 11-6 (180 mg, 84%).

[0621] LCMS: MS(+H): 479, Purity: 84%.

[0622] (7) Preparation of compound 11-7

[0623]

[0624] To a solution of tert-butyl 4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 11-6 (180 mg, 0.37 mmol) in 1,4-dioxane (5 mL), HCl (2 mL, 1 M) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethyl)phenyl)ethane-1-one 11-7 (180 mg, 100%), as the hydrochloride salt of 11-7.

[0625] LCMS: MS(+H): 379, Purity: 85%.

[0626] (8) Preparation of compound 11-8

[0627]

[0628] DIEA (174 mg, 1.35 mmol) was added to a mixture of 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethyl)phenyl)ethane-1-one 11-7 (180 mg, 0.41 mmol) in ACN (5 mL), and the mixture was stirred at room temperature for 5 minutes. Then (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (80 mg, 0.27 mmol) was added, and the mixture was stirred at 60 °C for 2 hours. The mixture was cooled to room temperature, diluted with EA (50 mL), and the combined organic layers were washed with brine (30 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography. The residue was eluted with PE / EA (2:1) to give (S)-2-((4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 11-8 (150 mg, 56%).

[0629] LCMS: MS(+H): 637, Purity: 56%.

[0630] (9) Preparation of compound 11

[0631]

[0632] Add (4 mL) of THF to a solution of (S)-2-((4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 11-8 (150 mg, 0.23 mmol), then add a solution of H2O (1 mL) of LiOH (17 mg, 0.7 mmol), and stir the mixture at room temperature for 5 hours. The mixture was purified by pre-HPLC (0.05% NH3.H2O / ACN: 20%-35%) to give (S)-2-((4-(6-((4-acetyl-2-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 11 (35 mg, yield: 43%).

[0633] LCMS:[M+1] + =623, purity: 100%.

[0634] 1H-NMR (400MHz, DMSO) δ8.21(t,J=6.5Hz,3H),7.86–7.76(m,2H),7.70–7.63(m,1H),7.55(d,J=8.6Hz,1H ),6.89(d,J=7.2Hz,1H),6.76(d,J=8.1Hz,1H),5.62(s,2H),5.08(d,J=7.3Hz,1H),4.77(dd,J=15.2,7. 1Hz,1H),4.72–4.54(m,1H),4.49–4.30(m,2H),3.91(d,J=13.4Hz,1H),3.74(d,J=13.4Hz,1H),2.93(d, J=11.7Hz,1H),2.86–2.53(m,6H),2.47–2.28(m,2H),2.15(dt,J=22.7,11.3Hz,2H),1.83–1.47(m,5H).

[0635] Example 12

[0636] (S)-2-((4-(6-((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 12)

[0637]

[0638] (1) Preparation of compound 12-2

[0639]

[0640] To 15 mL of a DMF solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (500 mg, 1.79 mmol), NaH (108 mg, 2.69 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 30 min. Then, 12-1 (456 mg, 1.79 mmol) was added to the reaction mixture at room temperature for 30 min. The reaction mixture was poured into water (100 mL), extracted with EA (60 mL × 3), washed with brine, dried, and concentrated to a crude product. This crude product was further purified by column chromatography (PE / EA = 0–10%) to give tert-butyl 4-(6-((2-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 12-2 (250 mg, 34%).

[0641] 1H NMR(400MHz, CDCl3)δ7.64(dd,J=7.8,1.5Hz,1H),7.56(t,J=2.1Hz,1H),7.53–7.48(m,2H),6.68(dd,J=22.8,7.5Hz,2H), 5.45(s,2H),4.36–3.99(m,3H),3.96–3.85(m,7H),2.71(tt,J=11.7,3.7Hz,1H),1.91–1.64(m,4H),1.47(d,J=8.7Hz,9H).

[0642] (2) Preparation of compound 12-3

[0643]

[0644] LiOH (60.4 mg, 2.7 mmol) was added to a THF / H₂O (4 mL) solution of tert-butyl 4-(6-((2-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 12-2 (250 mg, 0.54 mmol), and the mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to 7 with 1N HCl (10 mL × 5) extracted with EA, washed with brine, dried, and concentrated to obtain the product 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-methoxybenzoic acid 12-3 (207 mg, 83%).

[0645] LCMS: rt = 2.21 min, [M+H] + =443, purity: 99%.

[0646] (3) Preparation of compound 12-4

[0647]

[0648] Add N,O-dimethylhydroxylamine hydrochloride (88 mg, 0.905 mmol), HATU (258 mg, 0.678 mmol), and DIEA (233 mg, 1.809 mmol) to a solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-methoxybenzoic acid 12-3 (207 mg, 0.452 mmol) in 5 mL of DMF, and stir for 10 minutes at room temperature. The reaction mixture was poured into water (30 mL), extracted with EA (20 mL × 3), washed with brine and dried, concentrated to crude product, and further purified by column chromatography (PE / EA = 0-47%) to give 12-4 tert-butyl 4-(6-((2-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid ester (190 mg, 86.8%).

[0649] LCMS: rt = 2.275 min, [M+H] + =486, purity: 94.9%.

[0650] (4) Preparation of compound 12-5

[0651]

[0652] 4-(6-(((2-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester 12-4 (190 mg, 0.39 mmol) was stirred at room temperature under nitrogen for 30 min in 5 mL THF. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution, extracted with EA, washed with brine and dried, and concentrated to give crude product, which was further purified by column chromatography (PE / EA = 0-22) to give 4-(6-(((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester 12-5 (120 mg, 69%).

[0653] 1 H NMR (400MHz, CDCl3) δ7.59–7.44(m,4H),6.69(dd,J=24.2,7.5Hz,2H),5.46(s,2H),4.32–4.04(m,3H),3.94 (s,3H),2.92–2.67(m,3H),2.60(s,3H),1.85(d,J=12.2Hz,2H),1.70(dd,J=12.3,3.4Hz,2H),1.48(s,9H).

[0654] (5) Preparation of compound 12-6

[0655]

[0656] To a solution of tert-butyl 4-(6-(((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 5 (120 mg, 0.27 mmol) in 5 mL of HCl / EA, the mixture was stirred at room temperature for 40 minutes. Without further reaction, the reaction mixture was concentrated to give crude product 1-(3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 6 (92 mg, 99% yield) as a yellow solid, which was used directly in the next step without purification.

[0657] LCMS: rt = 1.35 min, [M+H] + =341, purity: 97%.

[0658] (6) Preparation of compound 12-7

[0659]

[0660] Under nitrogen atmosphere and stirring at room temperature, DIEA (116 mg, 0.9 mmol) was added to 1-(3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 12-6 (92 mg, 0.27 mmol) in 10 mL of MeCN solution for 10 min. Then, Int-2 (52 mg, 0.18 mmol) was added to the reaction mixture at room temperature for 60 min. The reaction mixture was concentrated to a crude product and further purified by column chromatography (MeOH / DCM = 0-3%) to give methyl(S)-2-((4-(6-((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazolium-6-carboxylic acid ester 12-7 (100 mg, 62%).

[0661] LCMS: rt = 1.233 min, [M+H] + =599, Purity: 98%.

[0662] (7) Preparation of Compound 12

[0663]

[0664] To a solution of (S)-2-((4-(6-((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 12-7 (100 mg, 0.167 mmol) in THF / H2O (4 mL), LiOH (20 mg, 0.84 mmol) was added with stirring at room temperature for 15 hours, followed by 1N... The reaction mixture was adjusted to pH 6 with HCl and concentrated to obtain a crude product, which was further purified by preparative HPLC to give (S)-2-((4-(6-((4-acetyl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 12 (32 mg, 33%).

[0665] LCMS: rt = 2.28 min, [M+H] + =528, Purity: 99.2%.

[0666] 1 H NMR(400MHz,MeOD)δ8.29(d,J=0.9Hz,1H),7.96(dd,J=8.5,1.5Hz,1H),7.65(d,J=8.5Hz,1H),7.60–7.54(m,2H),7.5 0(dd,J=11.7,4.6Hz,2H),6.80(d,J=7.2Hz,1H),6.66(d,J=7.9Hz,1H),5.43(s,2H),5.24(qd,J=7.2,2.5Hz,1H),4.8 4(d,J=8.3Hz,1H),4.70(d,J=2.6Hz,2H),4.43(s,1H),4.07(d,J=13.9Hz,1H),4.00–3.87(m,4H),3.09(t,J=15.9Hz, 1H), 3.01 (d, J = 11.4Hz, 1H), 2.81–2.71 (m, 1H), 2.69–2.59 (m, 1H), 2.57 (s, 3H), 2.54–2.29 (m, 3H), 1.93–1.79 (m, 4H).

[0667] Example 13

[0668] (S)-2-((4-(6-((4-acetyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 13)

[0669]

[0670] (1) Preparation of compound 13-1

[0671]

[0672] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (0.88 g, 3.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.15 g, 4.3 mmol) was added in portions at 0 °C. After 30 minutes, a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (0.9 g, 3.2 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 2 hours, the reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 13-1 (1.4 g, 82%) of 4-(6-((4-bromo-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0673] LCMS: rt = 3.59 min, [M+1] + =484, Purity: 95%.

[0674] (2) Preparation of compound 13-2

[0675]

[0676] A reaction mixture of 13-1 (1.3 g, 2.71 mmol) of 4-(6-((4-bromo-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 13-1, tributyl(1-ethoxyvinyl)stanane (971 mg, 2.7 mmol) and Pd(PPh3)2Cl2 (98 mg) in DMF (15 mL) was added, and the mixture was stirred at N2 and 100 °C for 16 hours. The reaction mixture was analyzed by LC-MS. A saturated potassium fluoride solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine (20 mL × 2). The combined organic layers were dried over Na2SO4. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 13-2 (1.1 g, 86%) of 4-(6-((4-(1-ethoxyvinyl)-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0677] LCMS: rt = 1.686 min, [M+1]+ =475, Purity: 95%.

[0678] (3) Preparation of compound 13-3

[0679]

[0680] Add a solution of 4-(6-((4-(1-ethoxyvinyl)-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 13-2 (300 mg, 0.108 mmol) in HCl / EA / H2O (5 mL, 3 M). Stir the mixture at room temperature for 1.5 hours. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give 1-(3,5-difluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 13-3 (200 mg, 97%).

[0681] LCMS: rt = 2.1 min, [M+1] + =347, Purity: 90%.

[0682] (4) Preparation of compound 13-4

[0683]

[0684] The reaction mixture of 1-(3,5-difluoro-4-((((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 13-3 (0.18 g, 0.51 mmol) and DIEA (0.21 g, 1.7 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-acetyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 13-4 (0.18 g, 87%).

[0685] LCMS: rt = 2.4 min, [M+1] + =605, Purity: 90%.

[0686] (5) Compound 13

[0687]

[0688] Methyl (S)-2-((4-(6-(((4-acetyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 13-4 (0.18 g, 0.30 mmol) was dissolved in THF (3 mL), and then an aqueous solution of lithium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-(((4-acetyl-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 13 (93 mg, 52.5%).

[0689] LCMS: rt = 2.3 min, [M+1] + =591, Purity: 98%.

[0690] 1 H NMR(400MHz,MeOD)δ8.22(d,J=0.7Hz,1H),7.95(dd,J=8.4,1.4Hz,1H),7.65–7.48(m,4H),6.82(d,J=7.3Hz,1H ),6.56(d,J=8.1Hz,1H),5.53–5.40(m,2H),5.30(qd,J=7.1,2.9Hz,1H),4.97–4.89(m,1H),4.76(dd,J=15.3,2. 8Hz,1H),4.63(dt,J=14.1,7.1Hz,1H),4.49(dt,J=9.1,6.0Hz,1H),3.97(dd,J=46.1,13.6Hz,2H),3.01(dd,J=4 0.7,11.2Hz,2H),2.87–2.74(m,1H),2.71–2.48(m,5H),2.30(tdd,J=14.5,11.1,3.1Hz,2H),2.01–1.77(m,4H).

[0691] Example 14

[0692] (S)-2-((4-(6-((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 14)

[0693]

[0694] (1) Preparation of compound 14-2

[0695]

[0696] Under nitrogen atmosphere and at 80 °C with stirring, NBS (1112 mg, 6.25 mmol) and AIBN (97.6 mg, 0.59 mmol) were added to a solution of methyl 4-fluoro-3-methylbenzoate 14-1 (1 g, 5.95 mmol) in CCl4 (20 mL) for 16 hours. The reaction mixture was concentrated to give a crude product, which was further purified by column chromatography (PE / EA = 0-2%) to give methyl 3-(bromomethyl)-4-fluorobenzoate 14-2 (572 mg, 32%).

[0697] 1 H NMR (400MHz, CDCl3) δ8.12(dd,J=7.3,2.2Hz,1H),8.00(s,1H),7.13(t,J=9.0Hz,1H),4.52(s,2H),4.00–3.82(m,3H).

[0698] (2) Preparation of compound 14-3

[0699]

[0700] Under nitrogen atmosphere and with stirring at room temperature for 30 minutes, NaH (138.4 mg, 3.47 mmol) was added to 10 mL of a DMF solution of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester (644 mg, 2.32 mmol). Then, methyl 3-(bromomethyl)-4-fluorobenzoate 14-2 (572 mg, 2.32 mmol) was added to the reaction mixture at room temperature for 30 minutes. The reaction mixture was poured into water (100 mL), extracted with EtOAc (50 mL × 3), washed with brine, dried over Na2SO4, and concentrated to give a crude product, which was further purified by column chromatography (PE / EA = 0-18%) to give 4-(6-((2-fluoro-5-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 14-3 (210 mg, 20%).

[0701] LCMS: rt = 1.633 min, [M+H] + =445, purity: 90%.

[0702] (3) Preparation of compound 14-4

[0703]

[0704] LiOH (56.4 mg, 2.36 mmol) was added to a THF / H₂O (4 mL) solution of tert-butyl 4-(6-((2-fluoro-5-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 14-3 (210 mg, 0.47 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with 1N HCl and concentrated to give the crude product 3-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-4-fluorobenzoic acid 14-4 (187 mg, 98% yield), which can be used directly in the next step without purification.

[0705] LCMS: rt = 2.28 min, [M+H] + =432, Purity: 93%.

[0706] (4) Preparation of compound 14-5

[0707]

[0708] Add N,O-dimethylhydroxylamine (225.6 mg, 2.33 mmol), HATU (662 mg, 1.74 mmol), and DIEA (598.6 mg, 4.64 mmol) to 10 mL of DMF solution of 3-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-4-fluorobenzoic acid 4 (500 mg, 1.16 mmol) and stir for 10 minutes at room temperature. The reaction mixture was poured into water (100 mL), extracted with EtOAc (50 mL × 3), washed with brine, dried over Na2SO4 and concentrated to obtain the crude product, which was further purified by column chromatography (PE / EA = 0-33%) to obtain 14-5 tert-butyl 4-(6-((2-fluoro-5-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (410 mg, 74.5%).

[0709] LCMS: rt = 2.3 min, [M+H] + =474, Purity: 86%.

[0710] (5) Preparation of compound 14-6

[0711]

[0712] To a solution of tert-butyl 4-(6-((2-fluoro-5-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 14-5 (205 mg, 0.868 mmol) in 10 mL of THF, 2.5 mL of CH3MgBr was added, and the mixture was stirred at room temperature under nitrogen for 30 min. The reaction was monitored by LCMS. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give a crude product. This crude product was further purified by column chromatography (PE / EA = 0-18%) to give tert-butyl 4-(6-((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 14-6 (107 mg, 57.7% yield) as a colorless oil.

[0713] LCMS: rt = 2.47 min, [M+H] + =428.1, purity: 97.6%.

[0714] (6) Preparation of compound 14-7

[0715]

[0716] Add 106 mg (0.25 mmol) of tert-butyl 4-(6-(((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 14-6 to 5 mL of HCl / EA solution and stir for 40 minutes at room temperature. Concentrate the reaction mixture to give crude product 1-(4-fluoro-3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethyl-1-one 14-7 (80 mg, 98%), which can be used directly in the next step without purification.

[0717] LCMS: rt = 1.13 min, [M+H] + =328.1, purity: 54.5%.

[0718] (7) Preparation of compound 14-8

[0719]

[0720] Under nitrogen atmosphere and with stirring at room temperature, DIEA (106 mg, 0.82 mmol) was added to a solution of 1-(4-fluoro-3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 14-7 (80 mg, 0.247 mmol) in 10 mL of MeCN for 10 minutes. Then, Int-2 (48.2 mg, 0.165 mmol) was added to the reaction mixture at 60 °C for 16 hours. The reaction mixture was concentrated to a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give (S)-2-((4-(6-(((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 14-8 (70 mg, 47.6%).

[0721] LCMS: rt = 1.3 min, [M+1] + =587, Purity: 77%.

[0722] (8) Preparation of compound 14

[0723]

[0724] LiOH (14.3 mg, 0.597 mmol) was added to a THF / H2O (10 mL) solution of (S)-2-((4-(6-(((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 14-8 (70 mg, 0.12 mmol) and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with 1N HCl and concentrated to obtain a crude product, which was further purified by preparative HPLC to give (S)-2-((4-(6-(((5-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 14 (37 mg, 54.2%).

[0725] LCMS: rt = 2.1 min, MH+ = 573, purity: 99%.

[0726] 1H NMR(400MHz,MeOD)δ9.07(d,J=1.5Hz,1H),8.35–8.23(m,2H),7.95(dd,J=8.5,1.5Hz,1H),7.68–7.54(m,3H),6.83(d,J =7.2Hz,1H),6.74(d,J=7.9Hz,1H),5.54(s,2H),5.26(qd,J=7.1,2.7Hz,1H),4.76–4.59(m,2H),4.46(dt,J=9.1,6.0Hz, 1H),4.01(d,J=13.7Hz,1H),3.90(d,J=13.7Hz,1H),3.01(d,J=11.7Hz,1H),2.91(d,J=11.4Hz,1H),2.80(dtd,J=11.4, 8.2, 6.2Hz, 1H), 2.64–2.46 (m, 5H), 2.37–2.14 (m, 2H), 1.75 (ddd, J=21.1, 12.9, 7.4Hz, 4H), 1.37 (dd, J=7.0, 2.2Hz, 1H).

