GLP-1 receptor agonists and compositions and uses thereof

Abstract

Provided are GLP-1 receptor agonist compounds, as well as compositions and uses thereof, which can be used for the treatment or prevention of GLP-1 receptor mediated diseases or disorders and related diseases or disorders.

Description

[Technical field]

[0001] The present disclosure relates to GLP-1 receptor agonists and compositions and uses thereof, which compounds can be used to treat or prevent GLP-1 receptor mediated diseases or disorders and related diseases or disorders. [Background technology]

[0002] Diabetes mellitus is a chronic comprehensive disease characterized by impaired glucose metabolism due to absolute or relative insulin deficiency or reduced sensitivity of target cells to insulin, and is divided into type I diabetes and type II diabetes. Type II diabetes is an endocrine disease characterized by chronic elevation of blood glucose levels due to insulin resistance and / or insulin secretion deficiency. Type II diabetes patients account for more than 90% of diabetes patients.

[0003] Currently, the main types of drugs used to treat type II diabetes include insulin secretagogues, metformin, α-glycosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and its analogs, among which insulin and GLP-1 receptor agonists are among the most effective drugs for the treatment of diabetes. Insulin preparations are still the most widely used diabetes drug in the world, and about 30-40% of type II diabetes patients eventually require insulin. GLP-1 preparations mainly include exenatide, liraglutide, somalutide, etc., and are suitable for type II diabetes patients who cannot completely control blood sugar with a combination of metformin and sulfonylurea. However, current insulin preparations and GLP-1 preparations are essentially polypeptides and injection preparations. Even oral somalutide still has many restrictions on administration. Therefore, further development of small molecule GLP-1 agonists is necessary.

[0004] GLP-1 stimulates insulin secretion in a glucose-dependent manner and inhibits glucagon secretion in a glucose-dependent manner, so there is no risk of hypoglycemia. GLP-1 can increase insulin production by β-cells and improve β-cell response to glucose. GLP-1 can delay gastric emptying and reduce food intake, which can lead to weight loss. In addition, GLP-1 also has unique cardiovascular beneficial effects. GLP-1 receptor agonists are used in clinical practice in the transition period between oral hypoglycemic agents and insulin and can be used in combination with other drugs.

[0005] Other diseases associated with type 2 diabetes include diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity and hypertension.

[0006] GLP-1 receptor agonists are very promising drugs, and most of them are currently on the market as injections. Oral small molecule GLP-1 receptor agonists can improve patient compliance and will be the development trend of GLP-1 receptor agonists in the future. The development of small molecule GLP-1 receptor agonists is described in WO2009111700A2, WO2010114824A1, WO2017078352A1, KR10201801671A, WO2018056453A1 and WO2018109607A1.

[0007] There remains a need to develop small molecule GLP-1 receptor agonists that have improved properties in one or more of the following areas: GLP-1 receptor agonist activity, intestinal absorption, safety, and pharmacokinetics. Summary of the Invention

[0008] Content of disclosure In one aspect, the present disclosure provides compounds of formula I and II, as described in the Detailed Description section below: [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0009] The compounds of the present disclosure are GLP-1 receptor agonists. Preferred compounds of the present disclosure (e.g., compounds of formula II) have excellent GLP-1 receptor agonist activity, good intestinal absorption, and / or good safety and pharmacokinetic properties (e.g., metabolic stability, plasma binding, C max For example, some of the compounds of formula II have improved GLP-1 receptor agonist activity (e.g., lower EC 50 ) and / or have greater in vivo and / or in vitro safety and / or improved pharmacokinetic properties (e.g., metabolic stability, C max , half-life, and / or oral bioavailability).

[0010] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.

[0011] In one aspect, the disclosure provides the use of a compound of Formula I or Formula II, or a pharma- ceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating GLP-1 receptor-mediated diseases or disorders and related diseases or disorders.

[0012] In one aspect, the disclosure provides a method for preventing and / or treating GLP-1 receptor mediated diseases or disorders and related diseases or disorders in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or Formula II, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0013] In some embodiments, the GLP-1 receptor mediated disease or disorder and associated disease or disorder is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia and hyperinsulinemia.

[0014] Detailed Description In one aspect, the present disclosure provides a compound of formula I: [ka] [In the formula, [ka] indicates a single or double bond; W is selected from O, N, or NH; X1, X3 and X4 are independently selected from N and C; Y1 is selected from CH and N; Y2 is selected from CH, N and C; Y3 is selected from CH, N and C; Y4, Y5 and Y6 are independently selected from CH and N, and Y4, Y5 and Y6 are not simultaneously N; Ring A is selected from the group consisting of a benzene ring, thiophene, pyridine and piperidine; R1 is independently hydrogen, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or C 3-6 optionally substituted 1 to 3 times by heterocyclyl; R2 is 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 and -C 0-3 Alkylene-sulfonamide-R z wherein alkyl, amino, amido, sulfonyl, sulfonamido, and phosphoryl for R2 are optionally substituted 1 to 3 times by halogen or R w may be optionally substituted once by; R4 is independently hydrogen, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy, cyano, hydroxy, amino, amido, sulfonyl, and sulfonamido; R5 is independently hydrogen, halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6cycloalkyl, where alkyl, alkoxy and cycloalkyl for R5 are selected from the group consisting of halogen, hydroxy, -NR z , C.N., C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 optionally substituted 1 to 3 times by cycloalkyl; R0 is independently hydrogen, halogen, hydroxy, oxo, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 R is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, where the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl, and heteroaryl for R are, where valences permit, halogen, CN, NH, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 optionally substituted 1 to 3 times by cycloalkyl; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; When p is 2 or more, any two R5 may be further cyclized with ring C to form a 6-10 membered spiro ring or bridge ring, and the formed spiro ring and bridge ring are each independently selected from the group consisting of C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano or C 1-3 optionally substituted 1 to 3 times by alkoxy; When m is not 0 and p is not 0, any R4 and any R5 may be further cyclized to a 5-8 membered ring, and the ring formed may, if valences permit, be C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo or C 1-3optionally substituted 1 to 3 times by alkoxy; R w are independently CN, -CHCN, C 1-3 Alkyl, OH, C 1-3 Alkoxy, amide, sulfonyl, sulfonamide, NH2 and -NH-C 1-3 alkyl, where R w The alkyl group for 1-3 Alkyl, C 1-3 Haloalkyl, halogen, cyano, oxo or C 1-3 optionally substituted 1 to 3 times by alkoxy; R z are independently hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, aryl, and 5- to 6-membered heteroaryl, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy or 3- to 6-membered heterocyclyl] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0015] In formula I, the letters "B" and "C" in the rings are the names of the corresponding rings, i.e., the ring having Y2 and Y3 as shown in the formula may be referred to as ring C; the ring having Y1 as shown in the formula may be referred to as ring B; and so forth.

[0016] In some embodiments, X 1 is N.

[0017] In some embodiments, X3 is CH and X4 is N. In some embodiments, X3 is N and X4 is CH. In some embodiments, X3 and X4 are each N. In some preferred embodiments, X3 and X4 are each CH.

[0018] In some embodiments, R is independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6 Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or C 3-6 It may be optionally substituted 1 to 3 times by heterocyclyl.

[0019] In some embodiments, R2 is -CH2-R z is selected from.

[0020] In some embodiments, W is O.

[0021] In some embodiments, R z is preferably C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, where R z is C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3It is optionally substituted 1 to 3 times by alkoxy or 3-6 membered heterocyclyl.

[0022] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt or stereoisomer thereof has formula I-2 or formula I-2': [ka] [ka] [In the formula, [ka] indicates a single or double bond; X3 and X4 are independently selected from CH and N; Y2 is selected from CH, N and C; Y3 is selected from CH and N; Ring A is [ka] and optionally further substituted n times by R1; R1 is independently hydrogen, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6 Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or C 3-6 optionally substituted 1 to 3 times by heterocyclyl; Rz is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, [ka] wherein R z is halogen, cyano, C, if valence permits. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 optionally substituted 1 to 3 times by cycloalkyl or 3-6 membered heterocyclyl; R5 is independently hydrogen, halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl, where alkyl, alkoxy and cycloalkyl for R5 are selected from the group consisting of halogen, hydroxy, -NR z , C.N., C. 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 optionally substituted 1 to 3 times by cycloalkyl; n is an integer selected from 0, 1, or 2; and R y are independently hydrogen, halogen, oxo, C 1-3 Alkoxy, cyano, hydroxyl, amino, carboxyl, amide, sulfonyl, sulfonamide, C 1-3 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and phenyl, where R y The alkyl, alkoxy, cycloalkyl and heterocyclyl in the formula (I) may be optionally substituted 1 to 3 times with halogen, if valence permits. It has the structure:

[0023] In some embodiments, R z is cyclopropyl, cyclobutyl, [ka] is selected from the group consisting of:

[0024] In some embodiments, R z is cyclopropyl, cyclobutyl, [ka] is selected from the group consisting of:

[0025] In other embodiments, R z is C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3 It is optionally substituted 1 to 3 times by alkoxy or 3-6 membered heterocyclyl.

[0026] In some preferred embodiments, R z is C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 by alkyl, halogen or cyano, preferably C 1-3 Haloalkyl (preferably halomethyl), cyano-C 1-3 It is optionally substituted once by alkyl (preferably cyanomethyl) or halogen. In some embodiments, the halo or halogen is F or Cl. In some such embodiments, R z is preferably [ka] selected from the group consisting of; More preferably, [ka] selected from the group consisting of; Even more preferably, [ka] is selected from the group consisting of:

[0027] In some embodiments, R is independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6 Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and gC 3-6 Cycloalkyl is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or C 3-6 It is optionally substituted 1 to 3 times by heterocyclyl.

[0028] In some embodiments, R or [ka] teeth, [ka] is selected from the group consisting of:

[0029] In some other embodiments, any adjacent R and R are further cyclized into a 5-8 membered ring; 5-6Including carbocyclic rings, 5-8 membered heterocyclic rings, phenyl rings and 5-8 membered heteroaromatic rings, the rings formed may be optionally substituted 1 to 3 times, if valences permit, with alkyl, haloalkyl, halogen, cyano, alkoxy.

[0030] In some embodiments, when m is not 0 and p is not 0, any adjacent R4 and R5 may be further cyclized into a 5-8 membered ring, which is preferably [ka] wherein the 5-8 membered ring, if valences permit, is selected from the group consisting of C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo, C 1-3 It may be optionally substituted 1 to 3 times by alkoxy.

[0031] In some embodiments, when m is not 0 and p is not 0, any adjacent R4 and R5 may be further cyclized into a 5-8 membered ring, which is preferably [ka] where the 5-8 membered ring is C, if valences permit. 1-3 Alkyl, C 1-3 Haloalkyl, halogen, cyano, oxo or C 1-3 It may be optionally substituted 1 to 3 times by alkoxy.

[0032] In some embodiments, when m is not 0 and p is not 0, any adjacent R4 and R5 may be further cyclized into a 5-8 membered ring, which is [ka] wherein the 5-8 membered ring, if valences permit, can be selected from the group consisting of: 1-3 Alkyl, C1-3 Haloalkyl, halogen, cyano, oxo or C 1-3 It may be optionally substituted 1 to 3 times by alkoxy.

[0033] In some embodiments, the 5-8 membered ring [ka] teeth, [ka] and preferably selected from the group consisting of: [ka] and more preferably selected from the group consisting of [ka] wherein the 5-8 membered ring is, if valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, halogen, cyano, oxo or C 1-3 It may be optionally substituted 1 to 3 times by alkoxy.

[0034] In some of the above embodiments, the compound of formula I described in the present disclosure has the following structure: [ka] Ring D is the above 5-8 membered ring.

[0035] In some embodiments, R1 is selected from the group consisting of -F, -Cl, -CN, -OCH3, -OCH2CH3, -O-cyclopropyl, -CH3, -CH2CH3, -CH2CH2CH3, -(CH)2CH3, -COCH3, -CONH2, -CF3, -CHF2, -CH2F, -CH2CH2F, -CO-cyclopropyl, -COCH2F, -COCHF2, -CO-CH(CH3)2 and -CO-CH2CH3.

[0036] In some other embodiments, R1 is independently selected from halogen and -C 1-3 It is selected from the group consisting of alkoxy, preferably selected from the group consisting of F, Cl, methoxy, ethoxy, n-propoxy or isopropoxy, more preferably selected from the group consisting of F, Cl and methoxy.

[0037] In some embodiments, R4 is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is selected from the group consisting of alkoxy, cyano, hydroxyl and amino, and is more preferably hydrogen.

[0038] In some embodiments, R5 is selected from the group consisting of F, Cl, CH3, -OCH3, NH2, OH, -CH2CH3, -CH2OH, -NHCH3, -COCH3, -SO2CH3, -OCH2CH3, CF3, -CHF2, -CH2F, isopropyl, cyclopropyl, and fluorocyclopropyl.

[0039] In some other embodiments, R5 is independently selected from hydrogen and halogen, preferably selected from the group consisting of hydrogen, F and Cl.

[0040] In some embodiments, Y2 is C or CH.

[0041] In some embodiments, Y3 is C or N.

[0042] In another aspect, the present disclosure provides certain preferred compounds of formula I, or pharma- ceutically acceptable salts or stereoisomers thereof, comprising the formula II: [ka] [In the formula, [ka] indicates a single or double bond; W is selected from O, N, and NH; X3 and X4 are independently selected from CH, N and C; Y1 is selected from CH or N; Y2 is selected from CH, N or C; Y3 is selected from CH, N or C; R1 is independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; R2 is R z -C 1-3 alkylene-; R4 is independently hydrogen, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 is selected from the group consisting of alkoxy, cyano, hydroxy, amino, amido, sulfonyl and sulfonamido, and is preferably selected from the group consisting of hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 is selected from the group consisting of alkoxy, cyano, hydroxy and amino, more preferably hydrogen; R5 is independently hydrogen, halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl; preferably, R5 is independently selected from hydrogen and halogen; R0 is independently selected from the group consisting of hydrogen, hydroxyl and halogen; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; When m is not 0 and p is not 0, any R4 and any R5 may be taken together with the ring atoms of rings B and C therebetween to form a 5-8 membered ring, where valences permit, the 5-8 membered ring may be selected from the group consisting of C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo or C 1-3 optionally substituted 1 to 3 times by alkoxy; R z is C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy or 3- to 6-membered heterocyclyl] The present invention provides a compound having the structure: or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0043] In formula II, the letters "B" and "C" are the definitions of the corresponding rings, i.e., the ring with the indicated Y2 and Y3 may be referred to as ring C; the ring with the indicated Y1 may be referred to as ring B; and so forth.

[0044] In some preferred embodiments, R1 is independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkoxy is selected from the group consisting of

[0045] In some preferred embodiments, R0 is independently selected from hydrogen and halogen.

[0046] In some preferred embodiments, R z is C 3-6cycloalkyl and 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3 It is optionally substituted 1 to 3 times by alkoxy or 3-6 membered heterocyclyl.

[0047] In some embodiments, X3 is CH and X4 is N. In some embodiments, X3 is N and X4 is CH. In some embodiments, X3 and X4 are each N. In some preferred embodiments, X3 and X4 are each CH.

[0048] In some of the above embodiments, n is 1.

[0049] In some such embodiments, [ka] teeth, [ka] It is.

[0050] In some of the above embodiments, R2 is -CH2-R z is selected from.

[0051] In some of the above embodiments, W is O.

[0052] In some of the above embodiments, q is 1.

[0053] In some such embodiments, [ka] teeth, [ka] It is.

[0054] In some of the above embodiments, the compound has formula II-1: [ka] [In the formula, X3, X4, Y1, Y2, Y3, R z , R0, R1, R4, R5, m and p are as defined above for compounds of formula II. having a structure of Preferably, the compound of formula II-2: [ka] [In the formula, Y1, Y2, Y3, R z , R0, R1, R4, R5, m and p are as defined above for compounds of formula II. It has the structure:

[0055] In some of the above embodiments, R1 is independently hydrogen, halogen, C 1-3 Alkyl and C 1-3 alkoxy, preferably independently selected from the group consisting of halogen and C 1-3 Alkoxy is preferably selected from the group consisting of F, Cl, CH3O-, CH3CH2-O-, CH3CH2CH2-O- or (CH3)2CH-O-, more preferably selected from the group consisting of F, Cl and CH3O-.

[0056] In some of the above embodiments, [ka] teeth, [ka] It is.

[0057] In some embodiments of the above, R z is C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, where R z If valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 by alkyl, halogen or cyano, preferably C 1-3 Haloalkyl (preferably halomethyl), cyano-C 1-3 It is optionally substituted once with alkyl (preferably cyanomethyl) or halogen. In some embodiments, the halo or halogen is F or Cl.

[0058] In some preferred embodiments, R z teeth, [ka] selected from the group consisting of; Preferably, [ka] selected from the group consisting of; More preferably, [ka] is selected from the group consisting of:

[0059] In some of the above embodiments, R2 or [ka] is preferably [ka] is selected from the group consisting of:

[0060] In some of the above embodiments, Y2 is C or CH.

[0061] In some of the above embodiments, Y3 is C or N.

[0062] In some embodiments, the present disclosure provides a compound of formula II: [Wherein, Y2 is CH, Y3 is N, p is 0, and [ka] teeth, [ka] or Y2 is C, Y3 is C, p is an integer of 1, 2 or 3, and [ka] teeth, [ka] is] Some preferred compounds are provided:

[0063] In some embodiments of preferred compounds of formula II, Y2 is CH, Y3 is N, p is 0, and [ka] teeth, [ka] It is.

[0064] In some embodiments, the compound has formula II-3: [ka] [In the formula, X3, X4, Y1, R z, R0, R1, R4 and m are as defined above for compounds of formula II. having a structure of Preferably, the compound of formula II-4: [ka] [Where, Y1, R z , R0, R1, R4 and m are as defined above for compounds of formula II. It has the structure:

[0065] In some preferred embodiments, R z is selected from heteroatom-unsubstituted 3-6 membered heterocycloalkyl (preferably 3-4 membered heterocycloalkyl) having one O, preferably [ka] and; m is 0; R1 is F, Cl, CH3O-, CH3CH2-O-, CH3CH2CH2-O- or (CH3)2CH-O-, preferably F, Cl or CH3O-; and R0 is hydrogen, F or Cl, preferably hydrogen or F.

[0066] More preferably, [ka] teeth, [ka] It is.

[0067] In another preferred embodiment, R z is C 1-3 haloalkyl (preferably halomethyl, more preferably -CFH2 or -CClH2), cyano-C 1-3C optionally substituted with one substituent selected from the group consisting of alkyl (preferably cyanomethyl) and halogen (preferably F or Cl). 3-6 Cycloalkyl (preferably C 3-4 cycloalkyl), preferably [ka] and more preferably [ka] and; m is 0; R1 is F, Cl, CH3O-, CH3CH2-O-, CH3CH2CH2-O- or (CH3)2CH-O-, preferably F or Cl; and R0 is hydrogen, F or Cl, preferably hydrogen.

[0068] In another embodiment of the preferred compounds of formula II, Y2 is C, Y3 is C, p is 1, and [ka] teeth, [ka] and preferably [ka] where R5 is in the ortho position to Y3.

[0069] In some embodiments, the compound has formula II-5: [ka] [In the formula, X3, X4, Y1, R z , R0, R1, R4, R5 and m are as defined above for compounds of formula II. having a structure of Preferably, the compound of formula II-6: [ka] [Where, Y1, R z , R0, R1, R4, R5 and m are as defined above for compounds of formula II. It has the structure:

[0070] In some preferred embodiments, R5 is hydrogen or halogen, preferably F or Cl, more preferably F. In some preferred embodiments, R0 is hydrogen, F or Cl, preferably hydrogen. In some preferred embodiments, Y1 is N. In some preferred embodiments, R4 is hydrogen.

[0071] In some embodiments, the present disclosure provides a compound of formula II: [In the formula, m is not 0, p is not 0, any R4 and any R5 together with the ring atoms of ring B and ring C therebetween form a 5-8 membered ring, wherein the 5-8 membered ring has 0, 1, or 2 ring heteroatoms independently selected from N, O, and S, and the ring heteroatom(s) are not ring atoms of ring B or ring C, and wherein the 5-8 membered ring, if valences permit, is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy] Another preferred compound is provided:

[0072] In some preferred embodiments, m is 1, p is 1, and R4 and R5, taken together with the ring atoms of ring B and ring C therebetween, form a 5-8 membered ring, wherein the 5-8 membered ring has 0, 1, or 2 ring heteroatoms independently selected from N, O, and S, and the ring heteroatoms are not ring atom(s) of ring B or ring C, and wherein the 5-8 membered ring, if valences permit, is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo, C 1-3 It may be optionally substituted 1 to 3 times by alkoxy.

[0073] In some such embodiments, the compound has formula II-7: [ka] [In the formula, Ring D [ka] is a 5-8 membered ring as defined above; [ka] indicates a single or double bond; Y1, Y2 and Y3 are each as defined above for compounds of formula II; R y is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo and C 1-3 alkoxy; and R is 1, 2 or 3. Preferably, r is 1. It has the structure:

[0074] Preferably, the compound has the formula II-8: [ka] It has the structure:

[0075] Preferably, R y is hydrogen.

[0076] In some of the above embodiments, Ring D [ka] teeth, [ka] is selected from the group consisting of Preferably, [ka] is selected from the group consisting of More preferably, [ka] It is.

[0077] In some preferred embodiments, the compound has formula II-9: [ka] It has the structure:

[0078] In some of the above embodiments, Y3 is N. In some of the above embodiments, Y1 is N.

[0079] In some similar embodiments, [ka] teeth, [ka] ( [ka] ) is selected from.

