CN113801136B

CN113801136B - Imidazo heteroaryl derivative, preparation method and application thereof in medicine

Info

Publication number: CN113801136B
Application number: CN202110659950.5A
Authority: CN
Inventors: 杨方龙; 刘继红; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-06-16
Filing date: 2021-06-15
Publication date: 2023-04-07
Anticipated expiration: 2041-06-15
Also published as: CN113801136A

Abstract

The disclosure relates to imidazoheteroaryl derivatives, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to an imidazoheteroaryl derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, in particular an application of the derivative as a GLP-1 receptor agonist and an application of the derivative in preparation of drugs for treating and/or preventing diabetes.

Description

Imidazo heteroaryl derivative, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to an imidazo heteroaryl derivative, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to an imidazoheteroaryl derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a GLP-1 receptor agonist in treating diabetes.

Background

Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in the metabolism of sugars, lipids and proteins due to defective insulin secretion or action. Diabetes is a very ancient disease, and is caused by the fact that the blood glucose concentration is increased due to the absolute or relative lack of insulin in a human body, and then a large amount of sugar is discharged from urine, and symptoms such as polydipsia, diuresis, polyphagia, emaciation and the like appear.

Generally, there are two types of diabetes. Type I diabetics, i.e. insulin dependent diabetics, produce little or no insulin themselves. Insulin is a hormone used in the body to regulate glucose utilization. Type II diabetics, i.e. insulin independent diabetics, have the same or higher plasma insulin levels than non-diabetic patients. However, such patients develop resistance to insulin, which stimulates glucose and lipid metabolism in major insulin-sensitive tissue cells, such as muscle, liver, adipose tissue, and the like. Even with elevated plasma insulin levels, the patient's significant resistance to insulin cannot be overcome.

In addition to insulin resistance resulting from a reduction in the number of insulin receptors, insulin receptor deficiency, a mechanism that has not been fully understood to date. The insulin-responsive resistance results in failure of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, to effectively inhibit lipolysis in adipose tissue, and to regulate glucose production and secretion in the liver.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells of the lower digestive tract. GLP-1 plays a corresponding role by binding with a specific receptor which is widely existed, and organs in which the GLP-1 receptor is definitely existed at present comprise islet cells, gastrointestinal tract, lung, brain, kidney, hypothalamus and cardiovascular system, and GLP-1 receptor may exist in liver, adipose tissue and skeletal muscle. GLP-1 not only acts on beta cells to promote insulin secretion, but also acts on alpha cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the response of beta cells to GLP-1 after eating is deficient, and under certain conditions, the response is obviously enhanced after the continuous infusion of GLP-1. Since the duration of action of human autologous GLP-1 is very short (intravenous t1/2 & lt 1.5 minutes), human autologous GLP-1 is not suitable for clinical treatment of diabetes.

Peptidic GLP-1 receptor agonists (e.g., liraglutide, exenatide, etc.) have utility in improving blood glucose in type II diabetic patients by reducing fasting and postprandial glucose. However, because of the poor oral bioavailability and inconvenience of taking peptidic GLP-1, it is highly desirable to develop agonists of the small molecule GLP-1 receptor with good oral bioavailability.

Published GLP-1 receptor small molecule agonist patent applications include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1, WO2018056453A1, and the like.

Disclosure of Invention

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

wherein:

q is Q1 or Q2,

ring B is a 5-membered heteroaryl;

ring a is 6-membered aryl or 5-to 6-membered heteroaryl;

m is N atom or C atom;

is a single bond or a double bond; when M is N atom, is selected>

Is a single bond, when M is a C atom>

Is a single bond or a double bond;

y is selected from the group consisting of O atom, S atom, NR ⁷ And CR ¹⁰ R ¹¹ ；

Z ¹ 、Z ² 、Z ³ And Z ⁴ Are the same or different and are each independently CR ⁸ Or N;

W ¹ and W ² Are the same or different and are each independently selected from the group consisting of an O atom, an S atom, NR ⁹ And CR ¹² R ¹³ ；

