Fused imidazole compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to fused imidazole compounds, methods for their preparation and their use in medicine. In particular, the present disclosure relates to a fused imidazole compound of general formula (I), methods for their preparation, pharmaceutical compositions containing such compounds and their use as therapeutic agents, in particular as GLP-1 receptor agonists and in the manufacture of a medicament for the treatment and / or prevention of diabetes.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused imidazole compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to fused imidazole compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as GLP-1 receptor agonists in the treatment of diabetes. Background Technology

[0002] Diabetes mellitus is a multifactorial metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of glucose, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very ancient disease caused by an absolute or relative deficiency of insulin in the body, leading to elevated blood glucose levels, which in turn causes large amounts of glucose to be excreted in the urine, resulting in symptoms such as polydipsia, polyuria, polyphagia, and weight loss.

[0003] Generally, there are two types of diabetes. Type 1 diabetes, or insulin-dependent diabetes, is caused by the body producing very little or no insulin. Insulin is a hormone in the body that regulates glucose utilization. Type 2 diabetes, or insulin-independent diabetes, is caused by the body having plasma insulin levels that are the same as or higher than those of non-diabetic individuals. However, these patients develop insulin resistance, which stimulates glucose and lipid metabolism in major insulin-sensitive tissues such as muscle, liver, and adipose tissue. Even with increased plasma insulin levels, the significant insulin resistance cannot be overcome.

[0004] Insulin resistance arises not only from a reduced number of insulin receptors but also from insulin receptor defects, the mechanism of which is not yet fully understood. Insulin resistance prevents insulin from activating glucose uptake, oxidation, and storage in muscle tissue, and from effectively inhibiting lipolysis in adipose tissue and glucose production and secretion in the liver.

[0005] Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic hormone secreted by L-cells in the lower digestive tract. GLP-1 exerts its effects by binding to its widely distributed specific receptors. Organs where GLP-1 receptors are known to exist include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and cardiovascular system. GLP-1 receptors may also 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. Serum GLP-1 levels generally do not differ significantly among patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the β-cell response to GLP-1 after eating is defective, and under certain conditions, this response is significantly enhanced after continuous GLP-1 infusion. Because the duration of action of the body's own GLP-1 is very short (t1 / 2 < 1.5 minutes after intravenous injection), the body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0006] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the effect of lowering fasting and postprandial glucose and improving blood glucose in patients with type 2 diabetes. However, due to the poor oral bioavailability of peptide GLP-1 and the inconvenience of administration, there is a high demand for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0007] Published patent applications for small molecule GLP-1 receptor agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1, etc. Summary of the Invention

[0008] The purpose of this disclosure is to provide a compound of general formula (I), or a pharmaceutically usable salt thereof:

[0009]

[0010] in:

[0011] Q is either Q1 or Q2.

[0012]

[0013] Ring B is phenyl or a 5- or 6-membered heteroaryl group;

[0014] The ring C is a 5- or 6-membered heterocyclic group;

[0015] Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl;

[0016] It can be a single bond or a double bond;

[0017] when When it is a single bond, M is a nitrogen atom or CR. 9 ;when When it is a double bond, M is a carbon atom;

[0018] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 10 Or nitrogen atoms;

[0019] Each R 1 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] R 2 The group is selected from hydrogen atoms, alkyl, cycloalkyl, and heterocyclic groups; wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0021] Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0022] Each R 4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0023] Each R 5 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl and heterocyclic groups;

[0024] Each R 6 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl and heterocyclic groups;

[0025] R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0026] R 9 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, amino groups, hydroxyl groups, and hydroxyalkyl groups;

[0027] R 10 They may be the same or different each time they appear, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

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

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

[0030] p is 0, 1, 2 or 3;

[0031] q is 0, 1, or 2; and

[0032] g can be 0, 1, 2, 3, 4, or 5.

[0033] In some preferred embodiments of this disclosure, the compound represented by general formula (I), or a pharmaceutically usable salt thereof, wherein ring B is phenyl or pyridyl; preferably phenyl.

[0034] In some preferred embodiments of this disclosure, the compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IG), or a pharmaceutically acceptable salt thereof:

[0035]

[0036] in:

[0037] G 1 It consists of carbon or nitrogen atoms;

[0038] M, Q, R 1 To R 3 , n and m are as defined in general formula (I).

[0039] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (IG), or a pharmaceutically usable salt thereof, is a compound represented by general formula (II), or a pharmaceutically usable salt thereof:

[0040]

[0041] in:

[0042] Ring A, Ring C, M, R 1 To R 6 , n, m, p, q and g are as defined in general formula (I).

[0043] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), and (II), or pharmaceutically acceptable salts thereof, wherein Selected from:

[0044]

[0045] R 5a R 5b R 5c and R 5d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; preferably, R 5a R 5b R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0046] Rings A and R 4 R 6 p and g are as defined in general formula (I);

[0047] Preferably, for R 5a Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; preferably, R 5a It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; Cyclic A, R 4 R 6 p and g are as defined in general formula (I).