[0080] In some embodiments of the above, R z is selected from unsubstituted 3-6 membered heterocycloalkyl (preferably 3-4 membered heterocycloalkyl) having one O heteroatom, preferably [ka] and; R1 is F, Cl, CH3O-, CH3CH2-O-, CH3CH2CH2-O- or (CH3)2CH-O-, preferably F or Cl; and R0 is hydrogen, F or Cl, preferably hydrogen.

[0081] More preferably, [ka] teeth, [ka] It is.

[0082] In some embodiments, the present disclosure relates to the compound described above, [ka] That is, Preferably [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0083] The present disclosure relates to the compound: [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0084] The compounds provided by the present disclosure are GLP-1 receptor agonists, and some of the preferred compounds represented by formula I, particularly the compounds represented by formula II and their pharma- ceutically acceptable salts, have excellent GLP-1 receptor agonist activity. These GLP-1 receptor agonist compounds can treat and / or prevent GLP-1 receptor-mediated diseases or disorders and related diseases or disorders.

[0085] The compounds of Formula I or Formula II provided in this disclosure, as well as pharma- ceutically acceptable salts and stereoisomers thereof, can be used alone or in combination with at least one other therapeutic agent in treatment.

[0086] The present disclosure further provides pharmaceutical compositions comprising a compound of Formula I or Formula II above, or a pharma- ceutically acceptable salt or stereoisomer thereof, and one, two or more additional therapeutically active ingredients.

[0087] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula I or Formula II above, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.

[0088] The present disclosure also provides a pharmaceutical formulation comprising a compound of Formula I or Formula II above, or a pharma- ceutically acceptable salt or stereoisomer thereof, and one or more pharma- ceutically acceptable carriers, excipients, or diluents.

[0089] The pharma- ceutically acceptable carriers, excipients, and / or diluents that may be used in the pharmaceutical compositions or pharmaceutical formulations of the present disclosure may be any conventional carriers, excipients, and / or diluents in the field of pharmaceutical formulations.

[0090] Pharmaceutically acceptable salts as described herein include acid addition and base salts.

[0091] The pharma- ceutically acceptable salts described herein can exist in unsolvated and solvated forms.

[0092] The present disclosure further provides the use of the compounds of formula I or formula II above and their pharma- ceutically acceptable salts or stereoisomers in the manufacture of a medicament for the treatment and / or prevention of metabolic-related diseases or disorders, including GLP-1 receptor-mediated diseases or disorders and related diseases or disorders.

[0093] The present disclosure further provides a method of treating a disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or Formula II above, and pharma- ceutically acceptable salts or stereoisomers thereof, wherein said disease or disorder is a GLP-1 receptor mediated disease or disorder, or an associated disease or disorder.

[0094] In some embodiments, the GLP-1 receptor mediated disease or disorder is diabetes.In some embodiments, diabetes includes but is not limited to type I diabetes (T1D) and / or type II diabetes mellitus (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes.In some embodiments, the GLP-1 receptor mediated disease or disorder is hyperglycemia, insulin resistance, glucose intolerance.In some embodiments, the disease or disorder associated with GLP-1 receptor mediated disease or disorder includes diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataract), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity, hypertension.

[0095] In some embodiments, GLP-1 receptor mediated disease or disorder and related disease or disorder include but are not limited to diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia and hyperinsulinemia.Said diabetes includes but is not limited to T1D and / or T2DM, idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes.

[0096] The present disclosure further provides the use of the compounds of Formula I and Formula II, or pharma- ceutically acceptable salts or stereoisomers thereof, in the preparation of a GLP-1 receptor agonist related medicament.

[0097] In some embodiments, the GLP-1 receptor agonist related drug is for treating type II diabetes, type I diabetes and obesity.

[0098] definition The compounds of this disclosure are named according to their chemical structure. If the name of a compound conflicts with the chemical structure of the same compound, the chemical structure controls.

[0099] In this disclosure, unless otherwise defined, all scientific and technical terms used herein have the same meaning as those generally understood by those skilled in the art.Nevertheless, in order to better understand this disclosure, the definitions of some terms are provided below.If the definitions and interpretations of terms provided herein are different from those generally understood by those skilled in the art, the definitions and interpretations of terms provided herein shall prevail.

[0100] The compounds provided in the present disclosure and their pharmaceutically acceptable salts may exist in chiral form, i.e., S-configuration or R-configuration.The compounds provided in the present disclosure and their pharmaceutically acceptable salts may exist in achiral form.When the structure of the compounds described in the present disclosure is illustrated by one configuration, it is intended that other configurations or achiral forms are also disclosed.

[0101] The compounds described in this disclosure include the stereoisomers of the compounds.The stereoisomers described in this disclosure mean that when the compound of formula I or formula II has asymmetric carbon atom, there are enantiomers; when the compound has carbon-carbon double bond or cyclic structure, there are cis-trans isomers; when ketone or oxime exists in the compound, there are tautomers.In some embodiments, the stereoisomers described in this disclosure include but are not limited to enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and their mixtures.

[0102] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated in the present disclosure, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures thereof, such as enantiomer-enriched or diastereomer-enriched mixtures, and all of these mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are within the scope of the present disclosure.

[0103] Unless otherwise specified, the terms "enantiomers" or "optically active isomers" mean stereoisomers that are mirror images of each other.

[0104] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" arise because the double or single bonds of the carbon atoms forming the ring cannot rotate freely.

[0105] Unless otherwise specified, the term "diastereomers" means stereoisomers with two or more centers of chirality and which are not mirror images of one another.

[0106] Unless otherwise specified, "(+)" indicates right-handed, "(-)" indicates left-handed, and "(±)" indicates racemic.

[0107] Solid wedge connections, unless otherwise noted: [ka] and Wedge-shaped dashed bond [ka] is used to indicate the absolute configuration of a stereocenter, and a straight solid bond [ka] and straight dashed bonds [ka] The stereocenter has absolute configuration, but it is a wedge-shaped solid bond. [ka] Or is it a wedge-shaped dashed bond? [ka] Use this when you are not sure.

[0108] 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. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary reagent, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if there is a basic (e.g., amino) or acidic (e.g., carboxyl) functional group in the molecule, the molecule can be reacted with an appropriate optically active acid or base to form a diastereomeric salt, which can be subjected to diastereomeric separation by conventional techniques known to those skilled in the art, and then the pure enantiomer can be recovered. Furthermore, enantiomers and diastereomers are usually separated by chromatography using chiral stationary phases, optionally combined with chemical derivatization (e.g., generating carbamates from amines).

[0109] The term "pharmacologically acceptable" in this disclosure means that the compounds, materials, compositions and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0110] The term "pharmaceutically acceptable salt" in this disclosure refers to a salt of the compound of the present invention prepared from a compound having certain substituents of this disclosure and a relatively non-toxic acid or base. When a compound of this disclosure 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 pure solution or in a suitable inert solvent. When a compound of this disclosure 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 pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Some specific compounds of this disclosure contain both basic and acidic functional groups, and are amenable to conversion to any base or acid addition salt.

[0111] The pharma- ceutically acceptable salts of the present disclosure can be synthesized from a parent compound that contains an acid or base group by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0112] In this disclosure, the term "optionally" or "optionally" means that the subsequently described event or condition may occur, but does not necessarily have to occur, and that the description includes cases where the event or condition occurs and cases where it does not occur.

[0113] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (=O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur in aromatic groups. The term "optionally substituted" means substituted or unsubstituted. Unless otherwise specified, the type and number of substituents are arbitrary within the chemically achievable range.

[0114] In this disclosure, the term "optionally substituted" means both "substituted" and "unsubstituted."

[0115] When any variable (e.g., R) occurs more than once in a compound configuration or structure, it is defined independently at each occurrence. Thus, for example, if a group is substituted with 0-2 R, the group may be optionally substituted with up to 2 R, with each occurrence of R having an independent option. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0116] When the number of bonding groups is 0, such as (CRR)0-, it means that the bonding group is a single bond.

[0117] When the number of substituents is 0, it means that the substituent does not exist, for example, -A-(R)0 actually indicates that it is -A.

[0118] If a substituent is empty, it means that the substituent is not present, for example, if X is empty in AX, it means that the structure is actually A.

[0119] When one of the variables is selected from a single bond, it means that the two groups it attaches to are directly linked, e.g., when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0120] When a bond of a substituent may be bridged to two or more atoms in a ring, such a substituent may be bonded to any atom in the ring. For example, the structural unit: [ka] means that the substituent R may be substituted at any position of the cyclohexyl or cyclohexadiene. If the atom of a listed substituent to which the substituent is bonded is not specified, the substituent may be bonded at any of those atoms. For example, a pyridyl group as a substituent may be bonded to the substituent by any carbon atom of the pyridine ring.

[0121] When no bond direction is indicated for a listed linking group, the bond direction is arbitrary. For example, [ka] When the linking group L in the formula (I) is -MW-, the -MW- bonds the ring A and the ring B in the same direction as the reading order from left to right, [ka] Alternatively, ring A and ring B can be linked in the reverse reading order from left to right to form [ka] Combinations of linking groups, substituents and / or variants thereof are permissible only if such combinations may result in stable compounds.

[0122] Unless otherwise specified, if a group has one or more available bond sites, any one or more of the groups can be bonded to other groups by chemical bonds. If the site to which the chemical bond is attached is not specified and H atoms are present at the available bond sites, the number of H atoms at the available bond sites when bonded to a chemical bond will be reduced corresponding to the number of chemical bonds to which they are attached, resulting in a group with a corresponding valence number. The chemical bonds between said groups and other groups will be represented by straight solid line bonds. [ka] , straight dashed bond [ka] or wavy line [ka] For example, the straight solid bond in -OCH3 can be represented as Indicates that the group is bonded to another group through an oxygen atom; [ka] the straight dashed bond in indicates that the nitrogen atom in the group is bonded to another group through both ends thereof; [ka] The wavy lines in indicate that the phenyl group is bonded to other groups through the 1st and 2nd carbon atoms; [ka] Any available binding site on the piperidine group has at least four linking modes. [ka] It indicates that the group can be bonded to another group through one chemical bond, including the -N-. Even if the -N- represents an H atom, [ka] for, [ka] groups, such that when attached via one chemical bond, a corresponding reduction by one of the H's at this site occurs to give the corresponding monovalent piperidinyl.

[0123] Unless otherwise specified, the number of atoms in a ring is usually defined as the number of members constituting the ring. For example, a "5- to 7-membered ring" means a "ring" in which 5 to 7 atoms are arranged in a ring.

[0124] The terms "halo", "halogen" and "halogen atom" in the present disclosure refer to fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Preferably, the halogen atom as a substituent on an aryl group in the present disclosure is a fluorine atom and a chlorine atom. Preferably, the halogen atom as a substituent on an alkyl group in the present disclosure is a fluorine atom and a chlorine atom. C having a halogen atom as a substituent 1-6 Alkyl groups include, but are not limited to, bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, and 6,6,6-trifluorohexyl.

[0125] In this disclosure, the term “C 1-6 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbons, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-amyl, isoamyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl. 1-3 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbons, including, but not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0126] In this disclosure, the term “C 1-6 Alkoxy" is C 1-6 The term "C" refers to an alkyl-O-group, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-amyloxy, isoamyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylamyloxy, and 2-ethylbutoxy. 1-3 "Alkoxy" means C 1-3 It refers to an alkyl-O- group (including, but not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy).

[0127] In the present disclosure, the term "aryl" refers to a 6-14 membered all carbon monocyclic or fused polycyclic ring with a conjugated π electron system. (i.e. rings sharing adjacent pairs of carbon atoms) groups, preferably 6-10 membered rings, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclyl, where heterocyclyl is a heterocyclic group containing 1-3 ring heteroatoms independently selected from N, O and S; or further including a ternary nitrogen-containing fused ring containing a benzene ring.

[0128] The term "heteroaryl" or "heteroaryl ring" in the present disclosure refers to a heteroaromatic system having 5-14 ring atoms with 1-4 ring heteroatoms independently selected from N, O and S. The heteroaryl group is preferably 5-10 membered, more preferably 5- or 6-membered, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidine, thiadiazole, pyrazinyl, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidine or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, [ka] Including but not limited to:

[0129] Heteroaryl groups may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclylalkoxyl, cycloalkylthio, heterocyclylalkylthio, carboxyl, or carboxylic acid ester groups.

[0130] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" in this disclosure may be used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system consisting of 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N, O, and S(O)). p, p is 1 or 2). The 5-6 membered heteroaryl may be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered heteroaryl and 6-membered heteroaryl groups. Examples of 5-6 membered heteroaryl groups include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl). Examples include, but are not limited to, triazolyl, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl).

[0131] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens.

[0132] The term "3-8 membered heterocyclyl" in this disclosure refers to a non-aromatic cyclic group having 3 to 8 ring atoms having one or more ring heteroatoms independently selected from N, O, and S, and may be fully saturated (i.e., 3-8 membered heterocycloalkyl) or partially unsaturated. The heterocyclyl ring may be a 3-8 membered monocyclic ring, bicyclic ring, or spiro ring (including, but not limited to, oxetanyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuryl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, oxathianyl, dihydroindolyl, dihydroisoindolyl, tetrahydrodihydroindolyl, quinuclidinyl, azepinyl, and the like). Heterocyclyl, in some embodiments, has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclyl) or, in some other embodiments, has 5 to 8 ring atoms (i.e., 5-8 membered heterocyclyl). 3-6 membered heterocycloalkyl means a fully saturated 3-6 membered heterocyclyl that may have 1 or 2 heteroatoms independently selected from N, O, and S. Examples include, but are not limited to, oxetanyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolidine, thiazolidine, imidazolidine, pyrazolidine, thianyl, oxanyl, and oxathianyl.

[0133] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl group. Non-limiting examples include: [ka] There is.

[0134] In this disclosure, 3-8"Cycloalkyl" means a monovalent group obtained by removing any one hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, i.e., a cycloalkyl group having 3 to 8 carbons. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Two groups taken together form C 3-8 When a cycloalkyl ring is formed, the resulting group is a divalent group, 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. In some embodiments, the cycloalkyl group has 3 to 6 ring atoms (i.e., C 3-6 cycloalkyl).

[0135] The term "bridged ring" in the present disclosure refers to a 5-20 membered all carbon polycyclic group in which any two rings in the system share a pair of non-adjacent carbon atoms. The bridged ring may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The bridged ring is 6-14 membered, for example, 6-10 membered, more preferably 7-10 membered. Depending on the number of ring components, the bridged ring can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic bridged ring groups, more preferably bicyclic or tricyclic bridged ring groups. The bridged rings include: [ka] These include, but are not limited to:

[0136] Carbon atoms in the bridged ring may optionally be replaced by a heteroatom selected from O, S, and N, ie, "bridged heterocycles" are also included herein.

[0137] The term "bridged heterocycle" as used herein refers to a 5-14 membered polycyclic heterocyclic group in which any two rings in the system share a pair of non-adjacent carbon atoms, and the bridged heterocycle may contain one or more double atoms, but no ring has a completely conjugated pi-electron system, and one or more of the ring atoms is N, O, or S(O). m (m is an integer of 0 to 2), and the remaining ring atoms are carbon. The bridged heterocycle is preferably 6-10 membered, more preferably 7-10 membered. Depending on the number of ring components, the bridged heterocycle can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocycle, more preferably a bicyclic or tricyclic bridged heterocycle. The bridged heterocycle includes: [ka] These include, but are not limited to:

[0138] The term "spirocycle" in the present disclosure refers to a 5-20 membered polycyclic group in which the monocyclic rings in the system share one carbon atom (called a spiro atom). The spirocycle may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The spirocycle is preferably 6-14 membered, e.g., 6-10 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, the spirocycloalkyl group is classified as monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and dispirocycloalkyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl; [ka] Including, but not limited to:

[0139] Carbon atoms within the spiro ring may be optionally replaced by heteroatoms selected from O, S and N, ie, "spiro heterocycles" are also included herein.

[0140] The term "spiroheterocycle" as used herein refers to a 5-20 membered polycyclic heterocyclic group in which the monocyclic rings in the system share one carbon atom (called a spiro atom) and one or more of the ring atoms are N, O or S(O). m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Spiroheterocycles may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Spiroheterocycles are preferably 6-14 membered, for example 6-10 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and dispiroheterocyclyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; [ka] Including, but not limited to:

[0141] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0142] The compounds described in this disclosure are named according to their chemical structure. In the event that the name of a compound conflicts with the chemical structure of the same compound, the chemical structure takes precedence.

[0143] The present disclosure further provides the following embodiments: Embodiment 1: Formula I: [ka] [In the formula, [ka] indicates a single or double bond; W is selected from O, N, or NH; X1, X3 and X4 are independently selected from CH, N or C; Y1 is selected from CH or N; Y2 is selected from CH, N or C; Y3 is selected from CH, N or C; Y4, Y5 and Y6 are independently selected from CH or N, and Y4, Y5 and Y6 are not simultaneously N; Ring A is selected from the group consisting of a benzene ring, thiophene, or pyridine; R1 is independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6 Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or C 3-6 optionally substituted 1 to 3 times by heterocyclyl; R2 is 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 , -C0-3 Alkylene-sulfonyl-R z , -C 0-3 Alkylene-phosphoryl-R z and -C 0-3 Alkylene-sulfonamide-R z wherein alkyl, amino, amido, sulfonyl, sulfonamido, and phosphoryl in R2 are optionally substituted 1 to 3 times with halogen, if valence permits; w may be optionally substituted once by; R4 is independently hydrogen, halogen, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 selected from the group consisting of alkoxy, cyano, hydroxy, amino, amido, sulfonyl, and sulfonamido; R5 is independently hydrogen, halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl, where alkyl, alkoxy and cycloalkyl in R5 are selected from the group consisting of halogen, hydroxyl, -NR z , C.N.,C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 optionally substituted 1 to 3 times by cycloalkyl; R0 is independently hydrogen, halogen, hydroxy, oxo, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 R0 is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, where the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl, and heteroaryl in R0 are, if valences permit, halogen, CN, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 optionally substituted 1 to 3 times by cycloalkyl; n is an integer selected from 0, 1, 2, 3, or 4; m is an integer selected from 0, 1, or 2; p is an integer selected from 0, 1, 2 or 3; q is an integer selected from 0, 1, 2, 3, or 4; When p is 2 or more, any two R5 may be further cyclized with ring C to form a 6-10 membered spiro ring or bridging ring, where the formed spiro ring and bridging ring are, if valences permit, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, C 1-3 optionally substituted 1 to 3 times by alkoxy; When m is not 0 and p is not 0, any R4 and any R5 may be further cyclized into a 5-8 membered ring, where the ring formed, if valences permit, is selected from the group consisting of C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy; R w are independently CN, -CHCN, C 1-3 Alkyl, OH, C 1-3 Alkoxy, amide, sulfonyl, sulfonamide, NH2 and -NH-C 1-3 alkyl, where R w The alkyl in is C, if valence permits. 1-3 Alkyl, C 1-3 Haloalkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy; and R z are independently hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 is selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, aryl, and 5- to 6-membered heteroaryl, where R zIf valence permits, C 1-3 Alkyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, halogen, cyano, oxo, C 1-3 Optionally substituted 1 to 3 times by alkoxy, 3- to 6-membered heterocyclyl. or a pharma- ceutically acceptable salt thereof.

[0144] Embodiment 2: A compound according to embodiment 1, having formula I-2 or I-2': [ka] [ka] [In the formula, [ka] indicates a single or double bond; X3 and X4 are independently selected from CH or N; Y2 is selected from the group consisting of CH, N or C; Y3 is selected from CH or N; Ring A is [ka] and optionally further substituted n times by R1; R1 is independently hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, -CO-C 1-3 Alkyl, -CO-C 3-6 Cycloalkyl and -CO-NH-C 1-3 alkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl is independently selected from halogen, cyano, C 1-3Alkoxy, C 3-6 Cycloalkyl or C 3-6 optionally substituted 1 to 3 times by heterocyclyl; R z is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, [ka] selected from the group consisting of; R5 is independently hydrogen, halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 cycloalkyl, where alkyl, alkoxy and cycloalkyl in R5 are selected from the group consisting of halogen, hydroxyl, -NR z , C.N.,C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 optionally substituted 1 to 3 times by cycloalkyl; n is an integer selected from 0, 1, or 2; R y are independently hydrogen, halogen, oxo, C 1-3 Alkoxy, cyano, hydroxyl, amino, carboxyl, amide, sulfonyl, sulfonamide, C 1-3 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and phenyl, where R y The alkyl, alkoxy, cycloalkyl and heterocyclyl in may be optionally substituted 1 to 3 times with halogen, if valence permits. and pharma- ceutically acceptable salts thereof

[0145] Embodiment 3: In a compound according to embodiment 1, when o is not 0 and p is not 0, any adjacent R4 and R5 may be further cyclized into a 5-8 membered ring; the 5-8 membered ring may be C 5-6Compounds including carbocyclic rings, 5-8 membered heterocyclic rings, benzene rings, and 5-8 membered heteroaromatic rings, wherein the rings formed are optionally substituted, if valences permit, 1 to 3 times with alkyl, haloalkyl, halogen, cyano, alkoxy.

[0146] Embodiment 4: A compound according to embodiment 1, wherein the compound of formula I has the following sub-formula: [ka]

[0147] Embodiment 5: A compound according to embodiment 1, wherein n is selected from 1, 2 or 3; and / or p is selected from 0, 1 or 2.

[0148] Embodiment 6: A compound according to embodiment 1, wherein R1 may further independently be selected from the group consisting of F, Cl, CN, -OCH3, -OCH2CH3, -O-cyclopropyl, CH3, -CH2CH3, -CH2CH2CH3, -(CH)2CH3, -COCH3, -CONH2, CF3, -CHF2, -CH2F, -CH2CH2F, -CO-cyclopropyl, -COCH2F, -COCHF2, -CO-CH(CH3)2 and -CO-CH2CH3.