[0727] Example 15

[0728] (S)-2-((4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 15)

[0729]

[0730] (1) Preparation of compound 15-2

[0731]

[0732] To a DMF (20 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (1.4 g, 5.0 mmol, 1 eq), NaH (0.26 g, 6.5 mmol, 1.3 eq) was added for 30 minutes at 0 °C. Methyl 4-(bromomethyl)-3-fluorobenzoate 15-1 (1.6 g, 6.5 mmol, 1.3 eq) was added to the above solution, and the mixture was stirred at 25 °C for 2 hours. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with (PE / EA = 0-20%) to give 15-2 (1.1 g, 50%) of 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester.

[0733] 1 H NMR(400MHz, CD3Cl3)δ=7.81(dd,J=8.0,1.5Hz,1H),7.73(dd,J=10.4,1.5Hz,1H),7.62–7.44(m,2H),6.73(d,J=7.3Hz,1H),6.65( d,J=8.1Hz,1H),5.49(s,2H),4.20(s,1H),3.92(s,3H),2.77(d,J=43.3Hz,3H),2.05(s,1H),1.85(d,J=12.6Hz,2H),1.49(s,9H).

[0734] (2) Preparation of compound 15-3

[0735]

[0736] At 25 °C, 1.4 g (3.15 mmol, 1 eq) of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 15-3 was added to a THF (10 mL) solution of 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 15-3 in H2O (10 mL) and LiOH (0.378 g, 15.7 mmol, 5.0 eq) in H2O (10 mL). The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with HCl (1 N). The reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 15-3 (0.47 g, 34.7%).

[0737] LCMS: rt = 2.177 min, [M+1] + =431.2, Purity: 69.7%

[0738] (3) Preparation of compound 15-4

[0739]

[0740] A solution of 15-3-fluorobenzoic acid (0.470 g, 1.09 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (0.214 g, 2.18 mmol, 2.0 eq), DIEA (0.564 g, 4.37 mmol, 4.0 eq), and HATU (0.623 g, 1.64 mmol, 1.5 eq) in DMF (6 mL) was stirred at 25 °C for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O (80 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give 15-4 (0.440 g, 85.4%) of 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester.

[0741] LCMS: rt = 2.262 min, [M+1] + =474.3, purity: 98%.

[0742] (4) Preparation of compound 15-5

[0743]

[0744] A solution of tert-butyl 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 15-4 (0.19 g, 0.40 mmol, 1 eq) in HCl / EA (3 mL) was stirred at 25 °C for 30 min. The mixture was concentrated to give 3-fluoro-N-methoxy-N-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 15-5 (0.19 g, crude product).

[0745] LCMS: rt = 1.147 min, [M+1] + =374.1, purity: 79.6%.

[0746] (5) Preparation of compound 15-6

[0747]

[0748] At 25 °C, DIEA (0.274 g, 2.12 mmol, 5 eq) was added to a solution of 3-fluoro-N-methoxy-N-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 15-5 (0.190 g, 0.51 mmol, 1 eq) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.125 g, 0.42 mmol, 1 eq) in CH3CN (4 mL). The mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give (S)-2-((4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 15-6 (0.2 g, 62.3%).

[0749] LCMS: rt = 1.568 min, [M+H] + =632.5, purity: 100%.

[0750] (6) Preparation of compound 15

[0751]

[0752] At 25°C, LiOH (0.0012 g, 0.51 mmol, 5.0 eq) in 4 mL of H₂O (4 mL) was added to a solution of methyl (S)-2-((4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 15-6 (0.160 g, 0.25 mmol, 1 eq). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 15 (7 mg, 4.5%).

[0753] LCMS: rt = 1.224 min, [M+1] +=618.4, purity: 100%.

[0754] 1 H NMR (400MHz, CD3OD_SPE) δ8.18(d,J=0.8Hz,1H),7.93(dd,J=8.4,1.4Hz,1H),7.61–7.51(m,3H),7.46–7.32(m,2H),6.81(d,J=7.3Hz,1H ),6.64(d,J=8.1Hz,1H),5.48(s,2H),5.29(dd,J=7.3,2.7Hz,1H),4.92(d,J=7.1Hz,1H),4.73(dd,J=15.3,2.9Hz,1H),4.62(dt,J=14.2, 7.1Hz,1H),4.47(dt,J=9.1,6.0Hz,1H),3.99(d,J=13.6Hz,1H),3.88(d,J=13.6Hz,1H),3.48(s,3H),3.28(s,3H),3.01(d,J=11.2Hz,1H) ,2.91(d,J=11.1Hz,1H),2.86–2.73(m,1H),2.57(ddd,J=20.4,10.7,7.2Hz,2H),2.33–2.17(m,2H),1.83(ddd,J=23.2,11.9,6.1Hz,4H).

[0755] Example 16

[0756] (S)-2-((4-(6-((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 16)

[0757]

[0758] (1) Preparation of compound 16-2

[0759]

[0760] To 10 mL of a DMF solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (300 mg, 1.41 mmol), NaH (85 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 30 min. Then, 1-(4-(bromomethyl)phenyl)ethyl-1-one 16-1 (392 mg, 1.41 mmol) was added to the reaction mixture at room temperature for 30 min. The reaction mixture was poured into water (100 mL), extracted with EtOAc (50 mL × 3), washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. This crude product was further purified by vacuum distillation (EA / PE = 0-18%) to give tert-butyl 4-(6-((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 16-2 (140 mg, 24.3%).

[0761] LCMS: rt = 2.27 min, [M+H] + =411, purity: 99.7%.

[0762] (2) Preparation of compound 16-3

[0763]

[0764] To 5 mL of HCl / EtOAc solution containing 140 mg (0.34 mmol) of tert-butyl 4-(6-(((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 16-2, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated to give the crude product 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethyl-1-one 16-3 (100 mg, 95%).

[0765] LCMS: rt = 0.89 min, [M+H] + =311, Purity: 94.5%.

[0766] (3) Preparation of compound 16-4

[0767]

[0768] Under nitrogen atmosphere and with stirring at room temperature for 10 minutes, DIEA (139 mg, 1.07 mmol) was added to 10 mL of a MeCN solution of 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 16-3 (100 mg, 0.32 mmol). Then, Int-2 (63 mg, 0.22 mmol) was added to the reaction mixture at room temperature for 60 minutes. The reaction mixture was concentrated to give a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give (S)-2-((4-(6-(((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 16-4 (130 mg, 71%).

[0769] LCMS: rt = 1.07 min, [M+H] + =569, purity: 98.5%.

[0770] (4) Preparation of compound 16

[0771]

[0772] A solution of (S)-2-((4-(6-((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 16-4 (130 mg, 0.23 mmol) in THF / H2O (4 mL) was stirred and LiOH (27 mg, 1.14 mmol) was added for 16 hours at room temperature. The reaction mixture was adjusted to pH 6 with 1N HCl and concentrated to give a crude product, which was further purified by preparative HPLC to give (S)-2-((4-(6-((4-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 16 (52 mg, 43.7%).

[0773] LCMS: rt = 2.24 min, [M+H]+ = 555, purity: 100%.

[0774] 1H NMR (400MHz, MeOD) δ8.33(d,J=0.8Hz,1H),7.97(ddd,J=4.9,4.2,1.6Hz,3H),7.68(d,J=8.5Hz,1H ),7.63–7.48(m,3H),6.83(d,J=7.2Hz,1H),6.68(d,J=8.0Hz,1H),5.47(s,2H),5.26(qd,J=7.1,2. 5Hz,1H),4.83(s,1H),4.73(d,J=2.6Hz,2H),4.45(d,J=9.2Hz,1H),4.10(dd,J=39.9,14.0Hz,2H), 3.18(d,J=11.6Hz,1H),3.08(d,J=11.8Hz,1H),2.84–2.64(m,2H),2.56(s,6H),1.97–1.77(m,4H).

[0775] Example 17

[0776] (S)-2-((4-(6-((3-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 17)

[0777]

[0778] (1) Preparation of compound 17-1

[0779]

[0780] NBS (3.3 g, 18.7 mmol) and AIBN (294 mg, 1.78 mmol) were added to a solution of methyl 2-fluoro-3-methylbenzoate (3 g, 17.8 mmol) in CCl4 (2 mL). The mixture was stirred at 85 °C under an Ar atmosphere for 5 hours. The mixture was cooled to room temperature, diluted with DCM, and the combined organic layers were washed with brine (200 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography by elution with PE / EA (20:1) to give methyl 3-(bromomethyl)-2-fluorobenzoate 17-1 (2.2 g, 50%).

[0781] LCMS: MS(+2): 248, Purity: 95% (214nm)

[0782] 1H-NMR (400MHz, CDCl3) δ7.90 (ddd, J=8.5, 6.9, 1.8Hz, 1H), 7.59 (td, J=7.6, 1.8Hz, 1H), 7.20 (t, J=7.7Hz, 1H), 4.53 (d, J=1.2Hz, 2H), 3.94 (s, 3H).

[0783] (2) Preparation of compound 17-2

[0784]

[0785] To a mixture of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 17-1 (400 mg, 1.52 mmol) in DMF (4 mL) cooled to 0 °C, NaH (85 mg, 2.12 mmol) was added. The mixture was stirred at 0 °C under an Ar atmosphere for 10 min, followed by the addition of methyl 3-(bromomethyl)-2-fluorobenzoate (350 mg, 1.52 mmol). The mixture was stirred at room temperature for 3 h. The mixture was cooled to room temperature, diluted with EA (200 mL), and the combined organic layers were washed with brine (100 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give 4-(6-((2-fluoro-3-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 17-2 (320 mg, 47%).

[0786] LCMS: MS(-55): 391, Purity: 86% (214nm)

[0787] (3) Preparation of compound 17-3

[0788]

[0789] A solution of tert-butyl 4-(6-((2-fluoro-3-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 17-3 (320 mg, 0.47 mmol) in THF (4 mL) was added to a solution of LiOH (23 mg, 0.94 mmol) in water (1 mL), and the mixture was stirred at room temperature for 2 hours. The combined aqueous layers were extracted with EA (40 mL) to remove neutral impurities. The aqueous phase was acidified with HCl (1 M) to pH 5 and extracted with EA (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid (280 mg, 90%).

[0790] LCMS: MS(+H): 431, Purity: 98% (214nm)

[0791] (4) Preparation of compound 17-4

[0792]

[0793] N,O-dimethylhydroxylamine (68 mg, 1.12 mmol) and DIEA (477 mg, 3.7 mmol) were added to a DMF (8 mL) solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid (280 mg, 0.74 mmol) and HATU (425 mg, 1.12 mmol). The mixture was stirred at room temperature under an Ar atmosphere for 5 hours. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give tert-butyl 4-(6-((4-(methoxy(methyl)aminoformyl)-2-fluoro-benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 17-4 (230 mg, 79%).

[0794] LCMS: MS(+H): 524, Purity: 74% (214nm)

[0795] (5) Preparation of compound 17-5

[0796]

[0797] To an anhydrous THF solution of tert-butyl 4-(6-((4-(methoxy(methyl)aminoformyl)-2-fluoro-benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 17-4 (230 mg, 0.59 mmol), CH3MgBr (1 M) (3.0 mL) was added through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction was detected by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3), washed with brine (30 mL × 2), and the combined organic layers were dried over Na2SO4, concentrated, and purified under reduced pressure to give tert-butyl 4-(6-((4-acetyl-2-fluoro-benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 17-5 (210 mg, 45%).

[0798] LCMS: MS(+H): 429, Purity: 85% (214nm)

[0799] (6) Preparation of compound 17-6

[0800]

[0801] To a solution of tert-butyl 4-(6-(((4-acetyl-2-fluoro-benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 17-5 (210 mg, 0.49 mmol) in 1,4-dioxane (10 mL), HCl (5 mL, 1 M) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was detected by LCMS. The mixture was concentrated under reduced pressure to give 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluoro-phenyl)ethyl-1-one 17-6 (170 mg, 100%).

[0802] LCMS: MS(+H): 329, Purity: 95% (254nm)

[0803] (7) Preparation of compound 17-7

[0804]

[0805] DIEA (174 mg, 1.35 mmol) was added to a mixture of 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluoro-phenyl)ethyl-1-one 17-6 (150 mg, 0.41 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 5 minutes, and then (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (80 mg, 0.27 mmol) was added. The mixture was stirred at 60 °C for 2 hours. The mixture was cooled to room temperature, diluted with EA (50 mL), and the combined organic layers were washed with brine (30 mL). The mixture was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography. The residue was eluted with PE / EA (2:1) to give (S)-2-((4-(6-(((3-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 17-7 (130 mg, 85%).

[0806] LCMS: MS(+H): 587, Purity: 80% (254nm)

[0807] (8) Preparation of compound 17

[0808]

[0809] To a solution of (S)-2-((4-(6-(((3-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 17-7 (130 mg, 0.22 mmol) in THF (4 mL), a solution of LiOH (16 mg, 0.66 mmol) in H2O (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was detected by LCMS. The mixture was purified by pre-HPLC to give (S)-2-((4-(6-(((3-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 17 (45 mg, 43%).

[0810] LCMS:[M+1] + =573, Purity: 99.3%

[0811] 1 H-NMR (400MHz, DMSO) δ8.25 (s, 1H), 7.78 (ddd, J=16.8, 7.9, 2.2Hz, 3H), 7.63 (t, J=8.1Hz ,2H),7.31(t,J=7.6Hz,1H),6.88(d,J=7.3Hz,1H),6.69(d,J=8.2Hz,1H),5.45(s,2H),5. 17–5.04(m,1H),4.87–4.61(m,2H),4.53–4.31(m,2H),3.86(dd,J=68.0,13.5Hz,2H),3.0 4–2.51(m,7H),2.43(d,J=10.9Hz,2H),2.19(dd,J=25.5,10.9Hz,2H),1.88–1.60(m,4H).

[0812] Example 18

[0813] (S)-2-((4-(6-((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 18)

[0814]

[0815] (1) Preparation of compound 18-2

[0816]

[0817] Under a nitrogen atmosphere, NBS (3.64 g, 20.50 mmol) and AIBN (0.306 g, 1.868 mmol) were added to a mixture of 1-(m-tolyl)ethyl-1-one 18-1 (2.5 g, 18.68 mmol) in CCl4 (20 mL) at room temperature. The reaction mixture was stirred at 90 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was concentrated to give a crude compound, which was purified by column chromatography (PE / EA = 0-5%) to give 1-(3-(bromomethyl)phenyl)ethyl-1-one 18-2 (3.386 g, 85.3%).

[0818] 1 H NMR (400MHz, CDCl3) δ7.98(t,J=1.6Hz,1H),7.89(d,J=7.8Hz,1H),7.60(s,1H),7.47(d,J=7.7Hz,1H),4.53(s,2H),2.62(s,3H).

[0819] (2) Preparation of compound 18-3

[0820]

[0821] At 0 °C, NaH (107 mg, 2.69 mmol) was added in portions to a DMF (10 mL) solution of Int-3 (497 mg, 2.34 mmol). After stirring the reaction mixture at 0 °C for 1 hour, 1-(3-(bromomethyl)phenyl)ethyl-1-one 18-2 (500 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4 and filtered through a filter. The filtrate was concentrated to give the residue, which was purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 18-3 (350 mg, 41%).

[0822] 1H NMR(400MHz, CDCl3)δ7.90(d,J=7.8Hz,1H),7.67(d,J=7.6Hz,1H),7.54–7.4 4(m,2H),7.26–7.22(m,1H),6.73(d,J=7.2Hz,1H),6.64(d,J=8.1Hz,1H),5.4 3(s,2H),4.21(s,2H),2.84(t,J=12.1Hz,2H),2.72(dd,J=9.5,5.9Hz,1H),2. 62(s,3H),1.87(d,J=12.2Hz,2H),1.72(dd,J=12.6,3.7Hz,2H),1.49(s,9H).

[0823] (3) Preparation of compound 18-4

[0824]

[0825] A mixture of tert-butyl 4-(6-(((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 18-3 (200 mg, 0.486 mmol) in EA / HCl (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction mixture was concentrated to give 1-(3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 18-4 (180 mg, crude product).

[0826] LCMS: rt = 2.01 min, [M+1] + =311, purity: 86%.

[0827] (4) Preparation of compound 18-5

[0828]

[0829] The reaction mixture of 1-(3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 18-4 (180 mg, 0.58 mmol) and DIEA (196.9 mg, 2.32 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (112 mg, 0.39 mmol) was added and the mixture was heated at 60 °C for 12 h. The reaction solution was concentrated and purified by column chromatography (PE / EA = 0-50%) to give (S)-2-((4-(6-(((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 18-5 (80 mg, 32%).

[0830] LCMS: rt = 1.44 min, [M+1] + =569, purity: 88%.

[0831] (5) Preparation of compound 18

[0832]

[0833] A mixture of (S)-2-((4-(6-(((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 18-5 (80 mg, 0.141 mmol) in THF (3 mL) was added to a lithium hydroxide solution (4 N, 3 mL). The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-(((3-acetylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 18 (10 mg, 12.8%).

[0834] LCMS: rt = 2.223 min, [M+1] + =555, purity: 99%.

[0835] 1 H NMR (400MHz, MeOD) δ8.32(d,J=0.9Hz,1H),8.08(s,1H),7.97(dd,J=8.5,1.5Hz,1H),7.90(d,J=7.8Hz,1H),7.68(dd,J=7.9,4.6Hz,2H ),7.57(dd,J=8.2,7.4Hz,1H),7.47(t,J=7.7Hz,1H),6.81(d,J=7.2Hz,1H),6.65(d,J=7.8Hz,1H),5.46(s,2H),5.27(dd,J=7.4,2.5H z,1H),4.90(d,J=7.2Hz,1H),4.73(dd,J=15.4,2.6Hz,1H),4.62(dd,J=10.9,4.9Hz,1H),4.46(dt,J=9.2,5.9Hz,1H),4.07(dd,J=40. 3,13.9Hz,2H),3.18–3.12(m,1H),3.05(d,J=11.4Hz,1H),2.84–2.76(m,1H),2.72–2.65(m,1H),2.56–2.40(m,6H),1.95–1.85(m,4H).

[0836] Example 19

[0837] (S)-2-((4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 19)

[0838]

[0839] (1) Preparation of compound 19-2

[0840]

[0841] Under nitrogen protection at 0 °C, NaH (0.345 g, 8.62 mmol) was added fractionally to a solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (2.0 g, 7.19 mmol) in DMF (15 mL). After stirring the reaction mixture for one hour, 4-bromo-1-(bromomethyl)-2-fluorobenzene 19-1 (1.93 g, 7.19 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated salt solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid (PE / EA 0-20%) purification to give tert-butyl 4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 19-2 (2.17 g, 65%).

[0842] LCMS: rt = 2.332 min, [M+1] + =465, purity: 97%.

