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WO2008067713A1 - Compounds having substituted cyclopentane structure, their preparation methods and medical uses - Google Patents

Compounds having substituted cyclopentane structure, their preparation methods and medical uses Download PDF

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WO2008067713A1
WO2008067713A1 PCT/CN2007/002982 CN2007002982W WO2008067713A1 WO 2008067713 A1 WO2008067713 A1 WO 2008067713A1 CN 2007002982 W CN2007002982 W CN 2007002982W WO 2008067713 A1 WO2008067713 A1 WO 2008067713A1
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group
substituted
alkoxy
groups
alkyl
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Mingwei Wang
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Shanghai Institute of Materia Medica of CAS
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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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07C233/57—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
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/38—Unsaturated compounds containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • 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 cyclopentane structure, a process for the preparation thereof, and 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 (eg Alzheimer's disease) Medical use.
  • Glucagon like Peptide- 1 receptor, GLP-1R glucagon like Peptide- 1 receptor
  • GLP-1R glucagon like Peptide- 1 receptor
  • 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 is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. 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.
  • sulfonylurea hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, the potassium channel is blocked, and the potassium ion efflux is blocked, which leads to depolarization of the cell membrane, promotes the opening of the Ca 2+ channel, and causes extracellular calcium influx, intracellular.
  • the calcium ion concentration is increased, the release of insulin is triggered.
  • 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 damecon
  • glipizide mepyridone
  • gliclazide sucrose flat
  • 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 gutagon-like glucagon-like peptide-1 released by the enteroendocrine cells is activated by highly specific binding to GLP-IR. 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.
  • GLP-1 In vitro, GLP-1 promotes the differentiation of embryonic stem cells into cell-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 ⁇ -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) contendIn addition, GLP-1 also plays an important role in the cardiovascular system.
  • GLP-1 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).
  • GLP-1R small molecule agonists of GLP-1R
  • GLP-1 derivative developed by Danovo Nordisk, Denmark (trade name Liraglutide; 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).
  • An object of the present invention is to provide a compound represented by the following formula 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; A further object is to provide a pharmaceutical composition comprising a compound represented by the following formula; A further object of the present invention is to provide a compound represented by the following formula as a glucagon-like peptide-1 receptor modulator for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity ), cardiovascular disease and neurodegenerative diseases (such as
  • 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, 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 a metal thereof Complex:
  • X, ⁇ , Z are each (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • RR 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; Cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; substituted or unsubstituted aryl; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group;
  • R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; Unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the above compound of the formula is characterized by:
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, and RR 2 and R 3 are each independently:
  • R 7 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted d-containing halogen atom, dC 6 alkoxy group or hydroxyl group.
  • alkyl; C 2 -C 6 alkenyl group includes any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 Alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a facet atom, an alkoxy group of C6 or a hydroxyl group; a C 3 -C 6 cycloalkane Base; contains included!
  • a three-substituted pyranyl group containing an alkyl group including a hydrocarbon atom, CC 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 thienyl groups including an ethylthio group; 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 pyrrolyl groups, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; a C6 alkanoyl group; 3 ⁇ 4 atom, any c r c
  • R 8 is any one of the following substituents: H; -C 6 alkyl; any one, two or three substituted Cs including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group
  • An alkyl group of R C 6 a C 2 -C 6 alkenyl group; containing an alkoxy group or a hydroxyl group including a [3 ⁇ 4 atom, a -C 6 atom
  • R 9 and R 10 are independently of any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituents including a prime atom, an alkoxy group of -C 6 or a hydroxyl group.
  • Ci-C 6 alkyl C 2 -C 6 alkenyl group; a, any two or three substituents include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom includes any containing, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 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 CC 6 or a hydroxyl group; an aryl group; a furanyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an an
  • One, two or three substituted pyranyl groups containing an atomic group, a d-alkyl group, 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 thiol group, an ethylthio group; containing a halogen atom, c, - c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio 4 including one, two or three substituents of Pyrrolyl group;
  • An alkanoyl group of C,-C 6 an alkanoyl group of any one, two or three substituted C6 groups including a gas 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 such as an atom, an alkoxy group of d-Ce 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 C atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a ?
  • RH is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted OC 6 alkyls including a halogen atom, an alkoxy group of d- 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 prime atom, an alkoxy group of -C6 or a hydroxyl group; C 2 -C 6 alkynyl; contains included!
  • One, two or three substituted pyranyl groups Any atomic element, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three Substituted thienyl; 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyrrolyl groups including a base;
  • alkanoyl group of C r C 6 an alkanoyl group having any one, two or three substituted c r c 6 including a sulfonate atom, a d-alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; Contains included!
  • R 12 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a gas atom, an alkoxy group of dC 6 or a hydroxyl group.
  • An alkyl group of C rC 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 -C6 or a hydroxyl group; ; 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 - C 6 cycloalkyl; include a halogen atom-containing, 0 (: any 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -
  • a three-substituted furyl group 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, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, a thiol 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, 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, c r c 4 , a nitro 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; aryl Acyl; benzoyl; furanoyl; pyranoyl; thiophene acyl; pyrrolidinyl; , ⁇ ), n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • R, R 2 and R 3 are each independently:
  • R 14 and R 15 are each independently a substituent of any of the following: H; an alkyl group of d-Ce; or any one, two or three containing a surface atom, an alkoxy group of -C 6 or a hydroxyl group.
  • a substituted C r C 6 alkyl group a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 6 alkenyl group; a C 2 -C 6 alkynyl group; includes any containing [3 ⁇ 4 prime atoms, C6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 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 furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyri
  • R 4 , R 5 and R 6 are respectively: Wherein R 8 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted C groups including a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; C 2 -C 6 alkenyl group; includes any containing [3 ⁇ 4 prime atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group of a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a aryl group or a hydroxy group; a C 3 -C 6 ring; alkyl;!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furan group; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; containing pigment include 3 ⁇ 4 atoms, C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide 4!
  • any group, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two, three or substituted pyridyl; comprising comprising!
  • R 9 is independently a substituent of any of the following: H; an alkyl group of dC 6 ; 3 ⁇ 4 any prime atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 Any one, two or three substituted C 2 -C 6 alkenyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing a halogen atom, an alkoxy group or a hydroxyl group Any one, two or three substituted C 2 -C 6 alkynyl groups; a C 3 -C 6 cycloalkyl group; any one or two containing a halogen atom, an alkoxy group of d- or a hydroxyl group Or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl
  • a three-substituted aryl 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 ethylthio group Any one, two or three substituted pyridyl 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 substitutions including sulfhydryl, thiol and ethylthio Furanyl; containing comprising [3 ⁇ 4 atom, -C 4 alkyl group, a nitro group, a carboxyl group,
  • R n is any one of the following substituents: H; an alkyl group of CrC 6 ; any one, two or three substituted d-containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C 6 alkyl; C 2 -C 6 Hay-yl; a prime 13 ⁇ 4 contain any atoms including, dC alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 Hay-yl; and (2 - (: 6 alkynyl; Contains included!
  • C r C 6 alkanoyl; a 3 ⁇ 4 comprise any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkanoyl;! C 2 -C 6 of Any one, two or three substituted C 2 -C 6 alkenoyl groups including a 3 ⁇ 4 atom atom, a C 6 alkoxy group 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 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of a 3 atomic atom, an alkoxy group of dC 6 or a hydroxyl group; adamantyl decanoyl group, Substitu
  • R l2 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing an alkoxy group including a prime atom, C, or C 6 or a hydroxyl group.
  • C r C 6 Any one, two or three substituted dC 6 alkanoyl groups such as an alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; or an alkoxy group including a sulfonate atom, an alkoxy group or a hydroxyl group; Two or three substituted c 2 -c 6 enoyl groups; c 2 -c 6 alkynyl groups; any one, two or three substitutions including a halogen atom, an alkoxy group of d- or a hydroxyl group of
  • a C 2 -C 6 alkynyl group a C 3 -C 6 cycloalkanoyl group; any one, two or three substituted c 3 - including a ? 3 ⁇ 4 atom, an cc 6 alkoxy group or a hydroxyl group; c cycloalkanoyl 6; adamantane Yue group, a substituted adamantane Yue group; an aryl group; a benzyl group; furan Yue group; pyran Yue group; thiophene Yue group; pyrroyl; 1 ((: 13 ⁇ 4) [1 , n is 0-2, 0; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • RR 2 and R 3 are respectively independent:
  • R l6 is any of the following substituent groups: H; C r C 6 alkyl group; one, two or three substituents include a halogen atom contain any, d- alkoxy or hydroxy alkyl group, including the ; a C 2 -C 6 alkenyl; includes any pigment containing atoms, 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 includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl Alkyl; contains included!
  • R 4 , R 5 and R 6 are respectively:
  • R 8 is any one of the following substituents: H; an alkyl group of d-Ce; any one, two or three substituted groups including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group ( ⁇ - ( ⁇ alkyl; C 2 -C 6 alkenyl group; contain any include halogen atoms, alkoxy or hydroxy -C6 inner one, two or three substituents of a C 2 -C 6 alkenyl 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 -C6 or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any containing [3 ⁇ 4 prime atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benz
  • R 9 and R l() are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; 3 ⁇ 4 atom, any C r C 6 alkoxy or hydroxy, including one, two or three of the substituents -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 any alkoxy or hydroxy, including one, two or three substituents Hay a C 2 -C 6 group; a C 2 -C 6 alkynyl group; containing pigment include 3 ⁇ 4 atoms, C r C 6 alkyl!
  • Any one, two or three substituted C 2 -C 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group or a hydroxyl group containing a halogen atom, d- Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thiahaki; pyrrolyl; pyridyl; Any one or two of an atom, a C, a 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 fluorenyl group, a thiol group, and an ethylthio group.
  • three or substituted aryl include halogen atoms contained, the CC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group 4, Any group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; include halogen-containing Any one, two or three of an atom, an alkyl group of a d-C4, 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.
  • Substituted furanyl 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyranyl groups, including a 3 ⁇ 4 atom, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted thienyl groups including an amide 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, an alkoxy group Any one,
  • dC any alkoxy or hydroxy including 6, two or three Substituted dC 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing atom, ( ⁇ - one, two or three substituents at any of alkoxy or hydroxy (6, including a C 2 -C 6 alkenoyl; C 2 -C 6 alkynyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a C a cycloalkanoyl group of r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a 3 ⁇ 4 atomic atom, an alkoxy group of d- or a hydroxyl group; adamantyl decanoyl group , substituted adamantyl decanoyl; aroy
  • RH is any one of the following substituents: H; alkyl group of C R C 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group -C6 alkyl; C 2 -C 6 alkenyl; contains included! 3 ⁇ 4 atom, any CC 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 3 ⁇ 4 atom,!
  • Any one, two or three substituted C 2 -C 6 alkynyl groups such as a alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group containing a halogen atom, -C6
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl, nitro Any one, two or three substituted furanyl groups, 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 a d-C4, 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.
  • a substituted pyranyl group containing an alkyl group including a halogen atom, C rC 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 thienyl groups; 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, a carboxamide group, a fluorenyl group Any one, two or three substituted pyrrolyl groups such as thiol or ethylthio; d-C 6 alkanoyl; Any one, two or three substituted C aC 6 alkanoyl groups of a 3 atomic
  • R 12, R l3 are each independently any one of the following substituent groups: H; -C 6 alkyl group; a halogen atom include any one containing, C r C 6 alkoxy or hydroxy, including, two or three a substituted C, -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, R & lt alkoxy or hydroxy C 6 C inner one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkyne containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 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;
  • R, R 2 and R 3 are respectively independent:
  • R 17 and R l8 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 halogen atom, C, or C 6 or a hydroxyl group; three or substituted dC ⁇ alkyl; C 2 -C 6 alkenyl group; a!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group Alkynyl; C 3 -C 6 cycloalkyl; Any one, two or three substituted c 3 -c 6 cycloalkyl groups such as a halogen atom, a d-alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a C 4 atom, a nitro group, a carboxy group, an aldehyde
  • R 8 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted CrC 6 containing an alkoxy group including a halogen atom, C, -C 6 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 facet atom, an alkoxy group of dC 6 or a hydroxyl group; a 2- C6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a pertinar atom, an alkoxy group of CC 6 or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a prime atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group
  • Any one, two or three substituted furan groups including 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. Containing a 3 ⁇ 4 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 carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group, etc.
  • X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are:
  • R 9, R l () each independently is any of the following substituents: H; C r C 6 alkyl; containing any one include halogen atoms, alkoxy or hydroxy, including the C6, two or three a substituted C r C 6 alkyl group; a C 2 -C 6 fluorenyl group; any one, two or three substituted C 2 groups including a ?
  • two or three substituted aryl groups containing alkane, d-C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonium Any one, two or three substituted pyridyl groups including a thiol group; 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 carbon group Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, an aldehyde group, including a ?-?
  • Any one, two or three substituted pyranyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; containing a ?
  • 3 ⁇ 4 atom, dC 4 Any one, two or three substituted thienyl groups 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 methylthio group, an ethylthio group; Containing a halogen atom, d-alkyl group, nitro group, carboxyl group Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkoxy group; and includes any pigment containing 3 ⁇ 4 atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl;!
  • C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy or hydroxy group of dC 6 ; C 2 -C 6 alkynyl group; alkoxy group containing a halogen atom, d- Or one, two or three substituted C 2 -C 6 alkynyl groups, or 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; Yue group adamantane, substituted adamantane Yue group; aroyl Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (( 13 ⁇ 4) 11 , n is 0-2, O;
  • Substituted aryl containing an alkyl group including a ? atom, d-, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio including any one, two or three substituents pyridyl;!
  • 3 ⁇ 4 containing pigment comprising atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ?3 ⁇ 4 atom, a d-C4 group, a nitro group, a carboxyl group, an aldehyde group, Any one, two or three substituted pyranyl groups including an alkoxy 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, CC 4 , nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbonyl Group, any mercapto, Yue
  • any one, two or three of a 3 ⁇ 4 atomic atom, a C 6 alkoxy group or a hydroxyl group Substituted c 2 -c 6 enoyl; c 2 -c 6 alkynyl; any one, two or three substituted c containing an alkoxy group including a halogen atom, c, -c 6 or a hydroxyl group 2 - C6 alkynyl; C 3 -C 6 cycloalkanoyl; contains included!
  • R l2 and R l3 are each independently a substituent of any of the following: H; an alkyl group of C6; any one, two or three substituted Cs including a pertiny atom, alkoxy group of d- or a hydroxyl group.
  • -C 6 alkyl C 2 -C 6 alkenyl group; includes any containing halogen atoms, C alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; 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 ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one of a C, a C, a C 4 alkyl group, a nitro group
  • Two or three substituted aryl groups contain included! Any one or two of a 3 atomic atom, a d-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 a three-substituted pyridyl 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, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethane group Any one, two or three substitutions a furanyl group; containing a 3 ⁇ 4 atom, ( ⁇ -(: 4 alkyl, nitro, carboxyl
  • n is 0-2, O; S or NH;
  • X 2 is (CH 2 ) n , n is 0-2, 0; S or NH.
  • the compound or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, either alone or with pharmacology
  • An acceptable carrier or excipient is provided in combination.
  • the 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), heart Vascular disease and neurodegenerative diseases (such as Alzheimer's disease), etc. It relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease) and other methods.
  • 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.
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl; R 4 , R 5 , each independently of any of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl
  • the present invention relates to a combination preparation
  • 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.
  • the compound has the structure of the following general formula, and all of its stereo and optical isomers, or prodrugs having the same pharmacological action, esters thereof, solvates thereof or metal complexes thereof:
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; Unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 4 and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease, etc., achieves the efficacy of selectively stimulating the glucagon-like peptide-1 receptor, improving the symptoms and quality of life of the patient.
  • metabolic disorders including but not limited to diabetes, insulin 4 and obesity
  • cardiovascular diseases and neurodegenerative diseases eg Alzheimer's disease, etc., achieves the efficacy of selectively stimulating the glucagon-like peptide-1 receptor, improving the symptoms and quality of life of the patient.
  • 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.
  • 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 the phenomenon that the amount of body fat is too much, that a man weighs more than 25% of the ideal body weight or that the woman weighs more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overdose And too few activities are the cause of obesity.
  • “Alzheimer's Disease (Al, Alzheimer's disease, also known as Alzheimer's dementia) is a neurological system of degenerative diseases, clinical It manifests as a chronic impairment of intelligence and a chronic loss of memory.
  • 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 single Dosing can also be administered according to the treatment 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 sufficient homogeny to detect impurities by standard analytical methods used by those skilled in the art for evaluating purity, such as thin layer chromatography (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC).
  • 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 transport properties Precursors to mask their side effects or toxicity, improve the taste of the drug, or alter other characteristics. 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 association between two or more.
  • subject 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 and prevent diabetes and its complications. Any of the protective groups used herein, abbreviations for amino acids and other compounds, are consistent with their common, recognized abbreviations or the biochemical nomenclature issued by the IUPAC-IUB committee, unless specifically stated.
  • 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, or a pharmaceutically acceptable salt thereof, and All stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects:
  • X, ⁇ , Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; Unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture.
  • the compounds considered here include all A pharmaceutically active compound species, or a solution or mixture 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.
  • This compound was prepared by the synthesis described 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 any suitable acid in the form of their pharmaceutically acceptable salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, acid, phosphoric 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 mercaptosulfonic acid, ethylsulfonic acid or the like
  • an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can be used.
  • the present invention relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin 4 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 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 a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto , its ester, its solvate or its metal complex
  • a compound represented by the following formula or a pharmaceutically acceptable salt thereof and all of the stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto , its ester, its solvate or its metal complex
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 prevent 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.
  • the invention may be used alone or in combination with other diabetes therapeutics, including insulin sensitizers that are already on the market or to be marketed. compound of.
  • 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 associated disease or condition and its prognosis.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo material, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and the like.
  • international patent WO can be used 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 metabolic disorders include insulin sensitizers.
  • such a combination comprises a compound of the present invention 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
  • the metal complex and one or more therapeutic agents for metabolic disorders include insulin sensitizers, which are represented by the general formula: wherein X, Y, Z are (CH 2 ) n and n is 0-2, respectively. Oxygen, stone or nitrogen;
  • R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;
  • R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction is provided, the method comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above diseases or symptoms.
  • kits 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 controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction.
  • a kit comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the compounds of the invention are formulated for any suitable route of administration, such as intraluminal, subcutaneous, Intravenous injection, intra-monthly 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 which may be used in the present invention include, but are not limited to, those 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 compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier, a local or parenteral route, can be used depending on the needs of the administration.
  • Preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion may employ similar pharmaceutical vehicles, water known to those skilled in the art, Ethylene glycol, oil, buffer, sugar, preservatives, liposomes, etc.
  • 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 ml to about 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.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • 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 COOH ketone (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water, and cooled in a water-salt bath.
  • Sodium cyanide (1.67 eq) was added and stirred vigorously. When most of the sodium cyanide is dissolved and the temperature of the reaction solution falls below 5 ° C, an appropriate amount of concentrated hydrochloric acid is slowly added dropwise to maintain the reaction temperature between 5 ° C and 10 ° C. After the addition was completed, the ice bath was removed while vigorously stirring for 2 hours. After standing, the ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt. The aqueous layer was extracted with diethyl ether.
  • Reporter gene method detects the agonistic effects of compounds 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 0.07 nM.
  • Figure 2. Reporter gene method to detect the antagonism of exendin ⁇ 39 on GLP-1.
  • the concentration of GLP-1 was 0.05 nM, 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%.
  • Reporter gene expression induced by GLP-1 was inhibited with an IC 50 value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R.
  • Figure 3 Intracellular cAMP concentration detects the effect of GLP-1 on GLP-1R signaling.
  • the GLP-1 concentration gradient is 10, 1 , 0.1, 0.01, 0.001, 0.0001, 0 nM to 10 nM Induced cAMP activity was 100%, measured GLP-1 EC 50 value of 0.079 nM, suggesting that intracellular cAMP induced as GLP-1R agonist, 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.
  • HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector.
  • the column was ZORBAX SB-C18 (2.1 X 150 mm, 3.5 ⁇ ), the mobile phase was acetonitrile/water, the flow rate was 0.2 ml/min, and the detection wavelength was 254 nm.
  • the melting point was determined by 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 passed by AB Mariner type The instrument was measured by EI by a Finnigan MAT95 mass spectrometer. The materials used in the synthesis are commercially available products unless otherwise specified.
  • 3-Phenyl 1,2-cyclopentanedione (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water and cooled in an ice bath.
  • Sodium cyanide (1.67 eq) was added and stirred vigorously. When most of the sodium cyanide is dissolved and the temperature of the reaction solution falls below 5 ° C, an appropriate amount of concentrated hydrochloric acid is slowly added dropwise to maintain the reaction temperature between 5 ° C and 10 ° C. After the addition is complete, remove the water bath while stirring vigorously for 2 small Time. After standing, the ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt.
  • the aqueous layer was extracted with diethyl ether. The residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then, some of the hydrogen chloride gas is taken away by air, and then slowly added with 50% sodium hydroxide solution to adjust to alkaline. Cool in an ice bath, mechanically stir, add sodium hydroxide solid (0.6 eq), and steam to distill until free of ammonia and ketone. Dilute with water and extract with ether (discard). The aqueous layer was acidified with concentrated hydrochloric acid, cooled and filtered to give 3-phenyl-1,2-dihydroxy-1,2-cyclopentadicarbonitrile.
  • GLP-1R is a G protein-coupled receptor.
  • GLP-1R binds to an agonist, the Ga subunit of the G protein is activated to stimulate adenylate cyclase, resulting in an increase in 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 smear (HEK 293) stably transfected with the GLP-1R receptor gene expression vector and the luciferase reporter gene expression vector regulated by the cAMP response element was used to detect the response to the test compound.
  • Biology, 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 84:3434-3438 ) (A sample that induces expression of a luciferase reporter gene when screening for a compound, It is considered to have GLP-1R agonistic activity.
  • DMEM medium (GIBCO)
  • Forma CO2 incubator Forma
  • HE 293/GLP1R+Luc cells were incubated at 20,000/100 ⁇ /well into 96-well plates at 37 with DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night.
  • the GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in ⁇ /well. Incubation was carried out for 6 hours at 37 ° C under 5% CO 2 . Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit, and the Victor 2 reader was used for reading.
  • Exendin 9- 3 9 antagonism test to confirm the active compound has a receptor-specific activation of the reporter gene, we used the specificity of GLP-1R antagonist, exendin 9-3 9 (Eur. J. Pharmacol . 1994, 269 : 183-191; Metabolism 2004, 53:252-259. ) to verify whether it antagonizes the agonistic activity of the above representative compounds on GLP-1R.
  • 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 was cultured overnight. Dilute Exendin 9 _ 39 to a concentration gradient and add 1 ⁇ /well to the above 96-well microplate at 37 ⁇ . Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nMGLP-1 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 reading.
  • Exendin W9 dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2), IC 5 . The value was 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2. Antagonism of Exendin 9-39 on GLP-1 (% response, 100% response to 0.05 nM GLP-1)
  • the reporter gene detection method is a method for indirectly determining the level of intracellular cAMP concentration. To confirm that the active compound does increase the intracellular cAMP concentration, functional verification is performed directly using the cAMP test kit.
  • 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 ⁇ 'j kit (Applied Biosystems) Forma carbon dioxide Incubator (Forma) Victor 2 plate reader (Wallac) cAMP standard (provided with the kit, Applied Biosystems) 3.2 test 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 induced cAMP in cells (Table 3, FIG. 3), which EC 5.
  • the value of 0.079 nM suggests that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling.
  • Table 3 Induction of intracellular cAMP by GLP-1 (% response, 100% response to 10 nM GLP-1)
  • 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. Isotope labeling on cell membranes when the test compound is competitively bound to
  • 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) with an IC 5Q value of 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1 R

