Condensed imidazole derivatives, methods for preparing the same, and their pharmaceutical applications

Abstract

The present invention provides compounds for preparing drugs that treat and / or prevent diabetes as GLP-1 receptor agonists. [Solution] A condensed imidazole derivative represented by general formula (IM), a method for preparing the same, a pharmaceutical composition containing the derivative, and its uses as a therapeutic agent, particularly as a GLP-1 receptor agonist and in the preparation of drugs for treating and / or preventing diabetes, are provided. TIFF2026053592000243.tif5495

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and relates to condensed imidazole derivatives, methods for preparing the same, and their pharmaceutical applications. In particular, this disclosure relates to condensed imidazole derivatives represented by general formula (IM), methods for preparing the same, pharmaceutical compositions containing the derivative, and their use in the field of diabetes treatment as GLP-1 receptor agonists. [Background technology]

[0002] Diabetes mellitus is a multifactorial metabolic disease characterized by chronic hyperglycemia accompanied by impaired glucose, lipid, and protein metabolism due to defects in insulin secretion or action. Diabetes mellitus is a long-established disease in which an absolute or relative deficiency of insulin in the body leads to elevated blood glucose levels, and furthermore, large amounts of sugar are excreted in the urine, resulting in symptoms such as polydipsia, polyuria, polyphagia, and emaciation.

[0003] Generally, there are two types of diabetes. Type 1 diabetes, or insulin-dependent diabetes, involves the production of very little or no insulin. Insulin is a hormone that regulates glucose utilization in the body. Type 2 diabetes, or non-insulin-dependent diabetes, involves plasma insulin concentrations equal to or higher than those of non-diabetic patients. However, these patients exhibit insulin resistance, and this insulin stimulates glucose and lipid metabolism in key insulin-sensitive tissue cells, such as muscles, the liver, and adipose tissue. Even high plasma insulin concentrations cannot resolve the patient's significant insulin resistance.

[0004] Insulin resistance can result not only from a decrease in the number of insulin receptors but also from defects in insulin receptors, although its pathogenesis has not yet been fully elucidated. Due to insulin response resistance, insulin cannot activate glucose uptake, oxidation, and storage in muscle tissue, nor can it effectively suppress lipolysis in adipose tissue, nor glucose production and secretion in the liver.

[0005] Glucagon-like peptide-1 (GLP-1) is one of the incretin hormones secreted by L- cells in the lower gastrointestinal tract.

[0006] GLP-1 exerts its effects through binding to its widely distributed specific receptors. Currently, GLP-1 receptors have been identified in pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, the hypothalamus of the brain, and the cardiovascular system. Potential GLP-1 receptors may also be present in the liver, adipose tissue, and skeletal muscle. GLP-1 acts on β-cells to promote insulin secretion, while simultaneously acting on α-cells to suppress glucagon secretion. Serum GLP-1 levels generally do not differ significantly between patients with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. However, there is a defect in the β-cell response to GLP-1 after feeding, and under certain conditions, this response is significantly enhanced after continuous GLP-1 infusion. Because the duration of action of the body's own GLP-1 is very short (intravenous injection t1 / 2 < 1.5 minutes), the body's own GLP-1 is not used in the clinical treatment of diabetes.

[0007] Peptide GLP-1 receptor agonists (e.g., liraglutide, exenatide) reduce fasting and postprandial glucose levels and improve blood glucose levels in patients with type 2 diabetes. However, peptide GLP-1 has low oral bioavailability and is inconvenient to administer, so there is great interest in small molecule GLP-1 receptor agonists with good oral bioavailability.

[0008] Patent applications disclosed for GLP-1 receptor small molecule agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1, and WO2018056453A1, among others. [Overview of the project]

[0009] This disclosure aims to provide compounds represented by general formula (IM), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, Ring B is a phenyl group or a 5-membered or 6-membered heteroaryl group. M is either an N atom or a C atom. [ka] It is a single bond or a double bond, and when M is an N atom, [ka] It is a single bond, and when M is a carbon atom, [ka] It is either a single bond or a double bond. The ring C is a 6- to 7-membered heterocyclyl group, and the above 6- to 7-membered heterocyclyl group contains 1 to 2 heteroatoms selected from O atoms or S atoms. Ring A is an aryl group or a heteroaryl group, R 1 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 2This group is selected from hydrogen atoms, alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 3 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, oxo groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 4 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 5 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 6These are homologous or different and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, cyano groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. n is 0, 1, 2, or 3. m is 0, 1, 2, 3, or 4. p is 0, 1, 2, or 3. g is 0, 1, 2, 3, 4 or 5, and q is 0, 1, 2, 3, or 4.

[0010] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, Eventually, Ring B is a phenyl group or a 5-membered or 6-membered heteroaryl group. M is either an N atom or a C atom. [ka] It is a single bond or a double bond, and when M is an N atom, [ka] It is a single bond, and when M is a carbon atom, [ka] is a single bond or a double bond, ring C is a 6- to 7-membered heterocyclyl group, and the above 6- to 7-membered heterocyclyl group contains 1 to 2 heteroatoms selected from O atoms or S atoms, ring A is an aryl group or a heteroaryl group, R 1 are the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group, hydroxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, R 2 is a hydrogen atom, alkyl group, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, among which the above alkyl group, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, R 3 are the same or different and each independently is a hydrogen atom, halogen, alkyl group, oxo group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group, hydroxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, R 4These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 5 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 6 These are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. n is 0, 1, 2, or 3. m is 0, 1, 2, 3, or 4. p is 0, 1, 2, or 3. g is 0, 1, 2, 3, 4 or 5, and q is 0, 1, 2, 3, or 4.

[0011] In some preferred embodiments of this disclosure, the compound represented by the above general formula (IM), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by the general formula (IN), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. [ka] Eventually, Y 5 is an O atom or an S atom, Y 4 and Y 6 These are homologous or different, and each is independently of the O atom, S atom and -(CR). m R n ) k -Selected from, and as a condition, Y 4 and Y 6 It is not a heteroatom at the same time, R m and R n These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. Ring B, M, [ka] , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IM).

[0012] In some preferred embodiments of this disclosure, the compound represented by general formula (IM) or general formula (IN) above, or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (INa) or general formula (INb), or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. [ka] or [ka] Eventually, Y 5 is an O atom or an S atom, Y 4 and Y 6 These are homologous or different, and each is independently of the O atom, S atom and -(CR). m R n ) k -Selected from, and as a condition, Y 4 and Y 6 It is not a heteroatom at the same time, R m and R n These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. Ring B, M, [ka] , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IM).

[0013] In some preferred embodiments of this disclosure, the compound represented by the above general formula (IM), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by the general formula (I), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. [ka] Eventually, Y 1 is an O atom or an S atom, Y 2 and Y 3 These are homologous or different, and each is independently of the O atom, S atom and -(CR). m R n ) k -Selected from, and as a condition, Y 2 and Y 3 It is not a heteroatom at the same time, R m and R n These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. Ring B, M, [ka] , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IM).

[0014] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (IM), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, Eventually, Ring B is a phenyl group or a 5-membered or 6-membered heteroaryl group. M is either an N atom or a C atom. [ka] It is a single bond or a double bond, and when M is an N atom, [ka] It is a single bond, and when M is a carbon atom, [ka] It is either a single bond or a double bond. Y 1 is an O atom or an S atom, Y 2 and Y 3 These are homologous or different, and each is independently of the O atom, S atom and -(CR). m R n ) k -Selected from, and as a condition, Y 2 and Y 3 It is not a heteroatom at the same time, Ring A is an aryl group or a heteroaryl group, R m and R n These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 1 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 2This group is selected from hydrogen atoms, alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 3 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, oxo groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 4 These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 5 These are selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 6These are homologous or different and are independently selected from a hydrogen atom, alkyl group, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and each of these alkyl groups, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently and optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group. k is either 1 or 2. n is 0, 1, 2, or 3. m is 0, 1, 2, 3, or 4. p is 0, 1, 2, or 3, and q is 0, 1, 2, 3, or 4.

[0015] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM) or general formula (I), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, of which R 6These groups are homologous or different and are independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0016] In some preferred embodiments of this disclosure, the compound represented by general formula (IM) or general formula (I) above, or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (II), or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. [ka] Eventually, Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (I).

[0017] In some preferred embodiments of the present disclosure, a compound represented by the above-mentioned general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa), or general formula (INb), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a phenyl group, a pyridyl group, and a thienyl group.

[0018] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), or (INb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is a phenyl group or a thienyl group.

[0019] In some preferred embodiments of this disclosure, the compound represented by the above general formula (IM) or general formula (IN), or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (IIG), or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. [ka] Eventually, G is either a C atom or an N atom. Y 5 is an O atom or an S atom, Y 4 and Y 6 These are homologous or different, and each is independently of the O atom, S atom and -(CR). m R n ) k -Selected from, and as a condition, Y 4 and Y 6 It is not a heteroatom at the same time, R m and R nare the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, k is 1 or 2, M, ring A, R 1 ~R 6 , n, m, p and q are as defined in general formula (IM).

[0020] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (IN) or general formula (IIG), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIGa) or general formula (IIGb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, [Chemical formula] or [Chemical formula] Among them, G is a C atom or a N atom, Y 5 is an O atom or a S atom, Y 4 and Y 6 are the same or different and each independently an O atom, a S atom and -(CR m R n ) k - selected, provided that Y 4 and Y 6 are not heteroatoms simultaneously, R m and R nare the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, k is 1 or 2, M, ring A, R 1 ~R 6 , n, m, p, and q are as defined in general formula (IM).

[0021] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (IN), or general formula (IIG), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIN), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, [Chemical formula] Among them, Y 5 is an O atom or an S atom, Y 4 and Y 6 are the same or different and each independently an O atom, an S atom, and -(CR m R n ) k - and are selected, provided that Y 4 and Y 6 are not both heteroatoms at the same time, R m and R n are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, k is 1 or 2, M, ring A, R1 ~R 6 n, m, p, and q are as defined in general formula (IM).

[0022] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (IN), general formula (IIG), or general formula (IIN), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by general formula (IINa) or general formula (IINb), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt,

Chemical Structure

Chemical Structure

[0023] In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IN), general formula (INa), general formula (INb), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IIN), general formula (IINa), or general formula (IINb), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, among which Y 4 and Y 5 It is an O atom, and Y 6 Ha-(CR m R n ) k - and Y 5 and Y 6 It is an O atom, and Y 4 Ha-(CR m R n ) k - and k is 1 or 2, R m and R n These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy group, hydroxy C 1-6 Selected from alkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups.

[0024] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, among which Y 1 and Y 2 It is an O atom, and Y 3 Ha-(CR m R n ) k - and Y 1 and Y 3is an O atom, and Y 2 is -(CR m R n ) k -, k is 1 or 2, and R m and R n are as defined in general formula (I).

[0025] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (IN), general formula (IIG), or general formula (IIN), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by general formula (IIIN-1) or general formula (IIIN-2), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt, [Chemical formula] or [Chemical formula] Among them, k is 1 or 2, M, ring A, R 1 ~R 6 , n, m, p, and q are as defined in general formula (IM).

[0026] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IM), general formula (I), or general formula (II), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by general formula (III-1) or general formula (III-2), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt, [Chemical formula] or [Chemical formula] Eventually, k is either 1 or 2. M, ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IM).

[0027] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formula (IM), general formula (I), general formula (IN), general formula (INa), or general formula (INb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which, [ka] teeth [ka] Selected from, R 3 m is as defined in the general formula (IM).

[0028] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (II), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), or (III-2), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which, [ka] teeth, [ka] And R 3 is a hydrogen atom or C 1-6 It is an alkyl group, preferably, [ka] is [Chemistry] selected from

[0029] In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa), general formula (INb), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IIN), general formula (IINa), general formula (IINb), general formula (IIIN-1), general formula (IIIN-2), general formula (III-1) or general formula (III-2), or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof in the form of a pharmaceutically acceptable salt thereof, among which, [Chemistry] is [Chemistry] where R 3 and m are as defined in the general formula (IM).

[0030] In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa), general formula (INb), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IIN), general formula (IINa), general formula (IINb), general formula (IIIN-1), general formula (IIIN-2), general formula (III-1) or general formula (III-2), or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof in the form of a pharmaceutically acceptable salt thereof, among which, [Chemistry] is [Chemistry] where R 3is a hydrogen atom or C 1-6 It is an alkyl group, preferably, [ka] teeth [ka] They are selected from among them.

[0031] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), or (III-2) are provided in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, where M is CH.

[0032] In some preferred embodiments of the present disclosure, compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), or (III-2), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably ring A is a phenyl group, a 5- or 6-membered heteroaryl group and [ka] Ring C' is selected from a benzothiazolyl group, a phenyl group, and a pyridyl group, and more preferably, ring A is selected from a benzothiazolyl group, a phenyl group, and a pyridyl group.

[0033] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), or (III-2), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which, [ka] teeth [ka] Selected from, R 6 And q are as defined in the general formula (IM).

[0034] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which, [ka] teeth [ka] Selected from, R 6These are homologous or homologous and each is independently selected from a hydrogen atom, halogen, alkyl group, alkoxy group, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, of which the alkyl group, heterocyclylalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and q is 0, 1, 2, 3 or 4.

[0035] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] And R 6 And q are as defined in general formula (I).

[0036] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, preferably hydrogen atoms.

[0037] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 2 is C 1-6 It is an alkyl group, and among them, the above C 1-6 Alkyl groups can optionally include halogens, hydroxyl groups, and C 1-6 It is substituted with one or more substituents selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, preferably R 2 teeth [ka] That is the case.

[0038] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 3 These are homologous or different, and each independently consists of a hydrogen atom, a halogen, an oxo group, and C. 1-6 Selected from alkyl groups.

[0039] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 3 is a hydrogen atom or C 1-6 It is an alkyl group.

[0040] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6Selected from alkyl groups, preferably hydrogen atoms.

[0041] In some embodiments of this disclosure, the compound represented by the above general formula (IM) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 5 These are homologous or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group.

[0042] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 5 is a hydrogen atom or C 1-6 It is an alkyl group.

[0043] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 6 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups, cyano groups and halo C 1-6 Selected from alkyl groups, preferably a hydrogen atom, halogen, and C 1-6Selected from alkyl groups and cyano groups.

[0044] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R 6 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group and halo C 1-6 Selected from alkyl groups.

[0045] In some embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) are in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, where k is 1.

[0046] In some preferred embodiments of the present disclosure, the compounds represented by the above-mentioned general formulas (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), and (IINb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which R m and R nThese are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, preferably a hydrogen atom and C 1-6 It is an alkyl group.

[0047] In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IM), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 7-membered heterocyclyl group, the 6- to 7-membered heterocyclyl group comprises one or two heteroatoms selected from O atoms or S atoms, and M is a nitrogen atom or a carbon atom. [ka] It is a single bond or a double bond, and when M is an N atom, [ka] It is a single bond, and when M is a carbon atom, [ka] R is a single or double bond, ring B is a phenyl group or a 5-membered or 6-membered heteroaryl group, ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, n is 0, 1, or 2, R 2 is C 1-6 Alkyl alkyl groups or 3- to 8-membered heterocyclyl C 1-6 It is an alkyl group, and among them, the above C 1-6 Alkyl groups can optionally include halogens, hydroxyl groups, and C 1-6 Substituted with one or more substituents selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 3 These are homologous or different, and each independently consists of a hydrogen atom, a halogen, an oxo group, and C. 1-6Selected from alkyl groups, m is 0 or 1, R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, R 5 These are homologous or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, g is 0, 1, or 2, R 6 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups, cyano groups and halo C 1-6 It is selected from alkyl groups, and q is 0, 1, 2, or 3.

[0048] In some preferred embodiments of the present disclosure, the compounds represented by the above general formulas (IN), (INa), and (INb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, among which Y 4 and Y 5 It is an O atom, and Y 6 Ha-(CR m R n ) k - and Y 5 and Y 6 It is an O atom, and Y 4 Ha-(CR m R n ) k - and k is 1 or 2, R m and R n These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy group, hydroxy C 1-6Selected from alkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclyl groups, 6- to 10-membered aryl groups and 5- to 10-membered heteroaryl groups, M is a nitrogen atom or a carbon atom, ring B is a phenyl group or a 5- or 6-membered heteroaryl group, and ring A is a phenyl group, a 5- or 6-membered heteroaryl group and [ka] Selected from, the ring C' is a 5-membered or 6-membered heteroaryl group, R 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, n is 0, 1, or 2, R 2 is C 1-6 Alkyl alkyl groups or 3- to 8-membered heterocyclyl C 1-6 It is an alkyl group, and among them, the above C 1-6 Alkyl groups can optionally include halogens, hydroxyl groups, and C 1-6 Substituted with one or more substituents selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 3 These are homologous or different, and each independently consists of a hydrogen atom, a halogen, an oxo group, and C. 1-6 Selected from alkyl groups, m is 0 or 1, R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, R 5 is a hydrogen atom or C 1-6 It is an alkyl group, R 6 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups, cyano groups and halo C 1-6 It is selected from alkyl groups, and q is 0, 1, 2, or 3.

[0049] In some preferred embodiments of the present disclosure, the compounds represented by the above general formulas (IIG), (IIGa), and (IIGb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, where G is a nitrogen atom or a carbon atom, and Y 4 and Y 5 It is an O atom, and Y 6 Ha-(CR m R n ) k - and Y 5 and Y 6 It is an O atom, and Y 4 Ha-(CR m R n ) k - and k is 1 or 2, R m and R n Both are hydrogen atoms, and ring A is a phenyl group, a 5-membered or 6-membered heteroaryl group. [ka] Selected from, the ring C' is a 5-membered or 6-membered heteroaryl group, R 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, n is 0, 1, or 2, R 2 is C 1-6 Alkyl alkyl groups or 3- to 8-membered heterocyclyl C 1-6 It is an alkyl group, and among them, the above C 1-6 Alkyl groups can optionally include halogens, hydroxyl groups, and C 1-6 Substituted with one or more substituents selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 3 These are homologous or different, and each independently consists of a hydrogen atom, a halogen, an oxo group, and C. 1-6 Selected from alkyl groups, m is 0 or 1, R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, R 5 is a hydrogen atom or C 1-6It is an alkyl group, R 6 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups, cyano groups and halo C 1-6 It is selected from alkyl groups, and q is 0, 1, 2, or 3.

[0050] In some preferred embodiments of the present disclosure, the compounds represented by the above general formulas (IIG), (IIGa), and (IIGb), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, where G is a carbon atom and Y 4 and Y 5 It is an O atom, and Y 6 Ha-(CR m R n ) k - and k is 1, R m and R n All are hydrogen atoms, and ring A is selected from a benzothiazolyl group, a phenyl group, and a pyridyl group, R 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, n is 0, 1, or 2, R 2 is C 1-6 Alkyl alkyl groups or 3- to 8-membered heterocyclyl C 1-6 It is an alkyl group, and among them, the above C 1-6 Alkyl groups can optionally include halogens, hydroxyl groups, and C 1-6 Substituted with one or more substituents selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 3 These are homologous or different, and each independently consists of a hydrogen atom, a halogen, an oxo group, and C. 1-6 Selected from alkyl groups, m is 0 or 1, R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, R 5 is a hydrogen atom or C 1-6 It is an alkyl group, R 6These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups, cyano groups and halo C 1-6 It is selected from alkyl groups, and q is 0, 1, 2, or 3.