[0149] Embodiment 7: A compound according to embodiment 1, wherein R5 may further be selected from the group consisting of F, Cl, CH3, -OCH3, NH2, OH, -CH2CH3, -CH2OH, -NHCH3, -COCH3, -SO2CH3, -OCH2CH3, CF3, -CHF2, -CH2F, isopropyl, cyclopropyl and fluorocyclopropyl.

[0150] Embodiment 8: A compound according to embodiment 1, [ka] and pharma- ceutically acceptable salts thereof.

[0151] Embodiment 9: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 8, and a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0152] Embodiment 10: Use of a compound according to any one of embodiments 1 to 8 and its pharma- ceutically acceptable salts in the manufacture of a medicament for the treatment of a GLP-1 receptor mediated disease or a related disease.

[0153] Embodiment 11: A method for preventing and / or treating GLP-1 receptor mediated diseases and associated diseases, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 8 and its pharma- ceutically acceptable salts, wherein GLP-1 receptor mediated diseases and associated diseases include, but are not limited to, diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia and hyperinsulinemia.

[0154] Beneficial effects The compounds of the present disclosure are GLP-1 receptor agonists. Preferred compounds of the present disclosure (e.g., compounds of formula II) have excellent GLP-1 receptor agonist activity, good intestinal absorption, and / or excellent safety and / or pharmacokinetic properties (e.g., metabolic stability, plasma binding, C max For example, some of the compounds of formula II above have improved GLP-1 receptor agonist activity (e.g., EC 50 and / or higher in vivo and / or in vitro safety and / or improved pharmacokinetic properties (e.g., metabolic stability, C max , half-life and / or oral bioavailability).

[0155] The present disclosure will be described in more detail below with reference to specific examples, which are not intended to limit the scope of the present invention. Experimental methods for which no specific conditions are given in the examples of the present disclosure generally adopt conventional conditions or conditions suggested by the manufacturer. Reagents whose sources are not specified may be ordinary commercially available reagents.

[0156] Compound Identification and Characterization The 1H NMR spectra of this disclosure were measured using a Bruker instrument (400 MHz) and chemical shifts are reported in ppm. Tetramethylsilane (0.00 ppm) was used as the internal standard. 1H NMR is designated as follows: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublet, dt = doublet of triplet. Coupling constants, if any, are listed in Hz.

[0157] The mass spectra of this disclosure are determined by LC / MS instruments, and ionization can be performed by ESI or APCI.

[0158] Preparation Example The intermediate reaction material used in the manufacturing process was manufactured according to the manufacturing method described in WO2018109607A1.

[0159] SFC method System: Waters SFC 150 Column: Dr.maish Reprosil Chiral-MIC (DAICELCHIRALPAK(R)IC) Column size: 250*25 mm 10m Mobile phase A was supercritical CO2, mobile phase B was MeOH (ammonia in MeOH ±0.1% 7.0 mol / l), A:B=50:50 Wavelength: 214 nm Flow rate: 120ml / min Column temperature: room temperature Back pressure: 100bar Injection volume: 4mL Cycle time: 10 minutes Sample preparation: Dissolve the sample in approximately 20 mL of MeOH.

[0160] Preparation of intermediates Preparation of (S)-Methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Int-2) [ka]

[0161] (1) Preparation of Compound 1-2C To a stirred solution of t-BuOK (170 g, 1520 mmol, 2.5 eq) in t-BuOH (500 mL) at 60 °C under an argon atmosphere, MeSO + I - (335 g, 1520 mmol, 2.5 eq) was added portionwise. After 30 min, (S)-2-((benzyloxy)methyl)oxirane (1-1C) (100 g, 610 mmol, 1.00 eq) was added dropwise to the above mixture. The resulting mixture was stirred at 60° C. for 13 h. The mixture was cooled to room temperature and then filtered. The filter cake was washed with EtOAc (3×200 mL). The organic phases were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give (S)-2-((benzyloxy)methyl)oxetane (1-2C) (50.0 g, 46% yield).

[0162] 1 H NMR (400 MHz, 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, 4.3 Hz, 2H), 2.72 - 2.45 (m, 2H).

[0163] (2) Preparation of Compound 1-3C A solution of compound 1-2C (50 g, 280.9 mmol, 1.0 eq) and Pd / C (20 g, wet) in THF (200 mL) was stirred under H2 (4 MPa) for 16 h. The mixture was cooled to room temperature and then filtered. The filter cake was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give (S)-oxetan-2-ylmethanol (1-3C) (28 g, crude), which was used directly in the next step.

[0164] (3) Preparation of Compound 1-4C To a solution of compound 1-3C (28 g, 317.8 mmol, 1 eq) in THF (200 mL) 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. The mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL×3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column silica gel chromatography eluted with (EA / PE=0-10%) to give (S)-oxetan-2-ylmethyl-4-methylbenzenesulfonate (1-4C) (56 g, 72.7% yield).

[0165] 1 H NMR (400 MHz, CDCl3) δ =7.85 - 7.79 (m, 2H), 7.35 (dd, J = 8.6, 0.6 Hz, 2H), 5.00 - 4.83 (m, 1H), 4.68 - 4.38 (m, 2H), 4.16 (d, J = 4.0 Hz, 2H), 2.78 - 2.64 (m, 1H), 2.58 (d, J = 9.0 Hz, 1H), 2.45 (s, 3H).

[0166] (4) Preparation of Compound 1-5C To a solution of compound 1-4C (56 g, 231 mmol, 1 eq) in DMF (200 mL) was added NaN3 (22.5 g, 346.7 mmol, 1.5 eq). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The organic phases were combined, dried over Na2SO4, filtered and concentrated to give (S)-2-(azidomethyl)oxetane (1-5C) (20 g, crude), which was used directly in the next step.

[0167] (5) Preparation of Compound 1-6C A solution of compound 1-5C (20 g, crude) and Pd / C (8G) in THF (100 mL) was stirred under H2 at 25 °C for 16 h. The resulting mixture was filtered. The filter cake was washed with THF (3 x 100 mL). The filtrate was directly concentrated to give (S)-oxetan-2-ylmethylamine (1-6C) (3.8 g, crude).

[0168] 1 H NMR (400 MHz, DMSO) δ = 4.60 (dq, J = 6.5, 5.2 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.40 - 4.30 (m, 1H), 2.67 (t, J = 5.5 Hz, 2H), 2.57 - 2.51 (m, 1H), 2.38 (ddt, J = 10.8, 9.0, 7.0 Hz, 2H).

[0169] (6) Preparation of Compound 1-7C To a solution of compound 1-6C (3.8 g, 43.6 mmol, 1 eq) in THF (80 mL) 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. The mixture was stirred at 40° C. for 6 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography eluted with (EtOAc / petroleum ether=0-80%) to give (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (1-7C) (6.2 g, 53.4% ​​yield).

[0170] 1 H NMR(400 MHz, CDCl3) δ = 8.36 (s, 1H), 8.23 ​​(d, J = 8.9 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.26 (dd, J = 8.8, 1.7 Hz, 1H), 5.16 (tt, J = 7.4, 4.5 Hz, 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).

[0171] (7) Preparation of Compound 1-8C A solution of compound 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 h. The mixture was filtered. The filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated directly to give (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1-8C) (5.2 g, 94.5% yield).

[0172] LCMS: rt =1.201 min, [M+1] + =237.1, purity: 89.7%.

[0173] (8) Preparation of Compound Int-2 To a solution of compound 1-8C (1.0 g, 4.23 mmol, 1 eq) in THF (20 mL) was added 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). The mixture was stirred at 50 °C for 8 h. The mixture was diluted with saturated sodium bicarbonate solution NaHCO3 (20 mL) and extracted with EtOAc (10 mL × 3). The organic phases were combined, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel eluting with (EtOAc / petroleum ether=0-80%) to give (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Int-2) (1.1 g, 88% yield).

[0174] 1 H NMR(400 MHz, CDCl3) δ 8.12 (d, J = 0.9 Hz, 1H), 8.01 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 5.21 (ddd, J = 9.6, 7.3, 2.7 Hz, 1H), 5.03 (s, 2H), 4.69 - 4.45 (m, 3H), 4.34 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 2.76 (dtd, J = 11.5, 8.1, 6.0 Hz, 1H), 2.42 (ddt, J = 11.5, 9.2, 7.3 Hz, 1H).

[0175] Example 1: (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1) [ka] Synthetic Route [ka]

[0176] Preparation method Compound 1-2: To a solution of 1-1 (20.0 g, 98.0 mmol) in MeCN (500 mL) was added imidazole (10.0 g, 147.0 mmol) followed by TBSCl (16.3 g, 107.8 mmol). The mixture was stirred at room temperature for 5 h. H2O (500 mL) was added. The reaction solution was extracted with EtOAc (3 x 500 mL). The organic phases were combined, washed with brine (500 mL), dried (Na2SO4), filtered, concentrated and subjected to flash chromatography (SiO2, hexanes) to give 31 g of compound 1-2. Yield: 99.6%. 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (m, 3H), 4.62 (s, 2H), 0.81 (s, 9H), 0.00 (s, 6H).

[0177] Compound 1-3: To a solution of 1-2 (20.0 g, 62.8 mmol) in anhydrous THF (200 mL) at -78 °C under N2, N-BuLi (2.5 M in THF, 27.6 mL, 69.1 mmol) was added. The mixture was stirred at this temperature for 0.5 h, and then oxetan-3-one (4.5 g, 62.8 mmol) was obtained. The mixture was stirred at room temperature under N2 atmosphere for 2.5 h. The reaction solution was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic phases were combined, washed with brine (100 mL), dried (Na2SO4), filtered, concentrated, and subjected to flash chromatography (SiO2, 25% EtOAc-hexane) to give compound 1-3, 14 g. Yield: 71.0%. 1 H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.33 (m, 2H), 7.26 - 7.18 (m, 1H), 6.36 (s, 1H), 4.69 - 4.53 (m, 6H), 0.81 (s, 9H), -0.00 (s, 6H).

[0178] Compound 1-4: To a solution of 1-3 (14.0 g, 44.8 mmol) in anhydrous THF (200 mL) at 0° C., NaH (3.6 g, 89.7 mmol) was added. The mixture was stirred at room temperature for 2 h, then CS2 (3.6 g, 89.7 mmol) and MeI (6.4 g, 44.8 mmol) were added. The mixture was then stirred at 0° C. under N2 for 0.5 h. The reaction solution was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (3×200 mL). The organic phases were combined, washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to give compound 1-4, 14 g. The product was used directly in the next step without further purification.

[0179] Compound 1-5: To a solution of 1-4 (14.0 g, 44.8 mmol) in toluene (200 mL), (n-Bu)3SnH (26.2 g, 89.7 mmol) was added, followed by AIBN (736 mg, 4.4 mmol). The mixture was stirred for 0.5 h at 125 °C under N2 atmosphere. The reaction solution was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexane) to give compound 1-5 (8 g). Two-step yield: 60.6%. 1 H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J = 8.0 Hz, 1H), 7.23 - 7.16 (m, 2H), 4.91 (dd, J = 8.3, 5.9 Hz, 2H), 4.72 (s, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.30 - 4.18 (m, 1H), 0.88 (s, 9H), 0.07 (s, 6H).

[0180] Compound 1-6: To a solution of 1-5 (8.0 g, 43.0 mmol) in THF (200 mL) was added Et3N·HF3 (13.9 g, 86.0 mmol). The reaction solution was stirred at room temperature under N2 atmosphere for 16 h. The reaction solution was concentrated and purified by flash chromatography (SiO2, EtOAc-Hexane) to give compound 1-6 (5 g). Yield: 99.9%. 1H NMR (400 MHz, DMSO-d6) δ 7.44 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 9.1 Hz, 2H), 5.22 (t, J = 5.7 Hz, 1H), 4.92 (dd, J = 8.0, 6.1 Hz, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H), 4.30 - 4.18 (m, 1H).

[0181] Compound 1-7: To a solution of 1-6 (4.8 g, 26.3 mmol) in DCM (100 mL) at 0° C., NBS (5.2 g, 29.0 mmol) was added, followed by PPh3 (7.7 g, 29.0 mmol). The mixture was stirred for 5 h at room temperature under N2 atmosphere. H2O (100 mL) was added. The reaction solution was extracted with DCM (3×100 mL). The organic phases were combined, washed with brine (100 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (SiO2, EtOAc-hexane) to give compound 1-7, 2 g. Yield: 30.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (t, J = 8.0 Hz, 1H), 7.33 - 7.20 (m, 2H), 4.92 (dd, J = 8.3, 6.0 Hz, 2H), 4.70 (s, 2H), 4.60 (t, J = 6.3 Hz, 2H), 4.34 - 4.20 (m, 1H).

[0182] Compound 1-8: Compound 1-7 (600 mg, 2.45 mmol) and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (684 mg, 2.45 mmol) were added to the solvent DMF (50 mL). Then, Cs2CO3 (2.4 g, 7.37 mmol) was added. The reaction solution was stirred at room temperature for 16 h. H2O (50 mL) was added. The reaction solution was extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (SiO2, EtOAc-Hexane) to give 500 mg of compound 1-8. Yield: 45.9%. 1 H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.13 (d, J = 11.4 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.43 (d, J = 7.5 Hz, 3H), 5.33 (s, 1H), 4.45 (s, 2H), 4.14 (d, J = 14.0 Hz, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.80 (t, J = 12.9 Hz, 2H), 1.85 (d, J = 12.5 Hz, 2H), 1.57-1.61 (m 3H), 1.42 (s, 9H). / LC-MS (ESI) m / z: 443.2 [M + H] + .

[0183] Compound 1-9: To a solution of 1-8 (210 mg, 0.49 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction solution was stirred at room temperature for 3 h. The reaction solution was concentrated to give 250 mg of compound 1-9. LC-MS: MC20-1128-086C (ESI) m / z: 343.1 [M + H] + .

[0184] Compound 1-10: Compound 1-9 (200 mg, 0.58 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (172 mg, 0.58 mmol) were added to the solvent dioxane (20 mL) and MeCN (12 mL), and then K2CO3 (162 mg, 1.16 mmol) was added. The reaction solution was stirred at 65 °C for 3 h. H2O (20 mL) was obtained. The reaction solution was extracted with EtOAc (3 x 20 mL). The organic phases were combined, washed with brine (20 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (SiO2, EtOAc-hexane) to give compound 1-10 (60 mg). Yield: 22.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.1 Hz, 1H), 7.82 (dd, J = 8.5, 1.6 Hz, 1H), 7.70 - 7.59 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 11.3 Hz, 1H), 7.21 (d, J = 9.5 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.35 - 5.30 (m, 1H), 5.12 (qd, J = 7.0, 2.5 Hz, 1H), 4.90 (dd, J = 8.3, 6.0 Hz, 2H), 4.80-4.84 (m 1H), 4.65-4.71 (m, 1H), 4.58 (t, J = 6.4 Hz, 2H), 4.47 (dt, J = 8.3, 6.5 Hz, 1H), 4.37 (dt, J = 9.1, 5.9 Hz, 1H), 4.21-4.28 (m,1H), 3.94-4.02 (m,1H), 3.87 (s, 3H), 3.78 (d, J = 13.6 Hz, 1H), 3.01 (d, J = 9.4 Hz, 1H), 2.85 (d, J = 13.5 Hz, 1H), 2.73 - 2.59 (m, 2H), 2.27 (d, J = 10.0 Hz, 1H), 2.17 (d, J = 11.6 Hz, 1H), 1.76 (m, 4H). / LC-MS (ESI) m / z: 601.4 [M + H] + .

[0185] Compound 1: To a solution of 1-10 (60 mg, 0.1 mmol) in MeOH (1 mL) and THF (5 mL), 1M LiOH (2 mL) was added. The reaction solution was stirred at room temperature for 3 h. The reaction solution was concentrated and purified by preparative HPLC to give compound 1 (10.95 mg). Yield: 18.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.79 (dd, J1 = 4.0 Hz, , J2 = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 12.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.12 (m, 1H), 4.90 (dd, J = 8.0 Hz, 2H), 4.77 (dd, J1 = 4.0 Hz, J2 = 16.0 Hz, 1H), 4.64 (d, J = 4.0 Hz, 1H), 4.58 (m, 2H), 4.50 - 4.44 (m, 1H), 4.38 (m, 1H), 4.29 - 4.19 (m, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 1H), 2.71 (m, 1H), 2.64 - 2.56 (m, 1H), 2.47 - 2.42 (m, 1H), 2.21 (m, 2H), 1.73 (m, 4H).

[0186] Example 2: (S)-2-((4-(6-((2-chloro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 2) [ka]

[0187] Synthetic Route [ka]

[0188] Preparation method Compound 2-2: To a solution of 2-1 (1.2 g, 5.42 mmol), DMAP (13 mg, 0.11 mmol) and DIPEA (1.1 g, 8.13 mmol) in DCM / DMF (5:1, 36 mL) at 0° C., TBSCl (1.1 g, 7.59 mmol) was added portionwise with stirring. The mixture was then brought to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was subjected to reduced pressure to remove the solvent, and then extracted with EA three times. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-5% EA in PE) to give 2-2 (1.8 g, 99% yield). 1 H NMR (400 MHz, DMSO) δ 7.67 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 4.69 (s, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

[0189] Compound 2-3: To a solution of 2-2 (6.0 g, 17.87 mmol) in anhydrous THF (60 mL) at -78 °C, n-BuLi (8.0 mL, 2.5 M in hexane) was added dropwise with stirring. The mixture was stirred at the same temperature for 30 min. Then, oxetan-3-one (1.3 g, 17.87 mmol) was added. The mixture was brought to room temperature and stirred for another 2.5 h. After the reaction was completed, the mixture was quenched with water and then extracted with EA three times. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-30% EA in PE) to give 2-3 (4.4 g, 74% yield). 1H NMR (400 MHz, DMSO) δ 7.55-7.62 (m, 3H), 6.48 (s, 1H), 4.76 (d, J = 5.5 Hz, 4H), 4.66 (d, J = 6.8 Hz, 2H), 0.92 (s, 9H), 0.11 (s, 6H).

[0190] Compound 2-4: To a solution of 2-3 (1.0 g, 3.04 mmol) in anhydrous THF (10 mL) at 0° C., NaH (146 mg, 6.08 mmol) was added portionwise with stirring. The mixture was brought to room temperature and stirred for 2 h, then cooled to 0° C. CS2 (231 mg, 3.04 mmol) and MeI (431 mg, 3.04 mmol) were added. The mixture was stirred at 0° C. for another 0.5 h. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl and then extracted three times with EA. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 2-4 (1.37 g, crude), which was used directly in the next step without further purification.

[0191] Compound 2-5: To a solution of 2-4 (1.37 g, 3.27 mmol) in dry toluene (15 mL), AIBN (54 mg, 0.33 mmol) and n-Bu3SnH (1.90 g, 6.54 mmol) were added. The mixture was stirred at 125 °C for 0.5 h. After the reaction was completed, the reaction mixture was left to stand. KF (20 mL) was added. The mixture was stirred at room temperature for 2 h and extracted with EA three times. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-30% EA in PE) to give 2-5 (700 mg, 69% yield). 1 H NMR (400 MHz, DMSO) δ 7.67 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 4.69 (s, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

[0192] Compound 2-6: To a solution of 2-5 (366 mg, 1.17 mmol) in dry THF (5.0 mL) was added Et3N·HF3 (377 mg, 2.34 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was completed, the solvent was removed under reduced pressure. The resulting residue was purified by Prep-TLC (PE:EA=3:1) to give 2-6 (170 mg, 73% yield). 1 H NMR (400 MHz, DMSO) δ 7.53 (d, J = 7.8 Hz, 1H), 7.47 - 7.32 (m, 2H), 5.37 (t, J = 5.6 Hz, 1H), 4.92 (dd, J = 8.3, 6.0 Hz, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.55 (d, J = 5.6 Hz, 2H), 4.30 - 4.19 (m, 1H).

[0193] Compound 2-7: To a solution of 2-6 (170 mg, 0.86 mmol) and TEA (870 mg, 8.60 mmol) in anhydrous THF (10 mL) at 0° C., MsCl (197 mg, 1.72 mmol) was added dropwise with stirring. The mixture was brought to room temperature and stirred for 2 h. After the reaction was completed, the reaction mixture was extracted with DCM three times. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 2-7 (140 mg, crude), which was used directly in the next step.

[0194] Compound 2-8: To a solution of 2-7 (140 mg, 0.5 mmol), methyl 2-((4-(3-hydroxyphenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg) in anhydrous DMF (10 mL), Cs2CO3 (326 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 16 h. After the reaction was completed, the reaction mixture was extracted with EA three times. The organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by Prep-TLC (PE / EA=1:1) to give 2-8 (97 mg).1 H NMR (400 MHz, DMSO) δ 8.30 (d, J = 1.1 Hz, 1H), 7.82 (dd, J = 8.5, 1.5 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 7.9, 1.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 5.11 (dt, J = 6.8, 4.6 Hz, 1H), 4.90 (dd, J = 8.3, 6.0 Hz, 2H), 4.77-4.85 (m, 1H), 4.62-4.69 (m, 1H), 4.61 - 4.54 (m, 2H), 4.43-4.50 (m, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 4.29 - 4.19 (m, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.92-3.99 (m, 1H), 3.87 (s, 3H), 3.74-3.81 (m 1H), 2.99 (d, J = 10.5 Hz, 1H), 2.84 (d, J = 11.0 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.65 - 2.55 (m, 1H), 2.48 - 2.39 (m, 1H), 2.31 - 2.12 (m, 2H), 1.85 - 1.61 (m, 4H). LCMS: (ESI) m / z: 618.1 [M+H]+.

