TW202214610A - 6-oxo-3,6-dihydropyridine derivative, preparation method thereof, and medical use thereof - Google Patents

Abstract

The present disclosure relates to 6-oxo-3,6-dihydropyridine derivatives, their preparation methods and their medical use thereof. Specifically, the present disclosure relates to a 6-oxo-3,6-dihydropyridine derivative as shown in general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of same as a therapeutic agent, in particular the use thereof as a GLP-1 receptor agonist, and the use thereof in the preparation of drugs for the treatment and/or prevention of diabetes.

Description

6-Oxygen-3,6-dihydropyridine derivatives, their preparation method and their application in medicine

The present disclosure belongs to the field of medicine, and relates to a 6-oxo-3,6-dihydropyridine derivative, its preparation method and its application in medicine. In particular, the present disclosure relates to the 6-oxo-3,6-dihydropyridine derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as GLP-1 Use of receptor agonists in the treatment of diabetes.

Diabetes mellitus is a multi-causal metabolic disease characterized by chronic hyperglycemia accompanied by disturbances in glucose, lipid and protein metabolism due to defects in insulin secretion or action. Diabetes mellitus is a very old disease. It is caused by the absolute or relative lack of insulin in the human body. The glucose concentration in the blood increases, and then a large amount of sugar is excreted from the urine, resulting in symptoms such as polydipsia, polyuria, polyphagia, and weight loss.

Generally speaking, there are two types of diabetes. People with type 1 diabetes, known as insulin-dependent diabetes, produce little or no insulin themselves. Insulin is a hormone that the body uses to regulate glucose utilization. Type II diabetics, ie insulin-independent diabetics, have plasma insulin levels that are the same as or higher than non-diabetic patients. However, such patients are resistant to insulin, These insulins stimulate glucose and lipid metabolism in major insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even elevated plasma insulin levels do not overcome the patient's marked resistance to insulin.

Insulin resistance is caused by a decrease in the number of insulin receptors as well as insulin receptor defects, the mechanism of which has not been fully understood so far. Insulin-responsive resistance results in the inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, and to effectively inhibit adipose tissue lipolysis and hepatic glucose production and secretion.

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

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

The disclosed GLP-1 receptor small molecule agonist patent applications include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1, and WO2018056453A1, among others.

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

in,

G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁶ or N;

W ¹ and W ² are the same or different, and are each independently selected from O atom, S atom, NR ⁷ and CR ⁸ R ⁹ ;

R ¹ is selected from hydrogen atom, alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl , wherein the alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkane alkenyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more of the substituents in;

R ² are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl;

R ³ are the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl;

R ⁴ is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl;

R ⁵ is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl;

R ⁶ is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl;

R ⁷ is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, amine group, hydroxyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group;

R ⁸ and R ⁹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine radical, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1, 2 or 3;

t is 0, 1, 2, or 3; and

p is 0, 1, 2, 3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I-1) or (I-2) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in,

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , n, p and t are as defined in general formula (I).

In some embodiments of the present disclosure, the compounds represented by the general formula (I), the general formula (I-1) and the general formula (I-2) or their tautomers, mesomers, racemates isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁶ ; wherein, the R ⁶ are the same or different, and each is independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), the general formula (I-1) and the general formula (I-2) or their tautomers, mesosomes, exoisomers Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G ¹ , G ² and G ³ are CH.

In some preferred embodiments of the present disclosure, the compounds represented by the general formula (I), the general formula (I-1) and the general formula (I-2) or their tautomers, mesosomes, exoisomers Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein W ¹ and W ² are O atoms.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in,

R ¹ to R ⁵ , n, p and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II-1) or (II-2) or a tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in,

R ¹ to R ⁵ , n, p and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound represented by (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof , wherein R ⁴ is C _1-6 alkyl.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound represented by (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof , wherein, R ⁴ is a C _1-6 alkyl group; preferably, the C _1-6 alkyl group is a methyl group.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound represented by (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof , wherein R ¹ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from halogen, hydroxyl, C _1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 substituted with one or more substituents in the membered heterocyclyl.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound represented by (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof , wherein R ¹ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from halogen, hydroxyl, C _1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 substituted with one or more substituents in the membered heterocyclic group; preferably, the C _1-6 alkyl group is substituted with a 3- to 6-membered heterocyclic group; more preferably, the C _1-6 alkyl group is methyl , the 3- to 6-membered heterocyclic group is an oxetanyl group.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ² is the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is the same or different, and each is independently a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ³ is selected from C _1-6 alkyl, hydrogen atom and halogen.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ³ is a hydrogen atom or a halogen.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ⁵ is the same or different, and each is independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is the same or different, and each is independently halogen.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, where p is 2.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II) -2) The compound represented by 2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ¹ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from halogen, hydroxyl, C _1-6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered substituted by one or more substituents in the heterocyclic group; R ² is the same or different, each independently a hydrogen atom or a C _1-6 alkyl group; R ³ is a hydrogen atom or a halogen; R ⁴ is a C _1-6 alkane R ⁵ is the same or different, and each is independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group.

Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure pertains to compounds of formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,

in,

R ^w is C _1-6 alkyl;

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1) or (IA-2) or a tautomer, meso, racemate, enantiomer, unpaired an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

R ^w is C _1-6 alkyl;

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

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

in,

R ^w is C _1-6 alkyl;

R ¹ to R ⁵ , p, t and n are as defined in general formula (IA).

Another aspect of the present disclosure relates to the compound represented by general formula (IIA-1) or (IIA-2) or its tautomer, meso, racemate, enantiomer, unpaired an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

R ^w is C _1-6 alkyl;

R ¹ to R ⁵ , p, t and n are as defined in general formula (IA).

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

Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

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

in,

R ^w is C _1-6 alkyl;

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (I-1) or (I-2) or its tautomer, meso, racemate, enantiomer, A method for a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (I) is subjected to chiral separation to obtain the compound of general formula (I-1) or (I-2),

in,

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

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

in,

R ^w is C _1-6 alkyl;

R ¹ to R ⁵ , p, t and n are as defined in general formula (II).

Another aspect of the present disclosure relates to a preparation of the compound represented by the general formula (II-1) or (II-2) or its tautomer, meso, racemate, enantiomer, A method for a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (II) is subjected to chiral separation to obtain the compound of general formula (II-1) or (II-2),

in,

R ¹ to R ⁵ , p, t and n are as defined in general formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), the general formula (I-1), the general formula (I-2), the general formula (II), the general formula (II-1), the compound represented by general formula (II-2) and Table A or its tautomer, meso, racemate, enantiomer, diastereomer or In admixture, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and table The compound represented by A, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound thereof Use of the pharmaceutical composition in the preparation of a medicament for agonizing GLP-1 receptors.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and table The compound represented by A, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound thereof The pharmaceutical composition is prepared for the treatment and/or prevention of type I diabetes mellitus, type II diabetes mellitus, latent immune diabetes mellitus in adults (LADA), adult-onset diabetes mellitus in the young (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, Use in medicaments for diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance; It is preferably used in the preparation of medicines for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease; wherein, the type I diabetes is preferably is idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance; the cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.

The present disclosure also relates to a method for agonizing the GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (I-1), formula (I-2), formula ( II), the compounds of general formula (II-1), general formula (II-2) and Table A or their tautomers, mesomers, racemates, enantiomers, non-pairs An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a treatment and/or prevention of type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), adult-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetes complicated by A method for treating obesity, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance; preferably A method for preventing type I diabetes, type II diabetes, obesity, diabetic complications, nonalcoholic steatohepatitis or cardiovascular disease, wherein the type I diabetes is preferably idiopathic type I diabetes; the insulin resistant Preferably it is hepatic insulin resistance; the cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease; it comprises administering to a patient in need a therapeutically effective amount of formula (I), Compounds of general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A or their tautomers , meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and The compounds shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or containing Its pharmaceutical composition, which is used as a medicine.

The present disclosure also relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and table The compound represented by A or its tautomer, meso, racemic isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as GLP-1 receptor agonists.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and table The compound represented by A, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound thereof A pharmaceutical composition for the treatment and/or prevention of type I diabetes mellitus, type II diabetes mellitus, latent immune diabetes mellitus in adults (LADA), adult-onset diabetes mellitus in the young (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, Diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance; more preferably type I Diabetes, type II diabetes, obesity, diabetic complications, nonalcoholic steatohepatitis or cardiovascular disease; wherein, the type I diabetes is preferably idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance The cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.