[0048] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), and (II), or pharmaceutically acceptable salts thereof, are selected from the compounds represented by general formulas (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof:

[0049]

[0050] in:

[0051] R 5a R 5b R 5c and R 5d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; preferably, R 5a R5b R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0052] R 9 Selected from hydrogen atoms, C 1-6 Alkyl and hydroxyl; preferably, R 9 It is a hydrogen atom;

[0053] Rings A and R 1 To R 4 R 6 , n, m, p and g are as defined in general formula (I).

[0054] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I) and (IG), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (III), or pharmaceutically acceptable salts thereof:

[0055]

[0056] in:

[0057] Rings A and Z 1 Z 2 Z 3 Z 4 M, R 1 R 2 R 3 R 6 To R 8 , n, m and g are as defined in general formula (I).

[0058] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), and (III), or pharmaceutically acceptable salts thereof, wherein: M is a CR 9 ;R 9 Selected from hydrogen atoms, C 1-6 Alkyl and hydroxyl; preferably, M is CR 9 ;R 9 It is a hydrogen atom.

[0059] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: for R 6 And g is as defined in general formula (I).

[0060] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), and (III), or pharmaceutically acceptable salts thereof, wherein: Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 10 R 10 As defined in general formula (I); or Z 1 For nitrogen atoms, Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 10 R 10 As defined in claim 1; preferably, Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 10 R 10 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or Z 1 For nitrogen atoms, Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 10 R 10 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

[0061] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: R 1 It is a hydrogen atom.

[0062] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: R 2 C 1-6 Alkyl; wherein the C 1-6 Alkyl groups are optionally selected from halogens, C 1-6 Alkoxy, C 1-6 The substituted group is one or more of the following: haloalkoxy, cyano, amino, hydroxyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; preferably, R 2 C1-6 Alkyl; wherein the C 1-6 The alkyl group may optionally be substituted with a 3- to 6-membered heterocyclic group; more preferably, R 2 for

[0063] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG), or a pharmaceutically acceptable salt thereof, wherein: for G 1 It consists of carbon or nitrogen atoms; R 1 and n are as defined in general formula (I); preferably, for G 1 It consists of carbon or nitrogen atoms; R 1 It is a hydrogen atom.

[0064] In some preferred embodiments of this disclosure, the compounds represented by general formulas (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: for R 1 and n are as defined in general formula (I); preferably, for R 1 It is a hydrogen atom.

[0065] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and oxo groups; preferably, R 3 It is a hydrogen atom.

[0066] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, wherein: each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 4 It is a hydrogen atom.

[0067] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I) and (II), or pharmaceutically acceptable salts thereof, wherein: each R 5 They may be the same or different, and each is independently a hydrogen atom or a carbon atom.1-6 alkyl.

[0068] In some preferred embodiments of this disclosure, the compounds represented by general formulas (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, wherein: R 5a R 5b R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0069] In some preferred embodiments of this disclosure, the compound represented by general formula (II-1), or a pharmaceutically acceptable salt thereof, wherein: R 5a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 5a It can be a hydrogen atom or a methyl group.

[0070] In some preferred embodiments of this disclosure, the compound represented by general formula (II-2), or a pharmaceutically acceptable salt thereof, wherein: R 5a R 5b and R 5c They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 5a R 5b and R 5c They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0071] In some preferred embodiments of this disclosure, the compound represented by general formula (II-3), or a pharmaceutically acceptable salt thereof, wherein: R 5a R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 5a R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0072] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein: each R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, each R 6 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0073] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), and (III), or pharmaceutically acceptable salts thereof, wherein: R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 7 and R 8 All are hydrogen atoms.

[0074] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, wherein g is 0, 1, or 2.

[0075] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (IG) and general formula (II), or pharmaceutically acceptable salts thereof, wherein q is 0 or 1.

[0076] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, are used, wherein n is 0 or 1.

[0077] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), (II-3), and (III), or pharmaceutically acceptable salts thereof, are used, wherein m is 0, 1, or 2.

[0078] In some preferred embodiments of this disclosure, the compounds represented by general formulas (I), (IG), (II), (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, are used, wherein p is 0 or 1.

[0079] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG), or a pharmaceutically acceptable salt thereof,

[0080] in:

[0081] M is CH or a nitrogen atom;

[0082] Q is selected from:

[0083]

[0084] for

[0085] G 1 It consists of carbon or nitrogen atoms;

[0086] R 1 It is a hydrogen atom;

[0087] R 2 C 1-6 Alkyl; wherein the C 1-6 The alkyl group may be optionally substituted with a 3- to 6-membered heterocyclic group;

[0088] R 3 It is a hydrogen atom;

[0089] R 4 It is a hydrogen atom;

[0090] R 5a R 5b R 5c and R 5d They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0091] Each R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; and

[0092] g can be 0, 1, or 2.

[0093] In some preferred embodiments of this disclosure, the compound represented by the general formula (IG), or a pharmaceutically acceptable salt thereof,

[0094] in:

[0095] M is CH or a nitrogen atom;

[0096] Q is

[0097] for

[0098] G 1 It consists of carbon or nitrogen atoms;

[0099] R 1 It is a hydrogen atom;

[0100] R 2 C 1-6 Alkyl; wherein the C 1-6 The alkyl group may be optionally substituted with a 3- to 6-membered heterocyclic group;

[0101] R 3 It is a hydrogen atom;

[0102] R 4 It is a hydrogen atom;

[0103] R 5a It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0104] Each R 6 They may be the same or different, and each is independently a hydrogen atom or a halogen; and

[0105] g can be 0, 1, or 2.

