Tetrahydroisoquinoline compound as well as preparation method and medical application thereof

Abstract

The invention relates to a tetrahydroisoquinoline compound, a preparation method thereof and application of the tetrahydroisoquinoline compound in medicine. Specifically, the invention relates to a tetrahydroisoquinoline compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the tetrahydroisoquinoline compound as a therapeutic agent, especially application of the tetrahydroisoquinoline compound as a GLP-1 receptor agonist. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a tetrahydroisoquinoline compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a tetrahydroisoquinoline compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a GLP-1 receptor agonist. Background Art

[0002] Diabetes is a multi-cause metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative lack of insulin in the human body, which leads to an increase in blood glucose concentration, followed by large amounts of sugar excreted in the urine, and symptoms such as polydipsia, polyuria, polyphagia and weight loss.

[0003] Generally speaking, there are two types of diabetes. People with type I diabetes, or insulin-dependent diabetes, produce little or no insulin of their own. Insulin is a hormone that regulates glucose utilization in the body. People with type II diabetes, or non-insulin-dependent diabetes, have plasma insulin levels that are the same or higher than those of non-diabetic people. However, these people are resistant to insulin, which stimulates glucose and lipid metabolism in the main insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even increased plasma insulin levels cannot overcome the patient's significant resistance to insulin.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] Disclosed patent applications for GLP-1 receptor small molecule agonists include WO2023151575A1, WO2021219019A1, WO2020207474A1, WO2021197464A1, WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1, etc. Summary of the invention

[0008] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] G 1 , G 2 and G 3 The same or different, and each independently is N or CR 7 ;

[0012] M 1 、M 2 、M 3 and M 4One of them is a carbon atom and is connected to Y, and the other three are the same or different and are each independently N or CR 8 ;

[0013] Cyclo 1 is a heterocyclic group or a heteroaryl group;

[0014] Cyclo 2 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a hydroxyl group, a cyano group, a cycloalkyl group and a heterocyclic group;

[0016] R 2 , R 3 and R 4 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a hydroxyl group, a cyano group, a cycloalkyl group and a heterocyclic group;

[0017] or R 2 , R 4 Together with the carbon atom it is attached to, it forms -CH-(CH2) v -CH-; v is 0, 1, 2, 3 or 4;

[0018] or R 3 , R 4 Together with the carbon atom it is attached to, it forms -CH-(CH2) u -CH-; u is 0, 1, 2, 3 or 4;

[0019] or R 2 , R 3 Together with the carbon atom to which it is attached, it forms ring D;

[0020] Ring D is a cycloalkyl group or a heterocyclyl group; the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] 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, hydroxyl, -OR 10 、-(CH2) x NR 9a R 9b、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, oxo, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0022] Each R 5 and R 6 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -OR 10 、-(CH2) x NR 9a R 9b 、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, oxo, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0023] T 1is selected from hydrogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein the alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl are each independently selected from halogen, cyano, nitro, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, -OR 10 、-(CH2) x NR 9a R 9b 、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, which are the same or different substituents;

[0024] X is selected from a bond, O, NR 01 and CR 11a R 11b ;

[0025] Y is selected from a bond, O, NR 02 and CR 12a R 12b ;

[0026] R 00 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0027] R 01 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0028] R 02 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0029] R 9a and R 9b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more identical or different substituents selected from an oxo group, a halogen group, a cyano group, an amino group, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group;

[0030] or R9a and R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0031] R 10 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic;

[0032] R 11a and R 11b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclic group; or R 11a and R 11b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0033] R 12a and R 12b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0034] p is 0, 1, 2, 3, 4 or 5;

[0035] q is 0, 1, 2, 3, 4, or 5;

[0036] x is 0, 1, 2, 3, or 4; and

[0037] t is 0, 1, or 2.

[0038] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof:

[0039]

[0040] in:

[0041] R 5a is a hydrogen atom or R 5 ;

[0042] Cyclo 2 , G 1 , G 2 , G 3 、T 1 , R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 and q are as defined in the general formula (I).

[0043] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein the ring Cy 2 is phenyl or 6-membered heteroaryl; in some embodiments, ring Cy 2 It is phenyl.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, 2 or 3; in some embodiments, q is 0, 1 or 2; in some embodiments, q is 2 or 3; in some embodiments, q is 2; in some embodiments, q is 3.