A "diabetic complication" is a complication caused by diabetes or hyperglycemia, and it may be an acute complex or a chronic complex. The term "acute complex" includes ketoacidosis and infectious diseases (eg, skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), and "chronic complexes" includes, eg, microangiopathy (eg disease), neuropathy (eg, sensory, motor, autonomic), and gangrene. The major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

"Coronary heart disease" includes myocardial infarction and angina pectoris.

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

The active compounds may be formulated in a form suitable for administration by any suitable route of hydrocarbon administration by conventional methods using one or more pharmaceutically acceptable carriers to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure can also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds are preferably presented in unit doses or in such a manner that the patient can self-administer in a single dose. Unit doses of a compound or composition of the present disclosure can be expressed as tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstituted powders, or liquids. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients and the like. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in 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 or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, The behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, the severity of the disease, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to traditional treatment protocols.

Glossary

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyhexyl Methylpentyl, 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-diethyl Hexyl, and its various branched chain isomers, etc. More preferably lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, th Dibutyl, 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-methyl pentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently and optionally selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 A straight or branched chain group having up to 20 carbon atoms, preferably an alkylene group having 1 to 12 carbon atoms, more preferably an alkylene group having 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylidene ( _-CH2- ), 1,1-ethylidene (-CH( _CH3 )-), 1,2-ethylidene ( _-CH2) CH ₂ )-, 1,1-propylidene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3-propylidene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from the group consisting of alkenyl, alkynyl, alkoxy group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more substituents of heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkane One or more substituents of oxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkane One or more substituents of oxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably containing 3 to 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between the single rings, which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as mono-spirocycloalkyl, double-spirocycloalkyl, or poly-spiro Cycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl. More preferably 3-member/5-member, 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain a or multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has complete Conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

、

和

等；較佳為

和

The cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached Rings together are cycloalkyl, non-limiting examples include

,

and

etc.; preferably

and

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituent is independently optionally selected from halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents in the group.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy group can be optionally substituted or unsubstituted, and when substituted, its substituent is preferably one or more of the following groups, which are independently selected from D atom, halogen, alkoxy, haloalkyl , one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or multiple substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur , the sulphur may be optionally oxygenated (i.e. to form sub- or s-), but does not include ring moieties of -O-O-, -O-S- or -S-S-, The remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), wherein 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contain 3 to 6 ring atoms, wherein 1-3 are heteroatoms; most preferably Contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine base, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, and one atom (called a spiro atom) is shared between the single rings, wherein one or more ring atoms are selected from nitrogen, oxygen and sulfur. A heteroatom, the sulfur can be optionally oxygen pendant (ie, to form arsenic or arsenic), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably 3-member/5-member, 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" 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, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, optionally with pendant oxygen (i.e., to form a susceptor or selenium). ) and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur optionally being pendant oxygen (ie, to form arsenic or arsenic), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes the above-mentioned heterocyclyl (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring, wherein, with the parent The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents in the group.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :

Aryl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, preferably independently and optionally selected from the group consisting of halogen, alkyl, alkoxy, Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents in .

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

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently and optionally selected from halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents in the group.

The aforementioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derivative residues, namely "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroaryl".

The term "amine protecting group" is used to protect the amine group with a group that is easy to remove in order to keep the amine group unchanged when the other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxy methyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, etc. These groups are optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro. The amino protecting groups are preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.

The term "hydroxyl protecting group" is a suitable group known in the art for hydroxyl protection, see literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C _1-10 alkyl or aryl) ₃ silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; can be C _1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 alkoxy C _{1-6 alkyl substituted by phenyl group or C 1-6 alkyl} substituted by phenyl, preferably C _1-4 alkyl substituted by C _1-4 alkoxy, for example: methyl, tert-butyl, Allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C _1-10 alkyl or aryl) acyl, For example: formyl, acetyl, benzyl, p-nitrobenzyl, etc.; can be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; can also be (C _1-6 alkoxy or C _6-10 aryloxy)carbonyl. The hydroxyl protecting group is preferably p-nitrobenzyl.

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

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

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

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

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

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

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

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

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

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

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

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

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "pendant oxygen" or "pendant oxygen" refers to "=O".

The term "carbonyl" refers to C=O.

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

The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, there are structures of the present disclosure, except that "deuterium" or "tritium" is used in place of hydrogen, or ^18F -fluorine label ( ^18F isotope) is used instead of fluorine, ^or11C- , ^13C- , ^or14C -rich Compounds that set carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein, the deuterated form of the compound is that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using general techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

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

"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted with the corresponding number of substituents. Those of ordinary skill in the art can determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

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

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in a case can be determined by those with ordinary knowledge in the art based on general experiments.