R ^m And R ⁿ Together form = O;

or R ^m And R ⁿ The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^a and R ^b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a,Alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ selected from the group consisting of hydrogen atoms, alkyl groups, heterocyclylalkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, heterocyclylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ² the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ³ and R ⁶ The same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with a substituent selected from the group consisting of halogenOne or more substituents selected from the group consisting of aryl, heteroaryl, aryl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁴ selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

R ⁷ and R ⁹ The same or different and each is independently selected from the group consisting of hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, amino group, hydroxyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ⁸ the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ¹⁰ 、R ¹¹ 、R ¹² and R ¹³ The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1,2,3 or 4;

m is 0, 1,2,3, 4 or 5;

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

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

In some preferred embodiments of the present disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is thienyl.

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

wherein:

R ¹ 、R ² 、R ^m 、R ⁿ m, Q and n are as defined in formula (I).

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ^m And R ⁿ Together form = O; or R ^m And R ⁿ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compounds represented by formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein

Selected from the group consisting of: />

R ² And n is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Z is ¹ 、Z ² And Z ³ Is CR ⁸ ，Z ⁴ Is a N atom, R ⁸ Are the same or different and are each independently a hydrogen atom or a halogen; and/or Y is an O atom.

In some preferred embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is ¹ And W ² Is an O atom.

In some preferred embodiments of the present disclosure, the compounds represented by general formula (I) and general formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring a is phenyl.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Q is Q3 or Q4:

r is 0, 1,2 or 3;

R ³ to R ⁶ 、R ⁸ 、R ^a 、R ^b M, p and t are as defined in formula (I).

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ¹ Is C _1-6 Alkyl radical, wherein said C _1-6 Alkyl is optionally selected from halogen, hydroxy, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ¹ Is C _1-6 Alkyl radical, wherein said C _1-6 Alkyl is optionally selected from halogen, hydroxy, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; preferably, said C _1-6 Alkyl is substituted with a 3 to 6 membered heterocyclyl; more preferably, C is _1-6 Alkyl is methyl and the 3-to 6-membered heterocyclyl is oxetanyl.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ² Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ² The same or different, each independently a hydrogen atom.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers thereofA structure, meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ^a And R ^b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ^a And R ^b Are the same or different and are each independently a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ³ And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and cyano.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ³ And R ⁶ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen and a cyano group.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is C _1-6 An alkyl group.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is ⁴ Is methyl.

In some embodiments of the disclosure, the compound is a compound of formula (I)A compound of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Are the same or different and are each independently a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁸ Are the same or different and are each independently a hydrogen atom or a halogen.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 2.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Q is Q3;

is->

Wherein R is ² Are the same or different and are each independently a hydrogen atom or C _1-6 Alkyl, n is as defined in formula (I); r ¹ Is C _1-6 Alkyl radical, wherein said C _1-6 Alkyl is optionally selected from halogen, hydroxy, C _1-6 Alkoxy radical,3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; r ^a And R ^b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; r ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and cyano; r ⁸ The same or different, and each independently is a hydrogen atom or a halogen.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Q is Q4;

is->

Wherein R is ² Are the same or different and are each independently a hydrogen atom or C _1-6 Alkyl, n is as defined in formula (I); r ¹ Is C _1-6 Alkyl radical, wherein said C _1-6 Alkyl is optionally selected from halogen, hydroxy, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; r ⁴ Is C _1-6 An alkyl group; r is ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; r is ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and cyano.

Table a typical compounds of the present disclosure include, but are not limited to:

/>

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to compounds of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ^w is C _1-6 An alkyl group;

ring B, R ¹ 、R ² 、R ^m 、R ⁿ M, Q and n are as defined in formula (I).

Another aspect of the present disclosure relates to compounds of formula (IIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ^w is C _1-6 An alkyl group;

R ¹ 、R ² 、R ^m 、R ⁿ m, Q and n are as defined in formula (II).