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein for R 6 and q are as defined in Formula (I); in some embodiments, for R 6a , R 6b and R 6c are the same or different and are each independently a hydrogen atom or R 6 ; R 6 As defined in formula (I); in some embodiments, for R 6a and R 6b are the same or different and are each independently a hydrogen atom or R 6; R 6 As defined in formula (I); in some embodiments, for R 6a and R 6b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, cyano and 3 to 6 membered heterocyclic groups (preferably, R 6a is halogen; R 6b is cyano or halogen; more preferably, R 6a is halogen; R 6b is cyano); in some embodiments, for

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein M 1 、M 2 、M 3 and M 4 One of them is a carbon atom and is connected to Y, and the other three are the same or different and are each independently CR 8 ; R 8 As defined in the general formula (I); M 2 is a carbon atom and is connected to Y; M 1 、M 3 and M 4 The same or different, and each independently is N or CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 2 is a carbon atom and is connected to Y; M 1 N or CR 8 ;M 3 and M 4 The same or different, and each independently is CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 2 is a carbon atom and is connected to Y; M 1 N;M 3 and M 4 The same or different, and each independently is N or CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 2 is a carbon atom and is connected to Y; M 1 、M 3 and M 4 The same or different, and each independently is CR 8 ; R 8As defined in Formula (I); in some embodiments, M 2 is a carbon atom and is connected to Y; M 1 N or CR 8 ;M 3 and M 4 CH; R 8 As defined in Formula (I); in some embodiments, M 2 is a carbon atom and is connected to Y; M 1 、M 3 and M 4 For CH.

[0047] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein M 3 is a carbon atom and is connected to Y; M 1 、M 2 and M 4 The same or different, and each independently is N or CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 3 is a carbon atom and is connected to Y; M 1 、M 2 and M 4 The same or different, and each independently is CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 3 is a carbon atom and is connected to Y; M 1 、M 2 and M 4 For CH.

[0048] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein for M 1 、M 2 、M 3 and M 4 The same or different, and each independently is N or CR 8 ; R 2 , R 3 , R 4 and R 8 As defined in formula (I); in some embodiments, for M 1 、M 3 and M 4 The same or different, and each independently is N or CR 8; R 2 , R 3 , R 4 and R 8 As defined in formula (I); in some embodiments, for M 1 , R 2 , R 3 , R 4 and R 8 As defined in formula (I); in some embodiments, for R 2 , R 3 , R 4 and R 8 As defined in formula (I); in some embodiments, for R 2 , R 3 , R 4 and R 8 As defined in formula (I); in some embodiments, for

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 1a and R 1b A hydrogen atom.

[0050] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 7 ; G 2 CR 7 ; G 3 N or CR 7 ; R 7 As defined in formula (I); in some embodiments, G 1 CR 7 ; G 2 CR 7 ; G 3 N; R 7 As defined in formula (I); in some embodiments, G 1 CH; G 2 CH; G 3 N or CR7 ; R 7 As defined in formula (I); in some embodiments, G 1 CH; G 2 CH; G 3 is CH or N; in some embodiments, G 1 CH; G 2 CH; G 3 is N.

[0051] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein G 1 CH; G 2 For CH.

[0052] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0053]

[0054] in,

[0055] R 6a and R 6b are the same or different and are each independently a hydrogen atom or R 6 ;

[0056] Cyclo 1 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, M 1 、M 3 、M 4 and p are as defined in the general formula (I).

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein the ring Cy 1 is a 5-membered heterocyclyl or a 5-membered heteroaryl; in some embodiments, ring Cy 1 is a 5-membered heteroaryl; in some embodiments, ring Cy 1 is selected from triazolyl, oxadiazolyl and tetrazolyl; in some embodiments, cyclo Cy 1 is triazolyl or oxadiazolyl; in some embodiments, ring Cy 1 is triazolyl or tetrazolyl; in some embodiments, cyclo Cy 1 is triazolyl; in some embodiments, ring Cy1 It is oxadiazolyl.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, 3- to 6-membered cycloalkyl, -SH, -SR 10 、-S(O)R 10 and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 10 C 1-6 alkyl; in some embodiments, each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, 3- to 6-membered cycloalkyl, -SH, -SR 10 、-S(O)R 10 and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 10 C 1-6 alkyl; in some embodiments, each R 5 are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 5 The same or different, and each independently selected from C1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 5 The same or different, and each independently is C 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R 5 C 1-6 haloalkyl or oxo; in some embodiments, R 5 C 1-6 haloalkyl; in some embodiments, R 5 is oxo; in some embodiments, R 5 It is trifluoromethyl.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 1.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Selected from in:

[0061] In some embodiments, R 50 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered heterocyclyl and 3 to 8 membered heterocyclyl-C 1-6 Alkyl, each R 5a are the same or different and are each independently a hydrogen atom or R 5 , R 5 As defined in general formula (I);

[0062] In some embodiments, R 50 A hydrogen atom or C 1-6 Alkyl; each R 5a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, 3- to 6-membered cycloalkyl, -SH, -SR 10 、-S(O)R 10 and -C(O)NR9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 10 C 1-6 alkyl;

[0063] In some embodiments, R 50 A hydrogen atom or C 1-6 Alkyl; each R 5a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0064] In some embodiments, R 50 A hydrogen atom or C 1-6 Alkyl; each R 5a The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl;

[0065] In some embodiments, R 50 is a hydrogen atom; R 5a C 1-6 Alkyl or C 1-6 Haloalkyl;

[0066] In some embodiments, R 50 is a hydrogen atom; R 5a C 1-6 Haloalkyl;

[0067] In some embodiments, R 50 is a hydrogen atom; R 5a It is trifluoromethyl.