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Abstract

Compounds having substituted cyclopentane structure represented by formulas I-IV, their preparation methods, and useful as glucagon like peptide-1 receptor regulator for prevention and/or treatment of metabolic disorders (including, but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease) and so on.

Description

一类具有取代环戊烷结构的化合物、 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戊烷结构的化合物、 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， 关闭钾离子 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， 第一代如曱苯碩丙脲， 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-IR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 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)。 由于上述明确的生理效 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 Liraglutide; 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表示的化合物的 药物组合物； 本发明的再一目的在于提供由以下通式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（如FIELD OF THE INVENTION The present invention relates to a class of compounds having a substituted cyclopentane structure, a process for the preparation thereof, and 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 (eg 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 is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. 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, the potassium channel is blocked, and the potassium ion efflux is blocked, which leads to depolarization of the cell membrane, promotes the opening of the Ca 2+ channel, and causes extracellular calcium influx, intracellular. When the calcium ion concentration is increased, the release of insulin is triggered. According to its advent, it was divided into two generations, the first generation such as benzoic acid, and the second generation including glibenclamide (excellent Hypoglycemic), gliclazide (damecon), glipizide (mepyridone) and gliclazide (sugar flat). 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 gutagon-like glucagon-like peptide-1 (GLP-1) released by the enteroendocrine cells is activated by highly specific binding to GLP-IR. 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 cell-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). Due to the above-mentioned clear physiological effects, since the discovery of this target in the mid-1980s, the search for small molecule agonists of GLP-1R has been a research hotspot of many new drug development institutions in the world. A number of internationally renowned multinational pharmaceutical companies are developing innovative GLP-1 drugs, such as the GLP-1 derivative developed by Danovo Nordisk, Denmark (trade name Liraglutide; 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 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; A further object is to provide a pharmaceutical composition comprising a compound represented by the following formula; A further object of the present invention is to provide a compound represented by the following formula as a glucagon-like peptide-1 receptor modulator for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity ), cardiovascular disease and neurodegenerative diseases (such as

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 such as 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, 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 a metal thereof Complex:

Figure imgf000006_0001
Figure imgf000006_0002
其中 X， Υ, Z, 分别为（CH2)n， n为 0-2, 氧， 硫或氮； 其中 R R2, R3各自独立地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
Figure imgf000006_0002
Wherein X, Υ, Z are each (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen; wherein RR 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; Cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; amide; carboxamide; fluorenyl; alkylthio; ether; thioether; substituted or unsubstituted aryl; a substituted or unsubstituted pyridyl group; a substituted or unsubstituted furyl group; a substituted or unsubstituted pyranyl group; a substituted or unsubstituted thienyl group; a substituted or unsubstituted pyrrolyl group;

R4, R5, R6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， 上述通式化合物的特征在于： R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; Unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. Preferably, the above compound of the formula is characterized by:

X， Υ, Z分别是 (CH2)n, n为 0-2， 氧， 硫或氮， R R2, R3分别 各自独立为：

Figure imgf000007_0001
其中 R7为下列任意一种取代基： H; C,-C6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 d- 的烷基； 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 C2-C6的烯基； C2-C6的炔基； 含有包括面素原子、 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！ 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 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有 包括 [¾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、 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 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 素原子、 d-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 者三个取代的吡喃基； 含有包括! ¾素原子、 C 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、 c,-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； C6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 d-C6的烷酰基； c2-c6的浠酰基； 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的烯酰基; c2-c6的炔酰基; 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的炔酰 基； C3-C6的环烷酰基； 含有包括! ¾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； 1为（0¾)11, n为 0-2, O; S或者 NH时； R4, R5, R6分别为:
Figure imgf000008_0001
X, Υ, Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, and RR 2 and R 3 are each independently:
Figure imgf000007_0001
Wherein R 7 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted d-containing halogen atom, dC 6 alkoxy group or hydroxyl group. alkyl; C 2 -C 6 alkenyl group; includes any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 Alkynyl group of -C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a facet atom, an alkoxy group of C6 or a hydroxyl group; a C 3 -C 6 cycloalkane Base; contains included! ¾ prime atoms, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; comprising comprising [¾ prime atoms, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue, Any one, two or three substituted aryl groups including an ethylthio 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, Any one, two or three substituted pyridyl groups including a carboxamide group, a fluorenyl group, a sulfonium group, and an ethylthio group; containing a pertinar atom, d-C4 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 single atom, a d-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, a thiol group, an ethylthio group. Or a three-substituted pyranyl group; containing an alkyl group including a hydrocarbon atom, CC 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 thienyl groups including an ethylthio group; 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 pyrrolyl groups, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; a C6 alkanoyl group; ¾ atom, any c r c 6 alkoxy or hydroxy, including one, two or three substituents of dC 6 alkanoyl; C 2 -C 6 acyl group Hay; include ¾ containing atom, D! Any one, two or three substituted c 2 -c 6 enoyl groups such as alkoxy or hydroxy; c 2 -c 6 alkynyl; containing an alkane including a halogen atom, c, -c 6 Any one, two or three substituted c 2 -c 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; an alkoxy group containing a ? 3⁄4 atom, dC 6 or Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; Thiophenanthryl; pyrrolyl hydrazide; 1 is (03⁄4) 11 , n is 0-2, O; S or NH; R 4 , R 5 , R6 are:
Figure imgf000008_0001

其中 R8为下列任意一种取代基： H; -C6的烷基； 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 CrC6的烷基； C2-C6的烯基； 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的烯基； c2-c6的炔基； 含有包括面素原子、 -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！ 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 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! ¾素原子、 d-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啶基； 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呋喃基； 含有包括 1¾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、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； C,-C6的烷酰基； 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 -C6的烷酰基； C2-C6的晞酰基； 含有 包括！ ¾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！ 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的炔酰 基； C3-C6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； 吡咯曱酰基； X2为（CH2)n, n为 0-2， O; S或者 NH; 或者 R4, R5, R6分别为：

Figure imgf000010_0001
Wherein R 8 is any one of the following substituents: H; -C 6 alkyl; any one, two or three substituted Cs including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group An alkyl group of R C 6 ; a C 2 -C 6 alkenyl group; containing an alkoxy group or a hydroxyl group including a [3⁄4 atom, a -C 6 atom Any one, two or three substituted c 2 -c 6 alkenyl groups, c 2 -c 6 alkynyl groups, including a facet atom, a C 6 alkoxy group or a hydroxyl group Any one, two or three substituted C 2 -C 6 alkynyl groups; C 3 -C 6 cycloalkyl groups; Any one, two or three substituted C 3 -C 6 cycloalkyl groups of a 3 atomic atom, a C 6 alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; Pyrrolyl; pyridyl; containing alkane, CrC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio Any one, two or three substituted aryl groups; containing an alkyl group including a ?3⁄4 atom, dC, 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 thiol group, an ethylthio group; containing a halogen atom, (C4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group) Any one, two or three substituted furanyl groups, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a 13⁄4 atom, an alkyl group, a nitro group, a carboxyl group, and an aldehyde group , alkoxy, amino, amide, carboxamide, fluorenyl Any one, two or three substituted pyranyl groups including a methylthio group or an ethylthio 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 Any one, two or three substituted thienyl groups including an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkyl group including a sulfonate atom, Cr C 4 , a nitro group, a carboxyl group Any one, two or three substituted pyrrolyl 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; a C,-C 6 alkane An acyl group; any one, two or three substituted -C 6 alkanoyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 2 -C 6 decanoyl group; Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy or hydroxy groups of dC 6 ; C 2 -C 6 alkynyl groups; containing a ? 3⁄4 atom, d- Any one, two or three substituted C 2 -C 6 alkynyl groups, alkoxy or hydroxy; C 3 -C 6 Cycloalkanoyl; containing an alkoxy group or a hydroxyl group including a 3⁄4 atom, CC 6 Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl form; aroyl; benzyl; furanoyl; pyranoyl; thiophene Acyl; pyrrolyl acyl; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000010_0001

其中 R9，R10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、 -C6的烷氧基或羟基在内的任意一个、 两个或者三 个取代的 Ci-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、 -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、 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 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 者三个取代的芳基； 含有包括 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啶基；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 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噻吩基；含有包括卤素原子、 c,-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；Wherein R 9 and R 10 are independently of any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituents including a prime atom, an alkoxy group of -C 6 or a hydroxyl group. a Ci-C 6 alkyl; C 2 -C 6 alkenyl group; a, any two or three substituents include a halogen atom-containing, C r C 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom includes any containing, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 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 CC 6 or a hydroxyl group; an aryl group; a furanyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a sulfonyl group, a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group , any mercapto, Yue thio, ethylthio, including one, two or three aryl group substituents; comprising comprising atom, - (4 alkyl group, a nitro group, Any one, two or three substituted pyridyl groups including a aryl 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 substituted furans 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 C4; Any of any of the following: including a 3⁄4 atom, an alkyl group of 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 ethylthio group, and the like. One, two or three substituted pyranyl groups; containing an atomic group, a d-alkyl group, 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 thiol group, an ethylthio group; containing a halogen atom, c, - c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio 4 including one, two or three substituents of Pyrrolyl group;

