CN101195612B - Compound with substituted cyclobutane structure, production method and medicine use thereof - Google Patents

Abstract

或

以及该类化合物的制备方法和将其作为一类胰高血糖样肽-1受体调节剂在预防和/或治疗代谢紊乱性疾病(包括但不局限于糖尿病、胰岛素抵抗和肥胖症)、心血管疾病和神经退行性疾病(如Alzheimer′s病)等中的应用。The present invention provides a class of compounds having a substituted cyclobutane structure represented by the following general formula I or II:

or

As well as the preparation method of this type of compound and its use as a class of glucagon-like peptide-1 receptor regulator in the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), heart Applications in vascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc.

Description

A class of compounds with substituted cyclobutane structure, its preparation method and medical use

technical field

The present invention relates to a class of compounds with a substituted cyclobutane structure, a preparation method and its role as a regulator of glucagon like peptide-1 receptor (GLP-1R) in the prevention and/or treatment of metabolic disorders Medical applications for diseases (including but not limited to diabetes, insulin resistance, obesity, etc.), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease), etc.

Background technique

Glucose metabolism disorder, especially diabetes, has become a major disease that seriously threatens human health and life in modern society. It is predicted that diabetes patients in the world are increasing at an annual rate of 6%, and by the end of 2006 there were 320 million patients (60 million people in my country, ranking second). Diabetes mellitus is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2. The basic pathophysiology of type 1 diabetes is absolute insulin deficiency, and the clinical treatment is mainly based on insulin supplementation. Therefore, it is also called insulin-dependent diabetes. Type 2 diabetes accounts for more than 95% of the affected population. Clinical studies have found that most patients with type 2 diabetes can synthesize normal or even excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"), resulting in Relatively insufficient insulin, also known as non-insulin-dependent diabetes. Insulin resistance is a key factor in the occurrence and development of type 2 diabetes. Drugs for the treatment of type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers and auxiliary measures. After the sulfonylurea hypoglycemic drugs bind to the receptors of the pancreatic β cell membrane, they close the potassium ion channel, block the outflow of potassium ion, lead to the depolarization of the cell membrane, promote the opening of the Ca2 ⁺ channel, and cause the extracellular calcium ion to flow in, and the intracellular An increase in calcium ion concentration triggers the release of insulin. According to its advent, it is divided into two generations, the first generation such as tolsulfamide, the second generation includes glibenclamide (glibenclamide), gliclazide (Damekang), glipizide (mepyridine) ) and gliquidone (sugar appropriate level) and so on. Biguanide hypoglycemic drugs can suppress appetite, increase the binding of insulin to receptors, promote the anaerobic glycolysis of glucose by cells, inhibit tissue respiration, and inhibit hepatic glycogenogenesis. The main ones are metformin, phenformin and buformin. Other hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), β3-adrenergic receptor modulators, glucagon receptor antagonists, fatty acid Metabolic disruptors, α-glucosidase inhibitors (such as acarbose, voglibose, miglitol, etc.), and aldose reductase inhibitors, etc.

Glucagon like peptide-1 receptor (GLP-1R) belongs to type B G protein-coupled receptor (GPCR). When the body takes in nutrients, the gut peptide hormone-glucagon-like peptide-1 (GLP-1) released by enteroendocrine cells is activated by highly specific binding to GLP-1R , Stimulate insulin secretion, inhibit glucagon production, reduce postprandial blood sugar and maintain it at a constant level. Under physiological conditions, the role of GLP-1 in stimulating insulin secretion depends on blood sugar concentration, and hypoglycemia will not occur due to continuous secretion. GLP-1 also has the function of promoting the proliferation and differentiation of β cells, as well as neuromodulation, delaying gastric emptying and reducing appetite. In vitro, GLP-1 can promote the differentiation of embryonic stem cells into β-like cells with insulin secretion function (J Endocrinol.2005, 186:343-52). GLP-1 acting on the central can promote cell survival and reduce apoptosis, reduce the neurotoxicity of β-amyloid peptide, inhibit the process of neurodegeneration and promote learning and memory, so it has recently been proposed to use GLP-1 for Alzheimer' Treatment of S disease (Ann N Y Acad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol ExpTher, 2002, 302: 881-888). In addition, GLP-1 also plays an important role in the cardiovascular system.

It has the effects of lowering blood pressure and dilating blood vessels. Acute injection of GLP-1 can improve the systolic function of the left ventricle in the experiment of myocardial hypertrophy. It can also reduce the injury of myocardial cells in the case of myocardial ischemia and reperfusion (J.Hypertens, 2003, 21: 1125-1135; Am J Physiol Endocrinol Metab, 2004, 287: E1209-E1215; Circulation, 2004, 110: 955-961; Diabetes, 2005, 54:146-151). Due to the above-mentioned clear physiological effects, since the discovery of this target in the mid-1980s, the search for small molecule agonists of GLP-1R has become a research hotspot of many new drug development institutions in the world.