[0843] (2) Preparation of compound 19-3

[0844]

[0845] N-BuLi (0.58 mL, 1.44 mmol) was added to a THF (5 mL) solution of 4-(6-(((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 19-2 (500 mg, 1.11 mmol) at -70 °C, and the mixture was stirred at -70 °C for 30 min under N2. The above solution was added dropwise to a THF (5 mL) solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 19-2A (384 mg, 2.22 mmol), and the mixture was stirred at -70 °C to -25 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated salt solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (PE / EA = 0-30%) to give 19-3 (240 mg, 43.45%) of 4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0846] LCMS: rt = 3.27 min, [M-55] + =443, purity: 96%.

[0847] (3) Preparation of compound 19-4

[0848]

[0849] A reaction mixture of 4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 19-3 (240 mg, 0.481 mmol) was added to EA / HCl (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction solution was concentrated to give (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(tetrahydro-2H-pyran-4-yl)methyl ketone 19-4 (200 mg, crude product).

[0850] LCMS: rt = 1.33 min, [M+1] + =399, purity: 97%.

[0851] (4) Preparation of compound 19-5

[0852]

[0853] A mixture of (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(tetrahydro-2H-pyran-4-yl)methyl ketone 19-4 (130 mg, 0.22 mmol) and DIEA (142.5 mg, 1.10 mmol) in CH3CN (5 mL) was stirred at room temperature for 10 minutes. Compound Int-2 (65 mg, 0.33 mmol) was added to the above solution, and the mixture was then stirred at 60 °C for 12 hours. The reaction solution was concentrated and then purified by column chromatography (MeOH / DCM = 0-5%) to obtain methyl (S)-2-((4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 19-5 (78 mg, 88%).

[0854] LCMS: rt = 1.933 min, [M+1] + =657, purity: 74%.

[0855] (5) Preparation of compound 19

[0856]

[0857] Lithium hydroxide solution (4N, 5mL) was added to a mixture of (S)-2-((4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 19-5 (78 mg, 0.12 mmol) in THF (5 mL). The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((2-fluoro-4-(tetrahydro-2H-pyran-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 19 (40 mg, 52%).

[0858] LCMS: rt = 2.09 min, [M+1] + =643, purity: 99%.

[0859] 1H NMR (400MHz, MeOD) δ8.21(s,1H),7.94(dd,J=8.5,1.3Hz,1H),7.77(d,J=7.9Hz,1H),7.71(d,J=10.7Hz,1H),7.63(t,J=7.6Hz,1H), 7.60–7.55(m,2H),6.82(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.50(t,J=8.7Hz,2H),5.30(d,J=4.4Hz,1H),4.94–4.88(m,1H),4.7 4(dd,J=15.3,2.9Hz,1H),4.65–4.59(m,1H),4.48(dt,J=9.2,6.0Hz,1H),4.00–3.85(m,4H),3.52(ddd,J=13.5,11.9,6.3Hz,3H),3. 02(d,J=11.4Hz,1H),2.91(d,J=11.1Hz,1H),2.81(dd,J=18.6,7.3Hz,1H),2.64–2.51(m,2H),2.32–2.20(m,2H),1.94–1.62(m,9H).

[0860] Example 20

[0861] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxacyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 20)

[0862]

[0863] (1) Preparation of compound 20-2

[0864]

[0865] At 0 °C, NaH (0.223 g, 9.30 mmol, 1.2 eq) was added to a DMF (20 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate 20-1A (2.15 g, 7.75 mmol, 1 eq). After 1 hour, methyl 4-(bromomethyl)-3-methoxybenzoate 20-1 (2 g, 7.75 mmol, 1 eq) was added to the above solution, and the mixture was stirred at 25 °C for 2 hours. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with (PE / EA = 0-20%) to give 20-2 (2.2 g, 62.3%) of 4-(6-((2-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester.

[0866] 1 H NMR (400MHz, CDCl3) δ7.64(dd,J=7.8,1.4Hz,1H),7.52(ddd,J=9.1,8.1,2.2Hz,3H),6.71(d,J=7.2Hz,1H),6 .65(d,J=8.1Hz,1H),5.45(s,2H),4.15(s,2H),3.92(d,J=4.7Hz,6H),2.71(s,3H),1.83(s,4H),1.48(s,9H).

[0867] (2) Preparation of compound 20-3

[0868]

[0869] At 25 °C, 2.1 g (4.60 mmol, 1 eq) of tert-butyl 4-(6-(((2-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 20-2 in THF (15 mL) was added to LiOH (0.551 g, 23.0 mmol, 5.0 eq) in H2O (15 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give 2.2 g (crude product) of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-methoxybenzoic acid 20-3.

[0870] LCMS: rt = 2.189 min, [M+1] + =443.3, purity: 94.9%.

[0871] (3) Preparation of compound 20-4

[0872]

[0873] HATU (2.7 g, 7.12 mmol, 1.5 eq) was added to a DMF (30 mL) solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-methoxybenzoic acid 20-3 (2.1 g, 4.75 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (0.93 g, 9.49 mmol, 2.0 eq), and DIEA (2.45 g, 18.9 mmol, 4.0 eq) in 6-(3 mL) of dimethyl hydroxylamine hydrochloride. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with H2O (150 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to give 20-4 (1.8 g, 80%) of 4-(6-((2-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0874] LCMS: rt = 2.332 min, [M+1] + =486.2, purity: 99.4%.

[0875] (4) Preparation of compound 20-5

[0876]

[0877] At 25 °C, cyclopropyl magnesium bromide (2 mL, 1 mmol, 2.0 eq) of tert-butyl 4-(6-((2-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 20-4 (0.5 g, 1 mmol, 1 eq) in THF (8 mL) was added. The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with H2O (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give 20-5 tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (0.35 g, 72.9%).

[0878] LCMS: rt = 1.836 min, [M+1] + =467.2, purity: 97.6%.

[0879] (5) Preparation of compound 20-6

[0880]

[0881] A solution of tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 20-5 (0.35 g, 0.75 mmol, 1 eq) in HCl / EA (6 mL) was stirred at 25 °C for 30 min. The mixture was concentrated to give cyclopropyl(3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone 20-6 (0.188 g, crude product).

[0882] LCMS: rt = 0.787 min, [M+1] + =367.2, purity: 97.8%

[0883] (6) Preparation of compound 20-7

[0884]

[0885] At 25 °C, DIEA (0.219 g, 1.7 mmol, 5 eq) was added to a solution of cyclopropyl (3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone 20-6 (0.187 g, 0.51 mmol, 1.5 eq) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.1 g, 0.34 mmol, 1 eq) in MeCN (6 mL). The mixture was stirred at 60 °C under an Ar atmosphere for 16 hours. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography by elution with DCM / MeOH (10:1) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 20-7 (0.167 g, 52.5% yield).

[0886] LCMS: rt = 1.639 min, [M+H] + =625.5, purity: 98.2%.

[0887] (7) Preparation of compound 20

[0888]

[0889] At 25 °C, LiOH (0.027 g, 1.12 mmol, 5.0 eq) in 3 mL of H₂O (3 mL) was added to a solution of (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 20-7 (0.14 g, 0.22 mmol, 1 eq) in 3 mL of THF. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and then purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 20 (60 mg, 44.1%).

[0890] LCMS: rt = 1.304 min, [M+H] + =611.2, Purity: 100%.

[0891] 1 H NMR (400MHz, MeOD) δ8.32(s,1H),7.97(dd,J=8.5,1.4Hz,1H),7.70–7.65(m,2H),7.62–7.57(m,1H),7.53(dd,J=13. 1,4.5Hz,2H),6.82(d,J=7.3Hz,1H),6.69(d,J=8.2Hz,1H),5.46(s,2H),5.25(dd,J=7.3,2.4Hz,1H),4.83(d,J=7.2 Hz,1H),4.73–4.58(m,2H),4.48–4.41(m,1H),4.08(dd,J=40.1,14.0Hz,2H),3.93(s,3H),3.11(dd,J=39.5,11.8Hz ,2H),2.79(ddd,J=40.4,22.0,16.8Hz,3H),2.48(dt,J=15.7,8.1Hz,3H),1.88(d,J=6.8Hz,4H),1.14–1.03(m,4H).

[0892] Example 21

[0893] (S)-2-((4-(6-((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 21)

[0894]

[0895] (1) Preparation of compound 21-2

[0896]

[0897] CBr4 (2.4 g, 7.4 mmol, 2 eq) and PPh3 (1.9 g, 7.4 mmol, 2 eq) were added to a DCM (10 mL) solution of (4-bromo-2-(trifluoromethoxy)phenyl)methanol 21-1 (1 g, 3.7 mmol, 1 eq). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography, eluting with PE, to give 4-bromo-1-(bromomethyl)-2-(trifluoromethoxy)benzene 21-2 (1.1 g, 90.2%).

[0898] 1 H NMR (400MHz, CDCl3) δ7.48–7.39 (m, 2H), 7.36 (d, J = 8.7Hz, 1H), 4.46 (s, 2H).

[0899] (2) Preparation of compound 21-3

[0900]

[0901] To a solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (0.756 g, 2.72 mmol, 1 eq) in DMF (8 mL), NaH (0.085 g, 3.5 mmol, 1.3 eq) was added for 30 min at 0 °C. Then, 4-bromo-1-(bromomethyl)-2-(trifluoromethoxy)benzene 21-2 (0.9 g, 2.72 mmol, 1 eq) was added, and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography, eluting with (PE / EA = 0-20%) to give tert-butyl 4-(6-((4-bromo-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 21-3 (0.74 g, 51.4%).

[0902] 1H NMR (400MHz, CDCl3) δ7.51(dd,J=8.1,7.4Hz,1H),7.46–7.40(m,3H),6.73(d,J=7.3Hz,1H),6.62(d,J=8.1Hz,1H),5.4 1(s,2H),4.18(d,J=23.3Hz,2H),2.92–2.65(m,3H),1.84(d,J=13.3Hz,2H),1.72–1.62(m,2H),1.49(d,J=3.8Hz,9H).

[0903] (3) Preparation of compound 21-4

[0904]

[0905] At 25 °C, Pd(PPh3)Cl2 (0.041 g, 0.06 mmol, 0.05 eq) was added to a DMF (10 mL) solution of 4-(6-((4-bromo-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 21-3 (0.62 g, 1.17 mmol, 1 eq) and tributyl(1-ethoxyvinyl)stanane (0.44 g, 1.23 mmol, 1.05 eq). The mixture was stirred at 100 °C under an Ar atmosphere for 16 hours. After stirring at 25 °C for 1 hour, KF solution was added to the reaction mixture. The mixture was diluted with EtOAc (80 mL), washed with H2O (150 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated under reduced pressure to give the residue. Add HCl (1 mol / L, 24 mL) and stir at 25 °C for 1 hour. Concentrate the combined organic layers under reduced pressure to obtain the residue. Purify the residue by silica gel column chromatography, eluting with PE / EtOAc (3:1), to give tert-butyl 4-(6-((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 21-4 (0.57 g, 98.7%).

[0906] 1H NMR (400MHz, CDCl3) δ7.91–7.81(m,2H),7.65(d,J=8.4Hz,1H),7.53(dd,J=8.1,7.4Hz,1H),6.74(d,J=7.3Hz,1H),6.66(d,J=8.1Hz,1H),5.5 3(s,2H),4.17(d,J=15.3Hz,2H),2.87–2.65(m,3H),2.61(s,3H),1.82(d,J=12.8Hz,2H),1.66(td,J=12.5,4.3Hz,2H),1.47(d,J=5.8Hz,9H).

[0907] (4) Preparation of compound 21-5

[0908]

[0909] At 25 °C and Ar, tert-butyl 4-(6-(((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 21-4 (0.2 g, 0.40 mmol, 1 eq) was added dropwise to a solution of HCl / EA (6 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated to give 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethoxy)phenyl)ethyl-1-one 21-5 (0.22 g, crude product).

[0910] LCMS: rt = 1.302 min, [M+1] + =395.0, purity: 54.6%.

[0911] (5) Preparation of compound 21-6

[0912]

[0913] At 25 °C, DIEA (0.219 g, 1.7 mmol, 5 eq) was added to a solution of 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-(trifluoromethoxy)phenyl)ethyl-1-one 21-5 (0.2 g, 0.51 mmol, 1.5 eq) and methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate Int-2 (0.1 g, 0.34 mmol, 1 eq) in MeCN (8 mL). The mixture was stirred at 60 °C under an Ar atmosphere for 16 hours. It was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give (S)-2-((4-(6-((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 21-6 (0.21 g, 63.6%).

[0914] LCMS: rt = 1.453 min, [M+H] + =653.1, purity: 97.02%.

[0915] (6) Preparation of compound 21

[0916]

[0917] At 25°C, a solution of LiOH (0.066 g, 2.76 mmol, 10 eq) in H₂O (3 mL) was added to a solution of (S)-2-((4-(6-((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 21-6 (0.18 g, 0.28 mmol, 1 eq) in THF (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-((4-acetyl-2-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 21 (44.9 mg, 25.5%).

[0918] LCMS: rt = 1.342 min, [M+H] + =569.1, purity: 98.5%.

[0919] 1HNMR (400MHz, CD3OD_SPE) δ8.30(d,J=9.1Hz,1H),7.96(t,J=7.7Hz,2H),7.86(s,1H),7.68(dd,J=10.8,8.4Hz,2H),7.60(t, J=7.8Hz,1H),6.84(d,J=7.3Hz,1H),6.69(d,J=8.2Hz,1H),5.53(s,2H),5.24(d,J=5.7Hz,1H),4.89(s,1H),4.70(d,J=13.3 Hz,1H),4.61(dd,J=13.9,7.7Hz,1H),4.44(dt,J=9.1,6.0Hz,1H),4.11(d,J=13.9Hz,1H),4.01(d,J=13.9Hz,1H),3.08(dd, J=38.5,11.2Hz,2H),2.84–2.61(m,2H),2.56(d,J=9.7Hz,3H),2.45(ddd,J=22.9,19.4,10.0Hz,3H),1.83(d,J=24.0Hz,4H).

[0920] Example 22

[0921] (S)-2-((6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 22)

[0922]

[0923] (1) Preparation of compound 22-2

[0924]

[0925] Under nitrogen protection at 0 °C, NaH (0.24 g, 6.07 mmol) was added fractionally to a DMF (10 mL) solution of 6-chloropyridin-2-ol (0.52 g, 4.05 mmol). After stirring the reaction mixture for 30 min, methyl 4-(bromomethyl)-3-fluorobenzoate 22-1 (1 g, 4.05 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (EA / PE = 0-20%) to give methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzoate 22-2 (1.08 g, 90%).

[0926] 1 H NMR (400MHz, CDCl3) δ7.84 (dd, J=7.9, 1.5Hz, 1H), 7.74 (dd, J=10.3, 1.5Hz, 1H), 7.63–7.5 1(m,2H),6.94(d,J=7.5Hz,1H),6.74(d,J=8.1Hz,1H),5.48(s,2H),3.93(d,J=4.7Hz,3H).

[0927] (2) Preparation of compound 22-3

[0928]

[0929] Under a nitrogen atmosphere, Pd(dppf)Cl2 (198 mg, 0.271 mmol) was added to a mixture of methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzoate 22-2 (800 mg, 2.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester (920.23 mg, 2.98 mmol) and Cs2CO3 (1.32 mg, 4.06 mmol) in dioxane (10 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction solution was concentrated and then purified by column chromatography (PE / EA = 0-10%) to give tert-butyl 6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate 22-3 (750 mg, 62.65%).

[0930] LCMS: rt = 3.69 min, [M-55] + =378, purity: 94%.

[0931] (3) Preparation of compound 22-4

[0932]

[0933] A mixture of tert-butyl 6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 22-3 (750 mg, 1.76 mmol) in THF (5 mL) was added to a lithium hydroxide solution (5 mL). The mixture was stirred with Ar at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered through a filter. The filtrate was concentrated to give 4-(((1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)oxy)methyl)-3-fluorobenzoic acid 22-4 (600 mg, 80%).

[0934] LCMS: rt = 3.06 min, [M+1] + =429, purity: 97%.

[0935] (4) Preparation of compound 22-5

[0936]

[0937] To a mixture of 4-(((1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-6-yl)oxy)methyl)-3-fluorobenzoic acid 22-4 (600 mg, 1.40 mmol), N,O-dimethylhydroxylamine (273.5 mg, 2.80 mmol), and HATU (799.2 mg, 2.10 mmol) in DMF (8 mL), DIEA (724.7 mg, 7.20 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered through a filter. The filtrate was concentrated to obtain the residue, which was purified by column chromatography (PE / EA = 0-50%) to give 22-5 tert-butyl 6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid (485 mg, 73.45%).

[0938] LCMS: rt = 2.037 min, [M+1] + =472, purity: 94%.

[0939] (5) Preparation of compound 22-6

[0940]

[0941] At 0 °C, a solution of cyclopropyl magnesium bromide in THF (1N, 5.14 mL) was added to a solution of 6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 22-5 (485 mg, 1.03 mmol) in anhydrous THF (16 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered through a filter. The filtrate was concentrated to obtain the residue, which was purified by column chromatography (EA / PE = 0-20%) to give 22-6 of 6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (190 mg, 40.82%).

[0942] LCMS: rt = 3.31 min, [M+1] + =453, purity: 93%.

[0943] (6) Preparation of compound 22-7

[0944]

[0945] A mixture of 6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 22-6 (190 mg, 0.419 mmol) in EA / HCl (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction solution was concentrated to give cyclopropyl(3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)oxy)methyl)phenyl)methyl ketone 22-7 (130 mg, 87.86%).

[0946] LCMS: rt = 2.25 min, [M+1] + =353, purity: 53%.

[0947] (7) Preparation of compound 22-8

[0948]

[0949] The reaction mixture of cyclopropyl (3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)oxy)methyl)phenyl) ketone 22-7 (130 mg, 0.368 mmol) and DIEA (237.36 mg, 1.84 mmol) in 8 mL of CH3CN was stirred at room temperature for 10 minutes. Then Int-2 (65 mg, 0.368 mmol) was added and the mixture was heated at 60 °C for 12 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (PE / EA = 0-30%) to give (S)-2-((6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ester 22-8 (50 mg, 17.3%).

[0950] LCMS:[M+1] + =611, rt=2.61min, purity: 78%.

[0951] (8) Preparation of compound 22

[0952]

[0953] A lithium hydroxide solution (4N, 5 mL) was added to a mixture of (S)-2-((6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 22-8 (50 mg, 0.081 mmol) in THF. The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 22 (7 mg, 14%).