C,-C6的烷酰基； 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 C6的烷酰基； C2-C6的烯酰基； 含有 包括卤素原子、 d-Ce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! ¾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； 吡咯曱酰基； 1为（0¾)11, n为 0-2， O; S或者 NH时； X2为（CH2)n, n为 0-2, 0; S或者 NH; 或者 R4, R5 , R6分别为：

Figure imgf000011_0001
An alkanoyl group of C,-C 6 ; an alkanoyl group of any one, two or three substituted C6 groups including a gas 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 such as an atom, an alkoxy group of d-Ce 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 C atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing a ? 3⁄4 atom, Cr Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups such as alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl form; aroyl; benzyl; furanoyl; Pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (03⁄4) 11 , n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000011_0001

其中 RH为下列任意一种取代基： H; C,-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 OC6的烷基； C2-C6的烯基； 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的烯基； C2-C6的炔基； 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 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! ¾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 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； 含有包括鹵素原子、 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 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、 c,-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；Wherein RH is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted OC 6 alkyls including a halogen atom, an alkoxy group of d- 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 prime atom, an alkoxy group of -C6 or a hydroxyl group; C 2 -C 6 alkynyl; contains included! ¾ atom, any CC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl; contains include halogen atoms, - any C 6 alkoxy or hydroxy inner one, two or three substituents of C 3 -C 6 cycloalkyl Aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, including: 3⁄4 atom, dC 4 groups, amide group, carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; atoms containing pigment include, CrC 4 alkyl group, 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 carbon group, an amide group, a decyl group, a thiol group, an ethylthio group; containing a halogen atom, dC 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 containing a halogen atom, 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, a thiol group, or an ethylthio group. One, two or three substituted pyranyl groups; Any atomic element, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three Substituted thienyl; 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyrrolyl groups including a base;

CrC6的烷酰基； 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 crc6的烷酰基； c2-c6的烯酰基； 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 （2-(36的浠酰基； c2-c6的炔酰基; 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 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； 吡咯曱酰基； X2为（CH2)n, n为 0-2， O; S或者 NH; 或者 R4 , R5， R6分别为： An alkanoyl group of C r C 6 ; an alkanoyl group having any one, two or three substituted c r c 6 including a sulfonate atom, a d-alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; Contains included! Any one, two or three substituted ( 2- (3 6 decanoyl; c 2 -c 6 alkynyl; 3'4 atomic group, d-alkoxy group or hydroxy group; any -C 6 alkoxy or hydroxy inner one, two or three substituents of c -C 6 alkynyl group of 2; C 3 -C 6 cycloalkyl group; comprising comprising ¾ atom, (! Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of C6 alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl ; pyranoyl; thiophene acyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; Or R 4 , R 5 , R 6 are:

^2^13 ^2^13

其中 R12 , R13各自独立为下列任意一种取代基： H; d- 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 C rC6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、 C rC6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、 0(：6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 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芳基； 含有包括卤素原子、 C rC4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- 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-C4的垸基、 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、 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 [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 CrC6的烷酰基； C2-C6的 烯酰基； 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 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! 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； 噻吩曱酰基； 吡咯曱酰基； ，为^!^)， n为 0-2， O; S或 者 NH时； X2为（CH2)n, n为 0-2， 0; S或者 NH。 当 R,， R2， R3分别各自独立为：

Figure imgf000014_0001
Wherein R 12 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a gas atom, an alkoxy group of dC 6 or a hydroxyl group. An alkyl group of C rC 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 -C6 or a hydroxyl group; ; 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 - C 6 cycloalkyl; include a halogen atom-containing, 0 (: any 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl ; furanyl; pyranyl; thiol group; pyrrolyl; pyridyl; containing alkane, Cr, alkyl, nitro, carboxyl, aldehyde, 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 or two of 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, or an ethylthio group. Or a three-substituted furyl group; 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, a thiol group, an ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, a thiol 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, 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, c r c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, Amine, amide, carboxamide, sulfhydryl, Thio, ethylthio, including any one, two or three takes a pyrrolyl group; an alkanoyl group of dC 6 ; an alkanoyl group containing any one, two or three substituted CrC 6 including a [3⁄4 atom atom, an alkoxy group of C C6 or a hydroxyl group; C 2 -C 6 Any one, two or three substituted C 2 -C 6 alkenoyl groups including an alkoxy group or a hydroxyl group of a [3⁄4 atom, C, -C 6 ; 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 dC 6 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; aryl Acyl; benzoyl; furanoyl; pyranoyl; thiophene acyl; pyrrolidinyl; , ^^^), n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH. When R, R 2 and R 3 are each independently:
Figure imgf000014_0001

其中 R14, R15各自独立为下列任意一种取代基： H; d-Ce的烷基； 含有包括面素原子、 -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 [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 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! 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、 crc4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳 酰胺基、 巯基、 曱石克基、 乙石充基在内的任意一个、 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 素原子、 c,-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； C,-C6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 d- 的烷酰基； C2-C6的 烯酰基； 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 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！ 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 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； 吡咯曱酰基； 1为(( )11， n为 0-2， 0; S或 者 NH时； X2为（CH2)n, n为 0-2, 0; S或者 NH时； Wherein R 14 and R 15 are each independently a substituent of any of the following: H; an alkyl group of d-Ce; or any one, two or three containing a surface atom, an alkoxy group of -C 6 or a hydroxyl group. a substituted C r C 6 alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 6 alkenyl group; a C 2 -C 6 alkynyl group; includes any containing [¾ prime atoms, C6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 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 furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a ? 3⁄4 atom, a CrC 4 group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy 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, an ethylthio group; and an alkane including a halogen atom and d- , Nitrate 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; , c r c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yueshikeji, ethyl 4-yl stone filling the inner one, two or a three-substituted furan 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 fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyranyl groups including a base; an alkyl group including a prime 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 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, an aldehyde group, Alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted pyrrolyl groups including a thiol group or an ethylthio group; a C,-C 6 alkanoyl group; optionally containing a surface atom, an alkoxy group of CrC 6 or a hydroxyl group One, two or three substituted d-alkanoyl; C 2 -C 6 enoyl; contains included! Any one, two or three substituted C 2 -C 6 alkenoyl groups of a C, a C, a C 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups such as a alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups, adamantyl, substituted adamantyl form; aroyl; benzyl Acyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (( ) 11 , n is 0-2, 0; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH;

R4, R5, R6分别为：

Figure imgf000015_0001
其中 R8为下列任意一种取代基： H; C,-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 C 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 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! 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 基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 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、 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！ ¾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呋喃基； 含有包括 [¾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 者三个取代的吡喃基； 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噻吩基；含有包括! ¾素原子、 C,-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-Cs的烷酰基； 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 -C6的烷酰基； C2-C6的晞酰基； 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； 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-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； X2为（CH2)n， n为 0-2， O; S或者 NH时； 或者 R4， R5, R6分别为：
Figure imgf000017_0001
R 4 , R 5 and R 6 are respectively:
Figure imgf000015_0001
Wherein R 8 is any one of the following substituents: H; C, -C 6 alkyl; any one, two or three substituted C groups including a halogen atom, an alkoxy group of d- or a hydroxyl group alkyl; C 2 -C 6 alkenyl group; includes any containing [¾ prime atoms, R & lt C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group of a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a aryl group or a hydroxy group; a C 3 -C 6 ring; alkyl;! ¾ containing pigment comprising atoms, C r C 6 alkoxy or hydroxy, including any one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furan group; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; containing pigment include ¾ atoms, C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide 4! any group, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two, three or substituted pyridyl; comprising comprising! Any one or two of a 3⁄4 atomic atom, an alkyl group of -C4, 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 Three substituted furanyl groups; including [3⁄4 atom, (C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethyl thio) Any one, two or three substituted pyranyl groups including a base; an alkyl group including a prime atom, d-, 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 mercapto group, an anthracenethio group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, C, -C 4 , a nitro group, a carboxyl group, an aldehyde group, Any one, two or three substituted pyrrolyl groups such as alkoxy, amino, amide, carboxamide, sulfhydryl, sulfonylthio, ethylthio; alkanoyl of d-Cs; any prime atom, C, -C 6 alkoxy group or a hydroxyl group, including one, two or three Substituted -C 6 alkanoyl; Xi is C 2 -C 6 acyl; contain any halogen atom includes, the CC 6 alkoxy or hydroxy, including one, two or three Substituted C 2 -C 6 alkenoyl; C 2 -C 6 alkynyl; any one, two or three substituted c 2 -c containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 6 alkynyl group; C 3 -C 6 cycloalkyl group; optionally containing atoms including vegetarian, dC 6 alkoxy or hydroxy, including one, two or three substituents of the cycloalkyl group c 3 -c 6 Adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrroyl; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000017_0001

其中 R9， 。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、 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、 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、 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； 噻吩基； 吡咯基； 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、 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、 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、 -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 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-Cj的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 疏基、 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、 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 d-C6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、 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^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； 噻吩曱酰基； 吡咯曱酰基； 1为(( 112)11, n为 0-2, O; S或 者 NH时； X2为（CH2)n， n为 0-2， 0; S或者 NH; 或者 R4, R5， R6分别为：

Figure imgf000018_0001
Where R 9 , . Each of them is independently a substituent of any of the following: H; an alkyl group of dC 6 ; ¾ any prime atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 Any one, two or three substituted C 2 -C 6 alkenyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing a halogen atom, an alkoxy group or a hydroxyl group Any one, two or three substituted C 2 -C 6 alkynyl groups; a C 3 -C 6 cycloalkyl group; any one or two containing a halogen atom, an alkoxy group of d- or a hydroxyl group Or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one or two of a 3 atomic atom, an alkyl group of a 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, or an ethylthio group. a three-substituted aryl 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 ethylthio group Any one, two or three substituted pyridyl 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 substitutions including sulfhydryl, thiol and ethylthio Furanyl; containing comprising [¾ atom, -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 prime 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 methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-Cj, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, any amine, amide, carboxamide group, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; -C 6 alkoxy group; a pigment containing atoms include, CC 6 Any one, two or three substituted dC 6 alkanoyl groups such as alkoxy or hydroxy; C 2 -C 6 enoyl; any atomic group including a halogen atom, C alkoxy group or a hydroxyl group one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl acyl of ; Contain any halogen atoms include, d- alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl ^ acyl; 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; an aryl group; Benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (( 11 2 ) 11 , n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000018_0001

其中 Rn为下列任意一种取代基： H; CrC6的烷基； 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 d- 的烷基； C2-C6的浠基； 含有包括 1¾素原子、 d-C 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； （ 2-(：6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； 噻吩基； 吡咯基； 吡啶基； 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 三个取代的芳基； 含有包括! ¾素原子、 C,-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、 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 素原子、 c,-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 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、 c,-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；Wherein R n is any one of the following substituents: H; an alkyl group of CrC 6 ; any one, two or three substituted d-containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C 6 alkyl; C 2 -C 6 Hay-yl; a prime 1¾ contain any atoms including, dC alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 Hay-yl; and (2 - (: 6 alkynyl; Contains included! Any one, two or three substituted C 2 -C 6 alkynyl groups including a C atom, a C 6 alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as d- alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; Pyridyl; any one containing a aryl group, a d-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 substituted aryl groups; containing an alkyl group including a ? 3⁄4 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, a fluorenyl group Any one, two or three substituted pyridyl groups including a thiol 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, Any one, two or three of the amide group, the carboxamide group, the fluorenyl group, the thiol group, the ethylthio group Furanyl; containing atoms include pigment, c, -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 prime 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; an alkyl group including a halogen atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, Any one, two or three substituted pyrrolyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group;

CrC6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! 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 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、 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、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基; 吩曱酰基； 吡咯曱酰基； X2为（CH2)n， n为 0-2, O; S或者 NH; 或者 R4, R5, 1 6分别为：

Figure imgf000020_0001
C r C 6 alkanoyl; a ¾ comprise any pigment containing atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents of C r C 6 alkanoyl;! C 2 -C 6 of Any one, two or three substituted C 2 -C 6 alkenoyl groups including a 3⁄4 atom atom, a C 6 alkoxy group 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 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of a 3 atomic atom, an alkoxy group of dC 6 or a hydroxyl group; adamantyl decanoyl group, Substituting adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; fenyl; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; Or R 4 , R 5 , and 16 are:
Figure imgf000020_0001

其中 Rl2， R13各自独立为下列任意一种取代基： H; d- 的烷基； 含有包括 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； (：2-03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 素原子、 C,-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 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、 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、 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、 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； d-Cs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 d-C6的烷酰基； c2-c6的 烯酰基； 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 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Wherein R l2 and R 13 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three containing an alkoxy group including a prime atom, C, or C 6 or a hydroxyl group. Substituted alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -C containing a 3⁄4 atom, C r C 6 alkoxy or hydroxy group 6 alkenyl group; (: 2-03 alkynyl; optionally include a halogen atom-containing, dC 6 alkoxy or hydroxy, including one, two or three substituents alkynyl of C 2 -C 6; 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 alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carbon, including a prime atom, C, -C 4 Any one, two or three substituted aryl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; 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 atom, c r c alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio 4 including one, two, or three substituted furanyl; containing pigment include ¾ atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue,! 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 , carboxamide, sulfhydryl, sulfonium Any one, two or three substituted thienyl groups including a thiol group; an alkyl group including a halogen atom, Ci-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, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkanoyl group of d-Cs; containing a ? 3⁄4 atom, C r C 6 Any one, two or three substituted dC 6 alkanoyl groups such as an alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; or an alkoxy group including a sulfonate atom, an alkoxy group or a hydroxyl group; Two or three substituted c 2 -c 6 enoyl groups; c 2 -c 6 alkynyl groups; any one, two or three substitutions including a halogen atom, an alkoxy group of d- or a hydroxyl group of

C2-C6的炔酰基； C3-C6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； 1为（(：1¾)[1， n为 0-2， 0; S或 者 NH时； X2为（CH2)n， n为 0-2, 0; S或者 NH。 当 R R2, R3分别各自独立为：

Figure imgf000021_0001
a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkanoyl group; any one, two or three substituted c 3 - including a ? 3⁄4 atom, an cc 6 alkoxy group or a hydroxyl group; c cycloalkanoyl 6; adamantane Yue group, a substituted adamantane Yue group; an aryl group; a benzyl group; furan Yue group; pyran Yue group; thiophene Yue group; pyrroyl; 1 ((: 1¾) [1 , n is 0-2, 0; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH. When RR 2 and R 3 are respectively independent:
Figure imgf000021_0001

其中 Rl6为下列任意一种取代基： H; CrC6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 的烷基； C2-C6的烯 ; 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的烯基； C2-C6的炔基； 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的炔基； C3-C6的环烷基； 含有包括！ ¾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 1¾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、 C,-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、 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、 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、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、 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 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的晞酰基； 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 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-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)11, n为 0-2， 0； S或者 NH时； Wherein R l6 is any of the following substituent groups: H; C r C 6 alkyl group; one, two or three substituents include a halogen atom contain any, d- alkoxy or hydroxy alkyl group, including the ; a C 2 -C 6 alkenyl; includes any pigment containing atoms, 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 includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl Alkyl; contains included! Any one, two or three substituted C 3 -C 6 cycloalkyl groups of a 3 atomic 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; pyridyl; Any one, two or three including a 13⁄4 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 Substituted aryl; 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyridyl groups, including a halogen atom, an alkyl group of CrC 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 furanyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, d-, a nitro group, a carboxyl 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 fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , and a nitrate Base, carboxyl group, aldehyde group, alkoxy group, amine group, 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, C, -C 4 , a nitro group, a carboxyl group, or an aldehyde group any alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; comprising comprising any prime atoms, d- alkoxy or hydroxy group including one, two or three substituents of c r c 6 alkanoyl; C 2 -C 6 acyl group Xi; comprising comprising [¾ prime atoms, CrC 6 Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy groups or hydroxyl groups; C 2 -C 6 alkynyl groups; alkoxy groups or hydroxyl groups containing a sulfonium atom, dC 6 Any one, two or three substituted C 2 -C 6 alkynyl groups; a C 3 -C 6 cycloalkanoyl group; any one containing a pertinyl group, a dC 6 alkoxy group or a hydroxyl group , two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; aroyl ; Benzoyl; furoyl; Yue-pyran group; Yue thienyl group; pyrrolidin Yue group; | is (0¾) 11, n is 0-2, 0; S, or NH;

R4, R5， R6分别为：

Figure imgf000023_0001
R 4 , R 5 and R 6 are respectively:
Figure imgf000023_0001

其中 R8为下列任意一种取代基： H; d-Ce的烷基； 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 (^-(^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 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 [¾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 1¾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！ ¾素原子、 C,-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! ¾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、 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、 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 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- 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、 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， 0; S或者 NH; 或者 R4, R5， R6分别为：