A number of internationally renowned multinational pharmaceutical companies are developing GLP-1 innovative drugs, such as the GLP-1 derivatives developed by Denmark's Novo Nordisk (trade name Liraglutide; entering phase III clinical trials) and American Amylin Pharmaceuticals and Eli Lilly The jointly developed GLP-1 analogue Exendin-4 (trade name Exenatide; was approved for marketing in April last year, and sales this year is expected to exceed US$1 billion). Except for GLP-1 and its peptide analogues, there is no report on the successful development of non-peptide small molecule GLP-1R agonists. Since peptide drugs are inconvenient to take orally, finding non-peptide GLP-1R modulators and developing new anti-diabetic drugs with independent intellectual property rights are the common concerns of many new drug research institutions.

Contents of the invention

The object of the present invention is to provide a class of compounds represented by the following general formula I or II and pharmaceutically acceptable salts thereof;

Another object of the present invention is to provide a method for preparing a compound represented by the following general formula I or II;

Another object of the present invention is to provide a pharmaceutical composition containing a compound represented by the following general formula I or II;

Another object of the present invention is to provide compounds represented by the following general formula I or II as glucagon-like peptide-1 receptor modulators in the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc.

The present invention provides glucagon-like peptide-1 receptor modulators, which increase the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Such as Alzheimer's disease) and other members of the drug. The present invention relates to a compound represented by the following general formula I or II, or a pharmaceutically acceptable salt thereof:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl;

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

Preferably, the compounds of the above formulas I and II are characterized in that: X, Y are (CH ₂ )n, n is 0-2; O; S or NH, R ₁ , R ₂ are each independently:

Where R ₅ is any one of the following substituents is H; C ₁ -C ₆ alkyl; contains any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Pyroyl; thiophenoyl; pyrroloyl; pyroyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH;

R ₃ and R ₄ are respectively:

Wherein R ₆ is any of the following substituents: H; C ₁ -C ₆ alkyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₇ and R ₈ are each independently any of the following substituents _{: H} ; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; _aryl ; benzyl; furyl; pyryl; thienyl; _pyrrolyl ; pyridyl; Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atom, Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including C ₁ -C ₆ alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl _{; Furoyl ; Pyroyl ;} Thienoyl _; 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Where R ₉ is any of the following substituents: H; C ₁ -C ₆ alkyl; any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Facyl; Thiphenoyl; Pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₁₀ and _{R 11} are each independently any of the following substituents: H; C _{1 -C 6} alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH.

When R ₁ and R ₂ are independently:

Wherein R ₁₂ and _{R 13} are each independently any of the following substituents _: H; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , When n is 0-2; O; S or NH;

R ₃ and R ₄ are respectively:

Wherein R ₆ is any of the following substituents: H; C ₁ -C ₆ alkyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₇ and R ₈ are each independently any of the following substituents _{: H} ; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen atoms, Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including C ₁ -C ₆ alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl _{; Furoyl ; Pyroyl ;} Thienoyl _; 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Where R ₉ is any of the following substituents: H; C ₁ -C ₆ alkyl; any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₁₀ and _{R 11} are each independently any of the following substituents: H; C _{1 -C 6} alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH.

In addition, more preferably, when R ₁ and R ₂ are each independently:

Wherein R ₁₄ is any of the following substituents: H; C ₁ -C ₆ alkyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Pyranoyl; thienyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH;

R ₃ and R ₄ are respectively:

Wherein R ₆ is any of the following substituents: H; C ₁ -C ₆ alkyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₇ and R ₈ are each independently any of the following substituents _{: H} ; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atom, Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including C ₁ -C ₆ alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl _{; Furoyl ; Pyroyl ;} Thienoyl _; 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Where R ₉ is any of the following substituents: H; C ₁ -C ₆ alkyl; any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Facyl; Thiphenoyl; Pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₁₀ and _{R 11} are each independently any of the following substituents: H; C _{1 -C 6} alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH.

When R ₁ and R ₂ are independently:

Wherein R ₁₅ and _{R 16} are each independently any of the following substituents _: H; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , When n is 0-2; O; S or NH,

R ₃ and R ₄ are respectively:

Wherein R ₆ is any of the following substituents: H; C ₁ -C ₆ alkyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any _one , two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₇ and R ₈ are each independently any of the following substituents _{: H} ; C ₁ -C ₆ alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atom, Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including C ₁ -C ₆ alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl _{; Furoyl ; Pyroyl ;} Thienoyl _; 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Where R ₉ is any of the following substituents: H; C ₁ -C ₆ alkyl; any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl -C ₆ alkenyl; C ₂ -C ₆ alkynyl; _C 2 -C 6 containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups alkynyl group; C ₃ -C ₆ cycloalkyl group; _C 3 -C 6 ring containing any one, two or _three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group Alkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy , amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group including any one, two or three substituted aryl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyridyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; containing halogen atom, any one or two of C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio Or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups, methylthio groups, Any one, two or three substituted pyranyl groups including ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amides Any one, two or three substituted thienyl groups including a carbon amido group, a mercapto group, a methylthio group, and an ethylthio group; a group containing a halogen atom, a C ₁ -C ₄ alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ -C ₆ alkanoyl ; containing any one, two or three substituted C ₁ -C ₆ alkanoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₂ -C ₆ alkenoyl groups; containing Any one, two or three substituted C ₂ -C ₆ alkenoyl groups including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C ₂ -C ₆ alkynoyl group; containing halogen atom, Any one, two or three substituted C ₂ -C ₆ alkynoyl groups including C ₁ -C ₆ alkoxy or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing halogen atoms, C ₁ -C ₆ Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including alkoxy or hydroxyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; Fenformyl; Thiphenoyl; Pyrroloyl; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH;