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

/>

Another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

R ^w is C _1-6 An alkyl group;

ring B, R ¹ 、R ² 、R ^m 、R ⁿ M, Q and n are as defined in formula (I).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

R ^w is C _1-6 An alkyl group;

R ¹ 、R ² 、R ^m 、R ⁿ m, Q and n are as defined in formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), and table a, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II) and table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for agonizing a GLP-1 receptor.

The present disclosure further relates to the use of a compound of formula (I), formula (II) and table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the manufacture of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), juvenile adult onset diabetes Mellitus (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, nonalcoholic fatty liver disease (NAFLD), parkinson's disease, dementia or insulin resistance; preferably for the manufacture of a medicament for the treatment and/or prevention of a disease selected from type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic 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.

The present disclosure also relates to a method of agonizing the GLP-1 receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) and table a or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), juvenile adult onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), parkinson's disease, dementia, insulin resistance, and hepatic insulin resistance; preferably a method for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular diseases, wherein said type I diabetes is preferably idiopathic type I diabetes; the insulin resistance is preferably hepatic insulin resistance; (ii) a The cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) and Table A, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to compounds of general formula (I), general formula (II) and table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of formula (I), formula (II) and table a or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are useful as GLP-1 receptor agonists.

The present disclosure further relates to compounds of formula (I), formula (II) and table a or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), juvenile adult onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, nonalcoholic fatty liver disease (NAFLD), parkinson's disease, dementia or insulin resistance; more preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic 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.

"diabetic complications" are complications arising from diabetes or hyperglycemia, and may be acute or chronic complexes. The term "acute complex" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, infections of the biliary system, respiratory infections, urinary tract infections), "chronic complex" includes, for example, microangiopathies (e.g., nephropathy, retinopathy), neuropathies (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders) 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, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in 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.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. Suitable unit doses may be from 0.1 to 1000mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

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

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

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

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The 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 parenterally acceptable non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and 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 water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug 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 drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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 an alkyl group containing 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2-) 1, 1-ethylene (-CH (CH 3) -), 1, 2-ethylene (-CH 2CH 2) -, and 1, 1-propylene (-CH (CH 2CH 3) -), 1, 2-propylene (-CH 2CH (CH 3) -), and 1, 3-propylene (-CH 2CH2CH 2-), 1, 4-butylene (-CH 2CH2CH2CH 2-), and the like. The alkylene group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio and oxo.

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

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, are preferably one or more groups independently selected from one or more substituents of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, 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 from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 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, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More 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 or 5-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic 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 of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring withThe rings to which the parent structures are attached are cycloalkyl, non-limiting examples of which include

Etc.; preferably->

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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 groups. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, are preferably one or more substituents independently selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but which does not include the cyclic portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 (e.g. 1,2,3 and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3, 4,5, 6, 7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiro heterocyclyl groups 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 the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulphur, which may optionally be oxo (i.e. form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and so on.

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

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

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

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

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

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived from the parent ring atom by the removal of one hydrogen atom, or those derived from the parent ring atom by the removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro. The amino protecting groups are preferably (trimethylsilyl) ethoxymethyl and tert-butyloxycarbonyl.

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5) ^Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group may be (C) _1-10 Alkyl or aryl) ₃ Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy-substituted C _1-6 Alkyl or phenyl substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy-substituted C _1-4 Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C) _1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; or (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl. The hydroxyl protecting group is preferably p-nitrobenzoyl.

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 the 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 an alkyl-S-group 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 the alkoxy group 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 hydroxyl 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 "mercapto" refers to-SH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= 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), -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 contain other isotopic derivatives. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the disclosure except for replacing hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enrichment carbon (C) of (C) ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or may be used as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the compound in deuterated form attached to a carbon atom is independently replaceable with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain comparable activity to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

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

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

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

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective for use in the body of a mammal and which has the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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

As used herein, the singular forms "a," "an," 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 meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

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

scheme one

The preparation method of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form or a pharmaceutically acceptable salt form thereof comprises the following steps:

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

Wherein:

R ^w is C _1-6 An alkyl group;

ring B, R ¹ 、R ² 、R ^m 、R ⁿ M, Q and n are as defined in formula (I).