Figure imgf000024_0001
Wherein R 8 is any one of the following substituents: H; an alkyl group of d-Ce; any one, two or three substituted groups including a halogen atom, C, -C 6 alkoxy group or a hydroxyl group ( ^ - (^ alkyl; C 2 -C 6 alkenyl group; contain any include halogen atoms, alkoxy or hydroxy -C6 inner one, two or three substituents of a C 2 -C 6 alkenyl 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 -C6 or a hydroxyl group; C 3 -C 6 cycloalkyl; includes any containing [¾ prime atoms, alkoxy or hydroxy dC 6, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; a benzyl group; Furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing a 13⁄4 atom, C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, fluorenyl , methylthio, ethylthio, including any one, two or three aryl group substituents; include halogen atom-containing, C r C 4 alkyl group, 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 thiol group, an ethylthio group; Any one, two or three of -C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, sulfhydryl, methylthio, ethylthio Substituted furanyl; containing 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, etc. Any one, two or three substituted pyranyl groups; 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, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a thiol group, an ethylthio group; 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 Base, amide group, carboxamide group, sulfhydryl group, sulfonium group, ethyl thio group Any one, two or three substituents pyrrolyl; C alkanoyl; containing any halogen atoms include, CrC 6 alkoxy or hydroxy, including An alkanoyl group of one, two or three substituted dC 6 ; an alkenoyl group of c 2 -c 6 ; any one, two or three substitutions including a halogen atom, an alkoxy group of d- or a hydroxyl group a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a! ¾ containing pigment comprising atoms, R & lt C C 6 alkoxy or hydroxy, including any one, two or three substituents of C 2- C6 alkynyl; C 3 -C 6 cycloalkanoyl; any one, two or three substituted C 3 -C containing an alkoxy group including a halogen atom, C r C 6 or a hydroxyl group 6 cycloalkanoyl; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; X 2 is (CH 2 ) n , n 0-2, 0; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000024_0001

其中 R9, Rl()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、 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、 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的浠基； 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 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； 噻哈基； 吡咯基； 吡啶基； 含有包括! ¾素原子、 C,-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、 C 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、 c,-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! ¾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- 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! ¾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 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、 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； CrC6的环烷酰基； 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 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； 1为（(：1¾)11， n为 0-2， 0; S或 者 NH时； X2为（CH2)n, n为 0-2, 0; S或者 NH; 或者 R4 , R5， R6分别为：

Figure imgf000025_0001
Wherein R 9 and R l() are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three of the substituents -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, dC 6 any alkoxy or hydroxy, including one, two or three substituents Hay a C 2 -C 6 group; a C 2 -C 6 alkynyl group; containing pigment include ¾ atoms, C r C 6 alkyl! Any one, two or three substituted C 2 -C 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group or a hydroxyl group containing a halogen atom, d- Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thiahaki; pyrrolyl; pyridyl; Any one or two of an atom, a C, a 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 fluorenyl group, a thiol group, and an ethylthio group. three or substituted aryl; include halogen atoms contained, the CC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group 4, Any group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; include halogen-containing Any one, two or three of an atom, an alkyl group of a d-C4, 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. Substituted furanyl; 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl sulfide Any one, two or three substituted pyranyl groups, including a 3⁄4 atom, dC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted thienyl groups including an amide 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, an alkoxy group Any one, two or three substituted pyrrolyl groups, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; an alkanoyl group of CrC 6 ; containing a ?? atom, dC any alkoxy or hydroxy, including 6, two or three Substituted dC 6 alkanoyl; C 2 -C 6 alkenyl group; a comprises containing atom, (^ - one, two or three substituents at any of alkoxy or hydroxy (6, including a C 2 -C 6 alkenoyl; C 2 -C 6 alkynyl group; a halogen atom-containing optionally include, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a C a cycloalkanoyl group of r C 6 ; any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a 3⁄4 atomic atom, an alkoxy group of d- or a hydroxyl group; adamantyl decanoyl group , substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; 1 is ((: 13⁄4) 11 , n is 0-2, 0; S or NH When X 2 is (CH 2 ) n , n is 0-2, 0; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000025_0001

其中 RH为下列任意一种取代基： H; C RC6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 -C6的烷基； C2-C6的烯基； 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 C2-C6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、 -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! ¾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； 含有包括面素原子、 C rC4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! ¾素原子、 C rC4 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、 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、 C rC4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、 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； d -C6的烷酰基； 含有包括！ ¾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 C rC6的烷酰基； C2-C6的烯酰基； 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 C2-C6的浠酰基; C2-C6的炔酰基; 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 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 吩甲酰基； 吡咯曱酰基； X2为（CH2)n, n为 0-2， O; S或者 NH; 或者 R4, R5, R6分别为：

Figure imgf000027_0001
Wherein RH is any one of the following substituents: H; alkyl group of C R C 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group -C6 alkyl; C 2 -C 6 alkenyl; contains included! ¾ atom, any CC 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 ¾ atom,! Any one, two or three substituted C 2 -C 6 alkynyl groups such as a alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group containing a halogen atom, -C6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups, including a hydroxy group; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; 3⁄4 atomic atom, d-C4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, sulfonyl group, ethyl thio group, or both Or a three-substituted aryl group; containing an alkyl group including a face 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 , ethylthio, including any one, two or three substituents pyridyl;! ¾ containing pigment comprising atoms, C r C 4 alkyl, nitro Any one, two or three substituted furanyl groups, 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 a d-C4, 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. a substituted pyranyl group; containing an alkyl group including a halogen atom, C rC 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 thienyl groups; 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, a carboxamide group, a fluorenyl group Any one, two or three substituted pyrrolyl groups such as thiol or ethylthio; d-C 6 alkanoyl; Any one, two or three substituted C aC 6 alkanoyl groups of a 3 atomic atom, a dC 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; Any one, two or three substituted C 2 -C 6 decanoyl groups, a C 2 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 decanoyl groups of a 3,4 atom, C, -C 6 alkoxy group 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 d- or a hydroxyl group; adamantane; Decanoyl, substituted adamantyl decanoyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, O; Or NH; or R 4 , R 5 , R 6 are:
Figure imgf000027_0001

其中 R12, Rl3各自独立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 C,-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、 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、 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； 噻喻基； 吡咯基； 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、 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； 食有包括卤素 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、 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、 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- 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 C6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 C C6的烷酰基； C2-C6的 烯酰基； 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Wherein R 12, R l3 are each independently any one of the following substituent groups: H; -C 6 alkyl group; a halogen atom include any one containing, C r C 6 alkoxy or hydroxy, including, two or three a substituted C, -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom include any containing, R & lt alkoxy or hydroxy C 6 C inner one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkyne containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group 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; thiol; pyrrolyl; pyridyl; ¾ prime atoms, C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including any one of 4, two two or three substituents of aryl; comprising pigment containing atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue, 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, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, an aldehyde group Any of alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio One, two or three substituted pyranyl groups; containing an alkyl group, a dC 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 fluorenyl group, a sulfonium group Any one, two or three substituted thienyl groups including a thiol group; 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, Any one, two or three substituted pyrrolyl groups such as a carboxamide group, a fluorenyl group, a thiol group or an ethylthio group; an alkanoyl group of CC 6 ; ¾ atom, any hydroxy or C r C 6 alkoxy inner one, two or three substituents of CC 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, d- of Any one, two or three substituted c 2 -c 6 alkenoyl groups such as alkoxy or hydroxy; c 2 -c 6 alkynyl; containing an alkoxy group including a halogen atom, d- or a hydroxyl group Any one, two or three replaced

C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括！ ¾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； 1为（( 1¾)11, n为 0-2， 0; S或 者 NH时； X2为（CH2)n, n为 0-2, 0; S或者 NH。 当 R,， R2, R3分别各自独立为：

Figure imgf000028_0001
C 2 -C 6 alkynyl; C 3 -C 6 cycloalkanoyl; contains included! Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups of a 3 atomic atom, a dC 6 alkoxy group or a hydroxyl group; an adamantyl decanoyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furanoyl; pyranoyl; thiophene; pyrrolyl; 1 (( 13⁄4) 11 , n is 0-2, 0; S or NH; X 2 is (CH 2 ) n , n Is 0-2, 0; S or NH. When R, R 2 and R 3 are respectively independent:
Figure imgf000028_0001

其中 R17, Rl8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、 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 d-C^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、 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- 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! ¾素原子、 C 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、 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、 C C4的烷基、 硝基、 羧基、 眵基、 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、 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、 C 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 鹵素原子、 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； CrC6的烷酰基； 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 CrC6的烷酰基； C2-C6的 烯酰基； 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、 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； 呋喃曱酰基； 吡 喃曱酰基； 噻吩曱酰基； 吡咯曱酰基； |为（0¾)11, n为 0-2， 0; S或 者 NH时； X2为（CH2)n, n为 0-2， O; S或者 NH时， R4， R5, Re分别为:

Figure imgf000030_0001
Wherein R 17 and R l8 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 halogen atom, C, or C 6 or a hydroxyl group; three or substituted dC ^ alkyl; C 2 -C 6 alkenyl group; a! ¾ containing pigment comprising atoms, C r C 6 alkoxy or hydroxy inner any one, two or three substituents of C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group Alkynyl; C 3 -C 6 cycloalkyl; Any one, two or three substituted c 3 -c 6 cycloalkyl groups such as a halogen atom, a d-alkoxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a C 4 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 thiol group, and a Any one, two or three substituted aryl groups including a thio 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 Any one, two or three substituted pyridyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C C4, a nitro group, a carboxyl group, a decyl group, an alkoxy group, an amine group Any one, two or three substituted furyl 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, Carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group Any one, two or three substituted pyranyl groups including a fluorenyl group, a thiol group, an ethylthio group; Any one or two of a 3⁄4 atom atom, an alkyl group of CC 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 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 ethylthio group Any one, two or three substituted pyrrolyl groups; an alkanoyl group of CrC 6 ; any one, two or three substituted C r C containing a pertinyl atom, a d-alkoxy group or a hydroxyl group 6 alkanoyl; C 2 -C 6 alkenyl group; a containing element includes any atom, -C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkenyl group; and 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 An alkanoyl group; any one or two containing a ? 3⁄4 atom, an alkoxy group of d- or a hydroxyl group A 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; Yue thienyl group; pyrrolidin Yue group; | is ( 03⁄4) 11 , n is 0-2, 0; S or When NH is; X 2 is (CH 2 ) n , n is 0-2, O; S or NH, R 4 , R 5 , Re are:
Figure imgf000030_0001

其中 R8为下列任意一种取代基： H; d-C6的烷基； 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 CrC6的烷基； C2-C6的烯基； 含有包括面素原子、 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 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、 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! ¾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! ¾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 者三个取代的吡喃基； 含有包括鹵素原子、 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噻吩基；含有包括! ¾素原子、 C,-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！ 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 的烷酰基； c2-c6的烯酰基； 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的烯酰基； C2-C6的炔酰基； 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的炔酰 基； C3-C6的环烷酰基； 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 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； 吡咯曱酰基； X2为（CH2)n， n为 0-2， O; S或者 NH; 或者 R4, R5, R6分别为：

Figure imgf000031_0001
Wherein R 8 is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted CrC 6 containing an alkoxy group including a halogen atom, C, -C 6 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 facet atom, an alkoxy group of dC 6 or a hydroxyl group; a 2- C6 alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a pertinar atom, an alkoxy group of CC 6 or a hydroxyl group; a C 3 -C 6 ring Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a prime atom, an alkoxy group of dC 6 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 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 sulfonium group Any one, two or three substituted aryl groups including a thiol group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde Any group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; containing pigment include ¾ atom, dC 4! Any one, two or three substituted furan groups including 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. Containing a 3⁄4 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 carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group, etc. Any one, two or three substituted pyranyl groups; 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, a carboxamide group, a fluorenyl group, an anthracene group Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a ? 3⁄4 atom, C, -C 4 Any one, two or three substituted pyrrolyl 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 fluorenyl group, a thiol group or an ethylthio group. ; d-alkanoyl; contains included! ¾ atom, any C r C 6 alkoxy or hydroxy, including one, two or three substituents of the alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, d- alkoxy including a hydroxyl group or any one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a containing element comprises a ¾ atoms, R & lt C 6 alkoxy or C! Any one, two or three substituted C 2 -C 6 alkynyl groups including a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing an alkoxy group including a ? 3⁄4 atom, d- or a hydroxyl group Any one, two or three substituted C 3 -C 6 cycloalkanoyl; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene acyl ; pyrrolidinyl; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000031_0001

其中 R9, Rl()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、 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的浠基； 含有包括! ¾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-Q^ 炔基； 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！ 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芳基； 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、 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、 - 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： 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! ¾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 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； CrC6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 d- 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、 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！ 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； 噻吩曱酰基； 吡咯曱酰基； 1为（( 1¾)11, n为 0-2, O; S或 者 NH时； X2为（CH2)n, n为 0-2, 0; S或者 NH; 或者 R4, R5, R6分别为：

Figure imgf000032_0001
其中 Ru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 Ci-C6的烷基； C2-C6的烯基; 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 C2-C6的烯基； C2-C6的炔基； 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 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！ ¾素原子、 d-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 三个取代的芳基； 含有包括! ¾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! 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呋喃基； 含有包括! ¾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、 C 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、 c,-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！ 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的烯酰基; c2-c6的炔酰基; 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的炔酰 基； C3-C6的环烷酰基； 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 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； 吡咯曱酰基； X2为（CH2)n， n为 0-2， O; S或者 NH; 或者 R4, R5, R6分别为：
Figure imgf000034_0001
Wherein R 9, R l () each independently is any of the following substituents: H; C r C 6 alkyl; containing any one include halogen atoms, alkoxy or hydroxy, including the C6, two or three a substituted C r C 6 alkyl group; a C 2 -C 6 fluorenyl group; any one, two or three substituted C 2 groups including a ? 3⁄4 atom, a dC 6 alkoxy group or a hydroxyl group ; -C 6 alkenyl; C 2 -Q ^ alkynyl; includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents a C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, C,-C 6 alkoxy group or a hydroxyl group; Benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one of a 3⁄4 atom atom, an alkyl group of 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, or an ethylthio group. , two or three substituted aryl groups; containing alkane, d-C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonium Any one, two or three substituted pyridyl groups including a thiol group; 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 carbon group Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, an aldehyde group, including a ?-? Any one, two or three substituted pyranyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; containing a ? 3⁄4 atom, dC 4 Any one, two or three substituted thienyl groups 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 methylthio group, an ethylthio group; Containing a halogen atom, d-alkyl group, nitro group, carboxyl group Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkoxy group; and includes any pigment containing ¾ atoms, C r C 6 alkoxy or hydroxy, including one, two or three substituents of d- alkanoyl;! C 2 -C 6 alkenyl group; a halogen atom-containing include, Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy or hydroxy group of dC 6 ; C 2 -C 6 alkynyl group; alkoxy group containing a halogen atom, d- Or one, two or three substituted C 2 -C 6 alkynyl groups, or 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 acyl; pyrrolyl hydrazide; 1 is (( 13⁄4) 11 , n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000032_0001
Wherein R u is any one of the following substituents: H; d-alkyl; any one, two or three substituted Ci-Cs including a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group 6 alkyl; C 2 -C 6 alkenyl; contains included! Any one, two or three substituted C 2 -C 6 alkenyl groups of a C, a C, a C 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; any prime atom, C, -C 6 alkoxy group or a hydroxyl group, including one, two or three substituents a C 2 -C 6 alkynyl group; C 3 -C 6 cycloalkyl; include a halogen atom-containing any C r C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 -C 6 cycloalkyl; aryl; benzyl; furyl; tetrahydropyranyl; thienyl; Pyrrolyl; pyridyl; contains included! Any one, two or three of a 3 atom atom, a dC 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 Substituted aryl; containing an alkyl group including a ? atom, d-, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio including any one, two or three substituents pyridyl;! ¾ containing pigment comprising atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbon Any one, two or three substituted furanyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ?3⁄4 atom, a d-C4 group, a nitro group, a carboxyl group, an aldehyde group, Any one, two or three substituted pyranyl groups including an alkoxy 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, CC 4 , nitro, carboxyl, aldehyde, alkoxy, amine, amide, carbonyl Group, any mercapto, Yue thio, ethylthio, including one, two or three substituents thienyl; include a halogen atom-containing, c, -c 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy Any one, two or three substituted pyrrolyl groups including an oxy group, an amine group, an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkanoyl group of c r c 6 ; any atom, c r c alkoxy or hydroxy 6 including one, two or three substituents of c r c 6 alkanoyl; c 2 -c 6 alkenyl group; comprising comprising! Any one, two or three of a 3⁄4 atomic atom, a C 6 alkoxy group or a hydroxyl group Substituted c 2 -c 6 enoyl; c 2 -c 6 alkynyl; any one, two or three substituted c containing an alkoxy group including a halogen atom, c, -c 6 or a hydroxyl group 2 - C6 alkynyl; C 3 -C 6 cycloalkanoyl; contains included! Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, an alkoxy group or a hydroxyl group; an adamantyl decanoyl group, a substituted adamantyl decanoyl group; an aroyl group; ; furanyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, O; S or NH; or R 4 , R 5 , R 6 are :
Figure imgf000034_0001