Or R ₃ and R ₄ are respectively:

Wherein R ₁₀ and _{R 11} are each independently any of the following substituents: H; C _{1 -C 6} alkyl; One or three substituted C ₁ -C ₆ alkyl groups; C ₂ -C ₆ alkenyl groups; containing any one, two or three of halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups substituted C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; containing any one, two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl C ₂ -C ₆ alkynyl group; C ₃ -C ₆ cycloalkyl group; C ₃ with any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group -C ₆ cycloalkyl; aryl; benzyl; furyl; pyryl; thienyl; pyrrolyl; pyridyl; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted aryl groups including alkoxy group, amino group, amido group, carbonamido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C Any one, two or three substituted pyridines including alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio of ₄ group; containing halogen atom, C ₁ -C ₄ alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group, etc. Any one, two or three substituted furyl groups; containing halogen atoms, C ₁ -C ₄ alkyl groups, nitro groups, carboxyl groups, aldehyde groups, alkoxy groups, amine groups, amido groups, carbon amido groups, mercapto groups Any one, two or three substituted pyranyl groups including , methylthio, and ethylthio; containing halogen atoms, C ₁ -C ₄ alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including amine group, amido group, carbon amido group, mercapto group, methylthio group, ethylthio group; containing halogen atoms, C ₁ -C ₄ alkyl groups, Any one, two or three substituted pyrrolyl groups including nitro, carboxyl, aldehyde, alkoxy, amine, amido, carbonamido, mercapto, methylthio, ethylthio; C ₁ - C ₆ alkanoyl; C ₁ -C 6 alkanoyl containing any one, _two or three substitutions including halogen atoms, C ₁ -C ₆ alkoxy or hydroxyl; C ₂ -C ₆ Alkenoyl group; _C 2 -C 6 alkenoyl group containing any one, two or three substitutions including halogen atom, C ₁ -C ₆ alkoxy group or hydroxyl group; C _{2 -C 6} alkynoyl group; Containing any one, two or three substituted C ₂ -C ₆ alkynoyl groups including halogen atoms, C ₁ -C ₆ alkoxy groups or hydroxyl groups; C ₃ -C ₆ cycloalkanoyl groups; containing Halogen Any one, two or three substituted C ₃ -C ₆ cycloalkanoyl groups including sub, C ₁ -C ₆ alkoxy or hydroxyl groups; adamantyl, substituted adamantyl; aroyl; Benzoyl; furoyl; pyroyl; thienoyl; pyrroloyl; X ₁ is (CH ₂ ) _n , n is 0-2; O; S or NH; X ₂ is (CH ₂ ) _n , n is 0-2; O; S or NH.

In addition, preferably, such compounds or pharmaceutically acceptable salts thereof are provided in the form of pharmaceutical compositions, either alone or in combination with pharmaceutically acceptable carriers or excipients. The present invention also provides a medicament comprising the above-mentioned compound for the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease) etc.

In another aspect, the present invention relates to methods for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). The method comprises administering an effective amount of a compound selectively modulating glucagon-like peptide-1 receptors or a pharmaceutically acceptable salt thereof to a subject in need or willing to receive treatment or prevention to prevent or treat the above-mentioned disease or symptoms. Preferably, the above-mentioned metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc., are formulated by the following general formula I or A compound represented by II or a pharmaceutically acceptable salt thereof for the prevention or treatment of:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

In another aspect, the present invention relates to a combined preparation, which includes a compound capable of selectively modulating the glucagon-like peptide-1 receptor, especially activating the function of the receptor, or a pharmaceutically acceptable salt thereof , or alone, or in combination with pharmaceutically acceptable carriers or excipients. The compound has the structure of the following general formula I or II:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

The present invention provides a kit comprising the above combination formulations. The present invention further provides the application of the above combined preparations for the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease) ), etc., to achieve the drug effect of selectively stimulating the glucagon-like peptide-1 receptor, and improve the patient's symptoms and quality of life.

In order to clarify the content of the invention and not to limit it, the invention is divided into the following subsections for a detailed description.

A definition

Unless otherwise defined, the technical and scientific terms used in the present invention have the same meaning as commonly understood in the field to which the present invention belongs. All patents, applications, published applications and other publications and sequences from GenBank and other databases mentioned herein are incorporated by reference in their entirety. If the definitions set forth in this section are contrary to, or inconsistent with, the definitions set forth in all patents, applications, published applications and other publications and sequences incorporated and referenced in GenBank and other databases referenced by this patent, the definitions set forth in this section shall The stated definition shall prevail.