[0051] Table A Typical compounds in this disclosure include, but are not limited to, the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0052] Another aspect of this disclosure relates to compounds represented by general formula (IMA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Ring C, Ring A, R 1 ~R 6 n, m, p, g, and q are as defined in the general formula (IM). It is an intermediate for preparing the general formula (IM).

[0053] Another aspect of this disclosure relates to a compound represented by general formula (INA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IN). It is an intermediate for preparing the general formula (IN).

[0054] Another aspect of this disclosure relates to compounds represented by general formula (INaA) or general formula (INbA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] or [ka] Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (IN). It is an intermediate for preparing general formula (INa) or general formula (INb).

[0055] Another aspect of this disclosure relates to a compound represented by general formula (IIGA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (IIG). It is an intermediate for preparing general formula (IIG).

[0056] Another aspect of this disclosure relates to a compound represented by general formula (IINA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IIN). It is an intermediate for preparing the general formula (IIN).

[0057] Another aspect of this disclosure relates to compounds represented by general formula (IIGaA) or general formula (IIGbA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] or [ka] Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IIGa) or general formula (IIGb). It is an intermediate for preparing the general formula (IIGa) or general formula (IIGb).

[0058] Another aspect of this disclosure relates to compounds represented by general formula (IINaA) or general formula (IINbA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] or [ka] Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IINa) or general formula (IINb). It is an intermediate for preparing the general formula (IINa) or general formula (IINb).

[0059] Another aspect of this disclosure relates to a compound represented by general formula (IIINA-1), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are as defined in the general formula (IIIN-1). It is an intermediate for preparing the general formula (IIIN-1).

[0060] Another aspect of this disclosure relates to a compound represented by general formula (IIINA-2), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are as defined in the general formula (IIIN-2). It is an intermediate for preparing the general formula (IIIN-2).

[0061] Another aspect of this disclosure relates to a compound represented by general formula (IA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (I). It is an intermediate for preparing general formula (I).

[0062] Another aspect of this disclosure relates to a compound represented by general formula (IIA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] Eventually, R w C 1-6 It is an alkyl group, Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6n, m, p, and q are as defined in general formula (IA). It is an intermediate for preparing general formula (II).

[0063] Another aspect of this disclosure relates to compounds represented by general formula (III-1A) or general formula (III-2A), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. [ka] or [ka] Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are as defined in general formula (IA). It is an intermediate for preparing general formula (III-1) or general formula (III-2).

[0064] Table B Typical intermediate compounds of this disclosure include, but are not limited to, the following: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0065] Another aspect of this disclosure relates to a compound represented by general formula (IM), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves hydrolyzing a compound of general formula (IMA) to obtain a compound of general formula (IM), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Ring C, Ring A, R 1 ~R6 n, m, p, g, and q are as defined in the general formula (IM).

[0066] Another aspect of this disclosure relates to a compound represented by general formula (IN), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves hydrolyzing a compound of general formula (INA) to obtain a compound of general formula (IN), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IN).

[0067] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (INa) or general formula (INb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] or [ka] This includes hydrolyzing a compound of general formula (INaA) to obtain a compound of general formula (INa), or hydrolyzing a compound of general formula (INbA) to obtain a compound of general formula (INb), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (INa) or general formula (INb).

[0068] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (INa) or general formula (INb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves chiral recalculating a compound of general formula (IN) to obtain a compound of general formula (INa) and a compound of general formula (INb), respectively. Eventually, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (INa) or general formula (INb).

[0069] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IIG), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves hydrolyzing a compound of general formula (IIGA) to obtain a compound of general formula (IIG), Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IIG).

[0070] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIGa) or general formula (IIGb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] or [ka] To obtain a compound of general formula (IIGa) by hydrolyzing a compound of general formula (IIGaA), or This method involves hydrolyzing a compound of general formula (IIGbA) to obtain a compound of general formula (IIGb), Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (IIGa) or general formula (IIGb).

[0071] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIGa) or general formula (IIGb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves chiral resolution of a compound of general formula (IIG) to obtain a compound of general formula (IIGa) and a compound of general formula (IIGb), among which, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (IIGa) or general formula (IIGb).

[0072] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IIN), or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes hydrolyzing a compound of general formula (IINA) to obtain a compound of general formula (IIN), Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IIN).

[0073] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IINa) or general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] or [ka] To obtain a compound of general formula (IINa) by hydrolyzing a compound of general formula (IINaA), or This method involves hydrolyzing a compound of general formula (IINbA) to obtain a compound of general formula (IINb), Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IINa) or the general formula (IINb).

[0074] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IINa) or general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves chiral recalculating a compound of general formula (IIN) to obtain a compound of general formula (IINa) and a compound of general formula (IINb), among which, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IINa) or the general formula (IINb).

[0075] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIN-1) or general formula (IIIN-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] or [ka] To hydrolyze a compound of general formula (IIINA-1) to obtain a compound of general formula (IIIN-1), or This includes hydrolyzing a compound of general formula (IIINA-2) to obtain a compound of general formula (IIIN-2), Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are defined as in general formula (IIIN-1) or general formula (IIIN-2).

[0076] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes hydrolyzing a compound of general formula (IA) to obtain a compound of general formula (I), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (I).

[0077] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] The method includes hydrolyzing a compound of general formula (IIA) to obtain a compound of general formula (II), Eventually, R w C 1-6 It is an alkyl group, Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (II).

[0078] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or general formula (III-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] or [ka] To obtain a compound of general formula (III-1) by hydrolyzing a compound of general formula (III-1A), or This includes hydrolyzing a compound of general formula (III-2A) to obtain a compound of general formula (III-2), Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are defined as in general formula (III-1) or (III-2).

[0079] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa), general formula (INb), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IIN), general formula (IINa), general formula (IINb), general formula (IIIN-1), general formula (IIIN-2), general formula (III-1), and general formula (III-2) or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

[0080] This disclosure further relates to the use of compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIN), (IIG), (IIGa), (IIGb), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2), or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof, in the preparation of agents for activating GLP-1 receptors.

[0081] This disclosure further relates to compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or the The present invention relates to the use of pharmaceutical compositions containing the above in the preparation of agents for treating and / or preventing type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance, and more preferably in the preparation of agents for treating and / or preventing type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0082] This disclosure further relates to the use of compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIG), (IIGa), (IIGb), (IIN), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for the treatment and / or prevention of idiopathic type 1 diabetes, adult latent autoimmune diabetes (LADA), juvenile-onset adult-type diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary heart disease.

[0083] The present disclosure further relates to a method for activating the GLP-1 receptor, comprising administering to a patient in need a therapeutically effective dose of a compound represented by formula (IM), formula (I), formula (II), formula (IN), formula (INa), formula (INb), formula (IIG), formula (IIGa), formula (IIGb), formula (IIN), formula (IINa), formula (IINb), formula (IIIN-1), formula (IIIN-2), formula (III-1), and formula (III-2) or in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof.

[0084] This disclosure further relates to a method for treating and / or preventing type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance, preferably type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease and cardiovascular disease, wherein a therapeutically effective amount of general formula (IM), general formula (I), general formula (I) is administered to the patient in need. I) A method comprising administering a compound represented by general formula (IN), general formula (INa), general formula (INb), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IIN), general formula (IINa), general formula (IINb), general formula (IIIN-1), general formula (IIIN-2), general formula (III-1) and general formula (III-2), or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0085] The disclosure further relates to treating and / or preventing idiopathic type 1 diabetes, latent autoimmune diabetes in adulthood (LADA), early-onset adult-onset diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease by administering to patients in need an effective dose of a compound represented by formula (IM), formula (I), formula (II), formula (IN), formula (INa), formula (INb), formula (IIG), formula (IIGa), formula (IIGb), formula (IIN), formula (IINa), formula (IINb), formula (IIIN-1), formula (IIIN-2), formula (III-1) and formula (III-2) or its tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof.

[0086] This disclosure further relates to compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIN), (IIG), (IIGa), (IIGb), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) used as pharmaceuticals, or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0087] This disclosure further relates to compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIN), (IIG), (IIGa), (IIGb), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) used as GLP-1 receptor agonists, or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0088] This disclosure further relates to general formulas (IM), general formula (I), and general formula ( II) The present invention relates to compounds represented by general formula (IN), general formula (INa), general formula (INb), general formula (IIN), general formula (IIG), general formula (IIGa), general formula (IIGb), general formula (IINa), general formula (IINb), general formula (IIIN-1), general formula (IIIN-2), general formula (III-1) and general formula (III-2), or in the form of tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0089] This disclosure further relates to compounds represented by general formulas (IM), (I), (II), (IN), (INa), (INb), (IIN), (IIG), (IIGa), (IIGb), (IINa), (IINb), (IIIN-1), (IIIN-2), (III-1), and (III-2) or in the form of tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for the treatment and / or prevention of idiopathic type 1 diabetes, adult latent autoimmune diabetes (LADA), juvenile-onset adult-type diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0090] "Diabetic complications" are complications resulting from diabetes or hyperglycemia, and may be acute or chronic. The term "acute complications" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), while "chronic complications" include, for example, microangiopathy (e.g., kidney disease, retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, autonomic neuropathy), and gangrene. The main diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0091] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0092] "Dementia" includes, for example, Alzheimer's disease, (early-onset dementia) EOD, vascular dementia, and diabetic dementia.

[0093] The active compound can be prepared in a form suitable for administration by any suitable route, and the composition of this disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable vectors. Accordingly, the active compound of this disclosure can be prepared in dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation. The compound of this disclosure may also be prepared in sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, tablets, or syrups.

[0094] As a general guideline, the active compound is preferably in the form of a unit dose or in a form that the patient can administer to themselves as a monotherapy. The unit dose of the compound or composition relating to this disclosure may be expressed as a tablet, capsule, cachet, bottled solution, drug powder, granules, tablet, suppository, regenerated powder, or liquid formulation. A preferred unit dose may be 0.1 mg to 1000 mg.

[0095] The pharmaceutical composition relating to this disclosure may contain one or more additives in addition to the active compound, and these additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, and excipients. Depending on the administration method, the composition may contain 0.1% to 99% by weight of the active compound.

[0096] The tablets comprise an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for mixing in the preparation of the tablets. These excipients may be inert excipients, granulators, disintegrants, binders, and lubricants. These tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period.

[0097] An oral formulation may be provided in the form of a soft gelatin capsule containing the active ingredient and an inert solid diluent, or the active ingredient and a water-soluble vector or oily solvent.

[0098] The aqueous suspension comprises an active substance and an excipient suitable for mixing in the preparation of the aqueous suspension. Such an excipient is a suspending agent, a dispersing agent, or a wetting agent. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0099] An oily suspension can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oily suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0100] The pharmaceutical compositions relating to this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0101] The pharmaceutical compositions relating to this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection formulation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by local injection in large quantities. Alternatively, it is preferable to administer the solution and microemulsion in a manner that can maintain a constant cycle concentration of the compound relating to this disclosure. A continuous intravenous infusion device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

[0102] The pharmaceutical compositions relating to this disclosure may be in the form of sterile injection water or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the appropriate dispersants or wetting agents and suspending agents according to known techniques. The sterile injection formulation may also be a sterile injection solution or suspension prepared in a parenterally acceptable, non-toxic diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any compounding fixative oil can be used. Fatty acids can also be used to prepare injection formulations.

[0103] The compounds relating to this disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore dissolves in the rectum to release the drug.

[0104] The compounds according to this disclosure can be administered by adding water to prepare aqueous suspensions of dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a wetting agent, a suspending agent, and one or more preservatives.

[0105] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, physical condition, behavior, diet, administration time, method of administration, excretion rate, drug composition, and disease severity. Furthermore, the optimal treatment method, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt, can be determined according to conventional treatment plans.

[0106] Explanation of terms Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0107] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12). 1-12 It is an alkyl group, more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Alkyl groups are non-limiting examples of alkyl groups: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methyl Hexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, This includes 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.Most preferably are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, and 2,3-dimethylbutyl group. The alkyl group may be substituted or not, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more groups independently and optionally selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0108] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (i.e., C 1-12An alkylene group, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group may be substituted or not, and if substituted, it may be substituted at any available linking site. The substituent is preferably one or more substituents selected from alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0109] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or not substituted. If substituted, it is preferable that the substituted group is one or more groups independently selected from D atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0110] The term "alkenyl group" refers to an alkyl group compound that contains at least one carbon-carbon double bond in its molecule, the definition of an alkyl group as described above. Preferably, it contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (i.e., C 2-12 Alkenyl group), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl group). The alkenyl group may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0111] The term "alkynyl group" refers to an alkyl group compound in which the molecule contains at least one carbon-carbon triple bond, the definition of an alkyl group as described above. Preferably, it contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (i.e., C 2-12 Alkynyl group), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl group). The alkynyl group may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0112] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) (i.e., 3- to 12-membered cycloalkyl groups), preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3- to 8-membered cycloalkyl groups), and more preferably 3 to 6 carbon atoms (i.e., 3- to 6-membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0113] The term "spirocycloalkyl group" refers to a polycyclic group with 5 to 20 members, in which monocyclic rings share one carbon atom (referred to as a spiro atom), and which may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g., bisspirocycloalkyl groups), preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 3 / 5 member, 3 / 6 member, 4 / 4 member, 4 / 5 member, 4 / 6 member, 5 / 5 member, or 5 / 6 member monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] .

[0114] The term "condensed cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares one pair of adjacent carbon atoms with other rings in the system, and one or more of these rings may contain one or more double bonds. Preferably, they are 6- to 14 members, and more preferably 7- to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic alkyl groups. Non-limiting examples of condensed cycloalkyl groups are: [ka] .

[0115] The term "crosslinked cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds. Preferably, it is 6- to 14-membered, and more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Depending on the number of rings, crosslinked cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] .

[0116] The above cycloalkyl rings include those in which the above cycloalkyl groups (including monocyclic, spirocyclic, fused, and crosslinked rings) are fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples thereof are: [ka] This includes, but [ka] It is preferable.

[0117] The cycloalkyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more substituents independently and optionally selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0118] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally substituted with an oxo group (i.e., forming a sulfoxide or sulfone), but without the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms being carbon. Preferably, the group contains 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) (i.e., a 3- to 12-membered heterocyclyl group), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms (i.e., a 3- to 8-membered heterocyclyl group); even more preferably, it contains 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl group), of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group), of which 1 to 3 are heteroatoms. Non-restrictive examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl groups. Polycyclic heterocyclyl groups include spiro-ring, fused, and bridging ring heterocyclyl groups.

[0119] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which monocyclic rings share one atom (called a spiro atom), one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, the spiroheterocyclyl group is classified into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, with the monospiroheterocyclyl group and the bisspiroheterocyclyl group being preferred. More preferably, a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka]

[0120] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares one pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, one or more of which ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings that make up the group, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic condensed heterocyclyl groups. Non-limiting examples of condensed heterocyclyl groups are: [ka] Includes.

[0121] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, bridged heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] .

[0122] The above heterocyclyl rings include those in which the above heterocyclyl group (including monocycles, spiroheterocycles, fused heterocycles, and bridged heterocycles) is fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0123] The heterocyclyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is independently and optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, one or more substituents.

[0124] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as a phenyl group and a naphthyl group. The above aryl ring includes those in which the above aryl ring is fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes.

[0125] The aryl group may or may not be substituted, and if substituted, it may be substituted at any available linkage point. Preferably, the substituent is one or more substituents independently and selectively selected from a hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0126] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, or 4) and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered), and more preferably 5- or 6-membered (i.e., a 5- or 6-membered heteroaryl group), such as a furanyl group, thienyl group, pyridyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, etc. The heteroaryl ring includes those in which the heteroaryl group is fused to an aryl group, heterocyclyl group, or cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples include: [ka] Includes.

[0127] The heteroaryl group may be substituted or not, and if substituted, it may be substituted at any available linkage point. Preferably, the substituent is one or more substituents independently and selectively selected from a hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0128] The above-mentioned cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group have one residue derived by removing one hydrogen atom from the ring atom of the parent group, or two residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent group, i.e., a "divalent cycloalkyl group", a "divalent heterocyclyl group", an "arylene group", and a "heteroarylene group".

[0129] In the chemical structure of the compounds described in this disclosure, [ka]

[0130] The compounds relating to this disclosure may be in the form of specific geometric or stereoisomers. This disclosure includes all cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as mixtures rich in enantiomers and diastereomers, and all such compounds are intended to be within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this disclosure. Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. To obtain one enantiomer of a compound of this disclosure, preparation may be carried out by asymmetric synthesis or inductive action with a chiral aid, thereby providing the required pure enantiomer by separating the resulting diastereomer mixture and assisting in the fission of the groups. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is divided by a conventional method known in the art, after which the diastereomer is recovered to obtain a pure product. Furthermore, the separation of the enantiomer and diastereomer is generally achieved by chromatography.

[0131] The term "amino protecting group" refers to a group that protects an amino group with an easily eliminated group so that the amino group is not altered when other parts of the molecule react. Non-limiting examples include (trimethylsilicone)ethoxymethyl group, tetrahydropyranyl group (THP), tert-butoxycarbonyl group (Boc), acetyl group, benzyl group, allyl group, and p-methoxybenzyl group. These groups can be optionally substituted with one to three substituents selected from halogen, alkoxy, or nitro groups. The above amino protecting groups are preferably (trimethylsilicone)ethoxymethyl group and tert-butoxycarbonyl group.

[0132] The term "hydroxy protecting group" refers to a group used to protect a hydroxyl group, as is known in this field, as described in the literature ("Protective Groups in Organic Synthesis", 5 Th The hydroxy protecting group in Ed. TW Greene & P. ​​GM Wuts is referenced. For example, preferably the above hydroxy protecting group is a triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc. (C 1-10 It may also be an alkyl or aryl)3-silane group, C 1-10 It may be an alkyl group or a substituted alkyl group, preferably an alkyl group substituted with an alkoxy group or an aryl group, more preferably C 1-6 C substituted with an alkoxy group 1-6 C substituted with alkyl or phenyl groups 1-6 The alkyl group is most preferably a methyl group, tert-butyl group, allyl group, benzyl group, methoxymethyl group (MOM), ethoxyethyl group, etc. 1-4 C substituted with an alkoxy group 1-4 It is an alkyl group, such as formyl group, acetyl group, benzoyl group, p-nitrobenzoyl, etc. (C 1-10 It may also be an alkyl or aryl acyl group, (C 1-6 It may also be an alkyl or 6- to 10-membered aryl) sulfonyl group, (C 1-6The hydroxy protecting group may be an alkoxy or a 6- to 10-membered aryloxy)carbonyl group. The hydroxy protecting group is preferably p-nitrobenzoyl.

[0133] The term "heterocyclylalkyl group" refers to an alkyl group substituted with one or more heterocyclyl groups, where the heterocyclyl group and alkyl group are as defined above.

[0134] The term "heteroarylalkyl group" refers to an alkyl group substituted with one or more heteroaryl groups, where the heteroaryl group and alkyl group are as defined above.

[0135] The term "cycloalkylalkyl group" refers to an alkyl group substituted with one or more cycloalkyl groups, where the cycloalkyl group and alkyl group are as defined above.