[0954] LCMS: Rt = 1.336 min, [M+1] + =597, Purity: 100%.

[0955] 1H NMR(400MHz,MeOD)δ8.33(s,1H),7.98(dd,J=8.5,1.5Hz,1H),7.85(dd,J=8.0,1.5Hz,1H),7.74–7.67(m,2H) ,7.63(t,J=7.8Hz,2H),7.06(d,J=7.5Hz,1H),6.75–6.67(m,2H),5.53(s,2H),5.25–5.18(m,1H),4.89(s,3H ),4.70(dd,J=15.3,2.6Hz,1H),4.60(d,J=6.0Hz,1H),4.44(dd,J=6.0,3.2Hz,1H),4.19(d,J=13.8Hz,1H),4 .07(d,J=13.8Hz,1H),2.87(d,J=4.1Hz,2H),2.81–2.70(m,2H),2.63(s,2H),2.49(s,1H),1.14–1.05(m,4H).

[0956] Example 23

[0957] (S)-2-((6-((4-acetyl-3-methoxybenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 23)

[0958]

[0959] (1) Preparation of compound 23-2

[0960]

[0961] Under nitrogen protection at 0 °C, NaH (194 mg, 4.85 mmol) was added in portions to a DMF (15 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate 23-1 (900 mg, 3.23 mmol). After stirring the reaction mixture for one hour, methyl 4-(bromomethyl)-2-methoxybenzoate (838 mg, 3.23 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated salt solution, dried over anhydrous MgSO4, concentrated, and the residue was purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((3-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 23-2 (610 mg, 44%).

[0962] LCMS: rt = 2.28 min, [M+1] + =457, purity: 96%.

[0963] (2) Preparation of compound 23-3

[0964]

[0965] A mixture of tert-butyl 4-(6-((3-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 23-2 (108 mg, 0.181 mmol) in THF (5 mL) was added to a lithium hydroxide solution (4 N, 5 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was extracted with DCM (15 mL × 3). The combined organic layers were washed with a saturated salt solution, dried over anhydrous Na2SO4, and concentrated to give 4-((((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-2-methoxybenzoic acid 23-3 (540 mg, crude product).

[0966] LCMS: rt = 2.25 min, [M-100] + =343, purity: 37%.

[0967] (3) Preparation of compound 23-4

[0968]

[0969] The reaction mixture of 4-((((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-2-methoxybenzoic acid 23-3 (480 mg, 1.08 mmol), N,O-dimethylhydroxylamine (210.7 mg, 2.16 mmol), HATU (615.6 mg, 1.62 mmol), and DIEA (558.3 ​​mg, 4.32 mmol) in DMF (10 mL) was mixed. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted three times with EA (20 mL), washed twice with saturated salt (30 mL), and concentrated to obtain the residue, which was purified by column chromatography (EA / PE = 0-50%) to give 23-4 tert-butyl 4-(6-((3-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid ester (450 mg, 85%).

[0970] LCMS: rt = 1.976 min, [M+1] + =486, purity: 93%.

[0971] (4) Preparation of compound 23-5

[0972]

[0973] 4-(6-((3-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 23-4 (400 mg, 0.824 mmol) was dissolved in anhydrous THF containing Ar2 (6 mL). CH3MgBr (1N, 4.12 mL) in THF was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by TLC. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (30 mL). The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to give 4-(6-(((4-acetyl-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 23-5 (300 mg, 82.67%).

[0974] LCMS: rt = 2.25 min, [M+1] + =441, purity: 90%.

[0975] (5) Preparation of compound 23-6

[0976]

[0977] The reaction mixture of 23-5 (200 mg, 0.113 mmol) of 4-(6-(((4-acetyl-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester) in EA / HCl (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction solution was concentrated to give 22-6 (173 mg, 89.55% yield) of 1-(2-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one as a white solid.

[0978] LCMS: rt = 1.298 min, [M+1] + =341, purity: 93%.

[0979] (6) Preparation of compound 23-7

[0980]

[0981] A reaction mixture of 1-(2-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 22-6 (173 mg, 0.50 mol), DIEA (219 mg, 1.7 mmol), and 10 mL of CH3CN was stirred at room temperature for 10 minutes. Then, Int-2 (0.10 g, 0.34 mmol) was added to the above solution, and the mixture was heated at 60 °C for 12 hours. The reaction solution was concentrated and purified by column chromatography (MeOH / DCM = 0-10%) to give methyl 2-((4-(6-((4-acetyl-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 23-7 (108 mg, 82.3%).

[0982] LCMS: rt = 2.41 min, [M+1] + =599, purity: 97%.

[0983] (7) Preparation of compound 22

[0984]

[0985] A mixture of methyl 2-((4-(6-(((4-acetyl-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 23-7 (108 mg, 0.181 mmol) in THF (5 mL) was added to a lithium hydroxide solution (4 N, 5 mL). The mixture was stirred at 40 °C for 2 hours. The mixture was concentrated and purified by pre-HPLC under alkaline conditions to give (S)-2-((6-(((4-acetyl-3-methoxybenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 23 (58 mg, 55%).

[0986] LCMS: rt = 1.300 min, [M+1] + =585, purity: 99%.

[0987] 1HNMR (400MHz, MeOD) δ8.17(s,1H),7.94(dd,J=8.4,1.4Hz,1H),7.65(d,J=8.0Hz,1H),7.58(t,J=7.9Hz,2H),7.20(s,1H),7.07(d, J=8.3Hz,1H),6.82(d,J=7.3Hz,1H),6.66(d,J=8.1Hz,1H),5.43(s,2H),5.28(dd,J=7.2,2.8Hz,1H),4.89(d,J=7.0Hz,1H),4.72( dd,J=15.3,2.9Hz,1H),4.64–4.56(m,1H),4.46(dt,J=9.1,5.9Hz,1H),3.99(d,J=13.6Hz,1H),3.90(d,J=11.6Hz,4H),3.03(d,J= 11.0Hz,1H),2.94(d,J=11.6Hz,1H),2.82–2.72(m,1H),2.62(s,1H),2.54(d,J=6.8Hz,4H),2.35–2.21(m,2H),1.91–1.80(m,4H).

[0988] Example 24

[0989] (S)-2-((4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 24)

[0990]

[0991] (1) Preparation of compound 24-1

[0992]

[0993] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (2 g, 7.2 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.21 g, 8.6 mmol) was added in portions at 0 °C. After 30 minutes, a solution of 4-(bromomethyl)-3-fluorobenzoate methyl ester (1.78 g, 7.2 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 2 hours, the reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 24-1 (2.02 g, 63%) of 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester.

[0994] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[0995] (2) Preparation of compound 24-2

[0996]

[0997] 2.0 g (4.5 mmol) of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 24-1 was dissolved in THF (15 mL), and then an aqueous solution of lithium hydroxide (15 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was monitored by LC-MS. The pH of the mixture was adjusted to 7-8 with dilute hydrochloric acid solution. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. Concentration yielded 1.7 g (87.6%) of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 24-2.

[0998] LCMS: rt = 2.85 min, [M+1] + =375, purity: 95%.

[0999] (3) Preparation of compound 24-3

[1000]

[1001] To 10 mL of a DMF solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 24-2 (500 mg, 1.16 mmol), dimethylamine (189 mg, 2.3 mmol), HATU (662.9 mg, 1.7 mmol), and DIEA (600 mg, 4.65 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water (30 mL), extracted with EA (20 mL × 3), washed with brine, and the combined organic layers were dried over Na2SO4. The mixture was concentrated to a crude product and further purified by column chromatography (PE / EA = 0–30%) to give 4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 24-3 (400 mg, 92.8%).

[1002] LCMS: rt = 2.275 min, [M+1] + =459, purity: 94.9%.

[1003] (4) Preparation of compound 24-4

[1004]

[1005] Add a solution of tert-butyl 4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 24-3 (400 mg, 0.875 mmol) in HCl / EA (10 mL, 4 M). Stir the mixture at room temperature for 1 hour. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give 3-fluoro-N,N-dimethyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 24-4 (320 mg, 97%).

[1006] LCMS: rt = 1.95 min, [M+1] + =359.1, purity: 97%.

[1007] (5) Preparation of compound 24-5

[1008]

[1009] The reaction mixture of 3-fluoro-N,N-dimethyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzamide 24-4 (0.182 g, 0.51 mmol) and DIEA (0.328 g, 2.55 mmol) in 10 mL CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 24-5 (0.18 g, 86%).

[1010] LCMS: rt = 2.19 min, [M+1] + =616, purity: 96%.

[1011] (5) Preparation of compound 24

[1012]

[1013] Methyl (S)-2-((4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 24-5 (0.18 g, 0.292 mmol) was dissolved in THF (4 mL), and then an aqueous solution of lithium hydroxide (4 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The pH of the mixture was adjusted to 5-6 with dilute hydrochloric acid solution (1M), concentrated, and purified by preparative HPLC (TFA) to give (S)-2-((4-(6-((4-(dimethylaminoformyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 24 (0.06 g, 34%).

[1014] LCMS: rt = 2.11 min, [M+1] + =602, purity: 98%.

[1015] 1H NMR (400MHz, MeOD) δ8.34(d,J=0.9Hz,1H),8.04(dd,J=8.5,1.5Hz,1H),7.81(dd,J=8.5,4.9Hz,1H),7.62(dt,J=15.2,7.8H z,2H),7.28–7.18(m,2H),6.92(d,J=7.3Hz,1H),6.75(d,J=8.2Hz,1H),5.51(s,2H),5.22(tt,J=7.1,3.6Hz,1H),4.85(d,J =3.8Hz,2H),4.78(dd,J=15.8,6.8Hz,1H),4.68(ddd,J=13.7,8.4,5.6Hz,2H),4.50–4.37(m,1H),3.94–3.79(m,2H),3.51– 3.35(m,2H),3.08(s,3H),3.04(d,J=7.3Hz,1H),2.98(s,3H),2.87–2.74(m,1H),2.51(dq,J=11.5,7.5Hz,1H),2.18(s,4H).

[1016] Example 25

[1017] (S)-2-((6-((2-fluoro-4-propionylbenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 25)

[1018]

[1019] (1) Preparation of compound 25-2

[1020]

[1021] At 0 °C, NaH (0.21 g, 8.6 mmol) was added fractionally to an anhydrous DMF (15 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (2 g, 7.2 mmol). After 30 minutes, a DMF (5 mL) solution of methyl 4-(bromomethyl)-3-fluorobenzoate (1.78 g, 7.2 mmol) was added to the reaction mixture via a sleeve. The reaction mixture was analyzed by LCMS after 2 hours. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried with Na2SO4 and concentrated to obtain the residue, which was purified by column chromatography (PE / EA = 0-20%) to give 25-2 (2.02 g, 63%) of 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[1022] LCMS: rt = 3.35 min, [M-55] + =389.1, purity: 96%.

[1023] (2) Preparation of compound 25-3

[1024]

[1025] 25-2 (2.0 g, 4.5 mmol) of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid was dissolved in THF (15 mL), and then an aqueous solution of lithium hydroxide (4 N, 15 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The pH of the mixture was adjusted to 7-8 with hydrochloric acid (1 N). The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give 25-3 (1.7 g, 87.6%) of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid.

[1026] LCMS: rt = 2.85 min, [M+1] + =375, purity: 95%.

[1027] (3) Preparation of compound 25-4

[1028]

[1029] HATU (2.34 g, 5.93 mmol) was added to a mixture of 25-3-((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid (1.7 g, 3.95 mmol), N,O-dimethylhydroxylamine (0.765 g, 7.9 mmol), and DIEA (2.04 g, 15.8 mmol) in DMF (25 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to obtain the residue, which was purified by column chromatography (PE / EA = 0-20%) to give 25-4 (1.6 g, 85.6%) of 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[1030] LCMS: rt = 2.42 min, [M+1] + =474, purity: 97%.

[1031] (4) Preparation of compound 25-5

[1032]

[1033] 4-(6-(((2-fluoro-4-(methoxy-4-propionylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 25-4 (0.4 g, 0.84 mmol) was dissolved in anhydrous THF (10 mL) with Ar2. CH3CH2MgBr (2N, 2 mL) was added to the above reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated to obtain the residue, which was purified by column chromatography to give 4-(6-(((2-fluoro-4-propionylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 25-5 (0.4 g, 86%).

[1034] LCMS: rt = 0.94 min, [M+1] + =387, purity: 97%.

[1035] (5) Preparation of compound 25-6

[1036]

[1037] A mixture of tert-butyl 4-(6-(((2-fluoro-4-propionylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 25-5 (400 mg, 0.903 mmol) in EA / HCl (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 1-(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)prop-1-one 25-6 (450 mg, crude product).

[1038] LCMS: rt = 0.94 min, [M+1] + =344, purity: 98%.

[1039] (6) Preparation of compound 25-7

[1040]

[1041] A mixture of 1-(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)prop-1-one 25-6 (0.20 g, 0.59 mmol) and DIEA (0.202 g, 1.6 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 minutes. Then Int-2 (0.115 g, 0.39 mmol) was added, and the mixture was heated at 60 °C for 12 hours. The reaction solution was concentrated to obtain the residue, which was purified by column chromatography (PE / EA = 0-50%) to give (S)-2-((6-(((2-fluoro-4-propionylbenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 25-7 (230 mg, 89%).

[1042] LCMS: rt = 2.57 min, [M+1] + =601, Purity: 86%

[1043] (7) Preparation of compound 25

[1044]

[1045] Lithium hydroxide solution (4N, 5mL) was added to a mixture of (S)-2-((6-(((2-fluoro-4-propionylbenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 25-7 (230 mg, 0.38 mmol) in THF (5 mL). The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by pre-HPLC under alkaline conditions to give (S)-2-((6-((2-fluoro-4-propionylbenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 25 (43 mg, 19%).

[1046] LCMS: Rt = 2.4 min, [M+1] + =587, purity: 99%.

[1047] 1 H NMR(400MHz,MeOD)δ8.20(s,1H),7.94(dd,J=8.4,1.3Hz,1H),7.76(dd,J=8.0,1.5Hz,1H),7.68(dd,J=10.8,1.5Hz,1H),7.63–7.55(m,3H),6.8 1(d,J=7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.50(d,J=7.8Hz,2H),5.29(qd,J=7.1,2.9Hz,1H),4.91(dd,J=15.3,7.1Hz,1H),4.74(dd,J=15.3,2. 9Hz,1H),4.62(dd,J=13.8,7.8Hz,1H),4.48(dt,J=9.1,5.9Hz,1H),4.00(d,J=13.6Hz,1H),3.89(d,J=13.6Hz,1H),3.04–2.89(m,4H),2.79(dd d,J=16.1,8.6,5.6Hz,1H),2.57(ddt,J=15.7,10.8,5.8Hz,2H),2.26(dtd,J=14.8,11.1,3.9Hz,2H),1.89–1.76(m,4H),1.12(t,J=7.2Hz,3H).

[1048] Example 26

[1049] (S)-2-((4-(6-((4-acetyl-3-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 26)

[1050]

[1051] (1) Preparation of compound 26-2

[1052]

[1053] NaH (172 mg, 4.30 mol) was added to a DMF (15 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (921 mg, 3.31 mol) at 0 °C. After stirring the reaction mixture for 2 hours, methyl 4-(bromomethyl)-2-fluorobenzoate (900 mg, 3.64 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue, which was purified by vacuum distillation (PE / EA = 0-10%) to give tert-butyl 4-(6-((3-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 26-2 (900 mg, 61.19%).

[1054] LCMS:rt=,[M-55] + =398, purity: 93%.

[1055] (2) Preparation of compound 26-3

[1056]

[1057] Lithium hydroxide solution (4N, 10 mL) was added to a mixture of tert-butyl 4-(6-((3-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 26-2 (800 mg, 1.80 mmol) in THF (10 mL). The mixture was stirred with Ar at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 6 by gradually adding dilute HCl (1N). The mixture was then diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-2-fluorobenzoic acid 26-3 (620 mg, 82%).

[1058] LCMS: rt = 1.86 min, [M+1] + =357, purity: 92%.

[1059] (3) Preparation of compound 26-4

[1060]

[1061] HATU (820.8 mg, 2.16 mmol) was added to a mixture of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-2-fluorobenzoic acid 26-3 (620 mg, 1.44 mmol), N,O-dimethylhydroxylamine (280.91 mg, 2.88 mmol), and DIEA (744.4 mg, 5.76 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction mixture was extracted with EtOAc (30 mL × 3) by quenching with water (30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to obtain the residue, which was purified by vacuum distillation (PE / EA = 0-50%) to give 26-4 tert-butyl 4-(6-((3-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (569 mg, 83%).

[1062] LCMS: rt = 2.001 min, [M+1] + =474, purity: 95%.

[1063] (4) Preparation of compound 26-5

[1064]

[1065] 4-(6-((3-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 26-4 (0.569 g, 1.2 mmol) was dissolved in anhydrous THF (15 mL) containing Ar2. A solution of CH3MgBr in THF (1 N, 5 mL) was added to the reaction mixture via a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl solution and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue, which was purified by vacuum distillation to give 4-(6-(((4-acetyl-3-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 26-5 (457 mg, 88%).

[1066] LCMS: rt = 1.35 min, [M-55] + =373, purity: 99%.

[1067] (5) Preparation of compound 26-6

[1068]

[1069] The reaction mixture of 4-(6-(((4-acetyl-3-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 26-5 (457 mg, 1.07 mmol) in EA / HCl (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LCMS. The reaction mixture was concentrated to give 1-(2-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 26-6 (400 mg, 56%).

[1070] LCMS: rt = 2.07 min, [M+1] + =329, purity: 99%.

[1071] (6) Preparation of compound 26-7

[1072]

[1073] The reaction mixture of 1-(2-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 26-6 (160 mg, 0.512 mmol) and DIEA (197 mg, 1.364 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 minutes. Then, Int-2 (100 mg, 0.34 mmol) was added to the above solution and the mixture was heated at 60 °C for 12 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (PE / EA = 0-50%) to give (S)-2-((6-(((4-acetyl-3-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 26-7 (200 mg, 70%).

[1074] LCMS: rt = 1.09 min, [M+1] + =587, purity: 97%.

[1075] (7) Preparation of compound 26

[1076]

[1077] Lithium hydroxide solution (4N, 5 mL) was added to a mixture of (S)-2-((6-(((4-acetyl-3-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 26-7 (200 mg, 0.34 mmol) in THF (5 mL). The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated to obtain a residue, which was purified by pre-HPLC under alkaline conditions to give (S)-2-((4-(6-(((4-acetyl-3-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 26 (80 mg, 40%).