As used herein, "a" or "an" means "at least one" or "one or more".

As used herein, "metabolic disorder disease" refers to related symptoms and/or diseases caused by metabolic disorders of sugar, fat or protein caused by various reasons.

As used herein, "diabetes mellitus" refers to a metabolic disease of multiple etiologies characterized by chronic hyperglycemia with disturbances in carbohydrate, fat and protein metabolism due to defects in insulin secretion and/or action. With the prolongation of diabetes, if the metabolic disorder in the body is not well controlled, it can lead to chronic complications in organs such as eyes, kidneys, nerves, blood vessels and heart, and eventually blindness, lower limb gangrene, Uremia, stroke or myocardial infarction, even life-threatening.

As used herein, "insulin resistance" refers to the decreased sensitivity of peripheral tissues in the body to insulin, and the resistance of target tissues such as muscle and fat to the action of insulin to promote glucose uptake. Insulin resistance is ubiquitous in type 2 diabetes, accounting for more than 90%, and is one of the main factors for the pathogenesis of type 2 diabetes.

As used herein, "obesity" refers to an excessive amount of body fat, a phenomenon in which a man weighs more than 25% of an ideal body weight or a woman weighs more than 30% of an ideal body weight. Genetic factors, hypothalamic disorders, endocrine disorders, overeating and too little activity are all causes of obesity.

As used in this article, "Alzheimer's Disease (AD, also known as Alzheimer's dementia) is a progressive degenerative disease of the nervous system, clinically manifested as chronic weakening of intelligence and memory. of chronic loss.

As used herein, "cardiovascular disease" includes heart disease, pulmonary heart disease, hypertension, hyperlipidemia, and the like. It has the characteristics of "high morbidity, high mortality, high disability rate, high recurrence rate" and "many complications".

An "effective amount" of a compound used in the treatment of a particular disease as used herein refers to an amount sufficient to improve or alleviate to some extent the symptoms associated with the disease. This dose can be administered as a single dose or as a regimen. This dose is curative of the disease, but is typically administered to ameliorate the symptoms. Repeat dosing may be necessary to improve symptoms.

As used herein, "pharmaceutically acceptable salts, esters or other derivatives" include any salts, esters or derivatives which can be readily prepared by known methods by those skilled in the art. The compounds thus derived and produced can be administered to animals and humans without toxic effects. The compound is either pharmaceutically active or a prodrug.

As used herein, "treating" refers to amelioration of disease and symptoms in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine.

As used herein, "improving" the symptoms of a particular disease by administering a particular pharmaceutical composition means that any relief, whether permanent, temporary, long-term, or transient, is attributable to or related to the effects of the pharmaceutical composition. application related.

As used herein, "substantially pure" means sufficiently homogeneous that no impurities are detectable by standard analytical methods used by those skilled in the art to assess purity, such as thin layer chromatography (TLC), gel electrophoresis and High performance liquid chromatography (HPLC). Or sufficiently pure means that even further purification does not change the detectable physicochemical properties of the substance, such as enzymatic activity and biological activity. Methods for purifying compounds to obtain substantially chemical purity are well known to those skilled in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers or isomers. In such cases, further purification may increase the specific activity of the compound.

As used herein, "prodrug" refers to an in vivo administered compound that can be metabolized, or converted, into a biologically, pharmaceutically or therapeutically active form. To manufacture prodrugs, the pharmaceutically active compound is modified such that the active compound is reproduced by metabolic processes. Prodrugs can be engineered to alter their metabolic stability, or their transport properties, to mask their side effects or toxicity, to modify the taste of the drug, or to alter other properties. With knowledge of pharmacokinetics and drug metabolism in vivo, once a pharmaceutically active compound is known, one skilled in the art can design prodrugs of the compound. [See Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392].

The term "substantially" is the same or uniform or similar, and can be changed in context according to the understanding of those skilled in the art to related technologies, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, and most Preferably at least 95% identical.

As used herein "composition" means any mixture. Can be solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.

As used herein, "combination" refers to any combination of two or more.

The term "subject" as used herein includes humans and animals such as dogs, cats, cows, pigs, rodents and the like. Experienced practitioners should understand that the subject is suitable and willing to treat metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc. For treatment and prevention.

Any abbreviations for protective groups, amino acids and other compounds used herein are consistent with their commonly used, recognized abbreviations or biochemical names issued by the IUPAC-IUB committee, unless otherwise specified.

Beta glucagon-like peptide-1 receptor modulator

The present invention provides modulators of glucagon-like peptide-1 receptor function, which increase the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegeneration Members of drugs such as diseases such as Alzheimer's disease. The present invention relates to a compound represented by the following general formula I or II, or a pharmaceutically acceptable salt thereof:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

The compounds of the invention may be in one specific stereoisomer, for example the R- or S-configuration, or mixtures thereof, for example, racemic mixtures. Compounds contemplated here include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are their hydration types, such as aqueous solutions of these compounds, hydrolysates or ionized products; and these compounds may contain varying numbers of bound water molecules.

The compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compounds are prepared using the synthetic methods cited in Section F below.

Also preferably, the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention may be prepared with any suitable acid in the form of a pharmaceutically acceptable salt thereof. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; Sulfonic acids such as methanesulfonic acid, ethylsulfonic acid, etc.; arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, etc. can be used.

C treatment and prevention methods

The present invention relates to methods for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease) and the like. The method includes administering an effective amount of a compound that selectively activates glucagon-like peptide-1 receptors or a pharmaceutically acceptable salt thereof to a subject in need or willing to receive treatment or prevention to treat or prevent the above diseases or symptoms.

Preferably, the above-mentioned diseases are treated or prevented by administering an effective amount of a compound represented by the following general formula I or II or a pharmaceutically acceptable salt thereof:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

Any subject, preferably a mammal, more preferably a human, can be controlled by the present method.

The method can be used to prevent and treat metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease) and the like. A preferred disease or condition is any disease or condition caused by or accompanied by insulin secretion and/or dysfunction.

When preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), the present invention can be used alone or in combination with other diabetes treatment drugs that have been marketed or will be marketed, including insulin sensitizers compound of. Any suitable drug for the treatment of metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, may be used in combination with the compounds of the present invention. Among them, typical insulin sensitizers include rosiglitazone and pioglitazone.

In a preferred embodiment of the present invention, the above-mentioned insulin sensitizers are not administered when using the compounds of the present invention. More preferably, the compounds of the present invention are used to treat or prevent diseases or symptoms caused by drug resistance or toxic side effects of the above listed or to be marketed diabetes treatment drugs (including insulin sensitizers).

The compounds of the present invention may be administered by any suitable method alone, or in combination with other suitable diabetes therapeutic agents, including insulin sensitizers. For example, the compound of the present invention, or a pharmaceutically acceptable salt thereof can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically.

In specific embodiments, the method further comprises diagnosing and evaluating the prognosis of the disease or condition in the subject. Any suitable method may be used for diagnosing and assessing the relevant disease or condition and its prognosis. Diagnosis and prognosis may be based on the detection and/or identification of any or all of the in vivo substances, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids, or other pathological and clinical markers, etc., and associated symptoms. For example, the diagnostic or prognostic methods disclosed in International Patent WO 01/44815 and US Patent 5,571,674 can be used.

D Combination Formulations, Kits and Methods of Combination

On the other hand, the present invention also relates to a combined preparation, which includes a compound that selectively regulates the function of the glucagon-like peptide-1 receptor, or a pharmaceutically acceptable salt thereof, and one or more Medications for the treatment of metabolic disorders include insulin sensitizers.

Preferably, the combination includes the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic drugs for metabolic disorders including insulin sensitizers, and the compound is represented by the following general formula I or II:

All stereo and optical isomers thereof, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects.

Wherein X and Y are (CH ₂ ) _n , n is 0-2; O; S or NH.

Wherein R ₁ and R ₂ are each independently any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxyl; aldehyde; alkoxy; amine; aminoalkyl; amido; Carbonamido; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or Unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

R ₃ , R ₄ are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; aminoalkyl; amido; carbonamido; alkylthio; substituted or unsubstituted substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.

Any suitable diabetes treatment drug including insulin sensitizers may be used in the combination formulations of the present invention. In a specific embodiment, one or more of the above-mentioned therapeutic drugs for diabetes including insulin sensitizers may be included in the combination preparation of the present invention.

In another specific embodiment, there is provided a method of treating or preventing a disease or symptom caused by or accompanied by insulin secretion and/or dysfunction, the method comprising administering to a subject in need and willing to receive treatment or prevention an effective amount of The above-mentioned combined preparation, or a pharmaceutically acceptable salt thereof, can treat or prevent the above-mentioned diseases or symptoms.

In another specific embodiment, there is provided a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and using the compound or a pharmaceutically acceptable salt thereof to prevent and treat insulin secretion and/or Instructions for use for diseases or symptoms caused by or associated with the disorder.

In yet another embodiment, a kit is provided, comprising the above combination preparation and instructions for using the combination preparation to treat or prevent diseases or symptoms caused by or accompanied by insulin secretion and/or dysfunction.

E formulation and dosage

According to the present invention, the compounds of the present invention, alone or in combination with other agents, carriers or excipients, are formulated for any suitable route of administration, such as intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection Injected, taken orally, or topically. The method may employ formulations for parenteral administration, administered as single doses in ampoules, or in multi-dose containers by injection with added buffer. The formulations may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles. The formulation may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In addition, before use, the active ingredient can be formulated in powder form with a suitable carrier, sterile pyrogen-free water or other solvents. Foams, gels, ointments, salves, transdermal patches, or creams may be used for topical administration of the present invention.

Pharmaceutical compositions and methods for administration that can be used in the present invention include, but are not limited to, those described in U.S. Patent Nos. 5,736,154, 6,197,801 B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374 B1 and 5,686,102.