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein for R 50 A hydrogen atom or C 1-6 Alkyl, R5a is a hydrogen atom or R 5 , R 5 As defined in formula (I); in some embodiments, for R 50 A hydrogen atom or C 1-6 Alkyl, R 5a is a hydrogen atom or R 5 , R 5 As defined in formula (I); in some embodiments, for R 50 A hydrogen atom or C 1-6 Alkyl, R 5a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, for R 50 A hydrogen atom or C 1-6 Alkyl, R 5a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, for R 50 is a hydrogen atom, R 5a C 1-6 haloalkyl; in some embodiments, for R 50 is a hydrogen atom, R 5a C 1-6 haloalkyl; in some embodiments, for R 5a C 1-6 Halogenated alkyl.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0070] In some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, for

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 5a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, 3- to 6-membered cycloalkyl, -SH, -SR 10 、-S(O)R 10 and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 10 C 1-6 alkyl; in some embodiments, each R 5a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 5a The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 5a are the same or different and are each independently selected from methyl, trifluoromethyl, difluoromethyl and -C(O)NH2; in some embodiments, each R 5a The same or different, and each independently is C1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R 5a C 1-6 haloalkyl; in some embodiments, each R 5a are the same or different and are each independently selected from methyl, trifluoromethyl and difluoromethyl; in some embodiments, R 5a It is trifluoromethyl.

[0072] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof:

[0073]

[0074] in,

[0075] R 5a is a hydrogen atom or R 5 ;

[0076] G 3 , T 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , Y, M 1 、M 3 and M 4 As defined in general formula (II).

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein T 1 Selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl-C 1-6 Alkyl, the C 1-6 Alkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl-C 1-6 The alkyl groups are each independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -S(O)2-C 1-6In some embodiments, T 1 is a 3- to 8-membered cycloalkyl-C 1-6 alkyl; in some embodiments, T 1 for In some embodiments, T 1 For one or more -S(O)2-C 1-6 Alkyl substituted C 1-6 alkyl; in some embodiments, T 1 for In some embodiments, T 1 is a 3- to 8-membered heterocyclic group-C 1-6 alkyl; in some embodiments, T 1 for In some embodiments, T 1 Selected from

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 2 A hydrogen atom.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3 A hydrogen atom.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4 A hydrogen atom.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 2is a hydrogen atom; and / or R 3 is a hydrogen atom; and / or R 4 A hydrogen atom.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 8 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R 8 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 8 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 8 A hydrogen atom.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein M 1 CR 8 ; R 8 As defined in the general formula (I); M 1 is N or CH; in some embodiments, M 1 is CH; in some embodiments, M 1 is N.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein M 3 CR 8 ; R 8 As defined in the general formula (I); M 3 CR 8 ; R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; in some embodiments M 3 CR 8 ; R 8 is a hydrogen atom or a halogen; in some embodiments, M 3 is N or CH; in some embodiments, M 3 For CH.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein M 4 CR 8 ; R 8 As defined in the general formula (I); M 4 CR 8 ; R 8 is a hydrogen atom or a halogen; in some embodiments, M 4 is N or CH; in some embodiments, M 4 For CH.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein M 1 N or CR 8 ; and / or M 3 CR 8 ; and / or M 4 CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 1 CR 8 ; and / or M 3 CR 8 ; and / or M 4 CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 1 N; and / or M 3 CR 8 ; and / or M 4 CR 8 ; R 8 As defined in Formula (I); in some embodiments, M 1 CR 8 ; and / or M 3 CR 8 ; and / or M 4 CR 8 ; Each R 8 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, M 1 is N or CH; and / or M 3 CR 8 ; R 8 As defined in formula (I); and / or M 4 is CH; in some embodiments, M 1 is N or CH; and / or M 3CR 8 ; R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; and / or M 4 is CH; in some embodiments, M 1 is N or CH; and / or M 3 is CH; and / or M 4 is CH; in some embodiments, M 1 is CH; and / or M 3 is CH; and / or M 4 For CH.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 6 are the same or different and are each independently selected from halogen, C 1-6 alkyl, cyano, and 3 to 6 membered heterocyclyl; in some embodiments, each R 6 are the same or different and are each independently halogen or cyano; in some embodiments, each R 6 are the same or different and are each independently F or cyano.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 6a Selected from hydrogen atoms, halogens, C 1-6 alkyl, cyano, and 3 to 6 membered heterocyclyl; in some embodiments, R 6a is a hydrogen atom or a halogen; in some embodiments, R 6a is halogen; in some embodiments, R 6a For F.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 6b Selected from hydrogen atoms, halogens, C 1-6 alkyl, cyano, and 3 to 6 membered heterocyclyl; in some embodiments, R 6b is selected from hydrogen, halogen and cyano; in some embodiments, R 6b is halogen or cyano; in some embodiments, R 6b It is cyano.