其中 Rl2, Rl3各自独立为下列任意一种取代基： H; C6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 C,-C6的烷基； C2-C6的烯基； 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 C2-C6的烯基； C2-C6的炔基； 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！ ¾素原子、 C,-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！ ¾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 的呋喃基； 含有包括! ¾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- 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 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 d-C6的烷酰基； C2-C6的 烯酰基； 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、 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； ，为^!^)。， n为 0-2， O; S或 者 NH时； 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 和神经退行性疾病 (如 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： Wherein R l2 and R l3 are each independently a substituent of any of the following: H; an alkyl group of C6; any one, two or three substituted Cs including a pertiny atom, alkoxy group of d- or a hydroxyl group. , -C 6 alkyl; C 2 -C 6 alkenyl group; includes any containing halogen atoms, C alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkenyl group of ; C 2 -C 6 alkynyl group; a halogen atom includes any containing, C, -C 6 alkoxy or hydroxy, including one, two or three substituents a C 2 -C 6 alkynyl group; 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 ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one of a C, a C, a 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 fluorenyl group, a thiol group, or an ethyl thio group. Two or three substituted aryl groups; contain included! Any one or two of a 3 atomic atom, a d-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 a three-substituted pyridyl 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, an amine group, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethane group Any one, two or three substitutions a furanyl group; containing a 3⁄4 atom, (^-(: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonylthio, B) Any one, two or three substituted pyranyl 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, 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, d-, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group group, an amine group, an amide group, carboxamide group, an optionally 'mercapto group, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; atoms containing pigment comprising Any one, two or three substituted dC 6 alkanoyl groups such as an alkoxy group or a hydroxyl group of C C6; a C 2 -C 6 alkenoyl group; an alkoxy group or a hydroxyl group including a halogen atom, d- Any one, two or three substituted C 2 -C 6 enoyl groups; 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 6 -C. 3 a cycloalkanoyl group; any one, two or three substituted c 3 -c 6 cycloalkanoyl groups including a 3⁄4 atom atom, an alkoxy group of dC 6 or a hydroxyl group; adamantyl decanoyl group, substituted adamantane Decanoyl; aroyl; benzoyl; furanoyl; pyranoyl; thiophene acyl; pyrrolidinyl; , ^^^), n is 0-2, O; S or NH; X 2 is (CH 2 ) n , n is 0-2, 0; S or NH. Further preferably, the compound or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, either alone or with pharmacology An acceptable carrier or excipient is provided in combination. The 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), heart Vascular disease and neurodegenerative diseases (such as Alzheimer's disease), etc. It relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease) and other methods. 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 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 action for prevention or treatment:

Figure imgf000036_0001
Figure imgf000036_0002
其中， X， Υ, Z, 分别为 (CH2)n, n为 0-2, 氧， 硫或氮；
Figure imgf000036_0001
Figure imgf000036_0002
Wherein X, Υ, Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;

R, , R2, R3各自独立地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； R4, R5, 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的结构， 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： R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl; R 4 , R 5 , each independently of 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. 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. The compound has the structure of the following general formula, and all of its stereo and optical isomers, or prodrugs having the same pharmacological action, esters thereof, solvates thereof or metal complexes thereof:

Figure imgf000037_0001
Figure imgf000037_0001

II

Figure imgf000037_0002
其中 X, Y, Ζ, 分别为（CH2)n, η为 0-2， 氧， 硫或氮； II
Figure imgf000037_0002
Wherein X, Y, Ζ, respectively (CH 2 ) n , η is 0-2, oxygen, sulfur or nitrogen;

R, , R2, R3各自独立地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； R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; Unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;

R4, R5, R6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 4氏抗和肥胖症）、 心血管疾病和神经退^"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 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 4 and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's disease, etc., achieves the efficacy of selectively stimulating the glucagon-like peptide-1 receptor, improving the symptoms and quality of life of the patient. To clarify the contents of the invention and not to be limited thereto, the invention is divided into the following subsections. Detailed Description.

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 4亍性蜕变性疾病， 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" 是指足够均勾， 通过本领域技术人员为评 价纯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 the Gene Bank and other databases referred to herein are referenced in full revenue. 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 sugar, fat, or Related symptoms and/or diseases caused by metabolic disorders such as proteins. 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 the phenomenon that the amount of body fat is too much, that a man weighs more than 25% of the ideal body weight or that the woman weighs more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overdose And too few activities are the cause of obesity. As used in this article, "Alzheimer's Disease (Al, Alzheimer's disease, also known as Alzheimer's dementia) is a neurological system of degenerative diseases, clinical It manifests as a chronic impairment of intelligence and a 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 single Dosing can also be administered according to the treatment 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 sufficient homogeny to detect impurities by standard analytical methods used by those skilled in the art for evaluating 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 substance, such as enzymatic activity and biological activity. Methods for producing substantially chemically pure compounds for purification are 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 transport properties Precursors to mask their side effects or toxicity, improve the taste of the drug, or alter other characteristics. 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糖尿病及 其并发症进行治疗和预防。 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 the same or are homogenous or similar, and the understanding of the relevant art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, in accordance with the understanding of the relevant art. 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 association between two or more. The term "subject" 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 and prevent diabetes and its complications. Any of the protective groups used herein, abbreviations for amino acids and other compounds, are consistent with their common, recognized abbreviations or the biochemical nomenclature issued by the IUPAC-IUB committee, unless specifically 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、 胰岛素氐抗和肥胖 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, or a pharmaceutically acceptable salt thereof, and All stereo and optical isomers, or prodrugs, esters, solvates or metal complexes thereof having the same pharmacological effects:

Figure imgf000042_0001
Figure imgf000042_0002
其中， X， Υ, Z, 分别为（CH2)n， n为 0-2, 氧， 硫或氮；
Figure imgf000042_0001
Figure imgf000042_0002
Wherein X, Υ, Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;

R, , R2， R3各自独立地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； R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;

R4, R5, R6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。 R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; Unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. The compounds of the invention may be a specific stereoisomer, such as the R- or S-configuration, or mixtures thereof, for example, a racemic mixture. The compounds considered here include all A pharmaceutically active compound species, or a solution or mixture 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.

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、 酸、 磷酸等； 有 机酸诸如曱酸、 乙酸、 丙酸、 苯曱酸、 马来酸、 富马酸、 琥珀酸、 酒 石酸、 柠檬酸等； 烷基磺酸如曱基磺酸、 乙基磺酸等； 芳基磺酸如苯 磺酸、 对曱苯磺酸等均可使用。 This compound was prepared by the synthesis described 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 any suitable acid in the form of their pharmaceutically acceptable salts. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, acid, phosphoric 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 mercaptosulfonic acid, ethylsulfonic acid or the like; an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like 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 4氏抗和肥胖症）、 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: C Therapeutic and Prophylactic Methods The present invention relates to the prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin 4 and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). Methods. The method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound that 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 a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and all of the stereo and optical isomers thereof, or a prodrug having the same pharmacological action thereto , its ester, its solvate or its metal complex To treat or prevent:

Figure imgf000044_0001
Figure imgf000044_0001

Figure imgf000044_0002
Figure imgf000044_0002

III IV 其中， X, Υ, Z, 分别为（CH2)n， n为 0-2， 氧， 硫或氮； III IV wherein X, Υ, Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen;

R, , R2, R3各自独立地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； R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;

R4, R5 , R6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 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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 prevent 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, insulin resistance and obesity, the invention may be used alone or in combination with other diabetes therapeutics, including insulin sensitizers that are already on the market or to be marketed. compound of. 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 WO 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， 和一种或多种代谢紊乱性疾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代谢紊乱性疾病 治疗药物包括胰岛素增敏剂， 该化合物由以下通式表示： 其中 X， Y, Z, 分别为（CH2)n, n为 0-2， 氧， 石 或氮； Suitable 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 associated disease or condition and its prognosis. Diagnosis and prognosis can be based on detecting and/or identifying any or all of the in vivo material, such as glycated hemoglobin, enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers, and the like. For example, international patent WO can be used 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 metabolic disorders include insulin sensitizers. Preferably, such a combination comprises a compound of the present invention 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 The metal complex and one or more therapeutic agents for metabolic disorders include insulin sensitizers, which are represented by the general formula: wherein X, Y, Z are (CH 2 ) n and n is 0-2, respectively. Oxygen, stone or nitrogen;

Figure imgf000046_0001
Figure imgf000046_0001

Figure imgf000046_0002
Figure imgf000046_0002

III IV  III IV

R, , R2， R3各自独立地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； R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl;

R4, R5, R6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。 在另一个特定实施方案中， 提供了一种治疗或预防由胰岛素分泌 和 /或功能障碍引起或伴随的疾病或症状的方法， 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 接受的盐来防治由胰岛素分泌和 /或功能紊乱引起或伴随的疾病或症状 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 用所述联合制剂治疗或预防由胰岛素分泌和 /或功能紊乱引起或伴随的 疾病或症状的使用说明。 R 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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. In another specific embodiment, a method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction is provided, the method comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above 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 controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction. In still another embodiment, a kit is provided comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.

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、 月几内注射、 真皮内注射、 口月 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 的緩沖剂注射给药。 制剂可采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 B l、 5,741,511 、 5,886,039、 5,941,868、 6,258,374B 1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， 胶嚢， 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 - 羟基-丙基- β -环糊精紧密混和。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毫升到 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, such as intraluminal, subcutaneous, Intravenous injection, intra-monthly 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 which may be used in the present invention include, but are not limited to, those 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 compound of the present invention, alone or in combination with other preparations, may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as β-cyclodextrin and 2-hydroxy-propyl-β-cyclodextrin. Finely mixed. A special carrier, a local or parenteral route, can be used depending on the needs of the administration. Preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion, may employ similar pharmaceutical vehicles, water known to those skilled in the art, Ethylene glycol, oil, buffer, sugar, preservatives, liposomes, etc. 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 ml to about 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. A preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid. Alternatively, the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably 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F preparation method

0 ^ ^ NH2 ^ NH2 .HCI ^ 、K NH2 _ ^0 ^ ^ NH 2 ^ NH 2 .HCI ^ , K NH 2 _ ^

CN ^COOH A COOH

Figure imgf000049_0001
取氰化钠 （ leq )溶于适量的水中， 加入氯化铵（l.leq ), 室温下 搅拌， 当氯化铵完全溶解后， 加入上述酮 （leq ) 的曱醇溶液。 反应温 度迅速上升， 继续搅拌 2 小时。 加水稀释， 用苯提取。 苯层用水洗， 用 6N盐酸提取氨基腈。 合并酸液， 回流 2 小时， 加水稀释。 减压蒸馏， 去除酮和其他的 挥发性物质。 加氨水调节 PH至弱碱性，冷却至室温。有黄色的晶体出现。过滤， 滤饼用少量的水洗， 然后用乙醚和 95 %的热乙醇洗。 干燥得到氨基酸。 取上述氨基酸（ leq )溶于氢氧化钠溶液（ 1.25eq )， 冷却至 30°C以 下， 同时滴加酰氯（ l.leq )和氢氧化钠溶液（2eq )， 始终维持反应液 呈弱碱性。 滴加结束后继续搅拌 0.5小时。 加浓盐酸调节 PH至酸性， 冷却， 过滤得到粗品。 用乙醇重结晶得到产物。 。 ~~ - ^ 0H ^ - 0Η —— - 、κ0Η ―CN ^COOH A COOH
Figure imgf000049_0001
Sodium cyanide (leq) was dissolved in an appropriate amount of water, ammonium chloride (l.leq) was added, and the mixture was stirred at room temperature. After the ammonium chloride was completely dissolved, the above ketone (leq) sterol solution was added. Reaction temperature The degree rises rapidly and stirring is continued for 2 hours. Dilute with water and extract with benzene. The benzene layer was washed with water, and the aminonitrile was extracted with 6N hydrochloric acid. The combined acid solutions were refluxed for 2 hours and diluted with water. Distillation under reduced pressure to remove ketones and other volatile materials. Add ammonia to adjust the pH to weakly alkaline and cool to room temperature. There are yellow crystals appearing. After filtration, the filter cake was washed with a small amount of water and then washed with diethyl ether and 95% hot ethanol. Dry to give amino acids. The above amino acid (leq) was dissolved in sodium hydroxide solution (1.25 eq), cooled to below 30 ° C, and acid chloride (l.leq) and sodium hydroxide solution (2 eq) were added dropwise, and the reaction solution was kept weakly alkaline. . Stirring was continued for 0.5 hours after the completion of the dropwise addition. Concentrated hydrochloric acid was added to adjust the pH to acidity, cooled, and filtered to give a crude material. Recrystallization from ethanol gave the product. . ~~ - ^ 0H ^ - 0Η —— - , κ 0Η ―

' CN ^ CONH2 ' COOH 尸 4-8 ' CN ^ CONH 2 ' COOH Corpse 4-8

jf o  Jf o

COOH 取酮 （0.67eq )溶于适量的乙醚和水中， 水盐浴冷却。 加入氰化 钠 （1.67eq ), 剧烈搅拌。 当大部分的氰化钠全部溶解后且反应液温度 降至 5°C以下，慢慢滴加适量的浓盐酸， 维持反应温度在 5°C到 10°C之 间。 滴加结束后， 移去冰浴， 同时剧烈搅拌 2 小时。 静置， 分离乙醚 层， 将水层倒入反应瓶中， 加水溶解盐。 水层再用乙醚提取， 合并乙 醚层， 蒸去乙醚。 将残余物倒入浓盐酸中， 并用氯化氢气体饱和， 放 置过夜。 然后先用空气带走部分氯化氢气体， 再慢慢滴加 50 %氢氧化 钠溶液调节至碱性。冰浴冷却，用机械搅拌，加入氢氧化钠固体（ 0.6eq )， 水蒸汽蒸馏直至无多余的氨和酮。 加水稀释， 乙醚提取（弃去）。 水层 用浓盐酸酸化， 冷却， 过滤得到 α -羟基酸。 取 α -羟基酸（ 0.69eq )加入酰氯（ 0.69eq )， 水浴加热反应。 冷却 析晶， 得产物。

Figure imgf000051_0001
The COOH ketone (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water, and cooled in a water-salt bath. Sodium cyanide (1.67 eq) was added and stirred vigorously. When most of the sodium cyanide is dissolved and the temperature of the reaction solution falls below 5 ° C, an appropriate amount of concentrated hydrochloric acid is slowly added dropwise to maintain the reaction temperature between 5 ° C and 10 ° C. After the addition was completed, the ice bath was removed while vigorously stirring for 2 hours. After standing, the ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt. The aqueous layer was extracted with diethyl ether. The residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then, some of the hydrogen chloride gas is taken away by air, and then slowly added with 50% sodium hydroxide solution to adjust to alkaline. The mixture was cooled in an ice-bath, and stirred with mechanical stirring, sodium hydroxide solid (0.6 eq) was added, and steam distilled until no excess of ammonia and ketone. Dilute with water and extract with ether (discard). Water layer Acidified with concentrated hydrochloric acid, cooled and filtered to give an a-hydroxy acid. The acid chloride (0.69 eq) was added to the α-hydroxy acid (0.69 eq), and the reaction was heated in a water bath. The crystallized was cooled to obtain a product.
Figure imgf000051_0001

在氮气保护下， 取 LDA ( 1.2mmol )溶于适量的四氢呋喃中， 冷 却至 - 50°C ,慢慢滴加羧酸（ 0.5mmol )， 维持该温度继续搅拌 30分钟， 50°C继续搅拌 2小时。 用液氮 /曱醇浴冷却至 - 100°C , 滴加硝基取代的 烯烃（ 1.5mmol ), 反应 5个小时， 反应液温度慢慢升至 0 - 10°C。 加入 适量的 17 %稀盐酸， 冰浴中搅拌过夜。 加水， 二氯曱烷提取， 依次用 水和饱和食盐水洗涤， 干燥。 蒸去溶剂上柱分离。 附图说明 图 1. 报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 ΙΟ ηΜ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 exendin^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, 以不力 σ exendin9-39的活性设为 100 %， 试验表明

