Thienopyridine glp-1 receptor agonists and uses thereof

Abstract

A series of thiophene GLP-1 receptor agonist compounds are provided, along with their preparation methods and pharmaceutical uses. The compound (I) can be used to prepare treatments or prevent GLP-1-mediated diseases and related diseases.

Description

Technical Field

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

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

[0003] Currently, the main classes of drugs available for treating type 2 diabetes include: insulin secretagogues, metformin, alpha-glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin, and analogues. Among these, insulin and GLP-1 receptor agonists are among the most effective diabetes treatments. Insulin remains the most widely used diabetes medication globally, with approximately 30-40% of type 2 diabetes patients eventually requiring insulin. GLP-1 inhibitors, such as exenatide, liraglutide, and semaglutide, are suitable for type 2 diabetes patients whose blood sugar cannot be adequately controlled by combined use of metformin, sulfonylureas, and other antibiotics. However, current insulin and GLP-1 inhibitors are primarily peptide drugs and injectable formulations. Even oral semaglutide has several limitations in its use. Therefore, further development of small molecule GLP-1 receptor agonists is still necessary.

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

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

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

[0007] Documents WO2009111700A2 disclose a series of oxadiazepine GLP-1 receptor agonist compounds; WO2010114824A1 discloses a series of substituted azoanthracene GLP-1 receptor agonist compounds; WO2017078352A1 discloses a series of cyclohexene derivative GLP-1 receptor agonist compounds; KR1020180101671A discloses a series of heteroaryl-substituted pyridine [1,2-a] pizimidazole derivative GLP-1 receptor agonist compounds; WO2018056453A1 discloses a series of pyrazolopyridine derivative GLP-1 receptor agonist compounds; and WO2018109607A1 discloses a series of GLP-1 receptor agonist compounds similar to those in this application. Summary of the Invention

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

[0009]

[0010] and its pharmaceutically acceptable salts, of which

[0011] T1 and T2 are independently selected from CH2, NH, O, and S, respectively;

[0012] W1 is selected from O, S, CH2, and NH;

[0013] W2 is selected from O, NH, CH2, and CR. y ;

[0014] Z1, Z2, Z3, and Z4 are each independently selected from CH, N, or C;

[0015] X1, X2, and X3 are each independently selected from CH, N, or C, and at most two of X1, X2, and X3 are N;

[0016] Ring B is selected from a benzene ring or a 5- to 7-membered heteroaromatic ring;

[0017] The ring C is selected from benzene rings, 4-8 membered heterocycles, 5-10 membered spirocycles, 5-10 membered bridged rings, and 5-7 membered heteroaromatic rings;

[0018] R1 is independently selected from R2, -carbonyl-R2, -carbonyl-amino-R2, -sulfonyl-R2, -amido-R2, -oxophosphoryl-R2, -amino-R2, -O-R2, wherein R2, amino, amide, sulfonyl, and oxophosphoryl in R1 may optionally be independently selected from R x The substituents are substituted 1 to 3 times;

[0019] R2 is independently selected from hydrogen, oxo, halogen, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, -C 1～6 Cycloalkoxy, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-8 membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl in R2 may optionally be independently selected from R x The substituents are substituted 1 to 3 times;

[0020] R3 is independently selected from hydrogen, oxo, halogen, -CN, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, amino, amide, sulfonyl, sulfonamide, -OH, -C 3～8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-8 membered heteroaryl, wherein R3 may be optionally selected independently from R, provided that the valence allows. y The substituents are substituted 1 to 3 times;

[0021] R4 is independently selected from hydrogen, halogen, and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, -C 1～3 Alkoxy, cyano, hydroxy, amino, amide, sulfonyl, sulfonamide;

[0022] R5 is independently selected from hydrogen, halogen, hydroxyl, -CN, and -C. 1～3 Alkyl, -C 1～3 Alkoxy, -C 1～3 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group in R5 may optionally be derived from a halogen, hydroxyl group, or -NR, provided that the valence allows. z -CN, -C 1～3 Alkyl, -C1～3 Alkoxy, -C 1～3 Cycloalkyl substitution 1 to 3 times;

[0023] R6 is selected from -R z -OR z -SR z -C 1～3 Alkyl, -C 1～3 Alkylene-R z -C 0～3 alkylene-amino-R z -C 0～3 alkylene-carbonyl-R z -C 0～3 alkylene-amide-R z -C 0～3 alkylene-sulfonyl-R z -C 0～3 alkylene-phosphoryl-R z -C 0～3 alkylene-sulfonamide-R z The alkyl, amino, amide, sulfonyl, sulfonamide, and phosphoryl groups in R6 may optionally be substituted by halogens 1 to 3 times or by R6, provided that the valence allows. w Replace 1 time;

[0024] R7 is selected from -COOH, -C(R) y ) n0 -COOH, -N(R) z ) n0 -COOH, -SO2-COOH and -SO2-NH-COOH, wherein -C(R) y ) n0 -in R y It can be connected to C in the form of a main chain and / or a side chain, wherein -N(R) z ) n0 -in R z They can be connected to N in the form of a main chain and / or a branch chain, where n0 is an integer selected from 0, 1, or 2; when n0 is 2, the two R... y Or R z It can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

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

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

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

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

[0029] When n is greater than or equal to 2, any two R1s can be further cyclized into 3- to 8-membered carbon rings, aromatic rings, heterocycles, or aromatic-heterocyclic rings. The resulting carbon rings and heterocycles can be arbitrarily chosen from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, C 1～3 Alkoxy substitution 1 to 3 times;

[0030] When m is 2, the two R3s can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

[0031] When m is 1 or 2, R1 and R3 can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

[0032] When p is greater than or equal to 2, any two R5s can be further converted with the ring C to form a 6- to 10-membered helical ring or bridged ring. The resulting helical ring and bridged ring can be arbitrarily formed from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, C 1～3 Alkoxy substitution 1 to 3 times;

[0033] When o is not 0 and p is not 0, any R4 and R5 can be further cyclically transformed into 5- to 8-membered rings. The resulting rings can be arbitrarily composed of C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0034] R w Independently selected from -CN, -CH2CN, -C 1～3 Alkyl, -OH, -C 1～3 Alkoxy, amide, sulfonyl, sulfonamide, -NH2, -NH-C 1～3 Alkyl, wherein the R w The alkyl group in the compound may optionally be converted from C1 to C2, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0035] R x Independently selected from hydrogen, halogen, oxo, C 1～6 Alkoxy, cyano, hydroxy, carboxyl, amino, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R xThe alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 The alkoxy group is substituted 1 to 3 times or optionally substituted once with a hydroxyl group;

[0036] R y Independently selected from hydrogen, halogen, oxo, -C 1～3 Alkoxy, cyano, hydroxy, amino, carboxyl, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, wherein R y Alkyl, alkenyl, alkynyl, amino, amide, alkoxy, cycloalkyl, heterocyclic, and heteroaryl groups may optionally be derived from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0037] R z Independently selected from hydrogen and C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl, wherein R z Subject to the allowable valence, C can be arbitrarily selected. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 The alkoxy group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0038] As one specific implementation, ring B can be further selected from:

[0039] Among them, ring B is preferably

[0040] As one specific implementation, the ring C can be further selected from:

[0041] Where ring C is preferably

[0042] Furthermore, the present invention provides a series of compounds as shown in Formula I-2,

[0043]

[0044] and its pharmaceutically acceptable salts, of which

[0045] ------ indicates whether the key exists or does not exist;

[0046] Z1 and Z4 are independently selected from CH and N, respectively;

[0047] X1, X2, and X3 are each independently selected from CH, N, or C, and at most two of X1, X2, and X3 are N;

[0048] Y1 is selected from CH or N;

[0049] Y2 is selected from CH, N, or C;

[0050] Y3 is selected from CH or N;

[0051] R1 is independently selected from R2, -carbonyl-R2, -carbonyl-amino-R2, -sulfonyl-R2, -amido-R2, -oxophosphoryl-R2, -amino-R2, -O-R2, wherein R2, amino, amide, sulfonyl, and oxophosphoryl in R1 may optionally be independently selected from R x The substituents are substituted 1 to 3 times;

[0052] R2 is independently selected from hydrogen, oxo, halogen, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, -C 1～6 Cycloalkoxy, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-8 membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl in R2 may optionally be independently selected from R x The substituents are substituted 1 to 3 times;

[0053] R3 is independently selected from hydrogen, oxo, halogen, -CN, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 1～6 Alkoxy, amino, amide, sulfonyl, sulfonamide, -OH, -C 3～8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-8 membered heteroaryl, wherein R3 may be optionally selected independently from R, provided that the valence allows. y The substituents are substituted 1 to 3 times;

[0054] R4 is independently selected from hydrogen, halogen, and -C. 1～3 Alkyl, -C 1～3Halogenated alkyl, -C 1～3 Alkoxy, cyano, hydroxy, amino, amide, sulfonyl, sulfonamide;

[0055] R5 is independently selected from hydrogen, halogen, hydroxyl, -CN, and -C. 1～3 Alkyl, -C 1～3 Alkoxy, -C 1～3 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group in R5 may optionally be derived from a halogen, hydroxyl group, or -NR, provided that the valence allows. z -CN, -C 1～3 Alkyl, -C 1～3 Alkoxy, -C 1～3 Cycloalkyl substitution 1 to 3 times;

[0056] R6 is selected from -R z -OR z -SR z -C 1～3 Alkyl, -C 1～3 Alkylene-R z -C 0～3 alkylene-amino-R z -C 0～3 alkylene-carbonyl-R z -C 0～3 alkylene-amide-R z -C 0～3 alkylene-sulfonyl-R z -C 0～3 alkylene-phosphoryl-R z -C 0～3 alkylene-sulfonamide-R z The alkyl, amino, amide, sulfonyl, sulfonamide, and phosphoryl groups in R6 may optionally be substituted by halogens 1 to 3 times or by R6, provided that the valence allows. w Replace 1 time;

[0057] R7 is selected from -COOH, -C(R) y ) n0 -COOH, -N(R) z ) n0 -COOH, -SO2-COOH and -SO2-NH-COOH, wherein -C(R) y ) n0 -in R y It can be connected to C in the form of a main chain and / or a side chain, wherein -N(R) z ) n0 -in R z They can be connected to N in the form of a main chain and / or a branch chain, where n0 is an integer selected from 0, 1, or 2; when n0 is 2, the two R...y Or R z It can be further cyclized into 3- to 8-membered carbon rings or heterocycles;

[0058] n is an integer selected from 0, 1, 2 or 3;

[0059] o is an integer selected from 0, 1, 2, 3 or 4;

[0060] p is an integer selected from 0, 1, 2, 3 or 4;

[0061] When n is greater than or equal to 2, any two R1s can be further cyclized into 3- to 8-membered carbon rings, aromatic rings, heterocycles, or aromatic-heterocyclic rings. The resulting carbon rings and heterocycles can be arbitrarily chosen from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, C 1～3 Alkoxy substitution 1 to 3 times;

[0062] When p is greater than or equal to 2, any two R5s can be further converted with the ring C to form a 6- to 10-membered helical ring or bridged ring. The resulting helical ring and bridged ring can be arbitrarily formed from C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, C 1～3 Alkoxy substitution 1 to 3 times;

[0063] When o is not 0 and p is not 0, any R4 and R5 can be further cyclically transformed into 5- to 8-membered rings. The resulting rings can be arbitrarily composed of C, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, oxo, C 1～3 Alkoxy substitution 1 to 3 times;

[0064] R w Independently selected from -CN, -CH2CN, -C 1～3 Alkyl, -OH, -C 1～3 Alkoxy, amide, sulfonyl, sulfonamide, -NH2, -NH-C 1～3 Alkyl, wherein the R w The alkyl group in the compound may optionally be converted from C1 to C2, provided that the valence allows. 1～3 Alkyl, C 1～3 Halogenated alkyl, halogen, cyano, C 1～3 Alkoxy substitution 1 to 3 times;

[0065] R x Independently selected from hydrogen, halogen, oxo, C 1～6 Alkoxy, cyano, hydroxy, carboxyl, amino, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C2～6 alkynyl group, -C 3～6 cycloalkyl, 3-6 membered heterocyclic, 6-8 membered aryl, 5-8 membered heteroaryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted by halogens 1 to 3 times or by hydroxyl groups 0 to 1 time, provided that the valence allows.

[0066] R y Independently selected from hydrogen, halogen, oxo, -C 1～3 Alkoxy, cyano, hydroxy, amino, carboxyl, amide, sulfonyl, sulfonamide, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 3～6 cycloalkyl, 3- to 6-membered heterocyclic groups, wherein R y Alkyl, alkoxy, cycloalkyl, and heterocyclic groups may optionally be substituted with halogens 1 to 3 times, provided that the valence allows.

[0067] R z Independently selected from hydrogen and C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered aryl or 5-6 membered heteroaryl, wherein R z Halogens, cyano groups, and C groups can be used optionally, provided the oxidation state allows. 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 The cycloalkyl group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0068] As a specific implementation, when o is not 0 and p is not 0, any adjacent R4 and R5 can be further cyclically converted into 5- to 8-membered rings; the 5- to 8-membered rings include C 5～6 The rings formed by carbon rings, 5- to 8-membered heterocycles, benzene rings, and 5- to 8-membered heteroaromatic rings may be optionally substituted 1 to 3 times by alkyl, haloalkyl, halogen, cyano, or alkoxy groups, provided that the valence allows.

[0069] As a specific implementation, when o is not 0 and p is not 0, any adjacent R4 and R5 can be further cyclically formed into 5- to 8-membered rings, wherein the 5- to 8-membered rings can be selected from... The resulting 5- to 8-membered rings can be arbitrarily composed of C, provided that the oxidation state allows. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogen, cyano, oxo, C 1-3 Alkoxy substitution occurs 1 to 3 times.

[0070] As a specific implementation, when o is not 0 and p is not 0, any adjacent R4 and R5 can be further cyclically formed into a 5- to 8-membered ring, wherein the 5- to 8-membered ring is preferably: The resulting 5- to 8-membered rings can be arbitrarily composed of C, provided that the oxidation state allows. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogen, cyano, oxo, C 1-3 Alkoxy substitution occurs 1 to 3 times.

[0071] As a specific implementation, when o is not 0 and p is not 0, any adjacent R4 and R5 can be further cyclically formed into 5- to 8-membered rings, wherein the 5- to 8-membered rings can be selected from: The resulting 5- to 8-membered rings can be arbitrarily composed of C, provided that the oxidation state allows. 1-3 Alkyl, C 1-3 Halogenated alkyl, halogen, cyano, oxo, C 1-3 Alkoxy substitution occurs 1 to 3 times.

[0072] As a specific implementation method, structural unit Further selections can be made from:

[0073] As one specific implementation, the compound of formula I described in this invention may have the following general formula:

[0074]

[0075] In one specific implementation, n is selected from 1, 2 or 3.

[0076] In one specific implementation, p is selected from 0, 1, or 2.

[0077] In one specific implementation, R1 may be further independently selected from -F, -Cl, -CN, -OCH3, -OCH2CH3, -O-cyclopropyl, -CH3, -CH2CH3, -CH2CH2CH3, -(CH)2CH3, -COCH3, -CONH2, -CF3, -CHF2, -CH2F, -CH2CH2F, -CO-cyclopropyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl.

[0078] In one specific implementation, R3 may be further selected from -F, -Cl, -CH3, -OCH3, -NH2, -OH, -CH2CH3, -CH2OH, -NHCH3, -COCH3, -SO2CH3, -OCH2CH3, -CF3, -CHF2, -CH2F, isopropyl, cyclopropyl, and fluorocyclopropyl.

[0079] As one specific implementation method, the R y It can be further selected from -F, -Cl, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, methoxy, amino, hydroxy, propyl, isopropyl, cyclopropyl, and cyclobutyl.

[0080] As one specific implementation, the -C(R) of R7 y ) n0 R in -COOH y It can be connected to C as a main chain and / or a side chain; when R y When connected to C of R7 as a main chain, R y It exists in the form of the corresponding subunit; when R y When connected to C of R7 in the form of a branch, R y It exists in the form of the corresponding saturated radical.