[1078] LCMS: rt = 1.08 min, [M+1] + =573, purity: 99%.

[1079] 1 H NMR (400MHz, MeOD) δ8.22(s,1H),7.95(dd,J=8.4,1.2Hz,1H),7.83(t,J=7.8Hz,1H),7.59(t,J=8.4Hz,2H),7.32(dd,J=12.5,10.2Hz,2H) ,6.82(d,J=7.3Hz,1H),6.68(d,J=8.2Hz,1H),5.45(s,2H),5.27(td,J=7.3,2.8Hz,1H),4.89(d,J=8.3Hz,1H),4.73(dd,J=15.3,2.8Hz,1H ),4.64–4.57(m,1H),4.46(dt,J=9.1,6.0Hz,1H),4.00(d,J=13.7Hz,1H),3.91(d,J=13.6Hz,1H),3.03(d,J=11.7Hz,1H),2.94(d,J=11.2 Hz,1H),2.78(ddd,J=16.2,8.8,5.8Hz,1H),2.65–2.59(m,1H),2.58–2.51(m,4H),2.28(ddd,J=20.1,11.4,7.7Hz,2H),1.86–1.77(m,4H).

[1080] Example 27

[1081] (S)-2-((4-(6-((4-acetyl-2-chlorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 27)

[1082]

[1083] (1) Preparation of compound 27-2

[1084]

[1085] 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-3 (0.8 g, 2.87 mmol) was dissolved in anhydrous DMF (10 mL), and then NaH (0.146 g, 0.86 mmol) was added in portions at 0 °C. After 30 minutes, a DMF solution of 4-(bromomethyl)-3-chlorobenzoate (0.757 g, 2.87 mmol) was added to the above solution through a sleeve. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to obtain the residue, which was purified by vacuum distillation (EA / PE = 0-20%) to give tert-butyl 4-(6-((2-chloro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 27-2 (0.8 g, 61%).

[1086] LCMS: rt = 3.48 min, [M+1] + =461, purity: 99%.

[1087] (2) Preparation of compound 27-3

[1088]

[1089] 4-(6-(((2-chloro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 27-2 (0.8 g, 1.74 mmol) was dissolved in THF (7 mL), and then an aqueous lithium hydroxide solution (4 N, 7 mL) was added. The mixture was stirred at room temperature for 20 hours. The pH of the mixture was adjusted to 7-8 with HCl (1 N), and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, and concentrated to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-chlorobenzoic acid 27-3 (0.6 g, 78%).

[1090] LCMS: rt = 3.85 min, [M+1] + =447, purity: 98%.

[1091] (3) Preparation of compound 27-4

[1092]

[1093] HATU (1.0 g, 2.7 mmol) was added to a mixture of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-chlorobenzoic acid 27-3 (0.8 g, 1.79 mmol), N,O-dimethylhydroxylamine (0.35 g, 3.59 mmol), and DIEA (0.93 g, 7.17 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to obtain the residue. The residue was purified by column chromatography (PE / EA = 0-20%) to obtain tert-butyl 4-(6-((2-chloro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate 27-4 (0.6 g, 69%).

[1094] LCMS: rt = 2.32 min, [M+1] + =490, purity: 98%.

[1095] (4) Preparation of compound 27-5

[1096]

[1097] 4-(6-(((2-chloro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 27-4 (0.6 g, 1.23 mmol) was dissolved in anhydrous THF (10 mL) with Ar2. Then, a CH3MgBr THF (1 N, 6.13 mL) solution was added to the above reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl solution and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to obtain the residue, which was purified by column chromatography to give 4-(6-(((4-acetyl-2-chlorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 27-5 (0.40 g, 73%).

[1098] LCMS: rt = 3.34 min, [M+1]+ =446, purity: 97%.

[1099] (5) Preparation of compound 27-6

[1100]

[1101] A mixture of tert-butyl 4-(6-(((4-acetyl-2-chlorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 27-5 (750 mg, 1.69 mmol) in EA / HCl (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 1-(3-chloro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 27-6 (622 mg, crude product).

[1102] LCMS: rt = 0.26 min, [M+1] + =345, purity: 54.27%.

[1103] (6) Preparation of compound 27-7

[1104]

[1105] The reaction mixture of 1-(3-chloro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 27-6 (0.175 g, 0.510 mmol) and DIEA (175 mg, 1.36 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 minutes. Int-2 (0.10 g, 0.34 mmol) was added, and the reaction mixture was concentrated by heating at 60 °C for 12 hours to obtain the residue. The residue was purified by column chromatography (PE / EA = 0-50%) to give (S)-2-((6-(((4-acetyl-2-chlorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 27-7 (200 mg, 98%).

[1106] LCMS: rt = 2.318 min, [M+1] + =601, Purity: 90%

[1107] (7) Preparation of compound 27

[1108] A lithium hydroxide solution (4N, 5 mL) was added to a mixture of (S)-2-((6-(((4-acetyl-2-chlorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 27-7 (100 mg, 0.166 mmol) in THF. The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by pre-HPLC under alkaline conditions to give (S)-2-((6-(((4-acetyl-2-chlorobenzyl)oxy)-3,6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 27 (80 mg, 40%).

[1109] LCMS: Rt = 1.68 min, [M+1] + =589, purity: 99%.

[1110] 1 H NMR(400MHz,MeOD)δ8.19(s,1H),8.00(d,J=1.7Hz,1H),7.93(dd,J=8.4,1.4Hz,1H),7.88(dd,J=8.0,1.7Hz,1H),7.65– 7.55(m,3H),6.83(d,J=7.2Hz,1H),6.70(d,J=8.0Hz,1H),5.55(s,2H),5.28(dd,J=7.3,2.7Hz,1H),4.73(dd,J=15.3,2. 9Hz,1H),4.62(dt,J=14.2,7.1Hz,1H),4.47(dt,J=9.1,6.0Hz,1H),3.98(d,J=13.6Hz,1H),3.88(d,J=13.6Hz,1H),3.0 0(d,J=10.6Hz,1H),2.91(d,J=11.6Hz,1H),2.83–2.75(m,1H),2.62–2.50(m,5H),2.32–2.19(m,2H),1.87–1.75(m,4H).

[1111] Example 28

[1112] (Compound 28)

[1113]

[1114] (1) Preparation of compound 28-2

[1115]

[1116] A reaction mixture of 6-chloropyridin-2-ol (2.5 g, 19.4 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (3.9 g, 19.4 mmol) in TOL (30 mL) was added. The mixture was heated at 110 °C for 72 hours. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-4-(6-hydroxypyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 28-2 (2.3 g, 40%).

[1117] LCMS: Rt = 1.68 min, [M+1] + =294, purity: 92%.

[1118] (2) Preparation of compound 28-3

[1119]

[1120] (S)-4-(6-hydroxypyridin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester 28-2 (1.2 g, 4.1 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (250 mg, 6.15 mmol) was added in portions at 0 °C. After 30 minutes, methyl 4-(bromomethyl)-3-fluorobenzoate (1.23 g, 4.5 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 1 hour, the reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. The product was concentrated and purified by column chromatography (PE / EA = 0-30%) to give (S)-4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 28-3 (960 mg, 51%).

[1121] LCMS: Rt = 3.25 min, [M+1] + =460, purity: 93%.

[1122] (3) Preparation of compound 28-4

[1123]

[1124] (S)-4-(6-(((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester 28-3 (0.96 g, 2.1 mmol) was dissolved in THF (8 mL), followed by the addition of an aqueous solution of lithium hydroxide (8 mL). The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. Concentration gave (S)-4-(((6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 28-4 (810 mg, 87%).

[1125] LCMS: Rt = 2.12 min, [M+1] + =446, purity: 90%.

[1126] (4) Preparation of compound 28-5

[1127]

[1128] Add (S)-4-(((6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid 28-4 (0.81 g, 1.8 mmol), N,O-dimethylhydroxylamine (0.355 g, 3.6 mmol), HATU (1.04 g, 2.7 mmol), and DIEA (0.94 g, 7.17 mmol) to a reaction mixture in DMF (15 mL). Stir the mixture at room temperature for 2 hours. Analyze the reaction mixture by LC-MS. Quench the reaction mixture by adding water. Extract the aqueous phase with EtOAc (50 mL × 3) and wash with brine (50 mL × 2). Dry the combined organic layers with Na2SO4. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give (S)-4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 28-5 (0.8 g, 90%).

[1129] LCMS: Rt = 2.32 min, [M+1] + =489, purity: 93%.

[1130] (5) Preparation of compound 28-6

[1131]

[1132] (S)-4-(6-(((2-fluoro-4-(methoxy-4-(methoxy-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester 28-5 (0.4 g, 0.82 mmol) was dissolved in anhydrous THF containing N2 (8 mL). CH3MgBr (1 M, 4.1 mL) was added via a sleeve during the reaction, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3), washed with brine (30 mL × 2), and the combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by combined column chromatography to give (S)-4-(6-((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester 28-6 (0.320 g, 88%).

[1133] LCMS: Rt = 2.26 min, [M+1] + =444, purity: 90%.

[1134] (6) Preparation of compound 28-7

[1135]

[1136] Add a solution of (S)-4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-carboxylic acid tert-butyl ester 28-6 (0.32 g, 0.723 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 0.5 h. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give (S)-1-(3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 28-7 (240 mg, 98%).

[1137] LCMS: Rt = 2.10 min, [M+1] + =344, purity: 90%.

[1138] (7) Preparation of compound 28-8

[1139]

[1140] The reaction mixture of (S)-1-(3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 28-7 (0.183 g, 0.51 mmol) and DIEA (0.328 g, 2.55 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then, Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The solution was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give 2-(((S)-4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylate 28-8 (0.16 g, 78%).

[1141] LCMS: Rt = 2.25 min, [M+1] + =602, purity: 85%.

[1142] (8) Preparation of compound 28

[1143]

[1144] 2-(((S)-4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylate 28-8 (0.16 g, 0.27 mmol) was dissolved in THF (3 mL), and then an aqueous solution of lithium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The solution was concentrated and purified by preparative HPLC (NH3·H2O) to give 2-(((S)-4-(6-(((4-acetyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid (48.3 mg, 32%).

[1145] LCMS: Rt = 2.28 min, [M+1] + =588, purity: 97%.

[1146] 1H NMR (400MHz, MeOD) δ8.28(s,1H),7.97(dd,J=8.5,1.5Hz,1H),7.77(d,J=7.9Hz,1H),7.66(dd,J=9.6,5.5Hz,2H),7.56(d,J=7.5Hz,1H),7.43(t,J=8. 0Hz,1H),6.26(d,J=8.1Hz,1H),6.12(d,J=7.8Hz,1H),5.42(s,2H),5.28(s ,1H),4.89(t,J=10.4Hz,1H),4.75(dd,J=15.5,5.9Hz,1H),4.60(dd,J=13. 8,7.9Hz,1H),4.52(d,J=13.9Hz,1H),4.33(dt,J=9.2,5.8Hz,1H),3.86(d, J=12.2Hz,1H),3.74(d,J=12.7Hz,1H),3.64(d,J=13.7Hz,1H),3.06(t,J=9 .9Hz,1H),2.88(dd,J=12.5,8.7Hz,1H),2.73(dd,J=14.7,10.7Hz,2H),2.5 7(s,4H),2.45(d,J=11.4Hz,1H),2.39–2.29(m,1H),1.17(d,J=6.2Hz,3H).

[1147] Example 29

[1148] (S)-2-((4-(6-((2-fluoro-4-(1-methylpiperidin-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 29)

[1149]

[1150] (1) Preparation of compound 29-2

[1151]

[1152] To a solution of tert-butyl 4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 29-1A (500 mg, 2.69 mmol) in 10 mL of THF, n-BuLi (0.7 mL, 1.74 mmol) was added, and the mixture was stirred for 30 minutes under nitrogen and at -70 °C. Then, compound 29-1 (625 mg, 1.34 mmol) was added to the reaction mixture, and the mixture was kept at -70 °C for 1 hour. The reaction mixture was poured into water (100 mL), extracted with EtOAc (60 m × 3), washed with brine, dried over Na2SO4 and concentrated to obtain the crude product, which was further purified by column chromatography (DCM / MeOH = 0-6%) to obtain 29-2 (80 mg, 3.6%) of 4-(6-((2-fluoro-4-(1-methylpiperidin-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester.

[1153] LCMS: rt = 2.5 min, [M+H] + =512.0, purity: 97.5%.

[1154] (2) Preparation of compound 29-3

[1155]

[1156] To a solution of tert-butyl 4-(6-((2-fluoro-4-(1-methylpiperidin-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 29-2 (50 mg, 0.097 mmol), the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated to give the crude product (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(1-methylpiperidin-4-yl)methyl ketone 29-3 (40 mg, 99%).

[1157] LCMS: rt = 1.7 min, [M+H] + =421.0, purity: 94%.

[1158] (3) Preparation of compound 29-4

[1159]

[1160] Under nitrogen atmosphere and stirred at room temperature for 10 minutes, (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)(1-methylpiperidine)

[1161] DIEA (62 mg, 0.48 mmol) was added to 10 mL of MeCN solution of (S)-2-((4-(6-((2-fluoro-4-(1-methylpiperidin-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 29-4 (28 mg, 43%). Then, Int-2 (28.5 mg, 0.098 mmol) was added to the reaction mixture at 60 °C for 16 hours. The reaction mixture was concentrated to a crude product and further purified by column chromatography (MeOH / DCM = 0-9%) to give (S)-2-((4-(6-((2-fluoro-4-(1-methylpiperidin-4-carbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 29-4.

[1162] LCMS: rt = 1.98 min, [M+H] + =670, purity: 98%.

[1163] (4) Preparation of compound 29

[1164]

[1165] LCMS: rt = 2.07 min, [M+H] + =656, purity: 98.6%.

[1166] 1 H NMR(400MHz,MeOD)δ8.20(s,1H),7.94(d,J=8.4Hz,1H),7.80–7.48(m,5H),7.25(s,1H),6.82(t,J=6.4Hz,1H),6.65(t,J =7.3Hz,1H),5.62–5.42(m,2H),5.30(d,J=4.6Hz,1H),4.92(dd,J=15.4,7.3Hz,2H),4.75(dd,J=15.1,2.7Hz,1H),4.65–4 .58(m,1H),4.49(dt,J=9.0,6.1Hz,1H),4.00(d,J=13.6Hz,1H),3.93–3.83(m,1H),3.01(d,J=10.4Hz,1H),2.90(d,J=10. 6Hz,3H),2.84–2.74(m,1H),2.67–2.48(m,2H),2.30(d,J=14.6Hz,4H),2.21(dd,J=19.9,11.3Hz,3H),1.96–1.64(m,8H).

[1167] Example 30

[1168] (S)-2-((4-(6-((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 30)

[1169]

[1170] (1) Preparation of compound 30-2

[1171]

[1172] The reaction mixture of 3-hydroxy-4-methylbenzoic acid (2.0 g, 13.2 mmol) and K₂CO₃ (5.4 g) in 40 mL of CH₃CN was heated at 65 °C for 24 hours, and CH₃CH₂I (6.2 g, 39.6 mmol) was added. After 24 hours, the mixture was concentrated and purified by column chromatography (PE / EA = 0-5%) to give ethyl 3-ethoxy-4-methylbenzoate 30-2 (2.4 g, 89%).

[1173] LCMS: rt = 3.69 min, [M+H] + =209, purity: 98%.

[1174] (2) Preparation of compound 30-3

[1175]

[1176] Ethyl 3-ethoxy-4-methylbenzoate 30-2 (2.3 g, 11.06 mmol), NBS (2.07 g, 11.6 mmol), and AIBN (0.2 g, 11.06 mmol) were added to CCl4 (30 mL). The mixture was stirred at 80 °C for 16 hours. The reaction was detected by LC-MS. The mixture was concentrated and purified by column chromatography (PE / EA = 0-5%) to give ethyl 4-(bromomethyl)-3-ethoxybenzoate 30-3 (2.5 g, 78%).

[1177] LCMS: rt = 3.1 min, [M+H] + =288, purity: 94%.

[1178] (3) Preparation of compound 30-4

[1179]

[1180] Int-3 (2.0 g, 8.0 mmol) was dissolved in anhydrous DMF (25 mL), and then NaH (0.385 g, 9.6 mmol) was added in portions at 0 °C. After 30 minutes, ethyl 4-(bromomethyl)-3-ethoxybenzoate 30-3 (2.2 g, 8.0 mmol) (5 mL DMF) solution was added to the reaction mixture through a tube. After 1 hour, the reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography (P / EA = 0-20%) to give tert-butyl 4-(6-((2-ethoxy-4-(ethoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 30-4 (0.86 g, 22%).

[1181] LCMS: rt = 1.7 min, [M+H] + =485, purity: 94%.

[1182] (4) Preparation of compound 30-5

[1183]

[1184] 4-(6-(((2-ethoxy-4-(ethoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 30-4 (0.86 g, 1.8 mmol) and MeOH (0.1 mL) were dissolved in THF (8 mL), and then an aqueous solution of lithium hydroxide (8 mL) was added. The mixture was stirred at 40 °C for 8 hours. The reaction mixture was analyzed by LC-MS. The aqueous phase was extracted with EA (20 mL × 3) and washed with brine (20 mL × 2). The combined organic layers were dried over Na2SO4. Concentration gave 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-ethoxybenzoic acid 30-5 (800 mg, 98%).

[1185] LCMS: rt = 2.2 min, [M+H] + =457, purity: 98%.

[1186] (5) Preparation of compound 30-6

[1187]

[1188] Add 30-5g (0.80g, 1.78g) of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-ethoxybenzoic acid.

[1189] The reaction mixture of N,O-dimethylhydroxylamine (0.346 g, 3.56 mmol), HATU (1.0 g, 2.67 mmol), and DIEA (0.916 g, 7.1 mmol) in DMF (15 mL) was stirred at room temperature for 1.5 h. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-ethoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 30-6 (0.73 g, 82%).

[1190] LCMS: rt = 3.15 min, [M+H] + =500, purity: 97%.

[1191] (6) Preparation of compound 30-7

[1192]

[1193] 4-(6-(((2-ethoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 30-6 (0.73 g, 1.46 mmol) was dissolved in anhydrous THF containing N2 (5 mL). CH3MgBr (1 M, 0.5 mL) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine (20 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by vacuum concentration to give 4-(6-(((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 30-7 (0.62 g, 93%).

[1194] LCMS: rt = 3.37 min, [M+H] + =455, purity: 98%.

