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 (I), 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. Each group in the general formula is defined in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180019894.7, application date April 2, 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 general formula (I), 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, lipid 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 equal to 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 WO2009111700, WO2010114824, WO2018109607, WO2019239319 and WO2018056453, etc. Summary of the invention

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

[0010]

[0011] in:

[0012] Q is Q0 or Q2,

[0013]

[0014] G 1 , G 2 and G 3 The same or different, and each independently is CR 7 or N atoms;

[0015] Z 1 , Z 2, Z 3 and Z 4 The same or different, and each independently is CR 8 or N atoms;

[0016] Y is selected from O atom, S atom, NR 9 and CR 10 R 11 ;

[0017] W 1 and W 2 are the same or different and are each independently selected from an O atom, a S atom, NR 12 and CR 13 R 14 ;

[0018] R a and R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are 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;

[0019] R 1 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] R 3are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0022] R 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0023] 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, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0024] R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] R 7 and R 8 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;

[0026] R 9 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0027] R 10 , R 11 , R 13 and R 14 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;

[0028] n is 0, 1, 2, 3, 4 or 5;

[0029] m is 0, 1, 2, 3, 4 or 5;

[0030] t is 0, 1, 2, or 3; and

[0031] p is 0, 1, 2, 3, 4 or 5.

[0032] The object of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] Q is Q1 or Q2,

[0036]

[0037] G 1 , G 2 and G 3 The same or different, and each independently is CR 7 or N atoms;

[0038] Z 1 , Z 2 , Z 3 and Z 4 The same or different, and each independently is CR 8 or N atoms;

[0039] Y is selected from O atom, S atom, NR 9 and CR 10 R 11 ;

[0040] W 1 and W 2 are the same or different and are each independently selected from an O atom, a S atom, NR 12 and CR 13 R 14 ;

[0041] R1 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0042] R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0043] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0044] R 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0045] 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, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0046] R 6are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0047] R 7 and R 8 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;

[0048] R 9 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0049] R 10 , R 11 , R 13 and R 14 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;

[0050] n is 0, 1, 2, 3, 4 or 5;

[0051] m is 0, 1, 2, 3, 4 or 5;

[0052] t is 0, 1, 2, or 3; and

[0053] p is 0, 1, 2, 3, 4 or 5.

[0054] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein G 1 is a CH or N atom; G 2 and G 3 are CH; preferably, G 1 , G 2 and G 3 All are CH.

[0055] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0056]

[0057] in:

[0058] R 1 , R 2 , Q and n are as defined in the general formula (I).

[0059] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein Z 1 , Z 2 and Z 3 The same or different, and each independently is CR 8 , Z 4 is a N atom; R 8 A hydrogen atom or a halogen.

[0060] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein Y is an O atom or an S atom.

[0061] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein Z 1 , Z 2 and Z 3 For CH, Z 4 is a N atom; and / or Y is an O atom.

[0062] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein W 1 and W 2 All of them are O atoms.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is selected from Q3, Q4, Q5 and Q6:

[0064]

[0065] R 3 -R 6 , R 8 , m, p and t are as defined in the general formula (I).

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is selected from Q3, Q4 and Q5:

[0067]

[0068] R 3 -R 6 , m, p and t are as defined in the general formula (I).

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Q is

[0070] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0071]

[0072] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (I).

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (IIIaa), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0074]

[0075] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (I).

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 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, or 3- to 6-membered heterocyclic group; preferably, R 1 C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with a 3- to 6-membered heterocyclic group; more preferably, R 1 for

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and cyano.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom or C 1-6 Alkyl; preferably C 1-6 alkyl.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; and / or R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1.

[0083] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IIIaa) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; preferably 2.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: G 1 is a CH or N atom; G 2 and G 3 All are CH; Q is R 1 for R2 are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl; R 4 A hydrogen atom or C 1-6 Alkyl; R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0 or 1; t is 0 or 1; and p is 0, 1 or 2.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Q is R 1 for R 2 are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl; R 4 A hydrogen atom or C 1-6 Alkyl; R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0 or 1; t is 0 or 1; and p is 0, 1 or 2.

[0086] Table A Typical compounds of the present disclosure include, but are not limited to:

[0087]

[0088]

[0089] Another aspect of the present disclosure relates to a compound represented by the general formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0090]

[0091]

[0092] in:

[0093] R w C 1-6 alkyl;

[0094] G 1 , G 2 , G3 , R 1 , R 2 , Q and n are as defined in the general formula (I).

[0095] Another aspect of the present disclosure relates to a compound represented by general formula (IIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0096]

[0097] in:

[0098] R w C 1-6 alkyl;

[0099] R 1 , R 2 , Q and n are as defined in the general formula (II).

[0100] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0101]

[0102] in:

[0103] R w C 1-6 alkyl;

[0104] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (III).

