Condensed imidazole derivative, preparation method thereof and application of condensed imidazole derivative in medicine

Abstract

The invention relates to a condensed imidazole derivative, a preparation method thereof and application of the condensed imidazole derivative in medicine. Specifically, the invention relates to a condensed imidazole derivative as shown in a general formula (IM), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, especially application of the derivative as a GLP-1 receptor agonist and application of the derivative in preparation of drugs for treating and / or preventing diabetes. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180050847.9, application date September 1, 2021, and invention name “Fused imidazole derivatives, preparation methods thereof and their application in medicine”. Technical Field

[0002] The present disclosure belongs to the field of medicine, and relates to a fused imidazole derivative, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a fused imidazole derivative represented by the general formula (IM), a preparation method thereof, a pharmaceutical composition containing the derivative, and its application as a GLP-1 receptor agonist in the field of treating diabetes. Background Art

[0003] Diabetes is a multi-cause metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative lack of insulin in the human body, which leads to an increase in blood glucose concentration, followed by large amounts of sugar excreted in the urine, and symptoms such as polydipsia, polyuria, polyphagia and weight loss.

[0004] Generally speaking, there are two types of diabetes. People with type I diabetes, or insulin-dependent diabetes, produce little or no insulin of their own. Insulin is a hormone that regulates glucose utilization in the body. People with type II diabetes, or non-insulin-dependent diabetes, have plasma insulin levels that are the same or higher than those of non-diabetic people. However, these people are resistant to insulin, which stimulates glucose and lipid metabolism in the main insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even increased plasma insulin levels cannot overcome the patient's significant resistance to insulin.

[0005] Insulin resistance is caused not only by a decrease in the number of insulin receptors, but also by insulin receptor defects, the mechanism of which has not yet been fully understood. Insulin resistance leads to the inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, and the inability to effectively inhibit adipose tissue lipolysis and the production and secretion of glucose in the liver.

[0006] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its corresponding effects by binding to its widely existing specific receptors. At present, the organs where GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system. GLP-1 receptors may be present in the liver, adipose tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also acts on α cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes. However, there is a defect in the response of β cells to GLP-1 after eating. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Since the duration of action of the human body's own GLP-1 is very short (t1 / 2 <1.5 minutes for intravenous injection), the human body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0007] Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) have the effect of reducing fasting and postprandial glucose and improving blood sugar in patients with type II diabetes. However, because the oral bioavailability of peptide GLP-1 is poor and inconvenient to take, small molecule GLP-1 receptor agonists with good oral bioavailability are highly desired.

[0008] Published patent applications for GLP-1 receptor small molecule agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1, etc. Summary of the invention

[0009] The object of the present disclosure is to provide a compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring B is phenyl or a 5- or 6-membered heteroaryl group;

[0013] M is a N atom or a C atom;

[0014] is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond;

[0015] Ring C is a 6- to 7-membered heterocyclic group containing 1 to 2 heteroatoms selected from O atoms or S atoms;

[0016] Ring A is an aryl group or a heteroaryl group;

[0017] R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0018] R 2 is selected from the group consisting of hydrogen, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0022] R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0023] n is 0, 1, 2 or 3;

[0024] m is 0, 1, 2, 3 or 4;

[0025] p is 0, 1, 2 or 3;

[0026] g is 0, 1, 2, 3, 4 or 5; and

[0027] q is 0, 1, 2, 3 or 4.

[0028] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0029] in:

[0030] Ring B is phenyl or a 5- or 6-membered heteroaryl group;

[0031] M is a N atom or a C atom;

[0032] is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond;

[0033] Ring C is a 6- to 7-membered heterocyclic group containing 1 to 2 heteroatoms selected from O atoms or S atoms;

[0034] Ring A is an aryl group or a heteroaryl group;

[0035] R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0036] R 2 is selected from the group consisting of hydrogen, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0037] R 3are the same or different and are each independently selected from hydrogen, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0038] R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0039] R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0040] R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0041] n is 0, 1, 2 or 3;

[0042] m is 0, 1, 2, 3 or 4;

[0043] p is 0, 1, 2 or 3;

[0044] g is 0, 1, 2, 3, 4 or 5; and

[0045] q is 0, 1, 2, 3 or 4.

[0046] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0047]

[0048] in:

[0049] Y 5is an O atom or a S atom;

[0050] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0051] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0052] k is 1 or 2;

[0053] Ring B, M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0054] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM) or the general formula (IN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (INa) or the general formula (INb), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0055]

[0056] in:

[0057] Y 5 is an O atom or a S atom;

[0058] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0059] R m and R nare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0060] k is 1 or 2;

[0061] Ring B, M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0062] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0063]

[0064] in:

[0065] Y 1 is an O atom or a S atom;

[0066] Y 2 and Y 3 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 2 and Y 3 Not all are heteroatoms;

[0067] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0068] k is 1 or 2;

[0069] Ring B, M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0070] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0071] in:

[0072] Ring B is phenyl or a 5- or 6-membered heteroaryl group;

[0073] M is a N atom or a C atom;

[0074] is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond;

[0075] Y 1 is an O atom or a S atom;

[0076] Y 2 and Y 3 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 2 and Y 3 Not all are heteroatoms;

[0077] Ring A is an aryl group or a heteroaryl group;

[0078] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0079] R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0080] R 2 is selected from the group consisting of hydrogen, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0081] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0082] R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0083] R 5 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0084] R 6 are the same or different and are each independently selected from hydrogen, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0085] k is 1 or 2;

[0086] n is 0, 1, 2 or 3;

[0087] m is 0, 1, 2, 3 or 4;

[0088] p is 0, 1, 2 or 3; and

[0089] q is 0, 1, 2, 3 or 4.

[0090] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM) or the general formula (I), or its tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 6the same or different and each independently selected from hydrogen, halogen, alkyl, alkoxy, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0091] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM) or the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0092]

[0093] in:

[0094] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (I).

[0095] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa) or general formula (INb), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridyl and thienyl.

[0096] In some preferred embodiments of the present disclosure, the compound represented by general formula (IM), general formula (I), general formula (II), general formula (IN), general formula (INa) or general formula (INb), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or thienyl.

[0097] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM) or the general formula (IN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIG), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0098]

[0099] in:

[0100] G is a C atom or a N atom;

[0101] Y 5 is an O atom or a S atom;

[0102] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0103] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0104] k is 1 or 2;

[0105] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0106] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (IN) or general formula (IIG), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIGa) or general formula (IIGb), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0107]

[0108] in:

[0109] G is a C atom or a N atom;

[0110] Y 5 is an O atom or a S atom;

[0111] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0112] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0113] k is 1 or 2;

[0114] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0115] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (IN) or general formula (IIG), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0116]

[0117] in:

[0118] Y 5 is an O atom or a S atom;

[0119] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0120] R m and R nare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0121] k is 1 or 2;

[0122] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0123] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (IN), general formula (IIG) or general formula (IIN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IINa) or general formula (IINb), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0124]

[0125]

[0126] in:

[0127] Y 5 is an O atom or a S atom;

[0128] Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms;

[0129] R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0130] k is 1 or 2;

[0131] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0132] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein Y 4 and Y 5 is an O atom, and Y 6 For-(CR m R n ) k -; or, Y 5 and Y 6 is an O atom, and Y 4 For-(CR m R n ) k -; k is 1 or 2; R m and R n are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy 1-6 Alkyl, cyano, amino, nitro, hydroxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0133] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein Y 1 and Y 2 is an O atom, and Y 3 For-(CR m R n ) k -; or, Y 1 and Y 3 is an O atom, and Y 2 For-(CR m R n ) k -; k is 1 or 2; R m and R n As defined in general formula (I).

[0134] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (IN), general formula (IIG) or general formula (IIN), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIIN-1) or general formula (IIIN-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0135]

[0136] in:

[0137] k is 1 or 2;

[0138] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0139] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I) or general formula (II), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III-1) or general formula (III-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0140]

[0141]

[0142] in:

[0143] k is 1 or 2;

[0144] M, Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IM).

[0145] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (IN), general formula (INa) or general formula (INb), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein Selected from R 3 and m are as defined in Formula (IM).

[0146] In some preferred embodiments of the present disclosure, the compound represented by the general formula (II), 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein for R 3 A hydrogen atom or C 1-6 Alkyl; preferably, Selected from

[0147] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein for R 3 and m are as defined in Formula (IM).

[0148] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein for R 3 A hydrogen atom or C 1-6 Alkyl; preferably, Selected from

[0149] In some preferred embodiments of the present disclosure, the 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) or general formula (III-2), or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein M is CH.

[0150] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is selected from phenyl, 5- or 6-membered heteroaryl and Ring C' is a 5- or 6-membered heteroaryl group; more preferably, Ring A is selected from benzothiazolyl, phenyl and pyridyl.

[0151] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein Selected from R 6 and q are as defined in Formula (IM).

[0152] In some preferred embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein Selected from R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; q is 0, 1, 2, 3 or 4.

[0153] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein for R 6 and q are as defined in the general formula (I).

[0154] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably a hydrogen atom.

[0155] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 alkoxy, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group or more substituents; preferably, R 2 for

[0156] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 3 are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 alkyl.

[0157] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 3 A hydrogen atom or C 1-6 alkyl.

[0158] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably a hydrogen atom.

[0159] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 5 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl.

[0160] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 5 A hydrogen atom or C 1-6 alkyl.

[0161] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl, preferably selected from hydrogen atoms, halogen, C1-6 Alkyl and cyano.

[0162] In some embodiments of the present disclosure, the compounds represented by the 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkyl.

[0163] In some embodiments of the present disclosure, the compounds represented by 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 their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein k is 1.

[0164] In some preferred embodiments of the present disclosure, the compounds represented by the 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) and general formula (IINb), or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R m and R n are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl groups, preferably hydrogen atoms and C 1-6 alkyl.

[0165] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein ring C is a 6- to 7-membered heterocyclic group, and the 6- to 7-membered heterocyclic group contains 1 to 2 heteroatoms selected from O atoms or S atoms; M is a nitrogen atom or a carbon atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond; Ring B is a phenyl group or a 5- or 6-membered heteroaryl group; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; n is 0, 1 or 2; R 2 C 1-6 Alkyl or 3 to 8 membered heterocyclic group C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more substituents selected from alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group; R 3 are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 Alkyl; m is 0 or 1; R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2; R 5 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; g is 0, 1 or 2; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl; q is 0, 1, 2 or 3.

[0166] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (IN), the general formula (INa) and the general formula (INb), or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein Y 4 and Y 5 is an O atom, and Y 6 For-(CR m R n ) k -; or, Y 5 and Y 6 is an O atom, and Y 4 For-(CR m R n ) k -; k is 1 or 2; R m and R n are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy 1-6 alkyl, cyano, amino, nitro, hydroxyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; M is a nitrogen atom or a carbon atom; Ring B is phenyl or a 5- or 6-membered heteroaryl; Ring A is selected from phenyl, 5- or 6-membered heteroaryl and Ring C' is a 5- or 6-membered heteroaryl group; R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; n is 0, 1 or 2; R 2 C 1-6 Alkyl or 3 to 8 membered heterocyclic group C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more substituents selected from alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group; R 3 are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 Alkyl; m is 0 or 1; R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2; R 5 A hydrogen atom or C 1-6 Alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl; q is 0, 1, 2 or 3.

[0167] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (IIG), the general formula (IIGa) and the general formula (IIGb), or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein G is a nitrogen atom or a carbon atom; Y 4 and Y 5 is an O atom, and Y 6 For-(CR m R n ) k -; or, Y 5 and Y 6 is an O atom, and Y 4 For-(CR m R n ) k -; k is 1 or 2; R m and R nare all hydrogen atoms; Ring A is selected from phenyl, 5- or 6-membered heteroaryl and Ring C' is a 5- or 6-membered heteroaryl group; R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; n is 0, 1 or 2; R 2 C 1-6 Alkyl or 3 to 8 membered heterocyclic group C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more substituents selected from alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group; R 3 are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 Alkyl; m is 0 or 1; R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2; R 5 A hydrogen atom or C 1-6 Alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl; q is 0, 1, 2 or 3.

[0168] In some preferred embodiments of the present disclosure, the compounds represented by the general formula (IIG), the general formula (IIGa) and the general formula (IIGb), or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein G is a carbon atom; Y 4 and Y 5 is an O atom, and Y 6 For-(CR m R n ) k -; k is 1; R m and R n are all hydrogen atoms; Ring A is selected from benzothiazolyl, phenyl and pyridyl; R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; n is 0, 1 or 2; R 2 C 1-6 Alkyl or 3 to 8 membered heterocyclic group C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more substituents selected from alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group; R 3are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 Alkyl; m is 0 or 1; R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2; R 5 A hydrogen atom or C 1-6 Alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl; q is 0, 1, 2 or 3.

[0169] Table A Typical compounds of the present disclosure include, but are not limited to:

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0182] Another aspect of the present disclosure relates to a compound represented by the general formula (IMA), or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0183]

[0184] in:

[0185] R w C 1-6alkyl;

[0186] Ring B, M, Ring C, Ring A, R 1 To 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).

[0187] Another aspect of the present disclosure relates to a compound represented by the general formula (INA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0188]

[0189] in:

[0190] R w C 1-6 alkyl;

[0191] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To 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).

[0192] Another aspect of the present disclosure relates to a compound represented by the general formula (INaA) or the general formula (INbA), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0193]

[0194] in:

[0195] R w C 1-6 alkyl;

[0196] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IN). It is an intermediate for preparing the general formula (INa) or the general formula (INb).

[0197] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGA), or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0198]

[0199] in:

[0200] R w C 1-6 alkyl;

[0201] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IIG). It is an intermediate for preparing the general formula (IIG).