[0195] Compound 2: To a solution of 2-8 (80 mg, 0.13 mmol) in THF / MeOH (1:1, 4.0 mL), LiOH (2 mL, 2 M aqueous solution) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed under reduced pressure. The resulting residue was purified by Prep-HPLC to give compound 2 (40 mg, 51% yield). 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 5.16 - 5.07 (m, 1H), 4.90 (dd, J = 8.0 Hz, 2H), 4.79 (dd, J1 = 6.0 Hz, J2 = 14.0 Hz,1H), 4.65 (d, J = 12.0 Hz, 1H), 4.57 (t, J = 10.0 Hz, 2H), 4.47 (dd, J1 = 8.0 Hz, J2 = 16.0 Hz, 1H), 4.38 (m, 1H), 4.29 - 4.19 (m, 1H), 3.95 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 16.0 Hz, 1H), 2.99 (d, J = 12.0 Hz, 2H), 2.84 (d, J = 8.0 Hz, 1H), 2.71 (m, 1H), 2.65 - 2.55 (m, 1H), 2.44 (m, 1H), 2.29- 2.11 (m, 2H), 1.85 - 1.61 (m, 4H).. / LCMS: (ESI) m / z: 603.4 [M+H]+.

[0196] Example 3: (S)-2-((4-(6-((2-methoxy-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 3) [ka]

[0197] Synthetic Route [ka]

[0198] Preparation method Compound 3-2: To a solution of (4-bromo-2-methoxyphenyl)methanol (2.0 g, 9.21 mmol) in anhydrous DCM (75 mL) and anhydrous DMF (15 mL) was added DMAP (23 mg, 0.18 mmol) and DIPEA (2.4 mL, 13.8 mmol). The mixture was then cooled to 0° C. and TBSCl (1.9 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated and subjected to flash chromatography (SiO2, hexane) to give 2.87 g of compound 3-2. 1 H NMR (400 MHz, DMSO) δ 7.20 (d, J = 8.3 Hz, 1H), 7.10 - 7.05 (m, 2H), 4.55 (s, 2H), 3.73 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

[0199] Compound 3-3: To a solution of 3-2 (2.87 g, 8.66 mmol) in anhydrous THF (30 mL) at -78 °C under N2, N-BuLi (2.5 M in THF, 3.8 mL, 9.52 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and then oxetan-3-one (0.5 mL, 8.66 mmol) was added. The mixture was then stirred at room temperature under N2 atmosphere for 2.5 h. The reaction solution was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (30 mL), dried (Na2SO4), filtered, concentrated, and subjected to flash chromatography (SiO2, 25% EtOAc-hexane) to give compound 3-3, 1.93 g. 1 H NMR (400 MHz, DMSO) δ 7.27 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 7.8, 1.2 Hz, 1H), 7.05 (s, 1H), 6.22 (s, 1H), 4.67 (d, J = 6.3 Hz, 2H), 4.64 - 4.58 (m, 4H), 3.72 (s, 3H), 0.83 (s, 9H), 0.51 (s, 6H).

[0200] Compound 3-4: To a solution of 3-3 (1.93 g, 5.94 mmol) in anhydrous THF (20 mL) at 0° C. was added NaH (476 mg, 11.89 mmol). The mixture was stirred at room temperature for 2 h, then CS2 (0.36 mL, 5.94 mmol) and MeI (0.37 mL, 5.94 mmol) were added at 0° C. under N2. The mixture was then stirred at 0° C. under N2 for 0.5 h. The reaction solution was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (3×20 mL). The organic phases were combined, washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated to give compound 3-4, 2.5 g. The product was used directly in the next step without further purification.

[0201] Compound 3-5: To a solution of 3-4 (2.5 g, 6.03 mmol) in toluene (25 mL), (n-Bu)3SnH (3.24 mL, 12.0 mmol) and AIBN (99 mg, 0.6 mmol) were added. The mixture was stirred for 0.5 h at 125 °C under N2 atmosphere. After adding KF (1.4 g), the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated and subjected to flash chromatography (SiO2, 20% EtOAc-hexane) to give 1.36 g of compound 3-5. 1 H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 6.6 Hz, 2H), 4.85 (dd, J = 8.4, 5.8 Hz, 2H), 4.57 (dd, J = 6.9, 6.0 Hz, 4H), 4.21 - 4.10 (m, 1H), 3.73 (s, 3H), 0.83 (s, 9H), -0.00 (s, 6H).

[0202] Compound 3-6: To a stirred solution of 3-5 (1.36 g, 4.4 mmol, 1.0 equiv) in THF (15 mL) was added Et3N HF (2.13 g, 13.2 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The reaction was quenched with H2O (10 mL). After extraction with (CHCl3:IPA (1:3)), the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The crude was purified by HPLC (gradient: 10% MeCN / 90% H2O, H2O-100% MeCN) to give compound 3-6, 734 mg. 1 H NMR (400 MHz, DMSO) δ 7.40 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 2H), 5.05 - 4.93 (m, 3H), 4.72 - 4.64 (m, 2H), 4.53 (d, J = 5.2 Hz, 2H), 4.32 - 4.21 (m, 1H), 3.85 (s, 3H).

[0203] Compound 3-7: To a solution of 3-6 (20 mg, 0.12 mmol) in anhydrous DCM (2 mL) was added MsCl (17 mg, 0.14 mmol) and TEA (0.16 mL, 1.21 mmol). The reaction mixture was stirred at 0 °C for 30 min and then quenched with water. After extraction with DCM, the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 70 mg of crude compound 3-7.

[0204] Compound 3-8: A mixture of 3-7 (70 mg, 0.25 mmol), methyl 2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (56 mg, 0.12 mmol) and Cs2CO3 (92 mg, 0.28 mmol) in DMF (5 mL) was stirred overnight at 50 °C. The reaction was quenched with H2O (10 mL). After extraction with EA (10 mL x 3), the organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (silica gel, eluted with 0-5% MeOH / DCM) to give compound 3-8 (10 mg).

[0205] Compound 3: In THF (0.5 mL), 3-8 (80 mg, 0.13 mmol) and LiOH (0.5 mL) were stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give compound 3, 12.85 mg. 1H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 4.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 5.12 (m, 1H), 4.92 (dd, J= 8.0 Hz, 2H), 4.77 (dd, J1= 6.0 Hz, J2= 14.0 Hz, 1H), 4.69 - 4.59 (m, 3H), 4.46 (dd, J = 6.0 Hz, J2= 14.0 Hz, 1H), 4.38 (m, 1H), 4.25 (m, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 1H), 3.01 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 1H), 2.71 (m, 1H), 2.59 (m, 1H), 2.49 - 2.41 (m, 1H), 2.29 - 2.13 (m, 2H), 1.75 (m,4H). / LC-MS: (ESI) m / z: 599.4 [M+H] + .

[0206] Example 4: 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) [ka]

[0207] Synthetic Route [ka]

[0208] Preparation method At 5° C., a solution of p-TsCl (4.94 mmol, 943 mg) in DCM (10 mL) was slowly added to 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (4.49 mmol, 500 mg) and DABCO (5.84 mmol, 656 mg) in DCM (10 mL), after a few minutes a white precipitate formed. The mixture was stirred at room temperature for 30 min and diluted with Et2O (15 mL). The white solid (DABCO-HCl) was filtered and washed with diethyl ether. The organic phases were combined, washed with 0.5% HCl (10 mL), dried (Na2SO4), evaporated and chromatographed on silica using EtOAc:heptane as eluent to give (1-(cyanomethyl)cyclopropyl)methyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, DMSO) δ 7.81 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 3.96 (s, 2H), 2.62 (s, 2H), 2.43 (s, 3H), 0.61 (s, 4H).

[0209] Compound 4-2: To a solution of 4-1 (900 mg, 4.59 mmol) and NH4Cl (1.96 g, 36.70 mmol) in EtOH at room temperature, Fe powder (1.03 g, 18.35 mmol) was added in H2O (1:1, 10 mL:10 mL). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (100 mL) and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give 4-2 (580 mg, crude).

[0210] Compound 4-3: To a solution of 4-2 (580 mg, 3.49 mmol) in tetrahydrofuran (10 mL), 2-chloro-1,1,1-trimethoxyethane (1.08 g, 6.98 mmol) was added, followed by p-toluenesulfonic acid monohydrate (66 mg, 0.35 mmol). The reaction mixture was heated to 45 °C and stirred for 16 h. H2O (30 mL) was added. The resulting solution was extracted with ethyl acetate (30 mL x 3). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with EA / PE 60-100%) to give 4-3 (420 mg, yield: 41%). 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.17 (d, J = 37.4 Hz, 1H), 7.93- 7.53 (m, 2H), 4.97 (s, 2H), 3.87 (s, 3H).

[0211] Compound 4-4: To a solution of 4-3 (39 mg, 0.16 mmol) in dioxane (5 mL) and MeCN (3 mL), 2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (80 mg, 0.16 mmol) and K2CO3 (47 mg, 0.33 mmol) were added. The mixture was stirred for 16 h at 65 °C under N2 atmosphere. H2O (10 mL) was added. The resulting solution was extracted with ethyl acetate (10 mL × 3). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with 5-10% MeOH / DCM) to give 4-4 (45 mg, yield: 48%). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.26 (s, 1H), 7.89 (dd, J = 8.5, 1.4 Hz, 1H), 7.41 (ddd, J = 9.7, 7.5, 2.2 Hz, 3H), 7.09 - 7.03 (m, 2H), 6.64 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 8.1 Hz, 1H), 5.35 (s, 2H), 5.00 (dd, J = 8.3, 6.1 Hz, 2H), 4.65 (t, J = 6.3 Hz, 2H), 4.12 (td, J = 8.1, 4.1 Hz, 1H), / LC-MS (ESI) m / z: 531.2 [M+H] + .

[0212] Compound 4-5: (1-(cyanomethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (11 mg, 0.04 mmol) and KOH (4 mg, 0.07 mmol) were added to a solution of 4-4 (20 mg, 0.03 mmol) in 5 mL of DMF. The reaction was heated to 40-45 °C with stirring for 5-6 h. Water (15 mL) was added. The mixture was extracted with CHCl (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil as crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H0, H0 to 100% MeCN) to give 48 mg of compound 4-5. LC-MS (ESI) m / z: 624.4 [M+H]+

[0213] Compound 4: A solution of 4-5 (48 mg, 0.07 mmol) in THF (0.5 mL) and LiOH (0.5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give compound 4 (2.15 mg). 1 H NMR (400 MHz, DMSO) δ 12.73 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 12.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 6.0 Hz, 1H), 7.26 (d, J = 12.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 12.0 Hz, 1H), 5.36 (s, 2H), 4.90 (dd, J1= 4.0 Hz, J2=8.0 Hz, 2H), 4.58 (t, J = 6.0 Hz, 4H), 4.30 - 4.18 (m, 1H), 3.86 (s, 2H), 2.98 (d, J = 8.0 Hz, 3H), 2.69 (s, 2H), 2.61 (s, 1H), 2.21 (t, J = 10 Hz, 2H), 1.83 - 1.68 (m, 4H), 0.73 (m, 4H). / LC-MS (ESI) m / z: 610.4 [M+H] + .

[0214] Example 5: 2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 5) [ka]

[0215] Synthetic Route [ka]

[0216] Preparation method Compound 5-2: In a glass-lined reactor, potassium carbonate (694 mg, 5.02 mmol) was added to a solution of 5-1 (200 mg, 1.00 mol) in tetrahydrofuran (5 mL), and the mixture was stirred for 10 min. A solution of (1-(aminomethyl)cyclopropyl)methanol (122 mg, 1.2 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at 20°C-30°C for 12 h. The resulting solution was extracted with ethyl acetate (10 mLx3). The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with 20-60% EA in PE) to give 5-2 (238 mg, yield: 84%). 1 H NMR (400 MHz, DMSO) δ 8.52 (t, J = 4.6 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 8.9, 1.7 Hz, 1H), 4.95 (t, / LC-MS (ESI) m / z: 281.2 [M+H]+

[0217] Compound 5-3: To a solution of 5-2 (238 mg, 0.84 mmol) and NH4Cl (363 mg, 6.79 mmol) in EtOH at room temperature, Fe powder (190 mg, 3.39 mmol) in H2O (1:1, 2 mL / 2 mL) was added. The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered through Celite. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine (10 mL) and dried over Na2SO4. The solvent was evaporated to dryness. The residue 5-3 (210 mg, crude) was obtained. LC-MS (ESI) m / z: 251.2 [M+H]+.

[0218] Compound 5-4: To a solution of 5-3 (3.6 g, 14.38 mmol) in tetrahydrofuran (50 mL), 2-chloro-1,1,1-trimethoxyethane (4.45 g, 28.77 mmol) was added, followed by p-toluenesulfonic acid monohydrate (274 mg, 1.44 mmol). The reaction mixture was heated to 45 °C and stirred for 16 h. H2O (100 mL) was added. The resulting solution was extracted with ethyl acetate (50 mL x 3). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with 60-100% EA in PE) to give 5-4 (3.1 g, yield: 81%). 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 8.5, 1.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 5.18 (s, 2H), 4.96 (t, J = 5.2 Hz, 1H), 4.47 (s, 2H), 3.89 (s, 3H), 3.01 (d, J = 5.1 Hz, 2H), 0.67 (t, J = 5.1 Hz, 2H), 0.53 (q, J = 4.6 Hz, 2H).

[0219] Compound 5-5: To a solution of 5-4 (56 mg, 0.18 mmol) in dioxane (6 mL) and MeCN (3 mL), 2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (80 mg, 0.18 mmol) and K2CO3 (100 mg, 0.72 mmol) were added. The mixture was stirred for 16 h at 65 °C under N2 atmosphere. H2O (10 mL) was added. The resulting solution was extracted with ethyl acetate (10 mL × 3). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluted with 5-10% MeOH / DCM) to give 5-5 (70 mg, yield: 63%). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.83 - 7.80 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.19-7.25 (m, 2H), 6.85 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.36 (s, 2H), 5.06 (t, J = 5.4 Hz, 1H), 4.90 (dd, J = 8.3, 6.0 Hz, 2H), 4.57 (d, J = 6.0 Hz, 3H), 4.29 - 4.19 (m, 1H), 3.92 (s, 2H), 3.88 (s, 3H), 3.04 (d, J = 5.4 Hz, 2H), 2.96 (s, 2H), 2.68 - 2.55 (m, 2H), 2.18-2.26 (m, 2H), 1.83 - 1.66 (m, 4H), 0.65 (s, 2H), 0.53 (s, 2H).

[0220] Compound 5-6: 5-5 (60 mg, 0.09 mmol) was dissolved in 5 mL of DCM, and diethylaminosulfur trifluoride (31 mg, 0.19 mmol) was added. The mixture was reacted at room temperature overnight, cooled in an ice bath, and saturated sodium bicarbonate solution (20 mL) was added dropwise, followed by extraction with DCM (20 mL*3). The organic layer was concentrated to dryness with anhydrous sodium sulfate to obtain the crude product, which was purified by reverse phase to obtain 62 mg of compound 5-6. LC-MS (ESI) m / z: 617.2 [M+H]+.

[0221] Compound 5: A solution of 5-6 (62 mg, 0.1 mmol) and LiOH (0.5 mL) in THF (0.5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% HO, 0.1% FA to 100% MeCN) to give compound 5 (4.35 mg). 1 H NMR (400 MHz, DMSO) δ = 8.38 (s, 1H), 8.21 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 7.26 (d, J=12.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.85 (d, J=4.0 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 5.36 (s, 2H), 4.90 (dd, J= 8.0 Hz, 2H), 4.63 (s, 2H),4.59(t, J=6.0 Hz, 2H) 4.29 - 4.19 (m, 2H), 4.12 (s, 1H), 3.84 (s, 2H), 2.93 (d, J=8.0 Hz, 2H), 2.60 (m, 1H), 2.21 (t, J=12.0 Hz, 2H), 1.76 (m, 4H), 0.81-0.70 (m, 4H)., (ESI) m / z: 603.3 [M+H] +

[0222] Example 6: (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((5-(oxetan-3-yl)pyridin-2-yl)methoxy)pyridin-2-yl) piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 6) [ka]

[0223] Synthetic Route [ka]

[0224] Preparation method Compound 6-2: A mixture of 6-1 (20.0 g, 106.38 mmol) and imidazole (10.86 g, 159.57 mmol) was added to MeCN (200 mL), followed by TBSCl (17.64 g, 117.02 mmol). The mixture was stirred at room temperature for 16 h. Upon completion, the mixture was concentrated and purified by flash chromatography (SiO2, hexanes) to give 29 g of product 6-2. 1 H NMR (400 MHz, DMSO) δ 7.20 (d, J = 8.3 Hz, 1H), 7.10 - 7.05 (m, 2H), 4.55 (s, 2H), 3.73 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

[0225] Compound 6-3: To a solution of 6-2 (10.0 g, 33.08 mmol) in anhydrous THF (100 mL) at -78 °C under N2, N-BuLi (2.5 M in THF, 13.9 mL, 34.73 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and then SM2 (2.5 g, 34.73 mmol) was added. The mixture was then stirred at room temperature under N2 atmosphere for 3 h. The reaction solution was quenched with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic phases were combined, washed with brine (100 mL), dried (Na2SO4), filtered, concentrated, and subjected to flash chromatography (SiO2, EtOAc-hexane) to give product 6-3, 5.9 g. 1 H NMR (400 MHz, DMSO) δ 8.65 - 8.54 (1 H, m), 7.89 (1 H, dd, J =8.2, 2.4), 7.36 (1 H, dd, J= 8.1, 0.6), 6.41 (1 H, s), 4.72 - 4.65 (4 H, m), 4.61 (2 H, d, J =7.0), 0.84 - 0.81 (9 H, m), 0.03 - -0.03 (6 H, m).

[0226] Compound 6-4: To a solution of 6-3 (5.9 g, 20 mmol) in anhydrous THF (60 mL) at 0° C., NaH (1.6 g, 40 mmol) was added. The mixture was stirred at room temperature for 2 h, then CS2 (1.5 g, 20 mmol) and MeI (2.8 g, 20 mmol) were added at 0° C. under N2. The mixture was then stirred at 0° C. under N2 for 2 h. The reaction solution was quenched with saturated NH4Cl solution (40 mL) and extracted with EtOAc (3×60 mL). The organic phases were combined, washed with brine (60 mL), dried (Na2SO4), filtered, concentrated, and subjected to flash chromatography (SiO2, EtOAc-hexane) to give product 6-4, 3.3 g. 1H NMR (400 MHz, DMSO) δ 8.51 (1 H, d, J =2.3), 7.83 (1 H, dd, J =8.2, 2.4), 7.39 (1 H, d, J =8.2), 5.01 (2 H, d, J =8.3), 4.84 (2 H, d, J =8.4), 4.66 (2 H, s), 2.48 (3 H, s), 0.82 (9 H, d, J =2.9), -0.00 (6 H, d, J =3.1).

[0227] Compound 6-5: To a solution of 6-4 (3.0 g, 7.79 mmol) in toluene (100 mL), (n-Bu)3SnH (4.53 g, 15.58 mmol) and AIBN (130 mg, 0.78 mmol) were added. The mixture was stirred for 0.5 h at 125 °C under N2 atmosphere. After adding KF (1.7 G), the mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated and subjected to flash chromatography (SiO2, EtOAc-hexane) to give product 6-5 (1.9 g). 1 H NMR (400 MHz, DMSO) δ 8.37 (1 H, d, J =2.1), 7.84 (1 H, dd, J =8.1, 2.3), 7.35 (1 H, d, J =8.1), 4.85 (2 H, dd, J =8.4, 6.0), 4.65 (2 H, s), 4.55 - 4.49 (2 H, m), 4.23 - 4.14 (1 H, m), 0.82 (9 H, s), 0.02 - -0.05 (6 H, m)

[0228] Compound 6-6: To a stirred solution of 6-5 (600 mg, 2.15 mmol) in THF (10 mL) was added Et3N HF (692 mg, 4.29 mmol). The resulting mixture was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure and the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase column (gradient: MeCN-H2O) to give product 6-6, 300 mg. 1H NMR (400 MHz, DMSO) δ 8.45 (1 H, s), 7.91 (1 H, dd, J =8.1, 2.1), 7.48 (1 H, d, J =8.0), 5.37 (1 H, t, J =5.6), 4.95 (2 H, dd, J =8.4, 6.0), 4.68 - 4.59 (2 H, m), 4.55 (2 H, d, J =5.4), 4.28 (1 H, t, J =7.0).

[0229] Compound 6-7: To a solution of 6-6 (200 mg, 1.21 mmol) in anhydrous DCM (5 mL) was added MsCl (166 mg, 1.45 mmol) and TEA (123 mg, 12.12 mmol). The reaction mixture was stirred at 0 °C for 1 h and then quenched with water. After extraction with DCM, the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give product 6-7, 360 mg.

[0230] Compound 6-8: A mixture of 6-7 (360 mg, 1.48 mmol), (S)-methyl 2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.21 mmol) and Cs2CO3 (788 mg, 2.96 mmol) in DMF (10 ml) was stirred at 50 °C overnight. The reaction was quenched with H2O (10 ml). After extraction with DCM / MeOH (10 ml × 3), the organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (SiO2, EA-PE) to give product 6-8, 130 mg. 1H NMR (400 MHz, DMSO) δ 8.52 (1 H, d, J =2.2), 8.30 (1 H, d, J =1.3), 7.95 (2 H, s), 7.90 (1 H, dd, J =8.1, 2.3), 7.82 (2 H, dd, J =8.5, 1.6), 7.68 (1 H, s), 7.46 (1 H, d, J =8.1), 6.88 (1 H, dd, J =11.7, 7.5), 6.71 (1 H, t, J =14.6), 5.42 (2 H, s), 5.10 (1 H, d, J =6.9), 4.91 (2 H, dd, J =8.3, 6.0), 4.78 (2 H, d, J =7.2), 4.71 - 4.64 (1 H, m), 4.62 - 4.55 (2 H, m), 4.48 (1 H, d, J =4.9), 4.36 (1 H, dd, J =5.9, 3.1), 4.27 (1 H, s), 3.95 (1 H, dd, J =13.5, 9.0), 3.87 (3 H, s), 3.78 (1 H, t, J =12.7), 3.03 - 2.95 (1 H, m), 2.70 - 2.65 (1 H, m), 2.57 (1 H, dd, J =13.9, 8.9), 2.44 (1 H, dd, J =13.5, 6.4), 2.27 - 2.15 (2 H, m), 1.78 - 1.63 (4 H, m).

[0231] Compound 6: A solution of 6-8 (120 mg, 0.21 mmol) and LiOH (1 mL) in THF (1 mL) was stirred at room temperature for 1 h. The solvent was then removed under reduced pressure to give the crude product, which was purified by preparative HPLC to give 43.1 mg of compound 6. 1H NMR (400 MHz, DMSO) δ (400 MHz, DMSO) 8.52 (1 H, d, J =2.2), 8.10 (1 H, s), 7.90 (1 H, dd, J =8.0, 2.3), 7.76 (1 H, d, J =8.4), 7.68 - 7.62 (1 H, m), 7.46 (2 H, d, J =8.0), 6.87 (1 H, d, J =7.3), 6.72 (1 H, d, J =8.1), 5.41 (2 H, s), 5.10 (1 H, d, J =4.1), 4.91 (2 H, dd, J =7.9, 6.1), 4.72 (1 H, dd, J =15.1, 6.9), 4.65 - 4.55 (3 H, m), 4.48 (1 H, d, J =4.7), 4.37 (1 H, dt, J =9.2, 6.0), 4.28 (1 H, dd, J =15.2, 6.9), 3.90 (1 H, d, J =13.4), 3.73 (1 H, d, J =13.3), 2.96 (1 H, d, J =11.9), 2.82 (1 H, s), 2.67 (1 H, s), 2.57 (1 H, s), 2.45 (1 H, s), 2.16 (2 H, dt, J =11.7, 6.7), 1.82 - 1.58 (4 H, m). LC-MS: (ESI) m / z: 570.3 [M+H] + .

[0232] Example 7: (S)-2-((2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-5,8,10,11-tetrahydro-oxepino[4,3-b:6,5-c′]dipyridin-9(7H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 7) [ka]

[0233] Synthetic Route [ka]

[0234] Preparation method Compound 7-2: To a mixture of 2-chloro-6-hydroxynicotinic acid 7-1 (5.0 g, 29 mmol) in MeOH (40 mL) was added sulfuric acid (10 mL). The mixture was stirred at 80° C. for 16 h. The reaction was detected by LCMS. The reaction mixture was quenched with water and extracted with EA. The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give methyl 2-chloro-6-hydroxynicotinate (7-2) (4.5 g, 83%). LCMS: rt. = 2.1 min, [M+H] + =188, purity: 92%.

[0235] Compound 7-3: A mixture of 7-2 (3.4 g, 18.2 mmol), PMB-Cl (3.4 g, 21.2 mmol) and K2CO3 (3.76 g, 27.3 mmol) in DMF (50 ml) was added. The mixture was stirred at 80 °C under Ar2 for 2 h. The reaction was detected by LCMS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (100 ml x 3) and washed with brine (50 ml x 2). The organic phases were combined, dried over Na2SO4, concentrated and purified by elution (PE / EA = 0-20%) to give methyl 2-chloro-6-((4-methoxybenzyl)oxy)nicotinate (7-3) (2.9 g, 52%). LCMS: rt = 3.5 min, [M+H] + =308, purity: 95%.

[0236] Compound 7-4: 7-3 (2.9 g, 9.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid 1-4 methyl ester (4.16 g, 11.3 mmol), Cs2CO3 (6.16 g, 18.8 mmol) and Pd(dppf)Cl2 (0.69 g, 0.94 mmol) in 1,4-dioxane (80 ml) were added. The mixture was stirred at 110 °C under Ar2 for 16 h. The reaction was monitored by LCMS. The reaction mixture was concentrated and purified by elution (PE / EA=0-20%) to give 1'-(tert-butyl) 3,3'-dimethyl-6-((4-methoxybenzyl)oxy)-5',6'-dihydro-[2,4'-bipyridyl]-1',3,3'(2'H)-tricarboxylate (7-4) (2.5 g, 53.2%). LCMS: rt = 1.37 min, [M+H] + =513, purity: 95%.

[0237] Compound 7-5: 7-4 (1.5 g, 2.9 mmol) was dissolved in anhydrous THF (15 mL), and then LiAlH4 (0.222 g, 5.8 mmol) was added portionwise at 0 °C. After 10 min, the reaction was detected by LCMS. The reaction mixture was quenched with ice water (0.5 ml). The mixture was filtered and concentrated to give tert-butyl 3,5'-bis(hydroxymethyl)-6-((4-methoxybenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate (7-5) (1.2 g, 92%). LCMS: rt = 1.95 min, [M+H] + =457, purity: 88%.

[0238] Compound 7-6: A reaction mixture of 7-5 (1.1 g, 2.4 mmol) and camphorsulfonic acid (3.24 g, 9.6 mmol) in TOL (20 ml) was added. The mixture was heated at 110° C. for 1 h. The reaction was detected by LCMS. The reaction mixture was concentrated and purified by elution (MeOH / DCM=0-20%) to give 5,7,8,9,10,11-hexahydroxyoxepino[4,3-b:6,5-c′]bipyridin-2-ol (7-6) (0.4 g, 76%). LCMS: rt = 1.25 min, [M+H] + =219, purity: 96%.

[0239] Preparation of Int-5: Solution of 7-6 (0.35 g, 1.6 mmol), (BOC)2O (0.42 g, 1.9 mmol) and TEA in DCM (15 ml). The mixture was stirred at room temperature for 1 h. The reaction was detected by LCMS. The reaction mixture was concentrated and purified by elution (MeOH / DCM=0-10%) to give tert-butyl 2-hydroxy-5,8,10,11-tetrahydrooxepino[4,3-b:6,5-c']dipyridine-9(7H)-carboxylate (Int-5) (350 mg, 70%). LCMS: rt = 2.32 min, [M+H] + =319, purity: 95%. 1 H NMR (400 MHz, CDCl3) δ 12.63 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.49 (d, J = 9.1 Hz, 1H), 4.17 (s, 4H), 3.80 (s, 2H), 3.67 (t, J = 5.5 Hz, 2H), 2.72 (s, 2H), 1.51 (s, 9H).

[0240] Compound 7-7: Int-5 (0.3 g, 1.2 mmol) was dissolved in anhydrous DMF (5 mL) and then (45 mg, 1.44 mmol) was added portionwise at 0° C. After 5 min, a solution of 4-(bromomethyl)-3-fluorobenzonitrile (0.202 g, 1.2 mmol) (5 mL DMF) was added to the reaction via a sleeve tube. After 20 min, the reaction was detected by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (20 ml×3) and washed with brine (20 ml×2). The organic phases were combined, dried over Na2SO4, concentrated, and purified by elution (PE / EA=0-20%) to give product 7-7 (0.35 g, 83.3%). LCMS: rt = 2.21 min, [M+H] + =483.5, purity: 95%.

[0241] Compound 7-8: 7-7 (0.35 g, 0.78 mmol) was added to TFA / DCM (20 ml, 3 mL) and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was determined to be complete by LC-MS. The mixture was concentrated to give 7-8 (0.27 g, 98%). LCMS: rt = 1.21 min, [M+H] + =383.2, purity:92%.

[0242] Compound 7-9: The reaction mixture of 7-8 (0.27 g, 1.1 mmol) and DIEA (0.451 g, 3.5 mmol) in 20 mL of CH3CN was stirred at room temperature for 10 min. Then, Int-2 (206.5 g, 1.0 mmol) was added. The mixture was heated at 65 °C for 15 h. The reaction was detected by LC-MS. The reaction mixture was concentrated and purified by elution (MeOH / DCM = 0-8%) to give product 7-9 (250 mg, 59%). LCMS: rt = 2.51 min, [M+H] + =641.3, purity:95%.

[0243] Compound 7: 7-9 (0.25 g, 0.41 mmol) was dissolved in THF (4 mL), and then aqueous lithium hydroxide (4 mL) was added. The mixture was stirred at room temperature for 8 h. The reaction was detected by LC-MS. The reaction mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give compound 7 (0.13 g, 53%). 1 H NMR (400 MHz, MeOD) 1 H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.95 (dd, J = 8.4, 1.4 Hz, 1H), 7.59 (dd, J = 8.4, 4.1 Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.69 (d, J = 8.2 Hz, 1H), 5.45 (s, 2H), 5.32 - 5.22 (m, 1H), 5.05 (dd, J = 8.3, 6.0 Hz, 2H), 4.90 - 4.84 (m, 2H), 4.74 - 4.67 (m, 3H), 4.61 (dd, J = 13.8, 7.8 Hz, 1H), 4.46 (dt, J = 9.1, 6.0 Hz, 1H), 4.34 (s, 2H), 4.30 - 4.20 (m, 1H), 4.20 - 4.02 (m, 2H), 3.86 (s, 2H), 3.24 (t, J = 10.7 Hz, 2H), 2.87 - 2.68 (m, 5H), 2.59 - 2.46 (m, 1H).

[0244] Example 8: 1-((1-(cyanomethyl)cyclopropyl)methyl)-2-(2-fluoro-4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)benzyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 8) [ka]

[0245] Synthetic Route [ka]

[0246] Preparation method Compound 8-2: To a solution of 8-1 (3 g, 15.29 mmol) and NH4Cl (6.5 g, 122.35 mmol) in EtOH, Fe powder (3.4 g, 61.17 mmol) was added in H2O (1:1, 30 mL:30 mL). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (100 mL) and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give product 18-2 (2.3 g, crude). 1 H NMR (400 MHz, DMSO) δ 7.81 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 3.96 (s, 2H), 2.62 (s, 2H), 2.43 (s, 3H), 0.61 (s, 4H).

[0247] Compound 8-3: To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (3.5 g, 15.22 mmol) in DCM (40 mL) at room temperature, HOBT (2.1 g, 15.22 mmol) and EDCI (3.2 g, 16.61 mmol) were added. The mixture was stirred at room temperature for 30 min. Then, a solution of 8-2 (2.3 g, 13.84 mmol) in DCM (20 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with DCM and concentrated. The crude product was filtered 3-5 times with DCM. The filtrate was dried to give product 8-3 (3.9 g, crude). 1 H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.7, 1.8 Hz, 2H), 7.39 (d, J = 6.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 1H), 5.79 (s, 2H), 3.74 (d, J = 4.5 Hz, 5H).

[0248] Compound 8-4: A solution of 8-3 (3.9 g, 381.20 mmol) in AcOH (80 mL) was heated to 70 °C and stirred for 16 h. The resulting solution was extracted with ethyl acetate (100 mL) and NaHCO3 (eq.). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was reacted with MeOH:MeCN (20:1) to give product 8-4 (2 g). 1 H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 8.25 - 7.94 (m, 1H), 7.78 (d, J = 10.7 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.45 - 7.34 (m, 2H), 4.28 (d, J = 19.6 Hz, 2H), 3.84 (d, J = 9.7 Hz, 3H).

[0249] Compound 8-5: LiHMDS (2.75 ml, 2.75 mmol) was added to a mixture of 8-4 (500 mg, 1.37 mmol) in THF (5 ml) at 0° C. and stirred for 1 h. Then, 2-(1-ethylcyclopropyl)acetonitrile (401 mg, 2.75 mmol) was added to the mixture and stirred at 60° C. overnight. After that, the reaction was quenched with saturated NH4Cl. The aqueous phase was extracted with EtOAc and dried over Na2SO4. The organic phases were combined and concentrated. The residue was purified by SGC (EA / PE=0-50%) to give product 8-5 (100 mg).

[0250] Compound 8-6: A solution of 8-5 (100 mg, 0.22 mmol) and 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (83 mg, 0.32 mmol) was dissolved in dioxane (4 mL). Then, KOAc (65 mg, 0.65 mmol) was obtained. Under nitrogen atmosphere, PdCl2(dppf) / DCM (32 mg, 0.04 mmol) was added. The resulting mixture was stirred at 100 °C overnight. The mixture was quenched under reduced pressure and then extracted with EA. The organic phase was washed twice with brine, dried over Na2SO4, evaporated under reduced pressure to remove the solvent, and purified by flash column chromatography (silica gel, eluted with PE / EA=50%-80%) to give product 8-6 (80 mg).

[0251] Compound 8-8: A solution of CBr4 (4.0 g, 12.0 mmol) and 8-7 (2.0 g, 10.9 mmol) in DCM (20 mL) was added. The mixture was stirred at 0 °C under N2 for 10 min, then PPh3 (3.16 g, 12.0 mmol) was added at 0 °C. The mixture was stirred at room temperature under N2 atmosphere for 5 h. H2O (10 mL) was added. The reaction solution was extracted with DCM (3 mL) with stirring at room temperature. The organic phases were combined, washed with brine (10 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (SiO2, EtOAc-hexane) to give product 8-8 (941 mg).

[0252] Compound 8-9: A mixture of 8-8 (891 mg, 3.63 mmol), 6-bromopyridin-2-ol (632 mg, 3.63 mmol) and Cs2CO3 (1.3 g, 3.99 mmol) in DMF (10 ml) was stirred at room temperature overnight. The reaction was quenched with H2O (10 ml). After extraction with EA (10 ml x 3), the organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (silica gel, 0-50% = EA / PE solution) to give product 8-9 (1.06 g). 1H NMR (400 MHz, DMSO) δ 7.72 - 7.65 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 11.3, 1.3 Hz, 1H), 7.26 (dd, J = 7.6, 2.7 Hz, 2H), 6.92 (d, J = 8.1 Hz, 1H), 5.34 (s, 2H), 4.93 (dd, J = 8.3, 6.0 Hz, 2H), 4.61 (t, J = 6.3 Hz, 2H), 4.36 - 4.23 (m, 1H).

[0253] Compound 8-10: A solution of 8-6 (80 mg, 0.15 mmol) and 8-9 (49 mg, 0.14 mmol) was dissolved in dioxane (4 mL) and H2O (1 mL). Then, K2CO3 (40 mg, 0.28 mmol) was added. Under nitrogen atmosphere, PdCl2(dppf) / DCM (11 mg, 0.014 mmol) was added. The resulting mixture was stirred at 80 °C overnight. The mixture was quenched under reduced pressure and then extracted with EA. The organic phase was washed twice with brine, dried over Na2SO4, evaporated under reduced pressure to remove the solvent, and purified by flash column chromatography (silica gel, PE / EA = 50%-80%) to give product 8-10 (80 mg).

[0254] Compound 8: A solution of 8-10 (80 mg, 0.12 mmol) and LiOH (0.5 mL) in THF (0.5 mL) was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure to give the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give the product compound 8 (5.01 mg) and compound 8' (12.78 mg).

[0255] Compound 8: 11H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.96 - 7.89 (m, 2H), 7.82 (dd, J1= 10 Hz, J2= 18 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 12.0 Hz, 1H), 7.25 (d, J = 12.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.52 (s, 2H), 4.91 (dd, J1= 4.0 Hz, J2= 8.0 Hz, 2H), 4.60 (t, J = 6.0 Hz, 2H), 4.54 (s, 2H), 4.43 (s, 2H), 4.31 - 4.22 (m, 1H), 2.66 (s, 2H), 0.70 (s, 4H).

[0256] Compound 8': 1 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.96 - 7.89 (m, 2H), 7.84 (dd, J1= 8 Hz, J2= 16 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 12.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.53 (s, 2H), 4.91 (dd, J1= 4.0 Hz, J2= 8.0 Hz, 2H), 4.60 (t, J = 6.0 Hz, 2H), 4.49 (s, 2H), 4.43 (s, 2H), 4.30 - 4.23 (m, 1H), 2.65 (s, 2H), 0.70 (d, J = 12.0 Hz, 4H).

[0257] Example 9: 2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1-fluorocyclobutyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 9) [ka]

[0258] Synthetic Route [ka]

[0259] Preparation method Compound 9: A solution of 5-6 (62 mg mixture, 0.1 mmol) and LiOH (0.5 mL) in THF (0.5 mL) was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure to give the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% FA to 100% MeCN) to give compound 5 (4.35 mg) and compound 9 (4.09 mg). 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 11.2 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 4.94 - 4.80 (m, 4H), 4.58 (t, J = 6.3 Hz, 2H), 4.31 - 4.19 (m, 1H), 3.85 (s, 2H), 2.96 (d, J = 11.0 Hz, 2H), 2.61 (s, 1H), 2.24 (dd, J = 23.4, 12.2 Hz, 6H), 1.77 (dd, J = 29.8, 9.5 Hz, 6H).

[0260] Example 10: 2-(2-fluoro-4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)benzyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 10) [ka]

[0261] Synthetic Route [ka]

[0262] Preparation method Compound 10-4: To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.02 g, 4.39 mmol) in anhydrous DCM (10 mL) was added EDCI (919 mg, 4.79 mmol) and HOBt (593 mg, 4.39 mmol). After addition of 5-3 (1.0 g, 3.99 mmol), the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (10 ml) and DCM (10 ml), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% PE / EA) to give product 10-4 (992 mg).

[0263] Compound 10-5: A solution of 10-4 (992 mg, 2.13 mmol) in HOAc (20 ml) was stirred at 0° C. for 6 h. Then the reaction was quenched with saturated Na2HCO3. The aqueous phase was extracted with EtOAc and dried over Na2SO4. The organic phases were combined and concentrated. The residue was purified by SGC (EA / PE=0-50%) to give product 1-5 (620 mg). 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.78 (dd, J = 8.5, 1.3 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.40 (dd, J = 8.2, 1.7 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 4.89 (t, J = 5.2 Hz, 1H), 4.43 (d, J = 2.3 Hz, 4H), 3.87 (s, 3H), 3.10 (d, J = 5.2 Hz, 2H), 0.66 - 0.46 (m, 4H).

[0264] Compound 10-6: 10-5 (670 mg, 1.49 mmol) was dissolved in 30 mL of DCM and diethylaminosulfur trifluoride (0.2 mL, 1.49 mmol) was added. The mixture was reacted at 0°C for 1 h, cooled in an ice bath, and extracted with 20 mL of saturated sodium bicarbonate solution (20 mL*3). The organic phase was extracted with anhydrous sodium sulfate and concentrated to dryness to obtain the crude product. The residue was purified by SGC (EA / PE=0-30%) to obtain product 1-06 (189 mg). 1 H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.79 (dd, J = 8.5, 1.4 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 4.51 (s, 2H), 4.35 (s, 2H), 4.20 (s, 1H), 4.08 (s, 1H), 3.88 (s, 3H), 0.79 (d, J = 4.8 Hz, 2H), 0.70 (s, 2H).

[0265] Compound 10-7: A solution of 10-6 (80 mg, 0.17 mmol) and 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (68 mg, 0.26 mmol) was dissolved in dioxane (4 mL). Then, KOAc (52 mg, 0.53 mmol) was added. Under nitrogen atmosphere, PdCl2(dppf) / DCM (26 mg, 0.03 mmol) was added. The resulting mixture was stirred at 100 °C overnight. The mixture was quenched under reduced pressure and extracted with EA. The organic phase was washed twice with brine, dried over Na2SO4, and the solvent was removed by evaporation under reduced pressure, and purified by flash column chromatography (silica gel, PE / EA = 50%-80%) to give product 10-7 (50 mg).

[0266] Compound 10-8: A solution of 10-7 (50 mg, 0.1 mmol) and 8-9 (31 mg, 0.09 mmol) was dissolved in dioxane (4 mL) and H2O (1 mL). Then, K2CO3 (28 mg, 0.2 mmol) was added. Under nitrogen atmosphere, PdCl2(dppf) / DCM (8 mg, 0.01 mmol) was added. The resulting mixture was stirred at 80 °C overnight. The mixture was quenched under reduced pressure and extracted with EA. The organic phase was washed with brine twice, dried over Na2SO4, evaporated under reduced pressure to remove the solvent, and purified by flash column chromatography (silica gel, PE / EA = 50%-80%) to give product 10-8 (40 mg). 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 7.96 - 7.88 (m, 2H), 7.86 - 7.78 (m, 2H), 7.60 (dt, J = 15.7, 7.4 Hz, 3H), 7.45 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 11.3 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.53 (s, 2H), 4.92 (dd, J = 8.3, 6.0 Hz, 2H), 4.60 (t, J = 6.3 Hz, 2H), 4.54 (s, 2H), 4.43 (s, 2H), 4.28 (dd, J = 15.4, 7.7 Hz, 1H), 4.23 (s, 1H), 4.11 (s, 1H), 3.89 (s, 3H), 0.85 - 0.79 (m, 2H), 0.72 (s, 2H).

[0267] Compound 10: A solution of 10-8 (40 mg, 0.06 mmol) and LiOH (0.5 mL) in THF (0.5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give the product compound 10 (7.2 mg). 1H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.93-7.89 (m, 2H), 7.86 - 7.75 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.30 (d, J = 12.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.52 (s, 2H), 4.91 (dd, J1= 4.0 Hz, J2= 8.0 Hz, 2H), 4.60 (t, J = 6.0 Hz, 2H), 4.47 (s, 2H), 4.38 (s, 2H), 4.31 - 4.22 (m, 2H), 4.13 (s, 1H), 0.78-0.69 (m, 4H).

[0268] Example 11: (S)-2-(2-fluoro-4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 11) [ka]

[0269] Synthetic Route [ka]

[0270] Preparation method Compound 11-2: A solution of (S)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 0.21 mmol) and 8-9 (66 mg, 0.19 mmol) was dissolved in dioxane (8 mL) and H2O (2 mL). Then, K2CO3 (54 mg, 0.39 mmol) was added. Under nitrogen atmosphere, PdCl2(dppf) / DCM (14 mg, 0.019 mmol) was added. The resulting mixture was stirred at 80 °C overnight. The mixture was quenched under reduced pressure and then extracted with EA. The organic phase was washed twice with brine, dried over Na2SO4, evaporated under reduced pressure to remove the solvent, and purified by flash column chromatography (silica gel, 80%-100% PE / EA) to give product 11-2 (31 mg).

[0271] Compound 11: 11-2 (31 mg, 0.05 mmol) in THF (0.5 mL) and 1 N LiOH (0.5 mL) were stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give product compound 11 (9.35 mg). 1 H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.91 (t, J = 8.0 Hz, 2H), 7.87 - 7.75 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.44 - 7.22 (m, 4H), 6.86 (d, J = 8.0 Hz, 1H), 5.53 (s, 2H), 5.06 (s, 1H), 4.96 - 4.88 (m, 2H), 4.60 (dd, J1= 6.0 Hz, J2= 14.0 Hz, 3H), 4.48 (d, J = 16.0 Hz, 3H), 4.42 - 4.34 (m, 2H), 4.31 - 4.24 (m, 1H), 2.69 (m, 1H), 2.40 (m, 1H).

[0272] Example 12: 2-(((7a,11a)-2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-5,7a,8,10,11,11a-hexahydroxy oxepino[4,3-b:6,5-c']dipyridin-9(7H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 12) [ka]

[0273] Synthetic Route [ka]

[0274] Preparation method Compound 12-1: To a solution of methyl 2-chloro-6-methoxynicotinate (2 g, 10 mmol, 1.0 eq) in dioxane (50 mL), 1-(tert-butyl) 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (3.67 g, 10 mmol, 1.0 eq), K2CO3 (2.76 g, 20 mmol, 2.0 eq) and Pd(dppf)Cl2 (731 mg, 1 mmol, 0.1 eq) were added. The mixture was stirred for 16 h at 90 °C under N2 atmosphere. The reaction was monitored by LCMS. The mixture was directly concentrated to give a residue. The residue was purified by silica gel column chromatography eluting with (EA / PE=0-30%) to give 1'-(t-butyl) 3,3'-dimethyl-6-methoxy-5',6'-dihydro-[2,4'-bipyridine]-1',3,3'(2'H)-tricarboxylate 12-1 (1.1 g, 27.1% yield). LCMS: rt = 2.025 min, [M+H] + =407, purity:92%.

[0275] Compound 12-2: To a solution of 12-1 (0.83 g, 2 mmol, 1.0 eq) in THF (50 mL) at 0° C., LiAlH4 (152 mg, 4 mmol, 2.0 eq) was added, and then the mixture was stirred at 20° C. for 10 min. The reaction was detected by LCMS. H2O (0.2 mL), 15% NaOH solution (0.2 mL) and EtOAc (50 mL) were slowly added to the mixture. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give product 12-2 (630 mg, 90% yield). LCMS: rt =1.57 min, [M+H] + =351.0, purity: 90%.

[0276] Compound 12-3: A solution of 12-2 (300 mg, 0.286 mmol, 1.0 eq) and Pd / C (100 mg) in THF (15 mL) was stirred under H2 (15 psi) at 20 °C for 14 h. The reaction was detected by LCMS. The resulting mixture was filtered. The filter cake was washed with THF (3 x 20 mL). The filtrate was concentrated to give a residue, which was purified by column silica gel chromatography eluted with (PE / EA = 0-50%) to give product 12-3 (118 mg, 40% yield). LCMS: rt = 1.60 min, [M+H] + =353.2, purity: 95.9%.

[0277] Compound 12-4: To a solution of 12-3 (1.2 g, 3.4 mmol, 1.0 eq) in toluene (80 mL), camphorsulfonic acid (3.95 g, 17 mmol, 5.0 eq) was added. The mixture was stirred at 110° C. for 2 h. The reaction was detected by LCMS. The reaction mixture was directly concentrated to give a residue, which was purified by silica gel column chromatography eluting with (MeOH / DCM= 0-10%) to give product 12-4 (700 mg, 87.9% yield). LCMS: rt =1.528 min, [M+H] + =235.2, purity: 86.9%.

[0278] Compound 12-5: A solution of 12-4 (0.35 g, 1.5 mmol, 1.0 eq) in HBr (10 mL) was stirred at 120° C. for 6 h. The reaction was detected by LCMS. The reaction mixture was adjusted to PH=7 with NaOH (1N) and extracted with DCM (20 mL×3). The organic phases were combined, dried over Na2SO4, filtered and concentrated to give product 12-5 (200 mg, 60.6% yield). LCMS: rt =0.385 min, [M+H] + =221.1, purity:87.18%.

[0279] Compound 12-6: To a solution of 12-5 (200 mg, 0.91 mmol, 1.0 eq) in DCM (10 mL), TEA (184.2 mg, 1.82 mmol, 2.0 eq) and Boc2O (238 mg, 1.1 mmol, 1.2 eq) were added. The mixture was stirred at 25° C. for 2 h. The reaction was detected by LCMS. The mixture was directly concentrated to give a residue, which was purified by silica gel column chromatography eluting with (MeOH / DCM=0-10%) to give product 12-6 (190 mg, 65.5% yield). LCMS: rt =1.35 min, [M+H] + =343, purity: 93.8%.

[0280] Compound 12-7: 12-6 (190 mg, 594 mmol) in 10 mL of DMF was stirred with 3-(4-(bromomethyl)-3-fluorophenyl)oxetane (150 mg, 0.594 mmol) and NaH (35.6 mg, 0.89 mmol) under N2 at 25 °C for 0.5 h. The reaction was detected by LCMS. The reaction mixture was taken up in water (30 mL), extracted with DCM (20 mL x 3), washed with brine, dried and concentrated to give the crude product, which was further purified by elution (PE / EtOAc = 0-47%) to give 12-7 (260 mg, 70% yield). LCMS: rt = 2.32 min, [M+H] + =485, purity: 99.7%.

[0281] Compound 12-8: A solution of 12-7 (260 mg, 0.57 mmol) in 6 mL of HCl / EA was stirred at room temperature for 30 min. The reaction was monitored by LCMS. The reaction mixture was concentrated to give crude product 12-8 (200 mg). The product was used directly in the next step without purification. LCMS: rt =0.92 min, [M+H] + =385, purity: 98%.

[0282] Compound 12-9: DIEA (736.7 mg, 0.57 mmol) was added to 12-8 (200 mg, 0.57 mmol). Then, Int-2 (166.6 mg, 5.7 mmol) was added to the reaction mixture at 60 °C over 16 h. The reaction was detected by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by elution (PE / EtOAc = 0-5%) to give 12-9 (180 mg, yield: 50.3%). LCMS: rt = 1.053 min, [M+H] + =643, purity: 98.5%.

[0283] Compound 12-9-P1 and Compound 12-9-P2: Sample 12-9 (180 mg, 0.27 mmol) was further purified by the "SFC method" to obtain 12-9-P1 (60 mg, SFC rt = 2.176 min, yield: 67%) and 12-9-P2 (60 mg, SFC rt = 2.68 min, yield: 67%).

[0284] Compound 12-A: A solution of 12-9-P1 (60 mg, 0.09 mmol) in THF / HO (5 mL) was stirred with LiOH (22 mg, 0.92 mmol) at room temperature for 16 h. The reaction was detected by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by preparative HPLC to give compound 12-A (32.15 mg, yield: 71.2%). LCMS: rt =1.197 min, [M+H] + =629, purity: 100%. 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.94 (dd, J = 8.4, 1.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.58 (d, J = 8.2 Hz, 1H), 5.45 - 5.36 (m, 2H), 5.27 (qd, J = 7.1, 3.0 Hz, 1H), 5.06 (dd, J = 8.3, 6.1 Hz, 2H), 4.77 - 4.59 (m, 8H), 4.44 - 4.22 (m, 3H), 3.99 - 3.82 (m, 3H), 3.25 (d, J = 9.4 Hz, 1H), 2.96 (s, 1H), 2.83 - 2.74 (m, 1H), 2.65 - 2.29 (m, 6H).

[0285] Compound 12-B: To a solution of 12-9-P2 (60 mg, 0.09 mmol) in THF / H2O (5 mL), LiOH (22 mg, 0.9 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was detected by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by preparative HPLC to give 12-B (38.5 mg, yield: 72.3%). LCMS: rt =1.213 min, [M+H] + =629, purity: 100%. 1H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.93 (dd, J = 8.4, 1.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.59 (d, J = 8.2 Hz, 1H), 5.41 (q, J = 12.6 Hz, 2H), 5.25 (dt, J = 7.2, 4.8 Hz, 1H), 5.06 (dd, J = 8.2, 6.2 Hz, 2H), 4.73 - 4.62 (m, 9H), 4.49 (dt, J = 9.1, 6.0 Hz, 1H), 4.32 - 4.22 (m, 1H), 4.10 - 3.90 (m, 2H), 3.76 (d, J = 13.4 Hz, 1H), 3.25 (s, 1H), 2.94 - 2.77 (m, 2H), 2.71 - 2.27 (m, 6H).

[0286] Example 13: (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 13) [ka]

[0287] Synthetic Route [ka]

[0288] Preparation method Compound 13-2: To a mixture of 13-1 (1.0 g, 8.7 mmol) in DCE (10 mL), NaBH(OAc)3 (1.84 g, 8.7 mmol) and oxetan-3-one (0.63 g, 8.7 mmol) were added. The mixture was stirred at 30 °C for 16 h. The reaction was detected by LCMS. The reaction mixture was quenched with ice water. The mixture was extracted with EA. The organic phases (50 mL) were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 13-2 (1.48 g, 99.0%). LCMS: rt = 2.1 min, [M+H] + =172, purity: 92%.

[0289] Compound 13-3: A mixture of 13-2 (1 g, 5.84 mmol), TsCl (1.11 g, 5.84 mmol) and TEA (1.18 g, 11.68 mmol) in DMF (50 ml) was stirred at 20° C. for 2 h. The reaction was detected by LC-MS. The reaction mixture was quenched by adding water. The aqueous phase was extracted with EtOAc (100 ml×3) and washed with brine (50 ml×2). The organic phases were combined, dried over Na2SO4, concentrated and purified by elution (PE / EA=0-20%) to give 13-3 (1.1 g, 62%). LCMS: rt = 3.5 min, [M+H] + =326, purity: 94%.

[0290] Compound 13-4: A mixture of 13-3 (1 g, 3.1 mmol), methyl (S)-2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.34 g, 3.07 mmol) and Cs2CO3 (2 g, 6.15 mmol) in DMF (20 ml) was added. The mixture was stirred at 20 °C for 16 h. The reaction was detected by LC-MS. The mixture was concentrated and purified by elution (PE / EA = 0-20%) to give 13-4 (0.9 g, 33.2%). LCMS: rt = 1.37 min, [M+H] + =590.7, purity:96%.

[0291] Compound 13: Compound 13-4 (0.25 g, 0.41 mmol) was dissolved in THF (4 mL), and then aqueous lithium hydroxide (4 mL) was added. The mixture was stirred at room temperature for 8 h. The reaction was detected by LC-MS. The mixture was concentrated and purified by preparative HPLC (NH3·H2O) to give compound 13 (0.13 g, 53%). LCMS: rt = 1.225 min, [M+H] + =576.3, purity: 96%. 1 H NMR (400 MHz, MeOD)δ8.19 (s, 1H), 7.94 (dd, J = 8.4, 1.3 Hz, 1H), 7.61-7.48 (m, 2H), 6.78 (d, J = 7.3 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.28 (dt, J = 7.0, 4.3 Hz, 1H), 4.90 (d, J = 7.1 Hz, 1H), 4.66 (ddt, J = 16.2, 12.6, 4.6 Hz, 6H), 4.48 (dt, J = 9.1, 6.0 Hz, 1H), 4.16 (d, J = 5.9 Hz, 2H), 4.01 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.49 (dd, J = 13.0, 6.5 Hz, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 2.80 (dd, J = 14.7, 6.6 Hz, 3H), 2.68-2.49 (m, 2H), 2.29 (ddd, J = 21.6, 14.9, 9.8 Hz, 2H), 1.93-1.79 (m, 9H), 1.48-1.36 (m, 2H).

[0292] Example 14: (S)-2-((4-(6-((2-fluoro-4-(3-hydroxyoxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 14) [ka]

[0293] Synthetic Route [ka]

[0294] Preparation method Compound 14-2: To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetan-3-ol (2 g, 6.4 mmol, 1.0 eq) in THF (20 mL) was added TBAF (6.4 mL, 6.4 mmol, 1.0 eq). The mixture was stirred at room temperature for 30 min. The reaction was detected by TLC. The residue was washed with 20 mL of brine, dried over Na2SO4, and concentrated under pressure. The residue was eluted with PE / EtOAc (2:1) to give product 14-2 (1.2 g, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 11.12 - 10.98 (m, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H), 7.33 (d, J = 11.3 Hz, 1H), 4.90 (d, J = 7.0 Hz, 2H), 4.85 (d, J = 7.0 Hz, 2H), 4.78 (s, 2H).

[0295] Compound 14-3: To a solution of 14-2 (1 g, 5.1 mmol, 1.0 eq) in DCM (10 mL), PPh3 (1.338 g, 5.1 mol, 1.0 eq) was added and cooled at -30 °C, then CBr4 (1.691 g, 5.1 mmol, 1.0 Eq) was added. The mixture was reacted for 4 h. The reaction was detected by TLC, and NMR showed that the starting material reacted to form the product. The mixture was extracted with water and DCM, dried over Na2SO4, and subjected to silica gel column chromatography (EA / PE=0-10%) to give product 14-3 (0.5 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (p, J = 8.0 Hz, 2H), 7.37 (d, J = 11.3 Hz, 1H), 4.91 (d, J = 7.3 Hz, 2H), 4.85 (d, J = 7.4 Hz, 2H), 4.53 (s, 2H).

[0296] Compound 14-4: To a solution of 14-3 (250 mg, 0.905 mmol, 1.0 eq) in DMF (10 mL), methyl (S)-2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (434 mg, 0.9955 mmol, 1.1 eq) and Cs2CO3 (590 mg, 2 mmol, 2 eq) were added and subjected to nitrogen substitution reaction at room temperature for 16 h. The reaction was detected by TLC and NMR showed that the starting material reacted to produce the product. Purification was carried out by silica gel column chromatography (EA / PE=0-20%) to give product 14-4 (0.2 g, 33% yield). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.97 (dd, J = 8.5, 1.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 15.6, 7.9 Hz, 2H), 7.44 - 7.36 (m, 2H), 6.73 (d, J = 7.3 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 4.93 (dd, J = 6.9, 2.1 Hz, 2H), 4.82 (d, J = 7.1 Hz, 2H), 4.66 (ddd, J = 21.7, 14.6, 5.5 Hz, 2H), 4.42 (dt, J = 9.2, 6.0 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 2H), 2.96 (s, 1H), 2.88 (s, 1H), 2.52 - 2.40 (m, 1H), 2.29 (s, 2H), 2.04 (s, 2H), 1.26 (t, J = 7.1 Hz, 4H).

[0297] Compound 14: A solution of 14-4 (0.1 g, 0.016 mmol, 1 eq) in LiOH (5 mL) was reacted at room temperature for 3 h. The reaction was monitored by TLC. The reaction product was concentrated to give the crude product, which was purified by pre-HPLC to give the product compound 14 (50 mg, 40% yield). 1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.61 - 7.50 (m, 3H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 11.6 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.45 (s, 2H), 5.29 (d, J = 4.7 Hz, 1H), 4.91 (dd, J = 15.3, 7.0 Hz, 1H), 4.85 (s, 2H), 4.78 - 4.69 (m, 3H), 4.62 (dd, J = 13.8, 7.7 Hz, 1H), 4.48 (dt, J = 9.0, 6.0 Hz, 1H), 3.95 (dd, J = 44.4, 13.6 Hz, 2H), 3.04 (d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.0 Hz, 1H), 2.87 - 2.74 (m, 1H), 2.69 - 2.48 (m, 2H), 2.28 (ddd, J = 21.3, 12.5, 9.2 Hz, 2H), 2.01 - 1.73 (m, 4H).

[0298] Example 15: (S)-2-((4-(6-((2-fluoro-4-(3-fluoroxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 15) [ka]

[0299] Synthetic Route [ka]

[0300] Preparation method Compound 15-2: To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetan-3-ol (2 g, 6.4 mmol, 1.0 eq) in THF (20 mL) was added TBAF (6.4 mL, 6.4 mmol, 1.0 eq). The mixture was stirred at room temperature for 30 min. The reaction was detected by TLC. The residue was washed with 20 mL of brine, dried over Na2SO4, and concentrated under pressure. The residue was eluted with PE / EtOAc (2:1) to give 15-2 (1.2 g, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 11.12 - 10.98 (m, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H), 7.33 (d, J = 11.3 Hz, 1H), 4.90 (d, J = 7.0 Hz, 2H), 4.85 (d, J = 7.0 Hz, 2H), 4.78 (s, 2H).

[0301] Compound 15-3: To a solution of 15-2 (1 g, 5.1 mmol, 1.0 eq) in DCM (10 mL), PPh3 (1.338 g, 5.1 mmol, 1.0 eq) was added and dried at -30 °C, then CBr4 (1.691 g, 5.1 mmol, 1.0 eq) was added. The mixture was reacted for 4 h. The reaction was detected by TLC, and NMR showed that the starting material reacted to form the product. The mixture was extracted with water and DCM, dried over Na2SO4, and subjected to silica gel column chromatography (EA / PE=0-10%) to give product 15-3 (0.5 g, 50% yield). 1 H NMR (400 MHz, CDCl3) δ 7.44 (p, J = 8.0 Hz, 2H), 7.37 (d, J = 11.3 Hz, 1H), 4.91 (d, J = 7.3 Hz, 2H), 4.85 (d, J = 7.4 Hz, 2H), 4.53 (s, 2H).

[0302] Compound 15-4: To a solution of 15-3 (250 mg, 0.905 mmol, 1.0 eq) in DMF (10 mL), methyl (S)-2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (434 mg, 0.9955 mmol, 1.1 eq) and Cs2CO3 (590 mg, 2 mmol, 2 eq) were added and subjected to nitrogen exchange reaction at room temperature for 16 h. The reaction was detected by TLC and NMR showed that the starting material had reacted to form the product. Purification was carried out by silica gel column chromatography (EA / PE=0-20%) to give product 15-4 (0.2 g, 33% yield). 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.97 (dd, J = 8.5, 1.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 15.6, 7.9 Hz, 2H), 7.44 - 7.36 (m, 2H), 6.73 (d, J = 7.3 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 4.93 (dd, J = 6.9, 2.1 Hz, 2H), 4.82 (d, J = 7.1 Hz, 2H), 4.66 (ddd, J = 21.7, 14.6, 5.5 Hz, 2H), 4.42 (dt, J = 9.2, 6.0 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 2H), 2.96 (s, 1H), 2.88 (s, 1H), 2.52 - 2.40 (m, 1H), 2.29 (s, 2H), 2.04 (s, 2H), 1.26 (t, J = 7.1 Hz, 4H).

[0303] Compound 15-5: With nitrogen substitution, DAST (0.52 mg, 0.324 mmol, 2 eq) was slowly added to a solution of 15-4 (100 mg, 0.162 mmol, 1.0 eq) in DCM (3 ml) and cooled to 0° C. After addition, The reaction was carried out at room temperature for 2 h. The reaction was detected by TLC and LCMS to give product 15-5. LCMS: rt = 1.324 min, [M+H] + =619.2, purity: 57%.

[0304] Compound 15: A solution of 15-5 (0.1 g, 0.016 mmol, 1 eq) in LiOH (5 mL) was reacted at room temperature for 3 h. The reaction was monitored by TLC. The reaction product was concentrated to give the crude product, which was purified by pre-HPLC to give compound 15 (23.7 mg, 40% yield). 1 H NMR (400 MHz, CD3OD_SPE) δ 8.30 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.68 - 7.53 (m, 3H), 7.33 (dd, J = 23.4, 9.4 Hz, 2H), 6.81 (d, J = 7.1 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.46 (s, 2H), 5.27 (d, J = 6.6 Hz, 1H), 4.99 (dd, J = 21.1, 8.0 Hz, 3H), 4.82 - 4.68 (m, 3H), 4.66 - 4.57 (m, 1H), 4.46 (d, J = 8.1 Hz, 1H), 4.01 (dd, J = 45.2, 13.7 Hz, 2H), 3.04 (dd, J = 43.8, 10.7 Hz, 2H), 2.79 (s, 1H), 2.65 (s, 1H), 2.54 (d, J = 8.6 Hz, 1H), 2.37 (d, J = 9.1 Hz, 2H), 1.86 (d, J = 10.2 Hz, 4H).

[0305] Example 16: (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((4-(oxetan-3-yl)-2-(2,2,2-trifluoroethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16) [ka]

[0306] Synthetic Route [ka]

[0307] Preparation method Compound 16-2: To a stirred solution of methyl 4-bromo-2-hydroxybenzoate 16-1 (10 g, 43.5 mmol, 1.00 eq) in DMF (100 mL) was added Cs2CO3 (28 g, 87.0 mmol, 2.00 eq) in portions. To the above mixture was added 1,1,1-trifluoro-2-iodoethane (9.1 g, 43.5 mmol, 1.00 eq) at room temperature for 16 h. The reaction was detected by TLC. The mixture was diluted with H2O (300 mL) and extracted with EtOAc (100 mL x 3). The organic phases were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give product 16-2 (8.0 g, 46% yield). LCMS: rt =2.031 min, [M+1] + =312.9, purity: 89.7%.

[0308] Compound 16-3: To a solution of 16-2 (8 g, 25.6 mmol, 1.0 eq) in THF (50 mL) at 0° C., LiAlH4 (487 mg, 12.8 mmol, 2.0 eq) was added and the mixture was stirred at 20° C. for 10 min. The reaction was detected by LCMS. H2O (0.2 mL), 15% NaOH solution (0.2 mL) and EtOAc (50 mL) were slowly added to the mixture. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give product 16-3 (7 g, 90% yield).

[0309] Compound 16-4: To a solution of 16-3 (7 g, 24.6 mmol, 1 eq) in DCM (70 mL) at 25 °C, TBSCl (4.5 g, 29.52 mmol, 1.2 eq) and imidazole (2.5 g, 36.9 mmol, 1.5 eq) were added for 16 h. The reaction was detected by TLC. The mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The organic phases were combined, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column silica gel chromatography eluting with (EA / PE = 0-30%) to give product 16-4 (8.6 g, 72.7% yield). LCMS: rt = 1.932 min, [M+1] + =400.0, purity: 91.3%.

[0310] Compound 16-5: To 16-4 (4.5 g, 14.6 mmol, 1.0 eq) in THF (50 mL) at a temperature below -70 °C under nitrogen, n-BuLi (7.6 mL, 19.0 mmol, 1.3 eq) was added slowly over 0.5 h. Then, at a temperature below -65 °C, C3H4O2 (1.6 g, 21.9 mmol, 1.5 eq) was added to the reaction mixture with stirring over 2 h. The reaction was detected by TLC. The mixture was added slowly to H2O (10 mL) and EtOAc (10 mL) and purified by silica gel column chromatography eluting with (PE / EA = 0-50%) to give product 16-5 (1.8 g, 40% yield). LCMS: rt = 1.734 min, [M+1] + =393.1, purity: 93.5%.

[0311] Compound 16-6: To a solution of 16-5 (1.8 g, 4.6 mmol, 1.0 eq) in THF (20 mL) under nitrogen at a temperature below 10 °C, NaH (276 mg, 6.9 mmol, 1.5 eq) was added with stirring over 1 h, then CS2 (0.3 mL, 4.6 mmol, 1.0 eq) and CHI (0.3 mL, 4.6 mmol, 1.0 eq) were added with stirring over 0.5 h below 0 °C to the reaction mixture. The reaction was detected by LCMS. The mixture was slowly added to H2O (20 mL) and EtOAc (20 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated to give product 16-6 (1.2 g, 70% yield). LCMS: rt = 1.357 min, [M+H] + =483.1, Purity Purity: 80%.

[0312] Compound 16-7: To a solution of 16-6 (1.2 g, 2.5 mmol, 1.0 eq) in toluene (15 mL) under nitrogen, (n-Bu)3SnH (1.4 mL, 5.0 mmol, 2 eq) and AIBN (40.9 mg, 0.25 mmol, 0.1 eq) were added with stirring over 0.5 h. The reaction was monitored by LCMS. The crude product was purified by silica gel column chromatography eluting with (EA / PE=0-50%) to give product 16-7 (754 mg, 70% yield). LCMS: rt = 1.579 min, [M+H] + =377.2, purity: 93%.

[0313] Compound 16-8: To a solution of 16-7 (754 mg, 2.0 mmol, 1.0 eq) in THF (10 mL), TBAF (2.0 mL, 2.0 mmol, 1.0 eq) was added with stirring over 0.5 h. The reaction was detected by TLC. The reaction mixture was directly concentrated to give a residue, which was purified by column silica gel chromatography eluted with (PE / EA=0-50%) to give product 16-8 (481 mg, 80% yield). LCMS: rt = 1.157 min, [M+H] + =263.3, purity: 89.5%.

[0314] Compound 16-9: To a solution of 16-8 (380 mg, 1.45 mmol, 1.0 eq) in DCM (10 mL), CBr4 (482 mg, 1.45 mmol, 1.0 eq) was added and the system was cooled to 0°C-5°C with ice bath. At a temperature below 5°C, PPh3 (380 mg, 1.45 mmol, 1.0 eq) was added slowly with stirring to the reaction mixture over 0.5 h. The reaction was detected by TLC. The mixture was diluted with H2O and extracted with EtOAc (10 mL x 3). The organic phases were combined, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel column chromatography eluting with (EtOAc / petroleum ether = 0-30%) to give product 16-9 (90 mg, 78% yield). LCMS: rt = 1.462 min, [M+H] + =323.4, purity: 89.5%.

[0315] Compound 16-10: To a solution of 16-9 (100 mg, 0.31 mmol, 1.00 eq) in DMF (3 mL) was added Cs2CO3 (202 mg, 0.62 mmol, 2.00 eq) in portions. At room temperature, methyl (S)-2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (135 mg, 0.31 mmol, 1.00 eq) was added over 16 h to the above mixture. The reaction was monitored by TLC. The mixture was diluted with H2O (300 mL) and extracted with EtOAc (100 mL x 3). The organic phases were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue which was purified by column silica gel chromatography eluting with PE / EtOAc (3:1) to give product 16-10 (120 g, 80% yield). LCMS: rt = 1.754 min, [M+H] + =681.0, purity: 96.3%.

[0316] Compound 16: A solution of 16-10 (120 mg, 0.18 mmol, 1.0 eq) in THF / HO (5 mL) was stirred at room temperature for 16 h, and LiOH (43.2 mg, 1.8 mmol, 10 eq) was added. The reaction was monitored by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by preparative HPLC to give (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((4-(oxetan-3-yl)-2-(2,2,2-trifluoroethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as compound 16 (34.5 mg, yield: 63.2%). LCMS: rt = 1.297 min, [M+H] + =667.4, purity: 100%. 1 HNMR(400 MHz, MeOD) δ 8.21 (s, 1H), 7.94 (dd,J = 8.4, 1.1 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.80 (d,J = 7.4 Hz, 1H), 6.60 (d,J = 8.2 Hz, 1H), 5.42 (s, 2H), 5.27 (d,J = 4.3 Hz, 1H), 5.05 (dd,J = 8.3, 6.0 Hz, 2H), 4.90 (d,J = 7.1 Hz, 1H), 4.73 (dd,J = 13.6, 7.0 Hz, 3H), 4.66 - 4.57 (m, 3H), 4.45 (dt,J = 9.1, 5.9 Hz, 1H), 4.31 - 4.20 (m, 1H), 3.96 (dd,J = 43.2, 13.7 Hz, 2H), 3.00 (dd,J = 38.7, 11.4 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.69 - 2.59 (m, 1H), 2.57 - 2.48 (m, 1H), 2.37 - 2.23 (m, 2H), 1.88 (dt,J = 9.9, 6.8 Hz, 4H).

[0317] Example 17: 2-((2-((2-chloro-4-(oxetan-3-yl)benzyl)oxy)-5,7a,8,10,11,11a-hexahydroxy oxepino[4,3-b:6,5-c′]bipyridin-9(7H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 17) [ka]

[0318] Synthetic Route [ka]

[0319] Preparation method Compound 17-1: At 0° C., to a solution of 12-6 (120 mg, 0.375 mmol, 1.0 eq) in DMF (3 mL) was added NaH (22 mg, 0.56 mmol, 1.5 eq). After 15 min of reaction, a solution of 3-(4-(bromomethyl)-3-chlorophenyl)oxetane (97.5 mg, 0.375 mmol, 1.0 eq) in DMF was added dropwise to the reaction system. The ice bath was removed. The reaction was detected by LCMS. The crude product was fractionated by column chromatography to give product 17-1. LCMS: rt = 2.34 min, [M+H] + =501, purity: 86%.

[0320] Compound 17-2: In this system, TFA (1 mL) was added to a solution of 17-1 (380 mg, 0.76 mmol, 1.0 eq) in DCM (20 mL). The reaction was carried out at room temperature for 30 min. The reaction was detected by LCMS to give product 17-2. LCMS: rt = 1.337 min, [M+H] + =659, purity: 95%.

[0321] Compound 17-3: To a solution of 17-2 (304 mg, 0.76 mmol, 1.0 eq) in CH3CN (15 mL), DIEA (982.2 mg, 7.6 mmol, 10 eq) was added. The mixture was reacted for 5 min. Int-2 (202 mg, 0.68 mmol, 0.9 eq) was added to the system solution. The mixture was stirred at 600 °C overnight. The reaction was detected by LCMS. The crude product was isolated by column chromatography to give product 17-3. LCMS: rt = 1.337 min, [M+H] + =659, purity: 78%.

[0322] Compound 17: To a solution of 17-3 (680 mg, 1.03 mmol, 1.0 eq) in THF (20 ml) was added a solution of LiOH (247.2 mg, 5.2 mmol, 10 eq) in water (3 ml). The reaction was monitored by LCMS to give the product compound 17. LCMS: rt = 1.26 min, [M+H] + =645, purity: 77%.

[0323] Compounds 17-A and 17-B: Sample compound 17 (390 mg, 0.606 mmol) was further purified by the "SFC method" to obtain compound 17-A (65 mg, SFC rt = 2.178 min, yield: 56%) and compound 17-B (57 mg, SFC rt = 3.179 min, yield: 44%).

[0324] 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.84 (dd, J = 8.4, 1.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.58 (d, J = 8.2 Hz, 1H), 5.45 - 5.36 (m, 2H), 5.27 (qd, J = 7.1, 3.0 Hz, 1H), 5.06 (dd, J = 8.3, 6.1 Hz, 2H), 4.77 - 4.59 (m, 8H), 4.44 - 4.22 (m, 3H), 3.99 - 3.82 (m, 3H), 3.25 (d, J = 9.4 Hz, 1H), 2.96 (s, 1H), 2.83 - 2.74 (m, 1H), 2.67 - 2.29 (m, 6H).

[0325] 1 H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.93 (dd, J = 8.4, 1.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.22 - 7.16 (m, 2H), 6.59 (d, J = 8.2 Hz, 1H), 5.41 (q, J = 12.6 Hz, 2H), 5.25 (dt, J = 7.2, 4.8 Hz, 1H), 5.06 (dd, J = 8.2, 6.2 Hz, 2H), 4.73 - 4.62 (m, 9H), 4.49 (dt, J = 9.1, 6.0 Hz, 1H), 4.32 - 4.22 (m, 1H), 4.10 - 3.90 (m, 2H), 3.76 (d, J = 13.4 Hz, 1H), 3.25 (s, 1H), 2.94 - 2.77 (m, 2H), 2.70 - 2.27 (m, 6H).

[0326] Example 18: (S)-2-((4-(6-((2-(difluoromethyl)-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 18) [ka]

[0327] Synthetic Route [ka]

[0328] Preparation method Compound 18-1: Under nitrogen, at a temperature below -70 °C, to a solution of ((4-bromo-2-(difluoromethyl)benzyl)oxy)(tert-butyl)dimethylsilane (500 mg, 1.4 mmol, 1.0 eq) in THF (5 mL) was added n-BuLi (1 mL, 1.6 mmol, 1.3 eq) slowly with stirring over 0.5 h. Then, at a temperature below -65 °C, C3H4O2 was added slowly with stirring over 2 h to the reaction mixture. The reaction was detected by TLC. The mixture was added slowly with H2O (10 mL) and EtOAc (10 mL) and purified by silica gel column chromatography eluting with (EA / PE = 0-50%) to give product 18-1 (130 mg, 80% yield). LCMS: rt = 2.049 min, [M+H] + =345.1, purity: 86%.

[0329] Compound 18-2: To a solution of 18-1 (260 mg, 0.76 mmol, 1.0 eq) in THF (5 mL) under nitrogen at a temperature below 10 °C, NaH (60 mg, 1.5 mmol, 2 eq) was added with stirring over 1 h. Then, at a temperature below 0 °C, CS2 (0.05 mL, 0.76 mmol, 1 eq) and CHI (0.05 mL, 0.76 mmol, 1 eq) were added slowly with stirring over 0.5 h to the reaction mixture. The reaction was detected by LCMS. The mixture was slowly added to H2O (20 mL) and EtOAc (20 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated to give product 18-2 (150 mg, 70% yield). LCMS: rt = 1.572 min, [M+H] + =435.0, purity: 90%.

[0330] Compound 18-3: To a solution of 18-2 (252 mg, 0.63 mmol, 1.0 eq) in toluene (7 mL) under nitrogen, (n-Bu)3SnH (0.34 mL, 1.26 mmol, 2 eq) and AIBN (10.3 mg, 0.063 mmol, 0.1 eq) were added with stirring over 0.5 h. The reaction was monitored by LCMS. The crude product was purified by silica gel column chromatography eluting with (EA / PE = 0-50%) to give 18-3 (136 mg, 90% yield). LCMS: rt = 1.472 min, [M+H] + =329.1, purity: 96%.

[0331] Compound 18-4: To a solution of 18-3 (700 mg, 2.13 mmol, 1.0 eq) in THF (4 mL), TBAF (2.13 mL, 2.13 mmol, 1.0 eq) was added and stirred for 0.5 h. The reaction was detected by TLC. The reaction mixture was directly concentrated to give a residue, which was purified by column silica gel chromatography eluted with (PE / EA=0-50%) to give product 18-4 (500 mg, 90% yield). LCMS: rt = 1.132 min, [M+H] + =215.1, purity: 86.9%.

[0332] Compound 18-5: 18-5 (509 mg, 1.72 mmol, 1.0 eq), Cs2CO3 (1.12 g, 3.44 mmol, 2.0 eq), Xantphos (199 mg, 0.344 mmol, 0.2 eq) and Pd(dba)3 (157 mg, 0.172 mmol, 0.1 eq) were stirred at 100 °C for 4 h. The reaction was detected by LCMS. The toluene in the mixture was dried. The resulting mixture was dissolved in dichloromethane. The organic phases were combined and concentrated to give a residue, which was purified by column silica gel chromatography eluting with (PE / EA = 0-20%) to give product 18-5 (650 mg, 80% yield). LCMS: rt = 1.937 min, [M+H] + =475.2, purity: 87.18%.

[0333] Compound 18-6: To a solution of 18-5 (300 mg, 0.63 mmol) in 6 mL of DCM, TFA (1 mL) was added and stirred at room temperature for 30 min. The reaction was detected by LCMS. The reaction mixture was concentrated to give crude product 18-6 (200 mg). The crude product was used directly in the next step without purification. LCMS: rt = 1.371 min, [M+H] + =375.1, purity: 93.8%.

[0334] Compound 18-7: To a solution of 18-6 (200 mg, 0.54 mmol, 1.0 eq) in 15 mL of MeCN (10 mL), DIEA (696.6 mg, 5.4 mmol, 10 eq) was added and stirred at room temperature under nitrogen for 10 min. Then, at 60 °C, Int-2 (159 mg, 0.54 mmol, 1.0 eq) was added to the reaction mixture over 16 h. The reaction was monitored by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by elution (PE / EtOAc = 0-5%) to give product 18-7 (100 mg, yield: 50.3%). LCMS: rt = 1.013 min, [M+H] + =633.4, purity: 99.7%.

[0335] Compound 18: To a solution of 18-7 (100 mg, 0.16 mmol, 1.0 eq) in THF / HO (5 mL) at room temperature, LiOH (38 mg, 1.6 mmol, 10 eq) was added with stirring for 16 h. The reaction was detected by LCMS. The reaction mixture was concentrated to give the crude product, which was further purified by preparative HPLC to give compound 18 (40.86 mg, yield: 63.2%). LCMS: rt = 1.239 min, [M+H] + =619.2, purity:97.4%. 1 HNMR(400 MHz, CD3OD_SPE) δ 8.14 (d,J = 139.3 Hz, 2H), 7.69 - 7.50 (m, 5H), 7.13 (t,J = 55.2 Hz, 1H), 6.80 (s, 1H), 6.63 (d,J = 8.3 Hz, 1H), 5.53 (s, 2H), 5.27 (s, 1H), 5.06 (dd,J = 8.0, 6.3 Hz, 2H), 4.85 (s, 1H), 4.71 (dd,J = 17.0, 10.8 Hz, 3H), 4.60 (s, 1H), 4.45 (s, 1H), 4.32 - 4.25 (m, 1H), 4.01 (d,J = 29.4 Hz, 2H), 3.09 (s, 1H), 2.99 (s, 1H), 2.79 (s, 1H), 2.65 (s, 1H), 2.52 (s, 1H), 2.36 (s, 2H), 1.85 (s, 4H).

[0336] Example 20: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole e-6-carboxylic acid (compound 20) [ka] Compound 20, i.e., PF06882961, was prepared according to the preparation method described in WO2018109607A1.

[0337] Biological assays Experimental Example 1 - GLP-1R Agonist Activity Assay (1) Test equipment and reagents [Table 1]

[0338] (2) GLP-1R Kit GLP-1R-mediated agonist activity was measured in a cell-based assay using a homogeneous time-resolved fluorescence (i.e., HTRF)-based cAMP detection kit that measures intracellular cAMP levels. This method is a competitive immunoassay, allowing direct pharmacological characterization of compounds acting on Gs-coupled receptors in adherent or suspension cells.

[0339] A standard curve of native cAMP or unlabeled cAMP produced by cells competed with d2-labeled cAMP Red receptor binding to the monoclonal anti-cAMP Eu3+ cryptate donor, and the specific signal was inversely proportional to the cAMP concentration in the standard or test samples.

[0340] 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 the expression of GFP observed under a fluorescent microscope.

[0341] (3) Cultivation of GLP-1R-GFP-293A cells 293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat # 900-108), 1% Pen-3Trep (Sangom Biotech Cat # E607011-0100)] in a humidified incubator at 37°C with 5% CO2.

[0342] (4) cAMP Level Test Method Different concentrations of test compounds (in DMSO) were diluted 1:5 with distilled water in stimulation buffer and 500 μM 3-isobutyl-1-methylxanthine (IBMX; Meilunbiocat # MB5226) was added to obtain a 2x working solution of compound, which was then added in 5 μL to a white 384-well assay plate (Corning 3824) using a multichannel pipette. The final DMSO concentration in the buffer mixture was 1‰.

[0343] Cells were collected from T25 tissue culture flasks and centrifuged at 1000 rpm for 5 min at room temperature. The cell pellet was resuspended in 1 mL of stimulation buffer. A 20 μL sample of the cell suspension was counted in a STAR IC 1000 counter to determine cell viability and cell number per mL. The remaining cell suspension was adjusted with stimulation buffer using a multichannel pipette to obtain 2000 viable cells per well. 5 μL of cell suspension was added to each well of the plate already containing the compound. The plate was sealed and incubated at 37°C, 5% CO2 for 30 min.

[0344] After 30 min of incubation, 5 μL of d2-labeled cAMP and 5 μL of anti-cAMP cryptate (both diluted 1:20 in cell lysis buffer) were added to each well of the plate. The plate was then incubated for 60 min at room temperature and the change in HTRF signal was read on a Tecan Spark reader: absorbance values ​​at 340 nm (excitation) / 615 nm and 665 nm (emission). Raw data were converted to nM cAMP by interpolation from the cAMP standard curve and the effect was calculated as a percentage relative to a saturating concentration (400 nM) of the full agonist GLP-17-37 included in each plate. EC50 determinations were made based on the dose-response curves of the agonists and analyzed using a four-parameter logistic dose-response equation with a curve-fitting program.

[0345] This test proves that the compounds of the present disclosure activate GLP-1R signal transduction through cAMP pathway, and thus act as GLP-1R agonists.Test data shows the results in the form of geometric mean (EC50) based on the number of repetitions.

[0346] [Table 2]

[0347] Experimental Example 2 - hERG Potassium Channel Inhibition Test 1. Experimental materials: stable cell line HEK-hERG, lineage: HEK 293, source: Academy of Military Medical Sciences; [Table 3]

[0348] 2. Electrophysiological solutions Extracellular solution (mM): N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, NaCl 145, KCl 4, CaCl 2 2, MgCl 2 1, glucose 10; pH adjusted to 7.3-7.4 with sodium hydroxide; osmolality adjusted to 290-310 mOsm; filtered and stored at 4 °C.

[0349] Pipette 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; osmolarity adjusted to 290-310 mOsm; filter, fill, and store at -20 °C.

[0350] 3. Positive control compounds Positive control: amitriptyline hydrochloride or terfenadine Source: Sigma-Aldrich

[0351] 4. Preparation of Dosage Formulations Preparation of solvent control: A certain amount of DMSO was added to the extracellular solution to achieve the same DMSO content as the final test solution (if the DMSO contents of the test solutions differed, the maximum DMSO content was given priority) to exclude interference of DMSO with the cell's self-current.

[0352] Test sample preparation: The 10 mM stock solution above was prepared into a DMSO stock solution of the desired concentration (typically 1000 / 3 times the actual dosing concentration), which was finally diluted with extracellular fluid to the desired dosing concentration required for the experiment.

[0353] Preparation of positive control solution: Weigh out an appropriate amount of positive control compound and place it in a suitable container, then add a certain amount of DMSO and stir or shake extensively to dissolve all positive control compounds, prepare a 10 mM stock solution, and proportionally prepare a stock solution of the desired concentration. The resulting solution was finally diluted with extracellular fluid to the required administration concentration for the experiment.