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl, cyano, and 3 to 6 membered heterocyclyl; in some embodiments, R 6a is halogen; R 6b is cyano or halogen; in some embodiments, R 6a is halogen; R 6b It is cyano.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein R 6c Selected from hydrogen atoms, halogens, C 1-6 alkyl, cyano, and 3 to 6 membered heterocyclyl; in some embodiments, R 6c is a hydrogen atom or a halogen; in some embodiments, R 6c A hydrogen atom.

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano and C 1-6 alkoxy; in some embodiments, each R 7 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, each R 7 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 7 A hydrogen atom.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein G 3 is CH or N; in some embodiments, G 3 is N.

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein X is selected from O, CH2 and NH; in some embodiments, X is CH2; in some embodiments, X is O.

[0095] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or their pharmaceutically acceptable salts, wherein Y is selected from O, CH2 and NH; in some embodiments, Y is NH or O; in some embodiments, Y is O.

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein XY is selected from CH2-O, CH2-CH2 and CH2-NH; in some embodiments, XY is CH2-O or CH2-NH; in some embodiments, XY is CH2-O.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 11a and R 11b A hydrogen atom.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 12a and R 12b A hydrogen atom.

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2) or a pharmaceutically acceptable salt thereof, wherein R 01 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 01 A hydrogen atom.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 02 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 02 A hydrogen atom.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 9a and R 9b is a hydrogen atom; in some embodiments, R 9a is a hydrogen atom; R 9b C 1-6 alkyl; in some embodiments, R 9a and R 9b C 1-6 alkyl.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 10 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 10 is a hydrogen atom; in some embodiments, R 10 C 1-6 alkyl; in some embodiments, R 10 It is methyl.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R 00 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 00 A hydrogen atom.

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring Cy 2 is phenyl; each R 6 are the same or different and are each independently selected from halogen, C 1-6 alkyl, cyano and 3 to 6 membered heterocyclic group; q is 0, 1, 2 or 3; X is CH2; Y is selected from O, CH2 and NH; M 1 、M 2 、M 3 and M 4 One of them is a carbon atom and is connected to Y, and the other three are the same or different and are each independently CR 8 ; Each R 8 are the same or different and are each independently selected from hydrogen atoms, halogens, C1-6 Alkyl and C 1-6 Haloalkyl; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; R 1a and R 1b is a hydrogen atom; G 1 CR 7 ; G 2 CR 7 ; G 3 N or CR 7 ; Each R 7 are the same or different and are each independently a hydrogen atom or a halogen; T 1 for Cy 1 is a 5-membered heteroaryl group; R 5 C 1-6 Alkyl or C 1-6 Haloalkyl; p is 0 or 1.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring Cy 2 is phenyl; each R 6 are the same or different and are each independently halogen or cyano; q is 2; X is CH2; Y is O; M 2 is a carbon atom and is connected to Y; M 1 CH; M 3 CR 8 ; R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; M 4 CH; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; R 1a and R 1b is a hydrogen atom; G 1 CH; G 2 CH; G 3 N; T 1 for for R 50 is a hydrogen atom, R 5a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof, wherein the ring Cy 2 is phenyl; each R6 are the same or different and are each independently halogen or cyano; q is 2; X is CH2; Y is O; M 2 is a carbon atom and is connected to Y; M 1 CH; M 3 CR 8 ; R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; M 4 CH; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; R 1a and R 1b is a hydrogen atom; G 1 CH; G 2 CH; G 3 CH or N; T 1 for R 5a C 1-6 Halogenated alkyl.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6a is halogen; R 6b is halogen or cyano; Y is O; M 1 CR 8 ;M 3 CR 8 ;M 4 CR 8 ; Each R 8 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; G 3 CH or N; T 1 for for R 50 is a hydrogen atom, R 5a C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 6a is halogen; R 6b is cyano; Y is O; M 1 CR 8 ;M 3 CR8 ;M 4 CR 8 ; Each R 8 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; G 3 N; T 1 for for R 50 is a hydrogen atom, R 5a C 1-6 Halogenated alkyl.

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 6a is halogen; R 6b is halogen or cyano; Y is O; M 1 CR 8 ;M 3 CR 8 ;M 4 CR 8 ; Each R 8 are the same or different and are each independently a hydrogen atom or a halogen; R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 is a hydrogen atom; G 3 N; T 1 for R 5a C 1-6 Halogenated alkyl.

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

[0111]

[0112] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0113]

[0114] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt undergo a reductive amination reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0115] in:

[0116] R 1a and R 1b is a hydrogen atom;

[0117] Cyclo 1 , Cy 2 , G 1 , G 2 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 , p and q are as defined in the general formula (I).