[0202] Another aspect of the present disclosure relates to a compound represented by the general formula (IINA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0203]

[0204] in:

[0205] R w C 1-6 alkyl;

[0206] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To 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).

[0207] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGaA) or the general formula (IIGbA), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0208]

[0209] in:

[0210] R w C 1-6 alkyl;

[0211] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6, n, m, p and q are as defined in the general formula (IIGa) or the general formula (IIGb). It is an intermediate for preparing the general formula (IIGa) or the general formula (IIGb).

[0212] Another aspect of the present disclosure relates to a compound represented by the general formula (IINaA) or the general formula (IINbA), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0213]

[0214]

[0215] in:

[0216] R w C 1-6 alkyl;

[0217] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IINa) or the general formula (IINb). It is an intermediate for preparing the general formula (IINa) or the general formula (IINb).

[0218] Another aspect of the present disclosure relates to a compound represented by the general formula (IIINA-1), or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0219]

[0220] in:

[0221] R w C 1-6 alkyl;

[0222] M, Ring A, R 1 To 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).

[0223] Another aspect of the present disclosure relates to a compound represented by the general formula (IIINA-2), or a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0224]

[0225] in:

[0226] R w C 1-6 alkyl;

[0227] M, Ring A, R 1 To 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).

[0228] Another aspect of the present disclosure relates to a compound represented by general formula (IA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0229]

[0230] in:

[0231] R w C 1-6 alkyl;

[0232] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (I). It is an intermediate for preparing the general formula (I).

[0233] Another aspect of the present disclosure relates to a compound represented by general formula (IIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0234]

[0235] in:

[0236] R w C 1-6 alkyl;

[0237] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in general formula (IA). It is an intermediate for preparing general formula (II).

[0238] Another aspect of the present disclosure relates to a compound represented by general formula (III-1A) or general formula (III-2A), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0239]

[0240] in:

[0241] R w C 1-6 alkyl;

[0242] M, Ring A, R 1 To R 6 , k, n, m, p and q are as defined in the general formula (IA). It is an intermediate for preparing the general formula (III-1) or the general formula (III-2).

[0243] Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0257] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0258]

[0259] The compound of general formula (IMA) undergoes hydrolysis reaction to obtain a compound of general formula (IM),

[0260] in:

[0261] R w C 1-6 alkyl;

[0262] Ring B, M, Ring C, Ring A, R 1 To R 6 , n, m, p, g and q are as defined in the general formula (IM).

[0263] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0264]

[0265] The compound of general formula (INA) undergoes hydrolysis reaction to obtain a compound of general formula (IN),

[0266] in:

[0267] R w C 1-6 alkyl;

[0268] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IN).

[0269] 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 comprising:

[0270]

[0271] The compound of general formula (INaA) undergoes hydrolysis reaction to obtain the compound of general formula (INa), or the compound of general formula (INbA) undergoes hydrolysis reaction to obtain the compound of general formula (INb)

[0272] in:

[0273] R w C 1-6 alkyl;

[0274] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (INa) or Formula (INb).

[0275] 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 comprising:

[0276]

[0277] The compound of general formula (IN) is subjected to chiral separation to obtain a compound of general formula (INa) and a compound of general formula (INb);

[0278] in:

[0279] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (INa) or Formula (INb).

[0280] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0281]

[0282] The compound of general formula (IIGA) undergoes hydrolysis reaction to obtain a compound of general formula (IIG),

[0283] in:

[0284] R w C 1-6 alkyl;

[0285] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIG).

[0286] 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 comprising:

[0287]

[0288] The compound of general formula (IIGaA) undergoes hydrolysis reaction to obtain a compound of general formula (IIGa), or

[0289] The compound of general formula (IIGbA) undergoes hydrolysis reaction to obtain a compound of general formula (IIGb),

[0290] in:

[0291] R w C 1-6 alkyl;

[0292] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIGa) or Formula (IIGb).

[0293] 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 comprising:

[0294]

[0295] The compound of general formula (IIG) is subjected to chiral separation to obtain a compound of general formula (IIGa) and a compound of general formula (IIGb), wherein:

[0296] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIGa) or Formula (IIGb).

[0297] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0298]

[0299] The compound of general formula (IINA) undergoes hydrolysis reaction to obtain a compound of general formula (IIN),

[0300] in:

[0301] R w C 1-6 alkyl;

[0302] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IIN).

[0303] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IINa) or the general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0304]

[0305] The compound of general formula (IINaA) undergoes hydrolysis reaction to obtain a compound of general formula (IINa), or

[0306] The compound of general formula (IINbA) undergoes hydrolysis reaction to obtain a compound of general formula (IINb),

[0307] in:

[0308] R w C 1-6 alkyl;

[0309] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IINa) or Formula (IINb).

[0310] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IINa) or the general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0311]

[0312] The compound of general formula (IIN) is subjected to chiral resolution to obtain a compound of general formula (IINa) and a compound of general formula (IINb), wherein:

[0313] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IINa) or Formula (IINb).

[0314] 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0315]

[0316] The compound of general formula (IIINA-1) undergoes hydrolysis reaction to obtain a compound of general formula (IIIN-1), or

[0317] The compound of general formula (IIINA-2) undergoes hydrolysis reaction to obtain a compound of general formula (IIIN-2),

[0318] in:

[0319] R w C 1-6 alkyl;

[0320] M, Ring A, R 1 To R 6 , k, n, m, p and q are as defined in the general formula (IIIN-1) or the general formula (IIIN-2).

[0321] 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0322]

[0323] The compound of general formula (IA) undergoes hydrolysis reaction to obtain a compound of general formula (I),

[0324] in:

[0325] R w C 1-6 alkyl;

[0326] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6, n, m, p and q are as defined in the general formula (I).

[0327] 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0328]

[0329] The compound of general formula (IIA) undergoes hydrolysis reaction to obtain a compound of general formula (II),

[0330] in:

[0331] R w C 1-6 alkyl;

[0332] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (II).

[0333] 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0334]

[0335] The compound of general formula (III-1A) undergoes hydrolysis reaction to obtain a compound of general formula (III-1), or

[0336] The compound of general formula (III-2A) undergoes hydrolysis reaction to obtain a compound of general formula (III-2),

[0337] in:

[0338] R w C 1-6 alkyl;

[0339] M, Ring A, R 1 To R 6 , k, n, m, p and q are as defined in the general formula (III-1) or (III-2).

[0340] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound represented by the 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) of the present disclosure, or its tautomer, racemate, enantiomer, diastereomer or mixture form, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0341] The present disclosure further relates to the use of compounds represented by general formula (IM), general formula (I), general formula (II), 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 their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of drugs for stimulating GLP-1 receptors.

[0342] The present disclosure further relates to compounds 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 their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or Use of a pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and liver insulin resistance; preferably use of a pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0343] The present disclosure further relates to the use of compounds 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 their tautomers, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of drugs for the treatment and / or prevention of idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0344] The present disclosure also relates to a method for agonizing a GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount 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 their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

[0345] The present disclosure also relates to a method for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease and cardiovascular disease, which comprises administering a therapeutically effective amount of a drug of the general formula (IM ), compounds represented by 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 their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0346] The present disclosure also relates to a method for treating and / or preventing idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by the general formula (IM), the general formula (I), the general formula (II), the general formula (IN), the general formula (INa), the general formula (INb), the general formula (IIG), the general formula (IIGa), the general formula (IIGb), the general formula (IIN), the general formula (IINa), the general formula (IINb), the general formula (IIIN-1), the general formula (IIIN-2), the general formula (III-1) and the general formula (III-2) or its tautomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0347] The present disclosure further relates to a compound represented by general formula (IM), general formula (I), general formula (II), 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 its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same, which is used as a drug.

[0348] The present disclosure also relates to compounds represented by general formula (IM), general formula (I), general formula (II), 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 their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as GLP-1 receptor agonists.

[0349] The present disclosure further relates to compounds represented by formula (IM), formula (I), formula (II), formula (IN), formula (INa), formula (INb), formula (IIN), formula (IIG), formula (IIGa), formula (IIGb), formula (IINa), formula (IINb), formula (IIIN-1), formula (IIIN-2), formula (III-1) and formula (III-2) or their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably for treating and / or preventing a disease selected from type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease and cardiovascular disease.

[0350] The present disclosure further relates to compounds represented by general formula (IM), general formula (I), general formula (II), 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 their tautomers, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used to treat and / or prevent idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0351] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and they can be acute complexes or chronic complexes. The term "acute complexes" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary system infections, respiratory system infections, urinary tract infections), and "chronic complexes" include, for example, microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders), and gangrene. Major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0352] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0353] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia, and diabetic dementia.

[0354] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can also be formulated into a sustained release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, an emulsion, an injection, a dispersible powder or granules, a suppository, a lozenge or a syrup.

[0355] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0356] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0357] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0358] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0359] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0360] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0361] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0362] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0363] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0364] The disclosed compounds 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 which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0365] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0366] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0367] Terminology

[0368] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0369] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Most preferably, lower alkyl groups contain 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably independently selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0370] The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of an alkane radical, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12Alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene 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-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0371] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups, which are independently selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0372] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above. Preferably, the alkyl group contains 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0373] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably, the alkyl compound contains 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6Alkynyl). Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0374] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12-membered cycloalkyl), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, fused, and bridged rings.

[0375] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl or a multi-spirocycloalkyl (e.g., a double spiral cycloalkyl), preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0376]

[0377] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0378]

[0379] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0380]

[0381] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0382] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0383] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., 3 to 12-membered heterocyclyl), 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 1-3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclyl); more preferably, it contains 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl), of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclyl), of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. The polycyclic heterocyclic group includes spiro, fused and bridged heterocyclic groups.

[0384] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. It is more preferably a 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan monospiro heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0385]

[0386] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radicals include:

[0387]

[0388] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0389]

[0390] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0391] wait.

[0392] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic group, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0393] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0394]

[0395] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0396] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan (i.e., 5 or 6 yuan heteroaryl), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0397]

[0398] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0399] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the parent ring atom by removing one hydrogen atom, or two residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0400] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations.

[0401] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present 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. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually completed by using chromatography.

[0402] The term "amino protecting group" is to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl and p-methoxybenzyl. These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl and tert-butyloxycarbonyl.

[0403] The term "hydroxy protecting group" refers to a group known in the art as being suitable for protecting a hydroxy group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, etc.; can be (C 1-10 alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 alkyl or 6 to 10 membered aryl) sulfonyl; it may also be (C 1-6 The hydroxy protecting group is preferably a p-nitrobenzoyl group.

[0404] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0405] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0406] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0407] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0408] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0409] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0410] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0411] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0412] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0413] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0414] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0415] The term "hydroxy" refers to -OH.

[0416] The term "thiol" refers to -SH.

[0417] The term "amino" refers to -NH2.

[0418] The term "cyano" refers to -CN.

[0419] The term "nitro" refers to -NO2.

[0420] The term "oxo" refers to "=0".

[0421] The term "carbonyl" refers to C=O.

[0422] The term "carboxy" refers to -C(O)OH.

[0423] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above. The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-,13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. Wherein the deuterated form of the compound of formula (I) is that each available hydrogen atom connected to the carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound of formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0424] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0425] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0426] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0427] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0428] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0429] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0430] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0431] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0432] Synthesis method of the disclosed compound

[0433] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0434] Solution 1

[0435] The method for preparing the compound represented by the general formula (IM) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt comprises the following steps:

[0436]

[0437] The compound of general formula (IMA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IM),

[0438] in:

[0439] R w C 1-6 alkyl;

[0440] Ring B, M, Ring C, Ring A, R 1 To R 6 , n, m, p, g and q are as defined in the general formula (IM).

[0441] Solution 2

[0442] The method for preparing the compound represented by the general formula (IN) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt comprises the following steps:

[0443]

[0444] The compound of general formula (INA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IN),

[0445] in:

[0446] R w C 1-6 alkyl;

[0447] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IN).

[0448] Option 3

[0449] The present invention discloses a method for preparing a compound represented by general formula (INa) or general formula (INb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0450]

[0451] The compound of general formula (INaA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (INa), or

[0452] The compound of general formula (INbA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (INb)

[0453] in:

[0454] R w C 1-6 alkyl;

[0455] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (INa) or Formula (INb).

[0456] Option 4

[0457] The present invention discloses a method for preparing a compound represented by general formula (INa) or general formula (INb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0458]

[0459] The compound of general formula (IN) is subjected to chiral separation to obtain a compound of general formula (INa) and a compound of general formula (INb);

[0460] in:

[0461] Ring B, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (INa) or Formula (INb).

[0462] Option 5

[0463] The method for preparing the compound represented by the general formula (IIG) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0464]

[0465] The compound of general formula (IIGA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIG),

[0466] in:

[0467] R w C 1-6 alkyl;

[0468] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIG).

[0469] Option 6

[0470] The present invention discloses a method for preparing 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, comprising the following steps:

[0471]

[0472] The compound of general formula (IIGaA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIGa), or

[0473] The compound of general formula (IIGbA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIGb),

[0474] in:

[0475] R w C 1-6 alkyl;

[0476] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIGa) or Formula (IIGb).

[0477] Option 7

[0478] The present invention discloses a method for preparing 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, comprising the following steps:

[0479]

[0480] The compound of general formula (IIG) is subjected to chiral separation to obtain a compound of general formula (IIGa) and a compound of general formula (IIGb), wherein:

[0481] G, M, Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IIGa) or Formula (IIGb).

[0482] Option 8

[0483] The method for preparing the compound represented by the general formula (IIN) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0484]

[0485] The compound of general formula (IINA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIN),

[0486] in:

[0487] R w C 1-6 alkyl;

[0488] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (IIN).