The size of the dose for treatment or prophylaxis will vary depending on the severity of the condition and the route of administration. Dosage and frequency of administration will vary according to age, weight, health status and individual response of the patient.

It should be pointed out (and the treating physician should also know), that according to the toxicity and side effects, necessary measures must be taken to terminate, interrupt or reduce the treatment dose. On the contrary, if the clinical response is not obvious (excluding toxicity and side effects), doctors should adjust the treatment plan appropriately and increase the dose.

Any suitable route of administration can be used. Dosage forms include tablets, lozenges, bean capsules, dispersions, suspensions, solutions, capsules, films and the like.

In practice, the compounds of the present invention, alone or in combination with other preparations, can be mixed with pharmaceutical carriers or excipients, such as β-cyclodextrin and 2-hydroxy-propyl-β-cyclodextrin, in accordance with general pharmaceutical mixing techniques. Finely blend. According to the needs of administration, general carriers, special carriers for topical or parenteral routes can be used. Preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion, can use similar pharmaceutical media, water, glycol, oil, buffer, sugar, preservatives, liposomes, etc. known to those skilled in the art . Examples of such parenteral compositions include, but are not limited to, 5% w/v dextrose, saline or other solutions. The total dose of the compound of the present invention, administered alone or in combination with other formulations, may be administered via intravenous injection vials with a volume ranging from approximately 1 ml to 2000 ml. The amount of diluent will vary depending on the total dose administered.

The invention also provides a kit for implementing a treatment regimen. The kit comprises an effective dose of a compound of the present invention, alone or in combination with other agents, contained in one or more containers in a pharmaceutically acceptable form. The preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid. Alternatively, the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably sterile, in a container to reconstitute the complex Solutions are formed for injection purposes. Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.

In another embodiment, the kit according to the present invention further comprises a needle or syringe packaged, preferably in sterile form, and/or a packaged alcohol pad for the injectable composition. Instructions for use by a physician or patient can optionally be included.

F preparation method

The raw materials (0601-0610) used in the present invention are synthesized by referring to the synthesis method described in the Chinese patent (application number: 200310109331.0). The present invention is implemented through the following steps:

Dissolve compound 1 (1eq) and compound 2 (1eq) in an appropriate amount of methylene chloride, water, ethylene dichloride, DMSO, dioxane or a mixed solvent of the above solvents (or add a catalytic amount of benzophenone) , the reaction temperature is controlled between 0°C and 60°C, and placed under a 150W high-pressure mercury lamp or natural light for 1 day to 2 months, during which the reaction is detected and tracked by HPLC. The solvent was removed by lyophilization, and the residue was separated by reverse-phase silica gel column chromatography to obtain the product.

Description of drawings

Figure 1. Reporter gene method to detect the agonistic effect of compounds on GLP-1R

Detailed ways

Experimental Instruments and Reagents

HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector. The chromatographic column is ZORBAX SB-C18 (2.1×150mm, 3.5μm), the mobile phase is acetonitrile/water 65:35, the flow rate is 0.2ml/min, and the detection wavelength is 254nm. Melting point was measured by IA6304 melting point apparatus; NMR was measured by VarianMercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance instrument (solvent is CDCl ₃ , CD ₃ OD or DMSO-d ₆ ); ESI-MS was measured by AB Mariner type mass spectrometer The EI was measured by a Finnigan MAT95 mass spectrometer. The raw materials used in the synthesis are all commercially available products unless the source is specified.

The following specific examples further illustrate the present invention, but do not limit the present invention.

Embodiment 1: the preparation of compound GLP-A-1

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0601 (1 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-A-1 was obtained as light yellow powdery solid.

¹ HNMR (300MHz, DMSO-d ₆ ) 10.118 (2H, br.s), 8.615 (2H, br.s), 8.095 (2H, dd, J ₁ =4.8Hz, J ₂ =1.2Hz), 8.027 (2H , dd, _J1 = 3.9Hz, _J2 = 1.5Hz), 7.569 (4H, d, J = 8.4Hz), 7.365 (4H, d, J = 8.7Hz), 7.318 (2H, dd, J = _3.9 Hz, _J2 =5.1Hz), 7.280(2H, m), 7.260(2H, m), 7.203(2H, br.d, J=8.1Hz), 4.981(2H, s), 3.228(6H, s) , 2.015 (6H, s).

Embodiment 2: the preparation of compound GLP-A-2

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0602 (10 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-A-2 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ8.770 (2H, br.s), 8.090 (2H, d, J=5.1Hz), 8.026 (2H, d, J=3.9Hz), 7.2-7.5( 18H, m), 5.011 (2H, s), 3.231 (6H, s).

Embodiment 3: the preparation of compound GLP-B-1

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0603 (1.5g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-1 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.532 (2H, br.s), 8.433 (2H, br.s), 7.534 (4H, m), 7.428 (4H, d, J=8.7Hz), 7.329 (4H, d, J=8.4Hz), 7.234 (6H, m), 4.912 (2H, s), 1.453 (18H, s).