[0118] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0119]

[0120] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (I-1B) or its salt undergo a reductive amination reaction to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt;

[0121] in:

[0122] R 1a and R 1b is a hydrogen atom;

[0123] Cyclo 2 , G 1 , G 2 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5a , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 and q are as defined in the general formula (I).

[0124] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0125]

[0126] The compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof reacts with hydrazine hydrate to obtain a compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

[0127] in:

[0128] Cyclo 2 , G 1 , G 2 , G 3 、T 1 , R 1a , R 1b , R 2 , R 3 , R 4 , R 5a , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 and q are as defined in the general formula (I-2).

[0129] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0130]

[0131] The compound represented by the general formula (IIA) or its salt and the compound represented by the general formula (IIB) or its salt undergo a reductive amination reaction to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0132] in:

[0133] Cyclo 1 , G 3 、T 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , Y, M 1 、M 3 、M 4 and p are as defined in the general formula (II).

[0134] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0135]

[0136] The compound represented by the general formula (IIA) or its salt and the compound represented by the general formula (II-1B) or its salt undergo a reductive amination reaction to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0137] in:

[0138] G 3 、T 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 6b , Y, M 1 、M 3 and M 4 As defined in general formula (II-1).

[0139] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0140]

[0141] The compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof reacts with hydrazine hydrate to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0142] in:

[0143] G 3 、T 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 6b , Y, M 1 、M 3 and M 4 As defined in general formula (II-2).

[0144] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure as shown in the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0145] The present disclosure further relates to the use of a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for stimulating a GLP-1 receptor.

[0146] The present disclosure further relates to the use of a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a GLP-1 receptor agonist.

[0147] The present disclosure further relates to the use of the compounds shown in general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of medicaments for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and liver insulin resistance; preferably, the use of the compounds shown in general formula (I), (I-1), (I-2) or Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of medicaments for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0148] The present disclosure further relates to the use of a compound of the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0149] The present disclosure further 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), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0150] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by the GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0151] The present disclosure further relates to a method for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic fatty liver disease (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic fatty liver disease and cardiovascular disease.

[0152] The present disclosure further relates to a method for treating and / or preventing idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0153] The present disclosure further relates to a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0154] The present disclosure further relates to a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a GLP-1 receptor agonist.

[0155] The present disclosure further relates to a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for stimulating the GLP-1 receptor.

[0156] The present disclosure further relates to a compound represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and liver insulin resistance; preferably for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0157] The present disclosure further relates to a compound shown in the general formula (I), (I-1), (I-2), (II), (II-1), (II-2) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used to treat and / or prevent idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0158] Preferably, the GLP-1 receptor-mediated disease or condition described in the present disclosure is selected from type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and liver insulin resistance; preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0159] Preferably, the GLP-1 receptor mediated disease or condition described in the present disclosure is selected from idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0160] "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.

[0161] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0162] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia, and diabetic dementia.

[0163] 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 compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0164] As a general guide, the active compounds of the present disclosure are preferably in a unit dosage form, or in a form that a patient can self-administer in a single dose. The unit dosage form of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages can be 0.1 to 1000 mg.

[0165] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0166] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0167] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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 severity of the disease, 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 optimal 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.

[0179] Terminology

[0180] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0181] 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 having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C1-12 alkyl), more preferably an alkyl having 1 to 6 carbon atoms (i.e., C 1-6 alkyl). 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. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0182] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0183] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C 2-6 The term "alkenyl" refers to an alkylene group (alkylene group). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0184] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably, the alkyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 Alkynyl), more preferably alkynyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0185] 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 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls and bridged cycloalkyls.

[0186] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocycles, 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, spirocycloalkyl is divided into single spiral cycloalkyl or polyspirocycloalkyl (e.g., double spiral cycloalkyl), preferably single spiral cycloalkyl and double spiral cycloalkyl. More preferably, it is 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 / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0187] Its connection point can be at any position;

[0188] wait.

[0189] 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 or polycyclic condensed cycloalkyl (such as tricyclic, tetracyclic) can be divided, preferably dicyclo 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 / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0190] , whose connection points can be at any position;

[0191]

[0192] wait.

[0193] 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 or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0194] Its connection point can be at any position.

[0195] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0196] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0197] 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 selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0198] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14-membered heterocyclyl), of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms (i.e., 3 to 8-membered heterocyclyl) or 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, of which 1-3 are heteroatoms (e.g., 1, 2, and 3); more preferably, 3 to 8 ring atoms are included, of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; further preferably, 5 to 8 ring atoms (e.g., 5, 6, 7, and 8) (i.e., 5- to 8-membered heterocyclyl) are included, of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; most preferably, 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl) are included, of which 1-3 are heteroatoms; most preferably, 5-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0199] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan spiral heterocyclic group), more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan spiral heterocyclic group). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group or a multi-spiro heterocyclic group (e.g., a double spiral heterocyclic group), preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

[0200]

[0201] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan fused heterocyclic group), more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan fused heterocyclic group). According to the number of constituent rings, it can be divided into a bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0202]

[0203] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered bridged heterocyclic groups), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0204]

[0205] 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:

[0206] wait.