[0489] Option 9

[0490] The present invention discloses a method for preparing a compound represented by the general formula (IINa) or the general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0491]

[0492] The compound of general formula (IINaA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IINa), or

[0493] The compound of general formula (IINbA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IINb),

[0494] in:

[0495] R w C 1-6 alkyl;

[0496] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IINa) or Formula (IINb).

[0497] Plan 10

[0498] The present invention discloses a method for preparing a compound represented by the general formula (IINa) or the general formula (IINb), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0499]

[0500] The compound of general formula (IIN) is subjected to chiral resolution to obtain a compound of general formula (IINa) and a compound of general formula (IINb), wherein:

[0501] M.Y 4 , Y 5 , Y 6 , Ring A, R 1 To R 6 , n, m, p and q are as defined in Formula (IINa) or Formula (IINb).

[0502] Plan 11

[0503] The present invention discloses a method for preparing a compound represented by general formula (IIIN-1) or general formula (IIIN-2), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0504]

[0505] The compound of general formula (IIINA-1) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIIN-1), or

[0506] The compound of general formula (IIINA-2) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (IIIN-2),

[0507] in:

[0508] R w C 1-6 alkyl;

[0509] M, Ring A, R 1 To R 6 , k, n, m, p and q are as defined in the general formula (IIIN-1) or the general formula (IIIN-2).

[0510] Plan 12

[0511] The method for preparing the compound represented by the general formula (I) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt comprises the following steps:

[0512]

[0513] The compound of general formula (IA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (I),

[0514] in:

[0515] R w C 1-6 alkyl;

[0516] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (I).

[0517] Plan 13

[0518] The method for preparing the compound represented by the general formula (II) of the present invention, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt comprises the following steps:

[0519]

[0520] The compound of general formula (IIA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (II)

[0521] in:

[0522] R w C 1-6 alkyl;

[0523] Ring B, M, Y 1 , Y 2 , Y 3 , Ring A, R 1 To R 6 , n, m, p and q are as defined in the general formula (II).

[0524] Scheme 14

[0525] The present invention discloses a method for preparing a compound represented by general formula (III-1) or general formula (III-2), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0526]

[0527] The compound of general formula (III-1A) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (III-1), or

[0528] The compound of general formula (III-2A) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (III-2),

[0529] in:

[0530] R w C 1-6 alkyl;

[0531] M, Ring A, R 1 To R6 , k, n, m, p and q are as defined in the general formula (III-1) or (III-2).

[0532] In the above synthesis scheme, the alkaline reagent includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide and potassium tert-butoxide, and 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.

[0533] The reaction of the above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is 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. DETAILED DESCRIPTION

[0534] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0535] abbreviation:

[0536] 1. "Ts" refers to p-toluenesulfonyl;

[0537] 2. “Tf” refers to trifluoromethanesulfonyl.

[0538] Example

[0539] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0540] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0541] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0542] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0543] High performance liquid chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0544] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0545] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0546] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0547] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0548] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0549] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0550] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0551] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0552] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0553] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0554] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0555] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0556] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0557] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0558] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, D: ethyl acetate / dichloromethane / n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0559] Example 1

[0560] 2-((4-(3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 1

[0561] 2-((4-((S)-3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-12-((4-((R)-3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)

[0562] methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-2

[0563]

[0564] first step

[0565] 3-Bromo-2-(methoxymethoxy)phenol 1b

[0566] The 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 under stirring. Bromomethyl methyl ether (30.0 g, 240.0 mmol, 19.59 mL, Adamas Reagent Co., Ltd.) was added dropwise under ice bath. The mixture was stirred at room temperature for 2 hours, and 200 mL of water was added for washing. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (26.65 g, yield: 43.39%).

[0567] MS m / z(ESI):232.0[M-1]

[0568] Step 2

[0569] Ethyl 2-(3-bromo-2-(methoxymethoxy)phenoxy)acetate 1c

[0570] Compound 1b (3.02 g, 12.95 mmol) was dissolved in 10 mL of dimethyl sulfoxide, ethyl bromoacetate (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, and the temperature was raised to 95°C for 21 hours. 20 mL of water was added and stirred, and the mixture was extracted with ethyl acetate (20 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the title compound 1c (3.5 g, yield: 84.63%).

[0571] Step 3

[0572] 1-(Benzo[d]thiazol-2-yl)-2-(3-bromo-2-(methoxymethoxy)phenoxy)ethan-1-one 1e

[0573] Compound 1c (957 mg, 2.99 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to -78 °C under nitrogen protection, and n-butyl lithium (384 mg, 5.99 mmol, Adamas Reagent 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 bottle and reacted for 1 hour. The reaction was 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 residue was purified by silica gel column chromatography using eluent system B to obtain the title product 1e (1.20 g, yield: 98.02%).

[0574] MS m / z(ESI):409.0[M+1].

[0575] Step 4

[0576] 1-(Benzo[d]thiazol-2-yl)-2-(3-bromo-2-(methoxymethoxy)phenoxy)ethan-1-ol 1f

[0577] Compound 1e (600 mg, 1.46 mmol) was dissolved in 20 mL of ethanol, sodium borohydride (55.84 mg, 1.46 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added under ice bath, and stirred for 10 minutes. 20 mL of water was added and stirred, extracted with ethyl acetate (20 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the title compound 1f (570 mg, yield: 94.53%).

[0578] Step 5

[0579] 2-(2-(Benzo[d]thiazol-2-yl)-2-hydroxyethoxy)-6-bromophenol 1g

[0580] Compound 1f (570 mg, 1.39 mmol) was dissolved in 80 mL of dichloromethane, and 20 mL of a dioxane solution (4 mmol / mL) of hydrogen chloride was added under ice bath, and stirred for half an hour. The organic phase was concentrated, and 15 mL of a mixed solution of n-hexane and ethyl acetate (V:V=5:1) was added, and the mixture was slurried and filtered to obtain 1 g of the title compound (503 mg, yield: 98.95%).

[0581] Step 6

[0582] 2-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 1h

[0583] Compound 1g (350mg, 0.95mmol) was dissolved in 25mL of tetrahydrofuran, triphenylphosphine (375mg, 1.43mmol, China National Pharmaceutical Group Shanghai Chemical Reagent Co., Ltd.) was added, and diisopropyl azodicarboxylate (289mg, 1.43mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added dropwise under ice bath, and the reaction was continued for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (248mg, yield: 74.52%).

[0584] MS m / z(ESI):349.0[M+1].

[0585] Step 7

[0586] 4-(3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropiperidine

[0587] -1(2H)-tert-Butyl formate 1j

[0588] Compound 1h (220 mg, 0.63 mmol) was dissolved in 1,4-dioxane (20 mL), and 3,6-dihydro-2H-pyridine-1-tert-butyloxycarbonyl-1-boronic acid pinacol ester 1i (215 mg, 0.69 mmol), sodium carbonate (134 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium (73 mg, 63 μmol), and water (4 mL) were added. The mixture was heated to 90°C under nitrogen protection and stirred for 4 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with eluent system B to obtain the title compound 1j (230 mg, yield: 80.79%).

[0589] MS m / z(ESI):451.1[M+1].

[0590] Step 8

[0591] tert-Butyl 4-(3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate 1k

[0592] Compound 1j (230 mg, 0.51 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium on carbon (138 mg, 0.30 mmol) was added, and hydrogenation was carried out under one atmosphere of hydrogen at room temperature for 3 hours. The filtrate was filtered and concentrated to obtain the crude title compound 1k (230 mg), which was used directly in the next step without purification.

[0593] MS m / z(ESI):453.0[M+1].

[0594] Step 9

[0595] 2-(8-(Piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)benzo[d]thiazole 4-methylbenzenesulfonate 1l

[0596] Compound 1k (220 mg, 0.48 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure to give the crude title compound 11 (170 mg). The product was used directly in the next step without purification.

[0597] MS m / z(ESI):353.1[M+1].

[0598] Step 10

[0599] 2-((4-(3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 1n

[0600] Compound 11 (170 mg, 0.48 mmol) was dissolved in 20 mL of acetonitrile, compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1m (143 mg, 0.48 mmol, prepared by the method disclosed in intermediate 23 on page 69 of the specification of patent application WO2018109607A1), 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 solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain a mixture of diastereomers 1n (220 mg, yield: 74.24%).

[0601] MS m / z(ESI):611.2[M+1].

[0602] Step 11

[0603] 2-((4-(-3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 1

[0604] Compound 1n (20 mg, 0.032 mmol) was dissolved in a mixed solvent of 5 mL 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, and the mixture was reacted at 40°C for 16 hours. The mixture was cooled to room temperature, and the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and extracted with ethyl acetate (20 mL×2), and the organic layers were combined and concentrated, and purified by silica gel column chromatography with eluent system A to obtain a crude title diastereoisomer mixture 1 (20 mg).

[0605] Step 12

[0606] 2-((4-((S)-3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-1

[0607] 2-((4-((R)-3-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 1-2

[0608] Compound 1 (20 mg, 0.032 mmol) was subjected to chiral separation column preparation and concentrated under reduced pressure to obtain the title compound 1-1 (6 mg, yield: 30.70%) and the title compound 1-2 (6 mg, yield: 30.70%).

[0609] Compound 1-1:

[0610] Chiral HPLC analysis: retention time 3.859 minutes, chiral purity: 99% (chromatographic column: (separation conditions: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase hexane / EtOH (0.1% DEA+0.1TFA) = 20 / 80 (V / V))

[0611] MS m / z(ESI):597.2[M+1].

[0612] 1 H NMR(500MHz,DMSO-d6)δ12.46(s,1H),8.25(s,1H),8.18(d,1H),8.06(d,1H),7.81(d,1H),7.61(d,1H),7.5 4-7.58(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,1 H),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).

[0613] Compound 1-2:

[0614] Chiral HPLC analysis: retention time 2.999 minutes, chiral purity: 99% (chromatographic column: (separation conditions: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase hexane / EtOH (0.1% DEA+0.1TFA) = 20 / 80 (V / V))

[0615] MS m / z(ESI):597.2[M+1].

[0616] 1 H NMR(500MHz,DMSO-d6)δ12.46(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).

[0617] Example 2

[0618] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 2

[0619]

[0620] first step

[0621] 2-(4-Chloro-2-fluorophenyl)oxirane 2b

[0622] 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 Reagent Co., Ltd.) was added under ice bath, and stirred for 5 minutes. 4-Chloro-2-fluorobenzaldehyde 2a (2.0 g, 12.61 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, filtered, diluted with ethyl acetate (80 ml), washed with saturated ammonium chloride aqueous solution (30 mL × 2), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (650 mg, yield: 29.9%). 1 H NMR (500MHz, CDCl3) δ7.05-7.13(m,3H), 4.01-4.15(m,1H), 3.17(dd,1H), 3.75(dd,1H).

[0623] Step 2

[0624] 2-(4-Chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2d

[0625] 1-(4-Chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e

[0626] 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 Reagent Co., Ltd.) was added, and stirred at 130° C. for 2 hours. After cooling, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (210 mg, yield: 16.4%) and compound 2e (140 mg, yield: 10.9%).

[0627] 2d MS m / z(ESI):422.9[M-1].

[0628] 2d 1 H NMR(500MHz,DMSO-d6)δ7.69(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).

[0629] 2e 1H NMR(500MHz,DMSO-d6)δ7.64(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).

[0630] Step 3

[0631] 8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 2f

[0632] 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 Pharmaceutical Group Shanghai Chemical Reagent Co., Ltd.), cesium carbonate (912 mg, 2.80 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added in sequence, heated to reflux, and stirred for 18 hours. The mixture was cooled, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2f (380 mg, yield: 78.9%).

[0633] MS m / z(ESI):343.1[M-1].

[0634] 1 H NMR (500MHz, DMSO-d6) δ7.57(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).

[0635] Step 4

[0636] 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)

[0637] -5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2g

[0638] 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), and sodium carbonate (218 mg, 2.06 mmol) and tetrakis(triphenylphosphine)palladium (119 mg, 1.03 mmol) were added, and stirred at 90°C for 4 hours under nitrogen protection. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2g (410 mg, yield: 89.2%).

[0639] MS m / z(ESI):390.1[M-55].

[0640] 1 H NMR(500MHz, CDCl3)δ7.39(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,1 H),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).

[0641] Step 5

[0642] tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate

[0643] 2h

[0644] Compound 2g (220 mg, 0.49 mmol) was dissolved in ethyl acetate (10 mL) and 1,2-dichlorobenzene (0.5 mL, TCI (Shanghai) Chemical Industry Development Co., Ltd.), 10% palladium on carbon (50 mg, 0.47 mmol) was added, hydrogenated at room temperature under 1 atmosphere of hydrogen for 1 hour, filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2h (178 mg, yield: 80.5%). MS m / z (ESI): 392.1 [M-55].

[0645] 1H NMR(500MHz, CDCl3)δ7.40(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).

[0646] Step 6

[0647] 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine p-toluenesulfonate 2i

[0648] Compound 2h (178 mg, 0.40 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (189 mg, 0.99 mmol) was added, and stirred at 60°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude title product 2i (206 mg), which was used directly in the next step without purification.

[0649] MS m / z(ESI):348.1[M+1].

[0650] Step 7

[0651] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 2j

[0652] Compound 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 residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 2j (207 mg, yield: 57.7%).

[0653] MS m / z(ESI):606.2[M+1].

[0654] Step 8

[0655] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 2

[0656] Compound 2j (206 mg, 0.34 mmol) was dissolved in a mixed solution of 18 mL of acetonitrile and water (V / V=5:1), and lithium hydroxide monohydrate (71 mg, 1.69 mmol) was added and stirred at 40°C for 18 hours. After cooling to room temperature, citric acid aqueous solution (1 M) was added to adjust the pH to 5-6, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC (chromatographic column: Boston Phlex C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: 30%-50%, flow rate: 30 mL / min) to obtain the title diastereoisomer mixture 2 (120 mg, yield: 59.6%). MS m / z (ESI): 592.1 [M+1].