[0105] Another aspect of the present disclosure relates to a compound represented by the general formula (IIIaaA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0106]

[0107] in:

[0108] R w C 1-6 alkyl;

[0109] R 1 , R 2 , R 4 ~R 6, n, p and t are as defined in the general formula (IIIaa).

[0110] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0111]

[0112]

[0113]

[0114] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0115]

[0116] The compound of general formula (IA) undergoes hydrolysis reaction to obtain a compound of general formula (I),

[0117] in:

[0118] R w C 1-6 alkyl;

[0119] G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in the general formula (I).

[0120] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0121]

[0122] The compound of general formula (IIA) undergoes hydrolysis reaction to obtain a compound of general formula (II),

[0123] in:

[0124] R w C 1-6 alkyl;

[0125] R 1 , R 2 , Q and n are as defined in the general formula (II).

[0126] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0127]

[0128] The compound of general formula (IIIA) undergoes hydrolysis reaction to obtain a compound of general formula (III),

[0129] in:

[0130] R w C 1-6 alkyl;

[0131] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (III).

[0132] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIaa), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0133]

[0134] The compound of general formula (IIIaaA) undergoes hydrolysis reaction to obtain a compound of general formula (IIIaa),

[0135] in:

[0136] R w C 1-6 alkyl;

[0137] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (IIIaa).

[0138] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0139] The present disclosure further relates to the use of a compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for stimulating the GLP-1 receptor.

[0140] The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IIIaa) or shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same for the preparation of pharmaceutical compositions for the treatment and / or prevention of type I diabetes, type II diabetes, idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, pregnancy-induced diabetes The invention relates to a method for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance in a medicament; preferably, the method is used for preparing a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease.

[0141] 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 of formula (I), formula (II), formula (III), formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0142] The present disclosure also relates to a method for treating and / or preventing type I diabetes, type II diabetes, idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, and the like. disease, dementia, insulin resistance or hepatic insulin resistance; preferably a method for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease or cardiovascular disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IIIaa) or Table A or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0143] The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0144] The present disclosure also relates to a compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a GLP-1 receptor agonist.

[0145] The present disclosure further relates to a compound represented by formula (I), formula (II), formula (III), formula (IIIaa) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing type I diabetes, type II diabetes, idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance; more preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease.

[0146] "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.

[0147] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0148] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia, and diabetic dementia.

[0149] 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.

[0150] The dosage of the compounds or compositions used in the disclosed methods of treatment will generally vary with the severity of the disease, the patient's weight and the relative efficacy of the compounds. However, as a general guide, the active compound is preferably in a unit dose form, or in a form that the patient can self-administer in a single dose. The unit dose of the disclosed compounds or compositions can be expressed in tablets, capsules, cachets, bottles, powders, granules, lozenges, suppositories, reconstituted powders or liquid formulations. Suitable unit doses can be 0.1 to 1000 mg.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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, 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.

[0162] Terminology

[0163] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0164] 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, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples 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. More preferred are lower alkyl groups having 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, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0165] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably 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, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0166] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl 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, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0167] 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. 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.

[0168] 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 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0169] 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, a double spiral cycloalkyl or a multi-spirocycloalkyl, 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 single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0170]

[0171] 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:

[0172]

[0173] 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:

[0174]

[0175] 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 of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like; preferably indanyl and tetrahydronaphthyl.

[0176] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0177] 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, the substituent is preferably one or more of the following groups, which are independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0178] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, but excluding the ring part 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, 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); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0179] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiro atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds. 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 spiro atoms shared between rings, the spiro 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. More preferably, it is a 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0180]

[0181] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms of the polycyclic heterocyclic group with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, S (O) or S (O) 2 heteroatoms, and the remaining ring atoms are carbon. Preferably 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 radical include:

[0182]

[0183]

[0184] 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, sulfur, S(O) or S(O)2, 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 a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0185]

[0186] 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:

[0187]

[0188] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0189] 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:

[0190]

[0191]

[0192] The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0193] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 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, 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:

[0194]

[0195] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0196] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0197] 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, tert-butyloxycarbonyl, 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.

[0198] 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, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 The hydroxy protecting group is preferably a p-nitrobenzoyl group.

[0199] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

[0200] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0201] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0202] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0203] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0204] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0205] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0206] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0207] The term "hydroxy" refers to -OH.

[0208] The term "thiol" refers to -SH.

[0209] The term "amino" refers to -NH2.

[0210] The term "cyano" refers to -CN.

[0211] The term "nitro" refers to -NO2.

[0212] The term "oxo" or "oxo" refers to "=0".

[0213] The term "carbonyl" refers to C=O.

[0214] The term "carboxy" refers to -C(O)OH.

[0215] 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.

[0216] The present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds 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 better metabolic stability can be achieved when deuterated at certain specific sites, thereby obtaining certain therapeutic advantages.