[0207] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0208] 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:

[0209]

[0210] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0211] 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. The heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan) (i.e., 5 to 10 yuan heteroaryl), further preferably 8 to 10 yuan (e.g., 8, 9, or 10 yuan), more preferably 5 or 6 yuan (i.e., 5 or 6 yuan heteroaryl), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.; most preferably, a 5-membered heteroaryl. 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:

[0212]

[0213] wait.

[0214] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0215] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same parent ring atom or two different ring atoms by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0216] The term "amino protecting group" is to protect the amino group with a group that is easily removed in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonyl (Ts) and p-methoxybenzyl (PMB). These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro; the amino protecting group is preferably Boc or PMB.

[0217] The term "hydroxy protecting group" refers to a hydroxy derivative that is usually used to block or protect the hydroxyl group and reacts on other functional groups of the compound. As an example, preferably, the hydroxy protecting group is, for example, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl and p-nitrobenzoyl, etc.; the hydroxy protecting group is preferably MOM or TBDPS.

[0218] The term "alkynyl protecting group" refers to a group that is easily removed and introduced into the alkynyl group in order to keep the active hydrogen in acetylene or terminal alkyne unchanged when other parts of the molecule are reacted. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; the alkynyl protecting group is preferably TIPS.

[0219] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0220] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0221] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0222] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0223] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0224] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0225] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0226] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0227] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0228] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0229] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0230] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above.

[0231] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above.

[0232] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0233] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0234] The term "hydroxy" refers to -OH.

[0235] The term "thiol" refers to -SH.

[0236] The term "amino" refers to -NH2.

[0237] The term "cyano" refers to -CN.

[0238] The term "nitro" refers to -NO2.

[0239] The term "oxo" or "oxo" refers to "=0".

[0240] The term "carbonyl" refers to C=O.

[0241] The term "carboxy" refers to -C(O)OH.

[0242] 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.

[0243] MOM stands for methoxymethyl.

[0244] Boc refers to tert-butyloxycarbonyl.

[0245] TIPS refers to triisopropylsilyl.

[0246] TBS refers to tert-butyldimethylsilyl.

[0247] The compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation about a single bond, wherein energy differences due to stereostrain or other contributing factors form sufficiently high barriers to rotation to allow individual conformers to separate. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer. .

[0248] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactimide isomerizations. Keto-enol equilibrium examples are shown below:

[0249]

[0250] Another example:

[0251]

[0252] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomer.

[0253] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both Z-type and E-type are included. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0254] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0255] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F.36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0256] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0257] "Optionally" 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, "optionally C substituted with halogen or cyano 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0258] "Substituted" means that one or more hydrogen atoms, preferably 1 to 6, 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.

[0259] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0260] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0261] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0262] 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.

[0263] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0264] 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, not limiting.

[0265] Synthesis method of the disclosed compound

[0266] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0267] Solution 1

[0268] The method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0269]

[0270] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt undergo reductive amination reaction under alkaline conditions and the action of a reducing agent to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0271] in:

[0272] R 1a and R 1b is a hydrogen atom;

[0273] Cyclo 1 , Cy 2 , G 1 , G 2 , G 3 , T 1 , R 2 , R3 , R 4 , R 5 , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 , p and q are as defined in the general formula (I).

[0274] Solution 2

[0275] The method for preparing the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0276]

[0277] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (I-1B) or its salt undergo reductive amination reaction under alkaline conditions and the action of a reducing agent to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt;

[0278] in:

[0279] R 1a and R 1b is a hydrogen atom;

[0280] Cyclo 2 , G 1 , G 2 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5a , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 and q are as defined in the general formula (I).

[0281] Option 3

[0282] The method for preparing the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0283]

[0284] The compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof reacts with hydrazine hydrate to obtain a compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

[0285] in:

[0286] Cyclo 2 , G1 , G 2 , G 3 、T 1 , R 1a , R 1b , R 2 , R 3 , R 4 , R 5a , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 and q are as defined in the general formula (I-2).

[0287] Option 4

[0288] The method for preparing the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0289]

[0290] The compound represented by the general formula (IIA) or its salt and the compound represented by the general formula (IIB) or its salt undergo reductive amination reaction under alkaline conditions and the action of a reducing agent to obtain a compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0291] in:

[0292] Cyclo 1 , G 3 、T 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , Y, M 1 、M 3 、M 4 and p are as defined in the general formula (II).