Scheme two

The preparation method of the compound shown in the general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form or a pharmaceutically acceptable salt form thereof comprises the following steps:

subjecting the compound of formula (IIA) to hydrolysis reaction in the presence of a basic agent to obtain a compound of formula (II)

Wherein:

R ^w is C _1-6 An alkyl group;

R ¹ 、R ² 、R ^m 、R ⁿ m, Q and n are as defined in formula (II).

The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; lithium hydroxide or lithium hydroxide monohydrate is preferred.

The above reaction is preferably carried out in a solvent including, but 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-dimethylformamide and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) at 10 ^-6 (ppm) of a monomerThe bit is given. NMR was measured using Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

For MS measurement, agilent 1200/1290DAD-6110/6120Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: agilent, MS model: 6110/6120Quadrupole MS), water ACQuority UPLC-QD/SQD (manufacturer: waters, MS model: water ACQuority Qda Detector/waters SQ Detector) or THERMO Uorite 3000-Q active (manufacturer: THERMO, MS model: THERQ active)

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

Chiral preparation a Shimadzu LC-20AP preparative chromatograph was used.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

2- [ [4- [6- [ (4-cyano-2-fluoro-phenyl) methoxy ] -2-pyridyl ]3, 6-dihydro-2H-pyridin-1-yl ] methyl ] -1[ [ (2S) -oxetan-2-yl ] methyl ] thieno [2,3-d ] imidazole-5-carboxylic acid 1

First step of

5-Nitro-4- [ [ (2S) -oxetan-2-yl ] methylamino ] thiophene-2-carboxylic acid methyl ester 1c

The compound 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester 1a (305mg, 1.15mmol, prepared by the method disclosed in example 114, intermediate C, page 124 of the specification in patent application WO200399805 A1), the compound (S) -oxetan-2-ylmethylamine 1b (100mg, 1.15mmol, tokyo pharmacotechnical co., ltd.), triethylamine (580mg, 5.73mmol) were dissolved in tetrahydrofuran (10 mL), and stirred at 80 ℃ for 16 hours. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 1c (310 mg, yield: 90.1%).

MS m/z(ESI):273.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.64(t,1H),7.67(s,1H),4.92-4.87(m,1H),4.50-4.46(m,1H),4.38-4.34(m,1H),3.88(s,3H),3.82-3.70(m,2H),2.66-2.60(m,1H),2.49-2.44(m,1H)。

Second step of

5-amino-4- [ [ (2S) -oxetan-2-yl ] methylamino ] thiophene-2-carboxylic acid methyl ester 1d

Compound 1c (310mg, 1.14mmol) was dissolved in 20mL of tetrahydrofuran, and palladium on carbon (300mg, 10%) was added thereto, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. Celite was filtered through and concentrated to give the crude title product 1d (253 mg) which was used in the next reaction without purification.

MS m/z(ESI):243.0[M+1]。

The third step

2- (chloromethyl) -1- [ [ (2S) -oxetan-2-yl ] methyl ] thieno [2,3-d ] imidazole-5-carboxylic acid methyl ester 1e

Crude 1d (253mg, 0.69mmol) was dissolved in 10mL of acetonitrile, and 2-chloro-1, 1-trimethoxy-ethane (152mg, 1.05mmol, shanghai chemical technology Co., ltd.) and p-toluenesulfonic acid monohydrate (20mg, 0.1mmol, national pharmaceutical group chemical reagent Co., ltd.) were added and stirred at 60 ℃ for 1 hour. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system a to give crude title product 1e (71 mg) which was used in the next reaction without purification.