[0106] In some preferred embodiments of this disclosure, the compound represented by general formula (II-1), or a pharmaceutically acceptable salt thereof,

[0107] in:

[0108] for

[0109] R 1 It is a hydrogen atom;

[0110] R 2 C 1-6 Alkyl; wherein the C 1-6 The alkyl group may be optionally substituted with a 3- to 6-membered heterocyclic group;

[0111] R 3 It is a hydrogen atom;

[0112] R 4 It is a hydrogen atom;

[0113] R 5a It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0114] Each R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl;

[0115] R 9 It is a hydrogen atom; and

[0116] g can be 0, 1, or 2.

[0117] Table A lists typical compounds disclosed herein, including but not limited to:

[0118]

[0119]

[0120] Another aspect of this disclosure relates to compounds of general formula (IA), or pharmaceutically acceptable salts thereof.

[0121]

[0122] in:

[0123] R w C 1-6 alkyl;

[0124] Rings B, M, Q, R 1 To R 3 , n, and m are as defined in general formula (I). It is an intermediate for the preparation of compounds of general formula (I).

[0125] Another aspect of this disclosure relates to compounds represented by general formula (IGA), or pharmaceutically acceptable salts thereof.

[0126]

[0127] in:

[0128] R w C 1-6 alkyl;

[0129] M, Q, G 1 R 1 To R 3 , n, and m are as defined in general formula (IG). It is an intermediate for the preparation of compounds of general formula (IG).

[0130] Another aspect of this disclosure relates to compounds of general formula (IIA), or pharmaceutically acceptable salts thereof.

[0131]

[0132] in:

[0133] R w C 1-6 alkyl;

[0134] Ring A, Ring C, M, R 1 To R 6 n, m, p, q, and g are as defined in general formula (II). It is an intermediate for the preparation of compounds of general formula (II).

[0135] Another aspect of this disclosure relates to compounds of general formula (II-1A), or pharmaceutically acceptable salts thereof.

[0136]

[0137] in:

[0138] R w C 1-6 alkyl;

[0139] Rings A and R 1 To R 4 R5a R 6 R 9 n, m, p, and g are as defined in general formula (II-1). It is an intermediate for the preparation of compounds of general formula (II-1).

[0140] Another aspect of this disclosure relates to compounds of general formula (II-2A), or pharmaceutically acceptable salts thereof.

[0141]

[0142] in:

[0143] R w C 1-6 alkyl;

[0144] Rings A and R 1 To R 4 R 5a R 5b R 5c R 6 R 9 n, m, p, and g are as defined in general formula (II-2). It is an intermediate for the preparation of compounds of general formula (II-2).

[0145] Another aspect of this disclosure relates to compounds of general formula (II-3A), or pharmaceutically acceptable salts thereof.

[0146]

[0147] in:

[0148] R w C 1-6 alkyl;

[0149] Rings A and R 1 To R 4 R 5a R 5c R 5d R 6 R 9 n, m, p, and g are as defined in general formula (II-3). It is an intermediate for the preparation of compounds of general formula (II-3).

[0150] Another aspect of this disclosure relates to compounds of general formula (IIIA), or pharmaceutically acceptable salts thereof.

[0151]

[0152] in:

[0153] R w C 1-6 alkyl;

[0154] Rings A and Z 1 To Z 4 M, R 1 To R 3 R 6 To R 8 , n, m and g are as defined in general formula (III). It is an intermediate for the preparation of compounds of general formula (III).

[0155] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0156]

[0157]

[0158] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I), or a pharmaceutically usable salt thereof, the method comprising:

[0159]

[0160] Compounds of general formula (IA) undergo hydrolysis to yield compounds of general formula (I), or their pharmaceutically usable salts.

[0161] in:

[0162] R w C 1-6 alkyl;

[0163] Rings B, M, Q, R 1 To R 3 , n and m are as defined in general formula (I).

[0164] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IG), or a pharmaceutically usable salt thereof, the method comprising:

[0165]

[0166] Compounds of general formula (IGA) undergo hydrolysis to yield compounds of general formula (IG), or their pharmaceutically usable salts.

[0167] in:

[0168] R w C 1-6 alkyl;

[0169] M, Q, G 1 R 1 To R 3 , n and m are as defined in general formula (IG).

[0170] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II), or a pharmaceutically usable salt thereof, the method comprising:

[0171]

[0172] Compounds of general formula (IIA) undergo hydrolysis to yield compounds of general formula (II), or their pharmaceutically usable salts.

[0173] in:

[0174] R w C 1-6 alkyl;

[0175] Ring A, Ring C, M, R 1 To R 6 , n, m, p, q and g are as defined in general formula (II).

[0176] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1), or a pharmaceutically acceptable salt thereof, the method comprising:

[0177]

[0178] Compounds of general formula (II-1A) undergo hydrolysis to yield compounds of general formula (II-1), or their pharmaceutically usable salts.