[0657] 1 H NMR(500MHz,DMSO-d6)δ12.42-12.97(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).

[0658] Example 3

[0659] 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 3

[0660]

[0661] The synthetic route of Example 2 was adopted, and the raw material 2d in the third step was replaced with 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e to obtain the title diastereoisomer mixture 3 (7 mg, yield: 23.9%). MS m / z (ESI): 592.2 [M+1].

[0662] 1 H NMR(500MHz,DMSO-d6)δ12.56-12.77(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).

[0663] Example 4

[0664] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4

[0665]

[0666]

[0667] first step

[0668] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 4a 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 4b

[0669] Compound 2j (830 mg, 1.37 mmol) was chirally prepared (separation conditions: CHIRALPAK IG 250*20 mm, 5 μm (with protective column); mobile phase: hexane / EtOH (0.1% DEA) = 70 / 30 (V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title products (415 mg, yield: 47.6%) and (340 mg, yield: 39%).

[0670] Single configuration compound 4a (415 mg, yield: 47.6%) (short retention time):

[0671] MS m / z(ESI):606.0[M+1].

[0672] Chiral preparation: retention time 13.653 minutes.

[0673] Single configuration compound 4b (340 mg, yield: 39%) (longer retention time):

[0674] MS m / z(ESI):606.0[M+1].

[0675] Chiral preparation: retention time 16.422 minutes.

[0676] Step 2

[0677] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4

[0678] 4a (415 mg, 0.68 mmol) was dissolved in 36 mL of a mixed solvent of acetonitrile and water (V:V=6:1), and lithium hydroxide monohydrate (145 mg, 3.46 mmol) was added and stirred at 40°C for 18 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 5-6 with citric acid aqueous solution (1 M), extracted with ethyl acetate (30 mL×3), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (Gilson 281, chromatographic column: Boston Phlex C18 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: 30%-50%, flow rate: 30 mL / min) to obtain the title product 4 (310 mg, yield: 76.46%).

[0679] MS m / z(ESI):592.2[M+1].

[0680] 1 H NMR(500MHz,DMSO-d6)δ12.42-12.97(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).

[0681] Example 5

[0682] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 5

[0683]

[0684] first step

[0685] (R)-tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate 5a

[0686] (S)-tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate 5b

[0687] Compound 2g (3.50 g, 7.85 mmol) was chirally prepared (separation conditions: DAICEL AD chiral preparative column, 250*25mm, 10μm; mobile phase: Supercritical CO2:ETOH (+0.1% DEA) = 85:15 (V / V, flow rate: 70mL / min), collect the corresponding components, concentrate under reduced pressure to obtain the title products (1.62g, yield: 46.2%) and (1.65g, yield: 47.1%).

[0688] Single configuration compound 5a (1.62 g, yield: 46.2%) (short retention time):

[0689] MS m / z(ESI):389.9[M-55].

[0690] Chiral HPLC analysis: retention time 2.072 minutes, chiral purity: 98.76% (chromatographic column: DAICEL AD-3 100*3mm, 3μm; mobile phase: Supercritical CO2:ETOH (+0.1% DEA) = 95:5 ~ 60:40 (V / V).

[0691] Single configuration compound 5b (1.65 g, yield: 47.1%) (longer retention time):

[0692] MS m / z(ESI):389.9[M-55].

[0693] Chiral HPLC analysis: retention time 2.348 minutes, chiral purity: 98.44% (chromatographic column: DAICEL AD-3 100*3mm, 3μm; mobile phase: Supercritical CO2:ETOH (+0.1% DEA) = 95:5 ~ 60:40 (V / V).

[0694] Step 2

[0695] (S)-tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate 5c

[0696] 5b (600 mg, 1.35 mmol) was dissolved in a mixed solution of 13.2 mL of ethyl acetate and 1,2-dichlorobenzene (V:V=10:1), palladium / carbon (300 mg, 10%) was added, and hydrogen was replaced three times. The reaction was stirred at room temperature for 1 hour, and the mixture was filtered with celite pad. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 5c (530 mg, yield: 87.9%).

[0697] MS m / z(ESI):392.0[M-55].

[0698] 1 H NMR(500MHz, CDCl3)δ7.43(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).

[0699] Step 3

[0700] (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine 5d

[0701] 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 stirred at 0°C to room temperature for 2 hours. After concentration, saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×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 title compound 5d (411 mg), which was used directly in the next step without purification.

[0702] Step 4

[0703] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 5f

[0704] Compound 5d (411 mg, 1.18 mmol), compound (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carbonate methyl ester 5e (350 mg, 1.18 mmol, prepared by the method disclosed in intermediate 27 on page 72 of the specification of patent application WO2018109607A1) were dissolved in acetonitrile (40 mL), potassium carbonate (441 mg, 3.19 mmol) was added, heated to 70°C, and stirred for 3 hours. After concentration under reduced pressure, the title compound 5f (710 mg, yield: 98.9%) was obtained by purification by silica gel column chromatography with eluent system A.

[0705] MS m / z(ESI):607.2[M+1].

[0706] Step 5

[0707] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 5

[0708] 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), and lithium hydroxide monohydrate (246 mg, 5.86 mmol) was added. The mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the pH was adjusted to 5-6 with citric acid aqueous solution (1 M), and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T, 30*50 mm, 5 μm; mobile phase A: water (containing 10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; 15-minute gradient: 36%-49%, flow rate: 30 mL / min) to obtain the title product 5 (620 mg, yield: 89.4%). MS m / z (ESI): 593.1 [M+1].

[0709] 1H NMR(500MHz,DMSO-d6)δ7.96(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).

[0710] Example 6

[0711] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 6

[0712]

[0713]

[0714] First step (S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine

[0715] -1-tert-Butyl formate 6b

[0716] Compound 2f (260 mg, 0.76 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 6a (152 mg, 0.76 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 10 mL 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphine-2", 6"-diisopropoxy-1,1"-biphenyl) (2"-amino-1,1"-biphenyl-2-yl) palladium (II) (27 mg, 0.03 mmol, Bidex Technology Co., Ltd.) and cesium carbonate (493 mg, 1.51 mmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 90°C and stirred for 10 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. The organic phase was concentrated under reduced pressure and then analyzed by high performance liquid chromatography (chromatographic column: BostonPhlex Prep C18 150*30mm, 5μm; mobile phase 1: water (containing 10mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15 min gradient: 75%-95%, flow rate: 30mL / min) to obtain the title product 6b (10mg, yield: 3%).

[0717] MS m / z(ESI):463.1[M+1].

[0718] Step 2

[0719] (S)-1-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3-methylpiperazine 6c

[0720] Compound 6b (8 mg, 0.017 mmol) was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added at 0°C, and stirring was continued at this temperature for 2 hours. The reaction solution was warmed to room temperature and concentrated under reduced pressure to obtain the title product 6c (8 mg, yield: 97.1%).

[0721] MS m / z(ESI):363.1[M+1].

[0722] Step 3

[0723] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 6d

[0724] 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 temperature was raised to 70°C for reaction for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 6d (13 mg, yield: 94.9%).

[0725] MS m / z(ESI):621.2[M+1].

[0726] Step 4

[0727] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 6

[0728] 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, and the temperature was raised to 40°C for 6 hours. After the reaction solution was cooled, citric acid (2.5 M) was added to adjust the pH value to 5-6, and the solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: SharpSil-T Prep C18 50*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L of ammonium bicarbonate); mobile phase 2: acetonitrile; 17 minutes gradient: 30%-47%, flow rate: 30 mL / min) to obtain the title product 6 (10 mg, yield: 78.7%).

[0729] MS m / z(ESI):607.2[M+1].

[0730] 1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),7.78-7.80(dd,1H),7.55-7.60(m,3H),7.42-7.45(dd,1H),6.76-6.8 0(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).

[0731] Example 7

[0732] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 7

[0733]

[0734]

[0735] first step

[0736] (S)-tert-Butyl 2-methyl-4-(((trifluoromethanesulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate 7b

[0737] Compound (S)-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester 7a (5 g, 23.44 mmol, Nanjing Yaoshi Technology Co., Ltd.) was dissolved in 50 mL of tetrahydrofuran, cooled to -78 ° C under nitrogen protection, and lithium bistrimethylsilylamide (4.31 g, 25.76 mmol, Bidex Technology Co., Ltd.) was added dropwise, and the reaction was continued for half an hour, and 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 quenched with 50 mL of saturated ammonium chloride, extracted with 60 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7b (8 g, yield: 98.8%).

[0738] Step 2 (S)-2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropiperidin-1(2H)-carboxylic acid tert-butyl ester 7c

[0739] Compound 7b (7.5 g, 21.72 mmol) and biboronic acid pinacol ester (6.6 g, 25.99 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 100 mL of 1,4-dioxane, and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (1.9 g, 2.60 mmol) and potassium acetate (6.4 g, 65.20 mmol, Titan Technology Co., Ltd.) were added, nitrogen was replaced 3 times, and the mixture was heated to 80°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7c (6.0 g, yield: 85%).

[0740] Step 3

[0741] 2-Bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one 7b'

[0742] 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 then 10 mL of tetrahydrofuran suspension of tribromopyridinium salt (88 g, 275 mmol, Shaoyuan Technology Co., Ltd.) was added to the above system and reacted at room temperature for 2 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was diluted with 50 mL of ethyl acetate, washed with 50 mL of water, the organic layer was dried over anhydrous sodium sulfate, filtered and then spin-dried, the obtained solid was slurried with 11 mL of a mixed solution of ethyl acetate and n-hexane (V:V=1:10), filtered, and the filter cake was dried under reduced pressure to obtain the title product 7b' (64.6 g, yield: 95%).

[0743] Step 4

[0744] 3-Bromo-2-(methoxymethoxy)phenol 7d'

[0745] 3-Bromobenzene-1,2-diol 7c' (50 g, 264 mmol, Shanghai Bidex Technology Co., Ltd.) was dissolved in 1000 mL of dichloromethane, and bromomethoxymethane (33 g, 264 mmol, Shanghai Titan Technology Co., Ltd.) was added at 0°C, and stirring was continued for 2 hours at this temperature. 200 mL of water was added for washing, and the organic phase was dried and spin-dried. The 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].

[0746] Step 5

[0747] 2-(3-Bromo-2-(methoxymethoxy)phenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one 7e'

[0748] 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 temperature was raised to room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7e' (36 g, yield: 86.6%).

[0749] Step 6

[0750] (R)-2-(3-Bromo-2-(methoxymethoxy)phenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one 7f'

[0751] Compound 7e' (5 g, 12.4 mmol) was dissolved in 60 mL of tetrahydrofuran, and borane dimethyl sulfide complex (1.23 mg, 16.2 mmol, Shanghai Titan Technology Co., Ltd.) was added under nitrogen atmosphere, and the temperature was raised to 40°C, and diphenyl-[(2R)-pyrroline-2-yl]methanol was added in batches, and the reaction was carried out at 45°C for 3 hours. 5 mL of methanol was added to quench the reaction, and then 50 mL of water and 60 mL of ethyl acetate were added for extraction, and 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%).

[0752] Step 7

[0753] (R)-2-Bromo-6-(2-(4-bromo-2-fluorophenyl)-2-hydroxyethoxy)phenol 7g'

[0754] Compound 7f' (5 g, 12.3 mmol) was dissolved in a mixed solution of 100 mL of dichloromethane and dioxane hydrochloride (V:V = 4:1), heated to 35 ° C for 2 hours, and diphenyl-[(2R)-pyrrolidine-2-yl]methanol was added in batches, and reacted at 35 ° C for 2 hours. Concentrated under reduced pressure, 50 mL of water and 60 mL of ethyl acetate were added for extraction, and 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].

[0755] Step 8

[0756] (S)-8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 7h'

[0757] Compound 7g' (4 g, 11.1 mmol) was dissolved in 60 mL of tetrahydrofuran, and triphenylphosphine (4.35 g, 16.6 mmol, Sinopharm Shanghai Chemical Reagent Co., Ltd.) was added under nitrogen atmosphere, and diisopropyl azodicarboxylate (3.36 g, 16.6 mmol, Shaoyuan Technology Co., Ltd.) was added dropwise under ice bath, and the mixture was reacted at this temperature for 0.5 hour. The mixture was concentrated under reduced pressure, and 50 mL of water and 60 mL of ethyl acetate were added for extraction. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 7h' (2.5 g, yield: 65.8%).

[0758] MS m / z(ESI):342.9[M+1].

[0759] Step 9

[0760] (S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methyl-3,6-

[0761] Tert-Butyl dihydropyridine-1(2H)-carboxylate 7d

[0762] 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), and sodium carbonate (1.23 g, 11.6 mmol) and tetrakis(triphenylphosphine)palladium (670 mg, 0.58 mmol, Titan Technology Co., Ltd.) were added, and stirred at 90°C for 12 hours under nitrogen protection. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7d (1.2 g, yield: 44.8%).

[0763] MS m / z(ESI):404.1[M-55].

[0764] Step 10: (2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-2-methylpiperidine

[0765] -1-tert-Butyl formate 7e

[0766] 7d (1.2 g, 2.61 mmol) was dissolved in a mixed solution of 22 mL of ethyl acetate and 1,2-dichlorobenzene (V:V=10:1), 10% palladium carbon (240 mg, 0.52 mmol) was added, hydrogen was replaced 3 times, and stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain the title compound 7e (1.2 g, yield: 99.56%).

[0767] MS m / z(ESI):406.1[M-55].