[0081] As one specific implementation, the -N(R) of R7 z ) n0 R in -COOH z It can be connected to N in the form of a main chain and / or a side chain; when R z When connected to C of R7 as a main chain, R z It exists in the form of the corresponding subunit; when R y When connected to N of R7 in a branched manner, R z It exists in the form of the corresponding saturated radical.

[0082] As one specific implementation, the -C(R) of R7 y ) n R in -COOH y When it is methyl, "attached to C in the main chain form" means that... The structures are connected (i.e., R7 is -CH2- at this time), and the connection to C in the form of a branch refers to... The structures are connected (i.e., R7 is -CH3 at this time).

[0083] As one specific implementation, R6 is selected from -R z -OR z -SR z -C 1～3Alkylene-R z -C 0～3 alkylene-amino-R z -C 0～3 alkylene-carbonyl-R z The alkyl, amino, amide, sulfonyl, sulfonamide, and phosphoryl groups in R6 may optionally be substituted by halogens 1 to 3 times or by R6, provided that the valence allows. w Replace 1 time.

[0084] As one specific implementation method, the R z It can be further selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy. R z Halogens, cyano groups, and C groups can be used optionally, provided the oxidation state allows. 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 The cycloalkyl group or 3- to 6-membered heterocyclic group is substituted 1 to 3 times.

[0085] In one specific implementation, R1 may be further independently selected from -F, -Cl, -CN, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -COCH3, -CONH2, -CF3, -CHF2, -CH2F, -CH2CH2F, -CO-cyclopropyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl.

[0086] In one specific implementation, R2 may be further independently selected from -H, -CH3, -CHF2, -CH2F, -CF3, -CH2CH3, -CH2CH2F, -NH2, cyclopropyl, 5-6 membered heterocyclic group, and 5-6 membered heteroaryl.

[0087] In one specific implementation, R3 may be further selected from -F, -Cl, -CH3, -OCH3, -NH2, -OH, -CH2CH3, -CH2OH, -NHCH3, -COCH3, -SO2CH3, -OCH2CH3, -CF3, -CHF2, -CH2F, isopropyl, cyclopropyl, and fluorocyclopropyl.

[0088] As a specific implementation, R4 may be further selected from -CN, -CH3, -OH, -CH2OH, -CH2OCH3, -OCH3, -NH2, -NHCH3, -COCH3, and -OCH2CH3.

[0089] In one specific implementation, R5 is selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2OH, -OH, -CH2OCH3, -OCH3, -CH2CH2OH, -CH2CH2OCH3, isopropyl or cyclopropyl.

[0090] As one specific implementation, the R7 is selected from -COOH, -CH2COOH, -CH2CH2COOH, and -CH(CH3)COOH, wherein the R7 may optionally be substituted by a halogen 1 to 3 times, provided that the valence allows.

[0091] As one specific embodiment, the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:

[0092]

[0093] And its pharmaceutically acceptable salts.

[0094] As one specific embodiment, the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:

[0095]

[0096] And its pharmaceutically acceptable salts.

[0097] The compounds provided by this invention and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in treatment.

[0098] The present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.

[0099] The present invention also provides a pharmaceutical preparation comprising a compound of formula I and a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers; the pharmaceutical preparation is any clinically acceptable dosage form.

[0100] The compounds and pharmaceutically acceptable salts provided by this invention can be formulated into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated tablets, granules, powders, ointments, creams, drops, etc.; the compounds and pharmaceutically acceptable salts provided by this invention can be formulated into liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, suspensions, solutions, sprays, etc.

[0101] The pharmaceutical carriers and / or pharmaceutical diluents that can be used in the pharmaceutical compositions or pharmaceutical preparations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical preparations.

[0102] The pharmaceutically acceptable salts described in this invention include acid-value salts and basic salts.

[0103] The pharmaceutically acceptable salts described in this invention can exist in both non-solventized and solvated forms.

[0104] The present invention also provides the use of compounds as shown in Formula I and pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or metabolic-related diseases. The metabolic-related diseases include GLP-1-mediated diseases and related diseases, including but not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, etc.; wherein the diabetes includes, but is not limited to, type 1 diabetes mellitus (T1D) and / or type 2 diabetes mellitus (T2DM), idiopathic T1D, early-onset T2D, latent autoimmune diabetes mellitus, juvenile atypical diabetes mellitus, gestational diabetes mellitus, etc.

[0105] The present invention also provides a method for treating a disease, comprising administering to a patient in need a therapeutically effective amount of a compound as shown in Formula I and a pharmaceutically acceptable salt thereof, wherein the disease is a GLP-1 mediated disease or related disease; the disease includes, but is not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, etc.; wherein the diabetes includes, but is not limited to, type 1 diabetes mellitus (T1D) and / or type 2 diabetes mellitus (T2DM), idiopathic T1D, early-onset T2D, latent autoimmune diabetes mellitus, juvenile atypical diabetes mellitus, gestational diabetes mellitus, etc.

[0106] The compounds shown in Formula I and their pharmaceutically acceptable salts provided by this invention have excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1-mediated diseases and related diseases.

[0107] The compounds shown in Formula I and their pharmaceutically acceptable salts provided by this invention have excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1-mediated diseases and related diseases.

[0108] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of GLP-1 receptor agonist-related drugs.

[0109] In some embodiments of the present invention, the GLP-1 receptor agonist-related drugs are used to treat type II diabetes, type I diabetes, and obesity.

[0110] The compounds described in this invention are named according to their chemical structural formulas. If the name of the compound does not match the chemical structural formula when referring to the same compound, the chemical structural formula shall prevail.

[0111] Unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0112] The compounds and pharmaceutically acceptable salts provided by this invention may exist in chiral forms, i.e., S-configuration or R-configuration. The compounds and pharmaceutically acceptable salts provided by this invention may also exist in achiral forms. When the compounds described in this invention are illustrated with one configuration, it also indicates the disclosure of another configuration or achiral form.

[0113] The compounds described in this invention include stereoisomers of the compounds. The stereoisomers described in this invention refer to the following: when a compound as shown in Formula I contains an asymmetric carbon atom, it produces an enantiomer; when the compound contains a carbon-carbon double bond or a cyclic structure, it produces a cis-trans isomer; when the compound contains a ketone or oxime, it produces a tautomer. As a specific embodiment, the stereoisomers described in this invention include, but are not limited to: enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0114] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0115] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0116] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0117] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0118] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0119] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key This indicates that the center of the solid is an absolute configuration, but it is uncertain whether it is a wedge-shaped solid line key. or wedge-shaped dashed key Use wavy lines Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0120] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amine) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to form carbamates).

[0121] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0122] The term "pharmaceutically acceptable" in this invention means that, with respect to those compounds, materials, compositions and / or dosage forms, they are suitable for use in contact with human and animal tissues, within the limits of reliable medical judgment, without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0123] The term "pharmaceutically acceptable salt" in this invention refers to a salt of a compound of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When a compound of this invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When a compound of this invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0124] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0125] The term "optional" or "optionally" in this invention refers to an event or condition that may, but is not required, to occur as described below, and the description includes both cases where said event or condition occurs and cases where said event or condition does not occur.

[0126] The term "substituted" in this invention means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0127] The term "optionally replaced" in this invention refers to both "replaced" and "not replaced" scenarios.

[0128] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0129] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0130] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0131] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0132] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0133] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond to any atom on that ring, for example, a structural unit. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0134] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0135] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0136] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0137] In this invention, the term "halogen atom" refers to fluorine, chlorine, bromine, iodine, etc. Preferably, the halogen atom used as a substituent in the aryl group of this invention is a fluorine or chlorine atom. Preferably, the halogen atom used as a substituent in the alkyl group of this invention is a fluorine or chlorine atom. C having a halogen atom as a substituent... 1-6Alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, and 6,6,6-trifluorohexyl.

[0138] The term "C" in this invention 1～6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0139] The term "C" in this invention 1～6 "Alkoxy" refers to the carbon group. 1-6 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, and 2-ethylbutoxy.

[0140] In this invention, the term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a three-membered nitrogen-containing fused ring containing a benzene ring.

[0141] The term "heteroaryl" in this invention refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0142]

[0143] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0144] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" in this invention are used interchangeably. The term "5-6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0145] The term "alkoxy" in this invention refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester groups.

[0146] The term "halogenated alkyl" in this invention refers to an alkyl group that has been substituted with one or more halogens.

[0147] The term "3- to 8-membered heterocyclic group" in this invention refers to a non-aromatic cyclic group comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and may be fully saturated or partially unsaturated. The ring may be a 3- to 8-membered monocyclic, bicyclic, or spirocyclic group. Examples include, but are not limited to, oxacyclobutane, aziranebutane, piperazine, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, thiohexane, oxacyclohexane, thiazoxane, dihydroindolyl, isodihydroindolyl, tetrahydrodihydroindolyl, quininecycloyl, and azirzoyl.

[0148] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0149] The term "C" in this invention 3～8 "Cycloalkyl" refers to a monovalent group obtained by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons; that is, a cycloalkyl group with 3 to 8 carbons. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two groups together form a C12 group... 3～8 When cycloalkyl groups are formed, the resulting group can be divalent, such as cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl. Furthermore, the cycloalkane ring, carbide ring, and cyclohydrocarbon in cycloalkyl groups can be cross-linked rings.

[0150] The term "fused ring" in this invention refers to a 5- to 20-membered all-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Fused rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, fused rings can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. These include, but are not limited to:

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

[0152] The term "fused heterocycle" in this invention refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, and wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). t (Where t is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. The fused heterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, the fused heterocycle can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycle groups, preferably bicyclic or tricyclic, more preferably 5-membered / 3-membered, 5-membered / 4-membered, or 5-membered / 5-membered bicyclic fused heterocycle groups. Fused heterocycles include, but are not limited to:

[0153] The term "bridged ring" in this invention refers to a 5- to 20-membered all-carbon polycyclic group, wherein any two rings share two non-directly connected carbon atoms. The bridged ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Bridged rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Bridged rings include, but are not limited to:

[0154]

[0155] The carbon atom in the bridged ring can be optionally replaced by heteroatoms of O, S, or N, which also includes "bridged heterocycles".

[0156] The term "bridged heterocycle" in this invention refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. The bridged heterocycle may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. The bridging heterocycle is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, bridging heterocycles can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocycles, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Bridging heterocycles include, but are not limited to:

[0157]

[0158] The term "spirocyclic" in this invention refers to a 5- to 20-membered polycyclic group, wherein the monocyclic rings share a carbon atom (called a spiro atom), and the spirocyclic ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spirocyclic rings are preferably 6- to 14-membered, more preferably 7- to 10-membered. Spirocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups according to the number of shared spiro atoms between the rings, preferably monospirocyclic alkyl groups and bispirocyclic alkyl groups. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic alkyl groups are included, but are not limited to:

[0159] The carbon atom in a spiroring can be optionally replaced by heteroatoms of O, S, or N, which also includes "spiroheterorings".

[0160] In this invention, the term "spiroheterocycle" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein the monocyclic rings share a common atom (called a spiro atom), and one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Spiroheterocyclic rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic rings are preferably 6 to 14-membered, more preferably 7 to 10-membered. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiroatoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups are preferred. These include, but are not limited to:

[0161] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0162] The compounds described in this invention are named according to their chemical structural formulas. If the name of the compound does not match the chemical structural formula when referring to the same compound, the chemical structural formula shall prevail.

[0163] Unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail. Detailed Implementation

[0164] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are used to understand the methods and core ideas of the present invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention. Experimental methods in the embodiments of the present invention that do not specify specific conditions are generally under conventional conditions or according to the conditions recommended by the raw material or product manufacturer; reagents whose source is not specified are generally commercially available conventional reagents.

[0165] Experiment 1 - Compound Identification and Characterization

[0166] The present invention 1 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0167] The mass spectrometry of this invention is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0168]

[0169]

[0170]

[0171] Experiment 2 - Biological Testing Methods

[0172] (1) Testing instruments and reagents

[0173]

[0174]

[0175] (2) GLP-1R kit

[0176] GLP-1R-mediated agonist activity was determined using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit via a cell-based functional assay that measures cAMP levels in cells. This method is a competitive immunoassay. It enables the direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

[0177] The standard curve of naturally produced cAMP or unlabeled cAMP produced by cells competes with the red cAMP receptor labeled with d2 for binding to the monoclonal anti-cAMP cavitary compound europium donor. The specific signal is inversely proportional to the concentration of cAMP in the standard or experimental sample.

[0178] The human GLP-1R coding sequence (NCBI reference sequence NP_002053.3) was subcloned into pEGFP-N1 (tsingke), and cell lines stably expressing the receptor were isolated. The expression density of GLP-1R was confirmed by observing GFP expression under a fluorescence microscope.

[0179] (3) GLP-1R-GFP-293A cell culture

[0180] 293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), and 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100) and in a humidified incubator at 37°C with 5% CO2.

[0181] (4) cAMP level testing method

[0182] Different concentrations of each analyte (in DMSO) were diluted 1:5 in distilled water with stimulation buffer. 500 μM of 3-isobutyl-1-methylxanthin (IBMX; Meilunbiocat#MB5226) was added to obtain a 2X working solution. Then, 5 μL of the compound was added to a white 384-well assay plate (Corning 3824) using a multichannel pipette. The final DMSO concentration in the assay buffer mixture was 1‰.

[0183] Cells were collected from T25 tissue culture flasks and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 ml of stimulation buffer. A 20 μL sample of cell suspension was counted using a STAR IC1000 counter to determine cell viability and cell count per milliliter. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 live cells per well using a multichannel pipette. 5 μL of cell suspension was added to each well of an assay plate already containing the compound. The plate was sealed and incubated at 37°C with 5% CO2 for 30 minutes.

[0184] After 30 minutes of incubation, 5 μL of d2-labeled cAMP and 5 μL of anti-cAMP cavitation compound (both diluted 1:20 in cell lysis buffer) were added to each well of the assay plate. The plate was then incubated at room temperature, and after 60 minutes, changes in the HTRF signal were read using a Tecan Spark plate reader, measuring absorbance at 340 nm excitation and 615 nm emission. The raw data were converted to nM cAMP by interpolation from the cAMP standard curve, and the percentage effect was determined relative to the saturation concentration of the full agonist GLP-17-37 (400 nM) contained on each plate. EC 50 The determination was performed from agonist dose-response curves, which were analyzed using a curve fitting procedure with a 4-parameter logical dose-response equation.

[0185] This experiment demonstrates that the compound of the present invention activates GLP-1R signaling via the cAMP pathway, thus acting as a GLP-1R agonist. Experimental data are presented as the geometric mean (EC50) based on the number of repetitions listed. 50 The results are presented in the form of s).

[0186] Experimental results:

[0187]

[0188]

[0189] Experiment 3 - Inhibition of hERG potassium ion channels

[0190] 1. Experimental materials: Stable cell line HEK-hERG, strain: HEK 293, source: Academy of Military Medical Sciences;

[0191]

[0192] 2. Electrophysiological solutions

[0193] Extracellular fluid (mM): 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 145 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 10 Glucose. Adjust the pH to 7.3–7.4 with sodium hydroxide; adjust the osmotic pressure to 290–310 mOsm; filter and store at 4°C.

[0194] Electrode internal solution (mM): KCl 120, KOH 31.25, CaCl2 5.374, MgCl2 1.75, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 10, HEPES 10, Na2-ATP 4, pH adjusted to 7.2-7.3 with potassium hydroxide; osmotic pressure adjusted to 290-310 mOsm; filtered and dispensed, stored at -20℃.

[0195] 3. Positive control compound:

[0196] Positive control: Amitriptyline hydrochloride or terfenadine

[0197] Source: Sigma-Aldrich

[0198] 4. Preparation of drug delivery formulations

[0199] Solvent control preparation: Add a certain volume of DMSO to the extracellular fluid to make it contain the same amount of DMSO as the final test solution (if the test solution contains different amounts of DMSO, the maximum DMSO content shall prevail) to eliminate the interference of DMSO on the cell's own current.