[0217] "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.

[0218] "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.

[0219] "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.

[0220] "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 during the final isolation and purification of the compounds, or separately 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.

[0221] 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.

[0222] 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.

[0223] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0224] 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.

[0225] The compounds of the present disclosure may also 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, a compound having a structure of the present disclosure except that hydrogen is replaced by "deuterium" or "tritium", or by 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 disease, or as tracers for pharmacodynamic, pharmacokinetics or receptor studies.

[0226] Synthesis method of the disclosed compound

[0227] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0228] Solution 1

[0229] The method for preparing the compound represented by the general formula (I) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, comprises the following steps:

[0230]

[0231] The compound of general formula (IA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (I)

[0232] in:

[0233] R w C 1-6 alkyl;

[0234] G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in the general formula (I).

[0235] Solution 2

[0236] The method for preparing the compound represented by the general formula (II) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt comprises the following steps:

[0237]

[0238] The compound of general formula (IIA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (II)

[0239] in:

[0240] R w C 1-6 alkyl;

[0241] R 1 , R 2 , Q and n are as defined in the general formula (II).

[0242] Option 3

[0243] The method for preparing the compound represented by the general formula (III) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, comprises the following steps:

[0244]

[0245] The compound of general formula (IIIA) undergoes hydrolysis reaction in the presence of an alkaline agent to obtain a compound of general formula (III)

[0246] in:

[0247] R w C 1-6 alkyl;

[0248] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (III).

[0249] Option 4

[0250] The method for preparing the compound represented by the general formula (IIIaa) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, comprises the following steps:

[0251]

[0252] The compound of general formula (IIIaaA) undergoes hydrolysis reaction in the presence of an alkaline reagent to obtain a compound of general formula (IIIaa)

[0253] in:

[0254] R w C 1-6 alkyl;

[0255] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in the general formula (IIIaa).

[0256] The alkaline reagent in the above schemes 1 to 4 includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably lithium hydroxide or lithium hydroxide monohydrate.

[0257] The above reaction 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

[0258] 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.

[0259] Example

[0260] 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.

[0261] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0262] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0263] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0264] High performance liquid chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0265] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0266] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0267] 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.

[0268] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0269] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0270] 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.

[0271] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0272] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0273] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0274] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0275] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0276] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0277] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0278] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0279] 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.

[0280] TsOH is p-toluenesulfonic acid.

[0281] Example 1

[0282] (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1

[0283]

[0284] first step

[0285] 3-Fluoro-4-((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)oxy)methyl)benzonitrile 1b

[0286] Tert-butyl 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate 1a (96 mg, 234.4595 μmol, prepared by the method disclosed in Intermediate 4 on page 51 of the specification of patent application "WO2018109607") was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (133 mg, 699.2014 μmol) was added, and stirred at 60 ° C for 4 hours. Cool, filter, wash with ethyl acetate (10 mL), collect the organic phase, dry, filter, and concentrate under reduced pressure to obtain compound 1b (126 mg), which was used directly in the next step without purification.

[0287] MS m / z(ESI):310.1[M+1].

[0288] Step 2 (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1d

[0289] (S)-2-(Chloromethyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1c (55 mg, 186.6096 μmol, prepared by the method disclosed in Intermediate 23 on page 69 of the specification of patent application WO2018109607), compound 1b (121 mg, 185.0889 μmol) was dissolved in acetonitrile (10 mL), potassium carbonate (128 mg, 926.1571 μmol) was added, and stirred at 50°C for 5 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system A to obtain the title compound 1d (105 mg, yield: 99%).

[0290] MS m / z(ESI):568.1[M+1].

[0291] Step 3

[0292] (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1

[0293] Compound 1d (105 mg, 184.9865 μmol) was dissolved in a mixed solvent of acetonitrile (5 mL) and water (1 mL), lithium hydroxide (6 mg, 250.5397 μmol) was added, and stirred at 40°C overnight. After concentration, the pH of the citric acid solution was adjusted to 5-6, 2 mL of acetonitrile was added, and after dissolution, 1 (20 mg, yield: 19%) was prepared by high performance liquid chromatography.

[0294] MS m / z(ESI):554.2[M+1].

[0295] 1 H NMR (500MHz, DMSO-d6) δ8.26(s,1H),7.88(d,J=9.9Hz,1H),7.81(d,J=8.3Hz,1H),7.74-7.59(m,4H),7.09(d,J=7 .5Hz,1H),6.77(d,J=8.1Hz,1H),6.70(d,J=4.4Hz,1H),5.49(s,2H),5.11-5.01(m,1H),4.79(dd,J=15.2,7.3Hz, 1H),4.64(dd,J=15.3,2.8Hz,1H),4.50-4.43(m,1H),4.41-4.31(m,1H),4.06(d,J=13.5Hz,1H),3.91(d,J=13.5H z,1H),3.30-3.12(m,3H),2.73(q,J=5.3Hz,2H),2.65(dd,J=11.1,7.1Hz,1H),2.48(s,1H),2.39(t,J=9.5Hz,1H).