[0179] in:

[0180] R w C 1-6 alkyl;

[0181] Rings A and R 1 To R 4 R 5a R 6 R 9 , n, m, p and g are as defined in general formula (II-1).

[0182] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0183]

[0184] Compounds of general formula (II-2A) undergo hydrolysis to yield compounds of general formula (II-2), or their pharmaceutically usable salts.

[0185] in:

[0186] R w C 1-6 alkyl;

[0187] Rings A and R 1 To R 4 R 5a R 5b R 5c R 6 R 9 n, m, p and g are as defined in general formula (II-2).

[0188] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-3), or a pharmaceutically acceptable salt thereof, the method comprising:

[0189]

[0190] Compounds of general formula (II-3A) undergo hydrolysis to yield compounds of general formula (II-3), or their pharmaceutically usable salts.

[0191] in:

[0192] R w C 1-6 alkyl;

[0193] Rings A and R 1 To R 4 R 5a R 5c R 5d R 6 R 9 , n, m, p and g are as defined in general formula (II-3).

[0194] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III), or a pharmaceutically usable salt thereof, the method comprising:

[0195]

[0196] Compounds of general formula (IIIA) undergo hydrolysis to yield compounds of general formula (III), or their pharmaceutically usable salts.

[0197] in:

[0198] R w C 1-6 alkyl;

[0199] Rings A and Z 1 To Z 4 M, R 1 To R 3 R 6 To R 8 , n, m and g are as defined in general formula (III).

[0200] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0201] This disclosure further relates to the use of compounds of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for activating GLP-1 receptors.

[0202] This disclosure further relates to the use of compounds of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance; preferably in the preparation of medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease.

[0203] This disclosure further relates to the use of compounds of formula (I), formula (IG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of idiopathic type 1 diabetes, latent immune diabetes mellitus in adults (LADA), young adult-onset diabetes mellitus (MODY), gestational diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary artery disease.

[0204] This disclosure also relates to a method of activating GLP-1 receptors, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (IG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0205] This disclosure also relates to a method for treating and / or preventing type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance; preferably a method for treating type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease, comprising administering to the desired patient a therapeutically effective amount of a compound of formula (I), formula (IG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0206] This disclosure also relates to a method of treating and / or preventing idiopathic type 1 diabetes, latent immune diabetes mellitus in adults (LADA), young adult-onset diabetes mellitus (MODY), gestational diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary artery disease, comprising administering to a patient a therapeutically effective amount of a compound represented by general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), and general formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0207] This disclosure further relates to a compound of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0208] This disclosure also relates to a compound of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and shown in Table A, or a pharmaceutical composition comprising the thereof, which acts as a GLP-1 receptor agonist.

[0209] This disclosure further relates to a compound of general formula (I), general formula (IG), general formula (II), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance; preferably for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease.

[0210] This disclosure further relates to a compound of formula (I), formula (IG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of idiopathic type 1 diabetes, latent immune diabetes mellitus in adults (LADA), young adult-onset diabetes mellitus (MODY), gestational diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary artery disease.

[0211] "Diabetic complications" are complications arising from diabetes or hyperglycemia, and can be either acute or chronic complexes. The term "acute complex" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), while "chronic complex" includes, for example, microvascular diseases (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.

[0212] Coronary heart disease includes myocardial infarction and angina pectoris.

[0213] "Dementia" includes, for example, Alzheimer's disease, early-onset dementia (EOD), vascular dementia, and diabetic dementia.

[0214] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0215] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0216] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0217] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0218] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0219] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, 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 sweeteners.

[0220] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0221] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0222] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include 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, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0223] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0224] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0225] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0226] 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 activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0227] Terminology Explanation

[0228] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0229] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms (i.e., C64-C ... 1-20Alkyl group). The alkyl group is 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., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups). 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 their various branched isomers, etc. The most preferred are lower alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0230] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 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., C2). 1-20 Alkylene). The alkylene preferably has 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0231] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C64-C ... 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0232] The term "alkynyl" refers to an alkyl group in a molecule containing at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. The alkynyl group preferably has 2 to 6 carbon atoms (i.e., C64 ... 2-6(Alkyne group). The alkynyl group can be substituted or unsubstituted, and when substituted, it is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0233] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. The substituent is preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0234] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, preferably 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0235] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (such as bispirocycloalkyl) based on the number of shared spiro atoms between the rings, preferably monospirocycloalkyl or bispirocycloalkyl. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0236]

[0237] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 3-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, 6 / 6-membered, 6 / 7-membered, 7 / 5-membered, or 7 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0238]

[0239] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic, tricyclic, or tetracyclic bridged cycloalkyl being preferred, and bicyclic or tricyclic bridged cycloalkyl being more preferred. Non-limiting examples of bridged cycloalkyl groups include:

[0240]

[0241] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0242] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0243] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent having 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it has 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it has 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms (i.e., 3 to 8-membered heterocyclic groups); even more preferably, it has 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it has 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0244] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may be optionally oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic groups or polyspirocyclic groups (such as bispirocyclic groups) according to the number of shared spiro atoms between rings, with monospirocyclic or bispirocyclic groups being preferred. Most preferably, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered monospirocyclic groups are preferred. Non-limiting examples of spirocyclic groups include:

[0245]

[0246] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of 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, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, and tetracyclic groups, etc. Bicyclic or tricyclic fused heterocyclic groups are preferred, and more preferably, 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0247]

[0248] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), with the remaining ring atoms being carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

[0249]

[0250] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0251] wait.