[0200] Preparation of test sample: Prepare the above 10mM stock solution into DMSO stock solution of the required concentration according to the ratio (generally 1000 / 3 times the actual drug concentration). Finally, dilute the stock solution with extracellular fluid to the drug concentration required for the experiment.

[0201] Preparation of positive control solution: Weigh an appropriate amount of positive control sample and place it in a suitable container. Add a certain volume of DMSO and stir or shake thoroughly to dissolve it completely. Prepare a 10mM stock solution. Then prepare the stock solution of the required concentration according to the ratio. Finally, dilute the stock solution with extracellular fluid to the required drug concentration for the experiment.

[0202] Before using the working concentration solution, check for any precipitation. If precipitation occurs, dilute the stock solution to increase the final DMSO concentration in the extracellular fluid, but the final DMSO concentration in the extracellular fluid should not exceed 0.5%. Continuous perfusion from low to high concentrations is used in the experiment. After the experiment, any remaining test sample and positive control solutions are disposed of as waste.

[0203] 5. Experimental Design

[0204] Cell preparation:

[0205] After passage and culture HEK-293-hERG cells to a suitable state, wash the cells with PBS (or DPBS), digest and separate them with Tryple solution, resuspend the cells in culture medium, and store them in centrifuge tubes. After centrifugation, discard the supernatant, resuspend the cells in extracellular fluid, and store at 2-8°C. Before patch-clamp recording, add cells to a culture dish to ensure a certain cell density and that the cells are individually separated.

[0206] Concentration settings:

[0207] Compounds of the present invention 1、10 Amitriptyline or Terfenadine 1

[0208] Electrophysiological experiments:

[0209] hERG currents were recorded using whole-cell patch-clamp technique. Cell suspension was added to a small culture dish and placed on the stage of an inverted microscope. After cell attachment, the cells were perfused with extracellular fluid at a recommended flow rate of 1–2 mL / min. The glass microelectrode was fabricated in two steps using a microelectrode drawing instrument; after filling with electrode fluid, its water resistance was 2–5 MΩ.

[0210] After establishing the whole-cell recording mode, the clamping potential was maintained at -80 mV. A depolarization voltage of +60 mV was applied for 850 ms, followed by repolarization to -50 mV for 1275 ms to extract the hERG tail current. This pulse program was repeated every 15 seconds throughout the experiment.

[0211] After the current stabilizes, a continuous extracellular perfusion administration method is adopted, starting from low concentrations and gradually increasing to high concentrations. Perfusion is continued from a low concentration until the efficacy stabilizes, and then the next concentration is applied. This experiment will test the blocking effect of each test sample and the positive control on the hERG tail current (N≥2); the specific actual concentration can be adjusted according to the actual solubility and effect, and this is not considered a deviation from the protocol.

[0212] The definition of stable efficacy is: if the change in current value of the last 5 stimulation strips in each concentration administration phase is less than 10% of the mean (when the current is greater than or equal to 200 pA) or less than 30% of the mean (when the current is less than 200 pA), it can be considered stable. If it is unstable, the concentration data will not be used.

[0213] 6. Data Analysis

[0214] In data processing, when determining the blocking effect on hERG, the peak value of the tail current and its baseline were corrected. The effect of each compound at different concentrations was expressed as the tail current inhibition rate (IR). A SD ≤ 15 for the %IR at all cell concentrations was considered acceptable (except for outlier data).

[0215] IR = 100% × (peak tail current before administration - peak tail current after administration) / peak tail current before administration.

[0216] 7. Experimental Results:

[0217]

[0218] 8. Experimental conclusion: The compounds of this invention did not show hERG inhibitory activity.

[0219] Experiment 4 - (Human) Liver Microsomal Metabolic Stability

[0220] 1. Experimental Design: Concentration to be measured: 1 μM; Control compound: Testosterone; Culture conditions: Incubated at 37℃ for 0, 5, 15, 30, and 45 minutes; Assay method: LC-MS / MS; Calculation method: T 1 / 2 = 0.693 / K (K is the rate constant of ln[concentration] versus incubation time), Cl int =(0.693 / T) 1 / 2 )×(1 / (microsomal protein concentration (0.5mg / mL)))×proportional factor.

[0221] The following table shows the scaling factors for predicting intrinsic clearance in human microsomes:

[0222]

[0223] 2. Experimental Methods: 1. Preheat 0.1M K-buffer, 5nM MgCl2, pH=7.4; 2. Experimental solutions for the test compound and reference compound: 500μM additive solution: Add 5μL of 10mM stock solution to 95μL of... In ACN, the doping solution in 1.5 μM microsomes (0.75 mg / mL): Add 1.5 μL of 500 μM doping solution and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of K / Mg buffer; 3. 3× NADPH stock solution (6 mM, 5 mg / mL) is NADPH dissolved in buffer; 4. Dispense 30 μL of 1.5 μM doping solution containing 0.75 mg / mL microsomes to the assay plates designated for different time points (0, 5, 15, 30, 45 minutes); 5. At 0 minutes, add 150 μL of ACN containing IS to the wells of the plate, followed by 15 μL of NADPH stock solution (6 mM, step 3); 6. Pre-incubate all other plates at 37°C for 5 minutes; 7. Add 15 μL of NADPH stock solution to the plate. 8. Start the reaction and start timing with NADPH stock solution; 9. Terminate the reaction by adding 150 μL of ACN containing IS to the wells of the corresponding plate at 5, 15, 30 and 45 minutes; 10. After quenching, shake the plate on a shaker for 10 minutes (600 rpm / min) and then centrifuge at 6000 rpm for 15 minutes; 11. Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of water for LC / MS analysis.

[0224] 3. Analysis Methods:

[0225] Detection method: LC-MS / MS-11(8050), internal standard: tolbutamide, MS conditions: testosterone and analyte positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA in water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.

[0226] LC conditions:

[0227]

[0228] 4. Experimental Results (Human Microsomes):

[0229] 1 114.9 4 132.3 5 37.33 7 21.25 10 22.54 12 59.84

[0230] 5. Experimental Conclusion: The compound of this invention exhibits good stability in liver microsomes.

[0231] Preparation Examples

[0232] The intermediate reactants used in the preparation process were prepared according to the preparation method described in WO2018109607A1.

[0233] intermediate preparation method

[0234] The preparation method of intermediate Int-2,(S)-2-(chloromethyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester is as follows:

[0235]

[0236] (1) Preparation of compound 1-2C

[0237]

[0238] Me3SO4 was added in portions 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. + I - (335 g, 1520 mmol, 2.5 eq), after 30 minutes, (S)-2-((benzyloxy)methyl)ethylene oxide 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 another 13 hours. The mixture was cooled to room temperature and then filtered, and the filter cake was washed with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give (S)-2-((benzyloxy)methyl)oxetine, 1-2C (50.0 g, 46% yield).

[0239] 1 H NMR (400MHz, CDCl3) δ = 7.39–7.26 (m, 5H), 5.04–4.90 (m, 1H), 4.73–4.50 (m, 4H), 3.64 (qd, J = 11.0, 4.3Hz, 2H), 2.72–2.45 (m, 2H).

[0240] (2) Preparation of compounds 1-3C

[0241]

[0242] A solution of (S)-2-((benzyloxy)methyl)oxetane 1-2C (50 g, 280.9 mmol, 1.0 eq) and Pd / C (20 g, wet) in THF (200 mL) was stirred at 50 °C for 16 hours under H2 (4 MPa). The mixture was cooled to room temperature and then filtered, with the filter cake washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give (S)-oxetane-2-ylmethanol, 1-3C (28 g, crude product), which was used directly in the next step.

[0243] (3) Preparation of compounds 1-4C

[0244]

[0245] At 25 °C, TsCl (66.6 g, 349.6 mmol, 1.1 eq) and TEA (48.2 g, 476.7 mmol, 1.5 eq) were added to a THF (200 mL) solution of (S)-oxetane-2-ylmethanol 1-3C (28 g, 317.8 mmol, 1 eq). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel, eluting with (EA / PE = 0-10%) to give (S)-oxetane-2-ylmethyl 4-methylbenzenesulfonate, 1-4C (56 g, 72.7% yield).

[0246] 1 H NMR(400MHz, CDCl3)δ=7.85–7.79(m,2H),7.35(dd,J=8.6,0.6Hz,2H),5.00–4.83(m,1H),4.6 8–4.38(m,2H),4.16(d,J=4.0Hz,2H),2.78–2.64(m,1H),2.58(d,J=9.0Hz,1H),2.45(s,3H).

[0247] (4) Preparation of compounds 1-5C

[0248]

[0249] To a DMF (200 mL) solution of (S)-oxetane-2-ylmethyl-4-methylbenzenesulfonate 1-4C (56 g, 231 mmol, 1 eq), NaN3 (22.5 g, 346.7 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C for 12 hours. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give (S)-2-(azidomethyl)oxetane, 1-5C (20 g, crude product), which was used directly in the next step.

[0250] (5) Preparation of compounds 1-6C

[0251]

[0252] A solution of (S)-2-(azidomethyl)oxetane 1-5C (20 g, crude product) and Pd / C (8 g) in THF (100 mL) was stirred at 25 °C for 16 hours under H2 (15 Psi). The resulting mixture was filtered, and the filter cake was washed with THF (3 × 100 mL). The filtrate was directly concentrated to give (S)-oxetane-2-ylmethylamine, 1-6C (3.8 g, crude product).

[0253] 1 H NMR (400MHz, DMSO) δ = 4.60 (dq, J = 6.5, 5.2Hz, 1H), 4.52–4.43 (m, 1H), 4.40–4.30 (m ,1H),2.67(t,J=5.5Hz,2H),2.57–2.51(m,1H),2.38(ddt,J=10.8,9.0,7.0Hz,2H).

[0254] (6) Preparation of compounds 1-7C

[0255]

[0256] At 25 °C, methyl 3-fluoro-4-nitrobenzoate 1-6D (8.69 g, 43.6 mmol, 1.0 eq) and TEA (8.83 g, 87.2 mmol, 2 eq) were added to a THF (80 mL) solution of (S)-oxetane-2-ylmethylamine 1-6C (3.8 g, 43.6 mmol, 1 eq). The mixture was stirred at 40 °C for 6 hours. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography by elution with (EtOAc / petroleum ether = 0-80%) to give methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate, 1-7C (6.2 g, 53.4% ​​yield).

[0257] 1 H NMR (400MHz, CDCl3) δ = 8.36 (s, 1H), 8.23 ​​(d, J = 8.9Hz, 1H), 7.63 (d, J = 1.4Hz, 1H), 7.26 (dd, J = 8.8, 1.7Hz, 1H), 5.1 6(tt,J=7.4,4.5Hz,1H),4.81–4.55(m,2H),3.94(s,3H),3.71–3.55(m,2H),2.84–2.72(m,1H),2.70–2.52(m,1H).

[0258] (7) Preparation of compounds 1-8C

[0259]

[0260] A solution of methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate 1-7C (6.2 g, 23.3 mmol, 1.0 eq) and Pd / C (1.0 g, wet) in MeOH (100 mL) was stirred at 25 °C under H2 (1 atm) for 12 hours. The mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was directly concentrated to give methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate 1-8C (5.2 g, 94.5% yield).

[0261] LCMS: rt = 1.201 min, [M+1] + =237.1, purity: 89.7%.

[0262] (8) Preparation of compound Int-2

[0263]

[0264] Add 2-chloro-1,1,1-trimethoxyethane 1-8D (0.98 g, 6.35 mmol, 1.5 eq) and TsOH·H₂O (0.08 g, 0.423 mmol, 0.1 eq) to a THF (20 mL) solution of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate 1-8C (1.0 g, 4.23 mmol, 1 eq). Stir the mixture at 50 °C for 8 hours. Dilute the mixture with saturated sodium bicarbonate solution. Extract with NaHCO₃ (20 mL) and EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain the residue, which was purified by silica gel column chromatography and eluted with (EtOAc / petroleum ether = 0-80%) to give (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, Int-2 (1.1 g, 88% yield).

[0265] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=0.9Hz,1H),8.01(dd,J=8.5,1.5Hz,1H),7.79(d,J=8.5Hz,1H),5.21(ddd,J=9.6,7.3,2.7Hz,1H),5.03 (s,2H),4.69–4.45(m,3H),4.34(d,J=9.2Hz,1H),3.96(s,3H),2.76(dtd,J=11.5,8.1,6.0Hz,1H),2.42(ddt,J=11.5,9.2,7.3Hz,1H).

[0266] The preparation method of the intermediate Int-3,4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester is as follows:

[0267]

[0268] (1) Preparation of compound i-2A

[0269]

[0270] NaH was added to a mixture of 6-chloropyridin-2-ol i-1A (30.00 g, 231.58 mmol) and DMF (200 mL) at 0 °C. The reaction mixture was stirred with Ar2 at 0 °C for half an hour. Then BnBr (43.57 g, 254.74 mmol) was added to the above solution, and the mixture was stirred with Ar2 at room temperature for one hour. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated NaCl, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with (PE / EA = 0-20%) to give 2-(benzyloxy)-6-chloropyridine, i-2A (25 g, 47.18%).

[0271] 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m,3H),7.40–7.30(m,3H),6.91(dd,J=7.5,0.6Hz,1H),6.70(dd,J=8.2,0.6Hz,1H),5.36(s,2H).

[0272] (2) Preparation of compound i-4A

[0273]

[0274] Pd(dppf)Cl2 (8.25 g, 11.38 mmol) was added to a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate i-3A (35.19 g, 113.81 mmol), 6-chloropyridine-2-ol i-2A (25.00 g, 113.81 mmol), and Cs2CO3 (55.62 g, 170.71 mmol) in dioxane (200 mL). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was confirmed by LCMS, the mixture was concentrated to obtain the residue, which was purified by silica gel column chromatography and eluted with (EA / PE = 0-10%) to give tert-butyl 6-(benzyloxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid, i-4A (47.00 g, 59.9%).

[0275] LCMS: rt = 2.368 min, [M+1] + =367, purity: 75.78%.

[0276] (3) Preparation of compound Int-3

[0277]

[0278] Pd / C (4 g, wet) was added to a mixture of 6-(benzyloxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester i-4A (23 g, 62.76 mmol) in THF (200 mL). The mixture was stirred overnight with H2 at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (50 mL × 3). The combined filtrates were concentrated to give a residue, which was purified by silica gel column chromatography, eluting with (MeOH / DCM = 0–5%), to give 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester, Int-3 (9.2 g, 53%).

[0279] LCMS: rt = 0.94 min, [M-55] + =223, purity: 60%.

[0280] 1 H NMR (400MHz, CDCl3) δ11.32(s,1H),7.38(dd,J=9.1,6.9Hz,1H),6.42(d,J=8.5Hz,1H),6.03(d,J=6.8Hz,1H) ,4.25(s,2H),2.83(s,2H),2.61(dd,J=13.8,10.5Hz,1H),1.92(d,J=12.0Hz,2H),1.48(s,9H),1.25(s,2H).

[0281] The preparation method of intermediate Int-5,4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid is as follows:

[0282] (1) Preparation of compound i-2

[0283]

[0284] At 0 °C, NaH (0.26 g, 6.5 mmol, 1.3 eq) was added to a DMF (20 mL) solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate Int-3 (1.4 g, 5.0 mmol, 1 eq). The mixture was stirred at 0 °C for 30 min. Then, methyl 4-(bromomethyl)-3-fluorobenzoate Int-1 (1.6 g, 6.5 mmol, 1.3 eq) was added to the above solution, and the mixture was stirred at 25 °C for 2 h. TLC showed complete consumption of the starting material and the discovery of new spots. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with (PE / EA = 0-20%) to give tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylate i-2 (1.1 g, 50%).

[0285] 1 H NMR (400MHz, CDCl3) δ = 7.81 (dd, J = 8.0, 1.5Hz, 1H), 7.73 (dd, J = 10.4, 1.5Hz, 1H), 7.62–7.44 (m, 2H), 6.73 (d, J = 7.3Hz, 1H), 6.65 ( d,J=8.1Hz,1H),5.49(s,2H),4.20(s,1H),3.92(s,3H),2.77(d,J=43.3Hz,3H),2.05(s,1H),1.85(d,J=12.6Hz,2H),1.49(s,9H).