[0136] The term "cycloalkyloxy group" refers to a cycloalkyl-O- group, where cycloalkyl is defined as described above.

[0137] The term "heterocyclyloxy group" refers to a heterocyclyl-O-, of which the heterocyclyl group is defined above.

[0138] The term "alkylthio group" refers to an alkyl-S- group, where the alkyl group is defined as described above.

[0139] The term "haloalkyl group" refers to a group in which an alkyl group is substituted with one or more halogens, where the alkyl group is as defined above.

[0140] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above.

[0141] The term "deuterated alkyl group" refers to a group in which an alkyl group is substituted with one or more deuterium atoms, where the alkyl group is as defined above.

[0142] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, where the alkyl group is as defined above.

[0143] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0144] The term "hydroxyl group" refers to the -OH group.

[0145] The term "mercapto group" refers to the -SH group.

[0146] The term "amino group" refers to -NH2.

[0147] The term "cyano group" refers to -CN.

[0148] The term "nitro group" refers to -NO2.

[0149] The term "oxo group" refers to the group "=O".

[0150] The term "carbonyl group" refers to C=O.

[0151] The term "carboxyl group" refers to -C(O)OH.

[0152] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group), -C(O)O(cycloalkyl group), (alkyl group)C(O)O-, or (cycloalkyl group)C(O)O-, where alkyl groups and cycloalkyl groups are as defined above. The compounds relating to this disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotope-rich atoms. For example, a compound having the structure relating to this disclosure, with hydrogen substituted with "deuterium" or "tritium," or 18 F-Fluorine label ( 18 Fluorine is replaced with the fluorine isotope (F isotope), or 11 C-, 13 C-, or 14 C- rich carbon ( 11 C-, 13 C-, or 14 C-carbon label, 11 C-, 13 C-, or 14 Compounds in which carbon atoms are substituted with 1C isotopes are within the scope of this disclosure. Such compounds may be used, for example, as analytical tools or probes in biometric measurements, or as imaging tracers for in vivo diagnosis of diseases, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. Of these, the deuterated form of the compound of formula (I) is in which each available hydrogen atom bonded to the carbon atom can be independently substituted with a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound of formula (I) by referring to relevant literature. When preparing the deuterated form of the compound of formula (I), commercially available deuterated starting materials may be used, or it may be synthesized by deuterating reagents by conventional techniques, including, but not limited to, deuterated borane, trihydrobolanetetrahydrofuran solution, lithium aluminum hydride deuterated, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds can generally maintain activity equivalent to that of non-deuterated compounds, and when deuteration is present at a specific site, they can achieve superior metabolic stability and offer several therapeutic benefits.

[0153] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may or may not be present, and this description includes both cases in which the heterocyclyl group is substituted with an alkyl group and cases in which the heterocyclyl group is not substituted with an alkyl group.

[0154] "Substituting" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3, are substituted by a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, if an amino or hydroxyl group with free hydrogen is bonded to a carbon atom with an unsaturated (e.g., olefin) bond, it may become unstable.

[0155] "Pharmaceutical composition" indicates a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living organism and contribute to the absorption of the active ingredient, thereby further exerting biological activity.

[0156] A "pharmaceutically acceptable salt" is a salt of the compound relating to this disclosure, which is safe and effective when used in the body of a mammal and possesses the desired biological activity. Salts may be prepared individually during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for producing pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0157] With respect to drugs or pharmacological activators, the term "therapeutic effective dose" refers to a sufficient amount of the drug or agent that is non-toxic while producing the desired effect. The effective dose is determined on a human basis, depending on the subject's age and general condition, as well as the specific active substance. A suitable effective dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0158] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to patient tissues, have a reasonable profit-benefit ratio, and are effective for the desired use.

[0159] As used herein, the singular forms "one," "one type," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0160] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that the parameter may vary within ±10%, and more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, the number is generally given simply for illustrative purposes, not as a limitation.

[0161] Synthesis method of the compound related to this disclosure To achieve the objectives of this disclosure, this disclosure adopts the following technical proposals.

[0162] Technical proposal 1 The compound represented by the general formula (IM) relating to this disclosure, or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, is: [ka] The method includes the step of hydrolyzing a compound of general formula (IMA) in the presence of a basic reagent to obtain a compound of general formula (IM), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Ring C, Ring A, R 1 ~R 6 n, m, p, g, and q are as defined in the general formula (IM).

[0163] Technical proposal 2 The compound represented by the general formula (IN) relating to this disclosure, or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, is: [ka] The method includes the step of hydrolyzing a compound of general formula (INA) in the presence of a basic reagent to obtain a compound of general formula (IN), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IN).

[0164] Technical proposal 3 The compounds represented by general formula (INa) or general formula (INb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] or [ka] A step of hydrolyzing a compound of general formula (INaA) in the presence of a basic reagent to obtain a compound of general formula (INa), or The method includes the step of hydrolyzing a compound of general formula (INbA) in the presence of a basic reagent to obtain a compound of general formula (INb), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (INa) or general formula (INb).

[0165] Technical proposal 4 The compounds represented by general formula (INa) or general formula (INb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] This method involves chiral recalculating a compound of general formula (IN) to obtain a compound of general formula (INa) and a compound of general formula (INb), respectively. Eventually, [ka] , Ring B, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (INa) or general formula (INb).

[0166] Technical proposal 5 The compound represented by the general formula (IIG) relating to this disclosure, or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, [ka] The method includes the step of hydrolyzing a compound of general formula (IIGA) in the presence of a basic reagent to obtain a compound of general formula (IIG), Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IIG).

[0167] Technical proposal 6 The compounds represented by general formula (IIGa) or general formula (IIGb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] or [ka] A step of hydrolyzing a compound of general formula (IIGaA) in the presence of a basic reagent to obtain a compound of general formula (IIGa), or The method includes the step of hydrolyzing a compound of general formula (IIGbA) in the presence of a basic reagent to obtain a compound of general formula (IIGb), Eventually, R w C 1-6 It is an alkyl group, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6n, m, p, and q are as defined in general formula (IIGa) or general formula (IIGb).

[0168] Technical proposal 7 The compounds represented by general formula (IIGa) or general formula (IIGb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] This method involves chiral resolution of a compound of general formula (IIG) to obtain a compound of general formula (IIGa) and a compound of general formula (IIGb), among which, G, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (IIGa) or general formula (IIGb).

[0169] Technical proposal 8 The compound represented by the general formula (IIN) relating to this disclosure, or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, is: [ka] The method includes the step of hydrolyzing a compound of general formula (IINA) in the presence of a basic reagent to obtain a compound of general formula (IIN), Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are as defined in the general formula (IIN).

[0170] Technical proposal 9 The compounds represented by general formula (IINa) or general formula (IINb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] or [ka] A step of hydrolyzing a compound of general formula (IINaA) in the presence of a basic reagent to obtain a compound of general formula (IINa), or The method includes the step of hydrolyzing a compound of general formula (IINbA) in the presence of a basic reagent to obtain a compound of general formula (IINb), Eventually, R w C 1-6 It is an alkyl group, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IINa) or the general formula (IINb).

[0171] Technical proposal 10 The compounds represented by general formula (IINa) or general formula (IINb) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] This method involves chiral recalculating a compound of general formula (IIN) to obtain a compound of general formula (IINa) and a compound of general formula (IINb), among which, M, Y 4 , Y 5 , Y 6 , ring A, R 1 ~R 6 n, m, p, and q are defined as in the general formula (IINa) or the general formula (IINb).

[0172] Technical proposal 11 The compounds represented by general formula (IIIN-1) or general formula (IIIN-2) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] or [ka] A step of hydrolyzing a compound of general formula (IIINA-1) in the presence of a basic reagent to obtain a compound of general formula (IIIN-1), or The method includes the step of hydrolyzing a compound of general formula (IIINA-2) in the presence of a basic reagent to obtain a compound of general formula (IIIN-2), Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are defined as in general formula (IIIN-1) or general formula (IIIN-2).

[0173] Technical proposal 12 A compound represented by general formula (I) relating to this disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a method for preparing a pharmaceutically acceptable salt thereof, is: [ka] The method includes the step of hydrolyzing a compound of general formula (IA) in the presence of a basic reagent to obtain a compound of general formula (I), Eventually, R w C 1-6 It is an alkyl group, [ka] , Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (I).

[0174] Technical proposal 13 The compound represented by general formula (II) relating to this disclosure, or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The method includes the step of hydrolyzing a compound of general formula (IIA) in the presence of a basic reagent to obtain a compound of general formula (II), Eventually, R w C 1-6 It is an alkyl group, Ring B, M, Y 1 , Y 2 , Y 3 , ring A, R 1 ~R 6 n, m, p, and q are as defined in general formula (II).

[0175] Technical proposal 14 The compounds represented by general formula (III-1) or general formula (III-2) relating to this disclosure, or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are as follows: [ka] or [ka] A step of hydrolyzing a compound of general formula (III-1A) in the presence of a basic reagent to obtain a compound of general formula (III-1), or The method includes the step of hydrolyzing a compound of general formula (III-2A) in the presence of a basic reagent to obtain a compound of general formula (III-2), Eventually, R w C 1-6 It is an alkyl group, M, ring A, R 1 ~R 6 k, n, m, p, and q are defined as in general formula (III-1) or (III-2).

[0176] In the above synthesis plan, the basic reagent includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, and potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide. Preferably, lithium hydroxide or lithium hydroxide monohydrate is used.

[0177] The reaction of the above synthesis plan is preferably carried out in a solvent, and the solvents used include, but are not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. [Modes for carrying out the invention]

[0178] The present disclosure will be further described below in accordance with the examples, but these examples are not intended to limit the scope of the present disclosure.

[0179] Abbreviation: 1. "Ts" refers to the p-toluenesulfonyl group. 2. "Tf" refers to the trifluoromethylsulfonyl group.

[0180] Examples The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The values ​​are expressed in units of ppm. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0181] A Finnigan LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model number: Finnigan LCQ advantage MAX) was used for the MS measurements.

[0182] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0183] For chiral HPLC analysis, an Agilent 1260 DAD high-performance liquid chromatograph was used.

[0184] For preparative high-performance liquid chromatography, the Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs were used.

[0185] For chiral preparative chromatography, a Shimadzu LC-20AP preparative chromatograph was used.

[0186] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf200 (TELEDYNE ISCO) was used.

[0187] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0188] In silica gel column chromatography, silica gel of 200-300 mesh size, manufactured by Yantai Huanghai Silica Gel, was commonly used as a vector.

[0189] Kinase mean inhibition rate and IC 50 A NovoStar microplate reader (BMG GmbH, Germany) was used to measure the values.

[0190] The known starting materials relating to this disclosure may be synthesized by employing or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0191] In the examples, unless otherwise specified, all reactions can be carried out in an argon or nitrogen atmosphere.

[0192] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 L.

[0193] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 L.

[0194] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0195] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0196] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0197] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0198] In the examples, unless otherwise specified, the reaction temperature is room temperature, which is 20°C to 30°C.

[0199] Thin-layer chromatography (TLC) was used to monitor the progress of the reaction in the examples. The developing solvent used in the reaction, the eluent system for column chromatography used for purifying the compound, and the developing solvent system for thin-layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, and D: ethyl acetate / dichloromethane / n-hexane system. The volume ratio of the solvents may be adjusted according to the polarity of the compound, or by adding a small amount of triethylamine and a basic or acidic reagent such as acetic acid.

[0200] Example 1 2-((4-(3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 1 2-((4-((S)-3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 1-1 2-((4-((R)-3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 1-2 [ka] [ka] [ka] [ka]

[0201] Step 1 3-Bromo-2-(methoxymethoxy)phenol 1b Compound 3-bromobenzene-1,2-diol 1a (49.8 g, 263.48 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was dissolved in 600 mL of dichloromethane, and N,N-diisopropylethylamine (51.0 g, 394.60 mmol, 65.21 mL) was added while stirring. Bromomethylmethyl ether (30.0 g, 240.0 mmol, 19.59 mL, Adamas Reagents Co., Ltd.) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 2 hours. The mixture was washed with 200 mL of water, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 1b (26.65 g, yield: 43.39%). MS m / z (ESI): 232.0 [M-1].

[0202] Step 2 2-(3-bromo-2-(methoxymethoxy)phenoxy)ethyl acetate 1c Compound 1b (3.02 g, 12.95 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and ethyl bromo (2.16 g, 12.93 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and potassium carbonate (1.79 g, 12.95 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 95°C and reacted for 21 hours. 20 mL of water was added and the mixture was stirred. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the title compound 1c (3.5 g, yield: 84.63%).

[0203] Step 3 1-(benzo[d]thiazole-2-yl)-2-(3-bromo-2-(methoxymethoxy)phenoxy)ethane-1-one 1e Compound 1c (957 mg, 2.99 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to -78°C under the protection of nitrogen gas. n-butyllithium (384 mg, 5.99 mmol, Adamas Reagents Co., Ltd.) was added dropwise, and the reaction was continued for 1.5 hours. 2-bromobenzothiazole 1d (1.20 g, 5.60 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added to the reaction flask and the reaction was continued for 1 hour. The reaction was then quenched with 10 mL of saturated ammonium chloride solution, extracted with 60 mL of ethyl acetate, washed with saturated brine (20 mL), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 1e (1.20 g, yield: 98.02%). MS m / z (ESI): 409.0 [M+1].

[0204] Step 4 1-(benzo[d]thiazole-2-yl)-2-(3-bromo-2-(methoxymethoxy)phenoxy)ethane-1-ol 1f Compound 1e (600 mg, 1.46 mmol) was dissolved in 20 mL of ethanol, and sodium borohydride (55.84 mg, 1.46 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added under an ice bath and the mixture was stirred for 10 minutes. 20 mL of water was added and the mixture was stirred. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the title compound 1f (570 mg, yield: 94.53%).

[0205] Step 5 2-(2-(benzo[d]thiazole-2-yl)-2-hydroxyethoxy)-6-bromophenol 1g Compound 1f (570 mg, 1.39 mmol) was dissolved in 80 mL of dichloromethane, and 20 mL of dioxane hydrogen chloride solution (4 mmol / mL) was added under ice bath. The mixture was stirred for half an hour to concentrate the organic phase, and 15 mL of a mixed solution of n-hexane and ethyl acetate (V:V=5:1) was added to form a slurry. The mixture was filtered to obtain 1 g (503 mg, yield: 98.95%) of the title compound.

[0206] Step 6 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 1h 1 g (350 mg, 0.95 mmol) of the compound was dissolved in 25 mL of tetrahydrofuran, triphenylphosphine (375 mg, 1.43 mmol, China National Pharmaceutical Group Shanghai Chemical Reagents Co., Ltd.) was added, and diisopropyl azodicarboxylic acid (289 mg, 1.43 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added dropwise under an ice bath. The reaction was continued for 1 hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain 1 h (248 mg, yield: 74.52%) of the title compound. MS m / z (ESI): 349.0 [M+1].

[0207] Step 7 4-(3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropiperidine-1(2H)-tert-butyl formate 1j Compound 1h (220 mg, 0.63 mmol) was dissolved in 1,4-dioxane (20 mL), and 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-1-boronic acid pinacol ester 1i (215 mg, 0.69 mmol), sodium carbonate (134 mg, 1.26 mmol), tetrakis(triphenylphosphino)palladium (73 mg, 63 μmol), and water (4 mL) were added. The mixture was heated to 90°C under the protection of nitrogen gas and stirred for 4 hours. After cooling to room temperature and concentration, the mixture was purified using eluent system B by silica gel column chromatography to obtain the title compound 1j (230 mg, yield: 80.79%). MS m / z (ESI): 451.1 [M+1].

[0208] Step 8 4-(3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-formate tert-butyl 1k Compound 1j (230 mg, 0.51 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium-carbon (138 mg, 0.30 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atmosphere of hydrogen gas for 3 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, the title compound 1k (230 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 453.0 [M+1].

[0209] Step 9 2-(8-(piperidine-4-yl)-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 4-methylbenzenesulfonate 1l 1k (220 mg, 0.48 mmol) of compound was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated under reduced pressure to obtain 1 l (170 mg) of the crude product, the title compound. The product was used directly in the next step without purification. MS m / z (ESI): 353.1 [M+1].

[0210] Step 10 2-((4-(3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 1n 1 liter (170 mg, 0.48 mmol) of the compound was dissolved in 20 mL of acetonitrile. Compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 1 m (143 mg, 0.48 mmol) was added and prepared by the method disclosed in intermediate 23 on page 69 of the specification in patent application WO2018109607A1), and potassium carbonate (670 mg, 4.8 mmol) was added. The mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain a mixture of the title diastereomers 1 n (220 mg, yield: 74.24%). MS m / z (ESI): 611.2 [M+1].

[0211] Step 11 2-((4-(-3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 1 Compound 1n (20 mg, 0.032 mmol) was dissolved in 5 mL of a mixed solvent of acetonitrile and tetrahydrofuran (V:V=1:1), and lithium hydroxide monohydrate (5.5 mg, 0.13 mmol) and 1 mL of water were added at room temperature. The mixture was reacted at 40°C for 16 hours. After cooling to room temperature, the pH was adjusted to 6-7 with a 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated, and purified with eluent system A by silica gel column chromatography to obtain the crude product, mixture 1 (20 mg) of the title diastereomer.

[0212] Step 12 2-((4-((S)-3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 1-1 2-((4-((R)-3-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 1-2 Compound 1 (20 mg, 0.032 mmol) was fractionated using a chiral separation column and concentrated under reduced pressure to obtain title compound 1-1 (6 mg, yield: 30.70%) and title compound 1-2 (6 mg, yield: 30.70%). Compound 1-1: Chiral HPLC analysis: Retention time 3.859 minutes, chiral purity: 99% (Column: Separation conditions: CHIRALPAK IE 150 mm*4.6 mm, 5 μm, mobile phase hexane / EtOH (0.1% DEA + 0.1 TFA) = 20 / 80 (V / V)) MS m / z (ESI): 597.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.25 (s, 1H), 8.18 (d, 1H), 8.06 (d, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.54-7.58 (m, 1H), 7.46-7.49(m, 1H), 6.85-6.87 (m, 2H), 6.75-6.76(m, 1H), 5.31-5.34 (m, 1H), 5.08-5.13(m, 1H), 4.78-4.83 (m, 1H), 4.64-4.68(m, 2H), 4.47-4.53 (m, 2H), 4.36-4.39(m, 1H), 3.96-3.98 (m, 1H), 3.80-3.83 (m, 1H), 2.93-3.07 (m, 3H), 2.68-2.71 (m, 1H), 2.20-2.35 (m, 2H), 1.92-1.98 (m, 2H), 1.65-1.80 (m, 2H). Compounds 1-2: キラルHPLC analysis: retention time 2.999 minutes, キラル purity: 99% (カラム: (separation conditions: CHIRALPAK IE 150 mm*4.6 mm, 5 μm, mobile phase ヘキサン / EtOH(0.1%DEA+0.1TFA)=20 / 80(V / V)) MS m / z (ESI): 597.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.25 (s, 1H), 8.18 (d, 1H),8.06 (d, 1H), 7.81(d, 1H), 7.61 (d, 1H), 7.54-7.59 (m, 1H), 7.46-7.48(m, 1H), 6.85-6.87 (m, 2H), 6.75-6.76(m, 1H), 5.31-5.35 (m, 1H), 5.08-5.14(m, 1H), 4.78-4.83 (m, 1H), 4.64-4.68(m, 2H), 4.47-4.53 (m, 2H), 4.36-4.39(m, 1H), 3.96-3.98 (m, 1H), 3.80-3.83 (m, 1H), 2.93-3.07 (m, 3H), 2.68-2.71 (m, 1H), 2.20-2.34 (m, 2H), 1.92-1.98 (m, 2H), 1.65-1.80 (m, 2H).