[0293] Option 5

[0294] The method for preparing the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0295]

[0296] The compound represented by the general formula (IIA) or its salt and the compound represented by the general formula (II-1B) or its salt undergo reductive amination reaction under alkaline conditions and the action of a reducing agent to obtain a compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0297] in:

[0298] G 3 、T 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 6b , Y, M 1 、M 3 and M 4 As defined in general formula (II-1).

[0299] Option 6

[0300] The method for preparing the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0301]

[0302] The compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof reacts with hydrazine hydrate to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0303] in:

[0304] G 3 、T 1 , R 2 , R 3 , R 4 , R 5a , R 6a , R 6b , Y, M 1 、M 3 and M 4 As defined in general formula (II-2).

[0305] In the above schemes 3 and 6, the hydrazine hydrate can also be replaced by hydrazine, methylhydrazine, sulfonylhydrazine, isoniazid, semicarbazide, etc.

[0306] In the above synthesis scheme, the reagent providing the alkaline conditions includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent providing alkaline conditions is triethylamine.

[0307] In the above synthesis scheme, the reducing agent includes but is not limited to sodium acetate borohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium acetylborohydride, etc., preferably sodium acetate borohydride.

[0308] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, 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, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0309] 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.

[0310] Example

[0311] 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.

[0312] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0313] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0314] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0315] High performance liquid chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0316] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0317] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0318] 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.

[0319] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0320] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0321] The known starting materials of the present invention 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.

[0322] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0323] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0324] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0325] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0326] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0327] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0328] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0329] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0330] 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: petroleum ether / ethyl acetate system, 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.

[0331] Example 1

[0332] 4-(((2-((3-((1-cyanocyclopropyl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)

[0333] methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)-3-fluorobenzonitrile 1

[0334]

[0335] first step

[0336] 4-(((2-((3-((1-cyanocyclopropyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)-3-fluorobenzonitrile 1c

[0337] 3-Fluoro-4-(((1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)benzonitrile 1a (108 mg, prepared by the method disclosed in the intermediate of Example 2 on page 27 of the specification of patent application "CN115594669A") and triethylamine (0.5 mL) were dissolved in dichloromethane (10 mL), and 1-((2-formyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1b (60 mg, prepared by the method disclosed in Example 2 on page 27 of the specification of patent application "CN115594669A") was added. Prepared by the method disclosed in Example 66 intermediate on page 353 of the specification of patent application "WO2022028572A1"), stirred to dissolve, then added sodium acetate borohydride (79 mg), stirred at room temperature for 8 hours, poured the reaction solution into ice water (30 mL), extracted with dichloromethane (30 mL×3), washed with sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 1c (85 mg).

[0338] MS m / z(ESI):589.2[M+1].

[0339] Step 2

[0340] 4-(((2-((3-((1-cyanocyclopropyl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)

[0341] methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)-3-fluorobenzonitrile 1

[0342] Compound 1c (45 mg) and hydrazine hydrate (0.5 mL, 85% wt) were dissolved in ethanol (2 mL), heated to 80°C, stirred for 10 hours, cooled to room temperature, concentrated, and the residue was purified by high performance liquid chromatography (Waters 2545, chromatographic column: Sharpsil-T Prep C18, 150*30 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 20 minutes gradient: 40%-60%) to obtain the title compound 1 (15 mg). MS m / z (ESI): 588.2 [M+1].

[0343] 1 H NMR(500MHz,DMSO-d6)δ9.08(d,1H),8.45(d,1H),7.90(d,1H),7.76-7.67(m,2H),7.02(d,1H),6.80(dd,1H),6.74( d,1H),5.17(s,2H),3.92(s,2H),3.59(s,2H),3.20(s,2H),2.75-2.68(m,4H),1.36-1.32(m,2H),1.21-1.17(m,2H).

[0344] Biological evaluation

[0345] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0346] 1. Test Purpose

[0347] The purpose of this experiment is to test the agonist activity of the compound molecules on the hGLP-1 receptor. 50 The size of the molecule is used to evaluate the in vitro activity of the molecule. TM Luciferase Assay System (ONE-Glo TM Luciferase Assay System, Promega, E6110). Under the action of compound molecules, the downstream signaling pathway of GLP-1R is activated, causing the cAMP level to increase. The binding of cAMP to CRE can initiate the transcriptional expression of the luciferase gene downstream of CRE. The luciferase reacts with its substrate to emit fluorescence. Through ONE-GloTM The fluorescence signal measured by the reagent reflects the activity of the compound in stimulating the GLP-1 receptor.

[0348] 2. Experimental Methods

[0349] Construction of CHO-K1 / CRE-luc / hGLP-1 receptor stable cell line (hGLP-1 receptor plasmid self-constructed; CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / hGLP-1 receptor cells were digested, centrifuged and resuspended, the single cell suspension was mixed, and the live cell density was adjusted to 2.78×10 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 ).