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

As used herein, the singular forms "a" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and sometimes preferably within ±5%. As usual in the technical field The knowledgeable person will understand that when parameters are not critical, numbers are usually given for illustrative purposes only, not limitations.

Synthetic methods of compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable form The preparation method of the salt comprises the following steps:

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

in,

R ^w is C _1-6 alkyl;

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

Option II

The compound represented by the general formula (I-1) or (I-2) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or The preparation method of its mixture form or its pharmaceutically acceptable salt, comprises the following steps:

The compound of general formula (I) is separated by chiral HPLC to obtain the compound of general formula (I-1) or (I-2),

in,

G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in general formula (I).

third solution

The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable form The preparation method of the salt comprises the following steps:

The compound of general formula (IIA) undergoes a hydrolysis reaction in the presence of a basic reagent to obtain the compound of general formula (II)

in,

R ^w is C _1-6 alkyl;

R ¹ to R ⁵ , p, t and n are as defined in general formula (II).

Option 4

The compound represented by the general formula (II-1) or (II-2) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or The preparation method of its mixture form or its pharmaceutically acceptable salt, comprises the following steps:

The compound of general formula (II) is separated by chiral HPLC to obtain the compound of general formula (II-1) or (II-2),

in,

R ¹ to R ⁵ , p, t and n are as defined in general formula (II).

In the hydrolysis reaction, alkaline reagents include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N -diisopropylethylamine, n-butyllithium, diisopropylamine Lithium, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, Lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably lithium hydroxide or lithium hydroxide monohydrate.

The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate , n-hexane, dimethylsulfoxide, 1,4-dioxane, water, N,N -dimethylformamide and mixtures thereof.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[Example]

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10&lt;&quot; ⁶ &gt; (ppm). NMR was measured by Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl Silane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector) or THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral separation was performed using a Shimadzu LC-20AP preparative chromatograph.

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm to 0.2mm, and the specification used for TLC separation and purification products is 0.4 mm to 0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Accela ChemBio Inc. Darui Chemicals and other companies.

There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

Pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, ranging from 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography method include: : A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of solvent It can be adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-6-oxygen -3,6-Dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H-benzo[ d ]imidazole-6-carboxylic acid 1

first step

4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-6-oxo-3,6 - Dihydropyridine-1( 2H )-carboxylate tert-butyl ester 1c

Compound 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane 1a (287 mg, 0.84 mmol, using patent application WO2019239319A1 ( See the description on page 56 of the intermediate C4) disclosed method prepared), compound 6-side oxygen-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Cyclo-2-yl)-3,6-dihydropyridine-1( 2H )-carboxylate tert-butyl ester 1b (387 mg, 1.20 mmol, using patent application WO2011133733A1 (see description page 67 intermediate 6-12) prepared by the disclosed method) was dissolved in 10 mL of dioxane and 2 mL of water, sodium carbonate (266 mg, 2.51 mmol), tetrakistriphenylphosphine palladium (97 mg, 83.94 μmol) were added, and the mixture was stirred at 90° C. for 16 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product 1c (212 mg, yield: 55.2%).

MS m/z (ESI): 403.9 [M-55].

second step

4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-5,6-dihydropyridine- 2( 1H )-keto-p-toluenesulfonate 1d

Compound 1c (212 mg, 0.46 mmol), p-toluenesulfonic acid monohydrate (219 mg, 1.15 mmol) was dissolved in 20 mL of ethyl acetate and stirred at 60°C for 2 hours. Concentration under reduced pressure gave the crude title product 1d (245 mg, p-toluenesulfonate), which was used in the next reaction without purification.

MS m/z (ESI): 359.9 [M+1].

third step

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-6-oxygen -3,6-Dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H-benzo[ d ]imidazole-6-carboxylate methyl ester 1f

Compound 1d (150 mg, 0.213 mmol, p-toluenesulfonate) was dissolved in 10 mL of toluene, sodium hydride (34 mg, 0.85 mmol) was added at room temperature, refluxed and stirred for 1 hour, cooled to room temperature, and compound ( S )-2 was added -(chloromethyl)-1-( oxetan -2-ylmethyl)-1H-benzo[ d ]imidazole-6-carboxylate methyl ester 1e (63 mg, 0.213 mmol, using patent application WO2018109607A1 (prepared by the method disclosed in Intermediate 23) on page 69 of the specification), and stirred at room temperature for 20 hours. Add 10 mL of ice water to quench, extract with ethyl acetate (20 mL×3), wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. After concentration under reduced pressure, it was purified by silica gel column chromatography with eluent system A to obtain the title product 1f (55 mg, yield: 41.7%).

MS m/z (ESI): 617.9 [M+1].

the fourth step

2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-6-oxygen -3,6-Dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H-benzo[ d ]imidazole-6-carboxylic acid 1

Compound 1f (55 mg, 89 μmol) was dissolved in a mixed solvent of water, methanol and tetrahydrofuran (V:V:V=2:3:5), and lithium hydroxide monohydrate (37.4 mg, 0.89 mmol) was added at room temperature. under stirring for 16 hours. The pH of the citric acid solution was adjusted to 5 to 6, part of the solvent was removed by rotary evaporation under reduced pressure, 2 mL of N , N -dimethylformamide was added, and after dissolving, high performance liquid chromatography (Waters-2767, chromatography column: Boston Phlex Prep C18 5μm 30*150mm; mobile phase: water (10mM NH ₃ HCO ₃ ); 26%-46% acetonitrile gradient elution in 20min, flow rate: 30mL/min; detection wavelength: 214&254nm) Purification to obtain the title product 1 (35 mg, yield: 65.1%).

MS m/z (ESI): 604.0 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.75 (s, 1H), 8.30-8.23 (m, 1H), 7.82 (dd, 1H), 7.66 (d, 1H), 7.62-7.55 (m, 2H) ,7.38(dd,1H),7.12-6.98(m,2H),6.98-6.91(m,1H),6.51(dd,1H),5.13-4.99(m,2H),4.88(d,1H),4.76 (dd,1H),4.61(dt,1H),4.51-4.43(m,1H),4.36(dt,1H),3.68(t,2H),2.91-2.77(m,2H),2.76-2.65(m , 1H), 2.40-2.30 (m, 1H), 2.09 (s, 3H).

Example 2

2-((4-(2-(4-Chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane-4-yl)- 6-oxo-3,6-dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H- Benzo[ d ]imidazole-6-carboxylic acid 2

first step

4-Bromo-2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane 2a

The compound 3-bromo-4-fluorobenzene-1,2-diol (10g, 48.3mmol, Wuxi Jiehua Pharmaceutical Technology Co., Ltd.), 4-chloro-2-fluoroacetophenone (9.17g, 53.1mmol, Shao Yuan Technology (Shanghai) Co., Ltd.), p-toluenesulfonic acid monohydrate (275 mg, 1.45 mmol) was dissolved in 100 mL of toluene, and the mixture was refluxed for 24 hours. Concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain the title product 2a (1.5 g, yield: 8.5%).

second step

4-(2-(4-Chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-6-oxygen -3,6-Dihydropyridine-1( 2H )-carboxylate tert-butyl ester 2b

Using the synthetic route of Example 1, the first step starting material 1a was replaced with starting material 2a to obtain the title product 2b (620 mg, yield: 64.4%).

MS m/z (ESI): 422.1 [M-55].

third step

4-(2-(4-Chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane-4-yl)-5,6- Dihydropyridin-2( 1H )-one p-toluenesulfonate 2c

Using the synthetic route of Example 1, replacing the starting material 1c in the second step with the starting material 2b , the title product 2c (946 mg, yield: 99.9%) was obtained.

MS m/z (ESI): 378.1 [M+1].

the fourth step

2-((4-(2-(4-Chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane-4-yl)- 6-oxo-3,6-dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H- Benzo[ d ]imidazole-6-carboxylate methyl ester 2d

Using the synthetic route of Example 1, the raw material 1d in the third step was replaced with the raw material 2c to obtain the title product 2d (55 mg, yield: 78.0%).

MS m/z (ESI): 636.1 [M+1].

the fifth step

2-((4-(2-(4-Chloro-2-fluorophenyl)-5-fluoro-2-methylbenzo[ d ][1,3]dioxolane-4-yl)- 6-oxo-3,6-dihydropyridin-1( 2H )-yl)methyl)-1-((( S ) -oxetan -2-yl)methyl)-1H- Benzo[ d ]imidazole-6-carboxylic acid 2

Using the synthetic route of Example 1, replacing the raw material 1f of the fourth step with the raw material 2d , the title product 2 (26 mg, yield: 53.1%) was obtained.

MS m/z (ESI): 622.3 [M+1].

¹ H NMR (500MHz, DMSO- d ₆ )δ 12.75(s,1H), 8.26(d,1H), 7.82(dd,1H), 7.69(d,1H), 7.63-7.55(m,1H), 7.38 (dd,1H),7.01(dd,1H),6.84-6.71(m,2H),6.18(s,1H),5.18-5.00(m,2H),4.90(dd,1H),4.82-4.71(m ,1H),4.62(dd,1H),4.51-4.43(m,1H),4.34(dd,2H),3.68(dd,2H),2.86-2.66(m,1H),2.42-2.30(m,2H ), 2.06(d, Hz, 3H).

Example 3

2-((4-(( R )-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)- 6-Oxy-3,6-dihydropyridin-1( 2H )-yl)methyl)-1-(( S ) -oxetan -2-ylmethyl)-1H-benzo [ d ] Imidazole-6-carboxylic acid 1-A

2-((4-(( S )-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[ d ][1,3]dioxolane-4-yl)- 6-Oxy-3,6-dihydropyridin-1( 2H )-yl)methyl)-1-(( S ) -oxetan -2-ylmethyl)-1H-benzo [ d ] Imidazole-6-carboxylic acid 1-B

Compound 1 (161 mg, 0.27 mmol) was subjected to chiral separation (separation conditions: chiral separation column CHIRALPAK IG 20*250 mm, 5 μm, mobile phase: hexane/EtOH(0.1%TFA)=70/30/(V/ V), flow rate: 20 mL/min), the corresponding fractions were collected and lyophilized to obtain the title products 1-A (45 mg) and 1-B (46 mg).

Single configuration compound 1-A (shorter retention time):

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

¹ H NMR (500MHz, DMSO- d ₆ )δ 12.48-12.88(brs,1H), 8.20-8.30(m,1H), 7.82(dd,1H), 7.66(d,1H), 7.51-7.63(m, 2H), 7.37(dd, 1H), 7.00-7.10(m, 2H), 6.89-6.97(m, 1H), 6.49(s, 1H), 4.96-5.12(m, 2H), 4.87(d, 1H) ,4.76(dd,1H),4.56-4.65(m,1H),4.41-4.50(m,1H),4.36(dt,1H),3.68(t,2H),2.74-2.94(m,2H),2.65 -2.73(m, 1H), 2.30-2.39(m, 1H), 2.08(s, 3H).

Chiral HPLC analysis: retention time 6.213 minutes, chiral purity: 100.0% (chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 μm; mobile phase: hexane/EtOH/TFA=95/5/0.1 (V/V /V), flow rate: 1.0 mL/min).

Single configuration compound 1-B (longer retention time):

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

¹ H NMR (500MHz, DMSO- d ₆ )δ 12.58-12.81(brs,1H), 8.23-8.30(m,1H), 7.82(dd,1H), 7.67(d,1H), 7.54-7.64(m, 2H), 7.37(dd, 1H), 7.00-7.12(m, 2H), 6.89-6.98(m, 1H), 6.50(s, 1H), 4.98-5.12(m, 2H), 4.87(d, 1H) ,4.76(dd,1H),4.56-4.66(m,1H),4.43-4.50(m,1H),4.36(dt,1H),3.68(t,2H),2.77-2.89(m,2H),2.67 -2.73(m, 1H), 2.32-2.38(m, 1H), 2.08(s, 3H).

Chiral HPLC analysis: retention time 8.280 minutes, chiral purity: 100.0% (chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 μm; mobile phase; hexane/EtOH/TFA=95/5/0.1 (V/V /V), flow rate: 1.0 mL/min).

Biological evaluation

Test Example 1. Evaluation of GLP-1 Receptor Agonistic Activity

1. Purpose of the test

The purpose of this experiment is to test the agonistic activity of the compound molecules on the GLP-1 receptor, and to evaluate the in vitro activity of the molecules according to the EC ₅₀ size. In this experiment, the ONE-Glo ^TM Luciferase Assay System (ONE-Glo ^TM Luciferase Assay System, Promega, E6110) was used. Under the action of the compound molecules, the downstream signaling pathway of GLP-1R was activated, resulting in an increase in the level of cAMP. The binding of CRE can initiate the transcriptional expression of the luciferase gene downstream of CRE, and the luciferase reacts with its substrate to emit fluorescence. The fluorescence signal is determined by ONE-Glo ^TM reagent to reflect the activity of the compound to stimulate the GLP-1 receptor.