[0213] Example 2 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 2 [ka] [ka]

[0214] Step 1 2-(4-chloro-2-fluorophenyl)oxirane 2b Potassium tert-butoxide (1.70 g, 15.14 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added to tetrahydrofuran (30 mL), and trimethylsulfonium iodide (3.09 g, 15.14 mmol, Adamas Reagents Co., Ltd.) was added under ice bath, and the mixture was stirred for 5 minutes. 4-chloro-2-fluorobenzaldehyde 2a (2.0 g, 12.61 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, the mixture was filtered, diluted with ethyl acetate (80 mL), washed with saturated ammonium chloride aqueous solution (30 mL x 2), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 2b (650 mg, yield: 29.9%). 1 H NMR (500 MHz, CDCl3) δ 7.05-7.13 (m, 3H), 4.01-4.15 (m, 1H), 3.17(dd, 1H), 3.75(dd, 1H).

[0215] Step 2 2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2d 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e Compound 2b (520 mg, 3.01 mmol) and 2,6-dibromophenol 2c (759 mg, 3.01 mmol, TCI (Shanghai) Chemical Industry Development Co., Ltd.) were mixed, and sodium methoxide (16 mg, 0.30 mmol, Adamas Reagents Co., Ltd.) was added. The mixture was stirred at 130°C for 2 hours. After cooling, the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 2d (210 mg, yield: 16.4%) and compound 2e (140 mg, yield: 10.9%). 2d MS m / z (ESI):422.9 [M-1]. 2D 1H NMR (500 MHz, DMSO-d6) δ 7.69 (t, 1H), 7.63(d, 2H), 7.40 (dd, 1H), 7.35 (dd, 1H), 7.00 (t, 1H), 5.59 (t, 1H), 5.02 (t, 1H), 3.98-4.03 (m, 1H), 3.81-3.90 (m, 1H). 2e 1 H NMR (500 MHz, DMSO-d6) δ 7.64(d, 2H), 7.62 (t, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.02 (t, 1H), 5.82-6.01 (m, 1H), 5.28 (t, 1H), 4.07-4.12 (m, 1H), 3.95-4.00 (m, 1H).

[0216] Step 3 8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 2f Compound 2d (595 mg, 1.40 mmol) was dissolved in anhydrous toluene (8 mL), and S-1,1'-bi-2-naphthol (159 mg, 0.55 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), cuprous iodide (52 mg, 0.27 mmol, China National Pharmaceutical Group Shanghai Chemical Reagents Co., Ltd.), and cesium carbonate (912 mg, 2.80 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added in sequence. The mixture was heated under reflux and stirred for 18 hours. After cooling, the mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 2f (380 mg, yield: 78.9%). MS m / z (ESI): 343.1 [M-1]. 1 H NMR (500 MHz, DMSO-d6) δ 7.57 (dd, 1H), 7.54(t, 1H), 7.43 (dd, 1H), 7.19 (dd, 1H), 6.98 (dd, 1H), 6.85 (t, 1H), 5.58 (dd, 1H), 4.51 (dd, 1H), 4.20 (dd, 1H).

[0217] Step 4 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) -5,6-dihydropyridine-1(2H)-carboxylate tert-butyl 2g Compound 2f (354 mg, 1.03 mmol) and Compound 1i (350 mg, 1.13 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in 24 mL of a mixed solution of 1,4-dioxane and water (V / V=5:1). Sodium carbonate (218 mg, 2.06 mmol) and tetrakis(triphenylphosphin)palladium (119 mg, 1.03 mmol) were added, and the mixture was stirred at 90°C for 4 hours under the protection of nitrogen gas. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure to remove the solvent. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain 2 g (410 mg, yield: 89.2%) of the title compound. MS m / z (ESI): 390.1 [M-55]. 1 H NMR (500 MHz, CDCl3) δ 7.39 (t, 1H), 7.19-7.23 (m, 1H), 7.15 (dd, 1H), 6.83-6.89 (m, 2H), 6.77-6.81 (m, 1H), 5.76-5.91 (m, 1H), 5.32-5.46 (m, 1H), 5.41 (dd, 1H), 3.99-4.08 (m, 2H),3.97 (dd, 1H),3.43-3.69 (m, 2H),2.40-2.63 (m, 2H), 1.47 (s, 9H).

[0218] Step 5 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate tert-butyl 2h 2 g (220 mg, 0.49 mmol) of the compound was dissolved in ethyl acetate (10 mL) and 1,2-dichlorobenzene (0.5 mL, TCI (Shanghai) Chemical Industry Development Co., Ltd.), 10% palladium carbon (50 mg, 0.47 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atm of hydrogen gas for 1 hour. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain 2 h (178 mg, yield: 80.5%) of the title compound. MS m / z (ESI): 392.1 [M-55]. 1 H NMR (500 MHz, CDCl3) δ 7.40 (t, 1H), 7.21-7.24 (m, 1H), 7.16 (dd, 1H), 6.82-6.88(m, 1H), 6.76-6.81(m, 2H), 5.35-5.45(m, 1H), 4.40(dd, 1H), 4.09-4.33 (m, 2H), 3.96 (dd, 1H), 2.99-3.11 (m, 1H),2.67-2.90 (m, 2H), 1.72-1.91 (m, 2H), 1.58-1.69 (m, 2H), 1.46 (s, 9H).

[0219] Step 6 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine p-toluenesulfonate 2i Compound 2h (178 mg, 0.40 mmol) was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (189 mg, 0.99 mmol) was added. The mixture was stirred at 60°C for 2 hours. After cooling to room temperature and concentrating under reduced pressure, the crude product, title product 2i (206 mg), was obtained and used directly in the next reaction without purification. MS m / z (ESI): 348.1 [M+1].

[0220] Step 7 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 2j Compounds 1m (175 mg, 0.59 mmol) and 2i (206 mg, 0.59 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (410 mg, 2.97 mmol) was added, and the mixture was stirred at 60°C for 3 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain a mixture of the title diastereomers, 2j (207 mg, yield: 57.7%). MS m / z (ESI): 606.2 [M+1].

[0221] Step 8 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 2 Compound 2j (206 mg, 0.34 mmol) was dissolved in 18 mL of a mixture of acetonitrile and water (V / V=5:1), lithium hydroxide monohydrate (71 mg, 1.69 mmol) was added, and the mixture was stirred at 40°C for 18 hours. After cooling to room temperature, the pH was adjusted to 5-6 by adding aqueous citric acid solution (1 M), and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative assay (column: Boston Phlex C18 150 mm*30 mm, 5 μm, mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate), mobile phase 2: acetonitrile, gradient: 30%-50% for 15 minutes, flow rate: 30 mL / min) to obtain mixture 2 of the title diastereomer (120 mg, yield: 59.6%). MS m / z (ESI): 592.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.42-12.97 (brs, 1H), 8.20-8.28(m, 1H), 7.74-7.83 (m, 1H), 7.61 (d, 1H), 7.55-7.58 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 1H), 6.70-6.90 (m, 3H), 5.40-7.49 (m, 1H), 5.01-5.13 (m, 1H), 4.72-4.84 (m, 1H), 4.59-4.67 (m, 1H), 4.39-4.51 (m, 2H), 4.31-4.38 (m, 1H), 4.04-4.13 (m, 1H), 3.86-3.95 (m, 1H), 3.71-3.79 (m, 1H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 2H), 2.61-2.72 (m, 1H), 2.33-2.44 (m, 1H), 2.07-2.25 (m, 2H), 1.73-1.81 (m, 1H), 1.63-1.73 (m, 2H), 1.54-1.63 (m, 1H).

[0222] Example 3 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 3 [ka] Following the synthesis route of Example 2, starting material 2d in step 3 was replaced with 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e to prepare a mixture 3 (7 mg, yield: 23.9%) of the title diastereomer. MS m / z (ESI): 592.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.56-12.77 (brs, 1H), 8.23-8.31(m, 1H), 7.75-7.83 (m, 1H), 7.59-7.67 (m, 1H), 7.44-7.58 (m, 2H), 7.34-7.42 (m, 1H), 6.70-6.95 (m, 3H), 5.38-7.47 (m, 1H), 5.05-5.14 (m, 1H), 4.75-4.86 (m, 1H), 4.62-4.70 (m, 1H), 4.45-4.60 (m, 2H), 4.33-4.42 (m, 1H), 4.09-4.18 (m, 1H), 3.88-3.98 (m, 1H), 3.73-3.83 (m, 1H), 2.96-3.05 (m, 1H), 2.78-2.93 (m, 2H), 2.66-2.77 (m, 1H), 2.41-2.45 (m, 1H), 2.13-2.29 (m, 2H), 1.51-1.81 (m, 4H).

[0223] Example 4 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 4 [ka] [ka]

[0224] Step 1 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 4a 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 4b Compound 2j (830 mg, 1.37 mmol) was chirally fractionated (separation conditions: CHIRALPAK IG 250 mm*20 mm, 5 μm (with protective column), mobile phase: hexane / EtOH (0.1% DEA) = 70 / 30 (V / V), flow rate: 20 mL / min), the corresponding components were collected, concentrated under reduced pressure, and the title products (415 mg, yield: 47.6%) and (340 mg, yield: 39%) were obtained. Single-configuration compound 4a (415 mg, yield: 47.6%) (relatively short retention time): MS m / z (ESI): 606.0 [M+1]. Chiral preparative separation: Retention time 13.653 minutes. Single-configuration compound 4b (340 mg, yield: 39%) (relatively long retention time): MS m / z (ESI): 606.0 [M+1]. Chiral preparative: Retention time 16.422 minutes.

[0225] Step 2 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 4 4a (415 mg, 0.68 mmol) was dissolved in 36 mL of a mixed solvent of acetonitrile and water (V:V=6:1), lithium hydroxide monohydrate (145 mg, 3.46 mmol) was added, and the mixture was stirred at 40°C for 18 hours. The reaction mixture was cooled to room temperature, the pH was adjusted to 5-6 with aqueous citric acid (1 M), and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Gilson 281, column: Boston Phlex C18 150 mm*30 mm, 5 μm, mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate), mobile phase 2: acetonitrile, gradient: 30%-50% for 15 minutes, flow rate: 30 mL / min) to obtain the title product 4 (310 mg, yield: 76.46%). MS m / z (ESI): 592.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.42-12.97 (brs, 1H), 8.20-8.28(m, 1H), 7.74-7.83 (m, 1H), 7.61 (d, 1H), 7.55-7.58 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 1H), 6.70-6.90 (m, 3H), 5.40-7.49 (m, 1H), 5.01-5.13 (m, 1H), 4.72-4.84 (m, 1H), 4.59-4.67 (m, 1H), 4.39-4.51 (m, 2H), 4.31-4.38 (m, 1H), 4.04-4.13 (m, 1H), 3.86-3.95 (m, 1H), 3.71-3.79 (m, 1H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 2H), 2.61-2.72 (m, 1H), 2.33-2.44 (m, 1H), 2.07-2.25 (m, 2H), 1.73-1.81 (m, 1H), 1.63-1.73 (m, 2H), 1.54-1.63 (m, 1H).

[0226] Example 5 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formic acid 5 [ka] [ka]

[0227] Step 1 (R)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl 5a (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl 5b Two g (3.50 g, 7.85 mmol) of the compound was chiral-paritized (separation conditions: DAIEL CHIRALPAK® AD chiral preparative column, 250 mm*25 mm, 10 μm, mobile phase: Supercritical CO2:ETOH (+0.1%DEA) = 85:15 (V / V), flow rate: 70 mL / min), the corresponding components were collected, concentrated under reduced pressure, and the title products (1.62 g, yield: 46.2%) and (1.65 g, yield: 47.1%) were obtained. Single-configuration compound 5a (1.62 g, yield: 46.2%) (relatively short retention time): MS m / z (ESI): 389.9 [M-55]. Chiral HPLC analysis: Retention time 2.072 minutes, chiral purity: 98.76% (Column: DAIEL CHIRALPAK® AD-3 100 mm*3 mm, 3 μm, Mobile phase: Supercritical CO2:ETOH (+0.1%DEA) = 95:5~60:40 (V / V). Single-configuration compound 5b (1.65 g, yield: 47.1%) (relatively long retention time): MS m / z (ESI): 389.9 [M-55]. Chiral HPLC analysis: Retention time 2.348 minutes, chiral purity: 98.44% (Column: DAIEL CHIRALPAK® AD-3 100 mm*3 mm, 3 μm, Mobile phase: Supercritical CO2:ETOH (+0.1% DEA) = 95:5~60:40 (V / V).

[0228] Step 2 (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate tert-butyl 5c 5b (600 mg, 1.35 mmol) was dissolved in 13.2 mL of a mixed solution of ethyl acetate and 1,2-dichlorobenzene (V:V=10:1), palladium / carbon (300 mg, 10%) was added, the mixture was purged three times with hydrogen gas, and the reaction was carried out at room temperature for 1 hour with stirring. The mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated under reduced pressure. After purification with eluent system B by silica gel column chromatography, the title compound 5c (530 mg, yield: 87.9%) was obtained. MS m / z (ESI): 392.0 [M-55]. 1 H NMR (500 MHz, CDCl3) δ 7.43 (t, 1H), 7.25 (dd, 1H), 7.18 (dd, 1H), 6.89 (t, 1H), 6.85-6.80 (m, 2H), 5.44 (dd, 1H), 4.43 (dd, 1H), 4.24 (brs, 2H), 3.99 (dd, 1H), 3.11-3.05 (m, 1H), 2.81 (brs, 2H), 1.88 (d, 1H), 1.80 (d, 1H), 1.67-1.62 (m, 2H), 1.49 (s, 9H).

[0229] Step 3 (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine 5d Compound 5c (530 mg, 1.18 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added at 0°C, and the mixture was reacted with stirring for 2 hours at 0°C to room temperature. The mixture was concentrated, saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 5d (411 mg). The product was used directly in the next reaction without purification.

[0230] Step 4 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl 5f Compound 5d (411 mg, 1.18 mmol) and compound (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-methyl carbonate 5e (350 mg, 1.18 mmol, obtained by the method disclosed in intermediate 27 on page 72 of the specification in patent application WO2018109607A1) were dissolved in acetonitrile (40 mL), potassium carbonate (441 mg, 3.19 mmol) was added, and the mixture was heated to 70°C and reacted with stirring for 3 hours. After concentration under reduced pressure, the mixture was purified with eluent system A by silica gel column chromatography to obtain the title compound 5f (710 mg, yield: 98.9%). MS m / z (ESI): 607.2 [M+1].

[0231] Step 5 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formic acid 5 Compound 5f (710 mg, 1.17 mmol) was dissolved in 54 mL of a mixed solvent of acetonitrile, tetrahydrofuran, and water (V:V:V=5:3:1), lithium hydroxide monohydrate (246 mg, 5.86 mmol) was added, and the mixture was reacted at 40°C for 1 hour with stirring. After cooling to room temperature, the pH was adjusted to 5-6 with aqueous citric acid (1 M), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, concentrated under reduced pressure, and then purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T, 30 mm*50 mm, 5 μm, mobile phase A: water (containing 10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 36%-49% for 15 minutes, flow rate: 30 mL / min) to obtain the title product 5 (620 mg, yield: 89.4%). MS m / z (ESI): 593.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (d, 1H), 7.89 (d, 1H), 7.57 (dd, 1H), 7.53 (t, 1H), 7.43 (dd, 1H), 6.86-6.78 (m, 3H), 5.47 (dd, 1H), 5.17-5.12 (m, 1H), 4.81 (dd, 1H), 4.67 (dd, 1H), 4.50-4.42 (m, 2H), 4.37-4.33 (m, 1H), 4.10 (dd, 1H), 3.96 (d, 1H), 3.84 (d, 1H), 2.96 (d, 1H), 2.91-2.82 (m, 2H), 2.70-2.63 (m, 1H), 2.49-2.43 (m, 1H), 2.23-2.16 (m, 2H), 1.79-1.70 (m, 3H), 1.65-1.56 (m, 1H).

[0232] Example 6 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 6 [ka] [ka]

[0233] Step 1 (S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-formate tert-butyl 6b Compound 2f (260 mg, 0.76 mmol) and (S)-2-methylpiperazine-1-carboxylate tert-butyl 6a (152 mg, 0.76 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 10 mL of 1,4-dioxane. Methanesulfonic acid (2-dicyclohexylphosphino-2'',6''-diisopropoxy-1,1''-biphenyl)(2''-amino-1,1''-biphenyl-2-yl)palladium(II) (27 mg, 0.03 mmol, BiDe Technology Co., Ltd.) and cesium carbonate (493 mg, 1.51 mmol, Shaoyuan Technology Co., Ltd.) were added, and the mixture was heated to 90°C under a nitrogen atmosphere and stirred for 10 hours. The reaction mixture was cooled to room temperature, filtered, and the organic phase was concentrated under reduced pressure. The mixture was then purified by high-performance liquid chromatography (column: Boston Phlex Prep C18 150 mm*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; gradient: 75%~95% for 15 minutes; flow rate: 30 mL / min) to obtain the title product 6b (10 mg, yield: 3%). MS m / z (ESI): 463.1 [M+1].

[0234] Step 2 (S)-1-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3-methylpiperazine 6c Compound 6b (8 mg, 0.017 mmol) was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added at 0°C. The mixture was stirred at this temperature for 2 hours. The reaction mixture was raised to room temperature and concentrated under reduced pressure to obtain the title product 6c (8 mg, yield: 97.1%). MS m / z (ESI): 363.1 [M+1].

[0235] Step 3 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 6d Compound 6c (8 mg, 0.022 mmol) and compound 1m (7 mg, 0.023 mmol) were dissolved in 3 mL of acetonitrile, potassium carbonate (20 mg, 0.145 mmol, Shaoyuan Technology Co., Ltd.) was added at room temperature, and the mixture was heated to 70°C and reacted for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 6d (13 mg, yield: 94.9%). MS m / z (ESI): 621.2 [M+1].

[0236] Step 4 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 6 Compound 6d (13 mg, 0.021 mmol) was dissolved in 3 mL of acetonitrile, and 0.6 mL of water and lithium hydroxide monohydrate (8 mg, 0.19 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 6 hours. After cooling the reaction mixture, citric acid (2.5 M) was added to adjust the pH to 5-6. The mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (column: SharpSil-T Prep C18 50 mm*30 mm, 5 μm, mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate), the residue obtained was purified, and mobile phase 2: acetonitrile, gradient: 30%-47%, flow rate: 30 mL / min for 17 minutes) to obtain the title product 6 (10 mg, yield: 78.7%). MS m / z (ESI): 607.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.19(s, 1H), 7.78-7.80(dd, 1H), 7.55-7.60(m, 3H), 7.42-7.45(dd, 1H), 6.76-6.80(t, 1H), 6.58-6.60(dd, 1H), 6.48-6.51(dd, 1H), 5.41-5.43(dd, 1H), 5.13-5.18(m, 1H), 4.67-4.77(m, 2H), 4.44-4.49(m, 2H), 4.32-4.35 (d, 1H), 4.25-4.29(m, 1H), 4.07-4.11(dd, 1H), 3.59-3.62(d, 1H), 3.32-3.34(d, 1H), 3.02-3.05(d, 1H), 2.78-2.82(m, 1H), 2.64-2.69(m, 3H), 2.35-2.41(m, 3H), 1.09-1.10(d, 3H).