Embodiment 4: the preparation of compound GLP-B-2

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0604 (2.7 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 20-25 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-2 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.585 (2H, br.s), 8.451 (2H, br.s), 7.456 (4H, d, J=8.7Hz), 7.2-7.4 (12H, m ), 7.1-7.2 (8H, m), 6.854 (2H, d, J=7.8Hz), 4.926 (2H, s), 4.384 (4H, s), 1.463 (18H, s).

Embodiment 5: the preparation of compound GLP-B-3

NMR calibration: δH 2.51 ppm (DMSO-d ₆ ).

Compound 0605 (1.4g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-3 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.554 (2H, br.s), 8.527 (2H, br.s), 7.420 (4H, d, J=8.4Hz), 7.283 (4H, d, J =8.7Hz), 7.215(2H, br.s), 7.137(2H, d, J=9.0Hz), 7.092(2H, d, J=8.1Hz), 4.916(2H, br.s), 3.229(6H , s), 2.257 (6H, s), 1.450 (18H, s).

Embodiment 6: the preparation of compound GLP-B-4

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0606 (2.2 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-4 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.565 (2H, br.s), 8.215 (2H, br.s), 7.464 (8H, s), 7.436 (2H, m), 7.122 (2H, m ), 6.991 (2H, dd, _J1 = 4.5Hz, _J2 = 3.9Hz), 5.055 (2H, s), 1.465 (18H, s).

Embodiment 7: the preparation of compound GLP-B-5

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0607 (3.4g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, 1ml of water was added, and the irradiation was continued for 20-25 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-5 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.661 (2H, br.s), 8.220 (2H, m), 7.495 (4H, d, J=8.4Hz), 7.428 (4H, d, J=8.7 Hz), 7.4-7.6 (4H, m), 7.305 (4H, m), 5.875 (2H, s), 1.467 (18H, s).

Embodiment 8: the preparation of compound GLP-B-6

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0608 (5g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-6 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.584 (2H, br.s), 8.927 (2H, br.s), 8.055 (2H, d, J=5.1Hz), 7.977 (2H, d, J = 2.7Hz), 7.631 (4H, d, J = 8.4Hz), 7.546 (4H, d, J = 9.0Hz), 7.489 (4H, d, J = 8.7Hz), 7.275 (2H, dd, J ₁ = 4.5Hz, _J2 =3.9Hz), 7.053(4H, d, J=8.7Hz), 5.298(2H, s), 1.481(18H, s).

Embodiment 9: Preparation of Compound GLP-B-7

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0609 (2.6g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-7 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ9.542 (2H, br.s), 8.306 (2H, br.s), 7.2-7.5 (22H, m), 6.903 (4H, d, J=8.7Hz ), 5.066 (4H, s), 4.797 (2H, s), 1.462 (18H, s).

Embodiment 10: Preparation of compound GLP-C-1

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Compound 0610 (4.5 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-C-1 was obtained as light yellow powdery solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ8.513 (2H, br.s), 7347 (4H, m), 7.267 (4H, d, J=7.8Hz), 7.190 (4H, d, J=7.8 Hz), 7.143 (2H, d, J = 7.5 Hz), 7.042 (2H, d, J = 7.5 Hz), 4.880 (2H, s), 2.292 (6H, s), 2.137 (6H, s).

Example 11: Preparation of compound GLP-D-1

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 12: Preparation of compound GLP-D-2

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 13: Preparation of compound GLP-D-3

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 14: Preparation of compound GLP-D-4

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 15: Preparation of compound GLP-D-5

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 16: Preparation of compound GLP-D-6

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 17: Preparation of compound GLP-D-7

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 18: Preparation of compound GLP-D-8

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 19: Preparation of compound GLP-D-9

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 20: Preparation of compound GLP-D-10

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 21: Preparation of Compound GLP-D-11

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 22: Preparation of compound GLP-D-12

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 23: Preparation of compound GLP-D-13

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 24: Preparation of compound GLP-D-14

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 25: Preparation of compound GLP-D-15

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Example 26: Preparation of compound GLP-D-16

NMR calibration: δH 2.50 ppm (DMSO-d ₆ ).

Embodiment 27: biological activity test

1. Reporter gene expression detection

GLP-1R is a G protein-coupled receptor. When GLP-1R is combined with an agonist, the Gα subunit of the G protein is activated to stimulate adenylyl cyclase, resulting in an increase in intracellular cAMP levels. Because there is a cAMP response element in the promoter region of the pre-insulin gene, cAMP binds to the response element to initiate the transcription of the pre-insulin gene, thereby stimulating the expression and secretion of insulin (Diabetes, 2000, Vol. 49: 1156-1164). In this experimental method, a human embryonic kidney cell line (HEK 293) stably transfected with a GLP-1R receptor gene expression vector and a luciferase reporter gene expression vector regulated by a cAMP response element was used to detect its response to the tested compound (Cell Biology, 1992, Vol.89: 8641-8645; Proc. Natl. Acad. Sci. U.S.A. 1987, Vol. 84: 3434-3438). When screening compounds, samples that can induce luciferase reporter gene expression are considered to have GLP-1R agonistic activity.