[0252] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0253] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0254]

[0255] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0256] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered (i.e., 5- or 6-membered heteroaryl), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0257]

[0258] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0259] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene".

[0260] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl, and p-methoxybenzyl. These groups may optionally be substituted with 1-3 substituents selected from halogens, alkoxy groups, or nitro groups.

[0261] The term "hydroxyl protecting group" is a suitable group known in the art for protecting hydroxyl groups. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0262] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0263] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0264] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0265] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0266] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0267] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0268] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0269] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0270] The term "hydroxyl group" refers to -OH.

[0271] The term "thiol" refers to -SH.

[0272] The term "amino" refers to -NH2.

[0273] The term "cyano" refers to -CN.

[0274] The term "nitro" refers to -NO2.

[0275] The term "oxo" or "oxo" refers to "=O".

[0276] The term "carbonyl" refers to C=O.

[0277] The term "carboxyl group" refers to -C(O)OH.

[0278] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0279] The compounds disclosed herein contain their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0280] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0281] In the chemical structures of the compounds described in this disclosure, the " / " sign indicates that the configuration is not specified; that is, if a chiral isomer exists in the chemical structure, the " / " sign can be any configuration. or Or simultaneously include and Two configurations.

[0282] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0283]

[0284] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0285]

[0286] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0287] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0288] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0289] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0290] "Pharmacologically acceptable salts" refer to salts of the compounds disclosed herein that are safe and effective in mammalian use and possess the intended biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting suitable groups with suitable bases or acids. 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 both inorganic and organic acids.

[0291] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0292] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0293] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0294] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations.

[0295] The method for synthesizing the compounds disclosed herein

[0296] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0297] Option 1

[0298] The method for preparing the compound represented by general formula (I) of this disclosure, or a pharmaceutically acceptable salt thereof, includes the following steps:

[0299]

[0300] Compounds of general formula (IA) undergo hydrolysis under alkaline conditions to yield compounds of general formula (I), or their pharmaceutically usable salts.

[0301] in:

[0302] R w C 1-6 alkyl;

[0303] Rings B, M, Q, R 1 To R 3 , n and m are as defined in general formula (I).

[0304] Option 2

[0305] The method for preparing the compound represented by the general formula (IG) of this disclosure, or a pharmaceutically acceptable salt thereof, includes the following steps:

[0306]

[0307] Compounds of general formula (IGA) undergo hydrolysis under alkaline conditions to yield compounds of general formula (IG), or their pharmaceutically usable salts.

[0308] in:

[0309] R w C 1-6 alkyl;

[0310] M, Q, G 1 R 1 To R 3 , n and m are as defined in general formula (IG).

[0311] Option 3

[0312] The method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof includes the following steps:

[0313]

[0314] Compounds of general formula (IIA) undergo hydrolysis under alkaline conditions to yield compounds of general formula (II), or their pharmaceutically usable salts.

[0315] in:

[0316] R w C 1-6 alkyl;

[0317] Ring A, Ring C, M, R 1 To R 6 , n, m, p, q and g are as defined in general formula (II).

[0318] Option 4

[0319] The method for preparing the compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, as disclosed herein, includes the following steps:

[0320]

[0321] Compounds of general formula (II-1A) undergo hydrolysis under alkaline conditions to yield compounds of general formula (II-1), or their pharmaceutically usable salts.

[0322] in:

[0323] R w C 1-6 alkyl;

[0324] Rings A and R 1 To R 4 R 5a R 6 R 9 , n, m, p and g are as defined in general formula (II-1).

[0325] Option 5

[0326] The preparation method of the compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof includes the following steps:

[0327] Compounds of general formula (II-2A) undergo hydrolysis under alkaline conditions to yield compounds of general formula (II-2), or their pharmaceutically usable salts.

[0328] in:

[0329] R w C1-6 alkyl;

[0330] Rings A and R 1 To R 4 R 5a R 5b R 5c R 6 R 9 n, m, p and g are as defined in general formula (II-2).

[0331] Option Six

[0332] The method for preparing the compound represented by general formula (II-3) or a pharmaceutically acceptable salt thereof includes the following steps:

[0333]

[0334] Compounds of general formula (II-3A) undergo hydrolysis under alkaline conditions to yield compounds of general formula (II-3), or their pharmaceutically usable salts.

[0335] in:

[0336] R w C 1-6 alkyl;

[0337] Rings A and R 1 To R 4 R 5a R 5c R 5d R 6 R 9 , n, m, p and g are as defined in general formula (II-3).

[0338] Option 7

[0339] The method for preparing the compound of formula (III) disclosed herein, or a pharmaceutically acceptable salt thereof, includes the following steps:

[0340] Compounds of general formula (IIIA) undergo hydrolysis under alkaline conditions to yield compounds of general formula (III), or their pharmaceutically usable salts.