Figure imgf000051_0002
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 10 nM 所诱导的 cAMP活性为 100 % ., 测得 GLP-1的 EC50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 Under nitrogen protection, take LDA (1.2mmol) in an appropriate amount of tetrahydrofuran, cool to -50 ° C, slowly add carboxylic acid (0.5mmol), continue to stir at this temperature for 30 minutes, continue stirring at 50 ° C 2 hour. The mixture was cooled to -100 ° C with a liquid nitrogen/methanol bath, and a nitro-substituted olefin (1.5 mmol) was added dropwise thereto for 5 hours, and the temperature of the reaction solution was gradually raised to 0 - 10 °C. An appropriate amount of 17% dilute hydrochloric acid was added and the mixture was stirred overnight in an ice bath. Water was added, and dichloromethane was extracted, washed successively with water and saturated brine, and dried. The solvent was distilled off and the column was separated. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Reporter gene method detects the agonistic effects of compounds 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 0.07 nM. Figure 2. Reporter gene method to detect the antagonism of exendin^ 39 on GLP-1. The concentration of GLP-1 was 0.05 nM, the concentration gradient of exendin 9-39 was 10000, 1000, 100, 10, 1 , 0.1 , 0 nM, and the activity of σ exendin 9-39 was set to 100%.
Figure imgf000051_0002
Reporter gene expression induced by GLP-1 was inhibited with an IC 50 value of 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Figure 3. Intracellular cAMP concentration detects the effect of GLP-1 on GLP-1R signaling. The GLP-1 concentration gradient is 10, 1 , 0.1, 0.01, 0.001, 0.0001, 0 nM to 10 nM Induced cAMP activity was 100%, measured GLP-1 EC 50 value of 0.079 nM, suggesting that intracellular cAMP induced as GLP-1R agonist, 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。 色谱柱为 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 nm。 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型质傳仪测得， EI由 Finnigan MAT95型质谱仪测得。合成中所用原料除特别指明来源 外均为市售产品。 实施例 1 HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector. The column was ZORBAX SB-C18 (2.1 X 150 mm, 3.5 μιη), the mobile phase was acetonitrile/water, the flow rate was 0.2 ml/min, and the detection wavelength was 254 nm. The melting point was determined by 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 passed by AB Mariner type The instrument was measured by EI by a Finnigan MAT95 mass spectrometer. The materials used in the synthesis are commercially available products unless otherwise specified. Example 1

NMR定标： δΗ/C 7.26/77.0 ppm ( CDC13 ); 5H/C 2.50/39.51 ppm (DMSO-d6)。 NMR calibration: δΗ/C 7.26/77.0 ppm (CDC13); 5H/C 2.50/39.51 ppm (DMSO-d6).

Figure imgf000053_0001
Figure imgf000053_0001

Figure imgf000053_0002
取氰化钠 （ leq)溶于适量的水中， 加入氯化铵（l.leq), 室温下 搅拌， 当氯化铵完全溶解后， 加入上述 3-苯基 1, 2-环戊二酮 （leq) 的曱醇溶液。 反应温度迅速上升， 继续搅拌 2 小时。 加水稀释， 用苯 提取。 苯层用水洗， 用 6N盐酸提取 3-苯基 1, 2-二氨基 - 1 , 2 -环 戊二腈。 合并酸液， 回流 2 小时， 加水稀释。 减压蒸镏， 去除酮和其他的 挥发性物质。 加氨水调节 PH至弱碱性，冷却至室温。有黄色的晶体出现。过滤， 滤饼用少量的水洗， 然后用乙醚和 95%的热乙醇洗。 干燥得到 3-笨基 1， 2 -二氨基 - 1, 2-环戊二酸。 取上述 3-笨基 1， 2-二氨基 - 1， 2-环戊二酸（ leq)溶于氢氧化 钠溶液（ 1.25eq)， 冷却至 30°C以下， 同时滴加对 Boc氨基苯曱酰氯 ( Ueq)和氢氧化钠溶液（2eq)， 始终维持反应液呈弱碱性。 滴加结 束后继续搅拌 0.5小时。 加浓盐酸调节 PH至酸性， 冷却， 过滤得到粗 。 用乙醇重结晶得到产物。 同样方法得到以下产物：
Figure imgf000054_0001
Figure imgf000053_0002
Sodium cyanide (leq) is dissolved in an appropriate amount of water, ammonium chloride (l.leq) is added, and stirred at room temperature. When ammonium chloride is completely dissolved, the above 3-phenyl 1,2-cyclopentanedione is added. Leq) sterol solution. The reaction temperature rose rapidly and stirring was continued for 2 hours. Dilute with water and extract with benzene. The benzene layer was washed with water, and 3-phenyl 1,2-diamino-1,2-cycloglutaronitrile was extracted with 6N hydrochloric acid. The combined acid solutions were refluxed for 2 hours and diluted with water. Evaporate under reduced pressure to remove ketones and other volatile materials. Add ammonia to adjust the pH to weakly alkaline and cool to room temperature. There are yellow crystals appearing. After filtration, the filter cake was washed with a small amount of water and then washed with diethyl ether and 95% hot ethanol. Drying gives 3-phenyl 1,2-diamino-1,2-cycloglutaric acid. The above 3-styl 1,2-diamino-1,2-cycloglutaric acid (leq) was dissolved in a sodium hydroxide solution (1.25 eq), cooled to below 30 ° C, and the addition of Boc aminophenyl hydrazine was simultaneously added dropwise. The acid chloride (Ueq) and sodium hydroxide solution (2 eq) kept the reaction solution weakly alkaline. Stirring was continued for 0.5 hours after the completion of the dropwise addition. Add concentrated hydrochloric acid to adjust the pH to acidity, cool, and filter to obtain coarse . Recrystallization from ethanol gave the product. The same method yields the following products:
Figure imgf000054_0001

Figure imgf000054_0002
Figure imgf000054_0002

Figure imgf000055_0001
Figure imgf000055_0001

Figure imgf000055_0002
Figure imgf000055_0002

取 3-苯基 1, 2 -环戊二酮 （0.67eq)溶于适量的乙醚和水中， 冰 盐浴冷却。 加入氰化钠 （ 1.67eq), 剧烈搅拌。 当大部分的氰化钠全部 溶解后且反应液温度降至 5°C以下，慢慢滴加适量的浓盐酸， 维持反应 温度在 5°C到 10°C之间。 滴加结束后， 移去水浴， 同时剧烈搅拌 2小 时。 静置， 分离乙醚层， 将水层倒入反应瓶中， 加水溶解盐。 水层再 用乙醚提取， 合并乙醚层， 蒸去乙醚。 将残余物倒入浓盐酸中， 并用 氯化氢气体饱和， 放置过夜。 然后先用空气带走部分氯化氢气体， 再 慢慢滴加 50%氢氧化钠溶液调节至碱性。 冰浴冷却， 用机械搅拌， 加 入氢氧化钠固体（0.6eq),水蒸汽蒸馏直至无多余的氨和酮。加水稀释， 乙醚提取（弃去）。 水层用浓盐酸酸化， 冷却， 过滤得到 3-苯基 -1, 2 -二羟基- 1, 2-环戊二腈。 取 3-苯基 -1， 2 -二羟基 - 1, 2-环戊二腈 （ 0.69eq )加入对 Boc 氨基苯曱酰氯（0.69eq)， 水浴加热反应。 冷却析晶， 得产物。 同样方法得到以下产物： 3-Phenyl 1,2-cyclopentanedione (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water and cooled in an ice bath. Sodium cyanide (1.67 eq) was added and stirred vigorously. When most of the sodium cyanide is dissolved and the temperature of the reaction solution falls below 5 ° C, an appropriate amount of concentrated hydrochloric acid is slowly added dropwise to maintain the reaction temperature between 5 ° C and 10 ° C. After the addition is complete, remove the water bath while stirring vigorously for 2 small Time. After standing, the ether layer was separated, and the aqueous layer was poured into a reaction flask, and water was added to dissolve the salt. The aqueous layer was extracted with diethyl ether. The residue was poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas and stood overnight. Then, some of the hydrogen chloride gas is taken away by air, and then slowly added with 50% sodium hydroxide solution to adjust to alkaline. Cool in an ice bath, mechanically stir, add sodium hydroxide solid (0.6 eq), and steam to distill until free of ammonia and ketone. Dilute with water and extract with ether (discard). The aqueous layer was acidified with concentrated hydrochloric acid, cooled and filtered to give 3-phenyl-1,2-dihydroxy-1,2-cyclopentadicarbonitrile. 3-Phenyl-1,2-dihydroxy-1,2-cycloglutaronitrile (0.69 eq) was added to a solution of Boc aminobenzoic acid chloride (0.69 eq), which was heated in a water bath. The crystallized was cooled to obtain a product. The same method yields the following products:

Figure imgf000056_0001
Figure imgf000056_0001

实施例 3: Example 3:

Figure imgf000056_0002
在氮气保护下， 取 LDA ( 1.2mmol)溶于适量的四氢呋喃中， 冷却 至- 50°C， 慢慢滴加 3-苯基 1, 2-环戊二酮（0.5mmol), 维持该温度 继续搅拌 30分钟， 50°C继续搅拌 2小时。用液氮 /甲醇浴冷却至 - 100°C, 滴加 α-硝基取代苯乙烯（ 1.5mmol), 反应 5个小时， 反应液温度慢慢 升至 0- 10°C。 加入适量的 17%稀盐酸， 冰浴中搅拌过夜。 加水， 二 氯曱烷提取， 依次用水和饱和食盐水洗涤， 干燥。 蒸去溶剂上柱分离。 同样方法得到以下产物：
Figure imgf000056_0002
Under nitrogen protection, LDA (1.2 mmol) was dissolved in an appropriate amount of tetrahydrofuran, cooled to -50 ° C, and 3-phenyl 1,2-cyclopentanedione (0.5 mmol) was slowly added dropwise to maintain the temperature. Stir for 30 minutes and continue stirring at 50 °C for 2 hours. The mixture was cooled to -100 ° C with a liquid nitrogen/methanol bath, and α-nitro-substituted styrene (1.5 mmol) was added dropwise thereto for 5 hours, and the temperature of the reaction solution was gradually raised to 0 to 10 °C. An appropriate amount of 17% dilute hydrochloric acid was added and the mixture was stirred overnight in an ice bath. Water was added, and dichloromethane was extracted, washed successively with water and saturated brine, and dried. The solvent was distilled off and the column was separated. The same method yields the following products:

Figure imgf000057_0001
实施例 4: 体外药效学试验
Figure imgf000057_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 Ga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 )„ 本实睑方法采用稳定转染 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抹（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， 可诱导荧光素酶报 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 Ga subunit of the G protein is activated to stimulate adenylate cyclase, resulting in an increase in 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 smear (HEK 293) stably transfected with the GLP-1R receptor gene expression vector and the luciferase reporter gene expression vector regulated by the cAMP response element was used to detect the response to the test compound. Biology, 1992, Vol. 89:8641-8645; Proc. Natl. Acad. Sci. USA 1987, Vol. 84:3434-3438 ) „ A sample that induces expression of a luciferase reporter gene when screening for a compound, It is considered to have 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 清 （GIBCO公司） 1.1 Test materials and instruments Cell line: HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (self-built by National New Drug Screening Center) Fetal Niu Qing (GIBCO)

DMEM培养基（GIBCO公司） DMEM medium (GIBCO)

Steady-Glo™荧光素酶分析系统（Promega公司） 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);

Victor读板机（Wallac公司 ); Victor reading machine (Wallac);

1.2 试验方法 1.2 Test methods

HE 293/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。 HE 293/GLP1R+Luc cells were incubated at 20,000/100 μΐ/well into 96-well plates at 37 with DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. C cultured Night. The GLP-1 standard was diluted to a concentration gradient and then added to the above 96-well microplate in Ιμΐ/well. Incubation was carried out for 6 hours at 37 ° C under 5% CO 2 . Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit, and the Victor 2 reader was used for reading.

1.3 试验结果 研究结果表明 （表 1 , 图 1 ), GLP-1的 EC5o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 Test results The results of the study showed (Table 1, Figure 1) that the EC 5 o value of GLP-1 was 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  0.01 13.3

0.001 2.4  0.001 2.4

0.0001 0.4  0.0001 0.4

2. Exendin9-39拮抗试验 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 的特异性拮抗剂 exendin9-39 ( Eur. J. Pharmacol. 1994, 269: 183- 191 ; Metabolism 2004, 53:252-259. )来验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- 3 9 antagonism test to confirm the active compound has a receptor-specific activation of the reporter gene, we used the specificity of GLP-1R antagonist, exendin 9-3 9 (Eur. J. Pharmacol . 1994, 269 : 183-191; Metabolism 2004, 53:252-259. ) to verify whether it antagonizes the agonistic activity of the above representative compounds on GLP-1R.

2.1试验材料与仪器： 细胞抹： 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 wipe: HEK 293/GLP-1R+Luc with stable expression of GLP-1R and luciferase Cell strain (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 ( Invitrogen公司 ) G418 (Invitrogen)

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 3 方法 2.2 test 3 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 nMGLP-1 , 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. Dilute Exendin 9 _ 39 to a concentration gradient and add 1 μΐ/well to the above 96-well microplate at 37 μ. Incubate for 10 minutes at C, 5% C0 2 , then add 0.05 nMGLP-1 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 reading.

2.3试验结果 2.3 Test results

ExendinW9能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 IC5。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 W9 dose-dependently inhibited reporter gene expression induced by GLP-1 (Table 2, Figure 2), IC 5 . The value was 68.22 nM, indicating that its biological activity is mediated by GLP-1R. Table 2. Antagonism of Exendin 9-39 on GLP-1 (% response, 100% response to 0.05 nM GLP-1)

Exendin9-39 (nM) 目对活性（％) Exendin 9-39 (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 reporter gene detection method is a method for indirectly determining the level of intracellular cAMP concentration. To confirm that the active compound does increase the intracellular cAMP concentration, functional verification is performed directly using the cAMP test kit.

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 ^^'j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 ^^'j kit (Applied Biosystems) Forma carbon dioxide Incubator (Forma) Victor 2 plate reader (Wallac) cAMP standard (provided with the kit, Applied Biosystems) 3.2 test 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 的反应为 100% ) GLP-1 dose-dependently induced cAMP in cells (Table 3, FIG. 3), which EC 5. The value of 0.079 nM suggests that it acts as a GLP-1R agonist and plays a role in GLP-1R signaling. Table 3. Induction of intracellular cAMP by GLP-1 (% response, 100% response to 10 nM GLP-1)

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 |251标 GLP - 1进行竟争性结合时，细胞膜上的同位素标记 减少。 据此可评估化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. Isotope labeling on cell membranes when the test compound is competitively bound to |25 1 GLP-1 cut back. The affinity of the compound for the receptor can be evaluated accordingly (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/GLPlR+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)

Wallac MicroBata工作站 ( Perkin Elmer公司） Wallac 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 (Wallac) 4.2 Test Method Take 10 5 logarithmic growth phase of HEK 293/GLP1R+Luc cells at 25. Under the condition of C, 200 μl of the GLP-1 positive peptide (final concentration of 40 ρΜ) was incubated with the 125 1 standard test buffer for 4 hours, and a non-labeled positive peptide or a drug to be screened was added. 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 IC5Q值为 0.66 nM。 表 4. GLP-1对 GLP- 1 R的结合活力测试 GLP-1 specifically binds receptors to the 125 1 standard GLP-1 (Table 4, Figure 4) with an IC 5Q value of 0.66 nM. Table 4. Binding viability test of GLP-1 to GLP-1 R