[1195] (7) Preparation of compound 30-8

[1196]

[1197] Add a solution of tert-butyl 4-(6-(((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 30-7 (620 mg, 1.37 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 0.5 hours. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give 1-(3-ethoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethyl-1-one 30-8 (420 mg, 94%).

[1198] LCMS: rt = 1.03 min, [M+H] + =355, purity: 92%.

[1199] (8) Preparation of compound 30-9

[1200]

[1201] The reaction mixture of 1-(3-ethoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethyl-1-one 30-8 (0.18 g, 0.51 mmol) and DIEA (0.21 g, 1.7 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 30-9 (0.18 g, 87%).

[1202] LCMS: rt = 2.5 min, [M+H] + =613, purity: 92%.

[1203] (9) Preparation of compound 30

[1204]

[1205] Methyl (S)-2-((4-(6-(((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 30-9 (0.18 g, 0.29 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The solution was concentrated and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-(((4-acetyl-2-ethoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 30 (91.6 mg, 50%).

[1206] LCMS: rt = 2.15 min, [M+H] + =599, purity: 98%.

[1207] 1 H NMR (400MHz, MeOD) δ8.23(s,1H),7.95(d,J=8.5Hz,1H),7.54(ddd,J=34.2,14.3,8.1Hz,5H),6.80(d,J=7.3Hz,1H),6 .65(d,J=8.2Hz,1H),5.46(d,J=7.9Hz,2H),5.34–5.18(m,1H),4.84(d,J=7.0Hz,1H),4.70(dd,J=15.3,2.4Hz,1H),4. 59(dd,J=13.9,7.7Hz,1H),4.44(dt,J=9.1,6.0Hz,1H),4.13(q,J=6.9Hz,2H),3.95(dd,J=42.3,13.7Hz,2H),3.10–2 .88(m,2H),2.82–2.74(m,1H),2.64–2.48(m,5H),2.36–2.21(m,2H),1.83(dd,J=12.8,5.3Hz,4H),1.41–1.32(m,3H).

[1208] Example 31

[1209] (S)-2-((4-(6-((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 31)

[1210]

[1211] (1) Preparation of compound 31-2

[1212]

[1213] The reaction mixture of 3-hydroxy-4-methylbenzoic acid (2.0 g, 13.2 mmol) and K₂CO₃ (5.4 g) in 40 mL of CH₃CN was heated at 65 °C for 24 hours, and CH₃CH₂I (6.2 g, 39.6 mmol) was added. After 24 hours, the mixture was concentrated and purified by column chromatography (PE / EA = 0-5%) to give ethyl 3-ethoxy-4-methylbenzoate 31-2 (2.4 g, 89%) as a white solid.

[1214] LCMS: rt = 3.69 min, [M+H] + =209, purity: 98%.

[1215] (2) Preparation of compound 31-3

[1216]

[1217] Ethyl 3-ethoxy-4-methylbenzoate 31-2 (2.3 g, 11.06 mmol), NBS (2.07 g, 11.6 mmol), and AIBN (0.2 g) were added.

[1218] 11.06 mmol (g) was added to CCl4 (30 mL). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (PE / EA = 0-5%) to give ethyl 4-(bromomethyl)-3-ethoxybenzoate 31-3 (2.5 g, 78%).

[1219] LCMS: rt = 3.1 min, [M+H] + =288, purity: 94%.

[1220] (3) Preparation of compound 31-4

[1221]

[1222] Int-3 (1.4 g, 5 mmol) was dissolved in anhydrous DMF (25 mL), and then NaH (300 mg, 7.5 mmol) was added in portions at 0 °C. After 30 minutes, a solution of ethyl 4-(bromomethyl)-3-ethoxybenzoate 31-3 (1.5 g, 0.33 mmol) (5 mL DMF) was added to the reaction mixture through a sleeve. After 1 hour, the reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography (PE / EA = 0-20%) to give tert-butyl 4-(6-((4-bromo-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid 31-4 (1.6 g, 65%).

[1223] LCMS: rt = 1.8 min, [M+H] + =503, purity: 92%.

[1224] (4) Preparation of compound 31-5

[1225]

[1226] A reaction mixture of 4-(6-(((4-bromo-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 31-4 (700 mg, 1.4 mmol), tributyl(1-ethoxyvinyl)stanane (502 mg, 1.4 mmol), and Pd(PPh3)2Cl2 (98 mg) in DMF (20 mL) was added, and the mixture was stirred at 100 °C for 16 hours under N2. The reaction mixture was then stirred for 1 hour at room temperature by adding a saturated potassium fluoride solution, followed by adding HCl (1 M) (10 mL) and stirring for 1 hour at room temperature. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine (20 mL × 2). The combined organic layers were dried over Na2SO4. The product was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 31-5 (0.4 g, 61%) of 4-(6-((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester.

[1227] LCMS: rt = 3.27 min, [M+H] + =467, purity: 98%.

[1228] (5) Preparation of compound 31-6

[1229]

[1230] Add a solution of 4-(6-(((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 31-5 (400 mg, 0.86 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 0.5 hours. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give 1-(3-cyclopropoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 31-6 (300 mg, 94%).

[1231] LCMS: rt = 2.14 min, [M+H] + =367, purity: 97%.

[1232] (6) Preparation of compound 31-7

[1233]

[1234] The reaction mixture of 1-(3-cyclopropoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ethane-1-one 31-6 (0.186 g, 0.51 mmol) and DIEA (0.21 g, 1.7 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate methyl ester 31-7 (0.18 g, 85%).

[1235] LCMS: rt = 2.5 min, [M+H] + =625, purity: 95%.

[1236] (7) Preparation of compound 31

[1237]

[1238] Methyl (S)-2-((4-(6-(((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid 31-7 (0.18 g, 0.29 mmol) was dissolved in THF (3 mL), and then an aqueous solution of lithium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-(((4-acetyl-2-cyclopropoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 31 (81.8 mg, 46%).

[1239] LCMS: rt = 2.4 min, [M+H] + =611, purity: 98%.

[1240] 1 H NMR (400MHz, MeOD) δ8.29(s,1H),7.96(dd,J=8.5,1.3Hz,1H),7.85(d,J=1.4Hz,1H),7.65(d,J=8.5Hz,1H),7.60–7.52(m,2H),7.45(d,J=7.8Hz,1H), 6.79(d,J=7.3Hz,1H),6.65(t,J=7.1Hz,1H),5.37(s,2H),5.30–5.17(m,1 H),4.86–4.79(m,1H),4.64(ddd,J=21.7,14.6,5.2Hz,2H),4.44(dt,J=9.1 ,5.9Hz,1H),4.06(d,J=13.9Hz,1H),3.96(d,J=13.9Hz,1H),3.88(dq,J=8 .8,2.9Hz,1H),3.05(dd,J=38.7,11.2Hz,2H),2.83–2.72(m,1H),2.64(dt, J=15.2,7.7Hz,1H),2.56(d,J=8.8Hz,3H),2.54–2.46(m,1H),2.37(ddd,J =19.0,13.1,8.7Hz,2H),1.86(dd,J=26.3,19.2Hz,4H),0.86–0.64(m,4H).

[1241] Example 32

[1242] (S)-2-((4-(6-((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 32)

[1243]

[1244] (1) Preparation of compound 32-1

[1245]

[1246] At 25 °C, isopropyl magnesium bromide (2 mL, 1 mmol, 2.0 eq) was added to a THF (8 mL) solution of tert-butyl 4-(6-((2-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 20-4 (0.5 g, 1 mmol, 1 eq) (an intermediate from compound 20). The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with EtOAc (80 mL), washed with H2O (150 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give tert-butyl 4-(6-((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 32-1 (0.22 g, 45.8%).

[1247] 1 H NMR (400MHz, CDCl3) δ7.55–7.48(m,4H),6.72(d,J=7.2Hz,1H),6.66(d,J=8.1Hz,1H),5.46(s,2H),4.19(s,1H),3.93(s,3H),3. 60–3.50(m,1H),2.77(d,J=41.8Hz,3H),1.85(d,J=11.6Hz,2H),1.76–1.63(m,2H),1.48(d,J=4.7Hz,9H),1.22(d,J=6.8Hz,6H).

[1248] (2) Preparation of compound 32-2

[1249]

[1250] At 25 °C, under Ar, tert-butyl 4-(6-(((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 32-1 (0.2 g, 0.64 mmol, 1 eq) was added dropwise to a solution of HCl / EA (5 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated to give 1-(3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)-2-methylpropane-1-one 31-2 (0.2 g, crude product).

[1251] LCMS: rt = 1.029 min, [M+1] + =369.4. Purity: 98.4%.

[1252] (3) Preparation of compound 32-3

[1253]

[1254] At 25 °C, DIEA (0.219 g, 1.7 mmol, 5 eq) was added to a solution of 1-(3-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)-2-methylpropane-1-one 31-2 (0.188 g, 0.51 mmol, 1.5 eq) and Int-2 (0.1 g, 0.34 mmol, 1 eq) in MeCN (6 mL). The mixture was stirred at 60 °C under an Ar atmosphere for 16 hours. It was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give (S)-2-((4-(6-(((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 31-3 (0.2 g, 62.5%).

[1255] LCMS: rt = 1.483 min, [M+1] + =627.1, Purity: 100%.

[1256] (4) Preparation of compound 32

[1257]

[1258] At 25 °C, LiOH (0.027 g, 1.12 mmol, 5.0 eq) in 3 mL of H₂O (3 mL) was added to a solution of (S)-2-((4-(6-(((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 31-3 (0.14 g, 0.22 mmol, 1 eq) in 3 mL of THF. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by HPLC column, and then freeze-dried to give (S)-2-((4-(6-(((4-isobutyryl-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 32 (66 mg, 37.7%).

[1259] LCMS: rt = 2.50 min, [M+H] + =613.3, purity: 99.86%.

[1260] 1 H NMR (400MHz, MeOD) δ8.32(d,J=8.9Hz,1H),7.97(dd,J=8.5,1.3Hz,1H),7.67(d,J=8.5Hz,1H),7.61–7.52(m,2H),7.50(dd,J=11 .0,4.5Hz,2H),6.80(d,J=7.3Hz,1H),6.67(d,J=8.2Hz,1H),5.43(s,2H),5.23(dt,J=6.9,3.5Hz,1H),4.83(dd,J=15.4,7.0Hz, 1H),4.65(ddd,J=21.7,14.6,5.2Hz,2H),4.44(dt,J=9.1,5.9Hz,1H),4.10(dd,J=38.2,14.0Hz,2H),3.91(s,3H),3.60(dt,J=1 3.6, 6.8Hz, 1H), 3.13 (dd, J=37.0, 11.4Hz, 2H), 2.82–2.64 (m, 2H), 2.58–2.41 (m, 3H), 1.98–1.79 (m, 4H), 1.13 (d, J=6.8Hz, 6H).

[1261] Example 33

[1262] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxacyclobutane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 33)

[1263]

[1264] (1) Preparation of compound 33-1

[1265]

[1266] 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester Int-7 (0.4 g, 0.845 mmol) was dissolved in anhydrous THF containing Ar2 (10 mL). Cyclopropylmagnesium bromide (1 M) (4 mL) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography to give 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester 33-1 (0.35 g, 91%).

[1267] LCMS: rt = 2.18 min, [M+1] + =455, purity: 97%.

[1268] (2) Preparation of compound 33-2

[1269]

[1270] Add a solution of tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate 33-1 (350 mg, 0.77 mmol) in HCl / EA (10 mL, 3 M). Stir the mixture at room temperature for 1 hour. Analyze the reaction mixture by LC-MS. Concentrate the mixture to give cyclopropyl(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone 33-2 (260 mg, 95%).

[1271] LCMS: rt = 2.22 min, [M+1] + =355.1, purity: 85%.

[1272] (3) Preparation of compound 33-3

[1273]

[1274] The reaction mixture of cyclopropyl (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone 33-2 (200 mg, 0.564 mmol) and DIEA (364.6 mg, 2.82 mmol) in 15 mL of CH3CN was stirred at room temperature for 10 minutes. Then, (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Int-2A compound and methane (1:1) (175.9 g, 0.564 mmol) was added, and the mixture was heated at 60 °C for 12 hours. The reaction solution was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 33-3 (180 mg, 52% yield).

[1275] LCMS:rt=2.41,[M+1] + =614, purity: 87%.

[1276] (4) Preparation of compound 33

[1277]

[1278] To a mixture of (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 33-3 (180 mg, 0.293 mmol) in THF (5 mL), lithium hydroxide solution (5 mL) was added. The mixture was stirred with Ar at room temperature for 2 hours. The mixture was concentrated, purified by HPLC pretreatment, and freeze-dried to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, compound 33 (17 mg, 9.67%).

[1279] LCMS: rt = 1.336 min, [M+1] + =599, Purity: 100%.

[1280] 1H NMR(400MHz,MeOD)δ8.06(dd,J=18.3,8.3Hz,2H),7.79(ddd,J=12.3,9.4,1.5Hz,2H),7.65–7.55(m,2H),6.8 3(d,J=7.3Hz,1H),6.68(d,J=8.1Hz,1H),5.52(s,2H),5.35–5.26(m,1H),5.06(dd,J=14.8,6.7Hz,1H),4.94 –4.89(m,1H),4.64–4.58(m,1H),4.44(dd,J=6.0,3.0Hz,1H),4.11(dd,J=46.1,13.9Hz,2H),3.08(dd,J=34. 2,11.1Hz,2H),2.72(ddd,J=32.1,18.4,4.5Hz,3H),2.58–2.34(m,3H),1.95–1.79(m,4H),1.12–1.01(m,4H).

[1281] Example 34

[1282] (S)-2-((6-((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 34)

[1283]

[1284] (1) Preparation of compound 34-2

[1285]

[1286] 6-Chloropyridin-2-ol (1.0 g, 7.72 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (0.37 g, 9.26 mmol) was added fractionally at 0 °C. After 30 minutes, methyl 4-(bromomethyl)-3-fluorobenzoate (1.91 g, 7.72 mmol) (5 mL DMF) solution was added to the reaction mixture through a sleeve. The reaction mixture was analyzed by LC-MS after two hours. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by column chromatography (PE / EA = 0–30%) to give methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzoate 34-2 (1.2 g, 61%).

[1287] LCMS: rt = 3.017 min, [M+1] + =296, purity: 99%.

[1288] (2) Preparation of compound 34-3

[1289]

[1290] A reaction mixture was added to 1,4-dioxane (10 mL) of methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzoate 34-2 (1.2 g, 4.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.50 g, 4.87 mmol), Cs₂CO₃ (2.0 g, 6.05 mmol), and Pd(dtbpf)Cl₂ (0.26 g, 0.406 mmol). The mixture was stirred with N₂ at 100 °C for 16 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was concentrated and purified by column chromatography (PE / EA = 0-20%) to give 34-3 (1.3 g, 72%) of 6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester.

[1291] LCMS: rt = 3.381 min, [M+1] + =443.2, purity: 92%.

[1292] (3) Preparation of compound 34-4

[1293]

[1294] 6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 34-3 (1.2 g, 2.7 mmol) was dissolved in THF (12 mL), followed by the addition of lithium hydroxide aqueous solution (12 mL). The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The pH of the mixture was adjusted to 7-8 with dilute hydrochloric acid solution. The aqueous phase was extracted with EtOAc (50 mL × 3), washed with brine (50 mL × 2), and the combined organic layers were dried over Na2SO4. Concentration gave 4-(((1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)oxy)methyl)-3-fluorobenzoic acid 34-4 (1.0 g, 70%).

[1295] LCMS: rt = 2.99 min, [M+1] + =429.1, purity: 93%.

[1296] (4) Preparation of compound 34-5

[1297]

[1298] Add 4-(((1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-6-yl)oxy)methyl)-3-fluorobenzoic acid 34-4 (0.8 g, 1.87 mmol), N,O-dimethylhydroxylamine (0.36 g, 3.74 mmol), HATU (1.1 g, 2.81 mmol), and DIEA (0.96 g, 7.48 mmol) to a reaction mixture in DMF (15 mL). Stir the mixture at room temperature for 2 hours. Analyze the reaction mixture by LC-MS. Quench the reaction mixture by adding water. Extract the aqueous phase with EtOAc (50 mL × 3) and wash with brine (50 mL × 2). Dry the combined organic layers with Na2SO4. The product was concentrated and purified by column chromatography (PE / EA = 0-40%) to give 34-5 (0.8 g, 91%) of 6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester.

[1299] LCMS: rt = 2.42 min, [M+1] + =472, purity: 96%.

[1300] (5) Preparation of compound 34-6

[1301]

[1302] 0.7 g (1.48 mmol) of tert-butyl 6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid 34-5 was dissolved in anhydrous THF (12 mL) containing N2. CH3MgBr (1 M) (7.42 mL) was added via a sleeve during the reaction, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was analyzed by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The product was concentrated and purified by column chromatography to give 34-6 (0.49 g, 77%) of 6-((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester.

[1303] LCMS: rt = 2.28 min, [M+1] + =427, purity: 98%.

[1304] (6) Preparation of compound 34-7

[1305]

[1306] 6-((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 34-6 (260 mg, 0.609 mmol) was added to HCl / EA (8 mL, 3 M). The mixture was stirred at room temperature for 1 hour. The reaction mixture was analyzed by LC-MS. The mixture was concentrated to give 1-(3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridine]-6-yl)oxy)methyl)phenyl)ethane-1-one 34-7 (198 mg, 99%).

[1307] LCMS: rt = 1.83 min, [M+1] + =326, purity: 94%.

[1308] (7) Preparation of compound 34-8

[1309]

[1310] The reaction mixture of 1-(3-fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)oxy)methyl)phenyl)ethane-1-one 34-7 (0.166 g, 0.51 mmol) and DIEA (0.328 g, 2.55 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min, then Int-2 (0.10 g, 0.34 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction mixture was analyzed by LC-MS. The product was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to give (S)-2-((6-(((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 34-8 (0.19 g, 80%).

[1311] LCMS: rt = 2.35 min, [M+1] + =585, purity: 98%.

[1312] (8) Preparation of compound 34

[1313]

[1314] Methyl (S)-2-((6-(((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate 34-8 (0.19 g, 0.325 mmol) was dissolved in THF (4 mL), and then an aqueous solution of lithium hydroxide (4 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was analyzed by LC-MS. The pH of the mixture was adjusted to 5-6 with dilute hydrochloric acid solution (1 M). The mixture was concentrated and purified by preparative HPLC (TFA) to give (S)-2-((6-(((4-acetyl-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 34 (0.037 g, 20%).