[0768] Step 11 (2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)-2-methylpiperidine 7f

[0769] 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, warmed to room temperature, stirred for 1 hour, and concentrated under reduced pressure to remove the solvent to obtain the title compound 7f (940 mg, yield: 99.95%).

[0770] MS m / z(ESI):362.1[M+1].

[0771] Step 12

[0772] 2-(((2S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidin

[0773] 7g of methyl 1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0774] 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. The mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 7g (700 mg, yield: 43.5%).

[0775] MS m / z(ESI):620.2[M+1].

[0776] Step 13

[0777] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 7

[0778] Compound 7g (700 mg, 1.13 mmol) was dissolved in 20 mL of acetonitrile, 4 mL of water and lithium hydroxide monohydrate (300 mg, 7.15 mmol, Shaoyuan Technology Co., Ltd.) were added, and the temperature was raised to 40°C for 6 hours. After cooling, 2.5 M citric acid was added to adjust the pH value to 5-6, and a white solid was precipitated, which was filtered, and the filter cake was washed with water and dried to obtain the title product 7 (550 mg, yield: 80.39%).

[0779] MS m / z(ESI):606.2[M+1].

[0780] 1 H NMR(500MHz,DMSO-d6)δ12.73(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).

[0781] Example 8

[0782] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-carboxylic acid 8

[0783]

[0784]

[0785] first step

[0786] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-carboxylic acid methyl ester 8a

[0787] The trifluoroacetate of compound 6c (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 tetrabutylammonium iodide (10 mg, 0.03 mmol) were added at room temperature, and the temperature was raised to 50°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 8a (103 mg, yield: 85.8%).

[0788] MS m / z(ESI):622.2[M+1].

[0789] Step 2

[0790] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazole[4,5-b]pyridine-5-carboxylic acid 8

[0791] 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, and the temperature was raised to 40°C for 16 hours. After the reaction solution was cooled, citric acid (0.5 M) was added to adjust the pH value to 5-6, and the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: SharpSil-T PrepC18 50*30 mm, 5 μm; mobile phase: water (containing 10 mmol / L of ammonium bicarbonate); mobile phase: acetonitrile; 12 minutes gradient: 33%-45%, flow rate: 30 mL / min) to obtain the title product 8 (70 mg, yield: 69.5%).

[0792] MS m / z(ESI):608.2[M+1].

[0793] 1H NMR(500MHz,DMSO-d6)δ7.99(d,1H),7.91(d,1H),7.60-7.56(m,2H),7.45(d,1H),6.7 8(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,1 H),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).

[0794] Example 9

[0795] 2-((4-(2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 9

[0796]

[0797] first step

[0798] 1-(Benzo[d]thiazol-2-yl)-2-bromoethan-1-one 9b

[0799] 1-(Benzo[d]thiazol-2-yl)ethane-1-one 9a (1.77 g, 9.98 mmol, Bidex Technology Co., Ltd.) was added to tetrahydrofuran (60 mL), and a 10 mL tetrahydrofuran solution of pyridinium tribromide (1.77 g, 9.98 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added under ice bath, and reacted at room temperature for 2 hours. Filter, concentrate under reduced pressure to remove the solvent, and slurry with 15 mL of a mixed solution of n-hexane and ethyl acetate (V / V=10:1), filter, and dry the filter cake under reduced pressure to obtain the title product 9b (1.8 g, yield: 70.36%).

[0800] Step 2

[0801] 1-(Benzo[d]thiazol-2-yl)-2-(2-bromo-6-hydroxyphenoxy)ethan-1-one 9c

[0802] Compound 9b (0.8 g, 3.12 mmol) was dissolved in acetone (35 mL), sodium bicarbonate (839 g, 9.99 mmol) was added, compound 1a (591 mg, 3.12 mmol) dissolved in 5 mL acetone was added dropwise under ice bath, and the mixture was reacted at room temperature for 48 hours. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography with eluent system B to obtain the title product 9c (400 mg, yield: 35.16%).

[0803] MS m / z(ESI):365.9[M+1].

[0804] Step 3

[0805] 2-(2-(Benzo[d]thiazol-2-yl)-2-hydroxyphenoxy)-3-bromophenol 9d

[0806] Compound 9c (400 mg, 1.09 mmol) was dissolved in 20 mL of methanol, sodium borohydride (62.3 mg, 1.64 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added under ice bath, and stirred for 1 hour. 20 mL of water was added and stirred, extracted with ethyl acetate (20 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the title compound 9d (400 mg, yield: 99.44%).

[0807] MS m / z(ESI):367.9[M+1].

[0808] Step 4

[0809] 2-(5-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 9e

[0810] 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 Reagent Co., Ltd.) was added, and diisopropyl azodicarboxylate (331 mg, 1.63 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added dropwise under ice bath, and the reaction was continued for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 9e (300 mg, yield: 78.88%).

[0811] MS m / z(ESI):349.9[M+1].

[0812] Step 5

[0813] 4-(2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropiperidine

[0814] -1(2H)-tert-Butyl formate 9f

[0815] Compound 9e (230 mg, 0.66 mmol) was dissolved in 1,4-dioxane (20 mL), and compound 1i (245 mg, 0.79 mmol), sodium carbonate (140 mg, 1.32 mmol), tetrakis(triphenylphosphine)palladium (45.8 mg, 39 umol), and water (4 mL) were added, and the mixture was heated to 90°C under nitrogen protection and stirred for 4 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with eluent system B to obtain the title compound 9f (260 mg, yield: 87.36%).

[0816] MS m / z(ESI):451.1[M+1].

[0817] Step 6

[0818] tert-Butyl 4-(2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine-1-carboxylate 9 g

[0819] Compound 9f (230 mg, 0.51 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium on carbon (80 mg, 0.51 mmol) was added, and hydrogenation was carried out under one atmosphere of hydrogen at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to obtain the crude title compound 9g (230 mg), which was used directly in the next step without purification.

[0820] MS m / z(ESI):453.0[M+1].

[0821] Step 7

[0822] 2-(5-(Piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)benzo[d]thiazole 4-methylbenzenesulfonate 9h

[0823] Compound 9g (210 mg, 0.46 mmol) 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 concentrated under reduced pressure to give the crude title compound 9h (160 mg), which was used in the next step without purification.

[0824] MS m / z(ESI):353.1[M+1].

[0825] Step 8

[0826] 2-((4-(2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 9i

[0827] 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 of patent application WO2018109607A1), 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 solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain a mixture of diastereomers 9i (220 mg, yield: 79.35%).

[0828] MS m / z(ESI):611.2[M+1].

[0829] Step 9

[0830] 2-((4-(2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 9

[0831] Compound 9i (10 mg, 0.016 mmol) was dissolved in 3 mL of acetonitrile, and 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. The mixture was cooled to room temperature, and the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic layers were combined and concentrated, and purified by silica gel column chromatography with eluent system A to obtain the title diastereoisomer mixture 9 (6.5 mg, yield 66.52%).

[0832] MS m / z(ESI):597.2[M+1].

[0833] 1H NMR(500MHz,DMSO-d6)δ12.74(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).

[0834] Example 10

[0835] 2-((4-((R)-2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)

[0836] methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 10

[0837]

[0838] first step

[0839] 2-((4-((R)-2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)

[0840] 2-((4-((S)-2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 10a

[0841] Compound 9i (220 mg, 0.36 mmol) was chirally prepared, and its corresponding fractions 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).

[0842] Single configuration compound 10a:

[0843] Chiral HPLC analysis: retention time 8.674 minutes, chiral purity: 99%, (chromatographic column: CHIRALPAK IE150*4.6mm, 5μm (with guard column); mobile phase: hexane / EtOH (0.1% DEA) = 20 / 80 (V / V), flow rate: 1.0mL / min)

[0844] MS m / z(ESI):611.2[M+1].

[0845] Single configuration compound 10b:

[0846] Chiral HPLC analysis: retention time 11.188 minutes, chiral purity: 99%, (chromatographic column: CHIRALPAK IE150*4.6mm, 5μm (with guard column); mobile phase: hexane / EtOH (0.1% DEA) = 20 / 80 (V / V), flow rate: 1.0mL / min)

[0847] MS m / z(ESI):611.2[M+1].

[0848] Step 2

[0849] 2-((4-((R)-2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)

[0850] methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 10

[0851] Compound 10a (75 mg, 0.122 mmol) was dissolved in 8 mL of acetonitrile, and 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. The mixture was cooled to room temperature, and the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and extracted with ethyl acetate (20 mL×2). The organic layers were combined and concentrated, and purified by silica gel column chromatography with eluent system A to obtain the title product 10 (65 mg, yield: 88.70%).

[0852] MS m / z(ESI):595.2[M-1].

[0853] 1H NMR(500MHz,DMSO-d6)δ12.75(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).

[0854] Embodiment 11

[0855] 2-((4-((S)-2-(Benzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 11

[0856]

[0857] Compound 10b (75 mg, 0.122 mmol) was dissolved in 8 mL of acetonitrile, and 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. The mixture was cooled to room temperature, and the pH was adjusted to 6-7 with 5% aqueous citric acid solution, and extracted with ethyl acetate (20 mL×2). The organic layers were combined and concentrated, and purified by silica gel column chromatography with eluent system A to obtain the title product 11 (65.3 mg, yield: 89.55%).

[0858] MS m / z(ESI):595.2[M-1].

[0859] 1H NMR(500MHz,DMSO-d6)δ12.75(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).

[0860] Example 12

[0861] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (mixture of diastereomers) 12

[0862]

[0863] first step

[0864] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (mixture of diastereomers) 12a

[0865] 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 residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 12a (59 mg, yield: 56.8%).

[0866] MS m / z(ESI):607.2[M+1].

[0867] Step 2

[0868] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (mixture of diastereomers) 12

[0869] Compound 12a (59 mg, 0.10 mmol) was dissolved in a mixed solution of 12 mL of acetonitrile and water (V / V=5:1), and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added, and stirred at 40°C for 18 hours. After cooling to room temperature, citric acid aqueous solution (1 M) was added to adjust the pH to 5-6, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC (chromatographic column: SHarpsil-T 150*30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15-minute gradient: 35%-45%, flow rate: 30 mL / min) to obtain the title diastereoisomer mixture 12 (23 mg, yield: 39.9%). MS m / z (ESI): 593.1 [M+1].

[0870] 1 H NMR(500MHz,DMSO-d6)δ12.64-13.04(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).

[0871] Embodiment 13

[0872] 2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 13

[0873]

[0874] first step

[0875] 2-Bromo-1-(5-chloropyridin-2-yl)ethyl-1-one 13b

[0876] 1-(5-Chloropyridin-2-yl)ethyl-1-one (13a, 2.00 g, 12.86 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) was added to tetrahydrofuran (15 mL) and chloroform (30 mL), and pyridinium tribromide (4.30 g, 13.45 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, heated to 50°C, and stirred for 3 hours. The mixture was cooled to room temperature, washed with 1M hydrochloric acid (30 mL×2), water (30 mL×2), and saturated brine (30 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain the residue 13b (3.01 g), which was used directly in the next step without purification.

[0877] Step 2

[0878] 2-(3-Bromo-2-hydroxyphenoxy)-1-(5-chloropyridin-2-yl)ethyl-1-one 13c

[0879] Compound 1a (1.60 g, 8.47 mmol) was dissolved in acetonitrile (30 mL), cooled to 0°C, potassium carbonate (1.60 g, 11.58 mmol) and compound 13b (1.80 g, 7.68 mmol) were added, and stirred at 0°C for 2 hours. Ethyl acetate (50 mL) was added to dilute, washed with saturated brine (30 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain the residue 13c (2.0 g), which was used directly in the next step without purification.

[0880] MS m / z(ESI):343.9[M+1].

[0881] Step 3

[0882] 2-Bromo-6-(2-(5-chloropyridin-2-yl)-2-hydroxyethoxy)phenol 13d

[0883] 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 residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 13d (970 mg, yield: 48.2%).

[0884] MS m / z(ESI):346.0[M+1].

[0885] Step 4

[0886] 2-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)-5-chloropyridine 13e

[0887] Compound 13d (970 mg, 2.80 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, triphenylphosphine (1.10 g, 4.19 mmol) and diisopropyl azodicarboxylate (850 mg, 4.20 mmol) were added under nitrogen atmosphere, and stirred at 0°C for half an hour. Ethyl acetate (50 mL) was added for dilution, washed with water (30 mL × 2), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13e (880 mg, yield: 95.7%). MS m / z (ESI): 327.9 [M+1].

[0888] Step 5

[0889] tert-Butyl 4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate 13f

[0890] 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), and sodium carbonate (560 mg, 5.28 mmol) and tetrakis(triphenylphosphine)palladium (300 mg, 0.26 mmol) were added, and stirred at 90°C for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13f (610 mg, yield: 54.0%).

[0891] MS m / z(ESI):373.1[M-55].

[0892] Step 6

[0893] 4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine-1-carboxylic acid tert-butyl ester 13g

[0894] In an autoclave, compound 13f (290 mg, 0.68 mmol) was dissolved in methanol (50 mL), tri(triphenylphosphine)rhodium chloride (65 mg, 0.07 mmol) was added, and three atmospheres of hydrogen were replaced, heated to 60°C, and stirred for 14 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13g (216 mg, yield: 74.1%).

[0895] MS m / z(ESI):375.1[M-55].

[0896] Step 7

[0897] 5-Chloro-2-(8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)pyridine di-p-toluenesulfonate 13h

[0898] Compound 13g (200 mg, 0.46 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (180 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the crude title product 13h (313 mg) was obtained, which was used directly in the next step without purification.

[0899] MS m / z(ESI):331.1[M+1].

[0900] Step 8

[0901] 2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 13i

[0902] 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, heated to 50°C, and stirred for 5 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 13i (273 mg, yield: 99.9%).

[0903] MS m / z(ESI):589.2[M+1].