MS m/z(ESI):300.9[M+1]。

The fourth step

4- [ (6-chloro-2-pyridyl) oxymethyl ] -3-fluoro-benzonitrile methyl group for 1h

Potassium tert-butoxide (3.13g, 27.89mmol) was added to 40mL of tetrahydrofuran, and the internal temperature was maintained at 10-15 ℃ to add the compound 3-fluoro-4- (hydroxymethyl) benzonitrile 1f (2.81g, 18.59mmol, aikang Biotechnology, ltd.) in portions, and the mixture was stirred at this temperature for 45 minutes, and 1g (2.3g, 15.54mmol) of the compound 2, 6-dichloropyridine was added and the mixture was reacted at 15 ℃ for 3 hours. The reaction solution was poured into 200mL of water, 100mL of ethyl acetate was added, stirring was carried out, layers were separated, filtration was carried out, the filtrate was extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and after concentration under reduced pressure, purification was carried out by silica gel column chromatography with eluent system B to obtain the title compound 1h (2.50 g, yield: 51.1%).

MS m/z(ESI):263.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.70(t,1H),7.60(t,1H),7.50(d,1H),7.41(d,1H),6.98(d,1H),6.77(d,1H),5.51(s,2H)。

The fifth step

4- [6- [ (4-cyano-2-fluoro-phenyl) methoxy ] -2-pyridyl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 1j

The compound 4- [ (6-chloro-2-pyridyl) oxymethyl ] -3-fluoro-benzonitrile methyl group 1H (2.44g, 9.29mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1i (2.87g, 9.28mmol), anhydrous sodium carbonate (2.95g, 27.83mmol), tetratriphenylphosphine palladium (536mg, 463.84umol), water (3 mL), 1, 4-dioxane (15 mL), under the protection of argon, stirring at 90 ℃ for 16 hours. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 1j (3.60 g, yield: 94.6%).

MS m/z(ESI):410.1[M+1]。

The sixth step

3-fluoro-4- [ [6- (1, 2,3, 6-tetrahydropyridin-4-yl) -2-pyridinyl ] oxymethyl ] benzonitrile 4-tosylate salt 1k

Compound 1j (3.60g, 8.79mmol) was dissolved in 50mL of ethyl acetate, p-toluenesulfonic acid monohydrate (4.18g, 21.97mmol) was added, and the mixture was stirred at 60 ℃ for 4 hours to precipitate a solid, which was cooled, filtered, washed with 5mL of ethyl acetate, and dried to give the title product 1k (5.40 g, yield: 93.9%).

MS m/z(ESI):310.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.82(brs,2H),7.91(d,1H),7.78(t,1H),7.71(m,2H),7.49(d,4H),7.19(d,1H),7.12(d,4H),6.86(d,1H),6.72(brs,1H),5.52(s,2H),3.83-3.80(m,2H),3.31-3.35(m,2H),2.69-2.66(m,2H),2.29(s,6H)。

Seventh step

2- [ [4- [6- [ (4-cyano-2-fluoro-phenyl) methoxy ] -2-pyridyl ]3, 6-dihydro-2H-pyridin-1-yl ] methyl ] -1[ [ (2S) -oxetan-2-yl ] methyl ] thieno [2,3-d ] imidazole-5-carboxylic acid methyl ester 1l

Compound 1k (160mg, 0.24mmol), compound 1e (71mg, 0.24mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (170mg, 1.23mmol) was added, and the mixture was stirred at 50 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give 1l (100 mg) of the crude title product which was used in the next reaction without purification.

MS m/z(ESI):574.2[M+1]。

Eighth step

Compound 1l (100mg, 0.24mmol) was dissolved in 6mL of a mixed solvent of acetonitrile and water (V: V = 5) and added with lithium hydroxide monohydrate (11mg, 0.26mmol), followed by stirring at 40 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, adjusted to pH 5 to 6 with citric acid solution (1M), and 5mL of tetrahydrofuran was added to dissolve it, followed by purification by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title product 1 (50 mg, yield: 51.2%).