[0296] Example 2

[0297] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2

[0298]

[0299]

[0300] first step

[0301] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridine 2b

[0302] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2a (65 mg, 0.15 mmol, prepared by the method disclosed for intermediate C5 on page 55 of the specification of patent application WO2019239319) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) was added, stirred at 60°C for 4 hours, cooled, filtered, washed with ethyl acetate (10 mL), the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the title compound 2b (75 mg, di-p-toluenesulfonate), which was used directly in the next step without purification.

[0303] MS m / z(ESI):346.1[M+1].

[0304] Step 2

[0305] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 2c

[0306] Compound 2b (75 mg, 0.14 mmol, di-p-toluenesulfonate) was dissolved in 10 mL of acetonitrile, and compound 1c (40 mg, 0.14 mmol) and potassium carbonate (94 mg, 0.68 mmol) were 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 using eluent system A to obtain the title compound 2c (35 mg, yield: 42.7%).

[0307] MS m / z(ESI):604.1[M+1].

[0308] Step 3

[0309] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2

[0310] Compound 2c (35 mg, 0.06 mmol) was dissolved in 5 mL of acetonitrile, and lithium hydroxide monohydrate (3 mg, 0.07 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, concentrated to remove acetonitrile, and the residue was adjusted to pH 6-7 with citric acid solution, dissolved in acetonitrile, and subjected to high performance liquid chromatography to obtain the title compound 2 (20 mg, yield: 58.5%).

[0311] MS m / z(ESI):590.1[M+1].

[0312] 1 H NMR(500MHz,DMSO-d6)δ12.80(brs,1H),8.26(s,1H),7.81(d,1H),7.66(d,1H),7.57 -7.54(m,2H),7.33(d,1H),6.87-6.81(m,3H),6.39-6.36(m,1H),5.08-5.04(m,1H),4 .82-4.76(m,1H),4.68-4.63(m,1H),4.48-4.43(m,1H),4.39-4.33(m,1H),4.08-4.0 3(m,1H),3.92-3.88(m,1H),3.29-3.12(m,4H),2.79-2.63(m,3H),2.55-2.36(m,4H).

[0313] Example 3

[0314] 2-((6-(1-(4-chloro-2-fluorobenzyl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 3

[0315]

[0316] first step

[0317] 2-Chloro-6-(1-(4-chloro-2-fluorophenyl)ethoxy)pyridine 3c

[0318] Potassium tert-butoxide (672 mg, 5.98 mmol) was added to tetrahydrofuran (10 mL), 1-(4-chloro-2-fluorophenyl)ethanol 3b (523 mg, 2.99 mmol) was added at room temperature, stirred at this temperature for 45 minutes, 2,6-dichloropyridine 3a (444 mg, 3.00 mmol) was added, and stirred at room temperature for 1 hour. 50 mL of water was added, extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3c (700 mg, yield: 81.7%).

[0319] Step 2

[0320] 6-(4-Chloro-2-fluorophenyl)ethoxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester 3e

[0321] Compound 3c (309 mg, 999.32 μmol), anhydrous sodium carbonate (317 mg, 2.99 mmol), tetrakistriphenylphosphine palladium (58 mg, 50.19 μmol), water (4 mL), dioxane (16 mL), under argon protection, stirred at 90 ° C overnight. TLC showed that the reaction was complete. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3e (188 mg, yield: 43.5%).

[0322] MS m / z(ESI):433.1[M+1].

[0323] Step 3

[0324] 6-(1-(4-chloro-2-fluorophenyl)ethoxy)-1'2',3',6'-tetrahydro-2,4'-bipyridine 3f

[0325] Compound 3e (188 mg, 434.26 μmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid (206 mg, 1.08 mmol) was added, stirred at 60°C for 4 hours, cooled, filtered, washed with ethyl acetate (10 mL), the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the title compound 3f (294 mg, di-p-toluenesulfonate, yield: 99.9%).

[0326] MS m / z(ESI):333.1[M+1].

[0327] Step 4

[0328] 2-((6-((4-chloro-2-fluorophenyl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 3g

[0329] Compound 3f (270 mg, 398.69 μmol, 2TsOH) was dissolved in acetonitrile (5 mL) and potassium carbonate (135 mg, 976.80 μmol) was added, 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 A to obtain the title compound 3g (81 mg, yield: 69.6%). MS m / z (ESI): 591.1 [M+1].