[0904] Step 9

[0905] 2-((4-(3-(5-chloropyridin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 13

[0906] 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 stirred at 40°C for 16 hours. After cooling to room temperature, 5% citric acid aqueous solution was added to adjust the pH to 5-6, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Sharpsil-T Prep C18 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate); mobile phase: acetonitrile; 20-minute gradient: 35%-55%, flow rate: 30 mL / min) to obtain the title diastereoisomer mixture 13 (190 mg, yield: 71.3%).

[0907] MS m / z(ESI):575.2[M+1].

[0908] 1 H NMR(500MHz,DMSO-d6)δ8.68(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).

[0909] Embodiment 14

[0910] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 14

[0911]

[0912] First step (S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine-1-carboxylic acid tert-butyl ester 14j

[0913] Compound 7h' (206 mg, 0.60 mmol) and tert-butyl piperazine-1-carboxylate 14i (120 mg, 0.61 mmol, Shanghai Bidex Technology Co., Ltd.) were dissolved in 10 mL 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphine-2", 6"-diisopropoxy-1,1"-biphenyl) (2"-amino-1,1"-biphenyl-2-yl) palladium (II) (103 mg, 0.12 mmol, Bidex Technology Co., Ltd.) and cesium carbonate (391 mg, 1.204 mmol, Shaoyuan Technology Co., Ltd.) were added. Under nitrogen atmosphere, the mixture was heated to 110°C and stirred for 10 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 14j (90 mg, yield: 33.4%).

[0914] MS m / z(ESI):449.1[M+1].

[0915] Step 2

[0916] (S)-1-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazine 14k

[0917] Compound 14j (90 mg, 0.12 mmol) was dissolved in 15 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at 0°C. Stirring was continued at this temperature for 2 hours, and the temperature was slowly raised to room temperature. The mixture was concentrated under reduced pressure to obtain the title product 14k (40 mg, yield: 95.3%).

[0918] MS m / z(ESI):349.1[M+1].

[0919] Step 3

[0920] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 141

[0921] 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 temperature was raised to 60°C for reaction for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 14l (56 mg, yield: 80.4%).

[0922] MS m / z(ESI):607.1[M+1].

[0923] Step 4

[0924] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 14

[0925] Compound 141 (56 mg, 0.1 mmol) 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, and the temperature was raised to 40°C for 16 hours. After the reaction solution was cooled, citric acid (2.5 M) was added to adjust the pH value to 5-6, and the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: SharpSil-T Prep C18 50*30 mm, 5 μm; mobile phase: water (containing 10 mmol / L of ammonium bicarbonate); mobile phase: acetonitrile; 17 minutes gradient: 30%-47%) to obtain the title product 14 (15 mg, yield: 19.2%). MS m / z (ESI): 595.2 [M+1].

[0926] 1 H NMR(500MHz,DMSO-d6)δ8.19(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).

[0927] Embodiment 15

[0928] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-3a,6a-dihydro-1H-thienyl[2,3-d]imidazole-5-carboxylic acid 15

[0929]

[0930]

[0931] first step

[0932] (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester 15c

[0933] Compound 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester 15a (305 mg, 1.15 mmol, prepared by the method disclosed in Example 114 intermediate C on page 124 of the specification of patent application WO2003099805A1), compound (S)-oxetane-2-ylmethylamine 15b (100 mg, 1.15 mmol, Nanjing Yaoshi Technology Co., Ltd.), 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, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the title compound 15c (310 mg, yield: 90.1%).

[0934] MS m / z(ESI):273.1[M+1].

[0935] Step 2

[0936] (S)-5-amino-4-((oxetane-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester 15d

[0937] Compound 15c (310 mg, 1.14 mmol) was dissolved in 20 mL of tetrahydrofuran, palladium carbon (300 mg, 10%) was added, and stirred at room temperature for 2 hours under a hydrogen atmosphere. Filtered through celite and concentrated to obtain a crude title product 15d (253 mg), which was used directly in the next step without purification.

[0938] MS m / z(ESI):243.0[M+1].

[0939] Step 3

[0940] (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester 15e

[0941] The crude compound 15d (253 mg, 0.69 mmol) was dissolved in 10 mL of acetonitrile, and 2-chloro-1,1,1-trimethoxy-ethane (152 mg, 1.05 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol, Sinopharm Chemical Reagent Co., Ltd.) were added, and stirred at 60°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the crude title product 15e (71 mg), which was used directly in the next step without purification.

[0942] MS m / z(ESI):300.9[M+1].

[0943] Step 4

[0944] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-3a,6a-dihydro-1H-thiophene[2,3-d]imidazole-5-carboxylic acid methyl ester 15f

[0945] Compound 6c (70 mg, 0.19 mmol, TFA) and compound 15e (64 mg, 0.21 mmol) were dissolved in 5 mL of acetonitrile, potassium carbonate (134 mg, 0.97 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added at room temperature, and the temperature was raised to 50°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 15f (117 mg, yield: 96.7%). MS m / z (ESI): 627.1 [M+1].

[0946] Step 5

[0947] 2-(((S)-4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-3a,6a-dihydro-1H-thienyl[2,3-d]imidazole-5-carboxylic acid 15

[0948] 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, and the temperature was raised to 40°C for 16 hours. After the reaction solution was cooled, citric acid (0.5 M) was added to adjust the pH value to 5-6, and the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: SharpSil-T PrepC18 50*30 mm, 5 μm; mobile phase: water (containing 10 mmol / L of ammonium bicarbonate); mobile phase: acetonitrile; 20-minute gradient: 30%-50%) to obtain the title product 15 (72 mg, yield: 62.9%).

[0949] MS m / z(ESI):613.1[M+1].

[0950] 1 H NMR(500MHz,DMSO-d6)δ7.74(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).

[0951] Example 16

[0952] 2-((4-(3-(4-cyano-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 16

[0953]

[0954] The synthetic route of Example 2 was adopted, and the first step raw material 4-chloro-2-fluorobenzaldehyde 2a was replaced by 4-cyano-2-fluorobenzaldehyde to prepare the title diastereoisomer mixture 16 (16 mg, yield: 40.96%).

[0955] MS m / z(ESI):583.2[M-1].

[0956] 1 H NMR(500MHz,DMSO-d6)δ12.42-12.97(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).

[0957] Embodiment 17

[0958] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 17

[0959]

[0960] first step

[0961] 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1,2,3,6-tetrahydropyridine p-toluenesulfonate 17a

[0962] Compound 2g (202 mg, 0.45 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol) was added, and stirred at 60°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude title product 17a (234 mg), which was used directly in the next step without purification.

[0963] MS m / z(ESI):346.1[M+1].

[0964] Step 2

[0965] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 17b

[0966] Compound 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 residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 17b (213 mg, yield: 78.1%).

[0967] MS m / z(ESI):604.2[M+1].

[0968] Step 3

[0969] 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 17

[0970] Compound 17b (46 mg, 0.08 mmol) was dissolved in a mixed solution of 12 mL of acetonitrile and water (V / V=5:1), and lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added, and stirred at 40°C for 18 hours. After cooling to room temperature, citric acid aqueous solution (1 M) was added to adjust the pH to 5-6, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (chromatographic column: SHarpsil-T 150*30 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate); mobile phase: acetonitrile; 15-minute gradient: 35%-45%, flow rate: 30 mL / min) to obtain the title diastereoisomer mixture 17 (17 mg, yield: 37.8%). MS m / z (ESI): 590.1 [M+1].

[0971] 1H NMR(500MHz,DMSO-d6)δ12.58-12.99(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).

[0972] Embodiment 18

[0973] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 18

[0974]

[0975]

[0976] first step

[0977] 2-(4-Chloro-2-fluorophenyl)-2-methyloxirane 18b

[0978] 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 Reagent Co., Ltd.) was added under ice bath, and 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 stirred at room temperature for 16 hours, filtered, diluted with ethyl acetate (80 mL), washed with saturated ammonium chloride aqueous solution (50 mL × 2), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the title compound 18b (10.0 g, yield: 92.4%).

[0979] 1 H NMR (500MHz, 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).

[0980] Step 2

[0981] 2-Bromo-6-((2-(4-chloro-2-fluorophenyl)-1-hydroxypropan-2-yl)oxy)phenol 18c

[0982] 2-Bromo-6-((2-(4-chloro-2-fluorophenyl)-2-hydroxypropoxy)phenol 18d

[0983] Compound 18b (1.0 g, 5.35 mmol) and 1a (1.0 g, 5.29 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) were mixed, and sodium methoxide (30 mg, 0.555 mmol, Adamas Reagent Co., Ltd.) was added, and stirred at 120°C for 2 hours. After cooling, the residue was purified by silica gel column chromatography with eluent system B 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];

[0984] 18d MS m / z(ESI):375.2[M-1].

[0985] Step 3

[0986] 5-Bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxane 18e

[0987] 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 diisopropyl azodicarboxylate (243 mg, 1.20 mmol, China Pharmaceutical Group Shanghai Chemical Reagent Co., Ltd.) was added dropwise under nitrogen atmosphere at 0°C, and stirred at 0°C for half an hour. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2), concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18e (240 mg, yield: 84.0%).

[0988] 1 H NMR (500MHz, 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).

[0989] Step 4

[0990] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate 18f

[0991] Compound 18e (230 mg, 0.643 mmol) and compound 1i (198 mg, 0.640 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in a mixed solution of 1,4-dioxane and water (V / V=5:1) in 12 mL, and sodium carbonate (136 mg, 1.28 mmol) and tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol) were added. The mixture was stirred at 90°C for 4 hours under nitrogen protection. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18f (205 mg, yield: 69.3%). MS m / z (ESI): 404.0 [M-55].

[0992] 1H NMR(500MHz, 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).

[0993] Step 5

[0994] 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)piperidine-1-carboxylic acid tert-butyl ester 18g

[0995] 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 on carbon (50 mg, 0.087 mmol) was added, hydrogenated at room temperature under 1 atmospheric pressure of hydrogen for 1 hour, filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18g (200 mg, yield: 99.5%). MS m / z (ESI): 406.0 [M-55].

[0996] Step 6

[0997] 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidinium trifluoroacetate 18h

[0998] Compound 18g (80 mg, 0.173 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.1 mL) was added at 0°C, and stirred at 0°C for 2 hours. After concentration under reduced pressure, the crude title product 18h (62 mg) was obtained, which was used directly in the next step without purification.

[0999] MS m / z(ESI):362.0[M+1].

[1000] Step 7

[1001] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 18i

[1002] 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 residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 18i (94 mg, yield: 89.3%).

[1003] MS m / z(ESI):620.1[M+1].

[1004] Step 8

[1005] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 18

[1006] Compound 18i (94 mg, 0.151 mmol) was dissolved in a mixed solution of 6 mL of acetonitrile and water (V / V=5:1), and lithium hydroxide monohydrate (20 mg, 0.50 mmol) was added, and stirred at 40°C for 18 hours. After cooling to room temperature, an aqueous solution of citric acid (1 M) was added to adjust the pH to 5-6, and extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title diastereoisomer mixture 18 (50 mg, yield: 54.4%).

[1007] MS m / z(ESI):606.1[M+1].

[1008] 1H NMR(500MHz,DMSO-d6)δ12.75(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).

[1009] Embodiment 19

[1010] 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereoisomers) 19

[1011]

[1012]

[1013] The first step is (2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazine-1-yl

[1014] Tert-Butyl Formate 19a

[1015] Compound 2f (145 mg, 0.42 mmol) and compound 6a (85 mg, 0.42 mmol, Shaoyuan Technology Co., Ltd.) were dissolved in 10 mL 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphine-2", 6"-diisopropoxy-1,1"-biphenyl) (2"-amino-1,1"-biphenyl-2-yl) palladium (II) (71 mg, 0.08 mmol, Bidex Technology Co., Ltd.) and cesium carbonate (275 mg, 0.84 mmol, Shaoyuan Technology Co., Ltd.) were added. Under nitrogen environment, the mixture was heated to 90°C and stirred for 10 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 19a (40 mg, yield: 20.47%).

[1016] MS m / z(ESI):463.3[M+1].

[1017] Step 2

[1018] (3S)-1-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-3-methylpiperazine

[1019] 19b

[1020] Compound 19a (40 mg, 0.086 mmol) was dissolved in 10 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added at 0°C, and stirring was continued at this temperature for 2 hours. The reaction solution was warmed to room temperature and concentrated under reduced pressure to obtain the title product 19b (30 mg, yield: 95.7%).

[1021] MS m / z(ESI):363.3[M+1].

[1022] Step 3

[1023] 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (mixture of diastereomers) 19c

[1024] 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 temperature was raised to 60°C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain a mixture of the title diastereomers 19c (30 mg, yield: 58.4%). MS m / z (ESI): 621.2 [M+1].

[1025] Step 4

[1026] 2-(((2S)-4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 19

[1027] 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, and the temperature was raised to 40°C for 16 hours. After the reaction solution was cooled, citric acid (2.5 M) was added to adjust the pH value to 5-6, and the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (chromatographic column: SharpSil-T Prep C18 50*30 mm, 5 μm; mobile phase: water (containing 10 mmol / L of ammonium bicarbonate); mobile phase: acetonitrile; 17 minutes gradient: 30%-47%, flow rate: 30 mL / min) to obtain a mixture of the title diastereomers 19 (3 ​​mg, yield: 10.23%).

[1028] MS m / z(ESI):607.1[M+1].

[1029] 1H NMR(500MHz,DMSO-d6)δ8.25(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).

[1030] Embodiment 20

[1031] 2-((4-(3-(4-chloro-2-fluorophenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (mixture of diastereomers) 20

[1032]

[1033] The synthetic route of Example 2 was adopted, and the first step raw material 2a was replaced by 2-fluoro-4-chloroacetophenone (Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) to obtain a mixture of the title diastereomers 20 (46 mg, yield:

[1034] 56.83%).