MS m/z(ESI):560.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.94-7.87(m,1H),7.73-7.68(m,4H),7.10(d,1H),6.77(d,1H),6.73-6.67(m,1H),5.50(s,2H),5.06-5.01(m,1H),4.64-4.59(m,1H),4.52-4.44(m,2H),4.37-4.32(m,1H),3.90(d,1H),3.82(d,1H),3.23-3.15(m,2H),2.73-2.60(m,3H),2.49-2.43(m,2H),2.39-2.32(m,1H)。

Example 2

2- ((4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid 2

First step of

4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxan-4-yl) -1,2,3, 6-tetrahydropyridine 4-tosylate 2b salt

The compound, tert-butyl 4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxin-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate 2a (111mg, 0.25mmol, prepared using the method disclosed in patent application US20190382384A1, intermediate C5, page 32), p-toluenesulfonic acid monohydrate (237mg, 1.24mmol) was dissolved in ethyl acetate (10 mL) and stirred at 60 ℃ for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound 2b (129 mg, p-toluenesulfonate), which was used in the next reaction without purification. MS m/z (ESI) 346.1[ 2 ] M +1].

Second step of

Methyl 2- ((4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate 2c

Compound 1e (46mg, 0.15mmol) and compound 2b (129mg, 0.25mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (211mg, 1.53mmol) was added, followed by stirring at 50 ℃ for 16 hours. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give the title compound 2c (26 mg, yield: 27.9%).

MS m/z(ESI):610.1[M+1]。

The third step

Compound 2c (26mg, 42.62umol) was dissolved in 6mL of a mixed solvent of acetonitrile and water (V: V = 5) and added with lithium hydroxide monohydrate (3mg, 71.50umol) and stirred at 40 ℃ for 16 hours. Concentration, pH-adjustment to 5 to 6 with citric acid solution, addition of 2mL of tetrahydrofuran, dissolution and purification by high performance liquid chromatography (Waters-2767, elution: ammonium bicarbonate, water, acetonitrile) gave the title product 1 (4 mg, yield: 15.7%).

MS m/z(ESI):596.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ12.78(s,1H),7.82(s,1H),7.52-7.59(m,2H),7.34(dd,1H),6.89-6.80(m,3H),6.37(s,1H),5.10-5.00(m,1H),4.69-4.60(m,1H),4.57-4.42(m,2H),5.35(dq,1H),3.91(dd,1H),3.83(dd,1H),2.31-2.29(m,1H),3.24-3.12(m,2H),2.77-2.60(m,3H),2.46-2.31(m,2H),2.03(s,3H)。

Example 3

2- ((4- ((S or R) -2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- ((S) -oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid 3

/>

First step of

(S) -4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 3b

(R) -4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxan-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 3c

Chiral separation was performed on tert-butyl 4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate 3a (6.52g, 14.62mmol, prepared by the method disclosed in example intermediate C3 on page 54 of the specification of patent application WO2019239319A 1) (separation conditions: superchiral S-AD chiral preparation column, 2.1cm I.D.times.25 cm L; mobile phase: hexane/IPA =95/5 (V/V), flow rate: 16 mL/min) to collect the corresponding components, and concentration was performed under reduced pressure to obtain the title product (3.17 g, yield: 48.6%, 3.10g, yield: 47.5%).

(3.17 g, yield: 48.6%) Compound of Single configuration (shorter retention time):

chiral HPLC analysis: retention time 4.081 min, chiral purity: 99.7% (column: superchiral S-AD 150 x 4.6mm,5um; mobile phase: hexane/IPA =95/5 (V/V)).

MS m/z(ESI):390.1[M-55]。

(3.10 g, yield: 47.5%) Compound of Single configuration (longer Retention time):

chiral HPLC analysis: retention time 4.358 min, chiral purity: 99.2% (column: superchiral S-AD 150 x 4.6mm,5um; mobile phase: hexane/IPA =95/5 (V/V)).

MS m/z(ESI):390.1[M-55]。

Second step of

(S or R) -tert-butyl 4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxan-4-yl) piperidine-1-carboxylic acid tert-butyl ester 3d

The shorter retention time compound (820 mg, 1.84mmol) which had resolved from compound 3a was dissolved in methanol (50 mL), and tris (triphenylphosphine) rhodium chloride (170mg, 0.18mmol) was added and stirred under hydrogen pressure (50 psi) at 50 ℃ for 18 h. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title compound 3d (632 mg, yield: 76.7%).