[0286] (2) Preparation of compound Int-5

[0287]

[0288] At 25 °C, LiOH (0.378 g, 15.7 mmol, 5.0 eq) in 10 mL of THF was added to a solution of tert-butyl 4-(6-((2-fluoro-4-(methoxycarbonyl)benzyl)oxy)pyridin-2-yl)piperidin-1-carboxylic acid tert-butyl ester i-2 (1.4 g, 3.15 mmol, 1 eq) in 10 mL of H2O. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with HCl (1 N). The reaction mixture was diluted with 100 mL of H2O and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid, Int-5 (0.47 g, 34.7% yield).

[0289] LCMS: rt=2.177min, [M+1]+=431.2, purity: 69.7%.

[0290] The preparation method of the intermediate Int-7,4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester is as follows:

[0291] (1) Preparation of compound Int-7

[0292]

[0293] A solution of 4-(((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzoic acid Int-5 (0.470 g, 1.09 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (0.214 g, 2.18 mmol, 2.0 eq), DIEA (0.564 g, 4.37 mmol, 4.0 eq), and HATU (0.623 g, 1.64 mmol, 1.5 eq) in DMF (6 mL) was stirred at 25 °C for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O (80 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EtOAc (3:1) to give tert-butyl 4-(6-((2-fluoro-4-(methoxy(methyl)aminoformyl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate, Int-7 (0.440 g, 85.4% yield).

[0294] LCMS: rt=2.262min, [M+1]+=474.3, purity: 98%.

[0295] Preparation method of intermediate Int-2A,(S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[0296]

[0297] To a solution of methyl 6-chloro-5-nitropyridinecarboxylate 2A-1 (2.2 g, 10.34 mmol) in 20 mL of THF, (S)-oxetane-2-ylmethylamine (900 mg, 10.34 mmol) and TEA (2.0 g, 20 mmol) were added. The reaction mixture was stirred at 40 °C for 16 hours under nitrogen. The reaction mixture was concentrated to a crude product, which was further purified by column chromatography (MeOH / DCM = 0-3%) to give methyl (S)-5-nitro-6-((oxetane-2-ylmethyl)amino)pyridinecarboxylate 2A-2 (1.2 g, 45%). Ethyl acetate was added to a 5 mL MeOH solution of the obtained 2A-2 (1.2 g, 4.49 mmol), and Pd / C (500 mg) was added. The mixture was stirred at room temperature for 16 hours under H2 atmosphere. The reaction mixture was further purified and concentrated by filtration to give crude (S)-5-amino-6-((oxetane-2-ylmethyl)amino)pyridinecarboxylate methyl ester 2A-3 (840 mg, 78.9%). 2-chloroacetic anhydride (667 mg, 3.9 mmol) was added to a solution of 2A-3 (840 mg, 3.54 mmol) in 10 mL of THF, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution, extracted with EA (40 mL × 3), washed with brine, and concentrated to give crude product. Further purification by column chromatography (PE / EA = 10-51%) yielded (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester, Int-2A (422 mg, 43%).

[0298] LCMS: rt = 1.694 min, [M+H] + =296, purity: 98%.

[0299] Example 1

[0300] (S)-2-((4-(6-((5-acetylthiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 1)

[0301]

[0302] (1) Preparation of compounds 1-2

[0303]

[0304] NBS (279 mg, 1.57 mmol) was added to a mixture of compound 1-1 (200 mg, 1.43 mmol) and BPO (7 mg, 0.03 mmol) in CCl4 (5 mL). The reaction solution was then stirred at 80 °C for 8 hours, followed by quenching of the reaction mixture with a saturated solution of Na2S2O3 (5 mL). The solution was extracted with water (20 mL) and DCM (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Treatment by rapid chromatography (SiO2, 20% EtOAc-hexane) yielded 1-(5-(bromomethyl)thiophene-2-yl)ethyl-1-one, compound 1-2 (260 mg, 83%).

[0305] 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 3.8Hz, 1H), 7.12 (d, J = 3.8Hz, 1H), 4.67 (s, 2H), 2.54 (s, 3H).

[0306] (2) Preparation of compounds 1-3

[0307]

[0308] A mixture of compounds 1-2 (2 g, 9.13 mmol), compound 1-2-1 (3.05 g, 10.95 mmol), and K₂CO₃ (2.52 g, 18.26 mmol) in DMF (30 mL) was stirred at 50 °C for 16 h. H₂O (100 mL) was added, and the reaction solution was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 25% EtOAc-hexane) yielded tert-butyl 4-(6-((5-acetylthiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylate, compound 1-3 (2 g, 53%).

[0309] 1H NMR (400MHz, CDCl3) δ7.58(d,J=3.8Hz,1H),7.52(dd,J=8.1,7.5Hz,1H),7.12(d,J=3.8Hz,1H),6.75(d,J=7.3Hz,1H),6.62(d,J=8.1 Hz,1H),5.56(s,2H),4.22(s,2H),2.92–2.69(m,3H),2.53(s,3H),1.90(d,J=13.5Hz,2H),1.74(qd,J=12.6,3.8Hz,2H),1.48(s,9H).

[0310] (3) Preparation of compounds 1-4

[0311]

[0312] HCl / dioxane (2 mL) was added to a solution of compounds 1-3 (45 mg, 0.11 mmol) in EtOAc (2 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated to obtain a solid. The solid was dissolved in H₂O (5 mL) using NaHCO₃. 3 (eq) Adjusted to pH > 7, extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated to give 1-(5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)thiophen-2-yl)ethane-1-one, compound 1-4 (20 mg, 58.8%).

[0313] 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=3.8Hz,1H),7.68–7.61(m,1H),7.29(d,J=3.8Hz,1H),6.88(d,J=7.0Hz,1H),6.66(d,J=8.2Hz, 1H),5.58(s,2H),3.01(d,J=9.4Hz,1H),2.80–2.52(m,4H),2.51(s,3H),1.77(d,J=11.6Hz,2H),1.69–1.52(m,2H),1.24(s,1H).

[0314] LCMS(ESI) m / z: 317.0 [M+H] + .

[0315] (4) Preparation of compounds 1-5

[0316]

[0317] K₂CO₃ (175 mg, 1.26 mmol) was added to a mixture of compounds 1-4 (100 mg, 0.32 mmol) and 1-4-1 (98.2 mg, 0.32 mmol) in dioxane (2 mL) and CH₃CN (1 mL). The mixture was stirred at 60 °C for 16 hours. Water (10 mL) was added, and the solution was extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. Rapid chromatography (silica gel, eluted with 0-10% MeOH / DCM) yielded (S)-2-((4-(6-(((5-acetylthiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compounds 1-5 (50 mg, 27.6%).

[0318] 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.97(d,J=8.7Hz,1H),7.75(d,J=8.5Hz,1H),7.56(d,J=3.8Hz,1H),7.51(t,J= 7.8Hz,1H),7.12(d,J=3.7Hz,1H),6.75(d,J=7.3Hz,1H),6.60(d,J=8.2Hz,1H),5.56(s,2H),5.27–5.19(m,1H),4. 74(qd,J=15.5,4.2Hz,2H),4.61(dd,J=14.0,7.8Hz,1H),4.40(dt,J=9.2,6.0Hz,1H),3.96(d,J=11.2Hz,5H),2.97 (d,J=15.4Hz,2H),2.88(s,1H),2.79–2.60(m,2H),2.52(s,3H),2.30(dd,J=25.1,12.1Hz,2H),1.98–1.79(m,4H).

[0319] LC-MS (ESI) m / z: 576.0 [M+H] + .

[0320] (5) Preparation of compound 1

[0321]

[0322] LiOH (2 mL) was added to a solution of compounds 1-5 (50 mg, 0.08 mmol) in THF (0.5 mL) and MeOH (0.5 mL). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give (S)-2-((4-(6-(((5-acetylthiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, which was compound 1 (14.93 mg, 29.2%).

[0323] 1 H NMR(400MHz, DMSO-d6)δ8.04(s,1H),7.81(d,J=3.8Hz,1H),7.75(d,J=8.1Hz,1H),7.67–7.60(m,1H),7.41 (s,1H),7.29(d,J=3.8Hz,1H),6.91(d,J=7.2Hz,1H),6.67(d,J=8.4Hz,1H),5.58(s,2H),5.09(s,1H),4.6 9(s,1H),4.59(d,J=13.7Hz,1H),4.44(s,1H),4.37(d,J=9.1Hz,1H),3.90(d,J=13.5Hz,1H),3.75(d,J=13 .2Hz,1H),2.99(s,1H),2.87(s,1H),2.67(s,2H),2.48(s,3H),2.34–2.12(m,3H),1.82(d,J=12.1Hz,4H).

[0324] LC-MS (ESI) m / z: 561.3 [M+H] + .

[0325] Example 2

[0326] (S)-2-((4-(6-((4-acetylthiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 2)

[0327]

[0328] (1) Preparation of compound 2-2

[0329]

[0330] To a solution of compound 2-1 (1 g, 3.52 mmol) and N,O-dimethylhydroxylamine (750 mg, 3.87 mmol) in anhydrous DMF (20 mL), HATU (4 g, 5.28 mmol) and DIEA (4.54 g, 17.6 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then partitioned between water (50 mL) and EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated. Rapid chromatography (SiO₂, 0–100% EtOAc-hexane) yielded N-methoxy-N,5-dimethylthiophene-3-carboxamide, compound 2-2 (1.1 g, 84.6%).

[0331] 1 H NMR (400MHz, DMSO-d6) δ7.90(1H,d,J=1.4),7.20–7.10(1H,m),3.64(3H,s),3.23(3H,s),2.45(3H,d,J=1.1).

[0332] LCMS:(ESI)m / z:186.0[M+H] +

[0333] (2) Preparation of compounds 2-3

[0334]

[0335] Under nitrogen atmosphere and at 0°C, an anhydrous THF solution of compound 2-2 (500 mg, 2.7 mmol) in 3 mL was added dropwise to a THF solution of CH3MgBr (1.8 mL, 5.4 mmol). After quenching the reaction mixture with NH4Cl (eq), the reaction mixture was stirred at room temperature for 2 hours. The solution was extracted with water (10 mL) and EtOAc (10 mL × 3), the organic phase was washed with brine, and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give 1-(5-methylthiophene-3-yl)ethyl-1-one, compound 2-3 (310 mg, 82.0%).

[0336] 1 H NMR (400MHz, DMSO-d6) δ8.24(1H,d,J=1.4),7.17(1H,s),2.45(3H,d,J=0.9),2.44(3H,s).

[0337] LCMS:(ESI)m / z:141.0[M+H] +

[0338] (3) Preparation of compounds 2-4

[0339]

[0340] Compounds 2-3 (310 mg, 2.21 mmol), AIBN (7 mg, 0.044 mmol), and NBS (434 mg, 2.43 mmol) were administered in...

[0341] The mixture in CCl4 (6 mL) was stirred at 80 °C for 16 h, and then the reaction mixture was quenched with Na2S2O3 (eq). The solution was extracted with water (20 mL) and DCM (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Treatment by rapid chromatography (SiO2, 0-100% EtOAc-hexane) gave 1-(5-(bromomethyl)thiophene-3-yl)ethyl-1-one, compounds 2-4 (280 mg, 57.9%).

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.44(1H,s),7.50(1H,s),4.95(2H,s),2.41(3H,s).

[0343] LC-MS: (ESI) m / z: 219.0 [M+H] +

[0344] (4) Preparation of compounds 2-5

[0345]

[0346] A mixture of compounds 2-4 (280 mg, 1.28 mmol), 2-4-1 (427 mg, 1.53 mmol), and K₂CO₃ (353 mg, 2.56 mmol) in DMF (5 mL) was stirred at 50 °C for 16 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 0–100% EtOAc-hexane) yielded tert-butyl 4-(6-((4-acetylthiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylate, compound 2-5 (220 mg, 41.3%).

[0347] 1H NMR (400MHz, DMSO) δ8.42(1H,d,J=1.5),7.65(1H,dd,J=8.1,7.4),7.56(1H,d,J=1.3),6.90(1H,d,J=7.2),6.66(1H,d,J=8 .0),5.53(2H,s),4.06–4.02(2H,m),2.94–2.74(3H,m),2.46(3H,s),1.85(2H,d,J=12.8),1.71–1.59(2H,m),1.41(9H,s).

[0348] LCMS:(ESI)m / z:417.0[M+H] +

[0349] (5) Preparation of compounds 2-6

[0350]

[0351] A solution of compounds 2-5 (220 mg, 0.53 mmol) and HCl / dioxane (1 mL) in EtOAc (1.5 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated to obtain a solid, which was dissolved in water (5 mL). The pH of the solution was adjusted to >7 with NaHCO3 (eq), and the solution was extracted with EtOAc (5 mL × 3). The organic phases were combined, washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 1-(5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)thiophen-3-yl)ethane-1-one, which is compound 2-6 (120 mg, 71.8%).

[0352] 1 H NMR(400MHz,DMSO-d6)δ8.42(1H,d,J=1.4),7.67–7.61(1H,m),7.57(1H,d, J=1.2),7.21(1H,dd,J=27.2,7.3),6.86(1H,d,J=7.3),6.63(1H,d,J=8.1) ,5.54(2H,s),3.02(2H,d,J=12.0),2.68(1H,ddd,J=11.9,8.3,3.7),2.62– 2.54(2H,m),2.46(3H,s),1.78(2H,d,J=12.0),1.64(2H,dd,J=12.3,3.8).

[0353] LCMS:(ESI)m / z:316.0[M+H] +

[0354] (6) Preparation of compounds 2-7

[0355]

[0356] The mixture of compound 2-6 (120 mg, 0.379 mmol), compound 2-6-1 (123 mg, 0.417 mmol), and K2CO3 (209 mg, 1.516 mmol) in dioxane (12 mL) and CH3CN (6 mL) was stirred at 60 °C for 16 hours. The solution was extracted with water (30 mL) and DCM (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated. Treatment with rapid chromatography (SiO2, 0-100% EtOAc-hexane) yielded (S)-2-((4-(6-(((4-acetylthiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compounds 2-7 (140 mg, 64.2%).

[0357] 1 H NMR (400MHz, DMSO-d6) δ8.41(1H,d,J=1.5),8.29(1H,s),7.82(1H,dd,J=8.4,1.5),7.73–7.60(2H,m),7.56(1H,d, J=1.4),6.90(1H,d,J=7.2),6.64(1H,d,J=8.2),5.54(2H,d,J=1.6),5.11(1H,d,J=7.1),4.82(1H,dd,J=15.2,7.2 ),4.67(1H,dd,J=15.1,2.6),4.49–4.32(2H,m),4.01(1H,dd,J=13.2,6.1),3.87(3H,s),3.79(1H,d,J=13.3),3.0 3(1H,d,J=11.5),2.88(1H,d,J=10.7),2.74–2.61(2H,m),2.44(4H,s),2.23(2H,d,J=29.5),1.84(4H,d,J=17.5).

[0358] LC-MS: (ESI) m / z: 575.4 [M+H] +

[0359] (7) Preparation of compound 2

[0360]

[0361] Compounds 2-7 (100 mg, 0.17 mmol), a solution of LiOH (2 mL) in THF (0.5 mL), and a solution of MeOH (0.5 mL) were stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure to obtain the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give (S)-2-((4-(6-((4-acetylthiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, which was compound 2 (10.67 mg, 10.9%).

[0362] 1 H NMR (400MHz, DMSO-d6) δ8.41(1H,d,J=1.4),8.25(1H,s),7.80(1H,dd,J=8.4,1.5),7.63(2H,dd,J=12.1,5.7),7.5 6(1H,d,J=1.3),6.90(1H,d,J=7.2),6.64(1H,d,J=8.1),5.61–5.49(2H,m),5.11(1H,dt,J=7.0,4.4),4.79(1H,dd, J=15.2,7.2),4.65(1H,dd,J=15.2,2.7),4.39(2H,ddt,J=11.8,8.9,5.9),3.96(1H,d,J=13.5),3.78(1H,d,J=13.5 ),3.03(1H,d,J=10.5),2.88(1H,d,J=11.5),2.74–2.61(2H,m),2.44(4H,s),2.31–2.15(2H,m),1.92–1.73(4H,m).