[0341] in:

[0342] R w C 1-6 alkyl;

[0343] Rings A and Z 1 To Z 4 M, R 1 To R 3 R 6 To R8 , n, m and g are as defined in general formula (III).

[0344] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; preferably lithium hydroxide or lithium hydroxide monohydrate.

[0345] The reactions described above are preferably carried out in a solvent, which may include, but is not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. Detailed Implementation

[0346] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0347] MS measurements were performed using a Finnigan LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0348] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0349] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0350] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0351] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0352] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0353] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0354] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0355] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0356] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0357] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0358] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0359] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0360] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0361] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0362] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0363] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0364] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0365] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, and D: ethyl acetate / dichloromethane / n-hexane. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0366] Example 1

[0367] 2-((4-(2-(benzo[d]thiazol-2-ylmethyl)benzo[d][1,3]dioxacyclopentan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutan-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0368]

[0369]

[0370] first step

[0371] 2-((4-bromobenzo[d][1,3]dioxacyclopentan-2-yl)methyl)benzo[d]thiazole 1b

[0372] Compound 2-ethynylbenzo[d]thiazole 1a (807 mg, 5.07 mmol, prepared by the method disclosed in intermediate S29 of Example 13 in patent application CN110627610A) was dissolved in toluene (10 mL), and 3-bromocatechol (958 mg, 5.07 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) and dodecyltriruthenium dodecylcarbonyl (64.8 mg, 101 μmol, Shanghai Titan Technology Co., Ltd.) were added. The mixture was stirred at 100 °C for 16 hours. After cooling and concentration, the residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (170 mg, yield: 9.6%) and compound 1c (48 mg, yield: 2.7%).

[0373] MS m / z(ESI): 349.8 [M+1].

[0374] Step 2

[0375] 4-(2-(benzo[d]thiazolyl-2-ylmethyl)benzo[d][1,3]dioxacyclopentan-4-yl)-3,6-dihydropiperidine-1(2H)-tert-butyl formate 1d

[0376] Compound 1b (170 mg, 0.49 mmol) was dissolved in 1,4-dioxane (10 mL), and 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-1-boronic acid pinacol ester (166 mg, 0.54 mmol), sodium carbonate (103 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (56 mg, 48 μmol), and water (2 mL) were added. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 4 hours. After cooling to room temperature, the solution was concentrated and purified by silica gel column chromatography with eluent system B to give title compound 1d (209 mg, yield: 95%).

[0377] MS m / z(ESI):451.1[M+1].

[0378] Step 3

[0379] 4-(2-(benzo[d]thiazolyl-2-ylmethyl)benzo[d][1,3]dioxane-4-yl)piperidine-1-carboxylic acid tert-butyl ester 1e

[0380] Compound 1d (209 mg, 0.46 mmol) was dissolved in ethyl acetate (20 mL), and 10% palladium on carbon (50 mg, 0.12 mmol) was added. The mixture was stirred for 3 hours at room temperature under hydrogen at 1 atm. After filtration, the filtrate was concentrated to give crude title compound 1e (161 mg). The product was used directly in the next step without purification.

[0381] MS m / z(ESI):453.0[M+1].

[0382] Step 4

[0383] 2-((4-(piperidin-4-yl)benzo[d][1,3]dioxane-2-yl)methyl)benzo[d]thiazole 4-methylbenzenesulfonate 1f

[0384] Compound 1e (91 mg, 0.20 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) was added, the mixture was stirred at room temperature for 14 hours, and concentrated under reduced pressure to obtain crude title compound 1f (105 mg). The product was used directly in the next step without purification.

[0385] MS m / z(ESI): 353.1 [M+1].

[0386] Step 5

[0387] 2-((4-(2-(benzo[d]thiazol-2-ylmethyl)benzo[d][1,3]dioxacyclopentan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutan-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid methyl ester 1h

[0388] Compound 1f (105 mg, 0.20 mmol) was dissolved in acetonitrile (5 mL), and 1 g (58 mg, 0.20 mmol, prepared by the method disclosed in intermediate 23 on page 69 of patent application WO2018109607A1) of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ester was added. Potassium carbonate (140 mg, 1.01 mmol) was added, and the mixture was heated to 50 °C and stirred for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (63 mg, yield: 51.5%).

[0389] MS m / z(ESI): 611.2 [M+1].

[0390] Step 6

[0391] 2-((4-(2-(benzo[d]thiazol-2-ylmethyl)benzo[d][1,3]dioxacyclopentan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutan-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid

[0392] Compound 1h (63 mg, 0.10 mmol) was dissolved in acetonitrile (5 mL), and lithium hydroxide monohydrate (3 mg, 0.07 mmol) and water (1 mL) were added at room temperature. The mixture was reacted at 40 °C for 16 hours. After cooling to room temperature, the pH was adjusted to 6–7 with 5% citric acid aqueous solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layers were combined and concentrated, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 1 (21 mg, yield: 35.2%).

[0393] MS m / z(ESI): 597.1 [M+1].