[0350] 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 0.02mM, 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 5 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 enzyme reader (PHERAstar FS, BMG labtech).

[0351] 3. Data Analysis

[0352] The data were processed and analyzed using Microsoft Excel and Graphpad Prism 10. The EC values ​​of the compounds were obtained. 50 The results are shown in Table 1 below.

[0353] Table 1 Agonistic activity of the compounds disclosed herein on hGLP-1 receptor

[0354] Example No. <![CDATA[EC 50 (nM)]]> Emax(fold)

[0355] Conclusion: The compounds disclosed in the present invention have high agonist activity on GLP-1 receptor.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: G 1 , G 2 and G 3 The same or different, and each independently is N or CR 7 ; M 1 、M 2 、M 3 and M 4 One of them is a carbon atom and is connected to Y, and the other three are the same or different and are each independently N or CR 8 ; Cyclo 1 is a heterocyclic group or a heteroaryl group; Cyclo 2 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a hydroxyl group, a cyano group, a cycloalkyl group and a heterocyclic group; R 2 , R 3 and R 4 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a hydroxyl group, a cyano group, a cycloalkyl group and a heterocyclic group; or R 2 , R 4 Together with the carbon atom it is attached to, it forms -CH-(CH2) v -CH-; v is 0, 1, 2, 3 or 4; or R 3 , R 4 Together with the carbon atom it is attached to, it forms -CH-(CH2) u -CH-; u is 0, 1, 2, 3 or 4; or R 2 , R 3 Together with the carbon atom to which it is attached, it forms ring D; Ring D is a cycloalkyl group or a heterocyclyl group; the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, cycloalkyl, heterocyclyl, 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, hydroxyl, -OR 10 、-(CH2) x NR 9a R 9b 、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, oxo, cycloalkyl, heterocyclic radical, aryl and heteroaryl; Each R 5 and R 6 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -OR 10 、-(CH2) x NR 9a R 9b 、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, oxo, cycloalkyl, heterocyclic radical, aryl and heteroaryl; T 1 is selected from hydrogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein the alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl are each independently selected from halogen, cyano, nitro, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, -OR 10 、-(CH2) x NR 9a R 9b 、-NHC(O)R 10 、-C(O)R 10 、-C(O)OR 10 、-C(O)NR 9a R 9b 、-S(O) t R 10 、-S(O)2NR 9a R 9b 、-NR 00 S(O)2R 10 , cycloalkyl, heterocyclyl, aryl and heteroaryl, which are the same or different substituents; X is selected from a bond, O, NR 01 and CR 11a R 11b ; Y is selected from a bond, O, NR 02 and CR 12a R 12b ; R 00 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 01 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 02 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group and a cycloalkylalkyl group; R 9a and R 9b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more identical or different substituents selected from an oxo group, a halogen group, a cyano group, an amino group, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group; or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 10 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic; R 11a and R 11b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclic group; or R 11a and R 11b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 12a and R 12b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, or 5; x is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cyclic Cy 2 is phenyl or 6-membered heteroaryl; preferably, the ring Cy 2 It is phenyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: in, R 6a and R 6b are the same or different and are each independently a hydrogen atom or R 6 ; Cyclo 1 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, M 1 、M 3 、M 4 and p is as defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Selected from R 50 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered heterocyclyl and 3 to 8 membered heterocyclyl-C 1-6 Alkyl, each R 5a are the same or different and are each independently a hydrogen atom or R 5 , R 5 As defined in claim 1; and / or each R 5a are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and -C(O)NR 9a R 9b , R 9a and R 9b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 5a C 1-6 Haloalkyl; and / or T 1 Selected from C 1-6 Alkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl-C 1-6 Alkyl, the C 1-6 Alkyl, 3 to 8 membered cycloalkyl-C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl-C 1-6 The alkyl groups are each independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -S(O)2-C 1-6 The alkyl group is substituted with one or more identical or different substituents; preferably, T 1 for .

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom; and / or R 3 is a hydrogen atom; and / or R 4 is a hydrogen atom; and / or M 1 is CH; and / or M 3 is CH; and / or M 4 for CH; and / or R 6a and R 6b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl, cyano and 3 to 6 membered heterocyclic groups; preferably, R 6a is halogen; R 6b is cyano; and / or G 3 is CH or N; preferably, G 3 is N; and / or Y is O.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, which is the following compound:

7. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt undergo a reductive amination reaction to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; in: R 1a and R 1b is a hydrogen atom; Cyclo 1 , Cy 2 , G 1 , G 2 , G 3 , T 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, M 1 、M 2 、M 3 、M 4 , p and q are as defined in claim 1.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 in the preparation of a medicament for the treatment and / or prevention of type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance; preferably in the preparation of a medicament for the treatment and / or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 in the preparation of a medicament for the treatment and / or prevention of idiopathic type I diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

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