[0363] LC-MS:MC21-01-042R1,(ESI)m / z:561.1[M+H] +

[0364] Example 3

[0365] (S)-2-((4-(6-((5-acetylthiophene-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 3)

[0366]

[0367] (1) Preparation of compound 3-2

[0368]

[0369] NBS (139 mg, 0.78 mmol) was added to a mixture of compound 3-1 (100 mg, 0.71 mmol) and BPO (3.5 mg, 0.01 mmol) in CCl4 (2 mL). The reaction solution was then stirred at 80 °C for 16 hours, after which the reaction mixture was quenched with a saturated solution of Na2S2O3 (5 mL). The solution was extracted with water (20 mL) and DCM (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Treatment by rapid chromatography (SiO2, 20% EtOAc-hexane) yielded 1-(4-(bromomethyl)thiophene-2-yl)ethyl-1-one, compound 3-2 (40 mg, 25.8%).

[0370] 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 1.3Hz, 1H), 7.57 (d, J = 0.6Hz, 1H), 4.48 (s, 2H), 2.56 (s, 3H).

[0371] (2) Preparation of compound 3-3

[0372]

[0373] A mixture of compound 3-2 (40 mg, 0.18 mmol), compound 3-2-1 (61 mg, 0.22 mmol), and K₂CO₃ (50.5 mg, 0.37 mmol) in DMF (2 mL) was stirred at 50 °C for 16 hours. Water (5 mL) was added, and the reaction solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 25% EtOAc-hexane) yielded tert-butyl 4-(6-((5-acetylthiophene-3-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylic acid, compound 3-3 (22 mg, 29%).

[0374] 1H NMR (400MHz, CDCl3) δ7.76(s,1H),7.62(s,1H),7.52(t,J=7.7Hz,1H),6.74(d,J=7.3Hz,1H),6.61(d,J=8.2Hz,1H),5.36( s,2H),4.24(s,2H),2.94–2.67(m,3H),2.56(d,J=2.7Hz,4H),1.89(d,J=15.0Hz,2H),1.76(t,J=11.4Hz,2H),1.48(s,9H).

[0375] (3) Preparation of compounds 3-4

[0376]

[0377] HCl / dioxane (5 mL) was added to a solution of compound 3-3 (230 mg, 0.55 mmol) in EtOAc (5 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated to give a solid. The solid was dissolved in water (5 mL), and the pH was adjusted to >7 with NaHCO3 (eq). Extraction was performed with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 1-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)thiophen-2-yl)ethane-1-one, which is compound 3-4 (140 mg, 80%).

[0378] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=1.3Hz,1H),7.71–7.64(m,1H),7.55–7.49(m,1H),6.75(d,J=7.2Hz,1H),6.62(d,J=8.2 Hz,1H),5.38(s,2H),3.32(d,J=12.4Hz,2H),2.88–2.70(m,3H),2.56(d,J=2.3Hz,3H),2.02–1.83(m,4H),1.25(s,1H).

[0379] LCMS:(ESI)m / z:317.0[M+H] +

[0380] (4) Preparation of compounds 3-5

[0381]

[0382] K₂CO₃ (175 mg, 1.26 mmol) was added to a mixture of compound 3-4 (100 mg, 0.32 mmol) and compound 3-4-1 (93 mg, 0.32 mmol) in dioxane (6 mL) and CH₃CN (3 mL). The mixture was stirred at 60 °C for 16 hours. Water (10 mL) was added, and the solution was extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Rapid chromatography (silica gel, eluted with 0-10% MeOH / DCM) yielded (S)-2-((4-(6-(((5-acetylthiophene-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compounds 3-5 (100 mg, 55.1%).

[0383] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.97(d,J=9.5Hz,1H),7.76(s,2H),7.63(s,1H),7.51(dd,J=9.6,6 .0Hz,1H),6.75(d,J=7.3Hz,1H),6.60(d,J=8.2Hz,1H),5.37(s,2H),5.23(s,1H),4.74(d,J=8.8Hz,2H ),4.62(dd,J=14.7,7.2Hz,1H),4.40(s,1H),3.96(d,J=10.5Hz,5H),3.00(t,J=12.3Hz,2H),2.73(s,1 H),2.64(s,1H),2.54(s,3H),2.47(d,J=5.7Hz,1H),2.30(dd,J=25.5,12.1Hz,2H),1.95–1.80(m,4H).

[0384] LC-MS: (ESI) m / z: 575.3 [M+H] +

[0385] (5) Preparation of compound 3

[0386]

[0387] LiOH (5 mL) was added to a solution of compounds 3-5 (150 mg, 0.26 mmol) in THF (2 mL) and MeOH (2 mL). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give (S)-2-((4-(6-(((5-acetylthiophene-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, which was compound 3 (62.17 mg, 43.6%).

[0388] 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.98(d,J=5.2Hz,2H),7.80(d,J=8.3Hz,1H),7.63(t,J=7.7Hz,1H),7.47( d,J=8.3Hz,1H),6.88(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.36–5.29(m,2H),5.17–5.06(m,1H),4.66(ddd,J =17.8,15.2,4.7Hz,2H),4.51–4.32(m,2H),3.92(d,J=13.4Hz,1H),3.77(d,J=13.4Hz,1H),2.95(dd,J=45.6,1 1.0Hz,2H),2.67(dt,J=26.5,9.7Hz,2H),2.48(s,3H),2.47–2.40(m,1H),2.30–2.12(m,2H),1.90–1.65(m,4H).

[0389] LC-MS: (ESI) m / z: 561.3 [M+H] +

[0390] Example 4

[0391] (S)-2-((4-(6-((5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 4)

[0392]

[0393] (1) Preparation of compound 4-2

[0394]

[0395] A mixture of compound 4-1 (200 mg, 9.13 mmol), compound 4-1-1 (331 mg, 1.19 mmol), and K₂CO₃ (274 g, 1.98 mmol) in DMF (5 mL) was stirred at 50 °C for 16 hours. Water (20 mL) was added, and the reaction solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 25% EtOAc-hexane) yielded tert-butyl 4-(6-((5-cyanothiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylic acid, compound 4-2 (270 mg, 68.4%).

[0396] 1 H NMR (400MHz, CDCl3) δ7.60–7.44(m,2H),7.11(d,J=3.8Hz,1H),6.78(d,J=7.3Hz,1H),6.62(d,J=8.1Hz,1 H),5.57(s,2H),4.23(s,2H),2.94–2.68(m,3H),1.90(d,J=12.4Hz,2H),1.82–1.61(m,2H),1.49(s,9H).

[0397] LC-MS: (ESI) m / z: 344.1 [M+H] +

[0398] (2) Preparation of compound 4-3

[0399]

[0400] HCl / dioxane (5 mL) was added to a solution of compound 4-2 (270 mg, 0.68 mmol) in EtOAc (3 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated to give a solid. The solid was dissolved in water (10 mL), and the pH was adjusted to >7 with NaHCO3 (eq). Extraction was performed with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give (S)-2-((4-(6-(((5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compound 4-3 (190 mg, 94%).

[0401] 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=3.8Hz,1H),7.74–7.62(m,1H),7.39(d,J=3.8Hz,1H),6.91(d,J=7.3Hz,1H),6.69(d,J=8 .2Hz,1H),5.62(s,2H),3.11(dd,J=8.8,6.1Hz,2H),2.83–2.63(m,3H),1.84(d,J=11.9Hz,2H),1.70(m,J=12.3,4.1Hz,2H).

[0402] (3) Preparation of compound 4-4

[0403]

[0404] K₂CO₃ (369 mg, 2.67 mmol) was added to a mixture of compound 4-3 (190 mg, 0.67 mmol) and compound 4-3-1 (200 mg, 0.67 mmol) in dioxane (6 mL) and CH₃CN (3 mL). The mixture was stirred at 60 °C for 16 hours. Water (20 mL) was added, and the solution was extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. Rapid chromatography (silica gel, eluted with 0-10% MeOH / DCM) yielded (S)-2-((4-(6-(((5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compound 4-4 (240 mg, 64.4%).

[0405] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.97(d,J=9.0Hz,1H),7.75(d,J=8.5Hz,1H),7.56–7.49(m ,2H),7.11(d,J=3.1Hz,1H),6.79(d,J=7.4Hz,1H),6.60(d,J=8.4Hz,1H),5.57(s,2H),5.23(s ,1H),4.74(d,J=8.5Hz,2H),4.61(td,J=8.1,6.2Hz,1H),4.47–4.35(m,1H),3.97(d,J=14.9H z,5H),3.01(t,J=12.3Hz,2H),2.79–2.61(m,2H),2.40(m,3H),1.89(dd,J=28.0,11.6Hz,4H).

[0406] LC-MS: (ESI) m / z: 558.3 ​​[M+H] +

[0407] (4) Preparation of compound 4

[0408]

[0409] LiOH (2 mL) was added to a solution of compound 4-4 (50 mg, 0.09 mmol) in THF (1 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give (S)-2-((4-(6-(((5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, which is compound 4 (10.73 mg, 22.0%).

[0410] 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.88(d,J=3.8Hz,1H),7.80(dd,J=8.4,1.2Hz,1H),7.67(t,J=7.8Hz,1H),7.51 (d,J=8.4Hz,1H),7.37(d,J=3.8Hz,1H),6.93(d,J=7.3Hz,1H),6.68(d,J=8.2Hz,1H),5.62(s,2H),5.11(qd,J=7.1,3 .2Hz,1H),4.69(ddd,J=18.0,15.2,5.0Hz,2H),4.50–4.34(m,2H),3.94(d,J=13.4Hz,1H),3.78(d,J=13.4Hz,1H),3 .02(d,J=11.4Hz,1H),2.90(d,J=11.1Hz,1H),2.68(m,2H),2.48–2.39(m,1H),2.30–2.13(m,2H),1.92–1.69(m,4H).

[0411] LC-MS: (ESI) m / z: 544.3 [M+H] +

[0412] Example 5

[0413] (S)-2-((4-(6-((5-acetyl-3-chlorothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 5)

[0414]

[0415] (1) Preparation of compound 5-2

[0416]

[0417] HATU (2.89 g, 7.62 mmol) and DIEA (3.28 g, 25.40 mmol) were added to an anhydrous DMF (20 mL) solution of compound 5-1 (1 g, 5.08 mmol) and N,O-dimethylhydroxylamine (541 mg, 5.58 mmol). The reaction mixture was stirred at room temperature for 16 hours and then mixed between water (50 mL) and EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 0–100% EtOAc-hexane) yielded 4,5-dichloro-N-methoxy-N-methylthiophene-2-carboxamide, compound 5-2 (900 mg, 75.0%).

[0418] 1 H NMR (400MHz, DMSO-d6) δ7.76(1H,s),3.80(3H,s),3.29(3H,s).

[0419] LCMS:(ESI)m / z:240.0[M+H] +

[0420] (2) Preparation of compound 5-3

[0421]

[0422] A mixture of compound 5-2 (900 mg, 3.75 mmol), compound 5-2-1 (3.96 mL, 13.87 mmol), K₂CO₃ (1.6 g, 11.62 mmol), and (Ph₃P)₄Pd (433 mg, 0.37 mmol) in dioxane (10 mL) was stirred at 106 °C for 3 hours and then cooled to room temperature. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO₂, 40% EtOAc-hexane) to give 4-chloro-N-methoxy-N,5-dimethylthiophene-2-carboxamide, compound 5-3 (700 mg, 85.3%).

[0423] 1 H NMR (400MHz, DMSO-d6) δ7.62(1H,s),3.76(3H,s),3.27(3H,s),2.41(3H,s).

[0424] LCMS:MF12-MC21-01-066R1,(ESI)m / z:220.0[M+H] +

[0425] (3) Preparation of compound 5-4

[0426]

[0427] Under nitrogen atmosphere and at 0°C, an anhydrous THF solution of compound 5-3 (700 mg, 3.2 mmol) in 5 mL was added dropwise to a THF solution of CH3MgBr (2.1 mL, 6.4 mmol). After quenching the reaction mixture with NH4Cl (eq), the reaction mixture was stirred at room temperature for 2 hours. The solution was extracted with water (15 mL) and EtOAc (15 mL × 3), the organic phase was washed with brine, and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure to give 1-(4-chloro-5-methylthiophene-2-yl)ethyl-1-one, compound 5-4 (450 mg, 80.9%).

[0428] 1 H NMR (400MHz, DMSO-d6) δ7.93(1H,s),2.50(3H,s),2.44(3H,s).

[0429] LCMS:(ESI)m / z:175.1[M+H] +

[0430] (4) Preparation of compound 5-5

[0431]

[0432] A mixture of compound 5-4 (450 mg, 2.58 mmol), AIBN (8 mg, 0.052 mmol), and NBS (505 mg, 2.84 mmol) in CCl4 (10 mL) was stirred at 80 °C for 16 h, and then the reaction mixture was quenched with Na2S2O3. The solution was extracted with water (20 mL) and DCM (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Treatment by rapid chromatography (SiO2, 0–100% EtOAc-hexane) yielded 1-(5-(bromomethyl)-4-chlorothiophene-2-yl)ethyl-1-one, compound 5-5 (550 mg, 84.3%).

[0433] 1 H NMR(400MHz,DMSO-d6)δ8.00(1H,s),4.94(2H,s),2.55(3H,s).

[0434] LC-MS: (ESI) m / z: 253.0 [M+H] +

[0435] (5) Preparation of compounds 5-6

[0436]

[0437] A mixture of compound 5-5 (530 mg, 1.98 mmol), compound 5-5-1 (702 mg, 2.38 mmol), and K₂CO₃ (580 mg, 3.97 mmol) in DMF (10 mL) was stirred at 50 °C for 16 hours. The reaction mixture was then mixed between water (20 mL) and EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 0–100% EtOAc-hexane) yielded tert-butyl 4-(6-((5-acetyl-3-chlorothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-carboxylate, compound 5-6 (350 mg, 36.9%).

[0438] 1H NMR(400MHz,DMSO-d6)δ7.96(1H,s),7.70–7.60(1H,m),6.92(1H,d,J=7.3),6.71(1H,d,J=8.1),5.56(2H,s),4 .09–4.02(2H,m),2.96–2.75(3H,m),2.52(3H,s),1.80(2H,d,J=11.0),1.61(2H,dd,J=12.3,3.8),1.41(9H,s).

[0439] LCMS:(ESI)m / z:451.1[M+H] +

[0440] (6) Preparation of compounds 5-7

[0441]

[0442] A solution of compounds 5-6 (340 mg, 0.76 mmol) and EtOAc (3 mL) in HCl / dioxane (7 mL) was stirred at room temperature for 3 hours. The mixture was then concentrated to obtain a solid, which was dissolved in water (10 mL). The pH of the solution was adjusted to >7 with NaHCO3 (eq), and the solution was extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 1-(4-chloro-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)thiophen-2-yl)ethane-1-one, which is compound 5-7 (200 mg, 75.7%).

[0443] 1 H NMR (400MHz, DMSO-d6) δ7.98(1H,d,J=6.8),7.67(1H,t,J=7.8),6.89(1H,d,J=7.3),6.70(1H,d,J=8.2),5.57(2H,s),3.04(2H, d,J=12.1),2.68(1H,dd,J=9.5,5.8),2.61(2H,dd,J=12.1,10.1),2.52(3H,s),1.78(2H,d,J=11.2),1.62(2H,qd,J=12.3,3.9).

[0444] LCMS:(ESI)m / z:351.1[M+H] +

[0445] (7) Preparation of compounds 5-8

[0446]

[0447] The mixture of compound 5-7 (200 mg, 0.57 mmol), compound 5-7-1 (185 mg, 0.63 mmol), and K2CO3 (315 mg, 2.28 mmol) in dioxane (10 mL) and CH3CN (5 mL) was stirred at 60 °C for 16 hours. The solution was extracted with water (30 mL) and DCM (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated. Rapid chromatography (SiO2, 0-100% EtOAc-hexane) yielded (S)-2-((4-(6-(((5-acetyl-3-chlorothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate, compounds 5-8 (200 mg, 57.8%).