[0394] 1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),8.26(d,1H),8.05(dd,1H),7.97(d,1H),7.80(dd,1H),7.64( d,1H),7.48(tdd,1H),7.44–7.38(m,1H),6.75–6.69(m,3H),5.11–5.03(m,1H),4.75(ddd,1H),4.61 (ddd,1H),4.51–4.45(m,1H),4.36(dt,1H),3.93(d,1H),3.85(d,2H),3.77(d,1H),2.99(d,1H),2. 85(s,1H),2.74–2.66(m,1H),2.64–2.56(m,1H),2.44–2.35(m,1H),2.33–2.02(m,3H),1.72(d,4H).

[0395] Example 2

[0396] 2-((4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid 2

[0397]

[0398] first step

[0399] 4-Chloro-1-(2,2-Dimethoxypropyl)-2-fluorobenzene 2b

[0400] Compound 1-(4-chloro-2-fluorophenyl)prop-2-one 2a (1.0 g, 5.36 mmol) was dissolved in 4 mL of methanol, and trimethyl orthoformate (1.14 g, 10.71 mmol) and p-toluenesulfonic acid monohydrate (50.97 mg, 0.27 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 40 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give the title product 2b (1.1 g, yield: 88%).

[0401] Step 2

[0402] 4-Bromo-2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane 2c

[0403] Compound 2b (1.1 g, 4.73 mmol) was dissolved in 20 mL of toluene, followed by the addition of 3-bromocatechol (938 mg, 4.96 mmol, Leyan Technology) and p-toluenesulfonic acid monohydrate (45 mg, 0.24 mmol). Under nitrogen protection, the reaction flask was placed in an oil bath preheated to 90 °C and refluxed for 2 hours. After cooling to room temperature, the mixture was diluted with 25 mL of dichloromethane and then poured into 20 mL of saturated sodium bicarbonate solution. The mixture was extracted with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using eluent system B to give the title product 2c (0.66 g, yield: 39%).

[0404] Step 3

[0405] 4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2d

[0406] Compound 2c (300 mg, 0.84 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-1-boronic acid pinacol ester (311 mg, 1.01 mmol, Shaoyuan Technology Co., Ltd.), tetrakis(triphenylphosphine)palladium (97 mg, 83.9 μmol), and sodium carbonate (178 mg, 1.68 mmol) were dissolved in 28 mL of a mixture of 1,4-dioxane and water (V:V = 5:1). The mixture was heated to 90 °C under nitrogen protection and reacted at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 2d (370 mg, yield: 95.9%).

[0407] MS m / z(ESI):404.1[M-55].

[0408] Step 4

[0409] 4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane-4-yl)piperidine-1-carboxylic acid tert-butyl ester 2e

[0410] Compound 2d (370 mg, 0.8 mmol) was dissolved in 21 mL of a mixed solution of ethyl acetate and 1,2-dichlorobenzene (V:V = 20:1), and 10% palladium on carbon (43 mg, 0.4 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered, and the solvent was removed by concentration under reduced pressure to give the title compound 2e (370 mg, yield: 99%).

[0411] MS m / z(ESI):406.1 [M-55].

[0412] Step 5

[0413] 4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentan-4-yl)piperidine 2f

[0414] Compound 2e was dissolved in 3 mL of ethyl acetate, and p-toluenesulfonic acid monohydrate (335 mg, 1.76 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, 5 mL of saturated sodium bicarbonate solution was added to the reaction system, followed by extraction with 50 mL of ethyl acetate. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the title compound 2f (289 mg, yield: 99%).

[0415] MS m / z(ESI):362.1[M+1].

[0416] Step 6

[0417] 2-((4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester 2g

[0418] Compound 2f (289 mg, 0.8 mmol) and compound 1g (235 mg, 0.8 mmol) were mixed and dissolved in 20 mL of acetonitrile, followed by the addition of potassium carbonate (552 mg, 4.0 mmol), and the mixture was heated to 60 °C and reacted for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 2g (460 mg, yield: 93%).

[0419] MS m / z(ESI): 620.2 [M+1].

[0420] Step 7

[0421] 2-((4-(2-(4-chloro-2-fluorobenzyl)-2-methylbenzo[d][1,3]dioxapentane-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxecyclobutane-2-yl)methyl)-1H-benzo[d]imidazol-6-carboxylic acid 2

[0422] 2 g (60 mg, 96.7 μmol) of the compound was dissolved in 5 mL of acetonitrile, and 1 mL of water and lithium hydroxide monohydrate (41 mg, 967 μmol, Shaoyuan Technology Co., Ltd.) were added. The mixture was heated to 40 °C and reacted for 6 hours. After cooling, 2.5 M citric acid was added to adjust the pH to 5-6, and a white solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to give the title product 2 (32 mg, yield: 54%).

[0423] MS m / z(ESI): 606.2 [M+1].

[0424] 1 H NMR(500MHz,DMSO-d6)δ8.22(s,1H),7.81(d,1H),7.58(d,1H),7.35(q,2H),7.17(dd,1 H),6.74–6.53(m,3H),5.15-5.07(m,1H),4.82-4.73(m,1H),4.68-4.60(m,1H),4.51(q ,1H),4.44-4.36(m,1H),3.94(dd,1H),3.77(dd,1H),3.24(s,2H),3.01(d,1H),2.93-2 .70(m,3H),2.59-2.53(m,1H),2.48-2.42(m,1H),2.27-2.11(m,2H),1.82-1.55(m,6H).