[1315] LCMS: rt = 2.32 min, [M+1] + =571, purity: 98%.

[1316] 1H NMR(400MHz,MeOD)δ8.34(s,1H),8.04(dd,J=8.5,1.3Hz,1H),7.80(dd,J=12.1,5.0Hz,2H),7.76–7.67(m,2H), 7.63(t,J=7.6Hz,1H),7.19(d,J=7.4Hz,1H),6.84(d,J=8.2Hz,1H),6.75(s,1H),5.55(s,2H),5.26–5.13(m,1H ),4.94(s,2H),4.77(dd,J=15.8,6.9Hz,1H),4.69–4.57(m,2H),4.39(dt,J=9.2,5.9Hz,1H),4.22(s,2H),3.78 (d,J=5.5Hz,2H),2.99(s,2H),2.78(ddt,J=14.0,10.5,5.3Hz,1H),2.58(s,3H),2.48(tt,J=18.0,7.0Hz,1H).

[1317] Example 35

[1318] 2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 35)

[1319]

[1320] Preparation of intermediate cyclopropyl(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone:

[1321]

[1322] Int-7 (1.3 g, 2.75 mmol) was dissolved in anhydrous THF (20 mL) containing Ar2. Cyclopropylmagnesium bromide (1 M) (4.5 mL, 4.5 mmol) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was determined to be complete by LC-MS. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4, concentrated, and purified by elution to give tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid (1 g, 80%). LCMS: ESI (M + H) + =455

[1323] Add a solution of tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid (480 mg, 1.06 mmol) in HCl / EtOAc (8 mL, 3 M). Stir the mixture at room temperature for 0.5 hours. The reaction mixture was checked for completeness by LC-MS. The mixture was concentrated to give cyclopropyl(3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ketone (370 mg, 98%). LCMS: ESI (M+H) + =355

[1324] (1) Preparation of compound 35-2

[1325]

[1326] NaH (0.644 g, 16.1 mmol, 1.5 eq) was added to a DMF (20 mL) solution of 1H-imidazolium-4-onitrile (1 g, 10.8 mmol, 1.0 eq) and iodoethane (1.68 g, 10.8 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 10 °C for 1 h under a nitrogen atmosphere. TLC analysis was performed, and the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 1-ethyl-1H-imidazolium-4-onitrile, 35-2 (1.0 g crude product, 76.3% yield), which was used directly in the next step.

[1327] (2) Preparation of compound 35-3

[1328]

[1329] At 0 °C, LiAlH4 (0.628 g, 16.5 mmol, 1.0 eq) was added to a 20 mL solution of THF containing 35-2 (1 g, 8.26 mmol, 1.0 eq). The mixture was stirred at 70 °C for 2 hours under a nitrogen atmosphere. TLC analysis was performed, and the mixture was diluted with 50 mL of H2O and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give (1-ethyl-1H-imidazol-4-yl)methylamine, 35-3 (1.0 g crude), which was used directly in the next step without purification.

[1330] (3) Preparation of compound 35-4

[1331]

[1332] Methyl 3-fluoro-4-nitrobenzene (1.59 g, 8.0 mmol, 1.0 eq) and TEA (0.81 g, 8.0 mmol, 1.0 eq) were added to a 20 mL solution of THF containing 35-3 (1 g, 8.0 mmol, 1.0 eq). The mixture was stirred at 70 °C for 12 hours under a nitrogen atmosphere. The residue was obtained by LCMS monitoring and purified by silica gel column chromatography, eluting with (MeOH / DCM = 0-10%) to give methyl 3-(((1-ethyl-1H-imidazol-4-yl)methyl)amino)-4-nitrobenzene, 35-4 (1.0 g, 41.1% yield).

[1333] LCMS:ESI(M+H) + =305.1

[1334] (4) Preparation of compound 35-5

[1335]

[1336] Pd / C (200 mg, wet) was added to a 35-4 (1.0 g, 3.3 mmol, 1.0 eq) solution of MeOH (20 mL). The mixture was stirred at 10 °C for 12 hours under H2 (1 atm). The mixture was monitored by LCMS and filtered through a diatomaceous earth mat. The filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated to give methyl 4-amino-3-(((1-ethyl-1H-imidazol-4-yl)methyl)amino)benzoate, 35-5 (0.7 g, 77.4% yield).

[1337] LCMS: Rt = 0.634 min, [M+H] + =275.1

[1338] (5) Preparation of compound 35-6

[1339]

[1340] TsOH·H₂O (35 mg, 0.183 mmol, 1.0 eq) was added to a THF (20 mL) solution of 35-5a (0.5 g, 1.83 mmol, 1.0 eq) and 2-chloro-1,1,1-trimethoxyethane (0.562 g, 3.65 mmol, 2.0 eq). The mixture was stirred at 70 °C for 12 h. The mixture was concentrated by LCMS monitoring, and the residue was purified by silica gel column chromatography by elution with (MeOH / DCM = 0-10%) to give methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazol-6-carboxylate, 35-6 (0.3 g, 49.3% yield).

[1341] LCMS: Rt=1.049min,[M+1]+=333.0

[1342] (6) Preparation of compound 35-7

[1343]

[1344] The reaction mixture of cyclopropyl (3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl) ketone (0.38 g, 1.08 mmol) and DIEA (0.464 g, 3.6 mmol) in 15 mL of CH3CN was stirred at room temperature for 10 min. Then 35-6a (0.3 g, 0.9 mmol) was added, and the mixture was heated at 65 °C for 15 h. LC-MS monitoring, concentration, and purification by elution (MeOH / DCM = 0-5%) yielded methyl 2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylate, 35-7 (350 mg, 60%).

[1345] LCMS: Rt=1.5min, [M+1]+=651

[1346] (7) Preparation of compound 35

[1347]

[1348] 35-7 (0.15 g, 0.23 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 20 hours. The mixture was concentrated by LC-MS and purified by preparative HPLC (NH3·H2O) to give 2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-4-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid, compound 35 (39.6 mg, 27.4%).

[1349] LCMS: Rt=2.17min,[M+1]+=637

[1350] 1H NMR(400MHz,MeOD)δ8.16(s,1H),7.93(dd,J=8.4,1.3Hz,1H),7.82(dd,J=8.0,1.3Hz,1H),7.71( dd,J=10.8,1.2Hz,1H),7.65–7.53(m,4H),7.09(s,1H),6.79(d,J=7.3Hz,1H),6.65(d,J=8.2Hz, 1H),5.65(s,2H),5.50(s,2H),4.02–3.91(m,4H),3.02(d,J=11.4Hz,2H),2.74–2.59(m,2H),2.3 0(td,J=11.1,3.2Hz,2H),1.76(dd,J=23.7,7.3Hz,4H),1.33(t,J=7.3Hz,3H),1.12–0.99(m,4H).

[1351] Example 36

[1352] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-6-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 36)

[1353]

[1354] (1) Preparation of compound 36-1

[1355]

[1356] Under nitrogen atmosphere and at 90 °C, with stirring, KOAc (799 mg, 8.16 mmol), B2Pin2 (1541 mg, 6.08 mmol), and Pd(dppf)Cl2 (300 mg, 0.41 mmol) were added to 30 mL of a dioxane solution of methyl 3-bromo-5-fluoro-4-methylbenzoate (1.0 g, 4.08 mmol) for 16 hours. The reaction mixture was concentrated to a crude product, which was further purified by elution (PE / EA = 0-15%) to give methyl 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate, 36-1 (0.9 g, 75.6% yield).

[1357] LCMS: rt = 1.89 min, [M+H] + =298

[1358] (2) Preparation of compound 36-2

[1359]

[1360] Under nitrogen atmosphere and at room temperature, with stirring, NaOH (122.45 mg, 3.06 mg) and H2O2 (693.6 mg, 6.12 mmol) were added to a solution of 36-1 (900 mg, 3.06 mmol) in 20 mL THF / H2O for 16 hours. The reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (50 mL × 3). The extract was washed with brine, dried, and concentrated to give methyl 3-fluoro-5-hydroxy-4-methylbenzoate as the crude product of 36-2 (730 mg). The crude product was used directly in the next step without purification.

[1361] 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 7.31–7.23 (m, 1H), 3.91 (s, 3H), 2.21 (d, J = 1.0Hz, 3H).

[1362] (3) Preparation of compound 36-3

[1363]

[1364] To a solution of 36-2 (730 mg, 3.97 mmol) in 20 mL of MeCN, Cs₂CO₃ (2.58 g, 7.93 mmol) and CH₃I (676 mg, 4.76 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL), extracted with EA (50 mL × 3), washed with brine, dried, and concentrated to give the crude product methyl 3-fluoro-5-methoxy-4-methylbenzoate, 36-3 (650 mg). The crude product was used directly in the next step without purification.

[1365] 1 H NMR (400MHz, CDCl3) δ7.31 (dd, J=21.9, 13.3Hz, 2H), 3.90 (d, J=8.0Hz, 6H), 2.17 (d, J=1.8Hz, 3H).

[1366] (4) Preparation of compound 36-4

[1367]

[1368] Under nitrogen atmosphere and at 80 °C, NBS (643 mg, 3.28 mmol) and AIBN (53.8 mg, 0.328 mmol) were added to a solution of 36-3 (650 mg, 3.28 mmol) in 5 mL of CCl4 for 16 hours. The reaction mixture was concentrated to give a crude product, which was further purified by elution (PE / EA = 0-20%) to give methyl 4-(bromomethyl)-3-fluoro-5-methoxybenzoate, 36-4 (681 mg, 74.9% yield).

[1369] 1 H NMR (400MHz, CDCl3) δ7.37 (t, J = 4.1Hz, 2H), 4.56 (d, J = 1.1Hz, 2H), 3.99–3.89 (m, 6H).

[1370] (5) Preparation of compound 36-5

[1371]

[1372] Under nitrogen atmosphere and at room temperature, NaH (147.3 mg, 2.45 mmol) was added to 5 mL of a DMF solution of 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester (680 mg, 2.45 mmol) with stirring for 15 minutes. Then, under nitrogen atmosphere and at room temperature, 36-4 (680 mg, 2.45 mmol) was added to the reaction mixture with stirring for 30 minutes. The reaction mixture was poured into water (50 mL), extracted with EtOAc (30 mL × 3), washed with brine and dried, and concentrated to give a crude product. This crude product was further purified by elution (PE / EA = 0-30%) to give 4-(6-((2-fluoro-6-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester, 36-5 (400 mg, 34.6% yield).

[1373] LCMS: rt = 3.5 min, [M+H] + =475

[1374] (6) Preparation of compound 36-6

[1375]

[1376] To a THF / H₂O (10 mL) solution of 36-5 (400 mg, 0.844 mmol), LiOH (101.27 mg, 4.22 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to the crude product 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluoro-5-methoxybenzoic acid, yielding 36-6 (338 mg). The crude product was used directly in the next step without purification.

[1377] LCMS: rt = 2.2 min, [M+H] + =461

[1378] (7) Preparation of compound 36-7

[1379]

[1380] To a solution of 36-6 (338 mg, 0.73 mmol) in 5 mL of DMF, N,O-dimethylhydroxylamine (142.5 mg, 1.43 mmol), HATU (416.1 mg, 1.09 mmol), and DIEA (376.8 mg, 2.92 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water (50 mL), extracted with EtOAc (30 mL × 3), washed with brine, dried, and concentrated to give a crude product, which was further purified by elution (PE / EA = 0-52%) to give tert-butyl 4-(6-((2-fluoro-6-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 36-7 (440 mg, 95% yield).

[1381] LCMS: rt = 1.147 min, [M+H] + =504

[1382] (8) Preparation of compound 36-8

[1383]

[1384] To a solution of 36-7 (440 mg, 1.092 mmol) in 10 mL of THF, cyclopropylmagnesium bromide (5.5 mL, 5.5 mmol) was added with stirring at room temperature and under nitrogen for 30 min. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL), extracted with EtOAc (10 mL x 3), washed with brine, dried, concentrated, and given as a crude product. This crude product was further purified by elution (PE / EA = 0-33) to give tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-6-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 36-8 (480 mg, 90.9% yield).

[1385] LCMS: rt = 2.38 min, [M+H] + =485

[1386] (9) Preparation of compound 36-9

[1387]

[1388] To a solution of 36-8 (480 mg, 0.99 mmol) in 10 mL of HCl / EtOAc, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the crude product cyclopropyl(3-fluoro-5-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ketone, 36-9 (380 mg, 99% yield).

[1389] LCMS: rt = 1.36 min, [M+H] + =385

[1390] (10) Preparation of compound 36-10

[1391]

[1392] Under nitrogen atmosphere, the mixture was stirred at room temperature for 10 minutes, and DIEA (220 mg, 1.7 mmol) was added to 10 mL of 36-9 (196 mg, 0.5 mmol) MeCN solution. Then, Int-2 (100 mg, 0.34 mmol) was added to the reaction mixture at 60 °C, and the mixture was stirred for 16 hours. The reaction mixture was concentrated to a crude product, which was further purified by elution (PE / EA = 0-50%) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-6-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, 36-10 (160 mg, 73% yield).

[1393] LCMS: rt = 1.4 min, [M+H] + =643

[1394] (11) Preparation of compound 36

[1395]

[1396] To a solution of 36-10 (160 mg, 0.25 mmol) in THF / H₂O (10 mL), LiOH (30 mg, 1.25 mmol) was added with stirring at room temperature for 16 hours. The reaction mixture was concentrated to a crude product, which was further purified by preparative HPLC to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-6-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 36 (24.6 mg, 15.8% yield).

[1397] LCMS: rt = 1.306 min, [M+H] + =629

[1398] 1 H NMR(400MHz,MeOD)δ8.20(s,1H),7.94(dd,J=8.4,1.4Hz,1H),7.61–7.51(m,2H),7.45(d,J=9.4Hz,2H),6.81(d,J=7.3Hz,1H), 6.55(d,J=8.2Hz,1H),5.42(s,2H),5.34–5.25(m,1H),4.91(dd,J=15.3,7.0Hz,1H),4.74(dd,J=15.2,2.8Hz,1H),4.61(d,J=5. 6Hz,1H),4.47(dd,J=6.0,3.1Hz,1H),4.02(d,J=13.6Hz,1H),3.94–3.88(m,4H),3.06(s,1H),2.96(s,1H),2.79(td,J=7.8,4. 0Hz,2H),2.66(s,1H),2.55(dt,J=16.2,7.3Hz,1H),2.38–2.24(m,2H),1.99–1.84(m,4H),1.10(ddt,J=11.7,10.0,3.5Hz,4H).

[1399] Example 37

[1400] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 37)

[1401]

[1402] (1) Preparation of compound 37-2

[1403]

[1404] A solution of methyl 2-bromo-5-fluoro-4-methylbenzoate 37-1 (2 g, 8.13 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (2.5 g, 9.75 mmol), and KOAc (1.1 g, 12.2 mmol) in dioxane (20 mL) was added to Pd(dppf)Cl2 (0.59 g, 0.81 mmol), and stirred at 25 °C for 2 hours. The mixture was diluted with EtOAc (150 mL), washed with H2O (200 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give methyl 5-fluoro-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzoate, 37-2 (1.8 g, 75.6%).

[1405] LCMS: rt = 2.158 min, [M+H] + =295

[1406] (2) Preparation of compound 37-3

[1407]

[1408] H₂O₂ (1.38 g, 40.8 mmol) was added to a THF (20 mL) solution of 37-2 (1.8 g, 6.12 mmol) and NaOH (0.244 g, 6.12 mmol), and the mixture was stirred at 25 °C for 1 hour. TLC (PE / EtOAc (3:1)) showed complete consumption of the starting material. The mixture was diluted with saturated sodium sulfite (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give methyl 5-fluoro-2-hydroxy-4-methylbenzoate, 37-3 (0.790 g, 70.5%).

[1409] 1 H NMR (400MHz, CDCl3) δ10.44(s,1H),7.43(d,J=9.7Hz,1H),6.80(d,J=6.4Hz,1H),3.94(s,3H),2.28(d,J=1.4Hz,3H).

[1410] (3) Preparation of compound 37-4

[1411]

[1412] CH3I (0.63 g, 4.4 mmol, 1.2 eq) was added to a solution of 37-3 (0.68 g, 3.7 mmol, 1.0 eq) and Cs2CO3 (2.4 g, 7.4 mmol, 2 eq) in MeCN (15 mL) at 25 °C. The mixture was stirred at 25 °C under an Ar atmosphere for 16 hours. TLC (PE / EtOAc (10:1)) was used for monitoring. The mixture was diluted with EtOAc (120 mL), washed with H2O (150 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give methyl 5-fluoro-2-methoxy-4-methylbenzoate, 37-4 (0.4 g, 54.7%).

[1413] 1 H NMR (400MHz, CDCl3) δ7.49 (d, J = 9.7Hz, 1H), 6.77 (d, J = 6.0Hz, 1H), 3.88 (s, 6H), 2.31 (d, J = 1.5Hz, 3H).

[1414] (4) Preparation of compound 37-5

[1415]

[1416] At 25°C, NBS (0.396 g, 2.2 mmol, 1.1 eq) was added to a solution of 37-4 (0.4 g, 2.0 mmol, 1 eq) in 10 mL of CCl4. AIBN (0.033 g, 0.2 mmol, 1 eq) was added to the mixture, and the mixture was stirred at 80°C for 16 h. TLC monitoring was performed. The mixture was concentrated to obtain a residue, which was purified by column chromatography on silica gel, eluting with (PE / EA = 0-30%) to give methyl 4-(bromomethyl)-5-fluoro-2-methoxybenzoate, 37-5 (0.39 g, 70.0%).

[1417] 1 H NMR (400MHz, CDCl3) δ7.56–7.48(m,1H),6.97(d,J=5.8Hz,1H),4.48(s,2H),3.90(d,J=6.1Hz,6H).

[1418] (5) Preparation of compound 37-6

[1419]

[1420] Int-3 (0.40 g, 1.43 mmol) was dissolved in anhydrous DMF (8 mL), and then NaH (86 mg, 2.16 mmol) was added in portions at 0 °C. After 30 minutes, 37-5 (0.39 g, 1.41 mmol) of DMF (2 mL) was added to the reaction mixture through a tube. The reaction was monitored by LCMS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (20 mL × 3) and then with saline (20 mL).

[1421] ×2) Washing. The combined organic layers were dried with Na2SO4. Concentrated and purified by elution (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-5-methoxy-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate, 37-6 (0.32 g, 48%).