[0448] 1 H NMR (400MHz, DMSO-d6) δ8.30(1H,d,J=1.2),7.97(1H,s),7.83–7.77(1H,m),7.71–7.61(2H,m),6.92(1H,d,J=7.3),6. 70(1H,d,J=8.1),5.56(2H,s),5.11(1H,dd,J=7.2,2.3),4.83(1H,dd,J=15.2,7.2),4.68(1H,dd,J=15.2,2.6),4.46( 1H,dd,J=10.6,4.8),4.36(1H,dt,J=9.0,5.9),4.07–3.91(1H,m),3.87(3H,s),3.79(1H,d,J=13.5),3.01(1H,d,J=11 .5),2.86(1H,d,J=11.4),2.75–2.58(2H,m),2.50(3H,s),2.44(1H,s),2.22(2H,dd,J=27.9,2.8),1.89–1.68(4H,m).

[0449] LC-MS: (ESI) m / z: 609.2 [M+H] +

[0450] (8) Preparation of compound 5

[0451]

[0452] Compounds 5-8 (177 mg, 0.29 mmol), a solution of LiOH (4 mL) in THF (2.5 mL), and a solution of MeOH (1.5 mL) were stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure to obtain the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give (S)-2-((4-(6-((5-acetyl-3-chlorothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid, which was compound 5 (79.71 mg, 46.2%).

[0453] 1 H NMR (400MHz, DMSO-d6) δ8.10(1H,s),7.97(1H,s),7.80(1H,d,J=8.4),7.66(1H,t,J=7.7),7.44(1H,d,J=8.3),6.92(1H ,d,J=7.3),6.70(1H,d,J=8.2),5.56(2H,s),5.17–5.03(1H,m),4.73(1H,dd,J=15.2,6.9),4.64–4.56(1H,m),4.47(1H, dd,J=13.9,7.3),4.38(1H,dt,J=11.8,5.9),3.91(1H,d,J=13.3),3.76(1H,d,J=13.3),2.99(1H,d,J=10.8),2.88(1H, d,J=10.9),2.66(2H,dd,J=13.1,5.5),2.50(3H,s),2.46(1H,d,J=8.8),2.27–2.10(2H,m),1.79(4H,dd,J=16.6,10.3).

[0454] LC-MS: (ESI) m / z: 595.2 [M+H] +

[0455] Example 6

[0456] (S)-2-((4-(6-((5-(cyclopropanecarbonyl)thiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 6)

[0457]

[0458] (1) Preparation of compound 6-2

[0459]

[0460] At 0 °C and N2, cyclopropylmagnesium bromide (1.0 M THF solution, 47.6 mL, 47.6 mmol) was added dropwise to a solution of 6-1 (5.0 g, 39.6 mmol) in anhydrous THF (50 mL). The mixture was stirred at this temperature for 0.5 h, and then stirred at room temperature under N2 for 2.5 h. The reaction solution was quenched with H2O (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. Treatment with rapid chromatography (SiO2, EtOAc-hexane) yielded 6-2 (7 g, 99.9%).

[0461] 1 H NMR (400MHz, DMSO-d6) δ6.72(d,J=3.3Hz,1H),6.63–6.55(m,1H),5.37(d,J=4.9Hz,1H),4.08(dd,J=7.3,5.0Hz,1H),2.3 8(d,J=0.6Hz,3H),1.06(qt,J=7.9,5.0Hz,1H),0.47–0.42(m,2H),0.41–0.36(m,1H),0.28(ddd,J=9.3,4.2,1.4Hz,1H).

[0462] (2) Preparation of compound 6-3

[0463]

[0464] 6-2 (8.6 g, 51.12 mmol) was added to a solution of manganese oxide (44.44 g, 511.1 mmol) in DCE (172 mL). The mixture was stirred at 70 °C for 3 hours. The mixture was filtered off and the filtrate was concentrated. Treatment by rapid chromatography (SiO2, 16% EtOAc-hexane) yielded 6-3 (7 g, 83.8%).

[0465] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=4.0Hz,1H),6.81-2-6.79(m,1H),2.53(d,J=0.6Hz,3H),2.50-2.42(m,1H),1.23–1.17(m,2H),1.01-0.94(m,2H).

[0466] (3) Preparation of compound 6-4

[0467]

[0468] 6-3 (700 mg, 4.211 mmol) was added to a solution of BPO (20.4 mg, 0.0842 mmol) and NBS (824.4 mg, 4.632 mmol) in CCl4 (14 mL). The mixture was stirred at 80 °C for 16 hours. After dilution with EA, it was extracted with EA (200 mL × 3) and H2O. The organic layer was concentrated under vacuum. Treatment with rapid chromatography (SiO2, 16% EtOAc-hexane) yielded 6-4 (700 mg, yield: 67.9%).

[0469] 1 H NMR (400MHz, CDCl3) δ7.67–7.63(m,1H),7.14(d,J=3.8Hz,1H),4.68(s,2H),2.53-2.45(m,1H),1.29–1.21(m,2H),1.08–1.00(m,2H).

[0470] (4) Preparation of compound 6-5

[0471]

[0472] Compounds 6-4 (200 mg, 0.816 mmol) and 6-5-1 (340.6 mg, 1.224 mmol) were added to a solvent of DMF (2 mL), followed by the addition of Cs₂CO₃ (798 mg, 2.448 mmol). The mixture was stirred at room temperature under N₂ for 12 hours. Extraction was performed with H₂O (5 mL) and EA (10 mL x 3). The organic phase was washed with H₂O (10 mL x 3) and brine (10 mL) and dried over Na₂SO₄. The residue was concentrated and purified by rapid column chromatography to give compound 6-5 (168 mg, yield: 74.4%).

[0473] 1 H NMR (400MHz, DMSO-d6) δ7.66-7.54(m,2H),7.28(d,J=9.4Hz,2H),6.86(d,J=7.2Hz,1H),6.69(d,J=8.0Hz,1H),5.39(s,2H),4.74 (q,J=7.2Hz,4H),4.06–4.00(m,2H),3.03(s,3H),2.90–2.70(m,3H),1.74(d,J=12.0Hz,2H),1.57(d,J=12.1Hz,2H),1.42(s,9H).

[0474] (5) Preparation of compound 6-6

[0475]

[0476] Dissolve 6-5 (168 mg, 0.380 mmol) in a solvent containing TsOH·H2O (216.8 mg, 1.140 mmol) and EA (10 mL). Stir the mixture at 60 °C for 1 hour under N2 atmosphere. Stir the mixture at room temperature for 16 hours under N2 atmosphere. Filter, wash the filter cake with EA (5 mL x 3), and dry the filter cake to obtain 6-6 (130 mg).

[0477] LC-MS: (ESI) m / z: 343.1 [M+H] +

[0478] (6) Preparation of compounds 6-7

[0479]

[0480] The mixture of 6-6 (130 mg, 0.380 mmol) and 6-7-1 (112 mg, 0.380 mmol) was added to dioxane (9 mL) and MeCN (6 mL) solvents, followed by the addition of K₂CO₃ (419 mg). The mixture was stirred at 65 °C for 16 hours. The reaction solution was extracted with EA (100 mL x 3) and H₂O (100 mL). The organic phase was washed with brine (100 mL) and dried over Na₂SO₄. The residue was purified by column chromatography (PE:EA = 5:1) to give 6-7 (112 mg, yield: 49.1%).

[0481] LC-MS: (ESI) m / z: 601.3 [M+H] +

[0482] (7) Preparation of compound 6

[0483]

[0484] Compound 7-7 (40 mg, 0.0666 mmol) and 1 M LiOH (0.5 mL) were added to MeOH (0.5 mL) and THF (0.5 mL), and stirred at room temperature for 16 hours while removing the solvent under reduced pressure to obtain the crude product. The crude product was purified by HPLC. The crude product was purified by HPLC to obtain 5.78 mg of compound 6.

[0485] 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.00(d,J=3.8Hz,1H),7.78(d,J=8.4Hz,1H),7.65(t,J=7.8Hz,1H),7.49(d,J=8.4Hz,1H),7 .32(d,J=3.8Hz,1H),6.90(d,J=7.2Hz,1H),6.67(d,J=8.2Hz,1H),5.59(s,2H),5.13-5.06(m,1H),4.78-4.69(m,1H),4.65-4.55 (m,1H),4.49-4.41(m,1H),4.40-4.32(m,1H),3.92(d,J=13.4Hz,1H),3.76(d,J=13.4Hz,1H),3.17(s,1H),3.00(d,J=11.2Hz,1H ),2.87(d,J=11.2Hz,1H),2.80-2.73(m,1H),2.69–2.62(m,2H),2.46–2.40(m,1H),2.21(m,2H),1.78(m,4H),1.00–0.95(m,4H).

[0486] Example 7

[0487] (S)-2-((4-(6-((3-chloro-5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 7)

[0488]

[0489] (1) Preparation of compound 7-2

[0490]

[0491] DIEA (11.15 g, 86.3 mmol) was added to a DMF (50 mL) solution of 7-1 (3.4 g, 17.26 mmol). Then HATU (9.86 g, 25.89 mmol) was added. The mixture was stirred at room temperature for 0.5 h. Then NH4Cl (1 g, 18.98 mmol) was added. The mixture was stirred at room temperature for 16 h. H2O (100 mL) was added, and the reaction solution was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with H2O (3 × 100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated. Rapid chromatography (SiO2, hexane) gave 2.6 g of compound 7-2, yield: 76.9%.

[0492] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.80(s,1H),7.75(s,1H).

[0493] (2) Preparation of compound 7-3

[0494]

[0495] The mixture 7-2 (1.0 g, 5.10 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxoborane (3.5 M in THF, 5.4 mL, 18.87 mmol) were added to the solvent dioxane (10 mL). Then, K₂CO₃ (2.2 g, 15.81 mmol) and Pd(PPh₃)₄ (589 mg, 0.51 mmol) were added. The reaction solution was stirred at 106 °C for 3 hours. H₂O (10 mL) was added, and the reaction solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Purification by rapid chromatography (SiO₂, EtOAc-hexane) gave 300 mg of compound 7-3, yield: 33.4%.

[0496] δH(400MHz,DMSO-d6)7.96(1H,s),7.66(1H,s),7.49(1H,s),2.38(3H,s).

[0497] (3) Preparation of compound 7-4

[0498]

[0499] Burgess reagent (2.2 g, 9.08 mmol) was added to a 30 mL solution of 7-3 (530 mg, 3.03 mmol) in DCM. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. H₂O (30 mL) was added, and the reaction solution was extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. Rapid chromatography (SiO₂, EtOAc-hexane) yielded 390 mg of compound 7-4, in 81.9% yield.

[0500] 1 H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 2.46 (s, 3H).

[0501] (4) Preparation of compound 7-5

[0502]

[0503] NBS (483 g, 2.73 mmol) was added to a solution of 7-4 (390 mg, 2.48 mmol) in CCl4 (8 mL), followed by AIBN (6 mg, 0.05 mmol). The mixture was stirred at 80 °C for 16 hours under a N2 atmosphere. H2O (10 mL) was added, and the reaction solution was extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. Purification by rapid chromatography (SiO2, EtOAc-hexane) gave 416 mg of compound 7-5, yield: 71.2%.

[0504] δH(400MHz,DMSO-d6)8.08(1H,s),4.98(2H,s).

[0505] (5) Preparation of compound 7-6

[0506]

[0507] The mixture 7-5 (416 mg, 1.76 mmol) and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidin-1-carboxylate (590 mg, 2.11 mmol) were added to the solvent DMF (8 mL). Then, K₂CO₃ (482 mg, 3.52 mmol) was added. The reaction solution was stirred at 50 °C for 16 hours. H₂O (10 mL) was added, and the reaction solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Purification by rapid chromatography (SiO₂, EtOAc-hexane) gave 300 mg of compound 7-6, yield: 39.1%.

[0508] δH(400MHz,DMSO-d6)8.12(1H,s),7.75(1H,dd,J=8.1,7.4),7.00(1H,d,J=7.2),6.78(1H,d,J=8.1),5.63(2H,s), 4.17–4.04(2H,m),2.88(3H,ddd,J=11.7,8.2,3.6),1.87(2H,d,J=10.9),1.68(2H,td,J=12.5,4.1),1.47(10H,s).

[0509] (6) Preparation of compound 7-7

[0510]

[0511] To a solution of 7-6 (300 mg, 0.692 mmol) in EtOAc (2 mL), HCl·dioxane (4 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give 160 mg of compound 7-7, yield: 69.2%.

[0512] δH(400MHz,DMSO-d6)8.07(1H,s),7.68(1H,t,J=7.8),6.91(1H,d,J=7.3),6.70(1H,d,J=8.2),5.58(2H,s),3 .03(2H,d,J=11.7), 2.70(1H,t,J=11.8), 2.59(2H,t,J=11.6), 1.78(2H,d,J=1.2), 1.62(2H,td,J=12.2,3.8).

[0513] (7) Preparation of compounds 7-8

[0514]

[0515] The mixture 7-7 (160 mg, 0.479 mmol) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (155 mg, 0.527 mmol) were added to the solvents dioxane (6 mL) and MeCN (3 mL), followed by the addition of K₂CO₃ (265 mg, 1.917 mmol). The reaction solution was stirred at 60 °C for 16 hours. H₂O (10 mL) was added, and the reaction solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Purification by rapid chromatography (SiO₂, EtOAc-hexane) yielded 190 mg of compound 7-8, in 66.9% yield.

[0516] δH(400MHz,DMSO-d6)8.29(1H,s),8.07(1H,s),7.82(1H,dd,J=8.5,1.4),7.73–7.64(2H,m),6.94(1H,d,J=7. 3),6.71(1H,d,J=8.1),5.58(2H,s),5.11(1H,d,J=4.9),4.83(1H,dd,J=15.2,7.2),4.68(1H,dd,J=15.2,2.6) ,4.47(1H,d,J=5.8),4.42–4.33(1H,m),4.01–3.93(1H,m),3.87(3H,s),3.80(1H,d,J=13.6),3.01(1H,d,J=11 .4),2.87(1H,d,J=11.0),2.79–2.59(2H,m),2.43(1H,dd,J=18.9,8.2),2.31–2.16(2H,m),1.88–1.66(4H,m).

[0517] (8) Preparation of compound 7

[0518]

[0519] 1M LiOH (3 mL) was added to a solution of 7-8 (90 mg, 0.152 mmol) in MeOH (2 mL) and THF (1 mL). The reaction solution was stirred at room temperature for 2 hours, concentrated, and purified by preparative HPLC to give 3.26 mg of compound 7, yield: 18.6%.

[0520] δH(400MHz,DMSO-d6)8.38(1H,s),8.23(1H,s),8.06(1H,s),7.82(1H,d,J=8.4),7.68(1H,t,J=7.8),7.58(1H,d, J=8.3),6.94(1H,d,J=7.3),6.71(1H,d,J=8.1),5.58(2H,s),5.11(1H,d,J=4.2),4.79(1H,dd,J=15.0,6.9),4.65 (1H,d,J=13.1),4.47(1H,dd,J=13.5,7.4),4.41–4.32(1H,m),3.94(1H,d,J=13.5),3.83–3.73(2H,m),3.00(2H, d,J=11.5),2.88(1H,d,J=11.8),2.67(2H,d,J=8.0),2.45(1H,s),2.29–2.12(2H,m),1.78(4H,dd,J=37.9,13.2).

[0521] LC-MS: (ESI) m / z: 578.2 [M] + H] +

[0522] Example 8

[0523] (S)-2-((4-(6-((4-chloro-5-cyanothiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 8)

[0524]

[0525] (1) Preparation of compound 8-2

[0526]

[0527] A mixture of 8-1 (1.0 g, 5.84 mmol) in 6N HCl (5 mL) was cooled to 0 °C, and a solution of sodium nitrite (403 mg, 5.84 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 60 min. Then, the mixture was added to a concentrated solution of copper chloride (578 mg, 5.84 mmol). HCl (5 mL) was added at 0 °C, and the reaction mixture was stirred at room temperature, then heated to 65 °C until gas escape stopped. The reaction mixture was diluted with water, extracted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by rapid column chromatography (12% EtOAc / heptane) to give 780 mg of 8-2, in a yield of 70.9%.