[0354] Before using the solutions at the working concentrations, the presence or absence of precipitation was checked. If precipitation occurred, the stock solution was diluted to increase the final concentration of DMSO in the extracellular solution, but the final concentration of DMSO in the extracellular solution did not exceed 0.5%. Continuous perfusion from low to high concentrations was adopted in the experiment. After the experiment was completed, the remaining administration solutions of the test samples and positive control were treated as waste liquid.

[0355] 5. Experimental Protocol 1. Preparation of Cells After subculture of HEK-293-hERG cells to the appropriate condition, the cells were washed with PBS (or DPBS), digested and isolated with Tryple solution, then resuspended in medium and stored in a centrifuge tube. After centrifugation, the supernatant was discarded, and the cells were resuspended in extracellular solution for later use and stored at 2-8 °C. Before patch clamp recording, the cells were dropped onto a culture dish to ensure that the cells had a certain density and were isolated from each other.

[0356] Density Settings [Table 4]

[0357] Electrophysiological testing hERG currents were recorded using the whole-cell patch clamp technique. The cell suspension was added to a small petri dish and placed on the stage of an inverted microscope. After attachment, the cells were perfused with extracellular fluid at the recommended flow rate of 1-2 mL / min. Glass microelectrodes were prepared by two-stage pulling using a microelectrode puller, and the underwater resistance after filling the electrode with the internal solution was 2-5 MΩ.

[0358] After setting up the whole-cell recording mode, the clamp potential was maintained at -80 mV. A depolarizing voltage was applied to +60 mV for 850 ms, followed by a repolarization to -50 mV for 1275 ms to induce hERG tail currents. This series of pulse programming was repeated every 15 s throughout the experiment.

[0359] After the current was stabilized, an administration mode with extracellular continuous perfusion from low to high concentration was applied. Starting with a low concentration, perfusion was continued until the effect was stabilized, followed by perfusion with the next concentration. In this experiment, the blocking effect of test samples and positive controls on hERG tail currents was tested (N ≥ 2); the actual concentrations could be adjusted according to the actual solubility and effect and were not considered as deviations from the protocol.

[0360] Stable efficacy was defined as when the change in current value during the last five stimulations at each concentration was less than 10% of the average value (when the current value was 200 pA or more) or less than 30% (when the current value was less than 200 pA). If the change was unstable, the data for that concentration was not used.

[0361] 6. Data Analysis In data processing, the peak value and baseline of tail current were corrected when determining the blocking effect on hERG. The inhibition ratio (IR) of tail current was used to express the effect of compounds at different concentrations. SD≦15 of %IR of all cells at various concentrations was considered as the acceptable standard (abnormal data excluded).

[0362] IR = 100% × (peak value of tail current before administration - peak value of tail current after administration) / peak value of tail current before administration.

[0363] 7. Experimental Results [Table 5]

[0364] 8. Experimental conclusion: Compound 1 showed no hERG inhibitory activity and was highly safe.

[0365] Experimental Example 3 - Metabolic stability in (human) liver microsomes 1. Experimental design: Test concentration: 1 μM; Control compound: testosterone; Incubation conditions: 37 °C for 0, 5, 15, 30, and 45 min; Measurement method: LC-MS / MS; Calculation method: T 1 / 2 = 0.693 / K, where K is the rate constant for the ln[concentration] vs incubation time profile, Cl int =(0.693 / T 1 / 2 ) × (1 / (microsomal protein concentration (0.5 mg / mL))) × scaling factor.

[0366] Scaling factors for predicting intrinsic clearance in human microsomes are shown in the table below: [Table 6]

[0367] 2. Experimental procedure: 1. Pre-warm 0.1K-buffer, 5nM MgCl2, pH=7.4; 2. Test solutions of test compounds and reference compounds, 500μM spike solution: 5μL of 10mM stock solution was added to 95μL ACN; 1.5μM spike solution of microsomes (0.75Mg / mL): 1.5μL of 500μM spike solution and 18.75μL of 20Mg / mL liver microsomes were added to 479.75μL K / Mg buffer; 3. Prepare 3×NADPH stock solution (6mM, 5mg / mL) by dissolving NADPH in buffer; 4. Distribute 30μL of 1.5μM spike solution containing 0.75mg / mL microsome solution to designated plates at different time points (0min, 5min, 15min, 30min, 45min); 5. At 0min, add IS to ACN containing IS. 150 μL was added to the wells 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 min; 7. 15 μL of NADPH stock solution was added to the plate to start the reaction and time it; 8. 150 μL of ACN with IS was added to the corresponding plate wells to stop the reaction at 5 min, 15 min, 30 min, and 45 min, respectively; 9. After quenching, the plate was shaken on a shaker (600 rpm / min) for 10 min and centrifuged at 6000 rpm for 15 min; 10. 80 μL of supernatant was transferred from each well to a 96-well sample plate containing 140 μL of water for LC / MS analysis.

[0368] 3. Analysis method Detection method: LC-MS / MS-11(8050), internal standard: tolbutamide; MS conditions: positive ion ESI for testosterone and test compounds, negative ion ESI for tolbutamide; 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 1.8 um 2.1*50 mm.

[0369] [Table 7]

[0370] 4. Experimental results (human microsomes): [Table 8]

[0371] 5. Experimental Conclusion: Compounds 1-3, 7, 11 and 12-B showed good stability in liver microsomes.

[0372] Experimental Example 4 - Caco-2 cell transport experiment 1. Experimental Materials Caco-2 cells, passage 77; HBSS, Lot:G210713; ACN + IS (tolbutamide 200ng / mL);

[0373] 2. Cell culture: Caco-2 was grown in 96-well Falcon plates on polyethylene terephthalate (PET) at 2 × 105 cells / cm 2 The cells were seeded in 100 mL of 1000 mM NaCl until a confluent cell monolayer was formed on days 21 to 28. The medium was changed every 3–4 days.

[0374] 3. Experimental Protocol: Test compounds were diluted from 10 mM stock solutions to a concentration of 10 uM in transport buffer (HBSS without BSA) and applied to the apical or basolateral side of the cell monolayer. Incubation was performed for 120 min at 37°C, 5% CO2, and 95% relative humidity, and permeability of test compounds from A to B or B to A was measured in duplicate. Efflux rates of each compound were measured. Test and reference compounds were quantified by LC-MS / MS analysis based on analyte / IS peak area ratios.

[0375] 4. Experimental Determination: The apparent permeability coefficient Papp (cm / s) was calculated by the following formula: Papp=(dCr / dt) x Vr / (A×C0), where dCr / dt was the cumulative concentration of the compound in the recipient chamber, which was a function of time (S); Vr was the volume of the solution in the recipient chamber (apical: 0.1 mL, basolateral: 0.25 mL), and A was the surface area for transport, i.e., the area of ​​the monolayer, 0.0804 cm. 2 where C0 is the initial concentration in the donor chamber; The flux ratio was calculated using the following formula: Outflow ratio=Papp (BA) / Papp (AB); The recovery rate was calculated by the following formula: Recovery rate = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x C0) Total recovery rate = 100 × [(Vr × Cr) + (Vd × Cd) + (Vc × Cc)] / (Vd × C0), Here, Vd is the volume in the donor chamber (apical side: 0.1 mL, basolateral side: 0.25 mL), Cd and Cr are the final concentrations of the transported compound in the donor and recipient chambers, respectively, Cc is the compound concentration in the cell lysate, and Vc is the volume of the inserted well (0.1 mL in this experiment).

[0376] 5. LC / MS conditions: Detection method: LC-MS / MS-20 (TQ-6500+) & LC-MS / MS-11 (8050); Internal standard: Tolbutamide; MS conditions: Atenolol, Propranolol and test compounds positive ion ESI, Digoxin 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 1.8 um 2.1*50 mm.

[0377] [Table 9]

[0378] 6. Experimental results: [Table 10]

[0379] 7. Conclusion of the experiment The compounds of the present invention were well absorbed in the intestinal tract.

[0380] Experimental example 5: Toxicity experiment using mice Experimental Objective: Compound 1 and Compound 20 (control compound) were repeatedly administered by gavage to ICR mice for 14 days to evaluate the toxicity and toxicokinetics.

[0381] Experimental method: 212 ICR mice (SPF grade) (half male and half female). Groups 1-5 were used for toxicity testing, with 10 males and 10 females in each group; groups 6-9 were used for toxicokinetics testing, with 14 males and 14 females in each group (2 of which were reserve animals). Groups 1-5 were vehicle control (0 mg / kg), compound 1 at doses of 50 mg / kg, 100 mg / kg, and 200 mg / kg, and control compound at doses of 200 mg / kg, respectively, and groups 6-9 were dosed in the same manner as groups 2-5. Groups 1-9 were orally dosed once daily for 14 consecutive days.

[0382] Experimental Observations: In the toxicity study, two male animals (2 / 10) in the 200 mg / kg compound 20 group were confirmed to have died on the 5th and 12th days, respectively. In the toxicokinetic study, one female animal (1 / 14) in the 200 mg / kg compound 1 group was confirmed to have died on the 3rd day, and four male animals (4 / 14) in the 200 mg / kg compound 20 group were confirmed to have died on the 11th, 3rd, 3rd, and 4th days, respectively. The remaining animals survived until the end of the experiment. In the toxicity study, animals in the group administered 100 mg / kg compound 1 occasionally showed gait abnormalities, reduced activity, hair erection, and traumatic abnormalities presumed to be mechanical injuries, which were unrelated to the test compound 1. The other abnormalities were unrelated to the test article, as they were not dose-related and symptoms were reversible. In toxicity and toxicokinetic studies, decreased activity, pilonidal ectopic eczema, cold skin to the touch, arched posture, and prone posture were frequently observed in animals treated with 200 mg / kg compound 20. Serum biochemical analysis showed no significant toxicological changes related to compound 1 compared to vehicle controls. The increase in TBIL in the 200 mg / kg compound 20 group was considered to be related to compound 20.

[0383] Experimental results: Systemic exposure AUC of Compound 1 at 200 mg / kg in plasma of male animals on day 14 (0-t) , AUC (0-∞) and C max were 218148.74h*ng / mL, 199768.76h*ng / mL, and 81039.97ng / mL, respectively. In addition, the systemic exposure AUC (0-t) , AUC (0-∞) and C max were 291010.82h*ng / mL, 270696.18h*ng / mL, and 117480.84ng / mL, respectively. At the same time, the systemic exposure AUC of 200 mg / kg compound 20 in the plasma of male animals on day 14 was (0-t) , AUC (0-∞) and C maxwere 387293.58h*ng / mL, 253720.92h*ng / mL, and 91002.30ng / mL, respectively. In addition, the systemic exposure AUC of 200 mg / kg compound 20 in the plasma of female animals on day 14 was (0-t) , AUC (0-∞) and C max were 338,426.01 h*ng / mL, 331,124.48 h*ng / mL, and 104,210.33 ng / mL, respectively.

[0384] Experimental conclusion: Compound 1 and compound 20 were orally administered to ICR mice once a day for 14 consecutive days, and the non-toxic response dose level of compound 1 was 200mg / kg, and the non-toxic response dose level of compound 20 was less than 200mg / kg. That is, compound 1 had no significant toxicological effects on experimental animals at this investigated dose, and had a high safe dose level (high maximum tolerated dose). Compound 1 is safer than compound 20.

[0385] Experiment 6: Pharmacokinetics experiment using cynomolgus monkeys Experimental Objective: To evaluate the pharmacokinetic profile of Compound 1 and compare it with Compound 20 (reference compound).

[0386] Experimental Methods: Six male non-juvenile cynomolgus monkeys weighing 4-5 kg ​​were purchased from Huazheng Experimental Animal Center. The IV group was intravenously administered 2 mg / kg (5 mL / kg) (n=3), and the PO group was orally administered 20 mg / kg (10 mL / kg) (n=3). Approximately 500 μL of blood was collected from the cephalic and saphenous veins at each time point, centrifuged at 2,000 g for 5 min (4°C) within 15 min after collection, and used for subsequent analysis.

[0387] Test Results: [Table 11]

[0388] [Table 12]

[0389] [Table 13]

[0390] [Table 14]

[0391] Conclusion of the study: Compound 1 had a mean oral C max =12,657ng / mL, average AUC last = 34,538 and average F = 32.8%, it has good plasma binding rate and high oral bioavailability. The pharmacokinetic profile of compound 1 when administered orally is significantly better than that of the control compound 20.

[0392] In light of the foregoing, various modifications of the present invention in addition to those described herein are intended to fall within the scope of the appended claims. Each of the references cited in this application, including all patents, patent applications, journal articles, books, and other publications, is hereby incorporated by reference in its entirety.

Claims

1. Formula II: 【Chemical 1】 Wherein, [Chemical Formula 2] represents a single bond or a double bond; W is selected from O, N and NH; X 3 and X 4 are each independently selected from CH, N, and C; Y 1 is selected from CH and N; Y 2 is selected from CH, N, and C; Y 3 is selected from CH, N, and C; R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy, preferably selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy; R 2 is R z -C 1-3 alkylene-; R 4 is independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyano, hydroxy, amino, amide, sulfonyl and sulfonamide, preferably hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyano, hydroxy and amino, more preferably hydrogen; R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl; preferably, R 5 is independently selected from hydrogen and halogen; R 0 is independently selected from the group consisting of hydrogen, hydroxyl and halogen, preferably selected from hydrogen and halogen; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; When m is not 0 and p is not 0, any R 4 and any R 5 may combine with the ring atoms of ring B and ring C therebetween to form a 5- to 8-membered ring, where the 5- to 8-membered ring may be optionally substituted 1 to 3 times by C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo or C 1-3 alkoxy; R z is selected from cycloalkyl and 3- to 6-membered heterocyclyl, preferably C 3-6 is selected from cycloalkyl and 3- to 6-membered heterocycloalkyl having one or two heteroatoms independently selected from N, O and S, wherein R 3-6 is optionally substituted one to three times by C z alkyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen, cyano, oxo, C 1-3 alkoxy or 3- to 6-membered heterocyclyl] 1-3 optionally substituted one to three times by C a compound represented thereby or a pharmaceutically acceptable salt or stereoisomer thereof.

2. X 3 is CH, and X 4 is N; or X 3 is N, and X 4 is CH, or or X 3 and X 4 is N respectively; or Preferably, X 3 and X 4 are each CH, the compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

4. 【Fig. 3】 is 【Chemical Formula 4】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is.

5. R 2 is -CH 2 -R z The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from

6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W is O.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 1.

8. 【Fig. 5】 is [Chemical Formula 6] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is.

9. The compound has the structure of Formula II-1: 【Chemical Formula 7】 [wherein, X 3 , X 4 , Y 1 , Y 2 , Y 3 , R z , R 0 , R 1 , R 4 , R 5 , m and p are as defined in any one of claims 1 to 8]] ; Preferably, it has the structure of Formula II-2: 【Chemical 8】 [wherein, Y 1 , Y 2 , Y 3 , R z , R 0 , R 1 , R 4 , R 5 , m and p are as defined in any one of claims 1 to 8]] The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl and C 1-3 alkoxy, preferably independently selected from the group consisting of halogen and C 1-3 alkoxy, preferably F, Cl, CH 3 O-, CH 3 CH 2 -O-, CH 3 CH 2 CH 2 -O- or (CH 3 ) 2 CH - O-, and more preferably selected from the group consisting of F, Cl and CH 3 O-, the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. 【Chemical Formula 9】 is 【Chemical 10】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is.

12. R z is selected from cycloalkyl and 3- to 6-membered heterocycloalkyl having one or two heteroatoms independently selected from N, O, and S, where R 3-6 is optionally substituted once by C z alkyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen or cyano, preferably C 1-3 haloalkyl (preferably halomethyl), cyano-C 1-3 alkyl (preferably cyanomethyl) or halogen, and where halo or halogen is preferably F or Cl; R 1-3 is preferably z ​ 【Chemical 11】 selected from the group consisting of; more preferably, 【Chemical 12】 selected from the group consisting of; even more preferably, 【Chemical 13】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the group consisting of.

13. R2 is 【Chemical 14】 selected from the group consisting of. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. 【Fig. 15】 is 【Chemical 16】 selected from the group consisting of. The compound according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. Y 2 is C or CH; and / or Y 3 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is C or N.

16. Y 2 is CH, and Y 3 is N, p is 0, and 【Chemical 17】 is 【Chemical Formula 18】 or; Y 2 is C, and Y 3 is C, p is an integer of 1, 2 or 3, and 【Chemical 19】 is 【Chemical 20】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is.

17. Y 2 is CH, and Y 3 is N, p is 0, and 【Chemical 21】 is 【Chemical 22】 The compound according to claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, which is.

18. The compound has the structure of Formula II-3: 【Chemical 23】 [wherein, X 3 , X 4 , Y 1 , R z , R 0 , R 1 , R 4 and m are as defined in claim 1] ; Preferably, it has the structure of Formula II-4: 【Chemical 24】 [wherein, Y 1 , R z , R 0 , R 1 , R 4 and m are as defined in claim 1] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. R z is selected from unsubstituted 3- to 6-membered heterocycloalkyl (preferably 3- to 4-membered heterocycloalkyl) having 1 O heteroatom, preferably 【Chemical 25】 is; more preferably, 【Chemical 26】 is 【Chemical 27】 ; m is 0; R 1 is F, Cl, CH 3 O-, CH 3 CH 2 -O-, CH 3 CH 2 CH 2 -O- or (CH 3 ) 2 CH - O - and preferably is F, Cl or CH 3 O -; and R 0 The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 17 or 18, wherein R is hydrogen, F or Cl, preferably hydrogen or F.

20. R z is C 1-3 cycloalkyl optionally substituted by one substituent selected from the group consisting of haloalkyl (preferably halomethyl, more preferably -CFH 2 or -CClH 2 ), cyano-C 1-3 alkyl (preferably cyanomethyl) and halogen (preferably F or Cl), and is preferably 3-6 C 3-4 cycloalkyl (preferably C cycloalkyl), and preferably 【Chemical Formula 28】 is, and more preferably 【Chemical 29】 is; m is 0; R 1 is F, Cl, CH 3 O-, CH 3 CH 2 -O-, CH 3 CH 2 CH 2 -O- or (CH 3 ) 2 CH - O - and is preferably F or Cl; and R 0 The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 17 or 18, wherein R is hydrogen, F or Cl, preferably hydrogen.

21. Y 2 is C, and Y 3 is C, p is 1, and 【Chemical Formula 30】 is 【Chemical 31】 and preferably 【Chemical 32】 and wherein R 5 is a compound according to claim 16 or a pharmaceutically acceptable salt or stereoisomer thereof, which is in the ortho position of Y 3 ​

22. the compound has the structure of Formula II-5: 【Chemical 33】 [wherein, X 3 , X 4 , Y 1 , R z , R 0 , R 1 , R 4 , R 5 and m are as defined in claim 1] ; preferably, it has the structure of Formula II-6: 【Chemical 34】 [wherein, Y 1 , R z , R 0 , R 1 , R 4 , R 5 and m are as defined in claim 1] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. R 5 The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 21 or 22, wherein R is hydrogen or halogen, preferably F or Cl, more preferably F.

24. R 0 is hydrogen, F or Cl, preferably hydrogen; and / or Y 1 is N; and / or R 4 The compound according to any one of claims 21 or 22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is hydrogen.

25. When m is not 0 and p is not 0, any R 4 and any R 5 together with the ring atoms of ring B and ring C therebetween form a 5- to 8-membered ring, wherein the 5- to 8-membered ring independently has 0, 1 or 2 ring heteroatoms selected from N, O and S, the ring heteroatoms being not the ring atoms of ring B and ring C, and wherein the 5- to 8-membered ring, if valency permits, is C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy; Preferably, m is 1, p is 1, R 4 and R 5 together with the ring atoms of rings B and C therebetween form a 5- to 8-membered ring, wherein the 5- to 8-membered ring independently has 0, 1 or 2 ring heteroatoms selected from N, O and S, the ring heteroatoms are not ring atoms of rings B and C, and wherein the 5- to 8-membered ring, if valency permits, is C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 optionally substituted 1 to 3 times by alkoxy; More preferably, the compound has the structure of Formula II-7: 【Chemical 35】 [wherein Ring D: 【Chemical 36】 is a 5- to 8-membered ring; 【Chemical 37】 represents a single bond or a double bond; Y 1 , Y 2 and Y 3 are each as defined in claim 1; R y is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo and C 1-3 alkoxy; and r is 1, 2 or 3, preferably 1] ; Even more preferably, the compound has the structure of Formula II-8: 【Chemical 38】 [wherein, R y is preferably hydrogen] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

26. Ring D: 【Chemical 39】 is 【Chemical 40】 selected from the group consisting of preferably 【Chemical 41】 selected from the group consisting of More preferably 【Chemical 42】 The compound according to claim 25, or a pharmaceutically acceptable salt or stereoisomer thereof.

27. The compound has the structure of Formula II-9: 【Chemical 43】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

28. Y 3 is N; and / or Y 1 The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 25 to 27, wherein Y is N.

29. 【Fig. 44】 is 【Chemical 45】 selected from the group consisting of

30. R z is selected from unsubstituted 3- to 6-membered heterocycloalkyl having one O heteroatom (preferably 3- to 4-membered heterocycloalkyl), preferably 【Chemical Formula 46】 ; More preferably 【Chemical 47】 is 【Chemical 48】 ; R 1 is F, Cl, CH 3 O-, CH 3 CH 2 -O-, CH 3 CH 2 CH 2 -O- or (CH 3 ) 2 CH - O - and is preferably F or Cl; and R 0 The compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is hydrogen, F or Cl, preferably hydrogen.

31. 【Fig. 49】 【Chemical Formula 50】 The compound represented by Formula II according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

32. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

33. A medicament for treating GLP-1 receptor-mediated diseases or disorders and related diseases or disorders, comprising the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the GLP-1 receptor-mediated diseases or disorders and related diseases or disorders are preferably selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia and hyperinsulinemia.

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