The third step

(S or R) -4- (2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidine 3e

Compound 3d (632mg, 1.41mmol) was dissolved in ethyl acetate (25 mL), p-toluenesulfonic acid monohydrate (1.34g, 7.05mmol) was added, and stirring was carried out at 60 ℃ for 4 hours. Cooled to room temperature, concentrated under reduced pressure and dissolved in acetonitrile (25 mL), potassium carbonate (1.10 g, 8.00mmol) was added, and the mixture was stirred at 50 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 3e (175 mg, yield: 35.6%). MS m/z (ESI) 348.1[ 2 ] M +1].

The fourth step

Methyl 2- ((4- ((S or R) -2- (4-chloro-2-fluorophenyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- ((S) -oxetan-2-ylmethyl) -1H-thiazolo [2,3-d ] imidazole-5-carboxylate 3f

Compound 1f (104mg, 0.34mmol), compound 3e (118mg, 0.34mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (382mg, 2.76mmol) was added, followed by stirring at 50 ℃ for 7 hours. Cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 3f (50 mg, yield: 23.6%). MS m/z (ESI) 612.0[ 2 ] M +1].

The fifth step

Compound 3f (50mg, 0.08mmol) was dissolved in 6mL of a mixed solvent of acetonitrile and water (V: V = 5) and lithium hydroxide monohydrate (6 mg, 0.14mmol) was added and stirred at 40 ℃ for 3 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 5 to 6 with citric acid aqueous solution (1M), ethyl acetate (10 mL. Times.3) was extracted, the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title product 3 (20 mg, yield: 40.9%).

MS m/z(ESI):598.0[M+1]。

1H NMR(500MHz,DMSO-d ₆ )δ13.00(s,1H),7.79(s,1H),7.58-7.54(m,2H),7.34(dd,1H),6.80-6.72(m,3H),5.11-5.06(m,1H),4.66-4.61(m,1H),4.55-4.45(m,2H),4.38-4.35(m,1H),3.81(d,1H),3.71(d,1H),2.97(d,1H),2.87(d,1H),2.71-2.60(m,2H),2.44-2.37(m,1H),2.21-2.12(m,2H),2.02(s,3H),1.77-1.67(m,4H)。

Biological evaluation

Test example 1 evaluation of GLP-1 receptor agonistic Activity

1. Purpose of testing

The purpose of this experiment was to test the agonistic activity of the compound molecule at the GLP-1 receptor, according to EC ₅₀ Size the molecules were evaluated for in vitro activity. ONE-Glo was used in this experiment ^TM Luciferase assay System (ONE-Glo) ^TM Luciferase Assay System, promega, E6110), under the action of compound molecules, GLP-1R downstream signal pathways are activated to cause cAMP level to rise, cAMP and CRE are combined to start transcription expression of CRE downstream Luciferase genes, luciferase can emit fluorescence through reaction with substrates thereof, and the fluorescence can be emitted through ONE-Glo ^TM The reagent measures the fluorescence signal reflecting the activity of the compound for stimulating the GLP-1 receptor.

2. Experimental methods

CHO-K1/CRE-luc/GLP-1 receptor stable cell strain (GLP-1 receptor plasmid self-construction; CRE-luc plasmid Promega E8471) is constructed. CHO-K1/CRE-luc/GLP-1 receptor cells were digested, centrifuged, resuspended, single cell suspension was homogenized, viable cell density was adjusted to 2.5X 10 using cell culture medium (DME/F-12 +10% FBS) ⁵ cells/ml were added to a 96-well cell culture plate (Corning, # 3903) at 90. Mu.l/well. The plates were incubated in an incubator for 16 hours (37 ℃,5% CO) ₂ )。