[0330] Step 5

[0331] 2-((6-(1-(4-chloro-2-fluorophenyl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 3

[0332] Compound 3g (80 mg, 135.3475 μmol) was dissolved in acetonitrile (5 mL) and water (1 mL). Lithium hydroxide monohydrate (8 mg, 190.47 μmol) was added and stirred at 40°C overnight. Concentrate and adjust the pH to 5-6 with citric acid. Add 10 mL of water, extract with ethyl acetate (30 mL×3), dry with anhydrous sodium sulfate, filter and concentrate. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3 (35 mg, yield: 44.8%). MS m / z (ESI): 577.1 [M+1].

[0333] 1H NMR (500MHz, DMSO-d6) δ12.75(s,1H),8.26(d,J=1.6Hz,1H),7.82(dd,J=8.4,1.5Hz,1H),7.66(dd,J=8.1,3.2Hz,1H),7.45(td,J=8.2,2.7Hz,1H),7.4 1(dt,J=10.2,1.6Hz,1H),7.24(dt,J=8.4,1.5Hz,1H),7.03(dd,J=7.5,2.4 Hz,1H),6.72(d,J=8.1Hz,1H),6.60(td,J=3.7,1.9Hz,1H),6.35-6.26(m,1H ),5.05(ddd,J=7.4,5.0,2.7Hz,1H),4.79(dd,J=15.2,7.3Hz,1H),4.64(dt ,J=15.4,3.1Hz,1H),4.51-4.42(m,1H),4.36(ddd,J=6.1,3.2,1.8Hz,1H),4 .06(dd,J=13.5,3.4Hz,1H),3.90(dd,J=13.5,5.6Hz,1H),3.27-3.12(m,2H ),2.79-2.55(m,4H),2.46(s,1H),2.42-2.29(m,2H),1.57(d,J=6.6Hz,3H).

[0334] Example 4

[0335] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridine

[0336] -1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4

[0337]

[0338] The first step is (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridine 4-

[0339] Toluenesulfonate 4b

[0340] (S)-tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridine-1(2H)-carboxylate (4a, 88 mg, 0.20 mmol, prepared and chirally resolved by the method disclosed in the intermediate C5 in the example on page 55 of the specification of patent application WO2019239319) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (94 mg, 0.49 mmol) was added, stirred at 60°C for 4 hours, cooled, concentrated under reduced pressure, and washed with n-hexane (20 mL) to obtain a crude product 4b (102 mg, p-toluenesulfonate), which was used directly in the next reaction without purification.

[0341] MS m / z(ESI):345.9[M+1].

[0342] Step 2

[0343] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridine

[0344] -1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 4c

[0345] The crude compound 4b (102 mg, 0.20 mmol, p-toluenesulfonate) was dissolved in 10 mL of acetonitrile, and compound 1c (50 mg, 0.17 mmol) and potassium carbonate (117 mg, 0.85 mmol) were 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 using eluent system B to obtain the title compound 4c (88 mg, yield: 85.9%).

[0346] MS m / z(ESI):604.1[M+1].

[0347] Step 3

[0348] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridine

[0349] -1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4

[0350] Compound 4c (88 mg, 0.15 mmol) was dissolved in 5 mL of acetonitrile, and lithium hydroxide monohydrate (7 mg, 0.17 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, concentrated under reduced pressure to remove acetonitrile, and the residue was adjusted to pH 6-7 with citric acid solution, dissolved in acetonitrile, and purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 4 (50 mg, yield: 58.2%).

[0351] MS m / z(ESI):590.2[M+1].

[0352] 1 H NMR(500MHz,DMSO-d6)δ12.80(brs,1H),8.27(s,1H),7.81(d,1H),7.66(d,1H),7.57-7.54(m,2H) ,7.33(d,1H),6.87-6.81(m,3H),6.39-6.36(m,1H),5.08-5.04(m,1H),4.82-4.76(m,1H),4.68-4 .63(m,1H),4.48-4.43(m,1H),4.39-4.33(m,1H),4.17-4.06(m,1H),4.00-3.90(m,1H),3.32-3.1 9(m,2H),2.86-2.73(m,2H),2.70-2.64(m,1H),2.60-2.53(m,1H),2.46-2.34(m,2H),2.03(s,3H).

[0353] Example 5

[0354] (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 5

[0355]

[0356]

[0357] first step

[0358] 4-(((6-Bromopyridin-2-yl)thio)methyl)-3-fluorobenzonitrile 5b

[0359] 3-Fluoro-4-(mercaptomethyl)benzonitrile 5a (309 mg, 1.84 mmol, prepared by the method disclosed in the intermediate I-2 on page 26 of the specification of patent application US2012329788A1) was dissolved in toluene (10 mL), 2,6-dibromopyridine (450 mg, 1.89 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (90 mg, 0.10 mmol), N,N-diisopropylethylamine (600 mg, 4.64 mmol) were added, and microwaved at 100°C for 1 hour. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system B to obtain the title compound 5b (225 mg, yield: 37.6%).

[0360] MS m / z(ESI):325[M+1].