1.1 Test materials and instruments

Cell line: HEK 293/GLP-1R+Luc cell line with stable expression of GLP-1R and luciferase (built by the National Center for New Drug Screening)

Fetal bovine serum (GIBCO company)

DMEM medium (GIBCO company)

Steady-Glo ^TM Luciferase Assay System (Promega)

GLP-1 standard (Sigma company)

G418 (Invitrogen)

Forma carbon dioxide incubator (Forma company);

Victor ² plate reader (Wallac company);

Compounds to be tested: GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7

1.2 Test method

HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000 cells/100 μl/well, and cultured overnight at 37°C in DMEM containing 10% fetal bovine serum and 500 μg/ml G418. Dilute GLP-1 standard substance and test compounds GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7 respectively to a certain concentration gradient, and then add the above 96-well micropipette at 1 μl/well in the culture plate. Incubate for 6 hours at 37 °C, 5% _CO2 . The luciferase activity was detected according to the instructions of the Steady-Glo ^TM luciferase assay system kit, and the Victor ² plate reader was used for reading.

1.3 Test results

The research results showed ( FIG. 1 , Table 1 and Table 2 ), compounds GLP-A-1, GLP-B-3, GLP-B-6, and GLP-B-7 all showed certain agonistic activity. Taking the luciferase activity induced by 10nM GLP-1 as 100%, the highest reaction efficiencies of the above compounds were 48.8%, 45.3%, 49.3% and 19.7%, respectively, and the EC ₅₀ value of compound GLP-A-1 is 318.2nM. The EC ₅₀ value of GLP-1 in the same test system was 0.11nM.

Table 1. Reporter gene detects the agonistic activity of compound GLP-B-3 and GLP-B-6 (% response, taking the response of 10nM GLP-1 as 100%)

Table 2. Reporter gene detects the agonistic activity of compound GLP-B-7 and GLP-A-1 (% response, with the response of 10nM GLP-1 as 100%)

Claims (9)

1. acceptable salt on one type of compound that replaces the tetramethylene structure by having of representing of following general formula I or its pharmacology:

Wherein, X, Y are respectively NH;

R ₁, R ₂Be independently of one another respectively:

Wherein, R ₅Be following any one substituting group: benzyl; C ₁-C ₆Alkyloyl; Thenoyl; X ₁Be O;

R ₃, R ₄Be respectively:

Wherein, R ₆Be following any one substituting group: C ₁-C ₆Alkyloyl; C ₃-C ₆The cycloalkanes acyl group; X ₂Be NH;

Perhaps, R ₁, R ₂Be independently of one another respectively:

Wherein, R ₁₂Be following any one substituting group: H; C ₁-C ₆Alkyl;

R ₁₃Be following any one substituting group: benzyl; C ₁-C ₆Alkyloyl; Thenoyl; X ₁Be O; X ₂Be O;

R ₃, R ₄Be respectively:

Wherein, R ₆Be following any one substituting group: C ₁-C ₆Alkyloyl; C ₃-C ₆The cycloalkanes acyl group; X ₂Be NH.

2. one kind has the compound that replaces the tetramethylene structure, and said compound is:

3. one kind prepares the said method with the compound that replaces the tetramethylene structure of claim 1, is characterised in that compound 1 (1eq) and compound 2 (1eq) are dissolved in an amount of DMSO that temperature of reaction is controlled between 0 ℃～60 ℃; Placed under 150W high voltage mercury lamp or the natural light illumination 1 day to 2 months; Add an amount of water during this time and make and react completely, detect with HPLC and follow the tracks of reaction, lyophilize removes and desolvates; Residuum obtains product with the reversed-phase silica gel column chromatography separation

Wherein, R ₁, R ₂, R ₃, R ₄, X and Y definition with claim 1.

4. the described preparation method with the compound that replaces the tetramethylene structure of root a tree name claim 3, the benzophenone that adds catalytic amount when it is characterized in that reacting promotes reaction to carry out.

5. prevent and/or treat the purposes in the medicine of metabolism disorder property disease, cardiovascular disorder and nerve degenerative diseases according to claim 1 or 2 said compound or pharmaceutically acceptable salt thereofs in preparation.

6. pharmaceutical composition that is used to prevent and/or treat metabolism disorder property disease, cardiovascular disorder and nerve degenerative diseases, said composition contain as the claim 1 of activeconstituents or 2 described compounds and this compounds acceptable salt in treatment.

7. pharmaceutical composition according to claim 6 is characterized in that further containing acceptable carrier and vehicle on the pharmacology.

8. pharmaceutical composition as claimed in claim 6 is characterized in that said disease or symptom are because of causing medicine generation resistance or the toxic side effects that has gone on the market.

9. medicine box; It comprises acceptable salt on claim 1 or 2 described compounds or its pharmacology, and uses acceptable salt on said compound or its pharmacology to prevent and/or treat the explanation of metabolism disorder property disease, cardiovascular disorder and nerve degenerative diseases.

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