[0425] Biological evaluation

[0426] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0427] I. Purpose of the Test

[0428] The purpose of this experiment was to test the agonistic activity of the compound molecule on the GLP-1 receptor, according to EC... 50 Size is used to evaluate the in vitro activity of molecules. This experiment used ONE-Glo TM ONE-Glo Luciferase Assay System TM Luciferase AssaySystem (Promega, E6110) activates the downstream signaling pathway of GLP-1R under the action of the compound molecule, leading to an increase in cAMP levels. cAMP binds to CRE, which can initiate the transcriptional expression of the downstream luciferase gene. Luciferase reacts with its substrate to emit fluorescence, which is detected by ONE-Glo TM The fluorescence signal measured by the reagent reflects the activity of the compound in activating the GLP-1 receptor.

[0429] II. Experimental Methods

[0430] A stable CHO-K1 / CRE-luc / GLP-1 receptor cell line was constructed (GLP-1 receptor plasmid was self-constructed; CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / GLP-1 receptor cells were digested, centrifuged, and resuspended. The single-cell suspension was mixed thoroughly and the viable cell density was adjusted to 2.5 × 10⁶ cells / year using cell culture medium (DME / F-12 + 10% FBS). 5 Cells / mL were added to a 96-well cell culture plate (Corning, #3903) at a rate of 90 μL / well. The plate was incubated for 16 hours (37°C, 5% CO2).

[0431] Dissolve the compound in DMSO to prepare a stock solution with an initial concentration of 20 mM. The initial concentration of the small molecule compound was 0.2 mM, diluted 3-fold, and diluted 10 times, with the 11th spot being DMSO. Take another 96-well plate, add 95 μL of cell culture medium (DME / F-12 + 10% FBS) to each well, then add 5 μL of the test sample at different concentrations to each well, mix well, and then add 10 μL / well of the test sample at different concentrations to the cell culture plate, with each sample in duplicate. Incubate the culture plate in an incubator for 6 hours (37°C, 5% CO2). Remove the 96-well cell culture plate and add 100 μL of ONE-Glo to each well. TM The reagents were incubated at room temperature for 10 minutes. The chemiluminescence was measured using an ELISA reader (EnVision 2105, PE).

[0432] III. Data Analysis

[0433] The data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. The EC values ​​of the compounds disclosed in this paper were obtained. 50 The values ​​are shown in Table 1 below.

[0434] Table 1. EC5 values ​​of the GLP-1 receptor agonistic activity of the disclosed compounds. 50

[0435] Example number <![CDATA[EC 50 (nM)]]> Emax% 1 0.15 105 2 0.75 108

[0436] Conclusion: The compound disclosed herein exhibits high agonistic activity against the GLP-1 receptor.

Claims

1. A compound of general formula (II-1), or a pharmaceutically acceptable salt thereof: in: for or ; R 1 It is a hydrogen atom; R 2 C 1-6 Alkyl; wherein the C 1-6 The alkyl group may be optionally substituted with a 3- to 6-membered heterocyclic group; R 3 It is a hydrogen atom; R 4 It is a hydrogen atom; R 5a It is a hydrogen atom or a carbon atom. 1-6 alkyl; Each R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl; R 9 It is a hydrogen atom; g is 0, 1, or 2; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p can be 0, 1, 2, or 3.

2. The compound of general formula (II-1) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 for .

3. The compound of general formula (II-1) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5a It can be a hydrogen atom or a methyl group.

4. The compound of general formula (II-1) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 It can be a hydrogen atom or a halogen.

5. The compound of general formula (II-1) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: and .

6. A compound of general formula (II-1A), or a pharmaceutically acceptable salt thereof, in: R w C 1-6 alkyl; Rings A and R 1 To R 4 R 5a R 6 R 9 n, m, p and g are as defined in claim 1.

7. The compound of general formula (II-1A) according to claim 6, or a pharmaceutically acceptable salt thereof, selected from the following compounds: and .

8. A method for preparing a compound of general formula (II-1) according to claim 1, or a pharmaceutically acceptable salt thereof, the method comprising: Compounds of general formula (II-1A) undergo hydrolysis to give compounds of general formula (II-1) or their pharmaceutically usable salts; in: R w C 1-6 alkyl; Rings A and R 1 To R 4 R 5a R 6 R 9 n, m, p, and g are as defined in claim 1.

9. A pharmaceutical composition comprising a compound of formula (II-1) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of the compound of general formula (II-1) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for activating GLP-1 receptors.

11. Use of the compound of general formula (II-1) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for the treatment and / or prevention of GLP-1 receptor-mediated type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis, Parkinson's disease, dementia, and insulin resistance.

12. The use according to claim 11, wherein the drug is a drug for treating and / or preventing type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, hepatic insulin resistance, and cardiovascular disease.

13. Use of the compound of general formula (II-1) according to any one of claims 1 to 5, or a pharmaceutically usable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for the treatment and / or prevention of GLP-1 receptor-mediated idiopathic type 1 diabetes mellitus, latent immune diabetes mellitus in adults (LADA), young adult-onset diabetes mellitus (MODY), gestational diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary heart disease.

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