[0361] Step 2

[0362] tert-Butyl 6-((4-cyano-2-fluorobenzyl)thio)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate 5c

[0363] Compound 5b (255 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL), and N-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (220 mg, 0.71 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), anhydrous sodium carbonate (220 mg, 2.08 mmol), tetrakistriphenylphosphine palladium (40 mg, 0.03 mmol), water (3 mL) were added, and heated to 90°C under nitrogen atmosphere and stirred for 16 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system A to obtain the title compound 5c (260 mg, yield: 87.8%).

[0364] MS m / z(ESI):426.1[M+1].

[0365] Step 3

[0366] 3-Fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)thio)methyl)benzonitrile p-toluenesulfonate 5d

[0367] Compound 5c (125 mg, 0.29 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (170 mg, 0.89 mmol) was added, and the mixture was stirred at 60°C for 4 hours. The mixture was cooled, filtered, and washed with ethyl acetate (10 mL). The organic phase was collected, dried, filtered, and concentrated under reduced pressure to obtain the crude title product 5d (146 mg), which was used directly in the next step without purification.

[0368] MS m / z(ESI):326.1[M+1].

[0369] Step 4

[0370] (S)-2-((6-((4-cyano-2-fluorobenzyl)thio)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 5e

[0371] Compound 1c (80 mg, 0.27 mmol) and compound 5d (146 mg, 0.29 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (200 mg, 1.44 mmol) was added, and stirred at 50°C for 5 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography with eluent system B to obtain the title compound 5e (158 mg, yield: 99%). MS m / z (ESI): 584.2 [M+1].

[0372] Step 5

[0373] (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 5

[0374] Compound 5e (150 mg, 0.26 mmol) was dissolved in 6 mL of a mixed solvent of acetonitrile and water (V:V=5:1), lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added, and the mixture was stirred at 40°C for 16 hours. After concentration, the pH of the mixture was adjusted to 5-6 with citric acid solution, acetonitrile (2 mL) was added, and after dissolution, the mixture was purified by silica gel column chromatography with eluent system A to obtain the title compound 5 (90 mg, 61.5%).

[0375] MS m / z(ESI):570.1[M+1].

[0376] 1H NMR(500MHz,DMSO-d6)δ12.71(brs,1H),8.26(s,1H),7.86-7.80(m,2H),7.71-7.59(m, 4H),7.25(d,1H),7.17(d,1H),6.72(s,1H),5.08-5.04(m,1H),4.82-4.75(m,1H),4.67 -4.63(m,1H),4.54(s,2H),4.49-4.44(m,1H),4.38-4.32(m,1H),4.09-3.91(m,2H),3. 28-3.21(m,2H),3.17(s,2H),2.78-2.72(m,2H),2.69-2.62(m,1H),2.43-2.34(m,1H).

[0377] Example 6

[0378] (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-5-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 6

[0379]

[0380]

[0381] first step

[0382] 4-(((6-Chloro-3-fluoropyridin-2-yl)thio)methyl)-3-fluorobenzonitrile 6a

[0383] 3-Fluoro-4-(mercaptomethyl)benzonitrile 5a (280 mg, 1.67 mmol) was dissolved in toluene (10 mL), and 2,6-dichloro-3-fluoropyridine (280 mg, 1.69 mmol, Nanjing Yaoshi Technology Co., Ltd.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (80 mg, 0.09 mmol), N,N-diisopropylethylamine (550 mg, 4.26 mmol) were added, and microwaved at 100°C for 1 hour. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with eluent system B to give the title compound 6a (128 mg, yield: 25.8%).

[0384] MS m / z(ESI):297.0[M+1].

[0385] Step 2

[0386] 6-((4-cyano-2-fluorobenzyl)thio)-5-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester 6b

[0387] Compound 6a (128 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 mL), and N-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (22.15 g, 0.49 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), anhydrous sodium carbonate (100 mg, 0.94 mmol), tetrakistriphenylphosphine palladium (50 mg, 0.04 mmol), water (2 mL) were added, and heated to 90°C under nitrogen atmosphere 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 6b (126 mg, yield: 65.9%).

[0388] MS m / z(ESI):388.1[M-55].

[0389] Step 3

[0390] 3-Fluoro-4-(((5-fluoro-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-6-yl)thio)methyl)benzonitrile di-p-toluenesulfonate 6c

[0391] Compound 6b (126 mg, 0.28 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (160 mg, 0.84 mmol) was added, and the mixture was stirred at 60° C. for 4 hours. The mixture was cooled, filtered, and washed with ethyl acetate (10 mL). The organic phase was collected, dried, filtered, and concentrated under reduced pressure to obtain the crude title compound 6c (195 mg), which was used directly in the next step without purification.

[0392] Step 4

[0393] (S)-2-((6-((4-cyano-2-fluorobenzyl)thio)-5-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl

[0394] 6d)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0395] Compound 1c (60 mg, 0.20 mmol) and compound 6c (195 mg, 0.28 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (150 mg, 1.09 mmol) was added, and stirred at 50°C for 5 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography with eluent system B to obtain the title compound 6d (96 mg, yield: 78.4%). MS m / z (ESI): 602.1 [M+1].

[0396] Step 5

[0397] (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-5-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl

[0398] 6-(2-oxetanyl)-1-(2-oxetanylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0399] Compound 6d (86 mg, 0.14 mmol) was dissolved in 6 mL of a mixed solvent of acetonitrile and water (V:V=5:1), lithium hydroxide monohydrate (8 mg, 0.19 mmol) was added, and the mixture was stirred at 40°C for 16 hours. After concentration, the pH of the mixture was adjusted to 5-6 with citric acid solution, acetonitrile (2 mL) was added, and after dissolution, the mixture was purified by silica gel column chromatography with eluent system A to give the title compound 6 (26 mg, 31.0%).

[0400] MS m / z(ESI):588.2[M+1].

[0401] 1 H NMR(500MHz,DMSO-d6)δ12.77(brs,1H),8.26(d,1H),7.85(dd,2H),7.81(dd,1H),7.67 -7.60(m,4H),7.35(dd,1H),6.66(s,1H),5.09-5.04(m,1H),4.82-4.77(m,1H),4.67-4. 63(m,1H),4.60(s,2H),4.49-4.44(m,1H),4.38-4.34(m,1H),4.08-3.91(m,2H),3.28-3 .17(m,2H),2.78-2.71(m,2H),2.69-2.62(m,1H),2.54-2.51(m,1H),2.43-2.36(m,1H).

[0402] Example 7

[0403] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridine

[0404] -1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 7

[0405]

[0406]

[0407] first step

[0408] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 7b

[0409] The crude compound 4b (83 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL), and compound (S)-2-chloromethyl-3-(oxetanyl-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 7a (45 mg, 0.15 mmol, prepared by the method disclosed in intermediate P27 on page 85 of the specification of patent application WO2019239371A1) and potassium carbonate (100 mg, 0.72 mmol) were added, and 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 the title compound 7b (64 mg, yield: 69.5%).

[0410] MS m / z(ESI):605.1[M+1].

[0411] Step 2

[0412] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridine

[0413] -1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 7

[0414] Compound 7b (64 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), and lithium hydroxide monohydrate (5 mg, 0.12 mmol) and water (1 mL) were added at room temperature, and the mixture was reacted at 40°C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, and the residue was adjusted to pH 6-7 with citric acid solution, dissolved with acetonitrile, and purified by silica gel column chromatography with eluent system A to obtain the title compound 7 (15 mg, yield: 24.0%).

[0415] MS m / z(ESI):591.0[M+1].

[0416] 1H NMR(500MHz,DMSO-d6)δ8.14(d,1H),8.00(d,1H),7.57-7.53(m,2H),7.34-7.32(m,1H), 6.87-6.81(m,3H),6.39-6.36(m,1H),5.18-5.13(m,1H),4.85-4.81(m,1H),4.72-4.68(m ,1H),4.49-4.44(m,1H),4.38-4.34(m,1H),4.12(d,1H),4.01(m,1H),3.28-3.23(m,2H), 2.81-2.72(m,2H),2.69-2.64(m,1H),2.59-2.54(m,1H),2.48-2.39(m,2H),2.02(s,3H).

[0417] Biological evaluation

[0418] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0419] 1. Test Purpose

[0420] The purpose of this experiment is to test the agonist activity of the compound on the GLP-1 receptor and evaluate the in vitro activity of the molecule based on the EC50 size. 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.

[0421] 2. Experimental Methods

[0422] 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). 5 cells / 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 ).

[0423] 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).

[0424] 3. Data Analysis

[0425] 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.

[0426] Table 1 EC of the compounds disclosed herein for GLP-1 receptor agonist activity 50

[0427]

[0428]

[0429] Conclusion: The compounds disclosed in the present invention have good agonist activity on GLP-1 receptor.

[0430] Test Example 2. Effects of the compounds disclosed herein on hERG potassium ion channels

[0431] 1. Test Purpose

[0432] The blocking effect of the disclosed compounds on hERG potassium current was tested by fully automated patch clamp on a stable cell line transfected with hERG potassium channel

[0433] 2. Test Method

[0434] 2.1 Experimental Materials and Instruments

[0435] 2.1.1 Experimental materials:

[0436] 2.1.2 Experimental instruments:

[0437] Reagent name Supply Company Part Number FBS GIBCO 10099 Sodium pyruvate solution Sigma S8636-100ML MEM non-essential amino acid solution (100×) Sigma M7145-100ML G418 Sulfate Enzo ALX-380-013-G005 MEM Hyclone SH30024.01B hERG cDNA Origene - pcDNA3.1(+) invitrogen V79020 HEK293 human embryonic kidney cells Chinese Academy of Sciences Cell Bank Item No.GNHu18