[0237] Example 7 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 7 [ka] [ka]

[0238] Step 1 (S)-2-methyl-4-(((trifluoromethylsulfonyl)oxy)-3,6-dihydropyridine-1(2H)-tert-butyl formate 7b Compound (S)-2-methyl-4-oxopiperidine-1-formate tert-butyl 7a (5 g, 23.44 mmol, Nanjing Pharmaceutical and Stone Technology Co., Ltd.) was dissolved in 50 mL of tetrahydrofuran and cooled to -78°C under the protection of nitrogen gas. Lithium bis(trimethylsilyl)amide (4.31 g, 25.76 mmol, Bi De Technology Co., Ltd.) was added dropwise, and the reaction was continued for half an hour. N-phenylbis(trifluoromethanesulfonyl)imide (9.21 g, 25.78 mmol, Shaoyuan Technology Co., Ltd.) was added and the reaction was continued for 2 hours. The reaction was then quenched with 50 mL of saturated ammonium chloride, extracted with 60 mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7b (8 g, yield: 98.8%).

[0239] Step 2 (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropiperidine-1(2H)-tert-butyl formate 7c Compound 7b (7.5 g, 21.72 mmol) and bis(pinacolate)diborone (6.6 g, 25.99 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 100 mL of 1,4-dioxane. Further addition of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.9 g, 2.60 mmol) and potassium acetate (6.4 g, 65.20 mmol, Taitan Technology Co., Ltd.) was added, the mixture was purged three times with nitrogen gas, and the mixture was heated to 80°C and reacted for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title product 7c (6.0 g, yield: 85%).

[0240] Step 3 2-Bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one 7b' Compound 1-(4-chloro-2-fluorophenyl)ethane-1-one 7a' (46.51 g, 269 mmol, Shaoyuan Technology Co., Ltd.) was dissolved in 400 mL of tetrahydrofuran, and a tetrahydrofuran suspension of pyridinium tribromideonium salt (88 g, 275 mmol, Shaoyuan Technology Co., Ltd.) was added to the system and reacted at room temperature for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with 50 mL of ethyl acetate and washed with 50 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated and dried. The resulting solid was slurryed with a mixed solution of 11 mL of ethyl acetate and n-hexane (V:V=1:10), filtered, and the filtered cake was dried under reduced pressure to obtain the title product 7b' (64.6 g, yield: 95%).

[0241] Step 4 3-Bromo-2-(methoxymethoxy)phenol 7d' 3-bromobenzene-1,2-diol 7c' (50 g, 264 mmol, Shanghai Bi De Technology Co., Ltd.) was dissolved in 1000 mL of dichloromethane, and bromomethoxymethane (33 g, 264 mmol, Shanghai Taitan Technology Co., Ltd.) was added at 0°C. The mixture was stirred at this temperature for 2 hours. After washing with 200 mL of water, the organic phase was dried and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7d' (25 g, yield: 40.5%). MS m / z (ESI): 233.0 [M+1].

[0242] Step 5 2-(3-bromo-2-(methoxymethoxy)phenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one 7e' Compound 7d' (37.5 g, 103 mmol) and compound 7b' (30.5 g, 103 mmol) were dissolved in 200 mL of acetonitrile, potassium carbonate (28.5 g, 206 mmol, Shaoyuan Technology Co., Ltd.) was added at room temperature, and the mixture was heated to room temperature and reacted for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title product 7e' (36 g, yield: 86.6%).

[0243] Step 6 (R)-2-(3-bromo-2-(methoxymethoxy)phenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one 7f' Compound 7e' (5 g, 12.4 mmol) was dissolved in 60 mL of tetrahydrofuran, and under a nitrogen atmosphere, boranedimethyl sulfide complex (1.23 mg, 16.2 mmol, Shanghai Taitan Technology Co., Ltd.) was added. The temperature was raised to 40°C, and diphenyl-[(2R)-pyrrolidine-2-yl]methanol was added in several portions, and the reaction was carried out at 45°C for 3 hours. The reaction was quenched with 5 mL of methanol, and then extracted with 50 mL of water and 60 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title product 7f' (5 g, yield: 99.5%).

[0244] Step 7 (R)-2-bromo-6-(2-(4-bromo-2-fluorophenyl)-2-hydroxyethoxy)phenol 7g' Compound 7f' (5 g, 12.3 mmol) was dissolved in 100 mL of a mixed solution of dichloromethane and dioxane hydrochloride (V:V=4:1), and the mixture was heated to 35°C and reacted for 2 hours. Diphenyl-[(2R)-pyrrolidine-2-yl]methanol was added in several batches, and the mixture was reacted at 35°C for 2 hours. The mixture was concentrated under reduced pressure, extracted with 50 mL of water and 60 mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title product 7g' (4 g, yield: 89.7%). MS m / z (ESI): 358.9 [M-1].

[0245] Step 8 (S)-8-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 7h' 7 g' of compound (4 g, 11.1 mmol) was dissolved in 60 mL of tetrahydrofuran, and under a nitrogen atmosphere, triphenylphosphine (4.35 g, 16.6 mmol, Sinopharmaceutical Group Shanghai Chemical Reagents Co., Ltd.) was added. Diisopropyl azodicarboxylate (3.36 g, 16.6 mmol, Shaoyuan Technology Co., Ltd.) was added dropwise under an ice bath, and the mixture was reacted at this temperature for 0.5 hours. The mixture was concentrated under reduced pressure, extracted with 50 mL of water and 60 mL of ethyl acetate, dried on the organic phase, filtered, and then concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title product 7h' (2.5 g, yield: 65.8%). MS m / z (ESI): 342.9 [M+1].

[0246] Step 9 (S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methyl-3,6-dihydropyridine-1(2H)-tert-butyl formate 7d Compound 7h' (2.0 g, 5.82 mmol) and compound 7c (2.8 g, 8.66 mmol) were dissolved in 36 mL of a mixed solution of 1,4-dioxane and water (V:V=5:1). Sodium carbonate (1.23 g, 11.6 mmol) and tetrakis(triphenylphosphin)palladium (670 mg, 0.58 mmol, Taitan Technology Co., Ltd.) were added, and the mixture was stirred at 90°C for 12 hours under the protection of nitrogen gas. The mixture was cooled to room temperature, filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 7d (1.2 g, yield: 44.8%). MS m / z (ESI): 404.1 [M-55].

[0247] Step 10 (2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidine-1-formate tert-butyl 7e 7d (1.2 g, 2.61 mmol) was dissolved in 22 mL of a mixed solution of ethyl acetate and 1,2-dichlorobenzene (V:V=10:1), 10% palladium-carbon (240 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere with three substitutions using hydrogen gas. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent and obtain the title compound 7e (1.2 g, yield: 99.56%). MS m / z (ESI): 406.1 [M-55].

[0248] Step 11 (2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidine 7f 7e (1.2 g, 2.59 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0°C, 2 mL of trifluoroacetic acid was added, and the mixture was heated to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure to remove the solvent and obtain the title compound 7f (940 mg, yield: 99.95%). MS m / z (ESI): 362.1 [M+1].

[0249] Step 12 2-(((2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 7g Compound 1m (780 mg, 2.65 mmol) and compound 7f (940 mg, 2.60 mmol) were dissolved in 30 mL of acetonitrile, potassium carbonate (3.0 g, 21.71 mmol) was added, and the mixture was stirred at 60°C for 12 hours. After cooling to room temperature and concentrating under reduced pressure, the resulting residue was purified using eluent system A by silica gel column chromatography to obtain 7 g (700 mg, yield: 43.5%) of the title compound. MS m / z (ESI): 620.2 [M+1].

[0250] Step 13 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 7 7 g (700 mg, 1.13 mmol) of the compound was dissolved in 20 mL of acetonitrile, and 4 mL of water and lithium hydroxide monohydrate (300 mg, 7.15 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 6 hours. After cooling, 2.5 M citric acid was added to adjust the pH to 5-6, and a white solid precipitated. The mixture was filtered, the filter cake was washed with water, and after drying, the title product 7 (550 mg, yield: 80.39%) was obtained. MS m / z (ESI): 606.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.73 (brs, 1H), 8.27 (s, 1H), 7.79-7.81 (dd, 1H), 7.64-7.65 (d, 1H), 7.55-7.59 (m, 2H), 7.42-7.44 (dd, 1H), 6.79-6.87 (m, 3H), 5.47-5.49 (dd, 1H), 4.80-4.84 (m, 1H), 4.61-4.64 (dd, 2H), 4.39-4.53 (m, 3H), 4.06-4.12 (m, 2H), 3.86 (brs, 1H), 3.20-3.23 (m, 2H), 2.57-2.74 (m, 3H), 2.40-2.47 (m, 1H), 1.86-1.91 (m, 1H), 1.60-1.72 (m, 3H), 1.09-1.10 (d, 3H).

[0251] Example 8 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-formic acid 8 [ka] [ka]

[0252] Step 1 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-formate methyl 8a Compound 6c trifluoroacetate (70 mg, 0.19 mmol) and compound 5e (57 mg, 0.19 mmol) were dissolved in 5 mL of acetonitrile. Potassium carbonate (134 mg, 0.97 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and ammonium tetrabutyliodide (10 mg, 0.03 mmol) were added at room temperature, and the mixture was heated to 50°C and reacted for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 8a (103 mg, yield: 85.8%). MS m / z (ESI): 622.2 [M+1].

[0253] Step 2 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-formic acid 8 Compound 8a (103 mg, 0.165 mmol) was dissolved in 5 mL of acetonitrile, and 0.6 mL of water and lithium hydroxide monohydrate (35 mg, 0.83 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 16 hours. After cooling the reaction mixture, citric acid (0.5 M) was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. The mixture was purified by high-performance liquid chromatography (column: SharpSil-T Prep C18 50 mm*30 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 33%-45% for 12 minutes, flow rate: 30 mL / min) to obtain the title product 8 (70 mg, yield: 69.5%). MS m / z (ESI): 608.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 7.99(d, 1H), 7.91(d, 1H), 7.60-7.56 (m, 2H), 7.45(d, 1H), 6.78(t, 1H), 6.59(d, 1H) 6.49(d, 1H), 5.42(dd, 1H),5.23-5.18(m,1H), 4.80-4.71(m, 2H), 4.49-4.41(m, 3H), 4.19-4.14(m, 1H), 4.08(d, 1H), 3.60(d, 1H), 3.38(d, 1H), 3.05(d, 1H), 2.78 (t, 1H), 2.67-2.59(m, 3H), 2.56-2.53(m, 1H), 2.44-2.30(m, 2H), 1.11(d, 3H).

[0254] Example 9 2-((4-(2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 9 [ka] [ka]

[0255] Step 1 1-(benzo[d]thiazole-2-yl)-2-bromoethane-1-one 9b 1-(benzo[d]thiazole-2-yl)ethane-1-one 9a (1.77 g, 9.98 mmol, Bi De Technology Co., Ltd.) was added to tetrahydrofuran (60 mL), and 10 mL of tetrahydrofuran solution of pyridinium tribromideonium (1.77 g, 9.98 mmol, Shao Yuan Chemical Technology (Shanghai) Co., Ltd.) was added under an ice bath. The mixture was reacted at room temperature for 2 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and slurryed with 15 mL of a mixed solution of n-hexane and ethyl acetate (V / V=10:1). The mixture was filtered, and the filtered cake was dried under reduced pressure to obtain the title product 9b (1.8 g, yield: 70.36%).

[0256] Step 2 1-(benzo[d]thiazole-2-yl)-2-(2-bromo-6-hydroxyphenoxy)ethane-1-one 9c Compound 9b (0.8 g, 3.12 mmol) was dissolved in acetone (35 mL), sodium bicarbonate (839 g, 9.99 mmol) was added, and compound 1a (591 mg, 3.12 mmol) dissolved in 5 mL of acetone was added dropwise under ice bath. The mixture was reacted at room temperature for 48 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and purified with eluent system B by silica gel column chromatography to obtain the title product 9c (400 mg, yield: 35.16%). MS m / z (ESI): 365.9 [M+1].

[0257] Step 3 2-(2-(benzo[d]thiazole-2-yl)-2-hydroxyphenoxy)-3-bromophenol 9d Compound 9c (400 mg, 1.09 mmol) was dissolved in 20 mL of methanol, and sodium borohydride (62.3 mg, 1.64 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added under an ice bath and the mixture was stirred for 1 hour. 20 mL of water was added and the mixture was stirred. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the title compound 9d (400 mg, yield: 99.44%). MS m / z (ESI): 367.9 [M+1].

[0258] Step 4 2-(5-bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 9e Compound 9d (400 mg, 1.09 mmol) was dissolved in 20 mL of tetrahydrofuran, triphenylphosphine (429 mg, 1.63 mmol, China National Pharmaceutical Group Shanghai Chemical Reagents Co., Ltd.) was added, and diisopropyl azodicarboxylic acid (331 mg, 1.63 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added dropwise under an ice bath. The reaction was continued for 1 hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 9e (300 mg, yield: 78.88%). MS m / z (ESI): 349.9 [M+1].

[0259] Step 5 4-(2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropiperidine-1(2H)-tert-butyl formate 9f Compound 9e (230 mg, 0.66 mmol) was dissolved in 1,4-dioxane (20 mL), compound 1i (245 mg, 0.79 mmol), sodium carbonate (140 mg, 1.32 mmol), tetrakis(triphenylphosphin)palladium (45.8 mg, 39 μmol), and water (4 mL) were added. The mixture was heated to 90°C under the protection of nitrogen gas and stirred for 4 hours. After cooling to room temperature and concentration, the mixture was purified using eluent system B by silica gel column chromatography to obtain the title compound 9f (260 mg, yield: 87.36%). MS m / z (ESI): 451.1 [M+1].

[0260] Step 6 4-(2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-formate tert-butyl 9g Compound 9f (230 mg, 0.51 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium-carbon (80 mg, 0.51 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atmosphere of hydrogen gas for 3 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, 9 g (230 mg) of the title compound. The product was used directly in the next reaction without purification. MS m / z (ESI): 453.0 [M+1].

[0261] Step 7 2-(5-(piperidine-4-yl)-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 4-methylbenzenesulfonate 9h 9 g (210 mg, 0.46 mmol) of the compound was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid (176 mg, 0.92 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure to obtain the crude product, title compound 9h (160 mg), which was used directly in the next step without purification. MS m / z (ESI): 353.1 [M+1].

[0262] Step 8 2-((4-(2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 9i Compound 9h (160 mg, 0.45 mmol) was dissolved in 15 mL of acetonitrile, compound 1m (133 mg, 0.45 mmol, prepared by the method disclosed in intermediate 23 on page 69 of the specification in patent application WO2018109607A1) was added, potassium carbonate (670 mg, 4.8 mmol) was added, and the mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain a mixture 9i (220 mg, yield: 79.35%) of the title diastereomer. MS m / z (ESI): 611.2 [M+1].

[0263] Step 9 2-((4-(2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 9 Compound 9i (10 mg, 0.016 mmol) was dissolved in 3 mL of acetonitrile, lithium hydroxide monohydrate (5.5 mg, 0.13 mmol) and 0.6 mL of water were added at room temperature, and the mixture was reacted at 40°C for 16 hours. After cooling to room temperature, the pH was adjusted to 6-7 with a 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated, and purified with eluent system A by silica gel column chromatography to obtain mixture 9 of the title diastereomer (6.5 mg, yield 66.52%). MS m / z (ESI): 597.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.28 (d, 1H), 8.18 (d, 1H),8.06 (d, 1H), 7.81(d, 1H), 7.61-7.65 (m, 1H), 7.46-7.53(m, 2H),6.84-7.04 (m,3H),5.08-5.14 (m, 2H),4.64-4.72 (m, 2H),4.46-4.62 (m, 3H),3.96-3.98 (m, 1H),3.80-3.83 (m, 1H), 2.83-2.99 (m, 4H),2.68-2.70 (m, 1H), 2.40-2.49 (m, 1H), 2.20-2.45 (m, 4H), 1.65-1.80 (m, 2H).

[0264] Example 10 2-((4-((R)-2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 10 [ka] [ka]

[0265] Step 1 2-((4-((R)-2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 10a 2-((4-((S)-2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 10b Compound 9i (220 mg, 0.36 mmol) was chirally fractionated, the corresponding components were collected, and concentrated under reduced pressure to obtain the title products 10a (75 mg, 0.122 mmol) and 10b (75 mg, 0.122 mmol). Single-configuration compound 10a: Chiral HPLC analysis: Retention time 8.674 minutes, chiral purity: 99%, (Column: CHIRALPAK IE 150 mm*4.6 mm, 5 μm (with protective column), Mobile phase: Hexane / EtOH (0.1% DEA) = 20 / 80 (V / V), Flow rate: 1.0 mL / min) MS m / z (ESI): 611.2 [M+1]. Single-configuration compound 10b: Chiral HPLC analysis: Retention time 11.188 minutes, chiral purity: 99%, (Column: CHIRALPAK IE 150 mm*4.6 mm, 5 μm (with protective column), Mobile phase: Hexane / EtOH (0.1% DEA) = 20 / 80 (V / V), Flow rate: 1.0 mL / min) MS m / z (ESI): 611.2 [M+1].

[0266] Step 2 2-((4-((R)-2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 10 Compound 10a (75 mg, 0.122 mmol) was dissolved in 8 mL of acetonitrile, lithium hydroxide monohydrate (5.5 mg, 0.13 mmol) and 1.6 mL of water were added at room temperature, and the mixture was reacted at 40°C for 16 hours. After cooling to room temperature, the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated, and purified with eluent system A by silica gel column chromatography to obtain the title product 10 (65 mg, yield: 88.70%). MS m / z (ESI): 595.2 [M-1]. 1H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H),8.28 (d, 1H), 8.18 (d, 1H),8.07 (d, 1H), 7.81(d, 1H), 7.61-7.65 (m, 2H), 7.44-7.53(m,1H), 7.04 (d,1H), 6.80-6.98 (m,2H), 5.08-5.12 (m, 2H), 4.63-4.72 (m, 2H), 4.48-4.62 (m, 1H), 4.34-4.47(m, 2H), 3.96-3.98 (m, 1H), 3.80-3.82 (m, 1H), 2.82-3.06 (m, 4H), 2.68-2.74 (m, 1H), 2.40-2.49 (m, 1H), 2.23-2.32 (m,3H), 2.20-2.22 (m, 1H),1.65-1.80 (m, 2H).