Compounds were dissolved in DMSO and prepared as a stock solution with an initial concentration of 20 mM. The starting concentration of the small molecule compound was 0.2mM,3 fold diluted at 10 points, and DMSO at 11 points. Another 96-well plate is taken, 95. Mu.L of cell culture solution (DME/F-12 +10% FBS) is added into each well, 5. Mu.L of samples to be tested with different concentrations are added into each well, the mixture is mixed evenly, 10. Mu.L of samples to be tested with different concentrations are added into the cell culture plate, and each sample has two duplicate wells. Incubate the plates in the incubator for 6 hours (37 ℃,5% CO) ₂ ). The 96-well cell culture plate was removed and 100. Mu.L of ONE-Glo was added to each well ^TM Reagents, incubated for 10 minutes at room temperature. Chemiluminescence was measured in a microplate reader (EnVision 2105, PE).

3. Data analysis

Data were processed and analyzed using Microsoft Excel, graphpad Prism 5. To obtain the EC of the compound ₅₀ See table 1 below for values, results.

TABLE 1 EC for GLP-1 receptor agonistic activity of the compounds of this disclosure ₅₀

Example numbering	EC ₅₀ (nM)	Emax％
			1	0.42	101
2	1.38	98
			3	0.16	107

And (4) conclusion: the compounds of the present disclosure have good agonistic activity at the GLP-1 receptor.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

q is Q1 or Q2,

ring B is a 5-membered heteroaryl;

ring A is phenyl;

m is an N atom or a C atom;

is a single bond or a double bond; when M is N atom, is selected>

Is a single bond, when M is a C atom>

Is a single bond or a double bond;

y is an O atom;

W ¹ and W ² Is an O atom;

R ^m and R ⁿ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group;

R ^a and R ^b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

R ¹ selected from hydrogen atom, C _1-6 Alkyl and 3 to 6 membered cycloalkyl wherein said C is _1-6 Alkyl is optionally substituted with one or more 3-to 6-membered heterocyclyl;

R ² are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

R ³ and R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl and cyano;

R ⁴ selected from hydrogen atoms, halogens and C _1-6 An alkyl group;

R ⁵ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 HalogenatedAn alkyl group;

R ⁸ are the same or different and are each independently selected from a hydrogen atom or a halogen;

n is 0, 1,2,3 or 4;

m is 0, 1,2,3, 4 or 5;

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

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

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is thienyl.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, which is a compound represented by the general formula (II):

wherein:

R ¹ 、R ² 、R ^m 、R ⁿ m, Q and n are as defined in claim 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ^m And R ⁿ Is a hydrogen atom.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein

Selected from the group consisting of: />

R ² And n is as defined in claim 1.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein Z is ¹ 、Z ² And Z ³ Is CR ⁸ ，Z ⁴ Is a N atom, R ⁸ The same or different, and each independently is a hydrogen atom or a halogen.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein Q is Q3 or Q4:

r is 0, 1,2 or 3;

R ³ to R ⁶ 、R ⁸ 、R ^a 、R ^b M, p and t are as defined in claim 1.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ¹ Is C _1-6 Alkyl radical, wherein said C _1-6 Alkyl is optionally substituted with one or more 3-to 6-membered heterocyclyl.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ³ And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and cyano.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ⁴ Is C _1-6 An alkyl group.

11. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, which is selected from any one of the following compounds:

12. a compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof,

wherein:

R ^w is C _1-6 An alkyl group;

ring B, R ¹ 、R ² 、R ^m 、R ⁿ M, Q and n are as defined in claim 1.

13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from any one of the following:

14. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises the steps of:

wherein:

R ^w is C _1-6 An alkyl group;

ring B, R ¹ 、R ² 、R ^m 、R ⁿ M, Q and n are as defined in claim 1.

15. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the preparation of a medicament for agonizing a GLP-1 receptor.

17. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular diseases.

18. The use of claim 17, wherein the type I diabetes is idiopathic type I diabetes.

19. The use according to claim 17, wherein the cardiovascular disease is selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease.