WO2008067712A1 - Compounds having substituted cyclopropane structure, preparation method and uses thereof - Google Patents

Compounds having substituted cyclopropane structure, preparation method and uses thereof Download PDF

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WO2008067712A1
WO2008067712A1 PCT/CN2007/002975 CN2007002975W WO2008067712A1 WO 2008067712 A1 WO2008067712 A1 WO 2008067712A1 CN 2007002975 W CN2007002975 W CN 2007002975W WO 2008067712 A1 WO2008067712 A1 WO 2008067712A1
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group
alkoxy
halogen atom
substituted
alkyl
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PCT/CN2007/002975
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French (fr)
Chinese (zh)
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Mingwei Wang
Qing Liu
Na Li
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a class of compounds having a substituted cyclopropane structure, a process for the preparation thereof, and as a glucagon like peptide-1 receptor (Glucagon like peptide) 1 receptor, GLP-1R ) modulators in the prevention and / or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity, etc.), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease) Medical use.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity, etc.
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity, etc.
  • neurodegenerative diseases such as Alzheimer's disease
  • Medical use BACKGROUND OF THE INVENTION Disorders of glucose metabolism, especially diabetes, have become a major disease that threatens human health and life in modern society. It is predicted that diabetes patients worldwide are increasing at a rate of 6% per year.
  • Diabetes 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 and disease is the lack of absolute insulin secretion.
  • the clinical treatment is supplemented with insulin.
  • Lord it is also known as insulin-dependent diabetes.
  • Type 2 diabetes accounts for more than 95% of the diseased 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 development and progression of type 2 diabetes.
  • Therapeutic drugs for type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers, and ancillary measures. After the sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, it closes the 4-electrode channel and blocks the potassium ion efflux, leading to depolarization of the cell membrane, causing the Ca 2+ channel to open, causing extracellular calcium influx. The increase in intracellular calcium concentration triggers the release of insulin.
  • the biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis.
  • glibenclamide excellent Hypoglycemic
  • gliclazide domecon
  • glipizide mepyridin
  • gliclazone sucgar level.
  • the biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis.
  • hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), ⁇ 3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids.
  • Metabolic interference drugs such as ⁇ -glucosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors.
  • GLP-1 R belongs to type B G protein-coupled receptor (GPCR).
  • GLP-1 gutagonal peptide-1
  • the gutagonal peptide-1 (GLP-1) released by the enteroendocrine cells is activated by highly specific binding to GLP-1R. It stimulates insulin secretion, inhibits the production of glucagon, and lowers postprandial blood glucose and maintains it at a constant level. Under physiological conditions, the effect of GLP-1 on insulin secretion is dependent on blood glucose concentration, and hypoglycemia does not occur due to sustained secretion. GLP-1 also promotes the proliferation and differentiation of beta cells, as well as neuromodulation, delays gastric emptying, and reduces appetite. In vitro, GLP-1 promotes the differentiation of embryonic stem cells into beta-like cells with insulin secretion (J Endocrinol.
  • GLP-1 acts on the central nervous system to promote cell survival and reduce apoptosis, reduce the neurotoxicity of ⁇ -amyloid peptide, inhibit the progression of neurodegenerative diseases, and promote learning and memory. Therefore, GLP-1 has recently been proposed for Alzheimer's disease. Treatment ( Ann NY Acad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol Exp Ther, 2002, 302: 881- 888). In addition, GLP-1 also plays an important role in the cardiovascular system. It has the effect of lowering blood pressure and dilating blood vessels. Acute injection of GLP-1 can be used in cardiac hypertrophy.
  • GLP-1 drugs such as the GLP-1 derivative developed by Danovo Nordisk of Denmark (trade name Limglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Eli Lilly and Company
  • GLP-1 analogue Exendin-4 trade name Exenatide; was approved for marketing in April last year and is expected to exceed $1 billion in sales this year.
  • GLP-1 and its peptide analogs there have been no reports of successful development of non-peptide small molecule GLP-1R agonists.
  • An object of the present invention is to provide a compound represented by the following formula I and a pharmaceutically acceptable salt thereof; another object of the present invention is to provide a process for producing a compound represented by the following formula I; It is still another object of the invention to provide a pharmaceutical composition comprising a compound represented by the following formula I; A further object of the present invention is to provide a compound represented by the following Formula I as a glucagon-like peptide-1 receptor modulator in the prevention and/or treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and Obesity), cardiovascular disease and neurodegenerative diseases
  • the present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Members of drugs such as Alzheimer's disease).
  • the present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes:
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compound of the above formula I is a ring, characterized in that when X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, it is:
  • R 4 is any one of the following substituents: H; an alkyl group; any one, two or three substituted ( ⁇ - ⁇ 6 containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group) alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a ?
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, Any one, two or three substituted thienyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a fluorenyl group, an ethylthio group; containing a halogen atom, C r C Any one, two or three substituted pyrrole groups of 4 alkyl, nitro, carboxyl, aldehyde,
  • R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C!-Ce; any one, two or three containing an alkoxy group including a prime atom, d- or a hydroxyl group.
  • C r C 6 alkyl substituted C r C 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, d-alkoxy or hydroxy group Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a C 6 alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two three or substituted C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a pigment contain any atoms including, C r C 6 alkoxy or hydroxy, including one, Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; any one, two or three containing a halogen atom, a hydroxyl group of C r C 6 or a hydroxyl group Substituted
  • C r C 6 alkanoyl include a halogen atom contain any, -C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C r C 6 alkenoyl ;!
  • 3 ⁇ 4 comprise any pigment containing atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; and comprising Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; a formyl adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrroyl; Is (CH 2 ) classroom, n is 0-2, 0, S or H; or R 2
  • R n and R 12 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group including a ? 3 atom, a C 6 alkoxy group or a hydroxyl group; a substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group ; 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes contain any C, C r C 6 alkoxy or hydroxy, including one, two or three substituents 2 -C 6 alkynyl group of a cycloalkyl group of C r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom
  • C r C 4 Any one, two or three substituted thienyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two of an atom, a C, a C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group.
  • R 2 and R 3 are respectively: Wherein R 5 is any one of the following substituents: H; d-alkyl; any one, two or three substituted Ci-alkyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group ; (3 ⁇ 4- (36 alkenyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 An alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of d- or a hydroxyl group; a C 3 -C 6 naphthenic group; Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl
  • One, two or three substituted pyranyl groups Any one, two or three substitutions of a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group a thienyl group; containing an alkyl group including a cyclin atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted pyrrolyl groups; an alkanoyl group of Ci-C 6 ; any one, two or three substituted groups including a halogen atom
  • R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C r C 6 ; any one or two containing an alkoxy group including a prime atom, C r C 6 or a hydroxyl group.
  • a three-substituted alkyl group of dC 6 a C 2 -C 6 alkenyl group; any one, two or three substituted 3 ⁇ 4- ⁇ 6 groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom
  • Substituted furanyl containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thienyl groups including a thiol group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, - an nitro group, a carboxy group, an aldehyde
  • any C r C 6 alkoxy or hydroxy, including one, two or three substituents of the group C r C 6 alkenyl; C 2 - C 6 alkynyl group; a halogen atom-containing include, dC any of the 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; include halogen atom-containing alkyl, C 6 R & lt C Any one, two or three substituted C 3 -C 6 cycloalkane groups such as an oxy group or a hydroxy group; adamantyl formyl group, substituted adamantyl decanoyl group; aroyl group; benzyl group; furoyl group; Nor formyl; thiophene acyl; pyrrolyl acyl; (CH 2 ) n , n is 0-2,
  • R 9 and R 10 are each independently a substituent of any of the following: H; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c r c 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted c 2 -c 6 alkenyl groups such as alkoxy or hydroxy of c r c 6 ;
  • C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of (3 2 - (6 alkynyl; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group
  • R 13 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted C r C 6 containing a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; - (: 6 alkenyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl; any one, two or three substituted ( 2- ( 6 alkynyl; C 3 -C 6 ring) containing a aryl group or a hydroxy group including a aryl group or a d-Cs alkyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; ary
  • C r C 6 alkanoyl includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C r C 6 alkanoyl;
  • R 2 and R 3 are respectively:
  • R 5 is any of the following substituent groups: H; C r to C 6 alkyl; contain any include halogen atoms, alkoxy or hydroxy CrC 6 inner one, two or three substituents of (C6 to alkyl; - (: 6 alkenyl group; comprising comprising 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a!
  • a C 2 -C 6 alkynyl group any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of -C 6 or a hydroxyl group; Aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing arginyl, Cr C alkyl, nitro, carboxy, aldehyde, alkoxy, amine, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 ,
  • R 6 and R 7 are each independently a substituent of any of the following: H; -alkyl; any one, two or three substituted Cs including a pertiny alkoxy group or a hydroxyl group of dC 6 C 6 alkyl R < C 2 -C 6 alkenyl group; and one, two or three substituents include a halogen atom contain any, dC 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group
  • (2 - (6 alkenyl; containing pigment include 3 ⁇ 4 atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted (including 2 -( 6 alkynyl; C) including a halogen atom, a C 6 alkoxy group or a hydroxyl group a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an
  • 3 ⁇ 4 containing pigment comprising atoms, - alkoxy or hydroxy arbitrary inner one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group ugly; adamantane formyl, Substituting adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene acyl; pyrrolidinyl; Is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
  • R 9 and R 10 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom include containing, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups such as alkoxy or hydroxy; C 3 -C 6 cycloalkyl; containing alkoxy groups including a halogen atom, d- or Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as hydroxy; aryl; benz
  • Ru, R 15 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group or a hydroxyl group including a 3 ⁇ 4 atom, a C 6 atom Substituted C r C 6 alkyl; C 2 -C 6 alkenyl; contains included!
  • R 2 and R 3 are respectively: Wherein R 5 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom-containing optionally include, Cr alkoxy or hydroxy group including one, two or three substituents of C r C 6 An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 fluorenyl groups containing a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of -C 6 or a hydroxyl group; a cycloalkyl group of C r C 6 ; containing a halogen atom, Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy
  • Three substituted furanyl; containing pigment atoms include, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted thienyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted pyrrolyl
  • R 6 and R 7 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing a 3 ⁇ 4 atom, an alkoxy group or a hydroxyl group of d- Substituted ( ⁇ -( 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C containing a prime atom, dC 6 alkoxy or hydroxy group) 6 alkenyl; C 2 -C 6 alkynyl group; a!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted C r C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon group amide groups, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents
  • aryl groups containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, Any one, two or three substituted pyridyl groups including an ethylthio group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted furanyl groups including a mercapto group, a methylthio group, an ethylthio group; an alkyl group including a pertinar atom, C r C 4 , a nitro group, a carboxyl group, a keto group,
  • C r C 6 alkanoyl includes any pigment containing atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl; C 2 -C 6 alkenyl group of ; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; comprising comprising!
  • R 9 and R 10 are each independently from any of the following substituents: H; an alkyl group; any one, two or three substitutions including a sulfonate atom, a C 6 alkoxy group or a hydroxy group. a d-alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; normalization group; C 2 -C 6 alkynyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl
  • a three-substituted furyl group containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a thiol group or an ethylthio group; containing a halogen atom, a dC ⁇ alkyl group, a nitro group, a carboxyl
  • any hydroxy or C r C 6 alkoxy inner one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing a halogen atom, C Any one of alkoxy or hydroxy groups of r C 6 , Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; containing any one, two or three including a halogen atom, a decyloxy group of Ci-C 6 or a hydroxyl group Substituted
  • such a 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 present invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurological regressions. ( ⁇ mouth Alzheimer's disease) and so on.
  • the invention relates to methods of 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 to a subject in need or willing to receive treatment or prevention an effective amount of a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom.
  • the above metabolic disorders including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc.
  • administering an effective amount of a compound represented by the following formula I Or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects for prevention or treatment:
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; Alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; Substituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the present invention relates to a combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • This compound has the structure of the following formula I:
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; Sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Or unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; 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 combined preparation.
  • the present invention still further provides the use of the above combined preparation 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).
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases such as Alzheimer's disease.
  • To achieve selective stimulation of the glucagon-like peptide-1 receptor improve the patient's symptoms and quality of life.
  • metabolic disorder refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes.
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function.
  • insulin resistance refers to a decrease in the sensitivity of the surrounding tissues to insulin, and target tissues such as muscles and fats are resistant to insulin-induced glucose uptake. Insulin resistance is prevalent in type 2 diabetes, accounting for more than 90%, and is one of the main factors in the development of type 2 diabetes.
  • obesity refers to an excess of body fat, a man weighing more than 25% of the ideal body weight or a woman weighing more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overeating and too little activity are all causes of obesity.
  • Alzheimer's Disease (AD) also known as Alzheimer's dementia, is a progressive degenerative disease of the nervous system. Clinically manifested as chronic impaired intelligence and chronic loss of memory.
  • cardiac disease includes heart disease, pulmonary heart disease, hypertension, and hyperlipidemia. It has the characteristics of "high incidence, high mortality, high disability rate, high recurrence rate” and “more complications”.
  • an “effective amount” of a compound for treating a particular disease refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods.
  • 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.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes.
  • Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition.
  • substantially pure means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC) or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the material, such as enzymatic activity and biological activity.
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form. To produce a prodrug, the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes. Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties. By virtue of knowledge of pharmacokinetics and metabolism of the drug in the body, once the pharmaceutically active compound is known, one skilled in the art can design a prodrug of the compound. [See
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • union refers to any combination of two or more.
  • object includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • the present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, Members of the drug such as insulin resistance and obesity;), cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • the present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complex.
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or not Substituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture.
  • Compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compound is prepared by the synthetic procedure cited in Section F below. Further 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 invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, streptoic acid, etc.
  • organic acids such as citric acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • An alkylsulfonic acid such as methanesulfonic acid, ethylsulfonic acid or the like
  • an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • 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 to a subject in need or willing to receive treatment or prevention an effective amount of a compound which selectively agonizes the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases Or symptoms.
  • the above metabolic disorder is caused by administering an effective amount of the compound represented by the following formula I or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or the same pharmacological action therewith.
  • X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • a preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • metabolic disorders including but not limited to diabetes, islets
  • the compounds of the invention may be used alone or in combination with other therapeutic agents for diabetes, including insulin sensitizers, which are already on the market or to be marketed.
  • Any suitable metabolic disorder (including but not limited to diabetes, insulin resistance, and obesity) therapeutic agents can be used in combination with the compounds of the present invention.
  • typical insulin sensitizers include rosiglitazone and pioglitazone.
  • the above insulin sensitizer is not administered when the compound of the invention is used. More preferably, the compound of the present invention is used to treat or prevent a disease or symptom caused by the use of the above-mentioned diabetes therapeutic agents (including insulin sensitizers) which have been marketed or will be marketed to produce drug resistance or side effects.
  • the above-mentioned diabetes therapeutic agents including insulin sensitizers
  • Suitable diabetes treatments include the use of insulin sensitizers in combination.
  • it can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically with the compound of the present invention, or with a pharmaceutically acceptable salt thereof.
  • the method further comprises performing a diagnosis and prognostic assessment of the disease or condition of the subject to whom it is administered. Any suitable method can be used to diagnose and assess the relevant disease or condition and its prognosis.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo substances, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • in vivo substances such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • in vivo substances such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms.
  • international patent WO can be used.
  • the present invention also relates to a combination preparation comprising a compound which selectively modulates the function of the glucagon-like peptide-1 receptor, or a pharmacologically Acceptable salts, and one or more therapeutic agents for diabetes include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes and one or more therapeutic agents for diabetes include insulin sensitizers, which are represented by the following general formula I:
  • X and Y are respectively (C3 ⁇ 4) n and n is 0-2, oxygen, sulfur or nitrogen.
  • substituents hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
  • R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • Any suitable therapeutic agent for diabetes can be used in the combination formulations of the invention.
  • one or more of the above-described diabetes therapeutic agents including insulin sensitizers may be included in the combined preparation of the present invention.
  • a metabolic disorder including but not limited to diabetes, insulin resistance, and obesity
  • cardiovascular disease cardiovascular disease
  • a method of sexually transmitted diseases which comprises administering an effective amount of the above combined preparation, or a pharmaceutically acceptable salt thereof, to a subject in need and willingness to receive treatment or prevention, thereby treating or preventing the above-mentioned diseases or symptoms .
  • a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for the prevention and treatment of a metabolic disorder (including However, it is not limited to instructions for use such as diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • a kit is provided comprising the combination described above and the use of the combination to prevent metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular disease and neurodegenerative Instructions for use of diseases such as Alzheimer's disease.
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular Injection, intradermal injection, oral or topical medication.
  • the method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • Pharmaceutical compositions and methods for administration that can be used in the present invention include, but do not It is limited to the contents set forth in U.S. Patent Nos. 5,736,154, 6,197,801, B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • Dosage forms include tablets, troches, soy gums, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compounds of the present invention may be in accordance with conventional pharmaceutical mixing techniques with pharmaceutical carriers or excipients such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -bad dextrins. Tightly mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 to 2000 ml.
  • the amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • the preferred pharmaceutical form is with sterile saline, dextrose solution, buffered Solution, or other pharmaceutically acceptable sterile liquid combination.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • a pharmaceutically acceptable solution are physiological saline and dextrose solutions.
  • the kit of the invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the genetic method detects the agonistic effect of a compound on GLP-1R.
  • the GLP-1 concentration gradient was 10, 1, 0.1, 0.01, 0.001, 0.0001 nM, and the luciferase activity induced by ⁇ was 100%, and the EC 50 value of GLP-1 was measured to be 0.07 nM.
  • Figure 2. Reporter gene method to detect the antagonism of exendin 9 _ 39 on GLP-1.
  • the concentration of GLP-1 was 0.05 nM, and the concentration gradient of exendin 9-39 was 10000, 1000, 100, 10, 1, 0.1, 0 nM, and the activity of exendin 9-39 was set to 100%. The test showed exendin.
  • the GLP-1 concentration gradient was 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0 nM.
  • GLP-1 specifically binds GLP-1R to the 125 1 standard GLP-1 with an IC 5Q value of 0.66 nM.
  • the color pan column is ZORBAX SB-C18 (2.1 X 150 mm, 3.5 ⁇ )
  • the mobile phase is acetonitrile/water
  • the flow rate is 0.2 ml/min
  • the detection wavelength is 254 ⁇ .
  • Example 1 The melting point was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was performed by AB Mariner mass spectrometer It was measured that EI was measured by a Firmigan MAT95 spectrometer.
  • the materials used in the synthesis are commercially available products unless otherwise specified. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
  • Example 1 The melting point was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was performed by AB Mariner mass spectrometer It was measured that EI was measured by a Firmigan MAT95 spectrometer.
  • the materials used in the synthesis are commercial
  • the above amide (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to give an ester. The above ester and thionyl chloride were reacted by heating for 2 hours to obtain a cyclic compound.
  • Example 2 The starting acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester.
  • the above ester (2 eq) was heated to 1.80 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue.
  • An appropriate amount of 10% diethyl ether/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure.
  • the above compound having a substituted cyclopropane structure is dissolved in decyl alcohol, and a sodium hydroxide solution is added thereto, followed by heating to obtain a product.
  • the same method yields the following products:
  • Example 3 The raw material acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester.
  • the above ester (2 eq) was heated to 180 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue.
  • An appropriate amount of 10% acetamino/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure.
  • GLP-1R is a G protein-coupled receptor.
  • the Get subunit of the G protein is activated to stimulate adenylate cyclase, resulting in elevated intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the pre-insulin gene, cAMP binds to the response element to initiate transcription of the pre-insulin gene, thereby stimulating insulin expression and secretion (Diabetes, 2000, Vol.
  • the human embryonic kidney cell line (HEK 293) stably transfected with GLP-1R receptor gene expression vector and luciferase reporter gene expression vector regulated by cAMP response element was used to detect its response to the test compound (Celliology) , 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 84:3434-3438 ). Samples that induce fluorescein ⁇ reporter gene expression when screened for compounds, It has GLP-1R agonistic activity.
  • Test materials and instrument cell lines HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) Fetal bovine serum (GIBCO) DMEM medium (GIBCO) Steady-GloTM Luciferase Assay System (Promega)
  • Forma CO2 incubator Forma
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C was cultured overnight. The GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in ⁇ /well. At 37. C, cultured for 6 hours under 5% C0 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor 2 reader was used for readings.
  • DMEM medium (GIBCO)
  • HEK293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night. Dilute Exendin 9-39 to a concentration gradient and then add 1 ⁇ M/well to the 96-well microplate at 37. Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nM GLP-1 at 37. C, cultured for 6 hours under 5% C0 2 conditions. Press Steady- Glo TM Luciferase Assay System kit instructions detected luciferase activity, Victor 2 plate reader was read.
  • Exendin 9 . 3 dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2) with an IC 5Q value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2.
  • the method for detecting a reporter gene is a method for indirectly determining the level of intracellular cAMP concentration. In order to determine that the active compound can actually increase the intracellular cAMP concentration, directly by cAMP test The test kit is functionally verified.
  • Test materials and instrument cell lines HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) cAMP test kit (Applied Biosystems) Forma carbon dioxide incubator ( Forma) Victor 2 Plate Reader (Wallac) cAMP Standard (kit comes with Applied Biosystems) 3.2 Test-risk method
  • HEK 293 cells were inserted into a 96-well culture plate at 20,000 / lOOul / well, cultured overnight at 37 ° C, GLP-1 was diluted with disulfoxide, and added to the above 96-well microplate in lul / well. Incubate for 15 min at 37 ° C, 5% CO 2 . Intracellular cAMP levels were measured by cAMP-Screen DirectTM Systerm kit instructions.
  • GLP-1 dose-dependently induces intracellular cAMP production (Table 3, Figure 3) with an EC 5() value of 0.079 nM, suggesting that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling. effect.
  • Table 3 Induction of intracellular cAMP by GLP-1 (% response to 10 nM GLP-1
  • HEK 293/GLP1R+Luc cell line self-built by National New Drug Screening Center
  • Labeling compound 125 1 labeled GLP-1 (Amersham Biosciences)
  • GLP-1 specifically binds receptors to the 125 1 standard GLP-1 (Table 4, Figure 4), IC 5 . The value is 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1R

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Abstract

Disclosed are compounds having substituted cyclopropane structure represented by general formula I, method for preparing the same and uses as a kind of glucagons-1 acceptor regulators for preventing and/or treating metabolic disorder diseases (including but not limited by diabetes, insuline resistance and adiposis), angiocardiopathy and nerve regression diseases(such as Alzheimer's disease).

Description

—类具有取代环丙烷结构的化合物、 制备方法及其医学用途 技术领域 本发明涉及一类具有取代环丙烷结构的化合物、 制备方法以及其 作为胰高血糖样肽 - 1受体（ Glucagon like peptide- 1 receptor, GLP-1R ) 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 岛素抵抗和肥胖症等）、 心血管疾病、 神经退行性疾病（如 Alzheimer's 病）等的医学用途。 背景技术 糖代谢紊乱， 特别是糖尿病， 已成为现代社会严重威胁人类健康 与生命的主要疾病。据预测， 全世界糖尿病患者正以每年 6 %的速度递 增， 到 2006年末已有 3.2亿患者（我国为 6000万人， 占居第二位）。 糖尿病是一组由遗传和环境因素相互作用而引起的临床综合症， 主要 分为 1型和 2型， 其中 1型糖尿、病的基本病理生理为绝对性胰岛素分 泌不足， 临床治疗以补充胰岛素为主， 故又称为胰岛素依赖型糖尿病。 2型糖尿病占患病群体的 95%以上，临床研究发现绝大多数 2型糖尿病 患者可合成正常甚至过量的胰岛素， 但因靶细胞对胰岛素的敏感性降 低（也称 "胰岛素抵抗"）， 导致胰岛素相对不足， 又称为非胰岛素依赖 型糖尿病。 胰岛素抵抗是 2型糖尿病发生和发展过程中的关键因素。 2 型糖尿病的治疗药物包括磺脲类、 双胍类、 其他胰岛素增敏剂及辅助 措施等。 磺脲类降糖药物与胰腺 β 细胞膜的受体结合后， 关闭 4甲离子 通道， 阻断钾离子外流， 导致细胞膜去极化， 促使 Ca2+通道开放， 造 成胞外钙离子内流， 胞内钙离子浓度增加后， 触发胰岛素的释放。 按 其问世先后分为两代， 第一代如曱苯磺丙脲， 第二代包括格列本脲（优 降糖）、 格列齐特 （达美康）， 格列吡嗪（美吡哒）和格列喹酮 （糖适 平） 等。 双胍类降糖药物能抑制食欲， 增加胰岛素与受体的结合， 促 进细胞对葡萄糖的无氧酵解， 抑制组织呼吸， 抑制肝糖元异生。 主要 有二曱双胍、 苯乙双胍和丁双胍等。 其他降糖药主要包括噻唑烷二酮 类（Thiazolidinediones )药物（例如曲格列酮、 罗格列酮、吡格列酮等）、 β3-肾上腺素受体调节剂、胰高血糖素受体拮抗剂、脂肪酸代谢干扰药、 α-糖苷酶抑制药（例如阿卡波糖、 伏格列波糖、 米格列醇等）以及醛糖 还原酶抑制剂等。 胰高血糖素样肽 -1受体 ( Glucagon like peptide- 1 receptor, GLP-1 R ) 属于 B类型的 G蛋白偶联受体 ( G protein-coupled receptor, GPCR )。 当机体摄入营养物质时， 肠内分泌细胞释放的肠肽激素-胰高血糖素 样肽 -1 ( Glucagon like peptide-1 , GLP-1 ), 通过与 GLP-1R高度特异性 地结合使其活化， 刺激胰岛素分泌， 抑制胰高血糖素的产生， 使餐后 血糖降低并维持在恒定水平。 生理条件下， GLP-1 刺激胰岛素分泌的 作用依赖于血糖浓度， 不会因持续分泌而发生低血糖。 GLP-1 还具有 促进 β细胞的增殖和分化， 以及神经调节功能， 延迟胃排空， 降低食 欲。 在体外， GLP-1 能促进胚胎干细胞分化为具有胰岛素分泌功能的 类 β细胞 (J Endocrinol. 2005, 186:343-52)。 GLP-1作用于中枢能促进细 胞存活而减少凋亡， 降低 β-淀粉样肽的神经毒， 抑制神经退行性病变 的进程以及促进学习和记忆， 所以最近有人提出将 GLP-1 用于 Alzheimer's病的治疗 （ Ann N Y Acad Sci, 2004,1035:290-315; Nat Med, 2003,9: 1173-1179; Curr Alzheimer Res，2005， 2:377-385; J Pharmacol Exp Ther, 2002, 302:881—888 )。另外， GLP-1在心血管系统中也有重要作用。 它具有降低血压和扩张血管的作用， 急性注射 GLP-1 能在心肌肥大实 验中改善左心室的收缩功能。 它还能在心肌缺血后再灌注的情况下减 轻心肌细胞的损伤 （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)。 由于上迷明确的生理效 应， 自 80年代中期发现该靶点以来， 寻找 GLP-1R的小分子激动剂乃 是国际许多新药开发机构的研究热点。 多家国际著名跨国医药公司均在开发 GLP-1类创新药物， 如丹麦 Novo Nordisk公司开发的 GLP-1衍生物（商品名为 Limglutide;进入三 期临床试验）和美国 Amylin 医药公司和礼来公司联合开发的 GLP-1 类似物 Exendin-4 (商品名 Exenatide; 已于去年 4月份批准上市， 今年 销售额预计超出 10亿美元)。 目前除了 GLP-1及其多肽类似物外， 尚 无任何有关非肽类小分子 GLP-1R激动剂获得成功开发的报道。 由于 多肽药物不便口服， 寻找非肽类 GLP-1R调节剂， 开发具有自主知识 产权的新型抗糖尿病药物是目前许多新药研究机构所共同关注的方 向。 发明内容 本发明的目的在于提供一类由以下通式 I表示的化合物及其药学 上可以接受的盐； 本发明的另一目的在于提供一种制备由以下通式 I表示的化合物 的方法； 本发明的又一目的在于提供一种含有由以下通式 I表示的化合物 的药物组合物； 本发明的再一目的在于提供了由以下通式 I表示的化合物作为胰 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FIELD OF THE INVENTION The present invention relates to a class of compounds having a substituted cyclopropane structure, a process for the preparation thereof, and as a glucagon like peptide-1 receptor (Glucagon like peptide) 1 receptor, GLP-1R ) modulators in the prevention and / or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity, etc.), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease) Medical use. BACKGROUND OF THE INVENTION Disorders of glucose metabolism, especially diabetes, have become a major disease that threatens human health and life in modern society. It is predicted that diabetes patients worldwide are increasing at a rate of 6% per year. By the end of 2006, there were 320 million patients (60 million in China, ranking second). Diabetes 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 and disease is the lack of absolute insulin secretion. The clinical treatment is supplemented with insulin. Lord, it is also known as insulin-dependent diabetes. Type 2 diabetes accounts for more than 95% of the diseased 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 development and progression of type 2 diabetes. Therapeutic drugs for type 2 diabetes include sulfonylureas, biguanides, other insulin sensitizers, and ancillary measures. After the sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic β-cell membrane, it closes the 4-electrode channel and blocks the potassium ion efflux, leading to depolarization of the cell membrane, causing the Ca 2+ channel to open, causing extracellular calcium influx. The increase in intracellular calcium concentration triggers the release of insulin. According to its advent, it was divided into two generations, the first generation such as phenyl sulfonamide, and the second generation including glibenclamide (excellent Hypoglycemic), gliclazide (domecon), glipizide (mepyridin) and gliclazone (sugar level). The biguanide hypoglycemic agent can suppress appetite, increase the binding of insulin to the receptor, promote the anaerobic glycolysis of glucose, inhibit tissue respiration, and inhibit hepatic gluconeogenesis. There are mainly two bismuth bismuth, phenformin and butyl bismuth. Other hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), β3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids. Metabolic interference drugs, α -glucosidase inhibitors (such as acarbose, voglibose, miglitol, etc.) and aldose reductase inhibitors. Glucagon like peptide-1 receptor (GLP-1 R) belongs to type B G protein-coupled receptor (GPCR). When the body ingests nutrients, the gutagonal peptide-1 (GLP-1) released by the enteroendocrine cells is activated by highly specific binding to GLP-1R. It stimulates insulin secretion, inhibits the production of glucagon, and lowers postprandial blood glucose and maintains it at a constant level. Under physiological conditions, the effect of GLP-1 on insulin secretion is dependent on blood glucose concentration, and hypoglycemia does not occur due to sustained secretion. GLP-1 also promotes the proliferation and differentiation of beta cells, as well as neuromodulation, delays gastric emptying, and reduces appetite. In vitro, GLP-1 promotes the differentiation of embryonic stem cells into beta-like cells with insulin secretion (J Endocrinol. 2005, 186: 343-52). GLP-1 acts on the central nervous system to promote cell survival and reduce apoptosis, reduce the neurotoxicity of β-amyloid peptide, inhibit the progression of neurodegenerative diseases, and promote learning and memory. Therefore, GLP-1 has recently been proposed for Alzheimer's disease. Treatment ( Ann NY Acad Sci, 2004, 1035: 290-315; Nat Med, 2003, 9: 1173-1179; Curr Alzheimer Res, 2005, 2: 377-385; J Pharmacol Exp Ther, 2002, 302: 881- 888). In addition, GLP-1 also plays an important role in the cardiovascular system. It has the effect of lowering blood pressure and dilating blood vessels. Acute injection of GLP-1 can be used in cardiac hypertrophy. Improve the contractile function of the left ventricle during the test. It also reduces myocardial cell damage in the presence 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). Since the discovery of this target in the mid-1980s, the search for a small molecule agonist of GLP-1R has been a hot research topic in many international drug development institutions. A number of internationally renowned multinational pharmaceutical companies are developing innovative GLP-1 drugs, such as the GLP-1 derivative developed by Danovo Nordisk of Denmark (trade name Limglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Eli Lilly and Company The jointly developed GLP-1 analogue Exendin-4 (trade name Exenatide; was approved for marketing in April last year and is expected to exceed $1 billion in sales this year). In addition to GLP-1 and its peptide analogs, there have been no reports of successful development of non-peptide small molecule GLP-1R agonists. Due to the inconvenient oral administration of peptide drugs, the search for non-peptide GLP-1R modulators and the development of new anti-diabetic drugs with independent intellectual property rights are the common concerns of many new drug research institutions. Disclosure of the Invention An object of the present invention is to provide a compound represented by the following formula I and a pharmaceutically acceptable salt thereof; another object of the present invention is to provide a process for producing a compound represented by the following formula I; It is still another object of the invention to provide a pharmaceutical composition comprising a compound represented by the following formula I; A further object of the present invention is to provide a compound represented by the following Formula I as a glucagon-like peptide-1 receptor modulator in the prevention and/or treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and Obesity), cardiovascular disease and neurodegenerative diseases
(如 Alzheimer's病）等的医学用途。 本发明提供胰高血糖样肽- 1 受体调节剂， 增加了预防和 /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）等药物的成员。 本发 明涉及由以下通式 I表示的化合物，或其药物学上可接受的盐及其所有 的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其 溶剂化物或其金属配合物： Medical use (eg Alzheimer's disease). The present invention provides a glucagon-like peptide-1 receptor modulator, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases ( Members of drugs such as Alzheimer's disease). The present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes:
Figure imgf000006_0001
其中 X和 Y分别为 （CH2)n，n为 0-2， 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； 卤素； 烷烃; 环烷烃； 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基；
Figure imgf000006_0001
Wherein X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 优选地， 上述式 I的化合物为环状物， 其特征在于： 当 X, Y分 别是（CH2)n, n为 0-2, 氧， 硫或氮， 为:
Figure imgf000007_0001
R 2 , R 3 are each independently any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Preferably, the compound of the above formula I is a ring, characterized in that when X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, it is:
Figure imgf000007_0001
其中 R4为下列任意一种取代基： H; 的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 (^-〇6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括! ¾素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吟基； 吡咯基； 吡啶基； 含有 包括 素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酖胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括! ¾素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d- 的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱 υ基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 crc6的烷酰基； c2-c6的烯酰基； 含有 包括卤素原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C0的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括 素原子、 d- 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃曱酰基； 噻 吩曱酰基； 吡咯甲酰基； ^为 (C¾)n, n为 0-2, 0, S或者 NH时； , 分别为：
Figure imgf000008_0001
其中 R5为下列任意一种取代基： H; d- 的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C!-Qs的烷基； （2-( 6的烯基； 含有包括！ ¾素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基; 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括! ¾素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括！ ¾素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 d- 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯曱酰基； X2为 （CH2)ll5 n为 0-2, 0, S或者 NH; 或者 R2，R3分别为：Wherein R 4 is any one of the following substituents: H; an alkyl group; any one, two or three substituted (^-〇 6 containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group) alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a ? 3⁄4 atom, an -C 6 alkoxy group or a hydroxyl group; C 3 - C 6 cycloalkyl; includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furan a pyridyl group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group, a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Yue thio, ethylthio, including any one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl group, a nitro group, a carboxyl group Any aldehyde, alkoxy, amino, poison group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, C r Any one, two or three substituted alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio group of C 4 furanyl;! ¾ containing pigment comprising atoms, C r C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, Any one, two or three substituted thienyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a fluorenyl group, an ethylthio group; containing a halogen atom, C r C Any one, two or three substituted pyrrole groups of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonylthio, ethylthio group; C r C 6 alkanoyl; contain any halogen atoms include, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c r c 6 alkanoyl; c 2 -c 6 alkenoyl; includes any halogen atom-containing, c r c 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 0 alkenyl group; a C 2 -C 6 alkynyl group of Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; any alkoxy or hydroxy d- inner one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue-adamantyl group, a substituted adamantane formyl; aryl group; a benzyl group; Yue furyl group; Yue-pyran group; Yue thienyl group; pyrroyl; ^ is (C¾) n, n is 0-2, 0, S Or NH; , respectively:
Figure imgf000008_0001
Wherein R 5 is any of the following substituent groups: H; d- alkyl; C optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of -! Qs alkyl;! (2 - (6 alkenyl; containing pigment include ¾ atoms, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of a C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; include a halogen atom-containing, - any of alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; furanyl; Pyranyl; thienyl; pyrrolyl; pyridyl; Any one, including a halogen atom, an alkyl group of C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group, or both Or three substituted aryl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, Any one, two or three substituted pyridyl groups including an ethylthio group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, Any one, two or three substituted furanyl groups including a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group Any one, two or three substituted pyranyl groups including an amino group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , and a nitrate Base, carboxyl group, aldehyde group, alkoxy group, amine group, amide , Any carbon amide group, a mercapto group, methylthio, ethylthio, including one, two or three substituents thienyl; include a halogen atom-containing, C r C 4 alkyl, nitro, carboxyl, aldehyde any alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; comprising comprising a halogen atom, an optionally C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing ¾ atom,! Any one, two or three substituted C 2 -C 6 alkenoyl groups such as alkoxy or hydroxy groups of C r C 6 ; C 2 -C 6 alkynyl groups; Any one, two or three substituted C 2 -C 6 alkynyl groups including a C atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a halogen atom, d- Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups such as alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; Nor formyl; thiophene acyl; pyrrolyl acyl; X 2 is (CH 2 ) ll5 n is 0-2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000009_0001
其中 R6, R7各自独立为下列任意一种取代基： H; C!-Ce的烷基； 含有包括 素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 C6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 垸氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙^基在内的任意一 个、 两个或者三个取代的芳基； 含有包括 素原子、 d- 的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲^ L基、 乙疏基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 趁基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 -C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吟基； 含有包括 卤素原子、 d-O^ 烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d- 的烷酰基； 含有包括! ¾素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的炕氧基或羟基在内的任意一个、 两个或者三个取代的
Figure imgf000009_0001
Wherein R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C!-Ce; any one, two or three containing an alkoxy group including a prime atom, d- or a hydroxyl group. Substituted C r C 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, d-alkoxy or hydroxy group Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a C 6 alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carbon group Any one, two or three substituted aryl groups including an amide group, a fluorenyl group, a thiol group, and an ethyl group; Any one, two or three substituted pyridyl groups including a carboxy group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; any C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, a ^ L group, ethyl group, including a sparse, two or a three-substituted furyl group; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulphide group Any one, two or three substituted pyranyl groups, including a halogen atom, an alkyl group of -C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thioxyl groups including a thiol group, a thiol group, an ethylthio group, a halogen atom, a dO^ alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, Amine, amide, carboxamide, sulfhydryl, sulfhydryl Ethylthio, including any one, two or three substituents pyrrolyl; D- alkanoyl;! ¾ containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two three or substituted C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a pigment contain any atoms including, C r C 6 alkoxy or hydroxy, including one, Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; any one, two or three containing a halogen atom, a hydroxyl group of C r C 6 or a hydroxyl group Substituted
C2-C6的炔酰基； （¾-(36的环烷酰基； 含有包括卤素原子、 crc6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯甲酰基； ,为 （CH2)n, n为 0-2, 0, S或 者 NH; X2为 （C¾)ll5 n为 0-2, 0, S或者 NH; 或者 R2, R3分別为：
Figure imgf000011_0001
其中 R8为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C 々烯基； <¾-€6的炔基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括鹵素原子、 C 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；C 2 -C 6 alkynyl group of; (¾- (36 cycloalkyl group; a halogen atom include any containing, c r c 6 alkoxy or hydroxy, including one, two or three substituents of c 3 -c 6 cycloalkanoyl; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl acyl; furoyl; pyranoyl; thiophene acyl; pyrroyl group; , (CH 2 ) n , n is 0-2, 0, S or NH; X 2 is (C¾) ll5 n is 0-2, 0, S or NH; or R 2, R 3 are:
Figure imgf000011_0001
Wherein R 8 is any of the following substituent groups: H; C r C 6 alkyl; and one, two or three substituents include a halogen atom contain any, dC 6 alkoxy or hydroxy, including a C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents 々 a C 2 -C alkenyl group; An alkynyl group of <3⁄4-€ 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a pertiny atom or a hydroxyl group of C r C 6 ; C 3 -C 6 cycloalkyl; includes any pigment containing atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; aryl; benzyl; furan a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a cycline atom, C ar C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted aryl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Cr C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, hydrazine Any one, two or three substituted furanyl groups including a thiol group and an ethylthio group; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, Any one, two or three substituted pyranyl groups including an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , and a nitrate Any one, two or three substituted thienyl groups including a carboxyl group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substituted alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio Pyrrolyl group;
CrC6的烷酰基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； CrC6的烯酰基； 含有 包括! ¾素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括！ ¾素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯甲酰基； ！为 （CH2)„, n为 0-2， 0, S或者 H; 或者 R2, R3分别为：
Figure imgf000012_0001
其中 R9, 各自独立为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； ¾-(¾的烯基; 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 c2-c6的炔基； crc6的环浣基； 含有包括 卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3- (36的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 琉基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C ^烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d-C 的烷基、 硝基、 羧基、 S 基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻喻基； 含有包括 卤素原子、 d- 的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的烷酰基； 含有包括面素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； CrC6的环烷酰基； 含有包括 素原子、 的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯甲酰基； ,为 （CH2)n, n为 0-2, 0, S或 者 NH; X2为 （CH2)n, n为 0-2, 0, S或者 NH。 当 X, Y分别是（CH2)n，n为 0-2， 氧， 硫或氮， 为:
Figure imgf000014_0001
C r C 6 alkanoyl; include a halogen atom contain any, -C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C r C 6 alkenoyl ;! ¾ comprise any pigment containing atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; and comprising Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; a formyl adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrroyl; Is (CH 2 )„, n is 0-2, 0, S or H; or R 2 , R 3 are:
Figure imgf000012_0001
Wherein R 9, are each independently any of the following substituent groups: H; C r to C 6 alkyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl group; ¾- (¾ alkenyl groups; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of a C 2 -C 6 Alkenyl C 2 -C 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c 2 -c 6 alkynyl group; and R & lt c 6 c Any one, two or three substituted C 3 -(3 6 cycloalkyl; aryl; benzyl; furanyl; or a hydroxy group, including a halogen atom, an alkoxy group or a hydroxyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group Any one, two or three substituted aryl groups including a thiol group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one, two or three substituted pyridyl groups, including a halogen atom, a dC^alkyl group, a nitro group, a carboxyl group, an aldehyde group, or the like, a halogen group, a sulfonyl group, a thiol group, a thiol group, an alkylthio group, Alkoxy, amino, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio Any one, two or three substituted furanyl groups; containing an alkyl group including a halogen atom, dC, a nitro group, a carboxyl group, an S group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl group Any one, two or three substituted pyranyl groups including an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one, two or three substituted thiol groups including a carbonyl group, a carbhydryl group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, and an aldehyde group any embankment group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; comprising comprising surface atom, any hydroxy or C r C 6 alkoxy inner one, two or three substituents of C r C 6 alkyl group; a C 2 -C 6 alkenyl group; a containing element comprises atoms, C any r C 6 alkoxy or hydroxy, including, two or three Substituted C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a C optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents 2 -C 6 alkynyl; C r C 6 cycloalkanoyl; any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a prime atom, an alkoxy group or a hydroxyl group; Gold Alkanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; , (CH 2 ) n , n 0-2, 0, S or NH; X 2 is (CH 2 ) n , and n is 0-2, 0, S or NH. When X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, are:
Figure imgf000014_0001
其中 Rn， R12各自独立为下列任意一种取代基： H; d-C6的烷基； 含有包括! ¾素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； CrC6的环烷基； 含有包括 卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括 素原子、 CrC4的烷基、 硝基、 羧基、 基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 Cr C4的烷基、 硝基、 羧基、 酸基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括! ¾素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 C,-C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 crc6的烷酰基； c2-c6的 烯酰基； 含有包括 素原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代的（ 2-( 6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； CrC6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯甲酰基； ！为 （CH2)n, n为 0-2, 0, S或 者 NH; X2为 （C¾)n, n为 0-2, 0, S或者 NH时； Wherein R n and R 12 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group including a ? 3 atom, a C 6 alkoxy group or a hydroxyl group; a substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group ; 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes contain any C, C r C 6 alkoxy or hydroxy, including one, two or three substituents 2 -C 6 alkynyl group of a cycloalkyl group of C r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of -C6 or a hydroxyl group; an aryl group; group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; comprising pigment containing atoms, C r C 4 alkyl group, a nitro group, a carboxyl group, group, alkoxy, amine, amide, carboxamide any group, a mercapto group, methylthio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, C r C 4 to Any one, two or three substituted pyridyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two including a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group, or a three-substituted furyl group; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyranyl groups including a group; an alkyl group including a ? 3⁄4 atom, C r C 4 , Any one, two or three substituted thienyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two of an atom, a C, a C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group. three or substituted pyrrolyl; C r C 6 alkanoyl; one, two or three substituents of c r c contain any alkoxy include halogen atoms, C r C 6 alkoxy or hydroxy, including 6 An acyl group; an alkenoyl group of c 2 -c 6 ; any one, two or three substituted ( 2- ( 6 enoyl; C 2 ) containing an alkoxy group or a hydroxyl group including a cyclin atom, c r c 6 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; a cycloalkanoyl group of C r C 6 Any one, two or three substituted ones including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; c 3 -c 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; Yue furyl group; Yue-pyran group; Yue thienyl group; pyrroyl;! is (CH 2) n , n is 0-2, 0, S or NH; X 2 is (C3⁄4) n , n is 0-2, 0, S or NH;
R2, R3分别为：
Figure imgf000015_0001
其中 R5为下列任意一种取代基： H; d- 的烷基； 含有包括卤素 原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 Ci- 的烷基； （¾-(36的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括 素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括 素原子、 d- 的烷基、 硝基、 羧基、 趁基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括 素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； Ci-C6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 C 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； CrC6的环烷酰基； 含有包括 素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚垸曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩甲酰基； 吡咯甲酰基； X2为 （CH2)n, n为 0-2, O, S或者 NH; 或者 R2， R3分别为：
Figure imgf000017_0001
R 2 and R 3 are respectively:
Figure imgf000015_0001
Wherein R 5 is any one of the following substituents: H; d-alkyl; any one, two or three substituted Ci-alkyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group ; (¾- (36 alkenyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 An alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of d- or a hydroxyl group; a C 3 -C 6 naphthenic group; Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; Group; an aryl group; a benzyl group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; comprising pigment containing atoms, C r C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine Any one, two or three substituted aryl groups including a amide group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substitutions of an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group or an ethylthio group of r c 4 a furanyl group; optionally containing an atom, a d-alkyl group, a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, and the like. One, two or three substituted pyranyl groups; Any one, two or three substitutions of a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group a thienyl group; containing an alkyl group including a cyclin atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted pyrrolyl groups; an alkanoyl group of Ci-C 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; Alkanoyl group of C r C 6 ; alkenoyl group of C 2 -C 6 ; any one, two or three substituted C 2 -C 6 containing a halogen atom, an alkoxy group of -C 6 or a hydroxyl group Alkenoyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of C or a hydroxyl group; C r C 6 a cycloalkanoyl group; any one or two containing an alkoxy group including a prime atom, C r C 6 or a hydroxyl group or Three substituted C 3 -C 6 cycloalkyl group; a formyl adamantane, substituted adamantane embankment Yue group; an aryl group; a benzyl group; furoyl; formyl pyran; thenoyl; pyrroyl; X 2 Is (CH 2 ) n , n is 0-2, O, S or NH; Or R 2 and R 3 are:
Figure imgf000017_0001
其中 R6, R7各自独立为下列任意一种取代基： H; CrC6的烷基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； C2-C6的烯基; 含有包括卤素原子、 C C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 ¾-< 6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 隧基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； - 的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 crc6的烷酰基； c2-c6的 烯酰基； 含有包括卤素原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括 素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯甲酰基； X2为 （CH2)n, n为 0-2, O, S或 者 NH; 或者 R2, R3分别为：
Figure imgf000018_0001
其中 R8为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC 烷基； C2-C6的烯基； 含有包括 素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的（：2-( 6的烯基； C2-C6的炔基； 含有包括! ¾素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 素原子、 d-C4的烷基、 硝基、 羧基、 趁基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d-C4 的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 - 的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的 p塞 基；含有包括卤素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； 的烷酰基； 含有包括卤素原子、 crc6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 C 的烷酰基； C2-C6的烯酰基； 含有 包括！ ¾素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 CrC6的烯酰基； C2- C6的炔酰基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷醜基；金刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯曱酰基； 为 (CH2)n, n为 0-2, O, S或者 NH; 或者 R2，R3分别为：
Figure imgf000019_0001
Wherein R 6 and R 7 are each independently a substituent of any of the following: H; an alkyl group of C r C 6 ; any one or two containing an alkoxy group including a prime atom, C r C 6 or a hydroxyl group. a three-substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted 3⁄4-< 6 groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom, dC 4 alkyl, nitro, carboxyl, tunnel, alkoxy, amine, amide, carboxamide, any mercapto, Yue thio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, C r C alkyl 4 Any one, two or three substituted pyridyl groups, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one, two or three of a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, or an ethylthio group. Substituted furanyl; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thienyl groups including a thiol group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, - an nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group Base, amide group, carboxamide group, sulfhydryl group, hydrazine Any one, two or three taking sulfur or ethylthio group Substituted pyrrolyl; - alkanoyl; containing optionally include a halogen atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c r c 6 alkanoyl; c 2 -c 6 alkenoyl; includes any halogen atom-containing, c r c 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group of Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group ; furoyl; pyranoyl; thiophene; pyrroyl; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
Figure imgf000018_0001
Wherein R 8 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituted CrC An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted (: 2 -( 6 alkenyl groups) containing an alkoxy group or a hydroxyl group including a pertin atom, C r C 6 ; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a ? 3⁄4 atom, an alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; Furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkane, d-C4 alkyl, nitro, carboxy, decyl, alkoxy, amine, amide, carboxamide, Any one, two or three substituted aryl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group Carboxyl group, aldehyde Any one, two or three substituted pyridyl groups including a base, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkane having a halogen atom, dC 4 Any one, two or three substituted furyl groups including a nitro group, a carboxy group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group; Any one or two including a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group, or a three-substituted pyranyl group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted p-block groups; containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, Any one of thiol and ethylthio Two or three substituents pyrrolyl; alkanoyl; containing optionally include a halogen atom, c r c 6 alkoxy or hydroxy, including one, two or three substituents of C alkanoyl; C 2 - C 6 enoyl; contains included! ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of the group C r C 6 alkenyl; C 2 - C 6 alkynyl group; a halogen atom-containing include, dC any of the 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; include halogen atom-containing alkyl, C 6 R & lt C Any one, two or three substituted C 3 -C 6 cycloalkane groups such as an oxy group or a hydroxy group; adamantyl formyl group, substituted adamantyl decanoyl group; aroyl group; benzyl group; furoyl group; Nor formyl; thiophene acyl; pyrrolyl acyl; (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
Figure imgf000019_0001
其中 R9, R10各自独立为下列任意一种取代基： H; - 的烷基; 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 crc6的烷基； c2-c6的烯基； 含有包括卤素原子、 crc6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的烯基；Wherein R 9 and R 10 are each independently a substituent of any of the following: H; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of c r c 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted c 2 -c 6 alkenyl groups such as alkoxy or hydroxy of c r c 6 ;
C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的（32-( 6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 （^-^的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括！ ¾素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 鹵素原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； （2-€6的 烯酰基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of (3 2 - (6 alkynyl; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group Any one, two or three substituted aryl groups including a thiol group or an ethylthio group; containing an alkyl group including a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, and an amine group Any one, two or three substituted pyridyl groups including a amide group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, Aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted furan groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted pyranyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkane Any one, two or three substituted thienyl groups including an oxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-, and a nitrate any group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; dC 6 alkyl acyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; (2 - € 6 alkenoyl; include halogen-containing Any one or two of an atom, an alkoxy group or a hydroxyl group Or three substituted C 2 -C 6 alkenoyl; C 2 -C 6 alkynyl; containing halogen Any atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of
C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括！ ¾素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 CrC6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩曱酰基； 吡咯甲酰基； 1为 （CH2)n，n为 0-2, 0, S或 者 NH; X2为 （CH2)n, n为 0-2, 0, S或者 NH。 当 X, Y分别是（CH2)n, n为 0-2, 氧， 硫或氮， 为：
Figure imgf000021_0001
C 2 -C 6 alkynyl; C 3 -C 6 cycloalkanoyl; contains included! ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three cycloalkyl group substituted with a C r C 6; Yue group adamantane, substituted adamantane Yue group; an aryl group; Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrroyl group; 1 is (CH 2 ) n , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , n It is 0-2, 0, S or NH. When X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, it is:
Figure imgf000021_0001
其中 R13为下列任意一种取代基： H; d-C6的烷基； 含有包括卤素 原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷基； -(：6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基; 含有包括 素原子、 d-Cs的烷氧基或羟基在内的任意一个、 两个或者 三个取代的（ 2-( 6的炔基； C3-C6的环烷基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 CrC4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CVC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括 素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括鹵素原子、 d- 的烷基、硝基、羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；Wherein R 13 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted C r C 6 containing a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; - (: 6 alkenyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl; any one, two or three substituted ( 2- ( 6 alkynyl; C 3 -C 6 ring) containing a aryl group or a hydroxy group including a aryl group or a d-Cs alkyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyrazol a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, an anthracene group; Any one, two or three substituted aryl groups including a thio group or an ethylthio group; an alkyl group including a halogen atom, CVC 4 , a nitro group, Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substituted alkyl, nitro, carboxyl, benzyl, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio group of r C 4 Furanyl; Any one containing an atom, a C ar C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, Two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, Any one, two or three substituted thienyl groups including an ethylthio group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, Any one, two or three substituted pyrrolyl groups including a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group;
CrC6的烷酰基； 含有包括 素原子、 d-C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 C - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括！ ¾素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃曱酰基； 噻 吩甲酰基； 吡咯曱酰基； ！为 （CH2)n, n为 0-2, 0, S或者 NH时； C r C 6 alkanoyl; includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group of ; includes any pigment containing atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen-containing include Any one, two or three substituted C 2 -C 6 alkynyl groups including an atom, a C-alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; When (CH 2 ) n , n is 0-2, 0, S or NH;
R2，R3分别为：R 2 and R 3 are respectively:
Figure imgf000022_0001
Figure imgf000022_0001
其中 R5为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 ( C6的烷基； -(：6的烯基； 含有包括! ¾素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2- C6的炔基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 -C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 素原子、 CrC 烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括 素原子、 C!- 的坑基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻喻基；含有包括卤素原子、 CrC4 的浣基、 硝基、 羧基、 趁基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 -C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； CrC6的环烷酰基； 含有'包括 素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃曱酰基； 噻 吩曱酰基； 吡咯甲酰基； X2为 （CH2)n, n为 0-2, 0, S或者 NH; 或者 R2，R3分别为：
Figure imgf000024_0001
Wherein R 5 is any of the following substituent groups: H; C r to C 6 alkyl; contain any include halogen atoms, alkoxy or hydroxy CrC 6 inner one, two or three substituents of (C6 to alkyl; - (: 6 alkenyl group; comprising comprising ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a! a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of -C 6 or a hydroxyl group; Aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing arginyl, Cr C alkyl, nitro, carboxy, aldehyde, alkoxy, amine, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, Any one, two or three substituted pyridyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substituted furan groups of pit, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one or two containing a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Or three substituted pyranyl groups; Any atom, C r C alkyl, nitro, carboxyl, casein, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including one, two, or a three-substituted thiol group; a thiol group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, and a Any one, two or three substituted pyrrolyl groups including a thio group; an alkanoyl group of C r C 6 ; any one or two containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group; three substituted C r C 6 alkanoyl; C 2 -C 6 alkenyl group; and one, two or three substituents contain any element comprising atoms, C r C 6 alkoxy or hydroxy, including a C 2- C6 alkenoyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, a C 6 alkoxy group or a hydroxyl group alkynyl group; C r C 6 cycloalkyl group; optionally containing 'includes a prime atoms, C r C 6 alkoxy or hydroxy, including one, two Or three substituted C 3 -C 6 cycloalkanoyl; adamantyl formyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; Or R 2 and R 3 are:
Figure imgf000024_0001
其中 R6, R7各自独立为下列任意一种取代基： H; - 的烷基； 含有包括 素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻 p分基； 吡咯基； 吡啶基； 含有包括鹵素原子、 CrC4的烷基、 硝基、 羧基、 酸基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙石克基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d- 的烷基、 硝基、 羧基、 趁基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 （^-( 4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括 素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 -C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的垸酰基； 含有包括卤素原子、 d- 的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔醜基； 含有包括卤素 原子、 d-Cs的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2- C6的炔酰基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚坑曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯曱酰基； X2为 （CH2)n, n为 0-2, O, S或 者 NH; 或者 R2, R3分別为：
Figure imgf000025_0001
其中 Rs为下列任意一种取代基： H; -C6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷基； （2-( 6的烯基； 含有包括! ¾素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的（：2-( 6的炔基； C3-C6的环烷基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d-C4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻喻基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- 的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的婦酰基； 含有 包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括! ¾素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷醜基；金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃曱酰基； 噻 吩曱酰基； 吡咯曱酰基； ！为 （CH2)n，n为 0-2, O, S或者 NH; 或者 R2, R3分别为：
Figure imgf000026_0001
Wherein R 6 and R 7 are each independently a substituent of any of the following: H; -alkyl; any one, two or three substituted Cs including a pertiny alkoxy group or a hydroxyl group of dC 6 C 6 alkyl R &lt; C 2 -C 6 alkenyl group; and one, two or three substituents include a halogen atom contain any, dC 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 - a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group ; pyranyl; thiop group; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, C r C4, a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, any mercapto, thio Yue, Shi Keji b including one, two or three aryl group substituents; include halogen atom-containing, C r C 4 to Any one, two or three substituted pyridyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two including a halogen atom, an alkyl group of d-, a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group, or three substituted furanyl; containing a halogen atom include, (^ - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue, b Any one, two or three substituted pyranyl groups including a thio group; an alkyl group including a sulfonate atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, Any one, two or three substituted thienyl groups including a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, -C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkane Oxyl, amine, amide, carboxamide, sulfhydryl, Any one, two or three of thiol and ethylthio Substituted pyrrolyl; C r C 6 acyl group of the embankment; contain any halogen atoms include, d- alkoxy or hydroxy group including one, two or three substituents of C r C 6 alkanoyl; C 2 - C 6 alkenoyl; one, two or three substituents containing a C alkenoyl optionally include a halogen atom, R & lt C C 6 alkoxy or hydroxy, including 2 -C 6; and the C 2 -C 6 alkynyl Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of d-Cs or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a fluorenyl group, a substituted adamantyl decanoyl group; an aroyl group Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are :
Figure imgf000025_0001
Wherein and R s represents any of the following substituents: H; -C6 alkyl group; one, two or three substituents include a halogen atom-containing arbitrary, C r C 6 alkoxy or hydroxy, including a C r C 6 alkyl;! (2 - (6 alkenyl; containing pigment include ¾ atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted (including 2 -( 6 alkynyl; C) including a halogen atom, a C 6 alkoxy group or a hydroxyl group a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted aryl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-, Group, a carboxyl group, an aldehyde Any one, two or three substituted pyridyl groups including a base, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkane having a halogen atom, dC 4 Any one, two or three substituted furyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one or two including a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group, or a three-substituted pyranyl group; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, and a Any one, two or three substituted silylation groups including a thio group; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, Carboxamide, sulfhydryl, methylthio, ethylthio It is intended one, two or three substituents pyrrolyl; D- alkanoyl; containing optionally include a halogen atom, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 acyl women's; includes any pigment containing atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a! ¾ containing pigment comprising atoms, - alkoxy or hydroxy arbitrary inner one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group ugly; adamantane formyl, Substituting adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene acyl; pyrrolidinyl; Is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
Figure imgf000026_0001
其中 R9, R10各自独立为下列任意一种取代基： H; d-C6的烷基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻喻基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 酸基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 d-C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲疏基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的烷酰基； 含有包括面素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 - 的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的Wherein R 9 and R 10 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; Includes atoms of any element containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, any C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom include containing, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups such as alkoxy or hydroxy; C 3 -C 6 cycloalkyl; containing alkoxy groups including a halogen atom, d- or Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as hydroxy; aryl; benzyl; furyl; pyranyl; thiol; pyrrolyl; Any one, two or three of an atom, a d-alkyl group, a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group substituted aryl; include a halogen atom-containing, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbonyl 4 Group, any mercapto, Yue thio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, dC alkyl, nitro, carboxyl, aldehyde, alkoxy 4 Any one, two or three substituted furanyl groups including an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group Any one, two or three substituted pyranyl groups such as a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl group or an ethylthio group; , any of a C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three a substituted thienyl group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyridyl Group; C r C 6 alkanoyl; contain any pigment surface comprising atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of - alkanoyl; C 2 -C 6 of alkenoyl; contain any halogen atoms include, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; and comprising Including halogen Any atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of
C2-C6的炔酰基； CrC6的环烷酰基； 含有包括！ ¾素原子、 C C6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n, n为 0-2, 0, S或 者 NH; X2为 （CH2) n为 0-2, 0， S或者 NH。 当 X, Y分别是（CH2)n, n为 0-2, 氧， 硫或氮， R!为：
Figure imgf000028_0001
C 2 -C 6 alkynyl; C r C 6 cycloalkanoyl; contains included! Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, a C 6 alkoxy group or a hydroxyl group; an adamantyl formyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n is 0-2 , 0, S or NH. When X, Y are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, R! is:
Figure imgf000028_0001
其中 Ru, R15各自独立为下列任意一种取代基： H; d-C6的烷基; 含有包括; ¾素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括！ ¾素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的（3-06的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； p塞吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括 素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 CrC4的烷基、 硝基、 羧基、 隧基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个^者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d- 的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 crc6的烷酰基； c2-c6的 烯酰基； 含有包括卤素原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； （ 2-( 6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 crc6的炔酰基； crc6的环烷酰基； 含有包括卤素原子、 crc6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯甲酰基； ！为 （CH2)n, n为 0-2, O, S或 者 NH; X2为 （CH2)n， n为 0-2, 0, S或者 NH时， Wherein Ru, R 15 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three containing an alkoxy group or a hydroxyl group including a 3⁄4 atom, a C 6 atom Substituted C r C 6 alkyl; C 2 -C 6 alkenyl; contains included! ¾ atom, R & lt any C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom-containing include, any alkoxy or hydroxy C r C 6, including one, two or three substituents of C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group; a halogen atom include containing, C r C any of the 6 alkoxy or hydroxy, including one, two or three substituents (the cycloalkyl group of 3-06; aryl group; a benzyl group; furanyl; pyranyl; p-thiophene group; pyrrolyl a pyridyl group; containing any one including a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; , two or three aryl group substituents; including vegetarian containing atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group, a mercapto group, a sulfur Yue Any one, two or three substituted pyridyl groups including a thiol group; an alkyl group including a halogen atom, C r C 4 , Any one, two or three substitutions of a nitro group, a carboxyl group, a tunnel group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group a furanyl group; containing an alkyl group including a halogen atom, d-C4, a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and the like. Any one or two of three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted thienyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-C4, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted pyrrolyl groups including a amide group, an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkanoyl group of d-; containing a halogen atom, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include containing, c r c 6 alkoxy or hydroxy Any one, two or three substituted C 2 -C 6 enoyl groups; 2- ( 6 -alkynyl; acetylene group of any one, two or three substituted c r c 6 containing a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a cycloalkanoyl group of c r c 6 ; contain any halogen atom includes, c r c 6 alkoxy or hydroxy, including one, two or three substituents of c 3 -c 6 cycloalkyl group; a formyl adamantane, substituted adamantane Yue group; Aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; ! is (CH 2 ) n , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , when n is 0-2, 0, S or NH,
R2， R3分别为：
Figure imgf000029_0001
其中 R5为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 Cr 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 Cr C6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的浠基； C2-C6的炔基; 含有包括 素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； CrC6的环烷基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 素原子、 -C4的烷基、 硝基、 羧基、 基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括面素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括 1¾素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或 '者三个取代的呋喃基； 含有包括 素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括鹵素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 d-C4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； 的烷酰基； 含有包括卤素原子、 C,-C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 - 的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括 素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 c3-c6的环烷酰基；金刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃甲酰基; 吩曱酰基； 吡咯甲酰基； X2为 （CH2)n, n为 0-2, O, S或者 NH; 或者 R2, R3分别为：
Figure imgf000031_0001
R 2 and R 3 are respectively:
Figure imgf000029_0001
Wherein R 5 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom-containing optionally include, Cr alkoxy or hydroxy group including one, two or three substituents of C r C 6 An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 fluorenyl groups containing a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a prime atom, an alkoxy group of -C 6 or a hydroxyl group; a cycloalkyl group of C r C 6 ; containing a halogen atom, Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy group of dC 6 ; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; Pyridyl; containing any of a group including a aryl group, an alkyl group of -C 4 , a nitro group, a carboxyl group, a group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group , two or three substituted aryl groups; containing an alkyl group including a surface atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted pyridyl groups including a thio group or an ethylthio group; containing an alkyl group including a 13⁄4 atom atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or ', such as an amide group, a carboxamide group, a fluorenyl group, a thiol group, or an ethyl thio group. Three substituted furanyl; containing pigment atoms include, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted thienyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted pyrrolyl groups including an alkyl group, an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkanoyl group; and an alkane including a halogen atom, C, -C 6 Any one, two or three substituted-alkanoyl groups such as an oxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; an arbitrary alkoxy group including a halogen atom, C r C 6 or a hydroxyl group One, two or three substituted C 2 -C 6 enoyl groups; C 2 - An alkynyl group of C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups including a prime atom, an alkoxy group of C r C 6 or a hydroxyl group; an adamantyl decanoyl group, Substituting adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; phenanoyl; pyrroyl; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; Or R 2 and R 3 are:
Figure imgf000031_0001
其中 R6, R7各自独立为下列任意一种取代基： H; d- 的烷基； 含有包括! ¾素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 （^-( 6的烷基； C2-C6的烯基； 含有包括 素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括! ¾素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 CrC6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括 素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括! ¾素原子、 C!- 的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； -C6的烷酰基； 含有包括 素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括 素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯甲醜基； ,为 （CH2)n, n为 0-2, O, S或 者 NH; X2为 （CH2)n, n为 0-2, 0, S或者 NH; 或者 R2, R3分别为：
Figure imgf000032_0001
其中 R8为下列任意一种取代基： H; d- 的烷基； 含有包括卤素 原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 -( 6的烯基； C2-C6的炔基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C 々炔基； CrC6的环烷基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 Ci-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括 素原子、 CrC4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；Wherein R 6 and R 7 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing a 3⁄4 atom, an alkoxy group or a hydroxyl group of d- Substituted (^-( 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C containing a prime atom, dC 6 alkoxy or hydroxy group) 6 alkenyl; C 2 -C 6 alkynyl group; a! ¾ containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of a C 2 -C 6 Alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted C r C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon group amide groups, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; including vegetarian containing atoms, C r C alkyl 4 Any one, two or three substituted pyridyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one, two or three of an atom, an alkyl group of d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Substituted furanyl; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a ? 3⁄4 atom, C!-, a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carbon amide Base, sulfhydryl, sulfonium Any one, two or three substituted thienyl groups including a thiol group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group any group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; -C 6 alkoxy group; a pigment containing atoms including, C r C 6 alkoxy including a hydroxyl group or any one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include containing, C r C 6 alkoxy or hydroxy, including Any one, two or three substituted C 2 -C 6 alkenoyl groups; a C 2 -C 6 alkynyl group; or an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group; Two or three substituted C 2 -C 6 alkynyl groups; C 3 -C 6 cycloalkanoyl groups; any one, two or three containing a pertiny atom, an alkoxy group of CrC 6 or a hydroxyl group substituted C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group Yue furyl group; Yue-pyran group; thenoyl; pyrrolidin ugly group A; for (CH 2) n, n is 0-2, O, S or NH; X 2 is (CH 2) n, n is 0 -2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000032_0001
Wherein R 8 is any one of the following substituents: H; d-alkyl; any one, two or three substituted C r C 6 containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group alkyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of - (6 alkenyl; C 2 - Alkynyl group of C 6 ; any one, two or three substituted C 2 -C decynyl groups including a gas atom, alkoxy group of C r C 6 or a hydroxyl group; a cycloalkyl group of C r C 6 ; includes optionally containing a halogen atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyran Thiophene; pyrrolyl; pyridyl; Any one or two of a halogen atom, an alkyl group of Ci-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Or three substituted aryl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, Any one, two or three substituted pyridyl groups including an ethylthio group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted furanyl groups including a mercapto group, a methylthio group, an ethylthio group; an alkyl group including a pertinar atom, C r C 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group Any one, two or three substituted pyranyl groups, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , Nitro, carboxyl, aldehyde, alkoxy, amine, amide Any carbon amide group, a mercapto group, Yue thio, ethylthio, including one, two or three substituents thienyl; include a halogen atom-containing, c r c 4 alkyl, nitro, carboxyl, aldehyde, Any one, two or three substituted pyrrolyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group;
Cr C6的烷酰基； 含有包括 素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 d- 的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括！ ¾素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括 素原子、 rc6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 c3-c6的环烷酰基；金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃甲酰基； 噻 吩甲酰基； 吡咯曱酰基； 1为 (CH2)n，n为 0-2， 0， S或者 NH; 或者 R2, R3分别为：C r C 6 alkanoyl; includes any pigment containing atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl; C 2 -C 6 alkenyl group of ; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; comprising comprising! ¾ atom, - alkoxy or hydroxy arbitrary, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; comprising a pigment comprising atoms, r c any of the 6 alkoxy or hydroxy, including one, two or three substituents of c 3 -c 6 cycloalkyl group; a formyl adamantane, substituted adamantane formyl; aryl group; a benzyl group; an acyl furan Yue ; pyranoyl; thiophene; pyrrolyl; 1 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000033_0001
其中 R9， R10各'自独立为下列任意一种取代基： H; 的烷基； 含有包括 素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d- 的烷基； C2-C6的烯基; 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的歸基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻喻基； 吡咯基； 吡啶基； 含有包括鹵素原子、 d- 的烷基、 硝基、 羧基、 隧基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 CrC4的烷基、 硝基、 羧基、 隧基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d-C^ 烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d- 的烷酰基； 含有包括！ ¾素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 Ci-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的
Figure imgf000033_0001
Wherein R 9 and R 10 are each independently from any of the following substituents: H; an alkyl group; any one, two or three substitutions including a sulfonate atom, a C 6 alkoxy group or a hydroxy group. a d-alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; normalization group; C 2 -C 6 alkynyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkynyl group; a C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furanyl group; a pyranyl group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, a tunnel group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted aryl groups including a mercapto group, an anthracenethio group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , Any one, two or three substituted pyridyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two of an atom, a Cr C 4 alkyl group, a nitro group, a carboxyl group, a tunnel group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, or an ethylthio group. a three-substituted furyl group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a thiol group or an ethylthio group; containing a halogen atom, a dC^ alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group , carboxamide, sulfhydryl, sulfhydryl, Any of a group including two or three substituents pyrrolyl; D- alkanoyl; comprising comprising! ¾ atom, any hydroxy or C r C 6 alkoxy inner one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing a halogen atom, C Any one of alkoxy or hydroxy groups of r C 6 , Two or three substituted C 2 -C 6 alkenoyl groups; C 2 -C 6 alkynyl groups; containing any one, two or three including a halogen atom, a decyloxy group of Ci-C 6 or a hydroxyl group Substituted
C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括! ¾素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷醜基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯曱酰基； ！为 （CH2)n，n为 0-2, 0, S或 者 NH; X2为 （CH2)n, n为 0-2, 0, S或者 NH。 另外优选地， 该类化合物或其在药物学上可接受的盐是以药物组 合物的形式， 或单独， 或与药物学上可接受的载体或赋形剂联合提供。 本发明还提供了包括上述化合物的药物， 用于预防和 /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 4亍' )·生疾病 （ ^口 Alzheimer's病)等。 再一方面， 本发明涉及预防和 /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）等的方法。 该方法包括对需要或愿意接受治疗或 预防的对象， 给予有效量的、选择性地调节胰高血糖素样肽 - 1受体的 化合物或其药物学上可接受的盐， 以预防或治疗上述疾病或症状。 优 选地， 上述代谢紊乱性疾病 （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）等通过给 予有效量的由以下通式 I表示的化合物或其药物学上可接受的盐，及其 所有的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其溶剂化物或其金属配合物来预防或治疗：
Figure imgf000036_0001
其中 X和 Y分别为 （CH2)n, n为 0-2， 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； ！¾素； 烷烃； 环烷烃； 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基； Alkynyl of C 2 -C 6 acyl group; C 3 -C 6 cycloalkyl group;! ¾ containing pigment comprising atoms, R & lt alkoxy or hydroxy C 6 to C including any one, two or three substituents of C 3- C6 cycloalkane; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; Is (CH 2 ) n , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , and n is 0-2, 0, S or NH. Further preferably, such a 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 present invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurological regressions. (^ mouth Alzheimer's disease) and so on. In a further aspect, the invention relates to methods of 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 to a subject in need or willing to receive treatment or prevention an effective amount of a compound that selectively modulates the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for preventing or treating the above Disease or symptom. Preferably, the above metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease), etc., by administering an effective amount of a compound represented by the following formula I Or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects for prevention or treatment:
Figure imgf000036_0001
Wherein X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein is any of the following substituents: hydrogen; Alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; Substituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 另一方面， 本发明涉及联合制剂， 该联合制剂包括一种具有选择 性调节胰高血糖素样肽- 1受体， 尤其是激活该受体功能的化合物，或 其药物学上可接受的盐， 或单独， 或与药物学上可接受的载体或赋形 剂组合存在。 该化合物具有以下通式 I的结构: R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; 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 combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient. This compound has the structure of the following formula I:
Figure imgf000036_0002
及其所有的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其溶剂化物或其金属配合物。 ― 其中 X和 Y分别为 （CH2)n, n为 0-2, 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； 卤素； 烷烃； 环烷烃;. 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基；
Figure imgf000036_0002
And all its stereo and optical isomers, or prodrugs having the same pharmacological effects, Its ester, its solvate or its metal complex. ― where X and Y are respectively (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein is any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; Sulfhydryl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Or unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 本发明提供了包括上述联合制剂的药盒。 本发明还进一步提供了 应用上述联合制剂用于预防和 /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，达到选择性地激动胰高血糖素样肽 - 1受体的药效, 改善患者的症状和生命质量。 为了阐明发明内容且不受其局限， 对发明分成以下几个小节进行 详细描述。 R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; 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 combined preparation. The present invention still further provides the use of the above combined preparation 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). To achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life. In order to clarify the contents of the invention and not to be limited thereto, the invention will be described in detail in the following subsections.
A定义 除非另有定义， 本发明所用的技术和科学上的术语， 与本发明所 属领域的通用技术的一般理解具有相同意义。 本处提到的来源于基因 库和其他数据库的所有专利， 申请， 公布的申请和其他出版物和序列 被全面收入引用作为参考。 如果本节阐明的定义与本专利参用的来源 于基因库和其他数据库的所有专利， 申请， 公布的申请和其他出版物 和序列被收入和引用的定义阐述相反， 或不一致时， 以本节阐明的定 义为准。 本文所用， "一"或"一个"指"至少一个" 或"一个或多个"。 本文所用， "代谢紊乱性疾病"系指由各种原因造成的糖、 脂肪或 蛋白质等代谢失调而引起的相关症状和 /或疾病。 本文所用， "糖尿病"指一种多病因的代谢性疾病， 特点是慢性高 血糖， 伴随因胰岛素分泌及 /或作用缺陷引起的糖、 脂肪和蛋白质代谢 紊乱。 随着糖尿病得病时间的延长， 身体内的代谢紊乱如得不到很好 地控制， 可导致眼、 肾、 神经、 血管和心脏等组织等器官的慢性并发 症， 以致最终发生失明、 下肢坏疽、 尿毒症、 脑中风或心肌梗死， 甚 至危及生命。 本文所用， "胰岛素抵抗 "是指体内周围组织对胰岛素的敏感性降 低， 肌肉、 脂肪等靶组织对胰岛素促进葡萄糖摄取的作用发生了抵抗。 胰岛素抵抗普遍存在于 2型糖尿病中， 几乎占 90 %以上， 是 2型糖尿 病的发病主要因素之一。 本文所用， "肥胖症"是指体内脂肪的量过多， 男人体重超过理想 体重的 25%或女人体重超过理想体重的 30%的现象。 遗传因素、 下丘 脑病患、 内分泌紊乱、 饮食过量和活动太少都是产生肥胖症的原因。 本文所用， "阿尔茨海默病 （Alzheimer's Disease, AD, 又称早老 性痴呆 Alzheimer's dementia )是一种神经系统的进行性说变性疾病， 临床上表现为智力水平的慢性削弱及记忆的慢性丢失。 本文所用， "心血管疾病" 包括心脏病、 肺心病、 高血压和高脂血 症等。 具有 "发病率高， 死亡率高， 致残率高， 复发率高" 以及 "并 发症多" 的特点。 本文所用的用于治疗某一特定疾病的化合物的"有效量" 指足够 改善或在某种程度上减轻与此病相伴的症状的量。 这一剂量可以单一 剂量给药， 也可按照治疗方案给药。 这一剂量可治愈疾病， 但典型的 是为了改善该症状而给药。 为改善症状重复给药可能是需要的。 本文所用， "药物学上可接受的盐、 酯或其他衍生物" 包括领域技 术人员用已知方法易于制备的任何盐， 酯或衍生物。 这样衍生和生成 的化合物可对动物和人给药， 不具有毒性作用。 该化合物或是具有药 物活性， 或是药物前体。 本文所用， "治疗 "指疾病和症状用任何方式得以改善， 或其他有 益的改变。 治疗也包括本发明化合物在药物上的应用。 本文所用， 给予某一特定药物组合物"改善" 某一特定疾病的症状 是指任何减轻， 无论永久的， 临时的， 长时期的， 短暂的， 都能归因 于或与该药物组合物的施用有关。 本文所用， "基本上纯，，是指足够均匀， 通过本领域技术人员为评 价純度使用的标准分析方法探测不出杂质， 所述标准分析方法有如薄 层层析法（TLC ), 凝胶电泳和高效液相色谱法（HPLC )。 或者足够纯 也指即使进一步纯化也不能改变该物质可探测到的理化特性， 例如酶 活性和生物活性。 用于纯化化合物制得基本上化学纯的方法, 是本领 域技术人员所公知的。 然而基本上化学纯的化合物可以是立体异构体 或同分异构体的混合物。 在这种情况下， 进一步纯化也许会增加化合 物的比活性。 本文所用， "药物前体"是指一种体内给药的化合物 , 该化合物可 被代谢， 或转化为生物学上、 药物学上或治疗学上的活性形式。 为了 制造药物前体， 药物活性化合物将被修饰， 使该活性化合物通过代谢 过程再产生。 药物前体可被设计成改变其代谢稳定性， 或运输特性的 前体， 以掩盖其副作用或毒性， 改良药物的味觉， 或改变其他特性。 凭借药代动力学及药物体内代谢的知识， 一旦药物学上活性化合物为 已知， 本领域技术人员就可以设计出该化合物的药物前体。 [参见A Definitions Unless otherwise defined, the technical and scientific terms used in the present invention have the same meaning as the general understanding of the general art in the field to which the invention pertains. All patents, applications, published applications and other publications and sequences derived from gene banks and other databases referred to herein. It is referenced by a comprehensive income reference. If the definitions set forth in this section are inconsistent with, or inconsistent with, all patents, applications, published applications, and other publications and sequences derived from the Gene Bank and other databases referenced in this patent, or inconsistent, The definition of clarification shall prevail. As used herein, "a" or "an" refers to "at least one" or "one or more." As used herein, "metabolic disorder" refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes. As used herein, "diabetes" refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. As the time of diabetes is prolonged, the metabolic disorders in the body are not well controlled, leading to chronic complications of tissues such as the eyes, kidneys, nerves, blood vessels and heart, resulting in blindness, gangrene in the lower limbs, Uremic, stroke or myocardial infarction, even life-threatening. As used herein, "insulin resistance" refers to a decrease in the sensitivity of the surrounding tissues to insulin, and target tissues such as muscles and fats are resistant to insulin-induced glucose uptake. Insulin resistance is prevalent in type 2 diabetes, accounting for more than 90%, and is one of the main factors in the development of type 2 diabetes. As used herein, "obesity" refers to an excess of body fat, a man weighing more than 25% of the ideal body weight or a woman weighing more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overeating and too little activity are all causes of obesity. As used herein, "Alzheimer's Disease (AD), also known as Alzheimer's dementia, is a progressive degenerative disease of the nervous system. Clinically manifested as chronic impaired intelligence and chronic loss of memory. As used herein, "cardiovascular disease" includes heart disease, pulmonary heart disease, hypertension, and hyperlipidemia. It has the characteristics of "high incidence, high mortality, high disability rate, high recurrence rate" and "more complications". An "effective amount" of a compound for treating a particular disease as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease. This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable. As used herein, "pharmaceutically acceptable salts, esters or other derivatives" include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods. 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, "treatment" means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine. As used herein, administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant application. As used herein, "substantially pure," means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC) or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the material, such as enzymatic activity and biological activity. A method for purifying a compound to produce a substantially chemically pure, Is the skill Well known to those skilled in the art. However, a substantially chemically pure compound can be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound. As used herein, "prodrug" refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form. To produce a prodrug, the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes. Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties. By virtue of knowledge of pharmacokinetics and metabolism of the drug in the body, once the pharmaceutically active compound is known, one skilled in the art can design a prodrug of the compound. [See
Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392]。 术语"基本上 "相同或均勾或相似， 按照本领域技术人员对相关技 术的理解可在上下文中有所改变， 并且一般为至少 70%, 优选为至少 80%, 更优为至少 90% , 最优为至少 95%相同。 这里所用的"组合物 "指任何混合物。 可以是溶液、 混悬液、 液体、 粉末、 油膏、 水性的、 非水性的或它们的任何组合。 这里所用的 "联合，，指两种或多种之间的任何联合。 这里使用的术语"对象，，包括人和动物， 例如， 狗， 猫， 牛， 猪， 啮齿动物等。 有经验的实施者应可理解对象为适于并愿意对代谢紊乱 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）等进行治疗和预防。 这里使用的任何保护性基团，氨基酸和其他化合物的缩写， 与它们 通用的、 公认的缩写或 IUPAC-IUB委员会颁布生化命名一致， 除非特 别说明。 Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392]. The terms "substantially" are identical or otherwise hooked or similar, and the understanding of the relevant art by those skilled in the art may vary in the context and is generally at least 70%, preferably at least 80%, more preferably at least 90%. Optimally at least 95% identical. As used herein, "composition" refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof. As used herein, "union," refers to any combination of two or more. The term "object," as used herein, includes humans and animals, for example, 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 disease, and neurodegenerative diseases (such as Alzheimer's disease). And prevention. Any of the protective groups, abbreviations for amino acids and other compounds used herein, are consistent with their common, recognized abbreviations or the biochemical nomenclature issued by the IUPAC-IUB committee, unless otherwise stated.
B胰高血糖素样肽- 1受体调节剂 本发明提供胰高血糖素样肽 - 1受体功能的调节剂， 增加了预防和 /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）等药物的成员。 本发明涉及由以下通式 I表示的化合物，或其药物学上可接受的盐及其 所有的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其溶剂化物或其金属配合物。 B glucagon-like peptide-1 receptor modulator The present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, Members of the drug such as insulin resistance and obesity;), cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease. The present invention relates to a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, and all stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complex.
Figure imgf000041_0001
其中 X和 Y分别为 （CH2)n，n为 0-2, 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； 卤素； 烷烃； 环烷烃； 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基；
Figure imgf000041_0001
Wherein X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein any of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 本发明的化合物可以是一个特定的立体异构体，例如 R-或 S-构型， 或它们的混合物， 例如， 外消旋混合物。 这里考虑的化合物包括所有 具有药物活性的化合物种类， 或其溶液或混合物。 还包括其水合类型， 例如这些化合物的水溶液， 水解产物或电离产物； 并且这些化合物可 含有不同数量的结合水分子。 本发明的化合物可按照任何合适的方法来制备或合成。 优选地， 用以下面 F节中引证的合成法制备该化合物。 另外优选地， 该化合物或其药物学上可接受的盐以药物组合物的 形式提供， 或者单独， 或者与一种药物学上可接受的载体或赋形剂结 合。 本发明的化合物可用任何合适的酸以其药物学上可接受的盐的形 式来制备。 例如， 无机酸如盐酸、 氢溴酸、 硝酸、 硫酸、 碑酸等； 有 机酸诸如曱酸、 乙酸、 丙酸、 苯甲酸、 马来酸、 富马酸、 琥珀酸、 酒 石酸、 柠檬酸等； 烷基磺酸如甲基磺酸、 乙基磺酸等； 芳基磺酸如苯 磺酸、 对曱苯磺酸等均可使用。 R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or not Substituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. The compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture. Compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules. The compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compound is prepared by the synthetic procedure cited in Section F below. Further 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 invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, streptoic acid, etc.; organic acids such as citric acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; An alkylsulfonic acid such as methanesulfonic acid, ethylsulfonic acid or the like; an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
C治疗和预防方法 本发明涉及用于预防和 /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）等的方法。 该方法包括对需要或愿意接受治疗或预防 的对象， 给予有效量的、选择性地激动胰高血糖素样肽- 1受体的化合 物或其药物学上可接受的盐来治疗或预防上述疾病或症状。 优选地， 上述代谢紊乱性疾病通过给予有效量的由以下通式 I表示 的化合物或其药物学上可接受的盐， 及其所有的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其溶剂化物或其金属配合 物来治疗或预防：
Figure imgf000043_0001
其中 X和 Y分别为 （CH2)n，n为 0-2, 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； 素； 烷烃； 环烷烃； 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基； C Therapeutic and Prophylactic 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. . The method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound which selectively agonizes the glucagon-like peptide-1 receptor or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases Or symptoms. Preferably, the above metabolic disorder is caused by administering an effective amount of the compound represented by the following formula I or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or the same pharmacological action therewith. The drug, its ester, its solvate or its metal complex is used to treat or prevent:
Figure imgf000043_0001
Wherein X and Y are each (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein any of the following substituents: hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 可以用本方法防治任何对象， 优选哺乳动物， 更优选人。 本方法可用来防治代谢紊乱性疾病 （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。 优选的疾病或症状是任何由胰岛素分泌和 /或功能障碍引起或 伴随的疾病或症状。 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） 时， 可单独使用或与其他已经上市或将要上市的糖 尿病治疗药物包括胰岛素增敏剂联合使用本发明的化合物。 任何合适 的代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛素抵抗和肥胖症） 治疗药物均可与本发明的化合物联合使用。 其中， 典型的胰岛素增敏 剂包括罗格列酮和吡格列酮等。 在本发明的优选实施方案中 , 使用本发明化合物时不给予上述胰 岛素增敏剂。 更优选地， 用本发明的化合物治疗或预防因使用上述已 经上市或将要上市的糖尿病治疗药物 （包括胰岛素增敏剂） 而产生抗 药性或毒副反应所引起的疾病或症状。 R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Any subject can be controlled by this method, preferably a mammal, more preferably a human. The method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). A preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction. In the prevention and / or treatment of metabolic disorders (including but not limited to diabetes, islets In the case of cytokinesis and obesity, the compounds of the invention may be used alone or in combination with other therapeutic agents for diabetes, including insulin sensitizers, which are already on the market or to be marketed. Any suitable metabolic disorder (including but not limited to diabetes, insulin resistance, and obesity) therapeutic agents can 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 invention, the above insulin sensitizer is not administered when the compound of the invention is used. More preferably, the compound of the present invention is used to treat or prevent a disease or symptom caused by the use of the above-mentioned diabetes therapeutic agents (including insulin sensitizers) which have been marketed or will be marketed to produce drug resistance or side effects.
合适的糖尿病治疗药物包括胰岛素增敏剂联合使用。 例如， 可以通过 腔内注射， 皮下注射， 静脉内注射， 肌内注射， 真皮内注射， 口服或 局部以本发明的化合物给药， 或以其药物学上可接受的盐给药。 在具体实施方案中， 本方法进一步包括对给药对象的疾病或症状 进行诊断和预后评估。 可以使用任何适合的方法用于诊断和评估相关 疾病或症状及其预后。 诊断和预后可以基于检测和 /或鉴定任何或所有 的体内物质， 例如糖化血红蛋白、 酶、 抗原、 抗体、 核酸或其他病理 性和临床标记物等以及相关症状。 例如 , 可以使用国际专利 WOSuitable diabetes treatments include the use of insulin sensitizers in combination. For example, it can be administered by intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically with the compound of the present invention, or with a pharmaceutically acceptable salt thereof. In a specific embodiment, the method further comprises performing a diagnosis and prognostic assessment of the disease or condition of the subject to whom it is administered. Any suitable method can be used to diagnose and assess the relevant disease or condition and its prognosis. Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo substances, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and related symptoms. For example, international patent WO can be used.
01/44815和美国专利 5，571,674揭示的诊断或预后方法。 D联合制剂， 药盒和联合用药的方法 另一方面， 本发明也涉及联合制剂， 这种联合包括一种选择性调 节胰高血糖素样肽- 1受体功能的化合物， 或其药物学上可接受的盐， 和一种或多种糖尿病治疗药物包括胰岛素增敏剂。 优选地， 这种联合用药包括本发明化合物或其药物学上可接受的 盐， 及其所有的立体和光学异构体， 或者与其具有相同药理作用的前 药、 其酯、 其溶剂化物或其金属配合物和一种或多种糖尿病治疗药物 包括胰岛素增敏剂， 该化合物由以下通式 I表示： The diagnostic or prognostic method disclosed in U.S. Patent No. 5,571,674. D. Combination of Formulations, Kits and Combinations On the other hand, the present invention also relates to a combination preparation comprising a compound which selectively modulates the function of the glucagon-like peptide-1 receptor, or a pharmacologically Acceptable salts, and one or more therapeutic agents for diabetes include insulin sensitizers. Preferably, such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, and all of its stereo and optical isomers, or a prodrug having the same pharmacological action thereto, an ester thereof, a solvate thereof or Metal complexes and one or more therapeutic agents for diabetes include insulin sensitizers, which are represented by the following general formula I:
Figure imgf000045_0001
其中 X和 Y分別为 （C¾)n，n为 0-2, 氧， 硫或氮。 其中 为下列任意一种取代基： 氢； 素； 烷烃； 环烷烃； 羟基； 硝基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯 基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶 基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代 的噻吩基； 取代或未取代的吡咯基；
Figure imgf000045_0001
Wherein X and Y are respectively (C3⁄4) n and n is 0-2, oxygen, sulfur or nitrogen. Wherein any of the following substituents: hydrogen; alkane; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; sulfhydryl; Ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; Unsubstituted pyrrolyl;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 在本发明的联合制剂中可以使用任何合适的糖尿病治疗药物包括 胰岛素增敏剂。 在一个特定实施方案中， 用于本发明联合制剂中可以 包括上述糖尿病治疗药物包括胰岛素增敏剂中的一种或多种。 R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Any suitable therapeutic agent for diabetes, including insulin sensitizers, can be used in the combination formulations of the invention. In a specific embodiment, one or more of the above-described diabetes therapeutic agents including insulin sensitizers may be included in the combined preparation of the present invention.
.在另一个特定实施方案中， 提供了一种防治代谢紊乱性疾病 （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）等的方法， 该方法包括对需要和愿意接受 治疗或预防的对象给予有效量的上述联合制剂， 或其药物学上可接受 的盐， 从而治疗或预防上述疾病或症状。 在另一个特定实施方案中， 提供了一个药盒， 其中包括本发明的 化合物或其药物学上可接受的盐以及使用上述化合物或其药物学上可 接受的盐来防治代谢紊乱性疾病 （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）等的 使用说明。 在再一个实施方案中， 提供了一个药盒， 包括上述联合制剂及使 用所述联合制剂防治代谢紊乱性疾病 （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） 等的使用说明。 In another specific embodiment, a metabolic disorder (including but not limited to diabetes, insulin resistance, and obesity), cardiovascular disease, and neurodegenerative disorders are provided. A method of sexually transmitted diseases (such as Alzheimer's disease), which comprises administering an effective amount of the above combined preparation, or a pharmaceutically acceptable salt thereof, to a subject in need and willingness to receive treatment or prevention, thereby treating or preventing 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 the use of the above compound or a pharmaceutically acceptable salt thereof for the prevention and treatment of a metabolic disorder (including However, it is not limited to instructions for use such as diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease. In still another embodiment, a kit is provided comprising the combination described above and the use of the combination to prevent metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular disease and neurodegenerative Instructions for use of diseases such as Alzheimer's disease.
E配方和剂量 根据本发明， 本发明的化合物， 单独或与其它药剂， 载体或赋形 剂联合， 为任何合适的给药途径制定制剂， 例如腔内注射、 皮下注射、 静脉内注射、 肌内注射、 真皮内注射、 口服或局部用药。 本方法可以 使用注射给药制剂， 以单剂量的形式在安瓿， 或多剂量容器中与添加 的緩冲剂注射给药。 制剂可釆取以下形式如混悬液、 溶液或在油性或 水性媒介中的乳液。 制剂可以含有配方试剂如混悬剂、 稳定剂和 /或分 散剂。 此外， 使用前， 活性成分可以粉末形式与合适的载体， 无菌无 热源水或其他溶剂构成剂型。 本发明的局部用药可采用泡沫， 凝胶， 软膏， 油膏， 转皮膜片， 或膏状物。 本发明中可以使用的用于给药的药用组合物和方法包括， 但不局 限于， 美国专利 5,736,154、 6,197,801 B1、 5,741,511、 5,886,039 5,941,868、 6,258,374Β1和 5，686,102所阐述的内容。 治疗或预防的剂量大小会因病情的严重性和给药途径而有所变 化。 剂量和用药频度会因年龄、 体重、 健康状况和病人个体反应不同 而不同。 需要指出的是（诊治医生也应知道）， 根据毒性和副反应， 必须采 取必要措施终止、 中断或降低治疗剂量。 相反， 如果临床反应不明显 (排除毒性和副反应）， 医生应适当调整治疗方案， 提高剂量。 任何合适的给药途径均可被采用。 剂型包括片剂， 锭剂， 豆状胶 嚢， 分散剂， 悬浮剂， 溶液， 胶囊， 膜片及类似物等。 在实际应用中， 本发明的化合物， 单独或与其他制剂联合， 可以 按照一般药物学混合技术与药物载体或赋形剂， 例如 β -环糊精和 2 - 羟丙基 - β -坏糊精紧密混和。 根据投药的需要， 可采用通用载体、 局 部或非肠道途径的特殊载体。 制备非肠道剂型， 例如静脉内注射或灌 输的组合物， 可采用类似的药物媒质， 本领域技术人员所公知的水， 乙二醇， 油， 緩冲剂， 糖， 防腐剂， 脂质体等。 这种非肠道组合物的 例子包括， 但不限制于 5%W/V的右旋糖， 生理盐水或其他溶液。 本发 明的化合物的总剂量， 单独或和其他制剂联合给药， 可用小瓶静脉注 射液给药， 体积大约从 1亳升到 2000毫升。 根据给药的总剂量， 稀释 液量也会不同。 本发明还提供了实现治疗方案的药盒。 该药盒将有效剂量的本发 明化合物以药物学上可接受的形式单独或与其他试剂联合， 包含在一 个或多个容器中。 优选的药物形式是与无菌盐水， 右旋糖溶液， 緩冲 溶液， 或其他药物学上可接受的无菌液体合用。 或者， 组合物可被冻 干或干燥； 在这种情况下， 药盒任选地进一步将一种药物学上可接受 的溶液， 优选无菌的溶液包含在一个容器中， 以重新组成复合物形成 用于注射目的的溶液。 典型的药物学上可接受的溶液是生理盐水和右 旋糖溶液。 在另一个实施方案中， 本发明的药盒进一步包含用于注射组合物 的优选以无菌形式包装的针或针筒和 /或包装的酒精垫。 可任选地包括 供医生或患者使用的说明书。 Formulations and Dosages According to the invention, the compounds of the invention, alone or in combination with other agents, carriers or excipients, are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular Injection, intradermal injection, oral or topical medication. The method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer. The formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles. The formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents. In addition, prior to use, the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent. The topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste. Pharmaceutical compositions and methods for administration that can be used in the present invention include, but do not It is limited to the contents set forth in U.S. Patent Nos. 5,736,154, 6,197,801, B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102. The size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration. The frequency of dosing and medication will vary with age, weight, health status, and individual patient response. It should be pointed out that (the doctor should also know), according to toxicity and side effects, necessary measures must be taken to terminate, interrupt or reduce the therapeutic dose. Conversely, if the clinical response is not obvious (excluding toxicity and side effects), the doctor should adjust the treatment plan appropriately to increase the dose. Any suitable route of administration can be employed. Dosage forms include tablets, troches, soy gums, dispersing agents, suspending agents, solutions, capsules, films and the like. In a practical application, the compounds of the present invention, alone or in combination with other preparations, may be in accordance with conventional pharmaceutical mixing techniques with pharmaceutical carriers or excipients such as β-cyclodextrin and 2-hydroxypropyl-β-bad dextrins. Tightly mixed. Depending on the needs of the administration, a special carrier, a local or parenteral route, may be employed. For the preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion, similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. . Examples of such parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions. The total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 to 2000 ml. The amount of diluent will vary depending on the total dose administered. The invention also provides a kit for achieving a therapeutic regimen. The kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers. The preferred pharmaceutical form is with sterile saline, dextrose solution, buffered Solution, or other pharmaceutically acceptable sterile liquid combination. Alternatively, the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed. Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions. In another embodiment, the kit of the invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form. Instructions for use by a doctor or patient may optionally be included.
F制备方法 本发明是通过如下步骤实施的： F Preparation Method The present invention is carried out by the following steps:
Figure imgf000048_0001
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0002
V 化合物 II ( leq )溶于曱醇中， 滴加数滴浓^ <酸， 加热回流 8小时， 得到化合物 III。 将化合物 III ( 2eq )在氮气的保护下加热至 180°C , 慢慢滴加化合 物 IV ( leq ), 滴加的速度以维持反应温度 18(TC - 190°C为准。 冷却， 得到桔红色残余物。 加入适量的 10 %乙醚 /正戊烷， 过滤， 得到化合物 V。 化合物 V溶于曱醇， 加入氢氧化钠溶液， 加热水解得到产物 I。 附图说明 图 1.4艮告基因方法检测化合物对 GLP-1R的激动作用。 GLP-1浓 度梯度为 10, 1, 0.1, 0.01, 0.001, 0.0001 nM, 以 ΙΟηΜ所诱导的萤 光素酶活性为 100%， 测得 GLP-1的 EC50值为 0.07 nM。 图 2. 报告基因方法检测 exendin9_39对 GLP-1 的拮抗作用。 选取 GLP-1的浓度为 0.05 nM, exendin9-39的浓度梯度为 10000, 1000, 100， 10, 1, 0.1, 0 nM, 以不加 exendin9-39的活性设为 100%, 试验表明 exendin9.39能剂量依赖性地抑制由 GLP-1诱导的报告基因表达，其 IC50 值为 68.22 nM, 表明其生物活性是通过 GLP-1R介导的。 图 3. 细胞内 cAMP浓度检测 GLP-1对 GLP-1R信号传导的作用。 GLP-1浓度梯度为 10, 1, 0.1, 0.01, 0.001, 0.0001, 0 nM, 以 ΙΟηΜ 所诱导的 cAMP活性为 100 % , 测得 GLP-1的 EC5G值为 0.079 nM, 提 示其作为 GLP-1R激动剂， 可剂量依赖性地诱导细胞内 cAMP的产生。 图 4. 受体竟争性结合试验方法检测 GLP-1 对受体的亲和力。 GLP-1浓度梯度为 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0 nM。 GLP-1 可特异性地与 1251标 GLP-1竟争性结合 GLP-1R,其 IC5Q值为 0.66 nM。 具体实施方式 实验仪器及试剂 HP1100 HPLC系统， 具备二元梯度泵、 在线真空脱气机、 自动进 样器、 柱温箱和光电二极管阵列检测器。 色潘柱为 ZORBAX SB-C18 ( 2.1 X 150 mm, 3.5 μιη ), 流动相为乙腈 /水， 流速为 0.2 ml/min, 检测 波长为 254 ηπι。 熔点采用 IA6304 型熔点仪测定； NMR 由 Varian Mercury-300和 Varian Mercury Plus 400型核磁共振仪测得（溶剂为 CDC13, CD3OD或 DMSO-d6 ); ESI-MS由 AB Mariner型质谱仪测得， EI由 Firmigan MAT95型 谱仪测得。合成中所用原料除特别指明来源 外均为市售产品。 下面的具体实施例对本发明作进一步阐述， 但不限制本发明。 实施例 1 V compound II (leq) was dissolved in methanol, and a few drops of concentrated acid were added dropwise, and the mixture was heated under reflux for 8 hours to give compound III. Compound III (2eq) was heated to 180 ° C under the protection of nitrogen, and compound IV ( leq ) was slowly added dropwise, and the rate of addition was maintained to maintain the reaction temperature of 18 (TC - 190 ° C. Cooling, orange-red) Residue. Add appropriate amount of 10% diethyl ether / n-pentane, filter to give the compound V. Compound V was dissolved in methanol, added with a sodium hydroxide solution, and heated to give the product I. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1.4. The genetic method detects the agonistic effect of a compound on GLP-1R. The GLP-1 concentration gradient was 10, 1, 0.1, 0.01, 0.001, 0.0001 nM, and the luciferase activity induced by ΙΟηΜ was 100%, and the EC 50 value of GLP-1 was measured to be 0.07 nM. Figure 2. Reporter gene method to detect the antagonism of exendin 9 _ 39 on GLP-1. The concentration of GLP-1 was 0.05 nM, and the concentration gradient of exendin 9-39 was 10000, 1000, 100, 10, 1, 0.1, 0 nM, and the activity of exendin 9-39 was set to 100%. The test showed exendin. 9.39 report can be dose-dependently inhibited induced by GLP-1 gene expression, an IC 50 value of 68.22 nM, indicating that biological activity is mediated via the GLP-1R. Figure 3. Intracellular cAMP concentration detects the effect of GLP-1 on GLP-1R signaling. The GLP-1 concentration gradient was 10, 1, 0.1, 0.01, 0.001, 0.0001, 0 nM, and the cAMP activity induced by ΙΟηΜ was 100%, and the EC 5G value of GLP-1 was measured to be 0.079 nM, suggesting that it was used as GLP- The 1R agonist induces intracellular cAMP production in a dose-dependent manner. Figure 4. Receptor competitive binding assay method to detect the affinity of GLP-1 for receptors. The GLP-1 concentration gradient was 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0 nM. GLP-1 specifically binds GLP-1R to the 125 1 standard GLP-1 with an IC 5Q value of 0.66 nM. DETAILED DESCRIPTION OF THE INVENTION Experimental Instruments and Reagents HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector. The color pan column is ZORBAX SB-C18 (2.1 X 150 mm, 3.5 μιη), the mobile phase is acetonitrile/water, the flow rate is 0.2 ml/min, and the detection wavelength is 254 ηπι. The melting point was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 OD or DMSO-d 6 ); ESI-MS was performed by AB Mariner mass spectrometer It was measured that EI was measured by a Firmigan MAT95 spectrometer. The materials used in the synthesis are commercially available products unless otherwise specified. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention. Example 1
NMR定标： δ H/C 7.26/77.0 ppm ( CDC13 ); δ H C 2.50/39.51 ppm (DMSO-d6)。 NMR calibration: δ H/C 7.26/77.0 ppm (CDC13); δ H C 2.50/39.51 ppm (DMSO-d6).
H2N丫 COOH H 2 N丫COOH
H2N COOHH 2 N COOH
Figure imgf000050_0001
Figure imgf000050_0001
NHBoc NHBoc
Figure imgf000050_0002
化合物 2，3-二氨基丁二酸溶于适量 5 %氢氧化钠溶液中 , 冷却至 0 滴加对 BocNH苯曱酰氯（2.5eq ), 室温放置过夜， 用盐酸酸化至 pH=2, 乙醚提取， 浓干。 用乙醇 /水重结晶得到酰胺。 将上述酰胺（ leq )溶于曱醇中， 滴加数滴浓硫酸， 加热回流 8小 时， 得到酯。 将上述酯和氯化亚砜加热反应 2小时得到环和物。 将上述环和物 （2eq )在氮气的保护下加热至 180°C , 慢慢滴加苯 基重氮甲烷（leq ), 滴加的速度以维持反应温度 180°C - 190°C为准。 冷却， 得到桔红色残余物。 加入适量的 10 %乙醚 /正戊烷， 过滤， 得到 三元环和物。 将上述三元环和物溶于乙醇， 加入适量氢氧化钾水解得到产物。 同样方法得到以下产物：
Figure imgf000050_0002
The compound 2,3-diaminosuccinic acid was dissolved in an appropriate amount of 5% sodium hydroxide solution, and cooled to 0 dropwise to the mixture of BocNH benzoyl chloride (2.5 eq), allowed to stand overnight at room temperature, acidified to pH = 2 with hydrochloric acid, and extracted with diethyl ether. , thick and dry. Recrystallization from ethanol/water gave the amide. The above amide (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to give an ester. The above ester and thionyl chloride were reacted by heating for 2 hours to obtain a cyclic compound. The above ring and substance (2 eq) were heated to 180 ° C under the protection of nitrogen, and phenyldiazomethane (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue. An appropriate amount of 10% diethyl ether/n-pentane was added and filtered to obtain a three-membered ring. The above three-membered ring is dissolved in ethanol, and an appropriate amount of potassium hydroxide is added to obtain a product. The same method yields the following products:
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Figure imgf000052_0004
Figure imgf000052_0005
实施例 2
Figure imgf000053_0001
取原料酸（ leq )溶于曱醇中， 滴加数滴浓硫酸， 加热回流 8小时， 得到酯。 将上述酯 （2eq )在氮气的保护下加热至 1.80°C , 慢慢滴加化合物 苯基重氮曱烷（ leq ), 滴加的速度以维持反应温度 180°C - 190°C为准。 冷却， 得到桔红色残余物。 加入适量的 10 %乙醚 /正戊烷， 过滤， 得到 具有取代环丙烷结构的化合物。 将上述具有取代环丙烷结构的化合物溶于曱醇， 加入氢氧化钠溶 液， 加热水解得到产物。 同样方法得到以下产物：
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Figure imgf000052_0004
Figure imgf000052_0005
Example 2
Figure imgf000053_0001
The starting acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester. The above ester (2 eq) was heated to 1.80 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue. An appropriate amount of 10% diethyl ether/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure. The above compound having a substituted cyclopropane structure is dissolved in decyl alcohol, and a sodium hydroxide solution is added thereto, followed by heating to obtain a product. The same method yields the following products:
Figure imgf000053_0002
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0003
实施例 3
Figure imgf000054_0004
取原料酸（leq)溶于曱醇中， 滴加数滴浓硫酸， 加热回流 8小时， 得到酯。 将上述酯 （2eq)在氮气的保护下加热至 180°C, 慢慢滴加化合物 苯基重氮曱烷（ leq), 滴加的速度以维持反应温度 180°C - 190°C为准。 冷却， 得到桔红色残余物。 加入适量的 10%乙醜 /正戊烷， 过滤， 得到 具有取代环丙烷结构的化合物。
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0003
Example 3
Figure imgf000054_0004
The raw material acid (leq) was dissolved in methanol, a few drops of concentrated sulfuric acid was added dropwise, and the mixture was heated under reflux for 8 hours to obtain an ester. The above ester (2 eq) was heated to 180 ° C under the protection of nitrogen, and the compound phenyldiazonium (leq) was slowly added dropwise at a rate to maintain the reaction temperature of 180 ° C - 190 ° C. Cool to give an orange residue. An appropriate amount of 10% acetamino/n-pentane was added and filtered to obtain a compound having a substituted cyclopropane structure.
Figure imgf000055_0001
Figure imgf000055_0001
Figure imgf000056_0001
实施例 4: 体外药效学试验
Figure imgf000056_0001
Example 4: In vitro pharmacodynamic test
1.报告基因表达检测 1. Report gene expression detection
GLP-1R为 G蛋白偶联受体， 当 GLP-1R与激动剂结合后， G蛋白 的 Get亚单位被活化，刺激腺苷酸环化酶，导致细胞内 cAMP水平升高。 因前胰岛素基因的启动子区域存在 cAMP反应元件， cAMP与该反应 元件结合后， 启动前胰岛素基因的转录， 从而刺激胰岛素的表达和分 泌 ( Diabetes, 2000, Vol. 49:1156-1164 )„ 本实验方法采用稳定转染 GLP-1R受体基因表达载体和受 cAMP反应元件调节的荧光素酶报告 基因表达载体的人胚肾细胞株 ( HEK 293 ), 检测其对被测化合物的反 应 ( Cell Biology, 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. U.S.A. 1987, Vol. 84:3434-3438 ). 在对化合物进行筛选时， 可诱导荧光素晦报 告基因表达的样品， 视为具有 GLP-1R激动活性。 GLP-1R is a G protein-coupled receptor. When GLP-1R binds to an agonist, the Get subunit of the G protein is activated to stimulate adenylate cyclase, resulting in elevated intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the pre-insulin gene, cAMP binds to the response element to initiate transcription of the pre-insulin gene, thereby stimulating insulin expression and secretion (Diabetes, 2000, Vol. 49:1156-1164) The human embryonic kidney cell line (HEK 293) stably transfected with GLP-1R receptor gene expression vector and luciferase reporter gene expression vector regulated by cAMP response element was used to detect its response to the test compound (Celliology) , 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 84:3434-3438 ). Samples that induce fluorescein 晦 reporter gene expression when screened for compounds, It has GLP-1R agonistic activity.
1.1 试验材料与仪器 细胞株： GLP-1R和荧光素酶稳定表达的 HEK 293/GLP-lR+Luc 细 胞株（国家新药筛选中心自建） 胎牛血清（GIBCO公司） DMEM培养基（GIBCO公司） Steady-Glo™荧光素酶分析系统（Promega公司） 1.1 Test materials and instrument cell lines: HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) Fetal bovine serum (GIBCO) DMEM medium (GIBCO) Steady-GloTM Luciferase Assay System (Promega)
GLP-1标准品 （Sigma公司） GLP-1 Standard (Sigma)
G418 ( Invitrogen公司 ) G418 (Invitrogen)
Forma二氧化碳培养箱 （Forma公司 ); Forma CO2 incubator (Forma);
Victor2读板机（Wallac公司 ); Victor 2 plate reader (Wallac);
1.2 试-险方法 1.2 Test-risk method
HEK293/GLP1R+Luc细胞以 20,000个 /100 μΐ/孔接入 96孔培养板， 以含 10%胎牛血清和 500 g/ml G418的 DMEM培养基于 37。C培养过 夜。 将 GLP-1标准品稀释至一定浓度梯度， 然后以 Ι μΐ/孔加入上述 96 孔微量培养板中。在 37。C， 5%C02条件下培养 6小时。按 Steady- Glo™ 荧光素酶分析系统试剂盒说明检测荧光素酶活性， Victor2读板机进行 读数。 HEK293/GLP1R+Luc cells were incubated at 20,000/100 μΐ/well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C was cultured overnight. The GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in Ιμΐ/well. At 37. C, cultured for 6 hours under 5% C0 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor 2 reader was used for readings.
1.3 试验结果 研究结果表明 （表 1， 图 1 ), GLP-1的 EC50值为 0.07 nM。 表 1. 报告基因表达检测 GLP-1的激动活性（％反应， 以 lO nM GLP-1 的反应为 100% ) 1.3 Experimental results The results showed (Table 1, Figure 1), GLP-1 EC 50 value of 0.07 nM. Table 1. Reporter gene expression assay for agonistic activity of GLP-1 (% response, 100% response to lO nM GLP-1)
GLP-1终浓度 （nM) 相对激动活性 （％)  GLP-1 final concentration (nM) relative agonistic activity (%)
10 100.0  10 100.0
1 100.7  1 100.7
0.1 61.4  0.1 61.4
0.01 13.3 0.001 2.4 0.01 13.3 0.001 2.4
0.0001 0.4  0.0001 0.4
2. Exendin9-39抬抗试验 为确证活性化合物对报告基因的活化作用具有受体特异性， 我们采 用 GLP-1R 的特异性 4吉抗剂 exendin9-39 ( Eur. J. Pharmacol. 1994, 269: 183-191 ; Metabolism 2004, 53:252-259. )来臉证其能否拮抗上述代 表性化合物对 GLP-1R的激动活性。 2. Exendin 9-39 Upkase Assay To confirm the receptor specificity of the active compound for the activation of the reporter gene, we used the GLP-1R specific 4 anti-agent exendin 9-39 (Eur. J. Pharmacol. 1994, 269: 183-191; Metabolism 2004, 53: 252-259. ) to show whether it can antagonize the agonistic activity of the above representative compounds on GLP-1R.
2.1试验材料与仪器： 细胞林： GLP-1R和荧光素酶稳定表达的 HEK 293/GLP-1R+Luc 细 胞株（国家新药筛选中心自建） 胎牛血清（GIBCO公司） 2.1 Test materials and instruments: Cell line: HEK 293/GLP-1R+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) Fetal bovine serum (GIBCO)
DMEM培养基（GIBCO公司） DMEM medium (GIBCO)
Exendin 9-39 ( AnaSpec公司 ) Exendin 9-39 ( AnaSpec)
Steady-GloTM荧光素酶分析系统（Promega公司） Steady-Glo TM Luciferase Assay System (Promega)
G418 ( Inviti'ogen公司） G418 (Inviti'ogen)
Forma二氧化碳培养箱 ( Forma公司 )； Forma Carbon Dioxide Incubator (Forma);
Victor2读板机（Wallac公司 ); Victor 2 plate reader (Wallac);
2.2试—险方法 2.2 test-risk method
HEK293/GLP1R+Luc细胞以 20，000个 /100 μΐ/孔接入 96孔培养板， 以含 10%胎牛血清和 500 g/ml G418的 DMEM培养基于 37。C培养过 夜。 将 Exendin9-39稀释至一定的浓度梯度， 然后以 1 μΐ/孔加入上述 96 孔微量培养板中，在 37。C, 5%C02条件下孵育 10分钟， 然后加入 0.05 nM GLP-1 , 在 37。C， 5%C02条件下培养 6小时。 按 Steady- GloTM荧光 素酶分析系统试剂盒说明检测荧光素酶活性， Victor2读板机进行读数。 HEK293/GLP1R+Luc cells were incubated at 20,000/100 μΐ/well into 96-well culture plates at 37 in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night. Dilute Exendin 9-39 to a concentration gradient and then add 1 μM/well to the 96-well microplate at 37. Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nM GLP-1 at 37. C, cultured for 6 hours under 5% C0 2 conditions. Press Steady- Glo TM Luciferase Assay System kit instructions detected luciferase activity, Victor 2 plate reader was read.
2.3试验结果 2.3 Test results
Exendin9.3^ 剂量依赖性地抑制由 GLP-1诱导的报告基因表达（表 2, 图 2 ), 其 IC5Q值为 68.22 nM,表明其生物活性是通过 GLP-1R介导 的。 表 2. Exendin9-39对 GLP-1的拮抗作用 （％反应 , 以 0.05 nM GLP-1 的反应为 100% ) Exendin 9 . 3 ^ dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2) with an IC 5Q value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2. Exendin 9 - 39 Antagonism of GLP-1 (% reaction, a reaction to 0.05 nM GLP-1 as 100%)
Exendin9-39 (nM) 目对活性（％)  Exendin9-39 (nM) target activity (%)
10000 1.9  10000 1.9
1000 2.7  1000 2.7
100 38.9  100 38.9
10 91.0  10 91.0
1 97.1  1 97.1
0.1 101.2  0.1 101.2
0 100.0  0 100.0
3. 细胞内 cAMP浓度测定 因报告基因检测方法是间接判断细胞内 cAMP浓度水平的方法。 为确定活性化合物确实可使细胞内 cAMP浓度升高， 直接以 cAMP检 测试剂盒进行功能性验证。 3. Determination of intracellular cAMP concentration The method for detecting a reporter gene is a method for indirectly determining the level of intracellular cAMP concentration. In order to determine that the active compound can actually increase the intracellular cAMP concentration, directly by cAMP test The test kit is functionally verified.
3.1试验材料与仪器 细胞株： GLP-1R和荧光素酶稳定表达的 HEK 293/GLP-lR+Luc 细 胞株（国家新药筛选中心自建） cAMP检测试剂盒（ Applied Biosystems公司） Forma二氧化碳培养箱 （Forma公司） Victor2读板机（Wallac公司 ) cAMP标准品 （试剂盒自带， Applied Biosystems公司） 3.2试-险方法 3.1 Test materials and instrument cell lines: HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) cAMP test kit (Applied Biosystems) Forma carbon dioxide incubator ( Forma) Victor 2 Plate Reader (Wallac) cAMP Standard (kit comes with Applied Biosystems) 3.2 Test-risk method
HEK 293细胞以 20000个 /lOOul/孔接入 96孔培养板， 37°C培养过 夜， 用二曱亚砜将 GLP-1梯度稀释， 并以 lul/孔加入上述 96孔微量培 养板中。 37°C、 5%C02条件下培养 15 min。 按 cAMP-Screen DirectTM Systerm试剂盒说明检测细胞内 cAMP浓度水平。 HEK 293 cells were inserted into a 96-well culture plate at 20,000 / lOOul / well, cultured overnight at 37 ° C, GLP-1 was diluted with disulfoxide, and added to the above 96-well microplate in lul / well. Incubate for 15 min at 37 ° C, 5% CO 2 . Intracellular cAMP levels were measured by cAMP-Screen DirectTM Systerm kit instructions.
3.3试验结果 3.3 Test results
GLP-1剂量依赖性地诱导细胞内 cAMP的产生 （表 3 , 图 3 ), 其 EC5()值为 0.079 nM, 提示其作为 GLP-1R激动剂， 对 GLP-1R的信号 传导起了一定作用。 表 3. GLP-1对细胞内 cAMP的诱导作用（％反应，以 10 nM GLP-1
Figure imgf000061_0001
GLP-1 dose-dependently induces intracellular cAMP production (Table 3, Figure 3) with an EC 5() value of 0.079 nM, suggesting that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling. effect. Table 3. Induction of intracellular cAMP by GLP-1 (% response to 10 nM GLP-1
Figure imgf000061_0001
GLP-1终浓度 （nM) 相对活性 （％)  GLP-1 final concentration (nM) relative activity (%)
10 100.0  10 100.0
1 94.4  1 94.4
0.1 55.4  0.1 55.4
0.01 17.2  0.01 17.2
0.001 3.3  0.001 3.3
0.0001 1.1  0.0001 1.1
0 0  0 0
4、 受体结合活力测试 为确定活性化合物对受体的结合能力， 制备大量表达 GLP - 1R的 细胞， 以 1251标记的 GLP - 1作为配基， 同时加入待检测化合物。 当待 测化合物与 1251标 GLP - 1进行竟争性结合时，细胞膜上的同位素标记 减少。 据此可评估 ^；合物对受体的的亲和力 （J Mol Endocrinol. 2000 Vol.25:321-35; J Biomol Screen. 2000 Vol.5 :377-84 )= 4. Receptor binding activity test In order to determine the binding ability of the active compound to the receptor, a large amount of cells expressing GLP-1R were prepared, and 125 1 labeled GLP-1 was used as a ligand, and the compound to be detected was simultaneously added. When the test compound is competitively bound to the 125 1 standard GLP-1, the isotope labeling on the cell membrane is reduced. According to this, the affinity of the compound to the receptor can be evaluated (J Mol Endocrinol. 2000 Vol. 25:321-35; J Biomol Screen. 2000 Vol. 5 :377-84)=
4.1试验材料与仪器： 4.1 Test materials and instruments:
HEK 293/GLP1R+Luc 细胞株（国家新药筛选中心自建） 标记化合物： 1251标记的 GLP-1 ( Amersham Biosciences公司） HEK 293/GLP1R+Luc cell line (self-built by National New Drug Screening Center) Labeling compound: 125 1 labeled GLP-1 (Amersham Biosciences)
Walkc MicroBata工作站 （Perkin Elmer公司） Walkc MicroBata Workstation (Perkin Elmer)
TomTech 细胞收集器（TomTec公司） 闪烁液 ( Wallac公司 ) 4.2试验方法 取 105对数生长期的 HEK 293/GLP1R+Luc细胞，于 25。C条件下， 200μ1 测试緩冲液中， 与 1251标 GLP-1阳性肽（终浓度 40 ρΜ )共孵育 4小时， 同时加入非标记阳性肽或待筛选药物。 使用细胞收集器， 用洗 涤溶液洗涤细胞三次。 加入闪烁液， 在 Microbata计数器上读出每孔读 数。 . TomTech Cell Collector (TomTec) Scintillation Fluid (Walac) 4.2 Test method Take 10 5 logarithmic growth phase of HEK 293/GLP1R+Luc cells at 25. Under C conditions, incubate with 125 1 of the labeled GLP-1 positive peptide (final concentration 40 ρΜ) in 200 μl test buffer for 4 hours while adding non-labeled positive peptide or drug to be screened. The cells were washed three times with a washing solution using a cell harvester. Scintillation fluid was added and each well reading was read on a Microbata counter. .
4.3试验结果 4.3 Test results
GLP-1能特异性地与 1251标 GLP-1竟争性结合受体（表 4, 图 4 ), 其 IC5。值为 0.66 nM。 表 4. GLP-1对 GLP-1R的结合活力测试 GLP-1 specifically binds receptors to the 125 1 standard GLP-1 (Table 4, Figure 4), IC 5 . The value is 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1R
GLP-1终浓度 （nM) 125I标 GLP-1结合百分比 （％ ) GLP-1 final concentration (nM) 125 I standard GLP-1 binding percentage (%)
1000 0.0 1000 0.0
200 -2.0  200 -2.0
40 4.0  40 4.0
8 16.7  8 16.7
1.6 33.7  1.6 33.7
0.32 60.5  0.32 60.5
0.064 80.9  0.064 80.9
0 100.0  0 100.0

Claims

权利要求书
Figure imgf000063_0001
药 物学上可接受的盐及其所有的立体和光学异构体， 或者与其具有相同 药理作用的前药、 其酯、 其溶剂化物或其金属配合物： Claim
Figure imgf000063_0001
a pharmaceutically acceptable salt and all of its stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects:
Figure imgf000063_0002
其中 X和 Y分別为 (CH2)n, n为 0-2, 氧， 硫或氮； 为下列任意一种取代基： 氢； 卤素； 烷烃； 环烷烃； 羟基； 硝 基； 羧基； 醛基； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 巯基； 烷硫基； 醚； 硫醚； 取代或未取代的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未取代的吡喃基； 取代或未取代的噻 吩基； 取代或未取代的吡咯基；
Figure imgf000063_0002
Wherein X and Y are each (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen; any one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxyl; nitro; carboxy; Alkoxy; Amine; Amine; Amino; Amino; Carboxamide; Alkyl; Alkylthio; Ether; Thioether; Substituted or unsubstituted aryl; Substituted or unsubstituted pyridyl; a furanyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group;
R2, R3各自独立地为下列任意一种取代基： 氢； 烷烃； 环烷烃； 烷氧基； 胺基； 胺烷基； 酰胺基； 碳酰胺基； 烷硫基； 取代或未取代 的芳基； 取代或未取代的吡啶基； 取代或未取代的呋喃基； 取代或未 取代的吡喃基； 取代或未取代的噻吩基； 取代或未取代的吡咯基。 R 2 , R 3 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
2、 根据权利要求 1所述的具有取代环丙烷结构的化合物， 其特征 在于： 当 X, Y分别是 (CH2)n, n为 0-2, 氧， 硫或氮， 为： 其中 Rt为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 -C6的烷基； C2-C6的烯基； 含有包括卤素原子、 -C6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环綻基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 crc4的垸基、 硝基、 、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 d-C4的綻基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 crc4的烷基、 硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括鹵素原子、 C!- 的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻 p分基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；2. The compound having a substituted cyclopropane structure according to claim 1, wherein: when X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, Wherein Rt is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom include optionally containing, C r C 6 alkoxy or hydroxy, including one, two or three of the substituents -C An alkyl group of 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group of -C 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; C 3 -C Magenta 6 cycloalkyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furyl ; pyranyl; thienyl; pyrrolyl; pyridyl; containing fluorenyl, nitro, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, including halogen atom, c r c 4 Yue thio, ethylthio, including any one, two or three aryl group substituents; include a halogen atom-containing, 4 dC spindles group, a nitro group, Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, c r c Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio group; a halogen atom include containing, c r c alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including any of the 4 One, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, C!-, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl sulfide Any one, two or three substituted thiop groups including a thiol group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group , amide group, carboxamide group, sulfhydryl group, methylthio group, ethyl thio group Any one, two or three substituents pyrrolyl;
CrC6的烷酰基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的烯酰基； 含有 包括鹵素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 c2-c6的烯酰基； c2-c6的炔酰基； 含有包括卤素原子、 crc6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰 基； ¾ 6的环烷酰基； 含有包括卤素原子、 Cr 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环坑酰基；金刚浣曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰蓦； 呋喃甲酰基； 吡喃甲酰基； 噻 吩甲酰基； 吡咯甲酰基； 1为(0¾)11，11为 0-2， O, S或者丽时； An alkanoyl group of C r C 6 ; an alkanoyl group of any one, two or three substituted dC 6 containing a halogen atom, an alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; Any one, two or three of a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group Substituted c 2 -c 6 alkenyl group; a c 2 -c 6 alkynyl group; a halogen atom include any containing, R & lt c c 6 alkoxy or hydroxy, including one, two or three substituents c-2 -c 6 alkynyl group; a cycloalkyl group of 6 ¾; contain any halogen atoms include, Cr alkoxy or hydroxy group including one, two or three substituents of C 3 -C 6 cycloalkyl group of pits; Diamond Decanoyl, substituted adamantyl formyl; aroyl; benzylhydrazide; furoyl; pyranoyl; thiophene; pyrrolyl; 1 (03⁄4) 11 , 11 0-2, O, S Or Lishi;
R2, R3分别为：
Figure imgf000065_0001
其中 R5为下列任意一种取代基： H; C广 C6的烷基； 含有包括卤素 原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C 々烷基； C2-C6的烯基； 含有包括卤素原子、 的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； （ 2-( 6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； CrC6的环烷基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； '吡啶基； 含有 包括卤素原子、 d- 的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 C - 的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 C!- 的烷基、硝基、 、 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、硝基、 ½、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；R 2 and R 3 are respectively:
Figure imgf000065_0001
Wherein R 5 is any one of the following substituents: H; C-C 6 alkyl; any one, two or three substituted dC 含有 including a halogen atom, a C 6 alkoxy group or a hydroxyl group; An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group or a hydroxyl group; ( 2 -( 6 alkynyl; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a C 6 cycloalkyl, C R &lt; contain any halogen atom include, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyranyl ; thienyl; pyrrolyl; 'pyridyl; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, Any one, two or three substituted aryl groups including an ethylthio group; containing an alkyl group including a halogen atom, C - , a nitro group, Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, C r C Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio base; Any one or two containing a halogen atom, a C?- group, a nitro group, a aryl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or a three-substituted pyranyl group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, an aldehyde group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted thienyl groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted pyrrolyl groups including a fluorenyl group, a methylthio group, and an ethylthio group;
C广 C6的烷酰基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰 基； c3-c6的环烷酰基； 含有包括卤素原子、 crc6的烷氧基或羟基在 内的任意一个、两个或者三个取代的（¾-06的环烷酰基；金刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩甲酰基； 吡咯甲酰基； X2为 (CH2)n, n为 0-2, 0, S或者 NH; 或者 R2, R3分别为：
Figure imgf000066_0001
其中 R7各自独立为下列任意一种取代基： H; d-C6的烷基； 含有包括卤素原子、 Cr 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括鹵素原子、 。广^的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 c2-c6的炔基； c3-c6的环烷基； 含有包括 卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； p塞 p分基； 吡咯基； 吡 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 crc4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-Cj的烷基、 硝基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d- 的烷基、 硝基、 ½、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 d-C6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d-C6的烷酰基； c2-c6的 烯酰基； 含有包括卤素原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的烯酰基； c2-c6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； CrC6的环烷酰基； 含有包括卤素原子、 C C6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩曱酰基； 吡咯曱酰基； 为^！！ ， n为 0-2, O, S或 者 NH; X2为 (CH2)n，n为 0-2, O, S或者 NH; 或者 R2, R3分别为：
Figure imgf000068_0001
C 6 to C broad alkanoyl; includes any halogen atom-containing, -C 6 alkoxy or hydroxy, including one, two or three R & lt substituted C 6 to C alkyl group; a C 2 -C 6 alkenyl acyl; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a comprises containing Any one, two or three substituted c 2 -c 6 alkynyl groups such as a halogen atom, an alkoxy group or a hydroxyl group; a c 3 -c 6 cycloalkanoyl group; containing a halogen atom, c r c any of the 6 alkoxy or hydroxy, including one, two or three substituents of (¾-0 6 cycloalkyl group; a formyl adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; furoyl ; pyranoyl; thiophene; pyrroyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000066_0001
Wherein R 7 is each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three substituted C r C 6 containing a halogen atom, an alkoxy group of Cr or a hydroxyl group; alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; containing a halogen atom. Any of a wide range of alkoxy groups or hydroxyl groups One, two or three substituted c 2 -c 6 alkynyl groups; c 3 -c 6 cycloalkyl groups; any one or two containing a halogen atom, an alkoxy group of d- or a hydroxyl group a three-substituted C 3 -C 6 cycloalkyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a p-sepi group; a pyrrolyl group; a pyridyl group containing a halogen atom, dC 4 , an nitro group Any one, two or three substituted aryl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; c r c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including one, two or three Substituted pyridyl group; optionally containing an alkyl group including a halogen atom, d-Cj, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group One, two or three substituted furanyl groups; containing an alkyl group including a halogen atom, d-, a nitro group Any one, two or three substituted pyranyl groups, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; , c r c alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including any one, two or three a substituted thienyl group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group any one, two or three substituents pyrrolyl; dC 6 alkanoyl; contain any halogen atom include, dC 6 alkoxy or hydroxy, including one, two or three alkyl substituted dC 6 acyl; c 2 -c 6 alkenyl group; a halogen atom include any containing, R & lt c c 6 alkoxy or hydroxy, including one, two or three substituents of c 2 -c 6 alkenyl group; and c 2 Alkynyl group of -c 6 ; containing an alkoxy group or a hydroxyl group including a halogen atom, C r C 6 Including any one, two or three substituents of C 2 -C 6 alkynyl group; a C cycloalkyl group C 6 R &lt; a halogen atom includes contain any, alkoxy or hydroxy the CC including a 6, Two or three substituted c 3 -c 6 cycloalkanoyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyr Noryl; thiophene acyl; pyrrolidinyl; ! , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 2 , R 3 are:
Figure imgf000068_0001
其中 R8为下列任意一种取代基： H; CrC 坑基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醒基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 d- 的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吟基；含有包括卤素原子、 的浣基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； - 的烷酰基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的烯酰基； 含有 包括！ ¾素原子、 （^-(：6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 - 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩甲酰基； 吡咯甲酰基； ^为^！！ ， n为 0-2， O, S或者 NH; 或者 R2, R3分别为：
Figure imgf000069_0001
Wherein R 8 is any one of the following substituents: H; C r C pit group; any one, two or three substituted C r C containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group ; An alkyl group of 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group; C 3 -C 6 a cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a awake group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl group Any one, two or three substituted aryl groups including an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, Any one, two or three substituted pyridyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; containing a halogen atom, c r c Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio Any one or two containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethylthio group. Or a three-substituted pyranyl group; containing an alkyl group including a halogen atom, CrC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Foundation Any one, two or three substituted thioxyl groups; containing a halogen atom, a fluorenyl group, a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted pyrrolyl groups including a thio group or an ethylthio group; an alkanoyl group; any one, two or three containing a halogen atom, an alkoxy group or a hydroxyl group Substituted dC 6 alkanoyl; C 2 -C 6 alkenoyl; contains included! Any one, two or three substituted C 2 -C 6 alkenoyl groups such as a ^ atom, (^-( 6 alkoxy group or a hydroxyl group); a C 2 -C 6 alkynyl group; any atom, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; include a halogen atom-containing, - Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups; adamantyl formyl, substituted adamantyl form; aroyl; benzoyl; furoyl; Pyranoyl; thiophene; pyrroyl; ^ is ^!!, n is 0-2, O, S or NH; or R 2 , R 3 are:
Figure imgf000069_0001
其中 R9, R10各自独立为下列任意一种取代基： H; C广 C6的烷基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； C2-C6的烯基； 含有包括! ¾素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； (¾-( 6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻 p分基； 吡咯基； 吡1^； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 -C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 Ci-C4的烷基、 硝基、 ½、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d- 的烷基、 硝基、 ½、 基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子； d-Ct的烷基、 硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； - 的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括卤素原子、 C C6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯曱酰基； 为 （CH2)n, n为 0-2, O, S或 者 NH; X2为 （CH2)n， n为 0-2, O, S或者 ΝΉ; 当 X， Y分别是 (CH2)n, n为 0-2， 氧， 硫或氮， 为：
Figure imgf000071_0001
其中 Ru， R12各自独立为下列任意一种取代基： H; CrC 垸基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 CrC6的烷基； €2-( 6的烯基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的（¾-( 6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡1^； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 crc4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 C广 c4的烷基、 硝基、 ½、 酪基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括鹵素原子、 CrC4的烷基、 硝基、 、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 Cr 的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的炔酰基； C3-C6的环烷酰基； 含有包括卤素原子、 - 的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡 喃曱酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n, n为 0-2, O, S或 者 NH; X2为 （CH2)n，n为, 0-2, 0, S或者 NH时； Wherein R 9 and R 10 are each independently one of the following substituents: H; C-C 6 alkyl; any one, two or three containing a halogen atom, an alkoxy group of d- or a hydroxyl group. Substituted C r C 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C containing a 3⁄4 atom, C r C 6 alkoxy or hydroxy group 2 -C 6 alkenyl group; (¾- (6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl; C 3 -C 6 cycloalkyl; one, any two or three substituents include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including a C 3 -C 6 cycloalkyl Aryl; benzyl; furanyl; pyranyl; thiop-substyl; pyrrolyl; pyridyl 1 ^; containing alkyl group including halogen atom, dC 4 , nitro group, carboxyl group, aldehyde group, alkoxy group Any one, two or three substituted aryl groups including an amino group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, -C 4 , a nitrate Any one, two or three substituted pyridyl groups including a carboxy group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of alkyl, nitro, 1⁄2, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, of Ci-C 4 a substituted furanyl group; containing an alkyl group including a halogen atom, d-, a nitro group, a 1⁄2 group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group Any one, two or the like, methylthio or ethylthio a three-substituted thienyl group; containing an alkyl group including a halogen atom; d-Ct, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group within any one, two or three substituents pyrrolyl; - alkanoyl; containing optionally include a halogen atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of dC 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; and C 2 -C 6 alkynyl group; and one, two or three substituents at any C-alkynyl containing acyl group include a halogen atom, R & lt C C 6 alkoxy or hydroxy, including the 2 -C 6; C 3 -C 6 cycloalkyl group; a halogen atom includes contain any, the CC 6 alkoxy or hydroxy, including one, two or three substituents of c 3 -c 6 cycloalkyl group; Yue group adamantane, substituted adamantane Formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyr Is a decanoyl group; 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 ΝΉ; when X, Y are respectively (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, which is:
Figure imgf000071_0001
Wherein R u , R 12 are each independently one of the following substituents: H; C r C fluorenyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group C r C 6 alkyl; € 2 - (6 alkenyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of (¾- (6 alkynyl group; C 3 -C 6 cycloalkyl; contain any halogen atom includes, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl Benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl 1 ^; containing a halogen atom, dC 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, Any one, two or three substituted aryl groups including a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; containing a halogen atom, c r any c 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents of Pyridyl; containing an alkyl group including a halogen atom, C-C 4 , nitro, 1⁄2, keto, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted furanyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted pyranyl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a group, an alkoxy group, an amine group, an amide group Any one, two or three substituted thienyl groups including a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, and an alkane Oxyl, amine, amide, carboxamide, sulfhydryl, a Any one, two or three taking sulfur or ethylthio group a pyrrolyl group; an alkanoyl group of dC 6 ; an alkanoyl group having any one, two or three substituted dC 6 groups including a halogen atom, an alkoxy group of Cr or a hydroxyl group; a C 2 -C 6 alkenoyl group Any one, two or three substituted C 2 -C 6 alkenoyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; containing a halogen atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; containing include halogen atoms, - alkoxy Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups, including a hydroxy group; an adamantyl decanoyl group, a substituted adamantyl formyl group; an aroyl group; a benzyl group; a furanoyl group; Acyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is, 0-2, 0, S or NH Time;
R2， R3分别为：
Figure imgf000072_0001
其中 R5为下列任意一种取代基： H; CrC^々烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 (^-( 6的烷基； C2-C6的烯基； 含有包括鹵素原子、 -C6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基; 含有包括卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 (¾-( 6的炔基； C3-C6的环烷基； 含有包括卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醒基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 C广 C4的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括鹵素原子、 C - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 - 的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 -C6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代 CrC6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 d-C6的烷 氧基或羟基在内的任意一个、两个或者三个取代 C2-C6的炔酰基； C3-C6 的环烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一 个、 两个或者三个取代的 C3-C6的环烷酰基； 金刚烷曱酰基、取代金刚 烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰基； 吡咯曱酰基； X2为 (CH2)n, n为 0-2， 0, S或者 NH; 或者 R2, R3分别为：
Figure imgf000073_0001
其中 R6, 各自独立为下列任意一种取代基： H; d- 的烷基; 含有包括卤素原子、 C 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 （^-< 6的烷基； c2-c6的烯基； 含有包括卤素原子、 crc6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的烯基；R 2 and R 3 are respectively:
Figure imgf000072_0001
Wherein R 5 is any one of the following substituents: H; C r C 々 alkyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group ( ^-( 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, a C 6 alkoxy group or a hydroxyl group Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted (3⁄4-( 6 alkynyl); C 3 containing a halogen atom, a C 6 alkoxy group or a hydroxyl group; a C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group ; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a awake group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, an anthracene group Any one, two or three substituted aryl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, C-C 4 , a nitro group, Aldehyde Any one, two or three substituted pyridyl groups including a base, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing a halogen atom, c r c 4 Any one, two or three substituted furanyl groups such as an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group or an ethylthio group. Any one or two containing a halogen atom, a C-alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Or three substituted pyranyl groups; containing a halogen atom, an alkyl group, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted thienyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group Any one of methylthio or ethylthio , Two or three substituents pyrrolyl; C r to C 6 alkanoyl; include a halogen atom contain any, -C 6 alkoxy or hydroxy, including one, two or three of the substituents -C 6 of alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents C r C 6 alkenoyl; C 2 - An alkynyl group of C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an adamantyl decanoyl group, a substituted adamantyl form group; an aroyl group; Benzyl; furoyl; pyranoyl; thiophene; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000073_0001
Wherein R6, each independently of any one of the following substituents: H; d-alkyl; Any one, two or three substituted (^-< 6 alkyl groups; c 2 -c 6 alkenyl group including a halogen atom, a C alkoxy group or a hydroxyl group; containing a halogen atom, c r any c 6 alkoxy or hydroxy, including one, two or three substituents of c 2 -c 6 alkenyl group; and
CrC6的炔基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 c2-c6的炔基； c3-c6的环烷基； 含有包括 鹵素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡 ； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 酪基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括鹵素原子、 crc4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括鹵素 原子、 CrC4的烷基、 硝基、 羧基、 基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 crc4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 C2-C6的烯酰基； CrC6的炔酰基； 含有包括卤素原 子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代 c2-c6 的炔酰基； c3-c6的环烷酰基； 含有包括卤素原子、 crc6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 c3-c6的环烷酰基； 金刚烷 曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃曱 酰基；噻吩曱酰基； 吡咯甲酰基； X2为 (CH2)n, n为 0-2, 0, S或者 NH; 或者 R2, R3分别为：
Figure imgf000075_0001
其中 R8为下列任意一种取代基： H; d- 的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C6的浣基； C2-C6的烯基； 含有包括卤素原子、 d- 的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； CrC6的环烷基； 含有包括卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 C 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 C!- 的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括! ¾素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙石克基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 CrC4的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻分基；含有包括卤素原子、 CrC4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的烷酰基； 含有包括鹵素原子、 C - 的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃曱酰基； 噻 吩甲酰基； 吡咯甲酰基； X2为 (CH2)n，n为 0-2, 0， S或者 NH; 或者 , 分别为： Alkynyl group of C r C 6 ; any one, two or three substituted c 2 -c 6 alkynyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; a ring of c 3 -c 6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiophenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, d-, a nitro group, a carboxy group, a aryl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and a Any one, two or three substituted aryl groups including a thio group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon Any one, two or three substituted pyridyl groups including an amide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a group, an alkoxy group Any one of a group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group , two or three substituted furanyl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group Any one, two or three substituted pyranyl groups including a thiol group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group Any one, two or three substituted thienyl groups including a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, and a phenyl group any alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; comprising comprising a halogen atom, an optionally C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 Any one, two or three substitutions C, such as alkoxy or hydroxy 2- C6 alkenoyl; C r C 6 alkynyl; containing halogen Promoter, any R & lt c c 6 alkoxy or hydroxy, including one, two or three substituents c 2 -c 6 alkynyl group; a cycloalkyl group of c 3 -c 6; include a halogen atom-containing, R & lt c Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of c 6 alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl form; aroyl; benzyl; furan Acyl; pyranoyl; thiophene acyl; pyrroyl group; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 2 , R 3 are:
Figure imgf000075_0001
Wherein R 8 is any of the following substituent groups: H; d- alkyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three of the substituents dC 6 Alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C 6 alkenyl group including a halogen atom, d-alkoxy or hydroxy group; C 2 - An alkynyl group of C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a cycloalkyl group of C r C 6 ; Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; Pyrrolyl; pyridyl; containing a halogen atom, an alkyl group of C, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group, an ethylthio group, etc. Any one, two or three substituted aryl groups; containing an alkyl group including a halogen atom, C!-, a nitro group, an aldehyde group, Any alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; containing pigment include ¾ atoms, an alkoxy CrC 4! Any one, two or three substituted furyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethyl ketone group; Including a halogen atom, an alkyl group of d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, Any one, two or three substituted pyranyl groups including an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, Any one, two or three substituted thio groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing a halogen atom, Cr Any one, two or three substituted alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio group of C 4 pyrrolyl; C r C 6 alkanoyl; include a halogen atom-containing, C - of any alkoxy or hydroxy, including one, two or three substituents of dC 6 alkanoyl; C 2 -C 6 alkenyl of acyl; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a comprises containing any of halogen atom, C r C 6 alkoxy or hydroxy, including one, two or three Substituted C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C 6 cycloalkanoyl; adamantyl formyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrroyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or, respectively:
5 ti^^ XiRio 其中 R9, R10各自独立为下列任意一种取代基： H; 的烷基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； C2-C6的烯基； 含有包括鹵素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； (¾-(：6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的（¾- 的炔基； C3-C6的环烷基； 含有包括 卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 c3-c6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基; 吡1^； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 酪基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 crc4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 ½、 基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 5危基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 Ci-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； Q-C6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括！ ¾素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯曱酰基； 为(0¾)。， n为 0-2, O, S或 者 NH; 为 (CH2)n， n为 0-2, 0， S或者 ΝΉ; 当 X， Y分别是（CH2)n, η为 0-2, 氧， 硫或氮， 为：
Figure imgf000078_0001
其中 R13为下列任意一种取代基： H; d-C6的烷基； 含有包括卤 素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C 々烷基； C2-C6的烯基； 含有包括卤素原子、 的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的（¾ 6的炔基； C3-C6的环烷基； 含有包括卤素原子、 d-C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻哈基； 吡咯基； 吡啶基； 含有 包括卤素原子、 -C4的烷基、 硝基、 «、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括鹵素原子、 d-C4的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 Cr 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛碁、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d- 的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的烷酰基； 含有包括鹵素原子、 -C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 d- 的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 c2-c6的烯酰基； c2-c6的炔酰基； 含有包括卤素原子、 crc6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰 基； CrC6的环烷酰基； 含有包括鹵素原子、 C!- 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃曱酰基； 噻 吩曱酰基； 吡咯曱酰基； 为 （CH2)n, n为 0-2， O, S或者 NH时， ， 分别为：
Figure imgf000079_0001
其中 R5为下列任意一种取代基： H; CH 6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C6的烷基； （¾ 6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 -C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰 胺基、 碳酰胺基、 δ¾基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括鹵素原子、 Cr 的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括鹵素原子、 crc4 的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、硝基、 ^&、 醛基、 烷氧基、 胺基、 '酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； -C6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 -C6的烷酰基； C2-C6的烯酰基； 含有 包括鹵素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 C!- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯甲酰基； X2为 （CH2)n，n为 0-2， 0, S或者 H; 或者 R2, R3分別为：
Figure imgf000080_0001
其中 Re, R7各自独立为下列任意一种取代基： H; (：广^的坑基； 含有包括卤素原子、 CrC6的烷氣基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； -(¾的烯基； 含有包括卤素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； CrC6的块基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡^ 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 d-C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 ½、 醒基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括鹵素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括鹵素原子、 crc4的烷基、 硝基、 羧基、 趁基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻哈基； 含有包括 卤素原子、 d- 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 C!- 的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的烯酰基； c2-c6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； （ 3-( 6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n，n为 0-2， 0， S或 者 NH; X2为 （CH2)n， n为 0-2， 0， S或者 NH; 或者 , 分别为：
Figure imgf000082_0001
其中 R8为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C 的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 d-C4的烷基、 硝基、 ½、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙疏基在内 的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 crc4的烷基、 硝基、 ½、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d- 的烷基、硝基、 ½、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻分基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；5 ti^^ Xi R io wherein R 9 and R 10 are each independently one of the following substituents: H; an alkyl group; any one or two containing a halogen atom, an alkoxy group or a hydroxyl group; a three-substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; group; (¾- (: 6 alkynyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of (¾- alkynyl; C 3 - a C 6 cycloalkyl group; Any one, two or three substituted c 3 -c 6 cycloalkyl groups such as a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; Pyrrolyl; pyridinium 1 ^; containing a halogen atom, d-alkyl group, nitro group, carboxyl group, keto group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, methylthio group, ethyl thio group Any one, two or three substituted aryl groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted pyridyl groups including a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a 1⁄2 group, an alkoxy group, an amine group, Any one, two or three substituted furanyl groups including an amide group, a carboxamide group, a 5-carbyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, , aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, hydrazine Any one, two or three substituted pyranyl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group Any one, two or three substituted thienyl groups including a carbaryl group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, Ci-C 4 , a nitro group, a carboxyl group, or an aldehyde Any one, two or three substituted pyrrolyl groups, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkanoyl group of QC 6 ; any atom, a C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include containing, alkoxy Any one, two or three substituted C 2 -C 6 enoyl groups, including a hydroxyl group; a C 2 -C 6 alkynyl group; an alkoxy group having a halogen atom, C r C 6 or a hydroxyl group; within any one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 Cycloalkanoyl; comprising comprising! ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; (03⁄4). , n is 0-2, O, S or NH; is (CH 2 ) n , n is 0-2, 0, S or ΝΉ; when X, Y are (CH 2 ) n , η is 0-2, oxygen, sulfur or nitrogen, as:
Figure imgf000078_0001
Wherein R 13 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted dC decanes including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, an alkoxy group or a hydroxyl group; C 2 -C 6 Any one, two or three substituted (3⁄4 6 alkynyl group; C 3 -C 6 cycloalkyl group containing a halogen atom, - alkoxy group or a hydroxyl group; containing a halogen atom, Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy group of dC 6 ; aryl; benzyl; furyl; pyranyl; thiohaki; pyrrolyl ; pyridyl; containing a halogen atom, -C 4 alkyl, nitro, «, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio any one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl, nitro, aldehyde group, Any one, two or three substituted pyridyl groups including an oxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, Cr, and a nitro group Any one, two or three substituted furanyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; c r c any alkyl, nitro, carboxyl, aldehyde Acer, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including one, two or three Substituted pyranyl; containing an alkyl group including a halogen atom, d-, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted thienyl groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted pyrrolyl groups including a mercapto group, an anthracenethio group, an ethylthio group; an alkanoyl group of dC 6 ; or an alkoxy group including a halogen atom, -C 6 or a hydroxyl group , two or three substituents of d- alkanoyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents c-alkenyl group of 2 -c 6; c is 2 -c 6 alkynyl group; a halogen atom include any containing c, c c R & lt 6 alkoxy or hydroxy, including one, two or three substituents of 2 - Alkynyl group of c 6 ; cycloalkanoyl group of C r C 6 ; any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of C!- or a hydroxyl group; Acyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyr Yue acyl; Yue thienyl group; pyrrolidin Yue group; is (CH 2) n, n is 0-2, O, or S when NH,, respectively:
Figure imgf000079_0001
Wherein R 5 is any one of the following substituents: H; an alkyl group of CH 6 ; any one, two or three substituted dC 6 containing a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; alkyl; (¾ 6 alkenyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 - C 6 alkynyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl of alkyl; optionally include a halogen atom-containing, -C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyran a thiophenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an acyl group; Any group, carbonamide group, δ¾ group, methylthio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, C r alkyl, nitro, carboxyl, aldehyde Any one, two or three substituted pyridyl groups including a base, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing a halogen atom, c r c 4 Any one, two or three substituted furanyl groups such as an alkyl group, a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. ; contain any halogen atom includes, c r c, nitro, carboxyl, casein group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including a 4 , two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, dC 4 , nitro, ^&, aldehyde group, alkoxy group, amine group, 'amide group, carboxamide group, fluorenyl group, A Any one, two or three taking sulfur or ethylthio group Thienyl; include a halogen atom-containing, c r c alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio inner 4 any one, two or three substituents pyrrolyl; -C 6 alkoxy group; a halogen atom include any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of - Alkanoyl group of C 6 ; C 2 -C 6 alkenoyl group; any one, two or three substituted C 2 -C 6 alkenes including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group acyl; C 2 -C 6 alkynyl group; a! include a halogen atom-containing, C - of any alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 - C 6 cycloalkyl group; a halogen atom includes any containing, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; adamantane formyl, Substituting adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrole Formyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or H; or R 2 , R 3 are:
Figure imgf000080_0001
Wherein Re, R 7 are each independently one of the following substituents: H; (: a wide pit base; any one, two or three containing a halogen atom, an alkyl group or a hydroxyl group of C r C 6 a substituted dC 6 alkyl; - (¾ alkenyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of a C 2 -C 6 Alkenyl; C r C 6 block; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group or a hydroxyl group; C 3 -C 6 cycloalkyl; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furan a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, an anthracene group; Any one, two or three substituted aryl groups including a thio group or an ethylthio group; an alkyl group including a halogen atom, dC 4 , and a nitrate Any one, two or three substituted pyridyl groups including a carboxy group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substitutions of dC 4 alkyl, nitro, 1⁄2, awake, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio a furanyl group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methyl group, an ethyl group, and an ethyl group. Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted thioha groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Base, amide group, carboxamide group, thiol group, methylthio group, Thio, including any one, two or three substituents pyrrolyl; dC 6 alkanoyl;! Include a halogen atom-containing, C - alkoxy or hydroxy arbitrary, including one, two or three substituents An alkanoyl group of C r C 6 ; a C 2 -C 6 alkenoyl group; or an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group; Two or three substituents of c 2 -c 6 alkenyl group; a c 2 -c 6 alkynyl group; a halogen atom include any one containing, C r C 6 alkoxy or hydroxy, including, two or three a substituted C 2 -C 6 alkynyl group; a (3 - cycloalkyl group (6; includes any halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkanoyl; adamantyl decanoyl, substituted adamantyl formyl; aroyl; benzyl acyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or, respectively:
Figure imgf000082_0001
Wherein R 8 is any of the following substituent groups: H; alkyl C 6 to C R &lt; a, any two or three substituents include a halogen atom-containing, C R & lt alkoxy or hydroxy C 6 of the inner C alkyl; C 2 -C 6 alkenyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; C 3 -C 6 cycloalkyl; contain any include halogen atoms, alkoxy or hydroxy C 6 inner one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furyl ; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, A any thio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, dC 4 alkyl group, a nitro group ½, any aldehyde, alkoxy, amine, amide, carboxamide group, a mercapto group, methylthio group, ethylthio group, including a sparse, two or three substituted pyridyl; include a halogen atom-containing, C An alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, an anthracene of r c 4 Any one, two or three substituted furanyl groups including a methyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, c r c 4 , a nitro group, an aldehyde group, an alkoxy group, Any one, two or three substituted pyranyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, Any one, two or three substituted thio groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; c r c any alkyl, nitro, carboxyl, casein group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio 4, including one, two or three Substituted pyrrolyl;