[0528] 1 H NMR (400MHz, CDCl3) δ6.72 (d, J = 0.8Hz, 1H), 3.86 (s, 3H), 2.47 (s, 3H).

[0529] LC-MS:MC21-306-011-P(ESI)m / z:191.0[M+H] +

[0530] (2) Preparation of compound 8-3

[0531]

[0532] A solution of LiOH (196 mg, 8.18 mmol) in 1 mL of H₂O was added to a solution of 8-2 (780 mg, 4.09 mmol) in 4 mL of MeOH. The mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure to obtain a crude product. The crude product was dissolved in water, and the pH was adjusted to 2 with 1 mol / L hydrochloric acid. The mixture was filtered to obtain 8-3 (470 mg, crude product).

[0533] 1 H NMR (400MHz, DMSO-d6) δ6.96 (s, 1H), 2.46 (s, 3H).

[0534] (3) Preparation of compound 8-4

[0535]

[0536] NH4Cl (100 mg, 1.87 mmol) was added to a solution of 8-3 (300 mg, 1.70 mmol) in DMF (5 mL), followed by the addition of HATU (969 mg, 2.55 mmol) and DIEA (1.10 g, 8.49 mmol). The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Water (20 mL) was added, and the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (28% EtOAc in heptane solution) to give 120 mg of 8-4, in a yield of 40.2%.

[0537] 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.37(s,1H),6.94(s,1H),2.49(s,3H).

[0538] LC-MS:MC21-306-018-P,(ESI)m / z:176.0[M+H] +

[0539] (4) Preparation of compound 8-5

[0540]

[0541] Burgess reagent (651 mg, 2.73 mmol) was added to a 5 mL solution of DCM (160 mg, 0.91 mmol) of 8-4, and the mixture was stirred at room temperature for 16 hours. Water (10 mL) was added, and the solution was extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (25% EtOAc in heptane) to give 100 mg of 8-5, in 69.9% yield.

[0542] 1 H NMR (400MHz, DMSO-d6) δ7.16 (d, J = 1.0 Hz, 1H), 2.53 (d, J = 0.9 Hz, 3H).

[0543] (5) Preparation of compound 8-6

[0544]

[0545] NBS (124 mg, 0.20 mmol) was added to a mixture of 8-5 (100 mg, 0.63 mmol) and AIBN (2 mg, 0.01 mmol) in CCl4 (10 mL). The reaction solution was then stirred at 80 °C for 16 hours, after which the reaction mixture was quenched with a saturated solution of Na2S2O3 (5 mL). The solution was extracted with water (20 mL) and DCM (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Rapid chromatography (SiO2, 0-50% EtOAc / hexane) yielded 8-6 (50 mg, yield 33.6%).

[0546] 1 H NMR (400MHz, DMSO-d6) δ7.51 (s, 1H), 5.02 (s, 2H).

[0547] (6) Preparation of compounds 8-7

[0548]

[0549] A mixture of 8-6 (50 mg, 0.21 mmol), 8-6-1 (71 mg, 0.25 mmol), and K₂CO₃ (59 mg, 0.42 mmol) in DMF (3 mL) was stirred at 50 °C for 16 hours. After stirring, H₂O (10 mL) was added, and the reaction solution was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Treatment by rapid chromatography (SiO₂, 25% EtOAc-hexane) yielded 8-7 (40 mg, 44% yield).

[0550] 1 H NMR (400MHz, DMSO-d6) δ7.75–7.65(m,1H),7.50(s,1H),6.95(d,J=7.3Hz,1H),6.72(d,J=8.1Hz,1H),5.58(s,2H ),4.14–3.98(m,2H),2.83(t,J=11.7Hz,3H),1.84(d,J=12.7Hz,2H),1.60(qd,J=12.6,4.2Hz,2H),1.41(s,9H).

[0551] (7) Preparation of compound 8-8

[0552]

[0553] HCl / dioxane (2 mL) was added to a solution of 8-7 (40 mg, 0.09 mmol) in EtOAc (2 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated to obtain a solid. The solid was dissolved in H2O (3 mL), and the pH was adjusted to >7 with NaHCO3 (eq). The solid was extracted with EtOAc (5 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 8-8 (35 mg, crude product).

[0554] 1 H NMR (400MHz, DMSO-d6) δ7.73–7.63(m,1H),7.52(s,1H),6.91(d,J=7.3Hz,1H),6.70(d,J=8.1Hz,1H),5.5 9(s,2H),3.03(d,J=12.0Hz,2H),2.74–2.54(m,3H),1.78(d,J=13.0Hz,2H),1.60(qd,J=12.3,3.9Hz,2H).

[0555] (8) Preparation of compounds 8-9

[0556]

[0557] K₂CO₃ (58 mg, 0.42 mmol) was added to 8-8 (35 mg, 0.10 mmol) and 8-8-1 (31 mg, 0.10 mmol) in dioxins.

[0558] The mixture was placed in a solution of alkane (2 mL) and CH3CN (1 mL). The mixture was stirred at 60 °C for 16 hours. Water (5 mL) was added, and the solution was extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. Rapid chromatography (silica gel, eluted with 0-10% MeOH / DCM) was used to give 8-9 (34 mg, yield 54.8%).

[0559] LC-MS:MC21-306-030-P,(ESI)m / z:592.2[M+H] +

[0560] (9) Preparation of compound 8

[0561]

[0562] LiOH (2 mL) was added to a THF (2 mL) solution of 8-9 (34 mg, 0.06 mmol). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give compound 8 (3.11 mg, yield 9.3%).

[0563] 1H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.77(d,J=7.6Hz,1H),7.72–7.64(m,1H),7.50(s,1H),7.42(d,J=8.2Hz,1H),6.94(d,J= 7.3Hz,1H),6.70(d,J=8.2Hz,1H),5.58(s,2H),5.16–5.05(m,1H),4.72(dd,J=15.3,7.1Hz,1H),4.60(dd,J=15.6,3.2Hz,1H), 4.47(dd,J=13.7,7.7Hz,1H),4.36(dt,J=8.8,5.9Hz,1H),3.91(d,J=13.3Hz,1H),3.77(d,J=13.3Hz,1H),3.00(d,J=10.2Hz, 1H), 2.90 (d, J=11.4Hz, 1H), 2.67 (dt, J=13.4, 7.0Hz, 2H), 2.43 (dd, J=18.9, 7.9Hz, 1H), 2.29–2.13 (m, 2H), 1.90–1.69 (m, 4H).

[0564] LC-MS:MC21-306-037-P(ESI)m / z:578.0[M+H] +

[0565] Example 9

[0566] (S)-1-(oxetane-2-ylmethyl)-2-((4-(6-((5-(trifluoromethyl)thiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 9)

[0567]

[0568] (1) Preparation of compound 9-2

[0569]

[0570] CH3I (2.895 g, 20.4 mmol) was added dropwise to a solution of 9-1 (2 g, 10.2 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMF (80 mL) at 0 °C and N2. The reaction mixture was stirred at room temperature for 2 hours. Extraction was performed with EA and H2O (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The residue was purified by column chromatography to give 9-2 (2 g, 95.2%).

[0571] 1H NMR (400MHz, DMSO-d6) δ7.89-7.85 (m, 1H), 7.82 (d, J = 4.0Hz, 1H), 3.90 (s, 3H).

[0572] (2) Preparation of compound 9-3

[0573]

[0574] Under N2 atmosphere and at 0 °C, LiAlH4 (9.5 mL, 9.5 mmol) was added dropwise to a solution of 9-2 (2 g, 9.5 mmol) in 60 mL of THF. The reaction mixture was stirred at room temperature for 2 hours. The reaction was then quenched with sodium sulfate decahydrate. The solid was removed by filtration. The filtrate was concentrated to dryness to give the crude product. The residue was purified by column chromatography to give 9-3 (1.4 g, 82.4%).

[0575] 1 H NMR (400MHz, DMSO-d6) δ7.55-7.50(m,1H),7.05-7.00(m,1H),5.84-5.78(m,1H),4.70(d,J=5.6Hz,2H).

[0576] (3) Preparation of compound 9-4

[0577]

[0578] Mix 9-3 (1.4 g, 7.686 mmol), pph3 (2.416 g, 9.22 mmol), and NBS (1.641 g, 9.22 mmol) in a 35 mL solution of DCM. Stir the mixture at room temperature for 5 hours, dilute with DCM, and then extract with DCM (20 mL × 3) and H₂O. Purify the crude residue by SGC to give product 9-4 (1.3 g, 71.5%).

[0579] 1 H NMR (400MHz, DMSO-d6) δ7.58(s,1H),7.37–7.30(m,1H),5.06(s,2H).

[0580] (4) Preparation of compound 9-5

[0581]

[0582] The mixture of 9-4 (220 mg, 0.898 mmol) and 9-5-1 (375 mg, 1.347 mmol) was added to DMF (10 mL), followed by the addition of Cs₂CO₃ (878 mg, 2.693 mmol). The mixture was stirred in N₂ at room temperature for 12 hours. Extraction was performed with H₂O (50 mL) and EA (100 mL × 3). The organic phase was washed with H₂O (100 mL × 3) and brine (100 mL), and dried over Na₂SO₄. The residue was concentrated and purified by column chromatography to give 9-5 (200 mg, 65.1%).

[0583] 1 H NMR (400MHz, DMSO-d6) δ7.70–7.63(m,1H),7.60-7.57(m,1H),7.30(d,J=2.6Hz,1H),6.92(d,J=7.2Hz,1H),6.68(d ,J=8.0Hz,1H),5.59(s,2H),4.15–3.97(m,2H),2.95-2.70(m,3H),1.84(s,2H),1.73–1.54(m,2H),1.40(s,9H).1H NMR(400MHz,DMSO)

[0584] (5) Preparation of compound 9-6

[0585]

[0586] Mixture 9-5 (200 mg, 0.0678 mmol) and TsOH·H2O (255 mg, 0.204 mmol) were added to solvent EA (4 mL). The mixture was stirred in N2 at 60 °C for 1 hour. The mixture was then stirred in N2 at room temperature for 16 hours. The mixture was filtered, and the filter cake was washed with EA (5 mL x 3). The filter cake was dried to give product 9-6 (132.2 mg).

[0587] LC-MS: (ESI) m / z: 343.0 [M+H] +

[0588] (6) Preparation of compounds 9-7

[0589]

[0590] The mixture 9-6 (132 mg, 0.380 mmol) and 9-7-1 (113.2 mg, 0.380 mmol) were added to the solvents dioxane (3 ml) and MeCN (2 ml), followed by the addition of K₂CO₃ (425.3 mg). The mixture was stirred at 65 °C for 12 hours. The reaction solution was extracted with EA (100 ml × 3) and H₂O (100 ml), the organic phase was washed with brine (100 ml), and dried over Na₂SO₄. The residue was purified by column chromatography to give 9-7 (140 mg, 65.1%).

[0591] LC-MS: (ESI) m / z: 601.1 [M+H] +

[0592] (7) Preparation of compound 9

[0593]

[0594] 9-7 (140 mg, 0.233 mmol) and 1 M LiOH (1 mL) were added to MeOH (1 mL) and THF (1 mL) and stirred at room temperature for 16 hours. The crude product was purified by HPLC to obtain the title product (S)-1-(oxetane-2-ylmethyl)-2-((4-(6-((5-(trifluoromethyl)thiophene-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 9), 64.94 mg.

[0595] 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.76(d,J=8.2Hz,1H),7.68–7.62(m,1H),7.62–7.59(m,1H),7.42(d,J=8.0Hz,1H),7.32(s,1H) ,6.92(d,J=7.2Hz,1H),6.67(d,J=8.0Hz,1H),5.60(s,2H),5.10(d,J=4.2Hz,1H),4.75-4.67(m,1H),4.63–4.55(m,1H),4.49-4.42(m 1H),4.40-4.32(m,1H),3.91(d,J=13.4Hz,1H),3.76(d,J=13.4Hz,1H),3.01(d,J=11.0Hz,1H) ,2.90(d,J=7.6Hz,1H),2.71–2.61(m,2H),2.47–2.38(m,1H),2.30–2.12(m,2H),1.80(m,4H).

[0596] LC-MS:MC21-238-081(ESI)m / z:587.3[M+H] +

[0597] Example 10

[0598] 1-(oxetane-2-ylmethyl)-2-((4-(6-(thieno[2,3-c]pyridin-2-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid (compound 10)

[0599]

[0600] (1) Preparation of compound 10-2

[0601]

[0602] Under a nitrogen atmosphere, methyl 2-mercaptoacetate (401 mg, 3.78 mmol) was added to a solution of 10⁻¹ (1.0 g, 3.78 mmol) and Cs₂CO₃ (1.4 g, 4.16 mmol) in anhydrous THF (20 mL). The mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the mixture was filtered and concentrated, extracted three times with EA, and the combined organic layers were washed with water and brine, dried with anhydrous Na₂SO₄, filtered and concentrated to obtain 10⁻² (1.0 g, crude product).

[0603] 1 H NMR (400MHz, CDCl3) δ9.08(s,1H),8.65(s,1H),8.16(s,1H),4.01(s,3H).

[0604] LC-MS: (ESI) m / z: 273.9 [M+H]+

[0605] (2) Preparation of compound 10-3

[0606]

[0607] TEA (1.1 g, 11.01 mmol) and Pd / C (300 mg, 10% Pd) were added to a solution of 10⁻² (1.0 g, 3.67 mmol) in anhydrous THF / MeOH (3:1, 20 mL). The mixture was stirred at 50 °C for 24 hours under H₂ atmosphere. After the reaction was completed, the mixture was filtered and concentrated to obtain 10⁻³ (825 mg, crude product).

[0608] 1H NMR (400MHz, CDCl3) δ9.21 (s, 1H), 8.57 (d, J = 5.5Hz, 1H), 8.06 (s, 1H), 7.76 (d, J = 5.5Hz, 1H), 3.98 (s, 3H).

[0609] LC-MS: (ESI) m / z: 194.2 [M+H]+

[0610] (3) Preparation of compound 10-4

[0611]

[0612] LiAlH4 (13 mL, 1.0 M THF solution) was added dropwise to a 10⁻³ (2.5 g, 12.9 mmol) solution of anhydrous THF (25 mL) while stirring at 0 °C. The mixture was stirred at the same temperature for 0.5 h. After the reaction was complete, Na₂SO₄·10H₂O was slowly added to the reaction mixture. The mixture was then filtered and concentrated. The residue was purified by SGC (DCM of MeOH 0–10%) to give 10⁻⁴ (410 mg, yield 19%).

[0613] 1 H NMR (400MHz, DMSO) δ9.15 (s, 1H), 8.42 (d, J = 5.4Hz, 1H), 7.74 (dd, J = 5.4, 0.9Hz ,1H),7.35(d,J=0.8Hz,1H),5.85(t,J=5.8Hz,1H),4.82(dd,J=5.8,1.1Hz,2H).

[0614] LC-MS: (ESI) m / z: 166.2 [M+H]+

[0615] (4) Preparation of compound 10-5

[0616]

[0617] MsCl (83 mg, 0.72 mmol) and TEA (0.84 mL, 6.05 mmol) were added to a solution of 10⁻⁴ (100 mg, 0.6 mmol) in anhydrous DCM (5 mL). The reaction mixture was stirred at 0 °C for 30 min, then quenched with water. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give 147 mg of crude 10⁻⁵.

[0618] (5) Preparation of compound 10-6

[0619]

[0620] A mixture of 10⁻⁵ (147 mg, 0.6 mmol), methyl 2-((4-(6-hydroxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (50 mg, 0.12 mmol), and Cs₂CO₃ (217 mg, 0.66 mmol) in DMF (10 mL) was stirred overnight at 50 °C. The reaction was quenched with H₂O (10 mL), extracted with DCM (10 mL × 3), the organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give the residue. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H₂O, H₂O to 100% MeCN) to give 10⁻⁶ (30 mg).