[1035] MS m / z(ESI):606.3[M+1].

[1036] 1H NMR(500MHz,DMSO-d6)δ12.77(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),4.45-4.5 7(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).

[1037] Biological evaluation

[1038] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[1039] 1. Test Purpose

[1040] The purpose of this experiment is to test the agonist activity of compound molecules on GLP-1 receptors. 50 The size of the molecule is used to evaluate the in vitro activity of the molecule. TM Luciferase Assay System (ONE-Glo TM Luciferase Assay System, Promega, E6110). Under the action of compound molecules, the downstream signaling pathway of GLP-1R is activated, causing the cAMP level to increase. The binding of cAMP to CRE can initiate the transcriptional expression of the luciferase gene downstream of CRE. The luciferase reacts with its substrate to emit fluorescence. Through ONE-Glo TM The fluorescence signal measured by the reagent reflects the activity of the compound in stimulating the GLP-1 receptor.

[1041] 2. Experimental Methods

[1042] Construction of CHO-K1 / CRE-luc / GLP-1 receptor stable transfection cell line (GLP-1 receptor plasmid self-constructed; CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / GLP-1 receptor cells were digested, centrifuged and resuspended, the single cell suspension was mixed, and the live cell density was adjusted to 2.5×10 with cell culture medium (DME / F-12+10% FBS). 5cells / mL, 90 μL / well was added to a 96-well cell culture plate (Corning, #3903), and the culture plate was cultured in an incubator for 16 hours (37° C., 5% CO 2 ).

[1043] Dissolve the compound in DMSO and prepare a storage solution with an initial concentration of 20mM. The starting concentration of the small molecule compound is 0.2mM, dilute 3 times, dilute 10 points, and the 11th point is DMSO. Take another 96-well plate, add 95μL of cell culture medium (DME / F-12+10% FBS) to each well, then add 5μL of the sample to be tested at different concentrations to each well, mix well, and then add 10μL / well of the sample to be tested at different concentrations to the cell culture plate, and duplicate each sample. Incubate the culture plate in an incubator for 6 hours (37°C, 5% CO2). Take out the 96-well cell culture plate and add 100μL ONE-Glo to each well. TM Reagent, incubate at room temperature for 10 minutes, and measure chemiluminescence using an ELISA reader (EnVision 2105, PE).

[1044] 3. Data Analysis

[1045] The data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. The EC values ​​of the compounds were obtained. 50 The results are shown in Table 1 below.

[1046] Table 1 EC of the compounds disclosed herein for GLP-1 receptor agonist activity 50

[1047] Example No. <![CDATA[EC 50 (nM)]]> Emax% 1 0.56 109 2 0.42 108 4 0.74 103 5 0.12 107 6 0.34 102 7 0.09 105 8 0.29 112 9 2.05 104 10 1.19 103 11 1.68 104 12 1.72 114 13 1.76 108 14 1.79 104 15 2.04 102 16 1.42 116 17 9.9 112 18 18.4 103 19 1.25 109 20 51 90

[1048] Conclusion: The compounds disclosed in the present invention have high agonist activity on GLP-1 receptor.

[1049] Test Example 2: Effects of the compounds disclosed herein on hERG potassium channels

[1050] 1. Test Purpose

[1051] The manual patch clamp technique was used to evaluate the blocking effect of the disclosed compounds and positive compound 1 (see Example 7 compound on page 125 of WO2019239319A1) on hERG potassium current on a stable cell line transfected with hERG potassium channel. The structure of positive compound 1 is as follows:

[1052]

[1053] 2. Test Method

[1054] 1. Cell Culture

[1055] The cells used in this experiment were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels (provided by Sophion Bioscience, Denmark), and the cell generation was P5. The cells were cultured in a medium containing the following ingredients (all from Invitrogen): Ham's F12 medium, 10% (v / v) inactivated fetal bovine serum, 100 μg / mL hygromycin B, and 100 μg / mL geneticin.

[1056] CHO hERG cells were grown in a culture dish containing the above culture medium and cultured in an incubator at 37°C with 5% CO2. 24 to 48 hours before the electrophysiological experiment, CHO hERG cells were transferred to a round glass slide placed in a culture dish and grown in the same culture medium and culture conditions as above. The density of CHO hERG cells on each round glass slide needs to reach the requirement that most cells are independent and single.

[1057] 2. Experimental solution

[1058] Table 2: Composition of intracellular and extracellular fluids

[1059]

[1060] Table 3: Reagent details

[1061] Reagent name Part Number batch number Molecular weight supplier NaCl S1679-1KG WXBC1368V 58.44 Sigma KCl 31248-100G WXBC2571V 74.55 Sigma <![CDATA[CaCl2]]> 21114-1L BCBM6063V 110.98 Sigma <![CDATA[MgCl2·H2O]]> M7304-100G V900020-500G 203.30 Sigma HEPES H3375-1KG SLBP2246V 238.30 Sigma glucose G8270-1KG WXBC2393V 180.16 Sigma EGTA 03777-50G SLBP2807V 380.15 Sigma <![CDATA[Na2-ATP]]> A-7699-5G SLBJ8915V 551.14 Sigma NaOH 35254-1L BCBG6297V 40.00 Sigma KOH 232041-50G SLBK9251V 56.00 Sigma

[1062] 3. Electrophysiological Recording System

[1063] This experiment uses a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) to record whole-cell currents. A circular glass slide with CHO hERG cells growing on the surface is placed in an electrophysiological recording tank under an inverted microscope. The recording tank is continuously perfused with extracellular fluid (approximately 1 ml per minute). The experimental process uses conventional whole-cell patch clamp current recording technology. Unless otherwise specified, the experiments are performed at normal room temperature (~25°C). The cells are clamped at a voltage of -80mV. The cell clamping voltage is depolarized to +20mV to activate the hERG potassium channel, and then clamped to -50mV after 5 seconds to eliminate inactivation and generate tail current. The peak value of the tail current is used as the value of the hERG current size. After the hERG potassium current recorded in the above steps reaches stability under the continuous perfusion of extracellular fluid in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a stable state. Generally, the overlap of the three most recent continuous current recording lines is used as the criterion for judging whether the state is stable. After reaching a stable state, the cells are perfused with extracellular fluid until the hERG current returns to the size before the addition of drugs. One or more drugs, or multiple concentrations of the same drug, can be tested on one cell, but extracellular fluid flushing is required between different drugs. Cisapride (purchased from Sigma) was used in the experiment as a positive control to ensure that the quality of the cells used was normal.

[1064] 4. Experimental steps

[1065] To obtain the IC of a compound 50 , the following concentrations (30, 10, 3, 1, 0.3 and 0.1 μM) were selected for testing. Prior to the test, the compound was first prepared into a 10 mM DMSO stock solution using DMSO (Sigma), then diluted to 3, 1, 0.3 and 0.1 mM stock solutions in a gradient dilution manner, and diluted to the final μM test concentration using extracellular fluid. Except for the 30 μM compound test solution in which the final DMSO concentration was approximately 0.3%, the final DMSO concentration in the remaining compound solutions was 0.1%. The control test concentration of cisapride was 0.1 μM. All compound solutions were subjected to conventional 5 to 10 minutes of ultrasound and oscillation to ensure that the compound was completely dissolved.

[1066] The experimental data were analyzed using data analysis software provided by HEKAPatchmaster (V2x73.2), Microsoft Excel and GraphpadPrism5.0.

[1067] 5. Test results

[1068] The blocking effect of the disclosed compounds on hERG potassium current was determined by the above test, and the measured IC 50 See Table 4 for values.

[1069] Table 4: IC values ​​of the blocking effect of the disclosed compounds on hERG potassium channels 50

[1070] Example No. <![CDATA[IC 50 (μM)]]> 4 10.1 5 25.9 6 >30 12 26.1 Positive compound 1 4.6

[1071] Conclusion: The disclosed compounds have weak inhibitory effects on hERG and can reduce the side effects caused by the hERG pathway. Compared with the positive compound 1, the disclosed compounds have weaker inhibitory effects on hERG.

[1072] Test Example 3: Inhibitory effect of the disclosed compounds on human liver microsomal CYP450 enzymes

[1073] This test example is mainly used to evaluate the inhibitory effect of the disclosed compounds and positive compound 1 (specific structure see test example 2) on human liver microsomal CYP450 enzymes, and the following experimental method is used for determination.

[1074] 1. Experimental Materials and Instruments

[1075] 1. Phosphate buffer (20×PBS, purchased from Bioscientific),

[1076] 2. NADPH (ACROS, A2646-71-1),

[1077] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor 35),

[1078] 4. ABIQTrap 4000 LC / MS instrument (AB Sciex),

[1079] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA),

[1080] 6.CYP probe substrates.

[1081] 2. Experimental steps

[1082] 1. Solution Preparation

[1083] 1) Preparation of 100 mM phosphate buffer (PBS)

[1084] Take 50 mL of 2000 mM PBS solution, add 950 mL of ultrapure water, dilute to 1000 mL, mix well, and then adjust the pH of the solution to 7.4 with a pH meter to obtain a PBS solution with a pH of 7.4. Store it in a 4°C refrigerator (shelf life is 6 months).

[1085] 2) Preparation of NADPH solution

[1086] Accurately weigh an appropriate amount of NADPH powder, add PBS buffer solution to dissolve it, and prepare a solution with a concentration of 5mM for use (prepare it for immediate use).

[1087] 3) Preparation of liver microsome solution

[1088] Take an appropriate amount of human liver microsome storage solution (concentration is 20 mg / mL), dilute it with 7.5 mM MgCl2 solution to 0.25 mg / mL microsome solution, and set aside (prepare for immediate use).

[1089] 4) Preparation of MgCl2 solution

[1090] Weigh an appropriate amount of MgCl2 powder, prepare it into a 300mM stock solution with PBS solution, and store it in a 4℃ refrigerator for later use. Precisely add an appropriate amount of the solution and dilute it into a 7.5mM working solution by adding 100mM PBS solution (prepare and use immediately).

[1091] 5) Preparation of test compound solution

[1092] a. Accurately weigh an appropriate amount of the test compound standard, add DMSO to make a 30 mM stock solution, and store in a 4°C refrigerator.

[1093] b. Accurately pipette an appropriate amount of the stock solution, add an appropriate amount of DMSO solution to dilute to a series of solutions I with concentrations of 10, 3, 1, 0.3, 0.03 and 0.003 mM. Accurately pipette an appropriate amount of the above series of solutions I, add an appropriate amount of acetonitrile to dilute to a series of solutions II with concentrations of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM. Accurately pipette an appropriate amount of the above series of solutions II, add an appropriate amount of PBS to dilute to working solutions with concentrations of 150, 50, 15, 5, 1.5, 0.15, 0.015 μM, and set aside.

[1094] 6) Selection of CYP probe substrates and selective inhibitors

[1095] a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate and add DMSO to prepare a stock solution, the concentration of which is shown in Table 5 below.

[1096] b. Preparation of probe substrate working solution: Accurately pipette an appropriate amount of probe substrate stock solution, add PBS solution and dilute 200 times to obtain probe substrate working solution, the concentration of which is shown in Table 5 below.

[1097] Table 5:

[1098] CYP Probe substrate Stock solution concentration (mM) Working solution concentration (μM) 1A2 Phenacetin 12 60 2C19 (S)-Mephenytoin 20 100 3A4M Midazolam 3 15

[1099] 2. Liver Microsome Incubation and Sample Preparation

[1100] The protein concentration, substrate and inhibitor concentrations in the reaction system are shown in Table 6 below.

[1101] Table 6:

[1102]

[1103] 3. Operation process

[1104] 1) Accurately pipette 40 μL of human liver microsome solution (0.25 mg / mL), 20 μL of probe substrate solution and 20 μL of test compound solution into a 96-well plate and pre-incubate in a 37°C water bath for 5 minutes.

[1105] 2) After 5 minutes of pre-incubation, remove the sample and add 20 μL of 5 mM NADPH solution to start the reaction. Incubate in a 37°C water bath for 30 minutes. Each sample should be replicated in duplicate.

[1106] 3) After the incubation, 250 μL of acetonitrile solution containing the internal standard was added to terminate the reaction. After shaking at 800 rpm for 10 minutes, the mixture was centrifuged at 3700 rpm for 10 minutes. 100 μL of the supernatant was accurately pipetted and diluted with 80 μL of distilled water. The mixture was shaken at 800 rpm for 10 minutes. The supernatant was aspirated for LC-MS / MS analysis.

[1107] The values ​​were calculated by Graphpad Prism to obtain the IC values ​​of drugs for inhibition of phenacetin, CYP2C19(S)-mephenytoin and CYP3A4M midazolam metabolic sites in human liver microsomes. 50 See Table 7 for values.

[1108] Table 7: IC values ​​of the compounds disclosed herein for CYP1A2 phenacetin, CYP2C19 (S)-mephenytoin and CYP3A4M midazolam metabolic sites 50 value

[1109] Example No. <![CDATA[IC 50 (μM)-CYP1A2]]> <![CDATA[IC 50 (μM)-CYP2C19]]> <![CDATA[IC 50 (μM)-CYP3A4M]]> 4 >30 >30 >30 5 >30 >30 >30 6 >30 >30 >30 Positive compound 1 12.5 7.4 25.5

[1110] Conclusion: The disclosed compounds will not have metabolic drug interactions based on CYP1A2 phenacetin, CYP2C19 (S)-mephenytoin and CYP3A4M midazolam metabolic sites within the concentration range of 30 μM, and show better safety than positive compound 1.