[0267] Example 11 2-((4-((S)-2-(benzo[d]thiazole-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 11 [ka] [ka] Compound 10b (75 mg, 0.122 mmol) was dissolved in 8 mL of acetonitrile, lithium hydroxide monohydrate (5.5 mg, 0.13 mmol) and 1.6 mL of water were added at room temperature, and the mixture was reacted at 40°C for 16 hours. After cooling to room temperature, the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated, and purified with eluent system A by silica gel column chromatography to obtain the title product 11 (65.3 mg, yield: 89.55%). MS m / z (ESI): 595.2[M-1]. 1H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H),8.28 (d, 1H), 8.18 (d, 1H),8.07 (d, 1H), 7.81(d, 1H), 7.61-7.65 (m, 2H), 7.44-7.53(m,1H), 7.04 (d,1H), 6.80-6.98 (m,2H), 5.08-5.12 (m, 2H), 4.63-4.72 (m, 2H), 4.49-4.62 (m, 1H), 4.32-4.48(m, 2H), 3.96-3.98 (m, 1H), 3.80-3.82 (m, 1H), 2.83-3.08 (m, 4H), 2.68-2.72 (m, 1H), 2.40-2.49 (m, 1H), 2.23-2.32 (m,3H), 2.20-2.22 (m, 1H),1.65-1.80 (m, 2H).

[0268] Example 12 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formic acid (mixture of diastereomers) 12 [ka] [ka]

[0269] Step 1 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formate methyl (mixture of diastereomers) 12a Compound 5e (50 mg, 0.17 mmol) and compound 2i (89 mg, 0.17 mmol) were dissolved in acetonitrile (5 mL), potassium carbonate (118 mg, 0.85 mmol) was added, and the mixture was stirred at 60°C for 2 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title diastereomer mixture 12a (59 mg, yield: 56.8%). MS m / z (ESI): 607.2 [M+1].

[0270] Step 2 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-formic acid (mixture of diastereomers) 12 Compound 12a (59 mg, 0.10 mmol) was dissolved in 12 mL of a mixed solution of acetonitrile and water (V / V=5:1), lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added, and the mixture was stirred at 40°C for 18 hours. After cooling to room temperature, aqueous citric acid (1 M) was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative assay (column: Sharpsil-T 150 mm*30 mm, 5 μm, mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate), mobile phase 2: acetonitrile, gradient: 35%-45% for 15 minutes, flow rate: 30 mL / min) to obtain the title diastereomer mixture 12 (23 mg, yield: 39.9%). MS m / z (ESI): 593.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.64-13.04 (brs, 1H), 8.10(d, 1H), 7.97 (d, 1H), 7.56 (dd, 1H), 7.52 (t, 1H), 7.42 (dd, 1H), 6.75 -6.88 (m, 3H), 5.46 (dd, 1H), 5.07-5.21 (m, 1H), 4.77-4.88 (m, 1H), 4.66-4.76 (m, 1H), 4.42-4.53 (m, 2H), 4.31-4.40 (m, 1H), 4.04-4.15 (m, 1H), 3.85-4.01 (m, 2H), 2.80-3.01 (m, 3H), 2.62-2.73 (m, 1H), 2.38-2.48 (m, 1H), 2.12-2.29 (m, 2H), 1.58-1.84 (m, 4H).

[0271] Example 13 2-((4-(3-(5-chloropyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 13 [ka] [ka]

[0272] Step 1 2-Bromo-1-(5-chloropyridine-2-yl)ethyl-1-one 13b 1-(5-chloropyridine-2-yl)ethyl-1-one (13a, 2.00 g, 12.86 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was added to tetrahydrofuran (15 mL) and chloroform (30 mL), and pyridinium tribromideonium (4.30 g, 13.45 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added. The mixture was heated to 50°C and stirred for 3 hours. After cooling to room temperature, the mixture was washed sequentially with 1 M hydrochloric acid (30 mL x 2), water (30 mL x 2), and saturated saline solution (30 mL x 2). The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, yielding residue 13b (3.01 g), which was used directly in the next step without purification.

[0273] Step 2 2-(3-bromo-2-hydroxyphenoxy)-1-(5-chloropyridine-2-yl)ethyl-1-one 13c Compound 1a (1.60 g, 8.47 mmol) was dissolved in acetonitrile (30 mL), cooled to 0°C, and potassium carbonate (1.60 g, 11.58 mmol) and compound 13b (1.80 g, 7.68 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated saline solution (30 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, yielding residue 13c (2.0 g), which was used directly in the next step without purification. MS m / z (ESI): 343.9 [M+1].

[0274] Step 3 2-Bromo-6-(2-(5-chloropyridine-2-yl)-2-hydroxyethoxy)phenol 13d Compound 13c (2.00 g, 5.84 mmol) was dissolved in methanol (20 mL), sodium borohydride (0.11 g, 2.91 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 13d (970 mg, yield: 48.2%). MS m / z (ESI): 346.0 [M+1].

[0275] Step 4 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)-5-chloropyridine 13e Compound 13d (970 mg, 2.80 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and triphenylphosphine (1.10 g, 4.19 mmol) and diisopropyl azodicarboxylic acid (850 mg, 4.20 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 0°C for half an hour. The solution was diluted with ethyl acetate (50 mL), washed with water (30 mL x 2), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 13e (880 mg, yield: 95.7%). MS m / z (ESI): 327.9 [M+1].

[0276] Step 5 4-(3-(5-chloropyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) -3,6-dihydropyridine-1(2H)-tert-butyl formate 13f Compound 13e (860 mg, 2.63 mmol) and Compound 1i (900 mg, 2.91 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). Sodium carbonate (560 mg, 5.28 mmol) and tetrakis(triphenylphosphin)palladium (300 mg, 0.26 mmol) were added, and the mixture was stirred at 90°C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 13f (610 mg, yield: 54.0%). MS m / z (ESI): 373.1 [M-55].

[0277] Step 6 4-(3-(5-chloropyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-formate tert-butyl 13g In an autoclave, compound 13f (290 mg, 0.68 mmol) was dissolved in methanol (50 mL), chlorotris(triphenylphosphine)rhodium (65 mg, 0.07 mmol) was added, the mixture was purged with hydrogen gas at 3 atmospheres, heated to 60°C, and stirred for 14 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain 13 g (216 mg, yield: 74.1%) of the title compound. MS m / z (ESI): 375.1 [M-55].

[0278] Step 7 5-Chloro-2-(8-(piperidine-4-yl)-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)pyridine di-p-toluenesulfonate 13h 13 g (200 mg, 0.46 mmol) of the compound was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (180 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the crude product, the title product 13h (313 mg), was obtained and used directly in the next step without purification. MS m / z (ESI): 331.1 [M+1].

[0279] Step 8 2-((4-(3-(5-chloropyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 13i Compound 13h (313 mg, 0.46 mmol) and compound 1m (140 mg, 0.48 mmol) were dissolved in acetonitrile (20 mL), potassium carbonate (320 mg, 2.32 mmol) was added, and the mixture was heated to 50°C and stirred for 5 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title diastereomer mixture 13i (273 mg, yield: 99.9%). MS m / z (ESI): 589.2 [M+1].

[0280] Step 9 2-((4-(3-(5-chloropyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 13 Compound 13i (273 mg, 0.46 mmol) was dissolved in acetonitrile (10 mL) and water (2 mL), lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added, and the mixture was stirred at 40°C for 16 hours. After cooling to room temperature, the pH was adjusted to 5-6 by adding 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative assay (column: Sharpsil-T Prep C18 30 mm*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 35%-55% for 20 minutes, flow rate: 30 mL / min) to obtain mixture 13 of the title diastereomer (190 mg, yield: 71.3%). MS m / z (ESI): 575.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, 1H), 8.26 (d, 1H), 8.01 (dd, 1H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 6.90-6.73 (m, 3H), 5.35 (dd, 1H), 5.14-5.05 (m, 1H), 4.79 (dd, 1H), 4.65 (dd, 1H), 4.56 (dd, 1H), 4.53-4.46 (m, 1H), 4.38 (dtd, 1H), 4.29 (dd, 1H), 3.93 (dd, 1H), 3.78 (dd, 1H), 2.98 (dt, 1H), 2.84 (qd, 2H), 2.71 (ddtd, 1H), 2.43 (ddtd, 1H), 2.2-2.11 (m, 2H), 1.76-1.52 (m, 4H).

[0281] Example 14 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 14 [ka] [ka]

[0282] Step 1 (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine-1-formate tert-butyl 14j Compound 7h' (206 mg, 0.60 mmol) and piperazine-1-carboxylate tert-butyl 14i (120 mg, 0.61 mmol, Shanghai Bi De Technology Co., Ltd.) were dissolved in 10 mL of 1,4-dioxane. Methanesulfonic acid (2-dicyclohexylphosphino-2'',6''-diisopropoxy-1,1''-biphenyl)(2''-amino-1,1''-biphenyl-2-yl)palladium(II) (103 mg, 0.12 mmol, Bi De Technology Co., Ltd.) and cesium carbonate (391 mg, 1.204 mmol, Shao Yuan Technology Co., Ltd.) were added, and the mixture was heated to 110°C under a nitrogen atmosphere and stirred for 10 hours. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain the title product 14j (90 mg, yield: 33.4%). MS m / z (ESI): 449.1 [M+1].

[0283] Step 2 (S)-1-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine 14k Compound 14j (90 mg, 0.12 mmol) was dissolved in 15 mL of dichloromethane, 1 mL of trifluoroacetic acid was added at 0°C, and the mixture was stirred at this temperature for 2 hours. The temperature was then gradually increased to room temperature, and the mixture was concentrated under reduced pressure to obtain the title product 14k (40 mg, yield: 95.3%). MS m / z (ESI): 349.1 [M+1].

[0284] Step 3 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl 14l Compound 14k (40 mg, 0.12 mmol) and Compound 1m (35 mg, 0.12 mmol) were dissolved in 10 mL of acetonitrile, potassium carbonate (80 mg, 0.58 mmol, Shaoyuan Technology Co., Ltd.) was added at room temperature, and the mixture was heated to 60°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title product 14l (56 mg, yield: 80.4%). MS m / z (ESI): 607.1 [M+1].

[0285] Step 4 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 14 14 L (56 mg, 0.1 mmol) of the compound was dissolved in 10 mL of acetonitrile, and 2 mL of water and lithium hydroxide monohydrate (25 mg, 0.6 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 16 hours. After cooling the reaction mixture, citric acid (2.5 M) was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. The mixture was purified by high-performance liquid chromatography (column: SharpSil-T Prep C18 50 mm*30 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 30%-47% for 17 minutes) to obtain the title product 14 (15 mg, yield: 19.2%). MS m / z (ESI): 595.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.78-7.80 (dd, 1H), 7.55-7.57 (dd, 1H), 7.42-7.45 (t, 1H), 6.76-6.90 (m, 5H), 5.41-5.43 (m, 2H), 4.67-4.77 (d, 1H), 4.44-4.49 (d, 1H), 4.32-4.35 (m, 1H), 4.25-4.29 (m, 2H), 4.07-4.11 (dd, 1H), 3.75-3.79 (m, 3H), 3.22-3.24 (sbr, 4H), 3.62-3.65 (sbr, 4H), 1.98-2.02 (m, 2H).

[0286] Example 15 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-3a,6a-dihydro-1H-thieno[2,3-d]imidazole-5-formic acid 15 [ka] [ka]

[0287] Step 1 (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-formate methyl 15c Compound 4-bromo-5-nitrothiophene-2-formate methyl 15a (305 mg, 1.15 mmol, obtained by the method disclosed in intermediate C of Example 114 on page 124 of the specification in patent application WO2003099805A1), compound (S)-oxetane-2-ylmethylamine 15b (100 mg, 1.15 mmol, Nanjing Pharmaceutical and Stone Technology Co., Ltd.), and triethylamine (580 mg, 5.73 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at 80°C for 16 hours. After cooling to room temperature and concentrating under reduced pressure, the mixture was purified with eluent system B by silica gel column chromatography to obtain the title compound 15c (310 mg, yield: 90.1%). MS m / z (ESI): 273.1 [M+1].

[0288] Step 2 (S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-formate methyl 15d Compound 15c (310 mg, 1.14 mmol) was dissolved in 20 mL of tetrahydrofuran, palladium-carbon (300 mg, 10%) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered through diatomaceous earth and concentrated to obtain the crude product, title product 15d (253 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 243.0 [M+1].

[0289] Step 3 (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-methyl formate 15e The crude product 15d (253 mg, 0.69 mmol) of the compound was dissolved in 10 mL of acetonitrile, and 2-chloro-1,1,1-trimethoxyethane (152 mg, 1.05 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol, Sinopharmaceutical Group Chemical Reagents Co., Ltd.) were added. The mixture was stirred at 60°C for 1 hour. After cooling to room temperature and concentrating under reduced pressure, the mixture was purified with eluent system A by silica gel column chromatography to obtain the crude product, title product 15e (71 mg), which was used directly in the next reaction without further purification. MS m / z (ESI): 300.9 [M+1].

[0290] Step 4 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-3a,6a-dihydro-1H-thieno[2,3-d]imidazole-5-formate methyl 15f Compound 6c (70 mg, 0.19 mmol, TFA) and compound 15e (64 mg, 0.21 mmol) were dissolved in 5 mL of acetonitrile, and potassium carbonate (134 mg, 0.97 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added at room temperature. The mixture was heated to 50°C and reacted for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 15f (117 mg, yield: 96.7%). MS m / z (ESI): 627.1 [M+1].

[0291] Step 5 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-3a,6a-dihydro-1H-thieno[2,3-d]imidazole-5-formic acid 15 Compound 15f (117 mg, 0.186 mmol) was dissolved in 5 mL of acetonitrile, and 1 mL of water and lithium hydroxide monohydrate (40 mg, 0.953 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 16 hours. After cooling the reaction mixture, citric acid (0.5 M) was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. The mixture was purified by high-performance liquid chromatography (column: SharpSil-T Prep C18 50 mm*30 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 30%-50% for 20 minutes) to obtain the title product 15 (72 mg, yield: 62.9%). MS m / z (ESI): 613.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 7.74(s, 1H), 7.63-7.54(m, 2H), 7.44(dd, 1H), 6.78(t, 1H), 6.62-6.56(m, 1H), 6.49(d, 1H), 5.42(dd, 1H), 5.12(dd, 1H), 4.64-4.52(m, 2H), 4.49-4.43(m, 2H), 4.30-4.20(m, 2H), 4.08 (dd, 1H), 3.48(d, 1H), 3.31(d, 1H), 3.02(d, 1H), 2.78(d, 1H), 2.68-2.60(m, 3H), 2.52-2.56(m, 1H), 2.38-2.30(m, 2H), 1.08(d, 3H).

[0292] Example 16 2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 16 [ka] Following the synthesis route of Example 2, 4-chloro-2-fluorobenzaldehyde 2a, a starting material in Step 1, was replaced with 4-cyano-2-fluorobenzaldehyde to prepare a mixture 16 (16 mg, yield: 40.96%) of the title diastereomer. MS m / z (ESI): 583.2 [M-1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.42-12.97(brs, 1H), 8.26(s, 1H), 8.00(d, 1H), 7.74-7.82 (m, 2H), 7.63-7.68 (m, 2H), 6.70-6.82 (m, 3H), 5.55-5.60 (m, 1H), 5.01-5.08 (m, 1H), 4.79-4.84 (m, 1H), 4.59-4.65 (m, 1H), 4.39-4.48 (m, 2H), 4.31-4.36 (m, 1H), 4.04-4.12 (m, 1H), 3.86-3.93 (m, 1H), 3.71-3.78 (m, 1H), 2.91-2.99 (m, 1H), 2.77-2.86 (m, 2H), 2.61-2.69 (m, 1H), 2.33-2.41 (m, 1H), 2.07-2.19 (m, 2H), 1.73-1.81 (m, 1H), 1.63-1.69 (m, 2H), 1.54-1.63 (m, 1H).

[0293] Example 17 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(((S)-oxan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 17 [ka] [ka]

[0294] Step 1 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1,2,3,6-tetrahydropyridine p-toluenesulfonate 17a Two g (202 mg, 0.45 mmol) of the compound was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol) was added. The mixture was stirred at 60°C for 2 hours. After cooling to room temperature and concentrating under reduced pressure, the crude product, title product 17a (234 mg), was obtained and used directly in the next reaction without purification. MS m / z (ESI): 346.1 [M+1].

[0295] Step 2 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 17b Compounds 1m (133 mg, 0.45 mmol) and 17a (234 mg, 0.45 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (312 mg, 2.26 mmol) was added, and the mixture was stirred at 50°C for 18 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain a mixture of the title diastereomers 17b (213 mg, yield: 78.1%). MS m / z (ESI): 604.2 [M+1].

[0296] Step 3 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(((S)-oxan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 17 Compound 17b (46 mg, 0.08 mmol) was dissolved in 12 mL of a mixed solution of acetonitrile and water (V / V=5:1), lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added, and the mixture was stirred at 40°C for 18 hours. After cooling to room temperature, the pH was adjusted to 5-6 by adding aqueous citric acid solution (1 M), and the solution was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative assay (column: Sharpsil-T 150 mm*30 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 35%-45% for 15 minutes, flow rate: 30 mL / min) to obtain the title diastereomer mixture 17 (17 mg, yield: 37.8%). MS m / z (ESI): 590.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.58-12.99 (brs, 1H), 8.24(d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.53-7.58 (m, 1H), 7.51 (t, 1H), 7.36-7.42 (m, 1H), 6.80-6.87 (m, 2H), 6.74-7.79 (m, 1H), 5.77-5.86 (m, 1H), 5.44 (dd, 1H), 4.96-5.07 (m, 1H), 4.68-4.78 (m, 1H), 4.55-4.64 (m, 1H), 4.41-4.47 (m, 1H), 4.35-4.40 (m, 1H), 4.27-4.33 (m, 1H), 4.08-4.16 (m, 1H), 3.96-4.04 (m, 1H), 3.82-2.89 (m, 1H), 3.03-3.21 (m, 2H), 2.61-2.75 (m, 2H), 2.50-2.60 (m, 2H), 2.25-2.41 (m, 2H).

[0297] Example 18 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 18 [ka] [ka]

[0298] Step 1 2-(4-chloro-2-fluorophenyl)2-methyloxirane 18b Potassium tert-butoxide (7.73 g, 67.88 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added to tetrahydrofuran (200 mL), and trimethylsulfonium iodide (14.20 g, 69.58 mmol, Adamas Reagents Co., Ltd.) was added under an ice bath, and the mixture was stirred for 5 minutes. 1-(4-chloro-2-fluorophenyl)ethyl-1-one 18a (10.0 g, 57.94 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, diluted with ethyl acetate (80 mL), washed sequentially with saturated ammonium chloride aqueous solution (50 mL x 2), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding the title compound 18b (10.0 g, yield: 92.4%). 1 H NMR (500 MHz, CDCl3) δ7.36 (t, 1H), 7.13 (dd, 1H), 7.08 (dd, 1H), 2.97(d, 1H), 2.79(d, 1H), 1.60 (s, 3H).

[0299] Step 2 2-Bromo-6-((2-(4-chloro-2-fluorophenyl)-1-hydroxypropan-2-yl)oxy)phenol 18c 2-Bromo-6-((2-(4-chloro-2-fluorophenyl)-2-hydroxypropoxy)phenol 18d Compound 18b (1.0 g, 5.35 mmol) and 1a (1.0 g, 5.29 mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) were mixed, and sodium methoxide (30 mg, 0.555 mmol, Adamas Reagents Co., Ltd.) was added. The mixture was stirred at 120°C for 2 hours. After cooling, the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 18c (300 mg, yield: 14.9%) and compound 18d (240 mg, yield: 11.9%). 18c MS m / z (ESI): 375.2 [M-1]; 18d MS m / z (ESI):375.2 [M-1].