2. Experimental method

Construct CHO-K1/CRE-luc/GLP-1 receptor stably transfected cell line (GLP-1 receptor plasmid self-built; CRE-luc plasmid Promega E8471). The CHO-K1/CRE-luc/GLP-1 receptor cells were digested, resuspended after centrifugation, the single cell suspension was mixed, and the viable cell density was adjusted to 2.5 with cell culture medium (DME/F-12+10% FBS). ×10 ⁵ cells/ml, 90 μL/well was added to a 96-well cell culture plate (Corning, #3903). The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 16 hours.

Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM. The starting concentration of small molecule compounds was 0.2 mM, 3-fold dilution, 10 points of dilution, and the 11th point was 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 different concentrations of the samples to be tested to each well, mix well, and then add 10 μL to the cell culture plate Different concentrations of samples to be tested per well, two replicate wells for each sample. The plates were incubated in an incubator (37°C, 5% _CO2 ) for 6 hours. Take out the 96-well cell culture plate, add 100 μL of ONE-Glo ^TM reagent to each well, and incubate at room temperature for 10 minutes. Chemiluminescence was measured with a microplate reader (EnVision 2105, PE).

3. Data analysis

Data were processed and analyzed using Microsoft Excel, Graphpad Prism 5. The _EC50 values of the compounds were obtained and the results are shown in Table 1 below.

Table 1 EC ₅₀ of the disclosed compounds for GLP-1 receptor agonistic activity

Conclusion: The disclosed compounds have good agonistic activity on GLP-1 receptor.

Claims (16)

A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt:

in, G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁶ or N; W ¹ and W ² are the same or different, and are each independently selected from O atom, S atom, NR ⁷ and CR ⁸ R ⁹ ; R ¹ is selected from hydrogen atom, alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl , wherein the alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkane alkenyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more of the substituents in; R ² are the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl; R ³ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl; R ⁴ is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl; R ⁵ is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro group, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, substituted with one or more substituents of heterocyclyl, aryl and heteroaryl; R ⁶ are the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, nitro radicals, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁷ is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, amine group, hydroxyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; R ⁸ and R ⁹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine radical, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2 or 3; t is 0, 1, 2, or 3; and p is 0, 1, 2, 3, 4 or 5. The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are CH. The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein W ¹ and W ² are O atoms. The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in, R ¹ to R ⁵ , n, p and t are as defined in claim 1 . The compound represented by general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkyl group. The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally selected from halogen, hydroxyl, C _1-6 alkane substituted by one or more substituents of oxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl. The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group. The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from C _1-6 alkyl, hydrogen atom and halogen. The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is the same or different, and each is independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group. The compound represented by the general formula (I) according to any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:

A compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

in, R ^w is C _1-6 alkyl; G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in claim 1 . The compound represented by the general formula (IA) according to claim 11 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof selected from:

A kind of preparation of the compound represented by the general formula (I) as described in claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (IA) undergoes a hydrolysis reaction to obtain the compound of general formula (I), in, R ^w is C _1-6 alkyl; G ¹ , G ² , G ³ , W ¹ , W ² , R ¹ to R ⁵ , p, t and n are as defined in claim 1 . A pharmaceutical composition containing the compound represented by the general formula (I) as described in any one of claims 1 to 10 or a tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament for agonizing GLP-1 receptors. The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 14 in preparation for the treatment and/or prevention of type I diabetes mellitus, type II diabetes mellitus, latent immune diabetes mellitus in adults (LADA ), Maturity-Onset Diabetes of the Young (MODY), Malnutrition-Associated Diabetes, Gestational Diabetes, Diabetic Complications, Obesity, Hyperglycemia, Glucose Intolerance, Cardiovascular Disease, Cerebral Infarction, Stroke, Non-Alcoholic Fat Use in a medicament for NAFLD, Parkinson's disease, dementia or insulin resistance; preferably in the manufacture of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic Use in medicines for steatohepatitis or cardiovascular disease; wherein, the type I diabetes is preferably idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance; the cardiovascular disease is preferably selected From atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.