[1422] LCMS: rt = 3.35 min, [M+H] + =475

[1423] (6) Preparation of compound 37-7

[1424]

[1425] 37-6 (0.16 g, 0.34 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (1 N, 3 mL) was added. The mixture was stirred at 35 °C for 20 hours. The reaction was detected by LC-MS. The aqueous phase was extracted with EtOAc (10 mL × 3), washed with brine (10 mL × 2), and the combined organic layers were dried over Na₂SO₄. The solution was concentrated to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-5-fluoro-2-methoxybenzoic acid, 37-7 (0.15 g, 99% yield).

[1426] LCMS: rt = 2.16 min, [M+H] + =461

[1427] (7) Preparation of compound 37-8

[1428]

[1429] To 37-7 (0.15 g, 0.33 mmol), N,O-dimethylhydroxylamine (0.063 g, 0.65 mmol), and DIEA (0.186 g, 1.3 mmol).

[1430] HATU (0.186 g, 0.49 mmol) was added to a mixture in DMF (8 mL). The mixture was stirred at room temperature for 1 hour. The reaction was detected by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by elution (PE / EA = 0-45%) to give tert-butyl 4-(6-((2-fluoro-5-methoxy-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 37-8 (0.15 g, 90% yield).

[1431] LCMS: rt = 2.5 min, [M+H] + =504

[1432] (8) Preparation of compound 37-9

[1433]

[1434] 37-8 (0.15 g, 0.72 mmol) was dissolved in 10 mL of anhydrous THF containing Ar2. Cyclopropylmagnesium bromide (1 M) (1.2 mL, 1.08 mmol) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine. The combined organic layers were dried over Na2SO4 and concentrated to give tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 37-9 (0.14 g, 97% yield).

[1435] LCMS: rt = 3.95 min, [M+H] + =485

[1436] (9) Preparation of compound 37-10

[1437]

[1438] 37-9 (0.14 g, 0.29 mmol) was added to HCl / EtOAc (8 mL, 3 M), and the mixture was stirred at room temperature for 0.5 hours. The reaction was detected by LC-MS. The mixture was concentrated to give cyclopropyl(5-fluoro-2-methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)ketone, 37-10 (0.108 g, 98%).

[1439] LCMS: rt = 2.4 min, [M+H] + =385

[1440] (10) Preparation of compound 37-11

[1441]

[1442] The reaction mixture of 37-10 (0.108 g, 0.28 mmol) and DIEA (0.181 g, 1.4 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 min. Then, Int-2 (0.083 g, 0.28 mmol) was added and the mixture was heated at 65 °C for 15 h. The reaction was detected by LC-MS. The mixture was concentrated and purified by elution (MeOH / DCM = 0–5%) to give methyl (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, 37-11 (0.12 g, 67% yield).

[1443] LCMS: rt = 2.7 min, [M+H] + =643

[1444] (11) Preparation of compound 37

[1445]

[1446] 37-11 (0.12 g, 0.17 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (1 N, 3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction was detected by LC-MS. The mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 37 (27.1 mg, 23% yield).

[1447] LCMS: rt = 1.7 min, [M+H] + =629

[1448] 1 H NMR (400MHz, MeOD) δ8.23(s,1H),7.95(d,J=8.5Hz,1H),7.59(t,J=7.8Hz,2H),7.24(dd,J=13.4,7.8Hz,2H),6. 75(dd,J=61.1,7.8Hz,2H),5.47(s,2H),5.27(tt,J=7.3,3.6Hz,1H),4.89(dd,J=15.3,7.1Hz,1H),4.72(dd,J= 15.2,2.7Hz,1H),4.62(dd,J=13.9,7.8Hz,1H),4.47(dt,J=9.0,5.9Hz,1H),4.04–3.86(m,2H),3.83(s,3H),3. 09–2.87(m,2H),2.84–2.71(m,2H),2.67–2.47(m,2H),2.38–2.19(m,2H),1.94–1.75(m,4H),1.18–0.90(m,4H).

[1449] Example 38

[1450] (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 38)

[1451]

[1452] (1) Preparation of compound 38-2

[1453]

[1454] Methyl 2-bromo-5-fluoro-4-methylbenzoate 38-1 (1.0 g, 4.05 mmol), NBS (0.767 g, 4.25 mmol), and AIBN (70 mg, 0.45 mmol) were added to CCl4 (20 mL). The mixture was stirred at 80 °C for 16 hours. The reaction was monitored by TLC. The mixture was concentrated and purified by elution (PE / EA = 0.5%) to give methyl 2-bromo-4-(bromomethyl)-5-fluorobenzoate 38-2 (1.2 g, 90% yield).

[1455] LCMS: rt = 2.8 min, [M+H] + =325

[1456] (2) Preparation of compound 38-3

[1457]

[1458] Int-3 (0.86 g, 3.1 mmol) was dissolved in anhydrous DMF (10 mL), and then NaH (60%) (186 mg, 4.6 mmol) was added in portions at 0 °C. After 30 minutes, a solution of 38-2 (1.0 g, 3.1 mmol) in DMF (5 mL) was added to the reaction mixture through a sleeve. The reaction was monitored by TLC after 1 hour. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by elution (PE / EA = 0-20%) to give tert-butyl 4-(6-((5-bromo-2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 38-3 (0.7 g, 44% yield).

[1459] LCMS: rt = 3.5 min, [M+H] + =524

[1460] (3) Preparation of compound 38-4

[1461]

[1462] A reaction mixture of 38-3 (0.60 g, 1.14 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxane (3.5 M) (0.40 mL, 1.38 mmol), Cs₂CO₃ (0.75 g, 2.28 mmol), and Pd(dppf)Cl₂ (84 mg, 0.114 mmol) in 1,4-dioxane (15 mL) was added. The mixture was stirred with Ar₂ at 110 °C for 16 h, and the reaction was monitored by LC-MS. The mixture was concentrated and purified by elution (PE / EA = 0–30%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 38-4 (0.4 g, 65% yield).

[1463] LCMS: rt = 1.8 min, [M+H] + =503

[1464] (4) Preparation of compound 38-5

[1465]

[1466] 38-4 (0.4 g, 0.87 mmol) was dissolved in THF (5 mL), and then an aqueous lithium hydroxide solution (1 N, 5 mL) was added. The mixture was stirred at 35 °C for 20 hours. The reaction was detected by LC-MS. The aqueous phase was extracted with EtOAc (10 mL × 3) and washed with brine (10 mL × 2). The combined organic layers were dried over Na2SO4. The solution was concentrated to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-5-fluoro-2-methylbenzoic acid, 38-5 (0.38 g, 98% yield).

[1467] LCMS: rt = 3.27 min, [M+H] + =467

[1468] (5) Preparation of compound 38-6

[1469]

[1470] The reaction mixture of 38-5 (0.38 g, 0.86 mmol), N,O-dimethylhydroxylamine (0.166 g, 1.72 mmol), HATU (0.49 g, 1.28 mmol), and DIEA (0.5 g, 3.4 mmol) in DMF (10 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was detected by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine. The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by elution (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 38-6 (0.35 g, 83.5% yield).

[1471] LCMS: rt = 2.35 min, [M+H] + =488

[1472] (6) Preparation of compound 38-7

[1473]

[1474] 38-6 (0.35 g, 0.72 mmol) was dissolved in 10 mL of anhydrous THF containing Ar2. Cyclopropylmagnesium bromide (1 M) (3.6 mL, 3.6 mmol) was added to the reaction mixture through a sleeve, and the mixture was stirred at room temperature for 2 hours. The reaction was detected by LC-MS. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine. The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by vacuum concentration to give tert-butyl 4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate, 38-7 (0.30 g, 89% yield).

[1475] LCMS: rt = 3.47 min, [M+H] + =469

[1476] (7) Preparation of compound 38-8

[1477]

[1478] 38-7 (0.3 g, 0.64 mmol) was added to HCl / EtOAc (10 mL, 3 M). The mixture was stirred at room temperature for 0.5 h. The reaction was detected by LC-MS. The mixture was concentrated to give cyclopropyl(5-fluoro-2-methyl-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)phenyl)methyl ketone, 38-8 (0.23 g, 94% yield).

[1479] LCMS: rt = 2.35 min, [M+H] + =369

[1480] (8) Preparation of compound 38-9

[1481]

[1482] 38-8 (0.187 g, 0.51 mmol) in 10 mL of CH3CN and DIEA (0.21 g, 1.7 mmol) were stirred at room temperature for 10 minutes. Then Int-2 (0.10 g, 0.34 mmol) was added, and the mixture was heated at 65 °C for 15 hours. The reaction was detected by LC-MS. The mixture was concentrated and purified by elution (MeOH / DCM = 0-5%) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, 38-9 (0.18 g, 85% yield).

[1483] LCMS: rt = 2.7 min, [M+H] + =627

[1484] (9) Preparation of compound 38

[1485]

[1486] 38-9 (0.18 g, 0.29 mmol) was dissolved in THF (3 mL), and then an aqueous lithium hydroxide solution (1 N, 3 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction was detected by LC-MS. The mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give (S)-2-((4-(6-((4-(cyclopropanecarbonyl)-2-fluoro-5-methylbenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, compound 38 (59 mg, 34% yield).

[1487] LCMS: rt = 2.2 min, [M+H] + =599

[1488] 1 H NMR(400MHz,MeOD)δ8.21(d,J=0.8Hz,1H),7.94(dt,J=14.4,7.2Hz,1H),7.62–7.35(m,4H),6.80(d,J=7.2Hz,1 H),6.69–6.58(m,1H),5.53–5.36(m,2H),5.29(qd,J=7.1,2.9Hz,1H),4.95–4.87(m,1H),4.74(dd,J=15.3,2.9 Hz,1H),4.62(td,J=7.9,6.0Hz,1H),4.48(dt,J=9.1,6.0Hz,1H),3.95(dd,J=46.5,13.6Hz,2H),2.98(dd,J=42 .9,11.2Hz,2H),2.85–2.74(m,1H),2.66–2.49(m,2H),2.45–2.19(m,6H),1.96–1.74(m,4H),1.13–0.96(m,4H).

[1489] Example 39

[1490] 2-(((S)-4-(6-((4-(cyclopropanecarbonyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 39)

[1491]

[1492] (1) Preparation of compound 39-2

[1493]

[1494] The reaction mixture was added to a TOL (30 mL) with 6-chloropyridin-2-ol (2.5 g, 19.4 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (3.9 g, 19.4 mmol). The mixture was heated at 110 °C for 72 h. The reaction was detected by LC-MS. The mixture was concentrated and purified by elution (MeOH / DCM = 0–5%) to give (S)-4-(6-hydroxypyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, 39–2 (2.3 g, 40% yield).

[1495] LCMS: rt = 1.68 min, [M+H] + =294

[1496] (2) Preparation of compound 39-3

[1497]

[1498] 39-2 (1.2 g, 4.1 mmol) was dissolved in anhydrous DMF (15 mL), and then NaH (250 mg, 6.15 mmol) was added in portions at 0 °C. After 30 minutes, a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (1.23 g, 4.5 mmol) in DMF (5 mL) was added to the reaction mixture through a sleeve. The reaction was monitored by LC-MS after 1 hour. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine (50 mL × 2). The combined organic layers were dried over Na₂SO₄. Concentrated and purified by elution (PE / EA = 0-30%), to give (S)-4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, 39-3 (960 mg, 51% yield).

[1499] LCMS: rt = 3.25 min, [M+H] + =460

[1500] (3) Preparation of compound 39-4

[1501]

[1502] 39-3 (0.96 g, 2.1 mmol) was dissolved in THF (8 mL), and then an aqueous lithium hydroxide solution (1 N, 8 mL) was added. The mixture was stirred at room temperature for 20 hours. The reaction was detected by LC-MS. The aqueous phase was extracted with EtOAc (20 mL × 3) and washed with brine. The combined organic layers were dried over Na2SO4. Concentration gave (S)-4-(((6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid, 39-4 (810 mg, 87% yield).

[1503] LCMS: rt = 2.12 min, [M+H] + =446

[1504] (4) Preparation of compound 39-5

[1505]

[1506] The reaction mixture of 39-4 (0.81 g, 1.8 mmol), N,O-dimethylhydroxylamine (0.355 g, 3.6 mmol), HATU (1.04 g, 2.7 mmol), and DIEA (0.94 g, 7.17 mmol) in DMF (15 mL) was stirred at room temperature for 2 hours. The reaction was detected by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (50 mL × 3) and washed with brine. The combined organic layers were dried over Na2SO4. The mixture was concentrated and purified by elution (PE / EA = 0–20%) to give (S)-4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester, 39-5 (0.8 g, 90% yield).

[1507] LCMS: rt = 2.32 min, [M+H] + =489

[1508] (5) Preparation of compound 39-6

[1509]

[1510] At 25 °C, cyclopropylmagnesium bromide (0.15 g, 1 mmol, 2.0 eq) was added to a solution of 39-5 (0.3 g, 1 mmol, ...

Claims

1. Compounds of formula I-2: (I-2) Or its pharmaceutically acceptable salt. in: X is selected from carbonyl, methyloxyphosphoryl, and sulfonyl groups; ------ indicates that the key does not exist; W1 is 0; Y1 is N; Y2 is selected from CH, N, or C; Y3 is N; Z1, Z2, and Z3 are each independently selected from CH or N; R1 is selected from -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl group, -C 3~8 Cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, -NH2, -NH-C 1~6 Alkyl, -NH-C 1~6 Alkoxy, -NH-C 1~6 Cycloalkoxy, -NH-C 2~6 alkenyl, -NH-C 2~6 Alkyne group, -NH-C 3~8 Cycloalkyl, -NH-3~8-membered heterocyclic, -NH-6~8-membered aryl, -NH-5~8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic, aryl, or heteroaryl group in R1 is optionally selected independently from R1. x The substituents are substituted 1 to 3 times; R2 is independently selected from hydrogen, oxo, halogen, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl group, -C 1~6 Alkoxy, -C 1~6 Cycloalkoxy, -CN, 3-8 membered heterocyclic, aryl, 5-8 membered heteroaryl, or -CO-R1, wherein the alkyl, alkenyl, alkoxy, cycloalkoxy, heterocyclic, aryl, or heteroaryl group in R2 is optionally selected independently from R1. x The substituents are substituted 1 to 3 times; R4 is independently selected from hydrogen, halogen, and -C. 1~3 Alkyl, -C 1~3 Halogenated alkyl, -C 1~3 Alkoxy, cyano, hydroxyl, amino, amide, sulfonyl, sulfonamide; R5 is independently selected from hydrogen, halogen, hydroxyl, -CN, and -C. 1~3 Alkyl, -C 1~3 Alkoxy, -C 1~3 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group in R5 is optionally substituted by a halogen atom 1 to 3 times, provided that the valence allows; R6 is selected from -R z -OR z -SR z -C 1~3 Alkyl, -C 1~3 Alkylene-R z -C 0~3 alkylene-amino-R z -C 0~3 alkylene-carbonyl-R z -C 0~3 alkylene-amide-R z -C 0~3 alkylene-sulfonyl-R z -C 0~3 alkylene-phosphoryl-R z -C 0~3 alkylene-sulfonamide-R z The alkyl, amino, sulfonyl, or sulfonamide groups in R6 are optionally substituted 1 to 3 times by a halogen atom, or by R6, provided that the valence allows. w Replace 1 time; n is an integer selected from 0, 1, 2 or 3; o is an integer selected from 0, 1, 2, 3 or 4; p is an integer selected from 0 or 1; When o is not 0 and p is not 0, any R4 and R5 can be arbitrarily further cyclically transformed into 5- to 8-membered rings. The resulting rings can be arbitrarily composed of C, provided that the valence is allowed. 1~3 Alkyl, C 1~3 Halogenated alkyl, halogen, cyano, oxo, C 1~3 Alkoxy substitution 1 to 3 times; R w Independently selected from -CN, -CH2CN, -C 1~3 Alkyl, -OH, -C 1~3 Alkoxy, amide, sulfonyl, sulfonamide, -NH2, -NH-C 1~3 Alkyl, wherein the R w The alkyl group in the alkyl group may optionally be formed by C, provided that the valence allows. 1~3 Alkyl, C 1~3 Halogenated alkyl, halogen, cyano, oxo, C 1~3 Alkoxy substitution 1 to 3 times; R x Independently selected from hydrogen, halogen, oxo, C 1~6 Alkoxy, cyano, hydroxy, carboxyl, amino, amide, sulfonyl, sulfonamide, -C 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl group, -C 3~6 cycloalkyl, 3-6-membered heterocyclic, 6-8-membered aryl, 5-8-membered heteroaryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally composed of C10, provided that the valence allows. 1~3 Alkyl, C 1~3 Halogenated alkyl, halogen, cyano, oxo, C 1~3 Alkoxy substitution 1 to 3 times; R z Independently selected from hydrogen and C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl, wherein R z Subject to the allowable valence, C can be arbitrarily selected. 1~3 Alkyl, C 1~3 The alkyl halide, halogen, cyano, oxo, or 3- to 6-membered heterocyclic groups are substituted 1 to 3 times.

2. The compound according to claim 1, wherein: X is a carbonyl group; W1 is 0; Z1, Z2, and Z3 are each CH; and o is 1.

3. The compound according to claim 1, wherein Y2 is CH.

4. The compound according to claim 1, wherein Y2 is N.

5. The compound according to any one of claims 1-4, wherein R1 is selected from methyl, ethyl, isopropyl, cyclopropyl, -NH2, -NHCH3, pyridine, pyrimidine, hexahydropyridine, pyrrole, pyrazole, imidazole, wherein R1 is optionally substituted with a halogen 1 to 3 times; and / or The R2 mentioned therein is selected from halogens, -CN, and -C. 1~3 Alkyl or -C 1~3 Alkoxy groups, wherein the alkyl and alkoxy groups in R2 are optionally substituted 1 to 3 times by an F atom, provided that the valence allows; and / or R5 is selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CF3, -CH2OH, isopropyl, or cyclopropyl.

6. The compound according to any one of claims 1-4, wherein R2 is -F, -Cl, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -COCH3, -CONH2, -CF3, -CHF2, -CH2F, -CH2CH2F, cyclopropyl, or -O-cyclopropyl.

7. The compound according to any one of claims 1-4, wherein the R... z Selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, and ethoxy.

8. The compound according to claim 1, wherein n is 1 or 2; and / or, wherein o is 0 or 1.

9. The compound according to claim 1, wherein Z1 and Z2 are each independently CH.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical carrier.

12. Compounds selected from: , , , , , and , Or its pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising the compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical carrier.

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