[0300] Step 3 5-Bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxane 18e Compound 18c (300 mg, 0.798 mmol) was dissolved in dry tetrahydrofuran (15 mL), triphenylphosphine (315 mg, 1.20 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, and under a nitrogen atmosphere at 0°C, diisopropyl azodicarboxylic acid (243 mg, 1.20 mmol, China National Pharmaceutical Group Shanghai Chemical Reagents Co., Ltd.) was added dropwise, and the mixture was stirred at 0°C for half an hour. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL x 2), concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18e (240 mg, yield: 84.0%). 1 H NMR (500 MHz, CDCl3) δ7.37-7.32 (m, 3H), 7.14-7.11 (m, 2H), 6.83-6.79 (m, 1H), 4.57(dd, 1H), 4.25(ddd, 1H), 1.71 (dd, 3H).

[0301] Step 4 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) -3,6-dihydropyridine-1(2H)-carboxylate tert-butyl 18f Compound 18e (230 mg, 0.643 mmol) and Compound 1i (198 mg, 0.640 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in 12 mL of a mixed solution of 1,4-dioxane and water (V / V=5:1). Sodium carbonate (136 mg, 1.28 mmol) and tetrakis(triphenylphosphin)palladium (75 mg, 0.065 mmol) were added, and the mixture was stirred at 90°C for 4 hours under the protection of nitrogen gas. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure to remove the solvent. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 18f (205 mg, yield: 69.3%). MS m / z (ESI): 404.0 [M-55]. 1 H NMR (500 MHz, CDCl3) δ7.45 (t, 0.5H), 7.31 (t, 0.5H),7.14-7.07 (m, 2H), 6.96 (dd, 0.5H), 6.88(t, 0.5H), 6.82-6.75(m, 2H), 5.86 (d, 1H), 4.48 (dd, 1H), 4.18(dd, 1H), 4.11 (brs, 1H), 4.03 (brs, 1H), 3.65 (brs, 1H), 3.57 (brs, 1H), 2.55-2.35 (m, 2H), 1.68 (d, 3H), 1.51(d, 9H).

[0302] Step 5 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate tert-butyl 18g Compound 18f (200 mg, 0.434 mmol) was dissolved in ethyl acetate (10 mL) and 1,2-dichlorobenzene (1 mL, TCI (Shanghai) Chemical Industry Development Co., Ltd.), 10% palladium-carbon (50 mg, 0.087 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atmosphere of hydrogen gas for 1 hour. The solution was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain 18 g (200 mg, yield: 99.5%) of the title compound. MS m / z (ESI): 406.0 [M-55].

[0303] Step 6 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine trifluoroacetate 18h 18 g (80 mg, 0.173 mmol) of the compound was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.1 mL) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. After concentration under reduced pressure, 18 h (62 mg) of the crude product, the title product, was obtained and used directly in the next reaction without purification. MS m / z (ESI): 362.0 [M+1].

[0304] Step 7 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 18i Compound 1m (50 mg, 0.169 mmol) and 18h ​​(62 mg, 0.171 mmol) were dissolved in acetonitrile (5 mL), potassium carbonate (117 mg, 0.846 mmol) was added, and the mixture was stirred at 70°C for 2 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain a mixture 18i (94 mg, yield: 89.3%) of the title diastereomer. MS m / z (ESI): 620.1 [M+1].

[0305] Step 8 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 18 Compound 18i (94 mg, 0.151 mmol) was dissolved in 6 mL of a mixed solution of acetonitrile and water (V / V=5:1), lithium hydroxide monohydrate (20 mg, 0.50 mmol) was added, and the mixture was stirred at 40°C for 18 hours. After cooling to room temperature, the pH was adjusted to 5-6 by adding aqueous citric acid solution (1 M), extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain the title diastereomer mixture 18 (50 mg, yield: 54.4%). MS m / z (ESI): 606.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.27 (d, 1H), 7.80 (dd, 1H), 7.64 (d, 1H), 7.48(dt, 1H), 7.42 (t, 1H), 7.27 (dt, 1H), 6.91-6.82 (m, 2H), 6.75 (dd, 1H), 5.11-5.06 (m, 1H),4.78(dd, 1H), 4.67-4.61 (m, 2H), 4.54-4.46 (m, 1H), 4.40-4.35 (m, 1H), 4.16 (d, 1H), 3.92(d, 1H), 3.76 (d, 1H), 2.96 (t, 1H), 2.81 (t, 1H), 2.76-2.67 (m, 2H), 2.48-2.38 (m, 2H), 2.23-2.12 (m, 1H), 1.68 (t, 1H), 1.57-1.49 (m, 6H).

[0306] Example 19 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 19 [ka] [ka]

[0307] Step 1 (2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-formate tert-butyl 19a Compound 2f (145 mg, 0.42 mmol) and compound 6a (85 mg, 0.42 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 10 mL of 1,4-dioxane. Methanesulfonic acid (2-dicyclohexylphosphino-2'',6''-diisopropoxy-1,1''-biphenyl)(2''-amino-1,1''-biphenyl-2-yl)palladium(II) (71 mg, 0.08 mmol, Bi De Technology Co., Ltd.) and cesium carbonate (275 mg, 0.84 mmol, Shaoyuan Technology Co., Ltd.) were added, and the mixture was heated to 90°C under a nitrogen atmosphere and stirred for 10 hours. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title product 19a (40 mg, yield: 20.47%). MS m / z (ESI): 463.3 [M+1].

[0308] Step 2 (3S)-1-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3-methylpiperazine 19b Compound 19a (40 mg, 0.086 mmol) was dissolved in 10 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added at 0°C. The mixture was stirred at this temperature for 2 hours. The reaction mixture was raised to room temperature and concentrated under reduced pressure to obtain the title product 19b (30 mg, yield: 95.7%). MS m / z (ESI): 363.3 [M+1].

[0309] Step 3 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formate methyl (mixture of diastereomers) 19c Compound 19b (30 mg, 0.08 mmol) and compound 1m (24 mg, 0.08 mmol) were dissolved in 10 mL of acetonitrile, potassium carbonate (57 mg, 0.4 mmol, Shaoyuan Technology Co., Ltd.) was added at room temperature, and the mixture was heated to 60°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title diastereomer mixture 19c (30 mg, yield: 58.4%). MS m / z (ESI): 621.2 [M+1].

[0310] Step 4 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid 19 Compound 19c (30 mg, 0.05 mmol) was dissolved in 10 mL of acetonitrile, and 2 mL of water and lithium hydroxide monohydrate (10 mg, 0.24 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 40°C and reacted for 16 hours. After cooling the reaction mixture, citric acid (2.5 M) was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. The mixture was purified by high-performance liquid chromatography (column: SharpSil-T Prep C18 50 mm*30 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate), mobile phase: acetonitrile, gradient: 30%-47% for 17 minutes, flow rate: 30 mL / min) to obtain the title diastereomer mixture 19 (3 ​​mg, yield: 10.23%). MS m / z (ESI): 607.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.25(s, 1H), 7.78-7.80(dd, 1H), 7.62-7.65(m, 1H),7.55-7.60(m, 1H), 7.42-7.45(dd, 1H), 6.76-6.80(m, 1H), 6.58-6.60(dd, 1H), 6.48-6.5m(dd, 1H), 6.66(sbr, 1H), 5.41-5.43(dd, 1H), 5.13-5.18(m, 1H), 4.67-4.77(m, 2H), 4.44-4.49(m, 2H), 4.32-4.35 (d, 1H), 4.25-4.29(m, 1H), 4.07-4.11(dd, 1H), 3.59-3.62(d, 1H), 3.32-3.34(d, 1H), 3.02-3.05(d, 1H), 2.78-2.82(m, 1H), 2.64-2.69(m, 3H), 2.35-2.41(m, 3H), 1.09-1.10(d, 3H).

[0311] Example 20 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-formic acid (mixture of diastereomers) 20 [ka] Following the synthesis route of Example 2, starting material 2a in Step 1 was replaced with 2-fluoro-4-chloroacetophenone (Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) to prepare a mixture 20 of the title diastereomer (46 mg, yield: 56.83%). MS m / z (ESI): 606.3 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.77 (brs, 1H), 8.28 (s, 1H), 7.81 (d, 1H), 7.65 (d, 1H), 7.50 (dt, 1H), 7.38 (t, 1H), 7.30 (d, 1H), 6.83 (d, 1H), 6.78 (t, 1H), 6.68 (d, 1H), 5.06-5.11 (m, 1H), 4.82 (d, 1H), 4.68 (d, 1H), 4.45-4.57 (m, 2H), 4.35-4.42 (m, 1H), 4.16 (d, 1H), 3.98 (d, 1H), 3.82 (d, 1H), 2.95-3.08 (m, 2H), 2.84-2.94 (m, 1H), 2.66- 2.76 (m, 1H), 2.40-2.47 (m, 1H), 2.18-2.32(m, 2H), 1.73-1.86(m, 2H), 1.64-1.70 (m, 2H), 1.63 (s, 3H).

[0312] Biological evaluation Test Example 1: Evaluation of GLP-1 receptor agonist activity 1. Purpose of the examination This experiment was conducted to test the agonistic activity of compound molecules on the GLP-1 receptor, using EC. 50The aim is to evaluate the in vitro activity of molecules based on their size. This experiment uses ONE-Glo TM Luciferase Test System (ONE-Glo TM Using the Luciferase Assay System (Promega, E6110), under the action of a compound molecule, the GLP-1R downstream signaling pathway is activated, causing an increase in cAMP levels. When cAMP binds to CRE, it can trigger the transcriptional expression of the CRE downstream luciferase gene. When luciferase reacts with its substrate, it can emit fluorescence, and ONE-Glo TM The activating activity of the compound on the GLP-1 receptor was reflected by measuring the fluorescence signal with a reagent.

[0313] 2. Experimental Method Stable transformed cell lines of CHO-K1 / CRE-luc / GLP-1 receptor were constructed (self-construction of GLP-1 receptor plasmid, CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / GLP-1 receptor cells were digested, centrifuged, resuspended, and the single-cell suspension was homogeneously mixed. The viable cell density was then increased to 2.5 × 10⁶ in cell culture medium (DME / F-12 + 10% FBS). 5 The solution was adjusted to 100 cells / mL and added to 96-well cell culture plates (Corning, #3903) at 90 μL / well. The culture plates were incubated in an incubator for 16 hours (37°C, 5% CO2). The compound was dissolved in DMSO to prepare a stock solution with an initial concentration of 20 mM. The small molecule compound had an initial concentration of 0.2 mM, which was then diluted 3-fold, followed by 10 point dilutions, with the 11th point being DMSO. Another 96-well plate was taken, and 95 μL of cell culture medium (DME / F-12 + 10% FBS) was added per well, then 5 μL of different concentrations of the sample to be tested was added per well and mixed uniformly. Then, 10 μL / well of different concentrations of the sample to be tested was placed in the cell culture plate, with each sample in two parallel wells. The culture plate was incubated in an incubator for 6 hours (37°C, 5% CO2). The 96-well cell culture plate was removed, and 100 μL of ONE-Glo was added to each well.TM The reagents were added and incubated at room temperature for 10 minutes. Chemiluminescence was measured using a microplate reader (EnVision 2105, PE).

[0314] 3. Analysis of the data Data was processed and analyzed using Microsoft Excel and Graphpad Prism 5. The EC of the compounds was also analyzed. 50 Obtain the value, and refer to Table 1 below for the result.

[0315] [Table 3] Conclusion: The compounds described herein exhibit good activating activity against the GLP-1 receptor.

[0316] Test Example 2: Effect of the compound relating to this disclosure on hERG potassium ion channels 1. Purpose of the examination The blocking effect of the compounds described herein and positive compound 1 (see the compound in Example 7 on page 125 of WO2019239319A1) on the hERG potassium current was evaluated in stable cell lines transfected with hERG potassium channels using manual patch-clamp technology. The structure of positive compound 1 is as follows. [ka]

[0317] 2. Examination Method 1. Cell culture The cells used in this study were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG cDNA and stably expressing hERG channels, and the cell passage number was P5. The cells were cultured in a medium containing the following components (all derived from Invitrogen): Ham's F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / mL hygromycin B, and 100 μg / mL Geneticin. CHO hERG cells were grown in a culture dish containing the above-mentioned culture medium and cultured at 37°C in an incubator containing 5% CO2. 24–48 hours prior to the electrophysiological experiment, the CHO hERG cells were transferred to a circular glass plate placed in the culture dish and grown under the same culture medium and conditions as described above. The density of CHO hERG cells on each circular glass plate must satisfy the requirement that most cells are independent and singular.

[0318] 2. Experimental solution [Table 4]

[0319] [Table 5]

[0320] 3. Electrophysiology recording system In this experiment, whole-cell currents were recorded using a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany). Circular glass plates with CHO hERG cells growing on their surface were placed in the electrophysiological recording groove of an inverted microscope. The groove was continuously perfused with extracellular fluid (approximately 1 mL per minute). The experimental procedure employed standard whole-cell patch-clamp current recording techniques. Unless otherwise noted, all experiments were conducted at normal room temperature (below 25°C). Cells were clamped at a voltage of -80 mV. The cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV after 5 seconds to eliminate inactivity and generate a tail current. The peak value of the tail current was used as a numerical value for the magnitude of the hERG current. The hERG potassium current recorded in the above step is stabilized by continuous extracellular fluid perfusion in the recording groove. Further perfusion of pending drugs can then be performed until the inhibitory effect of the drug on the hERG current stabilizes. Generally, the overlap of the most recent three consecutive current recording lines is used as a criterion for determining stability. After stabilization, the cells were washed with extracellular fluid perfusion until the hERG current returned to its pre-drug level. One or more drugs, or multiple concentrations of the same type of drug, can be tested in a single cell, but washing with extracellular fluid is necessary when testing different drugs. Cisapride (purchased from Sigma) was used in the experiment as a positive control to ensure the quality of the cells used was adequate.

[0321] 4. Experimental Procedure Compound IC 50To obtain the desired results, the following concentrations (30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM) were selected and tested. Before testing, the compound was first prepared in 10 mM DMSO (Sigma) stock solution, and then diluted by gradient dilution to 3 μM, 1 μM, 0.3 μM, and 0.1 mM stock solutions, and finally diluted to the final μM test concentration with extracellular fluid. In the 30 μM compound test solution, the final DMSO concentration was approximately 0.3%, while the final DMSO concentration in each of the remaining concentrations was 0.1%. The control cisapride test concentration was 0.1 μM. All compound solutions were subjected to normal ultrasonic stirring and shaking for 5-10 minutes to ensure complete dissolution of the compound. The test data was analyzed using data analysis software provided by HEKA Patchmaster (V2x73.2), Microsoft Excel, and Graphpad Prism 5.0.

[0322] 5. Test results The blocking effect of the compounds relating to this disclosure on the hERG potassium current was measured by the above test, and the measured IC 50 The values ​​are shown in Table 4.

[0323] [Table 6] Conclusion: The compounds described herein have weak inhibitory effects on hERGs, can reduce side effects caused by hERG channels, and have weaker inhibitory effects on hERGs compared to positive compound 1.

[0324] Test Example 3: Inhibitory effect of the compound relating to this disclosure on human liver microsomal CYP450 enzyme. This test example is primarily intended to evaluate the inhibitory effect of the compound relating to this disclosure and positive compound 1 (see Test Example 2 for its specific structure) on the human liver microsomal CYP450 enzyme. The body was measured using the following experimental method.

[0325] 1. Materials and equipment for the experiment 1. Phosphate buffer (20×PBS, purchased from the biotechnology department), 2. NADPH (ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor35), 4. ABI QTrap 4000 Liquid Chromatograph Mass Spectrometer (AB Sciex) 5. ZORBAX Extend-C18, 3 mm × 50 mm, 3.5 μM (Agilent, Inc., USA) 6. CYP probe substrate.

[0326] 2. Experimental Procedure 1. Preparation of the solution 1) Preparation of 100 mM phosphate buffer (PBS) 50 mL of a 2000 mM PBS solution was taken, 950 mL of ultrapure water was added to dilute it to 1000 mL, and the mixture was thoroughly mixed. The pH of the solution was then adjusted to 7.4 using a pH meter to obtain a PBS solution with a pH of 7.4, which was stored in a refrigerator at 4°C (storage period: 6 months).

[0327] 2) Preparation of NADPH solution A suitable amount of NADPH powder was precisely weighed, dissolved in PBS buffer solution, and prepared to a concentration of 5 mM, ready for use (prepared just before use).

[0328] 3) Preparation of liver microsome solution An appropriate amount of human liver microsome stock solution (concentration 20 mg / mL) was taken, and a 7.5 mM MgCl2 solution was diluted with a 0.25 mg / mL microsome solution to prepare it for use (prepared just before use).

[0329] 4) Preparation of MgCl2 solution An appropriate amount of MgCl2 powder was weighed and prepared as a 300 mM stock solution with PBS solution. This stock solution was stored in a refrigerator at 4°C and prepared for use. An appropriate amount of this solution was precisely weighed and diluted with 100 mM PBS solution to make a 7.5 mM working solution (prepared just before use).

[0330] 5) Preparation of test compound solutions a. A suitable amount of the standard sample of the test compound was precisely weighed, and DMSO was added to prepare a stock solution with a concentration of 30 mM. This stock solution was then stored in a refrigerator at 4°C. b. An appropriate amount of the stock solution was precisely pipetteed, and an appropriate amount of DMSO solution was added to dilute it into a series of solutions I with concentrations of 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, and 0.003 mM. An appropriate amount of the above series of solutions I was precisely pipetteed, and an appropriate amount of acetonitrile was added to dilute it into a series of solutions II with concentrations of 3 mM, 1 mM, 0.3 mM, 0.1 mM, 0.03 mM, 0.003 mM, and 0.0003 mM. An appropriate amount of the above series of solutions II was precisely pipetteed, and an appropriate amount of PBS was added to dilute it into working solutions with concentrations of 150 μM, 50 μM, 15 μM, 5 μM, 1.5 μM, 0.15 μM, and 0.015 μM, and prepared for use.

[0331] 6) Selection of CYP probe substrates and selective inhibitors a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate, add DMSO to prepare the stock solution, and the concentrations are as shown in Table 5 below. b. Preparation of probe substrate working solution: A suitable amount of the probe substrate stock solution is precisely pipetted, and the solution is diluted 200-fold with PBS to obtain the probe substrate working solution. The concentration of the working solution is as shown in Table 5 below.

[0332] [Table 7]

[0333] 2. Incubation of liver microsomes and preparation of samples The protein concentrations, substrate concentrations, and inhibitor concentrations in the reaction system are shown in Table 6 below. [Table 8]

[0334] 3. Operation process 1) 40 μL of human liver microsome solution (0.25 mg / mL) was precisely pipetted, and 20 μL of probe substrate solution and 20 μL of test compound solution were placed in a 96-well plate and pre-incubated in a 37°C water bath for 5 minutes.