CrC6的烷酰基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素原子、 （ C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 crc6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 c3-c6的环炕酰基；金刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯甲酰基； ！为 （CH2)n, n为 0-2, 0, S或者丽； 或者 R2, R3分别为： M C r C 6 alkanoyl; include a halogen atom contain any, -C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl of acyl; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a comprises containing a halogen atom, a acetylene group of any one, two or three substituted c r c 6 such as a C 6 alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a halogen atom, dC 6 Any one, two or three substituted c 3 -c 6 cyclodecanoyl groups such as alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzoyl; furoyl; Pyranoyl; thiophene acyl; pyrrolyl; ! is (CH 2 ) n , n is 0-2, 0, S or 丽; or R 2 , R 3 are: M
X2R9 其中 R9, R1Q各自独立为下列任意一种取代基： H; C广 C6的烷基； 含有包括卤素原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； C2-C6的烯基； 含有包括卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基;. 含有包括卤素原子、 C广 c6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 c2-c6的炔基； c3-c6的环烷基； 含有包括 鹵素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 c3-c6的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡 ; 含有包括卤素原子、 的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 C广 c4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 -C4的烷基、 硝基、 ½、 酪基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 （^-( 4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 - 的烷基、 硝基、 ¾&、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； CrC6的烷酰基； 含有包括卤素原子、 CrC6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d-C6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； （¾-( 6的炔酰基； 含有包括卤素 原子、 -C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 (32-(：6的炔酰基； C3-C6的环烷酰基； 含有包括！ ¾素原子、 C6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 ¾ 6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n, n为 0-2, O, S或 者 NH; X2为 （CH2)n， n为 0-2, O, S或者 NH。 当 X， Y分别是（CH2)n，n为 0-2, 氧， 硫或氮， 为：
Figure imgf000085_0001
X2R9 wherein R 9 and R 1Q are each independently a substituent of any of the following: H; C C C 6 alkyl; any one or two containing a halogen atom, a C 6 alkoxy group or a hydroxyl group or a three-substituted alkyl group of dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; base; C 2 -C 6 alkynyl group; a halogen atom include any containing, broad c C 6 alkoxy or hydroxy, including one, two or three substituents of c -C 6 alkynyl group of 2; c 3 -. a cycloalkyl group of c 6 ; a cyclohexyl group of any one, two or three substituted c 3 -c 6 containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl group Any one, two or three substituted aryl groups including an ethylthio group; containing an alkyl group including a halogen atom, C-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one, two or three substituted pyridyl groups including a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, -C 4 , a nitro group, a phenyl group, a ketone group, Any one of an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group Two or three substituents furanyl; containing a halogen atom include, (^ - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio Any one, two or three substituted pyranyl groups including a thiol group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, Any one, two or three substituted thienyl groups including an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing an alkyl group including a halogen atom, - a nitro group, a nitro group, an aldehyde group, any alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; include halogen-containing any atom, C r C 6 alkoxy or hydroxy, including one, two or three substituents of dC 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 alkoxy Any one, two or three substituted C 2 such as a base or a hydroxyl group -C 6 enoyl group; (3⁄4-( 6 acetylene group; any one, two or three substituted groups including a halogen atom, a C 6 alkoxy group or a hydroxyl group (3 2 - (: 6) alkynyl group; C 3 -C 6 cycloalkyl group;! ¾ comprising optionally containing atom, a hydroxyl group or an alkoxy group of C 6, including one, two or three substituents of the cycloalkyl group ¾ 6; Kim Cycloalkanoyl, substituted adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n 0-2, O, S Or NH; X 2 is (CH 2 ) n , and n is 0-2, O, S or NH. When X, Y are (CH 2 ) n and n is 0-2, oxygen, sulfur or nitrogen, are:
Figure imgf000085_0001
其中 R14, R15各自独立为下列任意一种取代基： H; <^-( 6的烷基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的烷基； C2-C6的烯基； 含有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 鹵素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 CrC6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡1^； 含有包括卤素原子、 （ 的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 琉基、 曱硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 d-C4的浣基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 ^&、 基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CrC4的烷基、 硝基、 ½、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 鹵素原子、 d-C4的烷基、 硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； - 的烷酰基； 含有包括卤素原子、 - 的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 CrC6的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； CrC6的环烷酰基； 含有包括卤素原子、 d-C6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n，n为 0-2, 0, S或 者 NH; X2为 (CH2)n, n为 0-2, O, S或者 NH时， Wherein R 14 and R 15 each independently represent any one of the following substituents: H; <^-( 6 alkyl; any one or two containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group; Or an alkyl group of three substituted dC 6 ; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing a halogen atom, an alkoxy group of d- or a hydroxyl group; 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom-containing include, - any alkoxy or hydroxy inner one, two or three substituents a C 2 -C 6 alkynyl group; C 3 -C 6 cycloalkyl; includes any halogen atom-containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of C r C 6 cycloalkyl; aryl; benzyl ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl 1 ^; containing halogen atom, (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, Any one, two or three substituted aryl groups including a fluorenyl group, a thiol group, an ethylthio group; a fluorenyl group containing a halogen atom, dC 4 Any one, two or three substituted pyridyl groups, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; Any one, two or three of a halogen atom, an alkyl group of dC 4 , a nitro group, a ^, a group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Substituted furanyl; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, a 1⁄2, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, c r c 4 , Any one, two or three substituted thienyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substitutions of an atom, an alkyl group of a dC 4 , a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. pyrrolyl; - alkanoyl; contains include halogen atoms, - alkoxy or hydroxy arbitrary inner one, two or three substituents of C r C 6 alkanoyl; C 2 -C 6 alkenyl group of ; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen-containing include any atom, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; and R & lt C C 6 cycloalkyl group; a halogen atom-containing include, dC 6 any alkoxy or hydroxy, including one, two or three of the substituents of C 3 -C 6 cycloalkyl An acyl group; formyl adamantane, substituted adamantane formyl; aryl group; a benzyl group; furoyl; formyl pyran; thenoyl; pyrroyl; is (CH 2) n, n is 0-2, 0 , S or NH; X 2 is (CH 2 ) n , when n is 0-2, O, S or NH,
R2, R3分别为：
Figure imgf000086_0001
其中 R5为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C 々 基； （¾-(¾的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； CrC6的炔基; 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括卤素原子、 C C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡^¾ 含有包括卤素原子、 d-C4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙^基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 - 的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d-C4的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻吩基；含有包括卤素原子、 d-C4 的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；R 2 and R 3 are respectively:
Figure imgf000086_0001
Wherein R 5 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents of dC 々 group; (¾- (¾ alkenyl groups; optionally include a halogen atom-containing, C r C 6 alkoxy or hydroxy inner one, two or three substituents of the alkenyl group of C 2 -C 6; C Alkynyl group of r C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group; C 3 -C 6 a cycloalkyl group; any one, two or three substituted C 3 -C 6 naphthenes containing a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; Aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkyl, nitro, carboxyl, aldehyde, alkoxy, amine including halogen atom, C r C 4 Any one, two or three substituted aryl groups including a amide group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and a halogen atom, dC Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, fluorenyl, methylthio, ethyl Any one or two containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Or three substituted pyranyl groups; Any sub, dC alkyl, nitro, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including one, two or three substituents a thienyl group; optionally containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group One, two or three substituted pyrrolyl groups;
CrC6的烷酰基； 含有包括卤素原子、 的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 Ci-Cs的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 c「c6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； （：2-(¾的炔酰基； 含有包括鹵素原子、 c c6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰 基； CrC6的环烷酰基； 含有包括卤素原子、 - 的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环垸酰基；金刚烷甲酰基、 取代金刚垸曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯甲酰基； X2为 （CH2)n, n为 0-2， 0， S或者 H; 或者 R2，R3分別为：
Figure imgf000088_0001
An alkanoyl group of C r C 6 ; an alkanoyl group of any one, two or three substituted Ci-Cs including a halogen atom, an alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; Any one, two or three substituted C 2 -C 6 alkenoyl groups having a halogen atom, c "c 6 alkoxy group or a hydroxyl group; (: 2 - (3⁄4 alkynyl group; containing a halogen atom, cc any 6 alkoxy or hydroxy, including one, two or three substituents of c -C 6 alkynyl group of 2; C r C 6 cycloalkyl group; a halogen atom-containing include, - alkoxy or Any one, two or three substituted C 3 -C 6 cyclodecanoyl groups including a hydroxyl group; adamantyl formyl group, substituted adamantyl group; aroyl group; benzyl group; furoyl group; pyroyl group; Thiophenanthryl; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or H; Or R 2 and R 3 are:
Figure imgf000088_0001
其中 , R7各自独立为下列任意一种取代基： H; - 的烷基； 含有包括卤素原子、 CRC6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 d-C6的綻基； C2-C6的烯基； 含有包括卤素原子、 -C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C6的炔基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 c3-c6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 crc4的烷基、 硝基、 羧基、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括鹵素原子、 crc4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d- 的烷基、 硝基、 、 酪基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 CH 4的烷基、 硝基、 、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 琉基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 C!-C4的坑基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 d-C4的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d- 的烷酰基； 含有包括卤素原子、 -C6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d- 的烷酰基； C2-C6的 烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的烯酰基； C2-C6的炔酰基； 含有包括卤素 原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯甲酰基； 为 （CH2)n，n为 0-2, O, S或 者 NH; X2为 （CH2)n，n为 0-2, O, S或者 NH; 或者 R2, R3分别为：Wherein R 7 is each independently a substituent of any of the following: H; -alkyl; or any one, two or three substituted dCs including a halogen atom, an alkoxy group of C R C 6 or a hydroxyl group. 6 Magenta group; a C 2 -C 6 alkenyl group; a halogen atom includes any containing, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C 3 -C 6 a cycloalkyl group; any one, two or three substituted c 3 -c 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted aryl groups including a thio group or an ethylthio group; an alkyl group including a halogen atom, c r c 4 Any one, two or three substituted pyridyl groups, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of a halogen atom, a d-alkyl group, a nitro group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Substituted furanyl; containing an alkyl group including a halogen atom, CH 4 , a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; a pit group including a halogen atom, C!-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted thienyl groups including a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group , amide group, carboxamide group, sulfhydryl group, sulfonium group, ethyl sulphur Any one, two or three a pyrrolyl group; an alkanoyl group of d-; an alkanoyl group having any one, two or three substituted d- groups including a halogen atom, an alkoxy group of -C 6 or a hydroxyl group; C 2 -C 6 alkenoyl; contain any halogen atoms include, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; and comprising Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a halogen atom, C r any C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; a formyl adamantane, substituted adamantane formyl; aryl group; a benzyl group; furan Formyl; pyranoyl; thiophene; pyrrolyl; (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; or R 2 , R 3 are:
Figure imgf000089_0001
其中 R8为下列任意一种取代基： H; C广。6的坑基； 含有包括卤素 原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 (3广( 6的烷基； C2-C6的烯基； 含有包括卤素原子、 CrC6的烷氧基或羟 基在内的任意一个、 两个或者三个取代的 C2-C6的烯基； C2-C 々块基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C2-C6的炔基； C3-C6的环烷基； 含有包括鹵素原子、 CrC6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括卤素原子、 d-C4的烷基、 硝基、 羧基、 酪基、 烷氧基、 胺基、 酰 胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者 三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 、 醛 基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内 的任意一个、 两个或者三个取代的吡嚏基； 含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲疏基、 乙硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- 的烷基、 硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或 者三个取代的吡喃基； 含有包括卤素原子、 d- 的烷基、硝基、 、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在 内的任意一个、两个或者三个取代的噻喻基；含有包括卤素原子、 crc4 的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； - 的烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任 意一个、 两个或者三个取代的 的烷酰基； C2-C6的烯酰基； 含有 包括鹵素原子、 C C6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 C2-C6的烯酰基； C2-C6的块酰基； 含有包括卤素原子、 -C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在 内的任意一个、两个或者三个取代的 C3-C6的环烷酰基；金刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃甲酰基； 噻 吩曱酰基； 吡咯曱酰基； 为 （CH2)n, n为 0- 2, O, S或者丽； 或者 , 分别为：
Figure imgf000090_0001
Figure imgf000089_0001
Wherein R 8 is any one of the following substituents: H; C broad. 6 pit group; a halogen atom includes any containing, C r C 6 alkoxy or hydroxy, including one, two or three substituents (3 wide (6 alkyl; C 2 -C 6 alkenyl group ; optionally include a halogen atom-containing, C R & lt C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group of; C 2 -C 々 block group; include a halogen atom-containing Any one, two or three substituted C 2 -C 6 alkynyl groups of alkoxy or hydroxy group of dC 6 ; a C 3 -C 6 cycloalkyl group; containing a halogen atom, C r C 6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl Any one or two containing a halogen atom, an alkyl group of dC 4 , a nitro group, a carboxyl group, a keto group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Or three substituted aryl groups; containing an alkyl group including a halogen atom, C r C 4 , a nitro group, an aldehyde Any one, two or three substituted pyridinyl groups including an alkoxy group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and a halogen atom, c r c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methyl mercapto, ethylthio 4 including one, two or three substituents furan Any one or two containing a halogen atom, an alkyl group having a halogen atom, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group. Or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethyl sulfide group, including any one, two or three groups substituted thiazol Yu; include a halogen atom-containing, c r c 4 alkyl group, a nitro group, a carboxyl group, an acid group, an amine group, an amide group, carbon Any one of an amide group, a thiol group, a methylthio group, and an ethylthio group Two or three substituents pyrrolyl; - alkanoyl; containing optionally include a halogen atom, an alkoxy group or a hydroxyl dC 6, including one, two or three substituents of the alkanoyl; C 2 -C 6 Any one, two or three substituted C 2 -C 6 alkenoyl groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; a C 2 -C 6 block acyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups of a halogen atom, a C 6 alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a halogen atom, C r any C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; furan Decanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; (CH 2 ) n , n is 0-2, O, S or 丽; or, respectively:
Figure imgf000090_0001
其中 R9, R10各自独立为下列任意一种取代基： H; C!-Cs的炕基； 含有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 crc^ 烷基； c2-c6的烯基； 含有包括 素原子、 crc6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 (¾-< 6的烯基；Wherein R 9 and R 10 are each independently a substituent of any of the following: H; a thiol group of C!-Cs; Any one, two or three substituted c r c ^ alkyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an alkenyl group of c 2 -c 6 ; containing a acne atom, c r c 6 Any one, two or three substituted (3⁄4-< 6 alkenyl) groups such as alkoxy or hydroxy;
C2-C6的炔基； 含有包括卤素原子、 Cr 6的烷氧基或羟基在内的任意 一个、 两个或者三个取代的（32-( 6的炔基； C3-C6的环烷基； 含有包括 卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代 的 CrC6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d-C4的烷基、 硝基、 、 醛基、 烷氧 基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一 个、 两个或者三个取代的芳基； 含有包括卤素原子、 -C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素 原子、 d-C4的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代 的呋喃基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷 氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基；含有包括卤素原子、 -Cj的浣基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫 基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括 卤素原子、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取 代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 d-C6的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 crc6的烷酰基； c2-c6的 烯酰基； 含有包括卤素原子、 C 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的烯酰基； c2-c6的炔酰基； 含有包括卤素 原子、 crc6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰基； c3-c6的环烷酰基； 含有包括卤素原子、 crc6的烷氧 基或羟基在内的任意一个、 两个或者三个取代的 C3-C6的环烷酰基； 金 刚烷曱酰基、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡 喃甲酰基； 噻吩甲酰基； 吡咯曱酰基； 为 （CH2)n, n为 0-2， 0, S或 者 NH; 为 （CH2)n， n为 0-2， O, S或者 NH; a C 2 -C 6 alkynyl group; any one, two or three substituted (3 2 -( 6 alkynyl group; C 3 -C 6 ) containing a halogen atom, an alkoxy group of Cr 6 or a hydroxyl group; cycloalkyl; R & lt contain any C include a halogen atom, alkoxy or hydroxy CrC 6, including one, two, three or substituted C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyrazol a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, dC 4 , a nitro group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, Any one, two or three substituted aryl groups including an ethylthio group; containing an alkyl group including a halogen atom, -C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, or a carbon group Any one, two or three substituted pyridyl groups including an amide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an acid group, an alkoxy group , an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, etc. One, two or three substituents furanyl; containing a halogen atom include, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio 4 Any one, two or three substituted pyranyl groups including an ethylthio group; a thiol group including a halogen atom, -Cj, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, Any one, two or three substituted thienyl groups including a carboxamide group, a fluorenyl group, a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group, an aldehyde group, an alkoxy group Any one, two or three substituted pyrrolyl groups, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkanoyl group of dC 6 ; containing a halogen atom, dC 6 alkoxy or hydroxy, including any one, two or three substituents of c r c 6 alkanoyl; C 2 -C 6 alkenyl group; contains include halogen atoms, C alkoxy or hydroxyl group, including Any one, two or three substituted c 2 -c 6 alkenoyl; C 2 -C 6 alkynyl group; a halogen-containing include Atom, R & lt arbitrary c c 6 alkoxy or hydroxy, including one, two or three substituents of c -C 6 alkynyl group of 2; c 3 -c 6 cycloalkyl group; a halogen atom include containing, c any r c 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; furan Formyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2, 0, S or NH; (CH 2 ) n , n is 0-2, O, S or NH;
3、 根据权利要求 1至 2任意一项所述的具有取代环丙烷结构的化 合物， 其特征在于当分子中存在手性碳时 , 所述化合物为消旋体或光 学活性体。  The compound having a substituted cyclopropane structure according to any one of claims 1 to 2, characterized in that when a chiral carbon is present in the molecule, the compound is a racemate or an optically active substance.
4、 椐权利要求 1至 3任一项所述的具有取代环丙烷结构的化合物 的制备方法是通过如下步骤实施的： The method for producing a compound having a substituted cyclopropane structure according to any one of claims 1 to 3, which is carried out by the following steps:
R2 丫 COOH [¾ χ 〇00〇Η3 Ri— =Ν≡Ν R 2丫COOH [3⁄4 χ 〇00〇Η 3 Ri— =Ν≡Ν
R Y上 COOH R Y丄 COOCH3 IV RY on COOH RY丄COOCH 3 IV
II III  II III
Figure imgf000092_0001
Figure imgf000092_0001
V I 化合物 II ( leq )溶于曱醇中， 滴加数滴浓;琉酸， 加热回流 8小时， 得到化合物 III； 将化合物 ΙΠ ( 2eq )在氮气的保护下加热至 180°C , 慢慢滴加化合 物 IV ( leq ), 滴加的速度以维持反应温度 180°C - 190°C为准， 冷却， 得到桔红色残余物， 加入适量的 10 %乙醚 /正戊烷， 过滤， 得到化合物 V； 化合物 V溶于甲醇， 加入氢氧化钠溶液， 加热水解得到产物 I。 VI compound II ( leq ) is dissolved in decyl alcohol, a few drops are concentrated; citric acid is heated under reflux for 8 hours to obtain compound III; compound ΙΠ ( 2 eq ) is heated to 180 ° C under the protection of nitrogen, slowly dropping Add compound IV (leq), the rate of addition is maintained at a temperature of 180 ° C - 190 ° C, and cooled to obtain an orange-red residue. Add an appropriate amount of 10% diethyl ether / n-pentane and filter to obtain a compound. V; Compound V was dissolved in methanol, and a sodium hydroxide solution was added thereto, followed by heating to obtain a product I.
5、 根据权利要求 1至 3 中任意一项所述的具有取代环丙烷结构的 化合物或其药物学上可接受的盐用于制备预防和 /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）等的用途。 The compound having a substituted cyclopropane structure or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for use in the preparation of a prophylactic and/or therapeutic metabolic disorder (including but not limited to diabetes , insulin resistance and obesity), cardiovascular disease and neurodegenerative diseases (such as Alzheimer's disease).
6、 一种用于预防和 /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）等的药物组合物， 该组合物含有作为活性成分的权利 要求 1至 3中任一项所述的具有取代环丙烷结构的化合物以及这类化 合物在药物学上可接受的盐及其与其它分子或载体的连结物。 6. A pharmaceutical composition 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, etc. The composition contains, as an active ingredient, a compound having a substituted cyclopropane structure according to any one of claims 1 to 3 and a pharmaceutically acceptable salt of such a compound and a linker with other molecules or carriers.
7、 根据权利要求 6所述的药物组合物， 其特征在于进一步含有药 物学上可接受的载体和赋形剂。 7. A pharmaceutical composition according to claim 6 further comprising a pharmaceutically acceptable carrier and excipient.
8、 如权利要求 6所述药物组合物， 其特征在于所述疾病或症状可 以因对已经上市的治疗药物产生耐药性或毒副反应而引起。 8. A pharmaceutical composition according to claim 6 wherein the disease or condition is caused by resistance or toxic side effects to a therapeutic agent already marketed.
9、 一种联合制剂， 包括如权利要求 1至 3中任意一项所述的具有 取代环丙烷结构的化合物或其药物学上可接受的盐和其他治疗药物。 A combination preparation comprising the compound having a substituted cyclopropane structure according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and other therapeutic agents.
10、一种药盒，其包括权利要求 1至 3中任意一项所述的具有取代 环丙烷结构的化合物或其药物学上可接受的盐， 以及使用所述化合物 或其药物学上可接受的盐预防和 /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)等的说明。 A kit comprising the compound having a substituted cyclopropane structure according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and the use of the compound or a pharmaceutically acceptable compound thereof Salts 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) and the like.
11、 一种药盒， 其包括权利要求 9所迷的联合制剂， 和使用所述联 合制剂预防和 /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） 等的说明。 11. A kit comprising the combination of claim 9 and the use of said combination to prevent and/or treat metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular Description of diseases and neurodegenerative diseases (such as Alzheimer's disease).
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