[1111] Test Example 4: Time-dependent inhibition (TDI) of the compounds disclosed herein on the enzyme at the CYP2C19(S)-mephenytoin metabolic site in human liver microsomes

[1112] This test example is mainly used to evaluate the time-dependent inhibitory effect (TDI) of the disclosed compounds and positive compound 1 (specific structure see Test Example 2) on the enzyme at the human liver microsomal CYP2C19 (S) -mephenytoin metabolic site, and the following experimental method is used for determination.

[1113] 1. Experimental Materials and Instruments

[1114] 1. Phosphate buffer (20×PBS, purchased from Bioscientific),

[1115] 2. NADPH (ACROS, A2646-71-1),

[1116] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor 36),

[1117] 4. ABIQTrap 4000 LC / MS instrument (AB Sciex),

[1118] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA),

[1119] 6. CYP probe substrate ((S)-mephenytoin / 20 μM, powder purchased from J&K Technology Co., Ltd., Cat No. 303768) and positive control inhibitor (ticlopidine, powder purchased from SIGMA, Cat No. T6654-1G).

[1120] 2. Experimental steps

[1121] Prepare 100mM PBS buffer, use the buffer to prepare 15mM MgCl2 and 10mM NADPH solution, use 15mM MgCl2 to prepare 0.5mg / mL microsome solution, dilute the 30mM stock solution with DMSO to a series of solutions I with concentrations of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.1mM, 0.03mM, 0mM, and then dilute 10 times with acetonitrile (ACN), and finally dilute 50 times with phosphate buffer (PBS) to obtain a series of working solutions II to be tested (60, 20, 6, 2, 0.6, 0.2, 0.06, 0μM). Dilute the (S)-mephenytoin working solution to a concentration of 20μM with PBS.

[1122] The prepared series of working solutions to be tested were shaken and dispensed into 50 μL into the corresponding reaction plates (set +NADPH and -NADPH groups), with 3 parallels, and 20 μL of liver microsome working solution was added to each 96-well plate, and 10 μL of NADPH was added to the +NADPH group, and the plates were placed in a water bath at 37°C for incubation, and the timing began; after 30 minutes of incubation, the plates were taken out, and 20 μL of the corresponding substrate solution was added to the +NADPH group, and 20 μL of the corresponding substrate solution and 10 μL of NADPH were added to the -NADPH group, and the plates were placed in a water bath at 37°C for incubation, and the timing began; after 30 minutes of incubation, the plates were taken out and 250 μL of ACN solution containing the internal standard was used to terminate the reaction. Then the plates were shaken at 800 rpm for 10 minutes and centrifuged at 4000 rpm for 15 minutes. 100 μL of the supernatant was mixed with 80 μL of ultrapure water and transferred to LC-MS / MS analysis.

[1123] The values ​​were calculated by Graphpad Prism to obtain the IC of the drug for the CYP2C19(S)-mephenytoin site. 50 Value and IC 50 Transfer multiple (IC 50 The shift fold) values ​​are shown in Table 8.

[1124] Table 8: IC of the compounds disclosed herein against human liver microsomal CYP2C19(S)-mephenytoin metabolic sites 50 Value and IC 50 Transfer multiplier value

[1125]

[1126] Conclusion: Compared with positive compound 1, the disclosed compounds have no inhibitory effect on the human liver microsomal CYP2C19 (S) -mephenytoin metabolic site, and no TDI effect is observed, that is, no metabolic drug interaction based on CYP2C19 will occur, showing better safety.

[1127] Test Example 5: Pharmacokinetic evaluation of the disclosed compounds in mice

[1128] 1. Summary

[1129] Mice were used as test animals, and the drug concentration in plasma at different time points after oral gavage (ig) / intravenous injection (iv) of the disclosed compound was determined by LC / MS / MS method to study the pharmacokinetic behavior of the disclosed compound in mice and evaluate its pharmacokinetic characteristics.

[1130] 2. Experimental plan

[1131] 2.1 Trial Drugs

[1132] Example 4 compound and Example 5 compound.

[1133] 2.2 Experimental animals

[1134] Thirty-six female C57 mice were equally divided into 4 groups and purchased from Weitonglihua Experimental Animal Co., Ltd., with animal production license number: SCXK (Shanghai) 2017-0005.

[1135] 2.3 Drug preparation

[1136] A certain amount of the compound of Example 4 and the compound of Example 5 were weighed, 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) were added to dissolve them, and then 90% physiological saline was added to prepare a 0.1 mg / mL clear solution.

[1137] 2.4 Administration

[1138] Oral administration: The mice were administered intragastric administration, the dosage was 2.0 mg / kg, and the administration volume was 20.0 mL / kg.

[1139] Intravenous administration: The mice were intravenously administered, the dosage was 1.0 mg / kg, and the administration volume was 10.0 mL / kg.

[1140] 3. Operation

[1141] Mice were intragastrically administered with the compound of Example 4 and the compound of Example 5, and 0.1 mL of blood was collected from the eye socket before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -80°C for testing. The blood collection and centrifugation process was performed under ice bath conditions.

[1142] The mice were intravenously injected with the compounds of Example 4 and Example 5, and 0.1 mL of blood was collected before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, and the treatment was the same as that of the oral gavage group.

[1143] Determine the content of the test compound in mouse plasma after administration of different drug concentrations: take 25 μL of mouse plasma at each time after administration, add 200 μL of acetonitrile (containing 50 μL of internal standard solution camptothecin (100 ng / mL)), vortex mix for 1 minute, centrifuge for 10 minutes (4000 rpm), and take 0.5 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[1144] 4. Pharmacokinetic parameter results

[1145] Table 9: Pharmacokinetic parameters of the compounds of the present disclosure:

[1146]

[1147] Conclusion: The compounds disclosed in the present invention have good pharmacokinetic absorption activity in mice and have pharmacokinetic advantages.

[1148] Test Example 6: Pharmacokinetic evaluation of the disclosed compounds in dogs

[1149] 1. Summary

[1150] Dogs were used as test animals, and the drug concentrations in the plasma at different times after the compounds of the present disclosure were administered to dogs by gavage (ig) or intravenous injection (iv) were determined by LC / MS / MS method. The pharmacokinetic behavior of the compounds of the present disclosure in dogs was studied, and their pharmacokinetic characteristics were evaluated.

[1151] 2. Experimental plan

[1152] 2.1 Trial Drugs

[1153] Example 4 compound and Example 5 compound.

[1154] 2.2 Experimental animals

[1155] 12 male Beagle dogs were divided into 4 groups, provided by the animal reserve bank of Medicipia Pharmaceutical Technology (Shanghai) Co., Ltd. (999M-004). All animals were healthy Beagles with good physical examination.

[1156] 2.3 Drug preparation

[1157] Intragastric administration group: a certain amount of the compound of Example 4 and the compound of Example 5 were weighed, 5% volume of DMSO and 20% PEG400 were added to dissolve them, and then 55% physiological saline was added to prepare a 0.4 mg / mL clear solution.

[1158] Intravenous injection group: a certain amount of the compound of Example 4 and the compound of Example 5 were weighed, 5% volume of DMSO and 20% PEG400 were added to dissolve them, and then 55% physiological saline was added to prepare a 0.25 mg / mL clear solution.

[1159] 2.4 Administration

[1160] Intragastric administration: The dosage was 2 mg / kg and the administration volume was 50.0 mL / kg.

[1161] Intravenous administration: The dosage is 0.5 mg / kg and the administration volume is 20.0 mL / kg.

[1162] 3. Operation

[1163] Beagle dogs were intragastrically administered with the compounds of Example 4 and Example 5, and 1.0 mL of blood was collected from the forelimb vein before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 5 minutes (4°C), and plasma was separated within 1 hour and stored at -80°C for testing. Food was taken 3 hours after administration.

[1164] Beagle dogs were intravenously injected with the compounds of Example 4 and Example 5, and 0.1 mL of blood was collected before administration and at 5 minutes, 15 minutes, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24 hours after administration, and treated in the same manner as the oral gavage group. The blood collection and centrifugation process was performed under ice bath conditions.

[1165] Determination of the content of the test compound in beagle dog plasma after administration of different drug concentrations: 10 μL of beagle dog plasma at each time point after administration was taken, 200 μL of acetonitrile (containing internal standard solution camptothecin (100 ng / mL)) was added, vortexed for 1 minute, centrifuged for 7 minutes (18,000 rpm), and 6 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[1166] 4. Pharmacokinetic parameter results

[1167] Table 10: Pharmacokinetic parameters of the compounds of the present disclosure:

[1168]

[1169] Conclusion: The disclosed compounds have good pharmacokinetic absorption activity in dogs and have pharmacokinetic advantages.

Claims

1. A compound represented by the general formula (IM), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Ring B is phenyl or a 5- or 6-membered heteroaryl group; M is a N atom or a C atom; is a single bond or a double bond; when M is a nitrogen atom, is a single bond, when M is a C atom, is a single bond or a double bond; Ring C is a 6- to 7-membered heterocyclic group containing 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 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; R 2 is selected from the group consisting of hydrogen, alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, cyano, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 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.

2. The compound of the general formula (IM) according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 6 the same or different and each independently selected from hydrogen, halogen, alkyl, alkoxy, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

3. A compound of the general formula (IM) according to claim 1 or 2, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Y 5 is an O atom or a S atom; Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms; R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; k is 1 or 2; Ring B, M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

4. A compound represented by the general formula (IM) according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (INa), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: Ring B, M, Ring A, Y 4 , Y 5 , Y 6 , R 1 To R 6 , n, m, p and q are as defined in claim 3.

5. The compound represented by the general formula (IM) according to claim 1 or 2, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof: in: Y 1 is an O atom or a S atom; Y 2 and Y 3 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 2 and Y 3 Not all are heteroatoms; R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; k is 1 or 2; Ring B, M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

6. A compound of the general formula (IM) according to any one of claims 1 to 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridyl and thienyl.

7. A compound represented by the general formula (IM) according to any one of claims 1 to 6, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or thienyl.

8. A compound represented by the general formula (IM) according to any one of claims 1 to 3 and 6, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIG), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: 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 are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms; R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; k is 1 or 2; M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

9. A compound represented by the general formula (IM) according to any one of claims 1 to 4, 6 and 8, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIGa), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: 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 are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms; R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; k is 1 or 2; M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 8.

10. A compound of the general formula (IM) according to any one of claims 1 to 3 and 6 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIN), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Y 5 is an O atom or a S atom; Y 4 and Y 6 are the same or different and are each independently selected from an O atom, a S atom and -(CR m R n ) k -; The condition is Y 4 and Y 6 Not all are heteroatoms; R m and R n are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl; k is 1 or 2; M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

11. according to the compound shown in the general formula (IM) described in any one of claims 3, 4 and 6 to 10, or its tautomer, racemate, enantiomer, diastereomer or its mixture form or its pharmaceutically acceptable salt, wherein Y 4 and Y 5 is an O atom, and Y 6 For-(CR m R n ) k -; or, Y 5 and Y 6 is an O atom, and Y 4 For-(CR m R n ) k -; k is 1 or 2; R m and R n are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy 1-6 Alkyl, cyano, amino, nitro, hydroxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

12. A compound represented by the general formula (IM) according to any one of claims 1 to 3, 6 to 8, 10 and 11, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIN-1) or the general formula (IIIN-2), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: k is 1 or 2; M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

13. A compound according to any one of claims 1 or 2 and 5 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III-1) or formula (III-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: k is 1 or 2; M, Ring A, R 1 To R 6 , n, m, p and q are as defined in claim 1.

14. A compound according to any one of the general formula (IM) of claims 1 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from R 3 and m as defined in claim 1.

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

16. The compound of any one of claims 1 to 15, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is selected from phenyl, a 5- or 6-membered heteroaryl group and Ring C' is a 5- or 6-membered heteroaryl group.

17. A compound according to any one of the general formula (IM) of claims 1 to 16, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from R 6 and q as defined in claim 1.

18. A compound according to any one of the general formula (IM) of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably a hydrogen atom.

19. A compound according to any one of the general formula (IM) of claims 1 to 18, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 The alkylene group may be substituted by one or more substituents selected from the group consisting of alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group.

20. A compound according to any one of the general formula (IM) of claims 1 to 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen, halogen, oxo and C 1-6 Alkyl, preferably a hydrogen atom or a C 1-6 alkyl.

21. A compound according to any one of the general formula (IM) of claims 1 to 20, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably a hydrogen atom.

22. A compound according to any one of the general formula (IM) of claims 1 to 21, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl.

23. A compound according to any one of the general formula (IM) of claims 1, 3 to 22, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano and halo C 1-6 Alkyl, preferably selected from hydrogen atoms, halogen, C 1-6 Alkyl and cyano.

24. A compound according to the general formula (IM) described in any one of claims 1 to 23, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

25. A compound represented by the general formula (IMA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: R w C 1-6 alkyl; Ring B, M, Ring C, Ring A, R 1 To R 6 , n, m, p, g and q are as defined in claim 1.

26. The compound of the general formula (IMA) according to claim 25, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is selected from the following compounds:

27. A method for preparing a compound of the general formula (IM) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IMA) undergoes hydrolysis reaction to obtain a compound of general formula (IM), in: R w C 1-6 alkyl; Ring B, M, Ring C, Ring A, R 1 To R 6 , n, m, p, g and q are as defined in claim 1.

28. A pharmaceutical composition comprising a compound represented by the general formula (IM) according to any one of claims 1 to 24, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

29. Use of a compound represented by the general formula (IM) according to any one of claims 1 to 24, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for stimulating GLP-1 receptors.

30. Use of a compound represented by the general formula (IM) according to any one of claims 1 to 24, or its tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably, use of a compound represented by the general formula (IM) according to any one of claims 1 to 24, or its tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

31. Use of a compound represented by the general formula (IM) according to any one of claims 1 to 24, or its tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for treating and / or preventing idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

Images