[0335] 2) After pre-incubating for 5 minutes, the samples were removed, 20 μL of 5 mM NADPH solution was added to initiate the reaction, and the samples were incubated in a 37°C water bath for 30 minutes. Two parallel samples were prepared for each sample.

[0336] 3) After incubation was complete, the reaction was stopped by adding 250 μL of acetonitrile solution containing the internal standard, shaking at 800 rpm for 10 minutes, then centrifuged at 3700 rpm for 10 minutes, 100 μL of the supernatant was precisely pipetted and diluted with 80 μL of distilled water, then shaken at 800 rpm for 10 minutes, and the supernatant was aspirated and analyzed by LC-MS / MS.

[0337] The numerical values ​​were calculated using Graphpad Prism to determine the induction of drug inhibition against the human liver microsomal CYP1A2 phenacetin, CYP2C19 (S)-mephenytoin, and CYP3A4M midazolam metabolic sites. 50 The values ​​were obtained as shown in Table 7.

[0338] [Table 9] Conclusion: The compounds described herein do not exhibit metabolite interactions based on the CYP1A2 phenacetin, CYP2C19 (S)-mephenytoin, and CYP3A4M midazolam sites in the 30 μM concentration range, and demonstrate better safety than Positive Compound 1.

[0339] Test Example 4: Inhibitory effect of the compound relating to this disclosure on the time-dependent enzyme activity (TDI) of the human liver microsomal CYP2C19 (S)-mephenytoin metabolic site. This test example was primarily intended to evaluate the inhibitory effect of the compound relating to this disclosure and Positive Compound 1 (see Test Example 2 for its specific structure) on the time-dependent enzyme activity (TDI) of the human liver microsomal CYP2C19 (S)-mephenytoin metabolic site, and was specifically measured using the experimental method described below.

[0340] 1. Materials and equipment for the experiment 1. Phosphate buffer (20×PBS, purchased from the biotechnology department), 2. NADPH (ACROS, A2646-71-1), 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor 36), 4. ABI QTrap 4000 Liquid Chromatograph Mass Spectrometer (AB Sciex) 5. ZORBAX Extend-C18, 3 mm × 50 mm, 3.5 μM (Agilent, Inc., USA) 6. CYP probe substrate ((S)-mephenytoin / 20 μM, powder purchased from Bailingwei Technology Co., Ltd., Cat No. 303768), and positive control inhibitor (ticlopidine, powder purchased from SIGMA, Cat No. T6654-1G).

[0341] 2. Experimental Procedure A 100 mM PBS buffer was prepared, and a 15 mM MgCl2 and 10 mM NADPH solution was prepared in this buffer. A 0.5 mg / mL microsome solution was prepared with 15 mM MgCl2, and the stock solution with a concentration of 30 mM was diluted with DMSO to a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.1 mM, 0.03 mM, and 0 mM. These solutions were further diluted 10-fold with acetonitrile (ACN), and finally 50-fold with phosphate buffer (PBS) to obtain a series of awaiting work solutions II (60 μM, 20 μM, 6 μM, 2 μM, 0.6 μM, 0.2 μM, 0.06 μM, and 0 μM). These solutions were then diluted with PBS to a 20 μM (S)-mephenytoin work solution.

[0342] The prepared series of working solutions awaiting measurement were uniformly shaken, and 50 μL was dispensed into the corresponding reaction plates (+NADPH group and -NADPH group). Three parallel plates were set up, and 20 μL of liver microsome working solution was added to each 96-well plate. 10 μL of NADPH was added to each +NADPH group, and the plates were incubated in a water bath at 37°C, a countdown was started, and the plates were incubated for 30 minutes before being removed. The +NADPH group was supplemented with 20 μL of the corresponding substrate solution, and the -NADPH group was supplemented with 20 μL of the corresponding substrate solution and 10 μL of NADPH. The plates were incubated in a water bath at 37°C, a countdown was started, and the plates were incubated for 30 minutes before being removed. The reaction was stopped with 250 μL of ACN solution containing the internal standard. The shakers were then shaken at 800 rpm for 10 minutes, and the plates were centrifuged at 4000 rpm for 15 minutes. After uniformly mixing 100 μL of supernatant with 80 μL of ultrapure water, the analysis was performed using LC-MS / MS.

[0343] The numerical values ​​were calculated using Graphpad Prism to determine the IC for the CYP2C19 (S)-mephenytoin site of the drug. 50 Value and IC 50 Shift multiplier (IC 50 The shift-fold values ​​were obtained as shown in Table 8.

[0344]

Table 10

[0345] Test Example 5: Pharmacokinetic Evaluation of the Compound According to the Present Disclosure in Mice 1. Summary Using mice as test animals, the plasma drug concentrations of the compound according to the present disclosure at different time points in mice administered orally (ig) / intravenously (iv) were measured by the LC / MS / MS method. The pharmacokinetic behavior of the compound according to the present disclosure in mice was studied, and its pharmacokinetic characteristics were evaluated.

[0346] 2. Test Plan 2.1 Test Drug The compound of Example 4 and the compound of Example 5. 2.2 Test Animals 36 female C57 mice, evenly divided into 4 groups on average, purchased from Vital River Laboratory Animal Technology Co., Ltd., and the animal production license number was SCXK (Hu) 2017-0005. 2.3 Preparation of Drugs Weighed a certain amount of the compound of Example 4 and the compound of Example 5, added 5% by volume of DMSO and 5% of Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then added 90% of physiological saline to prepare a clear solution of 0.1 mg / mL. 2.4 Administration Oral administration: Administered orally to mice, and the dosage was 2.0 mg / kg for all, and the administration volume was 20.0 mL / kg for all. Intravenous injection administration: Administered intravenously to mice, and the dosage was 1.0 mg / kg for all, and the administration volume was 10.0 mL / kg for all.

[0347] 3. Operation Mice were administered the compounds from Example 4 and Example 5 intragastricly. 0.1 mL of blood was collected from the orbit before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour. The plasma was then stored at -80°C for measurement. The process from blood collection to centrifugation was performed under ice bath conditions. Mice were intravenously administered the compounds from Example 4 and Example 5. 0.1 mL of blood was collected before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1.0 hour, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, and 24 hours after administration, and processed in the same manner as the group administered intragastricly. The content of compounds awaiting measurement in the plasma of mice administered with different concentrations of the drug was measured as follows: 25 μL of mouse plasma was taken at each time point after administration, 200 μL of acetonitrile (containing 50 μL of internal standard solution of camptothecin (100 ng / mL)) was added, the mixture was vortexed for 1 minute, and the mixture was centrifuged for 10 minutes (4000 rpm). 0.5 μL of the supernatant was taken from the plasma sample and analyzed by LC / MS / MS.

[0348] 4. Results of pharmacokinetic parameters [Table 11] Conclusion: The compounds disclosed herein all exhibit excellent pharmacokinetic absorption activity in mice and possess pharmacokinetic advantages.

[0349] Test Example 6: Pharmacokinetic evaluation of the compound relating to this disclosure in dogs. 1. Summary Using dogs as test animals, plasma drug concentrations were measured at different time points in dogs administered the compounds described herein by intragastric (ig) / intravenous (iv) injection using LC / MS / MS. The pharmacokinetic behavior of the compounds described herein in dogs was studied, and their pharmacokinetic characteristics were evaluated.

[0350] 2. Test Plan 2.1 Test reagent Compound from Example 4 and compound from Example 5. 2.2 Test animals The animals were 12 male Beagle dogs, divided into four groups on average, and provided by the animal bank (999M-004) of Medisilon Puya Pharmaceutical Technology (Shanghai) Co., Ltd. All animals passed physical examinations and were healthy Beagle dogs with no abnormalities. 2.3 Preparation of drugs Intragastric administration group: A fixed amount of the compound from Example 4 and the compound from Example 5 were weighed, dissolved in 5% volume of DMSO and 20% PEG400, and then 55% physiological saline was added to prepare a 0.4 mg / mL clear solution. Intravenous administration group: Fixed amounts of the compound from Example 4 and the compound from Example 5 were weighed, dissolved in 5% volume of DMSO and 20% PEG400, and then 55% physiological saline was added to prepare a clear solution of 0.25 mg / mL. 2.4 Administration Intragastric administration: The dosage was 2 mg / kg in all cases, and the volume of administration was 50.0 mL / kg in all cases. Intravenous administration: The dose was 0.5 mg / kg in all cases, and the volume of administration was 20.0 mL / kg in all cases.

[0351] 3. Operation Beagle dogs were administered the compounds from Example 4 and Example 5 intragastricly. 1.0 mL of blood was collected from the forelimb vein before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000 rpm for 5 minutes (4°C), and the plasma was separated after 1 hour. The blood was stored at -80°C for measurement. The dogs were fed 3 hours after administration. Beagle dogs were intravenously administered the compounds from Example 4 and Example 5. 0.1 mL of blood was collected before administration and at 5 minutes, 15 minutes, 0.5 hours, 1.0 hour, 2.0 hours, 4.0 hours, 8.0 hours, 12.0 hours, and 24 hours after administration, and processed in the same manner as the group administered gastrically. The process from blood collection to centrifugation was carried out under ice bath conditions. The content of compounds awaiting measurement in the plasma of beagle dogs administered with different concentrations of the drug was measured as follows: 10 μL of plasma from beagle dogs was taken at each time point after administration, 200 μL of acetonitrile (containing the internal standard solution of camptothecin (100 ng / mL)) was added, the mixture was vortexed for 1 minute, and the mixture was centrifuged for 7 minutes (18,000 rpm). 6 μL of the supernatant was taken from the plasma sample and analyzed by LC / MS / MS.

[0352] 4. Results of pharmacokinetic parameters [Table 12] Conclusion: The compounds disclosed herein all exhibit excellent pharmacokinetic absorption activity in dogs and possess pharmacokinetic advantages.

Claims

1. A compound represented by the general formula (IM), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, Ring B is a phenyl group or a 5-membered or 6-membered heteroaryl group. M is either an N atom or a C atom. 【Chemistry 2】 It is a single bond or a double bond, and when M is an N atom, 【Transformation 3】 It is a single bond, and when M is a carbon atom, 【Chemistry 4】 It is either a single bond or a double bond. Ring C is a 6- to 7-membered heterocyclyl group, and the 6- to 7-membered heterocyclyl group contains one to two heteroatoms selected from O atoms or S atoms. Ring A is an aryl group or a heteroaryl group, R １ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ２ This group is selected from hydrogen atoms, alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ３ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, oxo groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ４ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ５ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R ６ These are homologous or different and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, cyano groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. n is 0, 1, 2, or 3. m is 0, 1, 2, 3 or 4, p is 0, 1, 2, or 3. g is 0, 1, 2, 3, 4 or 5, and q is 0, 1, 2, 3, or 4. Compounds represented by general formula (IM), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

2. R ６ These are homologous or different and are independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and among these alkyl groups, heterocyclylalkyl groups, cycloalkylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, each is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. A compound represented by the general formula (IM) described in claim 1, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. A compound represented by the general formula (IN), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 5】 Eventually, Y ５ is an O atom or an S atom, Y ４ and Y ６ are the same or different and each independently is an O atom, an S atom, and -(CR ｍ R ｎ ) ｋ -, provided that Y ４ and Y ６ are not heteroatoms at the same time R ｍ and R ｎ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. Ring B, M, 【Transformation 6】 , ring A, R １ ~R ６ n, m, p and q are as defined in claim 1. A compound represented by the general formula (IM) as described in claim 1 or 2, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. A compound represented by the general formula (INA), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 7】 Eventually, Ring B, M, 【Transformation 8】 Ring A, Y ４ , Y ５ , Y ６ , R １ ~R ６ n, m, p and q are as defined in claim 3. A compound represented by the general formula (IM) as described in any one of claims 1 to 3, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. A compound represented by general formula (I), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 9】 Eventually, Y １ is an O atom or an S atom, Y ２ and Y ３ They are homologous or different, and each is independently an O atom, an S atom and -(CR ｍ R ｎ ) ｋ - Selected from, and as a condition, Y ２ and Y ３ It is not a heteroatom at the same time, R ｍ and R ｎ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. Ring B, M, 【Chemistry 10】 , ring A, R １ ~R ６ n, m, p and q are as defined in claim 1. A compound represented by the general formula (IM) as described in claim 1 or 2, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. Ring B is selected from a phenyl group, a pyridyl group, and a thienyl group. A compound represented by the general formula (IM) as described in any one of claims 1 to 5, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

7. Ring B is a phenyl group or a thienyl group. A compound represented by the general formula (IM) as described in any one of claims 1 to 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

8. A compound represented by general formula (IIG), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 11】 Eventually, G is either a C atom or an N atom. Y ５ is an O atom or an S atom, Y ４ and Y ６ They are homologous or different, and each is independently an O atom, an S atom and -(CR ｍ R ｎ ) ｋ - Selected from, and as a condition, Y ４ and Y ６ It is not a heteroatom at the same time, R ｍ and R ｎ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. M, ring A, R １ ~R ６ n, m, p and q are as defined in claim 1. A compound represented by the general formula (IM) as described in any one of claims 1 to 3 and 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. A compound represented by general formula (IIGa), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 12】 Eventually, G is either a C atom or an N atom. Y ５ is an O atom or an S atom, Y ４ and Y ６ They are homologous or different, and each is independently an O atom, an S atom and -(CR ｍ R ｎ ) ｋ - Selected from, and as a condition, Y ４ and Y ６ It is not a heteroatom at the same time, R ｍ and R ｎ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. M, ring A, R １ ~R ６ n, m, p and q are as defined in claim 8. A compound represented by the general formula (IM) as described in any one of claims 1 to 4, 6, and 8, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

10. A compound represented by general formula (IIN), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 Eventually, Y ５ is an O atom or an S atom, Y ４ and Y ６ They are homologous or different, and each is independently an O atom, an S atom and -(CR ｍ R ｎ ) ｋ - Selected from, and as a condition, Y ４ and Y ６ It is not a heteroatom at the same time, R ｍ and R ｎ These are homologous or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. k is either 1 or 2. M, ring A, R １ ~R ６ n, m, p and q are as defined in claim 1. A compound represented by the general formula (IM) as described in any one of claims 1 to 3 and 6 to 8, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

11. Y ４ and Y ５ is an O atom, and Y ６ is -(CR ｍ R ｎ ), ｋ or Y ５ and Y ６ is an O atom, and Y ４ is -(CR ｍ R ｎ ), ｋ k is 1 or 2, and R ｍ and R ｎ are the same or different and each independently is a hydrogen atom, a halogen, a C １－６ alkyl group, a C ２－６ alkenyl group, a C ２－６ alkynyl group, a C １－６ alkoxy group, a halo C １－６ alkyl group, a halo C １－６ alkoxy group, a hydroxy C １－６ alkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a 3- to 8-member cycloalkyl group, a 3- to 8-member heterocyclyl group, a 6- to 10-member aryl group, and a 5- to 10-member heteroaryl group, A compound represented by the general formula (IM) as described in any one of claims 3, 4, and 6 to 10, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

12. A compound represented by general formula (IIIN-1) or general formula (IIIN-2), or in the form of its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 14】 or 【Chemistry 15】 Eventually, k is either 1 or 2. M, ring A, R １ ~R ６ n, m, p and q are as defined in claim 1. A compound represented by the general formula (IM) as described in any one of claims 1 to 3, 6 to 8, 10 and 11, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

13. A compound represented by general formula (III-1) or general formula (III-2), or in the form of its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 16】 or 【Chemistry 17】 Eventually, k is either 1 or 2. M, ring A, R １ ~R ６ , n, m, p and q are as defined in claim 1 A compound represented by the general formula (IM) as described in any one of claims 1 or 2 and 5 to 7, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

14. the below described [Chemistry 18] teeth 【Chemistry 19】 Selected from, R ３ m is as defined in claim 1, A compound represented by the general formula (IM) as described in any one of claims 1 to 7, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

15. M is CH. A compound represented by the general formula (IM) as described in any one of claims 1 to 13, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

16. Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably a phenyl group, a 5- or 6-membered heteroaryl group and 【Chemistry 20】 Selected from, the ring C' is a 5-membered or 6-membered heteroaryl group. A compound represented by the general formula (IM) as described in any one of claims 1 to 15, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

17. the below described 【Chemistry 21】 teeth 【Chemistry 22】 Selected from, R ６ and q are as defined in claim 1, A compound represented by the general formula (IM) as described in any one of claims 1 to 16, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

18. R １ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C １－６ Selected from alkyl groups, preferably hydrogen atoms, A compound represented by the general formula (IM) as described in any one of claims 1 to 17, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

19. R ２ is C １－６ It is an alkyl group, and among them, the C １－６ Alkyl groups can optionally include halogens, hydroxyl groups, and C13 １－６ Substituted with one or more substituents selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, A compound represented by the general formula (IM) as described in any one of claims 1 to 18, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

20. R ３ These are homologous or different, and each is independently a hydrogen atom, halogen, oxo group, and C １－６ Selected from alkyl groups, preferably a hydrogen atom or C １－６ It is an alkyl group. A compound represented by the general formula (IM) as described in any one of claims 1 to 19, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

21. R ４ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C １－６ Selected from alkyl groups, preferably hydrogen atoms, A compound represented by the general formula (IM) as described in any one of claims 1 to 20, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

22. R ５ These are homologous or different, and each is independently a hydrogen atom or C １－６ It is an alkyl group. A compound represented by the general formula (IM) as described in any one of claims 1 to 21, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

23. R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. １－６ Alkyl alkyl group, C １－６ Alkoxy groups, cyano groups and halo C １－６ Selected from alkyl groups, preferably a hydrogen atom, halogen, and C １－６ Selected from alkyl groups and cyano groups, A compound represented by the general formula (IM) as described in any one of claims 1, 3 to 22, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

24. the below described 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 Selected from the following compounds: A compound represented by the general formula (IM) as described in any one of claims 1 to 23, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

25. Compounds represented by general formula (IMA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, 【Chemistry 27】 Eventually, R ｗ C １－６ It is an alkyl group, 【Chemistry 28】 , ring B, M, ring C, ring A, R １ ~R ６ n, m, p, g and q are as defined in claim 1. Compounds represented by general formula (IMA), or in the form of tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

26. the below described 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 Selected from the following compounds: A compound represented by the general formula (IMA) described in claim 25, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

27. A method for preparing a compound represented by the general formula (IM) described in claim 1, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 【Transformation 33】 This method involves hydrolyzing a compound of general formula (IMA) to obtain a compound of general formula (IM), Eventually, R ｗ C １－６ It is an alkyl group, 【Transformation 34】 , ring B, M, ring C, ring A, R １ ~R ６ n, m, p, g and q are as defined in claim 1. method.

28. A compound represented by the general formula (IM) described in any one of claims 1 to 24, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients. Pharmaceutical composition.

29. A compound represented by the general formula (IM) described in any one of claims 1 to 24, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 28, in the preparation of a drug for activating the GLP-1 receptor. Purpose.

30. Uses of a compound represented by the general formula (IM) as described in any one of claims 1 to 24, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 28, in the preparation of agents for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance, preferably in the preparation of agents for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

31. Uses of a compound represented by the general formula (IM) as described in any one of claims 1 to 24, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 28, in the preparation of agents for the treatment and / or prevention of idiopathic type 1 diabetes, adult latent autoimmune diabetes (LADA), juvenile-onset adult-type diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

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