[0621] LC-MS:MC21-231-109-P,(ESI)m / z:584.2[M+H]+

[0622] (6) Preparation of compound 10

[0623]

[0624] A solution of 10⁻⁶ (30 mg, 0.05 mmol), LiOH (0.5 mL), and THF (0.5 mL) was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure to obtain the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H₂O, 0.1% NH₃·H₂O to 100% MeCN) to give 1.62 mg of compound 10.

[0625] 1H NMR (400MHz, DMSO) δ9.16(s,1H),8.41(d,J=5.4Hz,1H),8.06(s,1H),7.76(d,J=6.5Hz,2H),7.69–7.64(m,1H),7.59(s,1H) ,7.41(d,J=8.3Hz,1H),6.92(d,J=7.3Hz,1H),6.71(d,J=8.2Hz,1H),5.74(s,2H),5.11(m,J=6.9,3.2Hz,1H),4.70(dd,J=15 .2,6.8Hz,1H),4.58(dd,J=15.1,3.1Hz,1H),4.47–4.31(m,2H),3.90(d,J=13.4Hz,1H),3.75(d,J=13.4Hz,1H),3.00(d,J= 11.0Hz,1H),2.89(d,J=11.4Hz,1H),2.69–2.62(m,2H),2.42(dd,J=11.1,4.1Hz,1H),2.27–2.13(m,2H),1.90–1.72(m,4H).

[0626] LC-MS:MC21-231-114-P,(ESI)m / z:570.2[M+H] +

[0627] Example 11

[0628] (S)-2-((4-(6-((5-cyano-3-methylthiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 11)

[0629]

[0630] (1) Preparation of compound 11-2

[0631]

[0632] Compound 7 (60 mg, 0.101 mmol) and potassium trifluoro(methyl)borate (124 mg, 1.015 mmol) were added to toluene (20 mL) and H₂O (2 mL), followed by the addition of cataCXium-A-Pd-G₃ (4 mg, 0.005 mmol) and Cs₂CO₃ (100 mg, 0.304 mmol). The reaction solution was stirred at 90 °C for 16 hours. H₂O (20 mL) was added, and the reaction solution was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Purification by rapid chromatography (SiO₂, EtOAc-hexane) yielded 30 mg of compound 11-2, in 51.7% yield.

[0633] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=1.1Hz,1H),7.90(dd,J=8.5,1.5Hz,1H),7.68(d,J=8.5Hz,1H),7.45(dd,J= 8.1,7.5Hz,1H),7.27(s,1H),6.70(d,J=7.3Hz,1H),6.51(d,J=8.0Hz,1H),5.42(s,2H),5.23(s,1H),5.17( m,1H),4.67(m,2H),4.55(td,J=7.9,6.1Hz,1H),4.33(dt,J=9.1,5.9Hz,1H),3.92(s,2H),3.88(s,3H),3.4 1(s,1H),2.94(t,J=13.0Hz,2H),2.73–2.54(m,2H),2.43–2.36(m,1H),2.25(s,3H),1.95(d,J=4.0Hz,4H).

[0634] (2) Preparation of compound 11

[0635]

[0636] 1M LiOH (0.5 mL) was added to a 30 mg (0.05 mmol) THF solution of compound 11. The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by preparative HPLC to give 1 mg of compound 11, yield: 3.4%.

[0637] 1H NMR(400MHz, DMSO-d6)δ8.32(s,1H),8.24(s,1H),7.81(d,J=8.3Hz,1H),7.74(s,1H),7.67–7.59(m,2H), 6.91(d,J=7.4Hz,1H),6.67(d,J=8.2Hz,1H),5.55(s,2H),5.11(q,J=8.5Hz,1H),4.80(dd,J=15.4,6.9Hz ,1H),4.66(d,J=13.3Hz,1H),4.47(dd,J=13.6,7.4Hz,1H),4.37(m,1H),3.95(d,J=13.5Hz,1H),3.79(d, J=13.4Hz,1H),3.00(s,1H),2.89(s,1H),2.74–2.60(m,4H),2.46(s,1H),2.29(s,3H),1.84-1.71(m,4H).

[0638] LC-MS: (ESI) m / z: 558.2 [M+H] +

[0639] Example 12

[0640] (S-2-((2-((5-cyanothiophene-2-yl)methoxy)-5,8,10,11-tetrahydrooxoheptatrien[4,3-b:6,5-c']dipyridin-9(7H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 12)

[0641]

[0642] The preparation route for the intermediate 2-hydroxy-5,8,10,11-tetrahydrooxetane-heptadienetrien[4,3-b:6,5-c']bipyridine-9(7H)-carboxylate (12-i) is as follows.

[0643]

[0644] Sulfuric acid (10 mL) was added to a mixture of 2-chloro-6-hydroxynicotinic acid 12-1a (5.0 g, 29 mmol) in MeOH (40 mL). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with ice water, extracted with EA, and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give methyl 2-chloro-6-hydroxynicotinic acid 12-2a (4.5 g, 83% yield).

[0645] A reaction mixture of methyl 2-chloro-6-hydroxynicotinic acid 12-2a (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 with Ar₂ at 80 °C for 2 hours. The reaction mixture was determined to be complete 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. The combined organic layers were dried over Na₂SO₄. The mixture was concentrated and purified by elution (PE / EA = 0–20%) to give methyl 2-chloro-6-((4-methoxybenzyl)oxy)nicotinic acid 12-3a (2.9 g, 52% yield).

[0646] A reaction mixture was added to methyl 2-chloro-6-((4-methoxybenzyl)oxy)nicotinic acid 12-3a (2.9 g, 9.4 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-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). The mixture was stirred with Ar₂ at 110 °C for 16 hours. The reaction mixture was determined to be complete by LC-MS. The product 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'-bipyridine]-1',3,3'(2'H)-tricarboxylic acid ester 12-4a (2.5 g, 53.2% yield).

[0647] 12-4a (1.5 g, 2.9 mmol) was dissolved in anhydrous THF (15 mL), and then LiAlH4 (0.222 g, 5.8 mmol) was added in portions at 0 °C. After 10 minutes, the reaction mixture was checked by LC-MS to confirm completeness. The reaction mixture was quenched with ice water (0.5 mL). The mixture was filtered and concentrated to give tert-butyl 3,5'-di(hydroxymethyl)-6-((4-methoxybenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid 12-5a (1.2 g, 92% yield).

[0648] The reaction mixture of 12-5a (1.1 g, 2.4 mmol) and camphor sulfonic acid (3.24 g, 9.6 mmol) in TOL (20 mL) was added. The mixture was heated at 110 °C for 1 hour. The reaction mixture was determined to be complete by LC-MS. The mixture was concentrated and purified by elution (MeOH / DCM = 0-20%) to give 5,7,8,9,10,11-hexahydroxyoxetanetrien-[4,3-b:6,5-c']bipyridin-2-ol 12-6a (0.4 g, 76% yield).

[0649] A solution of 12-6a (0.35 g, 1.6 mmol) in DCM (15 mL) was added to (Boc)₂O (0.42 g, 1.9 mmol) and TEA (0.2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was determined to be complete by LC-MS. The mixture was concentrated and purified by elution (MeOH / DCM = 0–10%) to give 2-hydroxy-5,8,10,11-tetrahydrooxetrazine heptatrienone [4,3-b:6,5-c']bipyridine-9(7H)-carboxylate 12-i (350 mg, 70% yield). 1 H NMR (400MHz, CDCl3) δ12.63(s,1H),7.43(d,J=9.2Hz,1H),6.49(d,J=9.1Hz,1 H), 4.17 (s, 4H), 3.80 (s, 2H), 3.67 (t, J = 5.5Hz, 2H), 2.72 (s, 2H), 1.51 (s, 9H).

[0650] (1) Preparation of compound 12-1

[0651]

[0652] Add NaH (32.7 mg, 0.85 mmol) in portions to 12-i (200 mg, 0.65 mmol). Stir the reaction mixture for 5 minutes.

[0653] 5-(bromomethyl)thiophene-2-onitrile (131.5 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched by adding H₂O. The aqueous phase was extracted with EtOAc (30 mL × 3) and washed with brine (30 mL × 2). The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by elution to give 12⁻¹ (210 mg, 71.7% yield).

[0654] LCMS: rt=2.189min, [M+H]+=440.

[0655] (2) Preparation of compound 12-2

[0656]

[0657] Mix 12-1 (200 mg, 0.47 mmol) with an EtOAc / HCl (10 mL) solution. Stir the mixture at room temperature for 2 hours. The reaction mixture was checked for completeness by LCMS. The reaction solution was concentrated to give 12-2 (200 mg, crude product).

[0658] LCMS:rt=1.391min,[M+H]+=340

[0659] (3) Preparation of compound 12-3

[0660]

[0661] The reaction mixture of 12-2 (200 mg, 0.589 mmol) and DIEA (117.23 mg, 0.531 mmol) in 10 mL of CH3CN was stirred at room temperature for 10 minutes. Then, Int-2 (111.5 mg, 0.358 mmol) was added and the reaction mixture was concentrated by heating at 60 °C for 12 hours. The mixture was then purified by elution (MeOH / DCM = 0-5%) to give 12-3 (160 mg, 45% yield).

[0662] LCMS:rt=1.388min,[M+H]+=598

[0663] (4) Preparation of compound 12

[0664]

[0665] To a mixture of 12-3 (160 mg, 0.27 mmol) in THF (5 mL), a lithium hydroxide solution (1 N, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, purified by pre-HPLC, and lyophilized to give compound 12 (19.65 mg, 12.58% yield).

[0666] LCMS:rt=1.224min,[M+H]+=584

[0667] 1H NMR(400MHz,MeOD)δ8.18(s,1H),7.95(dd,J=8.4,1.5Hz,1H),7.65–7.57(m,3H),7.23(d,J =3.8Hz,1H),6.70(d,J=8.2Hz,1H),5.64(s,2H),5.27(d,J=6.7Hz,1H),4.72(dd,J=15.3,3 .0Hz,3H),4.61(dd,J=13.7,7.9Hz,2H),4.46(dd,J=5.9,3.1Hz,1H),4.37(s,2H),4.12(dd ,J=34.0,13.6Hz,2H),3.90(s,2H),2.85(s,4H),2.75(d,J=6.5Hz,1H),2.57–2.49(m,1H).

[0668] Example 13

[0669] (S)-1-(oxetane-2-ylmethyl)-2-((4-(6-((5-(pyrimidin-5-yl)thiophen-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 13)

[0670]

[0671] (1) Preparation of compound 13-2

[0672]

[0673] A mixture of 13-1 (871 mg, 4.52 mmol), 5-(tributylmethanesulfonyl)pyrimidine (2.2 mL, 6.77 mmol), Pd2(dba3)2 (828 mg, 0.90 mmol), and Cy3P (253 mg, 0.90 mmol) in dry DME (20 mL) was stirred at 90 °C for 16 h. The reaction solution was extracted with DCM / MeOH (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Rapid chromatography (SiO2, EtOAc-hexane) yielded 360 mg of compound 13-2.

[0674] 1 H NMR (400MHz, CDCl3) 9.09 (1H, s), 9.08 (2H, s), 7.61 (1H, d, J = 3.6), 7.06 (1H, d, J = 3.7), 5.64 (1H, t, J = 5.7), 4.69 (2H, d, J = 5.7).

[0675] LC-MS: (ESI) m / z: 193 [M+H] +

[0676] (2) Preparation of compound 13-3

[0677]

[0678] MsCl (257 mg, 2.24 mmol) and TEA (2.6 mL, 18.7 mmol) were added to a solution of 13-2 (360 mg, 1.87 mmol) in anhydrous DCM (5 mL). The reaction mixture was stirred at 0 °C for 30 min and then quenched with water. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give 13-3 (500 mg, crude product).

[0679] (3) Preparation of compound 13-4

[0680]

[0681] A mixture of 13-3 (500 mg, 1.84 mmol) and Cs₂CO₃ (663 mg, 2.03 mmol) in DMF (10 mL) was stirred overnight at 50 °C. The reaction was quenched with H₂O (10 mL). After extraction with DCM (10 mL × 3), the organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain the residue. The crude product was purified by HPLC (gradient: 10% MeCN / 90% H₂O, H₂O to 100% MeCN) to give 194 mg of compound 13-4.

[0682] LC-MS:MC21-663-034-P,(ESI)m / z:611.4[M+H] +

[0683] (4) Preparation of compound 13

[0684]

[0685] A solution of 13-4 (197 mg, 0.32 mmol), 0.5 mL of LiOH, and 0.5 mL of THF was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure to obtain the crude product, which was purified by HPLC (gradient: 10% MeCN / 90% H2O, 0.1% NH3·H2O to 100% MeCN) to give 64.79 mg of compound 13.

[0686] LC-MS:MC21-663-037-P,(ESI)m / z:597.3[M+H] +

[0687] 1 H NMR (400MHz, DMSO) δ9.09 (s, 1H), 9.06 (s, 2H), 8.26 (s, 1H), 7.81 (dd, J = 8.0Hz, 1H), 7.65 (m, 3H), 7.32 (d, J = 4.0Hz ,1H),6.91(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),5.67–5.54(m,2H),5.11(m,1H),4.79(dd,J1=8.0Hz,J2=16.0Hz 1H),4.65(dd,J=12.0Hz,1H),4.44(m,1H),4.36(m,1H),3.97(d,J=16.0Hz,1H),3.82(d,J=16.0Hz,1H),3.0 4(d,J=12.0Hz,1H),2.89(d,J=12.0Hz,1H),2.69(m,2H),2.42(m,1H),2.31–2.15(m,2H),1.96–1.72(m,4H).

[0688] The GLP-1 receptor agonist and its applications provided by this invention have been described in detail above. Specific embodiments have been used to illustrate the principles and implementation methods of this invention. These embodiments are merely illustrative and are intended to help understand the method and central ideas of this invention. It should be noted that those skilled in the art can make various improvements and modifications to this invention without departing from its principles, and these improvements and modifications also fall under the protection of the claims of this invention.

Claims

1. Compounds of Formula I-2 (I-2) and its pharmaceutically acceptable salts, in: ------ indicates that the key does not exist; Z1 and Z4 are each independently selected from CH; X1 is N; X2 and X3 are each independently C; Y1 is N; Y2 is CH; Y3 is N; R1 is independently selected from: R2, where R2 is selected from halogens, -C 1~6 Alkyl, cyano, or 5-8 membered heteroaryl; or -carbonyl-R2, where R2 is selected from -C 1~6 Alkyl or 3- to 8-membered cycloalkyl; -C in R2 1~6 Alkyl groups are optionally selected from R x The substituents are substituted 1 to 3 times; R4 is independently selected from hydrogen; R5 is independently selected from hydrogen; R6 is selected from -C1 alkylene-R z ; R7 is selected from -COOH; n is 1 or 2; o is an integer selected from 0, 1, 2, 3 or 4; p is an integer selected from 0, 1, 2, 3 or 4; When o is not 0 and p is not 0, any R4 and R5 can be further cyclically transformed into 5- to 8-element rings; R x Independently selected from halogens; R z Independently selected from 4- to 6-membered heterocycles; and The condition is that the compound is not: ,or .

2. The compound according to claim 1, wherein, When o is not 0 and p is not 0, any adjacent R4 and R5 can be further cyclically transformed into 5- to 8-membered rings; the 5- to 8-membered rings are selected from C 5~6 Carbon rings, 5-8 membered heterocycles, benzene rings, and 5-8 membered heteroaromatic rings.

3. The compound according to claim 2, wherein the 5- to 8-membered rings are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

4. The compound according to claim 2, wherein the 5- to 8-membered rings are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

5. The compound according to claim 1, wherein p is selected from 0 or 1.

6. The compound according to claim 1, wherein R1 is further independently selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -(CH)2CH3, -COCH3, -CF3, -CHF2, -CH2F, -CH2CH2F and -CO-cyclopropyl.

7. The compound according to claim 1, wherein the compound is: , , , , , , , , , , and its pharmaceutically acceptable salts.

8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical carrier.

9. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a medicament for the prevention and / or treatment of GLP-1 receptor agonist-mediated diseases or related diseases.

10. The application according to claim 9, wherein the GLP-1-mediated diseases and related diseases are selected from diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia.

Images