[0438] 2.2 Fully automated patch clamp experimental steps

[0439] The HEK293 cell line was transfected with pCDNA3.1(+) containing the hERG gene, and then a monoclonal HEK293-hERG stable cell line was selected by adding G418. The HEK293-hERG stable cell line was subcultured at a density of 1:4 in MEM / EBSS medium (10% FBS, 400μg / ml G418, 1% MEM non-essential amino acid solution (100×), 1% sodium pyruvate solution), and the fully automated patch clamp experiment was performed within 48-72 hours of culture. On the day of the experiment, the cells were digested with 0.25% trypsin (life technologies, 12563-029), collected by centrifugation, and washed with extracellular solution (140mM NaCl, 4mM KCl, 1mM

[0440]

[0441] Resuspend the cells in 1% MgCl2, 2mM CaCl2, 5mM D-glucose monohydrate, 10mM HEPES, pH7.4, 298mOsmol) to make a cell suspension. Place the cell suspension on the cell bank of the Patchliner instrument. The Patchliner instrument uses a negative pressure controller to add the cells to the chip (NPC-16), and the negative pressure attracts the single cells to the small holes of the chip. When the whole cell mode is formed, the instrument will obtain the hERG current according to the set hERG current and voltage program, and then the instrument automatically perfuses the compound from low concentration to high concentration. The current at each concentration of the compound and the blank control current are analyzed by the HEAK EPC10 patch clamp amplifier (Nanion) and the data analysis software provided by Pathlinersoftware and Pathcontrol HTsoftware.

[0442] 2.3 Test Results

[0443] The blocking effect of the disclosed compounds on hERG potassium current was determined by the above test, and the measured IC 50 See Table 2 for values.

[0444] Table 2 IC values ​​of the blocking effect of the disclosed compounds on hERG potassium ion channels 50

[0445] Example No. <![CDATA[IC 50 (μM)]]> 4 22

[0446] Conclusion: The disclosed compounds have weak inhibitory effects on hERG and can reduce the side effects caused by the hERG pathway.

Claims

1. A compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Q is Q0 or Q2, G 1 , G 2 and G 3 The same or different, and each independently is CR 7 or N atoms; Z 1 , Z 2 , Z 3 and Z 4 The same or different, and each independently is CR 8 or N atoms; Y is selected from O atom, S atom, NR 9 and CR 10 R 11 ; W 1 and W 2 are the same or different and are each independently selected from an O atom, a S atom, NR 12 and CR 13 R 14 ; R a and R b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are 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; R 1 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, 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, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 7 and R 8 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 9 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R 10 , R 11 , R 13 and R 14 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; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, or 3; and p is 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is Q1 or Q2, in: Y, Z 1 , Z 2 , Z 3 , Z 4 , W 1 , W 2 , R 3 ~R 6 , m, p and t are as defined in claim 1.

3. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein G 1 is a CH or N atom; G 2 and G 3 are CH; preferably, G 1 , G 2 and G 3 All are CH.

4. A compound of the general formula (I) according to any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: R 1 , R 2 , Q and n are as defined in claim 1.

5. A compound according to any one of the general formula (I) of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 and Z 3 All are CH, Z 4 is a N atom; and / or Y is an O atom.

6. A compound according to any one of the general formula (I) of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W 1 and W 2 All of them are O atoms.

7. A compound according to any one of claims 1 to 6, wherein Q is selected from Q3, Q4 and Q5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, of the general formula (I) described in claim 1: R 3 -R 6 , m, p and t are as defined in claim 1.

8. A compound of the general formula (I) according to any one of claims 1 to 7, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (III) is: R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in claim 1.

9. A compound of the general formula (I) according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIIaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in claim 1.

10. A compound according to any one of the general formula (I) of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 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 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic group.

11. A compound according to any one of the general formula (I) of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

12. A compound according to any one of the general formula (I) of claims 1 to 11, or a tautomer, mesomer, 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 atoms, halogens, C 1-6 Alkyl and cyano.

13. A compound according to any one of the general formula (I) of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom or C 1-6 Alkyl; preferably C 1-6 alkyl.

14. A compound according to any one of the general formula (I) of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; and / or R 6 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

15. A compound of the general formula (I) according to any one of claims 1 to 14, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

16. A compound represented by the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: R w C 1-6 alkyl; G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in claim 1.

17. The compound according to claim 16 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

18. A method for preparing the compound of general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IA) undergoes hydrolysis reaction to obtain a compound of general formula (I), in: R w C 1-6 alkyl; G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in claim 1.

19. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound of formula (I) according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for stimulating a GLP-1 receptor.

21. Use of the compound of formula (I) according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance; preferably, use of the compound of formula (I) according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease.

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