GLP-1终浓度 （ηΜ) 125ι标 GLP-1结合百分比 （％ ) GLP-1 final concentration (ηΜ) 125 ι 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 imgf000065_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 imgf000065_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 imgf000065_0002
Figure imgf000065_0003
其中 X， Υ, Z, 分别为 (CH2)n, n为 0-2， 氧， 硫或氮；
Figure imgf000065_0002
Figure imgf000065_0003
Wherein X, Υ, Z are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen; R, , R2， R3各自独立地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^ L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； R, R 2 , R 3 are each independently one of the following substituents: hydrogen; halogen; alkane; cycloalkane; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; Carboxamide; mercapto; alkyl; alkyl; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl Substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl; R4, R5, R6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 4 , R 5 , R 6 are each independently any one of the following substituents: hydrogen; alkane; cycloalkane; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; 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所述的具有取代环戊烷结构的化合物， 其特征 在于： 2. A compound having a substituted cyclopentane structure according to claim 1 wherein: X、 Y、 Ζ分别是 (CH2)n, n为 0-2, 氧， 硫或氮， R R2， R3分别 各自独立地为：
Figure imgf000066_0001
X, Y, and Ζ are (CH 2 ) n , n is 0-2, oxygen, sulfur or nitrogen, and RR 2 and R 3 are each independently:
Figure imgf000066_0001
 其中 R7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 Cr 的烷基； C2-C6的烯基； 含有包括！ ¾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 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! ¾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、 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！ ¾素原子、 C,-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 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 者三个取代的吡喃基； 含有包括卤素原子、 C 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 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； d- 的烷酰基； 含有包括！ ¾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 - 的烷酰基； C2-C6的烯酰基； 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 C2-C6的烯酰基； C2-C6的炔酰基； 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的炔酰 基； C3-C6的环烷酰基； 含有包括 [¾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； 呋喃曱酰基； 吡喃曱酰基； 噻 吩曱酰基； 吡咯曱酰基； 1为（( ¾)11, n为 0-2, O, S或者 NH时； R4, R5, Re分别为：
Figure imgf000067_0001
Wherein R 7 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, Cr Alkyl; C 2 -C 6 alkenyl; contains included! Any one, two or three substituted C 2 -C 6 alkenyl groups of a 3 atomic atom, an alkoxy group of dC 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; containing a [3⁄4 atom, C R & lt any C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl; comprising pigment containing atoms, C, - Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as C 6 alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; Pyridyl; containing an atom including a : 3⁄4 atom, a 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 fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted aryl groups; containing 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 carboxamide group, a fluorenyl group, Any one, two or three substituted pyridyl groups including thiol and ethylthio; Any one of a C, a C, a 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 or an ethylthio group; Two or three substituted furyl groups; containing an atom including a -C4, 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, a Any one, two or Three substituted pyranyl groups; containing an alkyl group including a halogen atom, C C4, 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 ethane group Any one, two or three substituted thienyl groups, including a sulfonate atom, an alkyl group of -C4, 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 thiol group, an ethylthio group; an alkanoyl group of d-; ¾ any prime atoms, C alkoxy or hydroxy group including one, two or three substituents of - alkanoyl; C 2 -C 6 alkenyl group; a containing element comprises a ¾ atoms, C, -C 6! Any one, two or three substituted C 2 -C 6 alkenoyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing an alkane including a [3⁄4] atom, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; containing an alkoxy group including a [3⁄4 atom atom, dC 6 or Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; Thiophenanthryl; pyrrolyl hydrazide; 1 is (( 3⁄4) 11 , n is 0-2, O, S or NH; R 4 , R 5 , Re are:
Figure imgf000067_0001
 其中 R8为下列任意一种取代基： H; d-C6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 CrC6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 C2-C6的烯基； C2-C6的炔基； 含有包括! ¾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！ 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 三个取代的芳基； 含有包括! ¾素原子、 d-Cj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！ ¾素原子、 C 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呋喃基； 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 者三个取代的吡喃基； 含有包括 (¾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、 c,-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；Wherein R 8 is any of the following substituent groups: H; dC 6 alkyl; includes any containing halogen atoms, C alkoxy or a hydroxyl group, including, two or three alkyl substituents of the C r C 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 CC 6 or a hydroxyl group; C 2 -C 6 alkynyl group;! ¾ element comprising optionally containing atoms, hydroxy or alkoxy C, including one, two or three substituents of C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group of 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; Alkyl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; ¾ prime atoms, C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including any one of 4, two Or a three-substituted aryl group; containing an alkyl group including a ?? atom, d-Cj, 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 pyridyl groups, including ethylthio; Any one, two or three of a 3 atomic atom, an alkyl group of a CC, 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 substituted furanyl group; optionally containing 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, and the like. One, two or three substituted pyranyl groups; containing ( 3⁄4 atomic atom, dC 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, Any one, two or three substituted thienyl groups including a thiol group or an ethylthio group; 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 Any one, two or three substituted pyrrolyl groups including a amide group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group; CrC6的烷酰基； 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 d- 的烷酰基； C2-C6的烯酰基； 含有 包括面素原子、 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的炔酰基； 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 C2-C6的炔酰 基； C3-C6的环烷酰基； 含有包括面素原子、 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， 0, S或者 NH; 或者 R4, R5, R6分别为:
Figure imgf000069_0001
其中 R9, R1()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、 d- 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 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 基； 吡咯基； 吡啶基； 含有包括! ¾素原子、 d-Ct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！ ¾素原子、 d-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 卤素原子、 c,-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的烷酰基； 含有包括! ¾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 c c6的烷酰基； c2-c6的 烯酰基； 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、 d-Ce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； 吡咯曱酰基； |为((：¾)11, n为 0-2， 0, S或 者 NH时；； X2为（CH2)n， n为 0-2 , 0, S或者 NH; 或者 R4, R5 , 1 6分别为：
Figure imgf000070_0001
C r C 6 alkanoyl; comprising comprising! Any one, two or three substituted d-alkanoyl groups of a 3 atomic atom, a C 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; containing a surface atom including C, - any C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a containing element comprises a ¾ atoms, the alkoxy -C6! Any one, two or three substituted C 2 -C 6 alkynyl groups such as an oxy group or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; an alkoxy group or a hydroxyl group including a surface element atom, dC 6 Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene Decanoyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; Or R 4 , R 5 , R 6 are:
Figure imgf000069_0001
Wherein R 9 and R 1() are each independently a substituent of any of the following: H; an alkyl group of C r C 6 ; any one or two of the group consisting of a prime atom, an alkoxy group of d- or a hydroxyl group. the three substituted dC 6 alkyl; C 2 -C 6 alkenyl group of; includes any halogen atom-containing C, C r C 6 alkoxy or hydroxy, including one, two or three substituents of 2 - An alkenyl group of C 6 ; a C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 groups containing an alkoxy group including a pertinar atom, C, or C 6 or a hydroxyl group; Alkynyl; C 3 -C 6 cycloalkyl; 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; Benzyl; furyl; pyranyl; thiol; pyrrolyl; pyridyl; containing alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide groups, carbonamide group, a sulfur group, Yue thio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, dC 4 alkyl 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 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. Furanyl; contains included! Any one, two or three of a 3 atom atom, a dC 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 substituted pyranyl group; 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 thiol group, an ethyl thio group Any one, two or three substituted thienyl groups; Any one or two of a halogen atom, an alkyl group of c, -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, or an ethylthio group. two or three substituents pyrrolyl; C r C 6 alkanoyl;! ¾ element comprising optionally containing atoms, C alkoxy or hydroxy group including one, two or three substituents cc of 6 alkanoyl; An alkenoyl group of c 2 -c 6 ; an enoyl group having any one, two or three substituted c 2 -c 6 groups including a [3⁄4 atomic atom, an alkoxy group of d- or a hydroxyl group; c 2 -c 6 alkynyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a prime atom, an alkoxy group of d-Ce or a hydroxyl group; adamantyl decanoyl group, substituted adamantyl decanoyl group; aroyl group ; benzoyl; Yue furyl group; Yue-pyran group; Yue thienyl group; pyrrolidin Yue group; | is ((: ¾) 11, n is 0-2 0, S or NH ;; X 2 is (CH 2) n, n is 0-2, 0, S or NH; or R 4, R 5, 1 6 are:
Figure imgf000070_0001
 其中 RH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-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、 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、 -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、 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、 -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； 含有包括面素原子、 - 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 者三个取代的吡喃基； 含有包括！ ¾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! ¾素原子、 C,-C4 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯 基、 甲疏基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； Cr 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的浠酰基； 含有 包括! ¾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! ¾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、 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 R4， R5, R6分别为： 其中 R12 , Rl 3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、 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 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、 C,-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-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、 -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、 -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、 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 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 代的吡咯基； CrC6的烷酰基； 含有包括 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 C,-C6的烷酰基； （ 2-( 6的 烯酰基； 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 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（( )11， n为 0-2， 0, S或 者 NH时； X2为（CH2)„, n为 0-2, 0, S或者 NH; 当 R, , R2， R3分别为：
Figure imgf000073_0001
Wherein RH is any one of the following substituents: H; an alkyl group of dC 6 ; an alkyl group containing any one, two or three substituted d- groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C 2 -C 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; contains included! ¾ any prime atoms, alkoxy or hydroxy CrC 6, including one, two or three substituents alkynyl of C 2 -C 6; C 3 -C 6 cycloalkyl; comprising comprising halogen atoms, C Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as alkoxy or hydroxy groups of r C 6 ; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl ; pyridyl; containing alkane, -C 4 alkyl, nitro, carboxy, aldehyde, alkoxy, amine, acyl Any one, two or three substituted aryl groups including an amine group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, or an aldehyde group Any one, two or three substituted pyridyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, -C4 Any one, two or three substituted furanyl 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, and an ethylthio group; Any one, two or three of a facet 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 Substituted pyranyl; contains included! Any one or two of a 3 atomic atom, an alkyl group of a 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 thienyl group; containing an alkyl group including a ? 3⁄4 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, a fluorenyl group, a methyl group Any one, two or three substituted pyrrolyl groups such as an ethylthio group; an alkanoyl group of C r C 6 ; any one or two containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a three-substituted C r C 6 alkanoyl group; a C 2 -C 6 decanoyl group; any one, two or three substituted Cs containing a ? 3⁄4 atom, a dC 6 alkoxy group or a hydroxyl group; 2- C6 alkenoyl; C 2 -C 6 alkynyl; any one, two or three substituted c 2 -c 6 containing a 3⁄4 atom, dC 6 alkoxy or hydroxy group Alkynyl; c 3 -c 6 cycloalkanoyl; any one or two containing a gas atom, alkoxy group of CC 6 or a hydroxyl group Or a three-substituted c 3 -c 6 cycloalkanoyl group; an adamantyl decanoyl group, a substituted adamantyl decanoyl group; an aroyl group; a benzyl group; a furanoyl group; a pyranoyl group; a thiophene acyl group; a pyrrolidinyl group; 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 4 , R 5 , R 6 are: Wherein R 12 and R l 3 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; or any one or two including a ? 3⁄4 atom, (C 6 alkoxy group or hydroxyl group) a three-substituted C r C 6 alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 - including a halogen atom, an alkoxy group of d- or a hydroxyl group. Alkenyl group of C 6 ; C 2 -C 6 alkynyl group; any one, two or three substituted C 2 -C 6 alkyne containing a halogen atom, an alkoxy group of C r C 6 or a hydroxyl group group; C r 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 r C 6 cycloalkyl; aryl Benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, C, -C4, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one, two or three substituted aryl groups, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; containing a halogen atom, dC Any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio 4, including one, two or three substituents pyridine Any one containing 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 carboxamide group, a fluorenyl group, an anthracenyl group, an ethylthio group, or the like. , two or three substituted furyl groups; containing a halogen atom, an alkyl group of -C4, 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 pyranyl groups including an ethylthio 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 carbon Any one, two or three substituted thienyl groups including an amide 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, an aldehyde group, an alkane Oxyl, amine, amide, carboxamide, hydrazine , Yue thio, ethylthio, including any one, two or three substituents pyrrolyl; CrC 6 alkanoyl; comprising pigment containing atoms, C, -C 6 alkoxy or Any one, two or three substituted C,-C 6 alkanoyl groups including a hydroxyl group; ( 2- ( 6 enoyl group; any one containing a sulfonate atom, a dC 6 alkoxy group or a hydroxyl group) , two or three substituted c 2 -c 6 enoyl groups; c 2 -c 6 alkynyl group; any one or two containing an alkoxy group including a halogen atom, c r c 6 or a hydroxyl group or a three-substituted C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkanoyl group; any one, two or three containing an alkoxy group including a ?3⁄4 atom, c r c 6 or a hydroxyl group; a substituted cycloalkyl group c 3 -c 6; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; furoyl; Yue-pyran group; Yue thienyl group; pyrrolidin Yue group; | is ( ( ) 11 , when n is 0-2, 0, S or NH; X 2 is (CH 2 ) „, n is 0-2, 0, S or NH; when R, R 2 , R 3 are:
Figure imgf000073_0001
 其中 R14, R15各自独立为下列任意一种取代基： H; d-C6的烷基； 含有包括卤素原子、 Ci-C6的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C C6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； 2-( 6的炔基； 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； 含有包括面素原子、 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芳基； 含有包括！ ¾素原子、 （^-( 4的烷基、 硝 基、 羧基、 醛基、 垸氧基、 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、 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、 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、 C,-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； 含有包括面素原子、 -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、 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 CrC6的炔酰基； CrC6的环烷酰基； 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 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(( 1¾)11, n为 0-2， O, S或 者 NH时； X2为（CH2)n, n为 0-2， 0, S或者 NH时； 4, R5, R6分别为：
Figure imgf000074_0001
Wherein R 14 and 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 including a halogen atom, Ci-C 6 or a hydroxyl group; Substituted alkyl group of CC 6 ; C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 olefins including a sulfonate atom, alkoxy group of dC 6 or a hydroxyl group group; 2- (6 alkynyl group; a halogen atom includes any containing, C, -C 6 alkoxy or hydroxy, including 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 3 -C 6 cycloalkyl; aryl; benzyl a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; a pyridyl group; an alkyl group including a surface atom, d-, a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted aryl groups including a sulfhydryl group, a thiol group, an ethylthio group, and a aryl group including a ^ 3⁄4 atom, (^-( 4 ) Alkyl, nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, Any one, two or three substituted pyridyl groups including an ethylthio group; containing an alkyl group including a halogen atom, -C4, 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 furanyl groups including a thiol group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C r C 4 , a nitro group, a carboxyl group, a ketone 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 fluorenyl group, a thiol group, and an ethylthio group; and an alkyl group including a halogen atom and d-C4; 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, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, and an ethylthio group. Or a three-substituted pyrrolyl group; - an alkanoyl group; Surface comprising atom, an alkoxy or hydroxy arbitrary -C 6 including one, two or three of d- substituted 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 such as a hydroxyl group; a C 2 -C 6 alkynyl group; or any one containing a halogen atom, an alkoxy group or a hydroxyl group , two or three substituents of C r C 6 alkynyl group; a C r C 6 cycloalkyl group; includes any pigment containing atoms, alkoxy or hydroxy dC 6, including one, two or three substituents the 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 ((1¾ 11 , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; 4, R 5 , R 6 are:
Figure imgf000074_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- 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 8 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen-containing include Any one, two or three substituted atoms such as an atom, d-alkoxy or hydroxy group CrC6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 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！ ¾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、 d-Ct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、 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! ¾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! ¾素原子、 d-Cj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、 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噻吩基；含有包括！ ¾素原子、 C,-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；C r C 6 alkyl; C 2 -C 6 alkenyl group; and one, two or three substituents include a halogen atom contain any, the CC 6 alkoxy or hydroxy, including a c 2 -c 6 alkenyl of groups; C 2 -c 6 alkynyl group; a! ¾ containing pigment comprising atoms, alkoxy or hydroxy CrC 6 including any one, two or three substituents a C 2 -C 6 alkynyl group; C 3 -C 6 cycloalkyl; contains included! Any one, two or three substituted C 3 -C 6 cycloalkyl groups of a 3 atomic 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; pyridyl; containing alkane, d-Ct alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio Any one, two or three substituted aryl groups; containing 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 carboxamide group, Any one, two or three substituted pyridyl groups including a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, Any one, two or three substituted furyl 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 ?3⁄4 atom, d-Cj, and a nitrate Base, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, hydrazine Any one, two or three substituted pyranyl groups including a thiol group or an ethylthio group; and a aryl group, a dC^ alkyl group, 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; Any one of a C, a C, a 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 fluorenyl group, a thiol group, or an ethyl thio group. Two or three substituted pyrrolyl groups; C,-C6的烷酰基； 含有包括！ ¾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 Ci-C6的烷酰基； c2-c6的烯酰基； 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 C2-C6的烯酰基； C2-C6的炔酰基； 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， 0， S或者 NH; 或者 R4, R5， R6分别为：
Figure imgf000076_0001
C,-C 6 alkanoyl; contains included! Any one, two or three substituted Ci-C 6 alkanoyl groups of a C atom, a C alkoxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; and an alkane including a pertinar atom, d- Any one, two or three substituted C 2 -C 6 alkenoyl groups such as an oxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; containing a ? 3⁄4 atom, 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 cycloalkanoyl; containing alkoxy groups including a halogen atom, CC 6 or Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; Thiophenanthryl; pyrrolidinyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000076_0001
 其中 R9， R1Q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、 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、 - 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 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、 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 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、 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、 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、 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、 C 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- 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-Qs的烷酰基； 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 d- 的烷酰基； C2-C6的 烯酰基； 含有包括 [¾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的晞酰基； 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； 1为(( ¾)11， n为 0-2, O, S或 者 NH时； X2为（CH2)n, n为 0-2, 0, S或者 NH; 或者 R4, R5, 1 6分别为：
Figure imgf000077_0001
Wherein R 9, R 1Q are each independently any of the following substituents:! H; dC 6 alkyl; containing pigment include ¾ atoms, C r C 6 alkoxy or hydroxy, including any one, two or a three-substituted-C 6 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 or a hydroxyl group; Alkenyl; ( 2- ( 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a pertiny atom, a C 6 alkoxy group or a hydroxyl group; C a 3- C 6 cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a C alkoxy group or a hydroxyl group; an aryl group; a benzyl group ; furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkane, CrC 4 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; an alkyl group including a halogen atom, d-C4, 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, 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 furyl group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, and an alkane Any one, two or three substituted pyranyl groups including an oxy group, an amine group, an amide group, a carboxamide group, a decyl group, a thiol group, an ethylthio group; an alkyl group including a sulfonate atom, C C4; 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, 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 pyrrolyl; d-Qs alkanoyl; contains included! Any one, two or three substituted d-alkanoyl groups of a 3 atomic atom, a d-alkoxy group or a hydroxyl group; a C 2 -C 6 alkenoyl group; containing a [3⁄4 atomic atom, dC 6 Any one, two or three substituted C 2 -C 6 decanoyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing an alkoxy group including a halogen atom, C r C 6 or Any one, two or three substituted C 2 -C 6 alkynyl groups including a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; an alkoxy group or a hydroxyl group containing a 3⁄4 atom atom, C r C 6 atom Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene Decanoyl; pyrrolyl acyl; 1 is (( 3⁄4) 11 , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; R 4 , R 5 , and 16 are respectively:
Figure imgf000077_0001
 其中 Ru为下列任意一种取代基： H; CrC6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- 的烷基； C2-C6的烯基； 含有包括! ¾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、 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、 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 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 三个取代的芳基； 含有包括 素原子、 C 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 [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呋喃基； 含有包括！ ¾素原子、 C 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、 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、 c,-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、 -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 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的烯酰基； C2-C6的炔酰基； 含有包括 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 吩曱酰基； 吡咯曱酰基； X2为（CH2)n, n为 0-2， O, S或者 NH; 或者 R4， R5, 分别为:
Figure imgf000079_0001
Wherein R u is any of the following substituents:. H; C r C 6 alkyl; and optionally containing a hydroxyl group or an alkoxy group include a halogen atom, -C 6 the inner one, two or three substituents of d An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a 3⁄4 atom atom, a dC 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; containing any one or two including a [3⁄4 atom, an alkoxy group or a hydroxyl group of d- or a three-substituted c 2 -c 6 alkynyl group; a c 3 -c 6 cycloalkyl group; any one, two or three containing an alkoxy group including a halogen atom, c, -c 6 or a hydroxyl group; Substituted c 3 -c 6 cycloalkyl; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkane, -C 4 alkyl, nitro, carboxy Any one, two or three substituted aryl 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; Any one, two or three substituted pyridyl groups including 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, and an ethylthio group. Containing any one of [ 3⁄4 atom, CrC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio) , two or three substituted furanyl; contains included! Any one or two of a 3 atomic atom, a C C4 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, or a three-substituted pyranyl 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 methylthio group, an ethylthio group Any one, two or three substituted thienyl groups; 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, a carbon amide Any one, two or three substituted pyrrolyl groups including a thiol group, a thiol group, an ethylthio group; an alkanoyl group; or an alkoxy group including a halogen atom, -C 6 or a hydroxyl group; , two or three substituted -C 6 alkanoyl; C 2 -C 6 alkenoyl; any one, two or three substitutions including a prime atom, an alkoxy group of d-Cs or a hydroxyl group a C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group; a containing element comprises atoms, C Alkoxy or hydroxy, including any one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 -C 6; comprising comprising! Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, an alkoxy group of a CrC 6 or a hydroxyl group; an adamantyl formyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furanoyl; pyranoyl; thio Phenyl; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 4 , R 5 are respectively:
Figure imgf000079_0001
 其中 R12， R13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、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 C,-C6的烷基； C2-C6的烯基； 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、 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、 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、 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、 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 [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、 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 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； 含有包括面素原子、 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、 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； 噻吩曱酰基； 吡咯曱酰基； 1为（( )11, n为 0-2, O, S或 者 NH时； X2为（CH2)n, n为 0-2, 0， S或者 NH; 当 R,， R2, R3为：
Figure imgf000080_0001
其中 Rl6为下列任意一种取代基： H; d-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 C 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！ 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、 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！ 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、 -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 素原子、 c,-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 |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、 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、 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 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,-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! ¾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； 吡咯曱酰基； 1为((：¾)11, n为 0-2， 0， S或者 NH时； R4, R5, 分别为：
Figure imgf000081_0001
其中 R8为下列任意一种取代基： H; -C6的烷基； 含有包括卤素 原子、 d-Qs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、 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的浠基； C2-C6的炔基； 含有包括! ¾素原子、 0( 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! ¾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 [¾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啶基； 含有包括 [¾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 [¾素原子、 C C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 曱石克基、 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； d- 的烷酰基； 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 -C6的烷酰基； C2-C6的烯酰基； 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的烯酰基； c2-c6的炔酰基； 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； 吡咯曱酰基； X2为 (CH2)n， n为 0-2, O, S或者 NH; 或者 R4， R5, R6分别为：
Figure imgf000083_0001
Wherein R 12 and R 13 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; C,-C 6 alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 - including a 3⁄4 atom, a C 6 alkoxy group or a hydroxyl group C 6 alkenyl; C 6 alkynyl, C R < 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 group of a C 3 -C 6 cycloalkyl group; any one, two or three substituted C r C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; comprising pigment containing atoms, CrC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group 4 Any one, two or three substituted aryl groups, a fluorenyl group, a thiol group, an ethylthio group; an alkane including a halogen atom, d-C4 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 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 ethylthio group, or a three-substituted furanyl group; an alkyl group including a ? 3⁄4 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, a thiol group, an ethyl sulphide group Any one, two or three substituted pyranyl groups, including a group of [ 3⁄4 atomic atoms, CrC 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carbon Any one, two or three substituted thienyl groups including an amide group, a fluorenyl group, a thiol group, an ethylthio group; Any one or two of a halogen atom, an alkyl group of C-C4, 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 three substituted pyrrolyl; CrC 6 alkanoyl; includes any pigment containing atoms, alkoxy or hydroxy -C6 inner one, two or three substituents of C r C 6 alkanoyl; C 2 - An alkenoyl group of C 6 ; any one, two or three substituted C 2 -C 6 alkenoyl groups including a surface atom, C,-C 6 alkoxy group or a hydroxyl group; C 2 -C 6 Alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a C 3 -C 6 cycloalkanoyl group; include! Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, a d-alkoxy group or a hydroxyl group; an adamantyl formyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; 1 is (( ) 11 , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; when R, R 2 , R 3 are:
Figure imgf000080_0001
Wherein R l6 is any one of the following substituents: H; an alkyl group of dC 6 ; an alkyl group containing any one, two or three substituted C C6 groups including a halogen atom, an alkoxy group of C6 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; a C 2 -C 6 alkyne; Base; contains included! ¾ atom, R & lt any C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl; include a halogen atom-containing Any one, two or three substituted C 3 -C 6 cycloalkyl groups of C-C6 alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; thienyl; pyrrole Base; pyridyl; contains included! ¾ prime atoms, C r C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, acyl Any one, two or three substituted aryl groups including an amine 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, or an aldehyde group Any one, two or three substituted pyridyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; and an alkane including a halogen atom, -C 4 Any one, two or three substituted furanyl 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, and an ethylthio group; 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, which includes a sulfhydryl atom, c, or c 4 , Two or three substituted pyranyl groups; containing an alkyl group including a | 3⁄4 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, Any one, two or three substitutions including thiol and ethylthio a thienyl 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted pyrrolyl groups; dc 6 alkanoyl group; any one, two or three substituted groups including a halogen atom, c, -c 6 alkoxy group or a hydroxyl group An alkanoyl group of c r c 6 ; an alkenoyl group of c 2 -c 6 ; any one, two or three substituted c 2 -c 6 containing an alkoxy group including a prime atom, c r c 6 or a hydroxyl group ; Alkenoyl; c 2 -c 6 alkynyl; any one, two or three substituted c 2 -c 6 venyl groups containing a halogen atom, c, -c 6 alkoxy group or hydroxyl group a C 3 -C 6 cycloalkanoyl group; a cycloalkanoyl group having any one, two or three substituted c r c 6 groups including a 3⁄4 atom atom, an alkoxy group of dC 6 or a hydroxyl group; adamantane Decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene acyl; pyrrolidinyl ; 1 is ((: 3⁄4) 11 , n is 0-2, 0, S or NH; R 4 , R 5 , respectively:
Figure imgf000081_0001
Wherein R 8 is any one of the following substituents: H; -C 6 alkyl; an alkane containing any one, two or three substituted C groups including a halogen atom, an alkoxy group of d-Qs or a hydroxyl group. a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 fluorenyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C 2 -C 6 alkynyl group; comprising comprising ¾ atom, any 0 (6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a! C 3 -C 6 cycloalkyl of 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 thiophenyl 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, a thiol group Any one, two or three substituted aryl groups, including an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, Any group, an alkoxy group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two, three or substituted pyridyl; comprising comprising [¾ prime atom, dC 4 Any one, two or three substituted furan groups including 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. Containing any one of [ 3⁄4 atomic atom, CC 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, fluorenyl group, ethyl thio group) , two or three substituted pyranyl groups; 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, a carboxamide group, a fluorenyl group, Any one, two or three substituted thienyl groups including a methylthio group, 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 , amide group, carboxamide group, sulfhydryl group, sulfonium group, ethyl thio group Any one, two or three substituted pyrrol groups; d-alkanoyl; any one, two or three substituted -C containing a ? 3⁄4 atom, a C C6 alkoxy group or a hydroxyl group 6 alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy group including one, two or three Substituted c 2 -c 6 alkenyl group; a c 2 -c 6 alkynyl group; a pigment contain any atoms including, R & lt c c 6 alkoxy or hydroxy, including one, two or three substituents c-2 -c 6 alkynyl; C 3 -C 6 cycloalkanoyl; any one, two or three substituted C 3 -C 6 ring containing a prime atom, an alkoxy group of CrC 6 or a hydroxyl group Alkanoyl; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; X 2 is (CH 2 ) n , n is 0- 2, O, S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000083_0001
 其中 R9, RIQ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、 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 -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； 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 素原子、 d-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、 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、 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、 -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! ¾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、 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 代的吡咯基； CrC6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 - 的烷酰基； C2-C6的 烯酰基； 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 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、 -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； 1为((： )11， n为 0-2, 0， S或 者 NH时； X2为（CH2)n， n为 0-2， 0, S或者 NH; 或者 R4， R5, ^分别为：
Figure imgf000084_0001
Wherein R 9 and R IQ are each independently one of the following substituents: H; dC 6 alkyl; ¾ prime atoms, alkoxy or hydroxy dC 6 including any one, two or three of the substituents -C 6 alkyl; C 2 -C 6 alkenyl group; a halogen atom include containing, C r C 6 Any one, two or three substituted C 2 -C 6 alkenyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; alkoxy group containing a halogen atom, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups, or a C 3 -C 6 cycloalkyl group; or an alkoxy group or a hydroxyl group including a halogen atom, C, -C 6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one, two or three substituted alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio group of dC* aryl; include a halogen atom-containing, dC alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto 4 Any one, two or three substituted pyridyl groups including a thiol group and an ethylthio group; 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 Any one, two or three substitutions of a base, a carboxamide group, a thiol group, a methylthio group, an ethylthio group a furanyl group; optionally containing a halogen atom, an alkyl group of -C4, 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 One, two or three substituted pyranyl groups; containing an alkyl group including a 3⁄4 atom, d-C4, 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 and an ethylthio group; containing an alkyl group including a halogen atom, a nitro group, a carboxyl group, a 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 sulfonium group, an ethylthio group; an alkanoyl group of CrC 6 ; an alkoxy group containing a C 3 C atom; C r C 6 Or any one, two or three substituted alkanoyl groups, or a C 2 -C 6 alkenoyl group; or any one or two, including a gas atom, a d- alkoxy group or a hydroxyl group; three or substituted C 2 -C 6 alkenyl group; a C 2 -C 6 alkynyl group of Contain any halogen atom include, d- alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkynyl group of; C 3 -C 6 cycloalkyl group; comprising including atom, 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; 1 is ((: ) 11 , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , n is 0- 2, 0, S or NH; or R 4 , R 5 , ^ are:
Figure imgf000084_0001
 其中 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 (：,-( 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、 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 |¾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 三个取代的芳基； 含有包括！ ¾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、 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、 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、 S荃基、 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! ¾素原子、 C,-C4 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咯基； CrC6的烷酰基； 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 c,-c6的烷酰基； c2-c6的烯酰基； 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 c2-c6的烯酰基; c2-c6的炔酰基; 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的炔酰 基； C3-C6的环烷酰基； 含有包括! ¾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、 取代金刚烷曱酰基； 芳酰基； 苄酰基； 呋喃曱酰基； 吡喃曱酰基; 吩曱酰基； 吡咯曱酰基； X2为（CH2)n， n为 0-2, 0， S或者 NH; 或者 R4, R5， 1 6分别为:
Figure imgf000086_0001
Wherein is any one of the following substituents: H; an alkyl group of dC 6 ; any one, two or three substituted (:, - ( 6 ) containing a halogen atom, an alkoxy group of d- 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 of CrC 6 or a hydroxyl group; C 2 - Alkynyl group of C 6 ; Any one, two or three substituted C 2 -C 6 alkynyl groups containing an alkoxy group or a hydroxyl group including a C atom, C, -C 6 ; a C 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 furyl group; a pyranyl group; a thienyl group ; pyrrolyl; pyridyl; containing an alkyl group including a ?3⁄4 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, a thiol group, an ethane group Any one, two or three substituted aryl groups, including the base; Any one, two or three of a 3 atomic 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 substituted pyridyl 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, and the like. Any one, two or three substituted furanyl groups; containing an alkyl group including a prime 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 pyranyl groups including a thiol group; an alkyl group including a halogen atom, - a nitro group, a carboxy group, an alkyl group, an alkoxy group, an amine group, an amide group Any one, two or three substituted thienyl groups, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, C, -C 4 , a nitro group, a carboxyl group , aldehyde group, alkoxy group, amine group, amide group, carboxamide group, Any thiol, Yue thio, ethylthio, including one, two or three substituents pyrrolyl; C r C 6 alkanoyl; comprising comprising! ¾ atom, any CC 6 alkoxy or hydroxy, including one, two or three substituents of C, -C 6 alkanoyl; C 2 -C 6 alkenyl group; comprising comprising ¾ atom,! any -C 6 alkoxy or hydroxy inner one, two or three substituents of c 2 -c 6 alkenyl group; a c 2 -c 6 alkynyl group; a halogen atom include containing, c, -c 6 Any one, two or three substituted c 2 -c 6 alkynyl groups such as alkoxy or hydroxy; C 3 -C 6 cycloalkanoyl; alkoxy containing a ? 3⁄4 atom, dC 6 Any one, two or three substituted c 3 -c 6 cycloalkanoyl groups; adamantyl decanoyl group, Substituting adamantyl decanoyl; aroyl; benzyl; furanoyl; pyranoyl; fenyl; pyrrolyl; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; Or R 4 , R 5 , and 16 are:
Figure imgf000086_0001
 其中 Rl2, R13各自独立为下列任意一种取代基： H; CrC6的烷基； 含有包括！ ¾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 C2-C6的烯基； C2-C6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 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！ ¾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-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、 C 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噻吩基； 含有包括 卤素原子、 d-Ct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,-C6的烷酰基； 含有包括! ¾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-C^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 C2-C6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 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； 吡咯曱酰基； 1为(0¾)11, n为 0-2 , 0, S或 者 NH时； X2为（CH2)n, n为 0-2 , 0, S或者 NH; 当 R R2， R3为：
Figure imgf000087_0001
Wherein R l2, R 13 are each independently any of the following substituent groups: H; C r C 6 alkyl group; comprising comprising! Any one, two or three substituted C r C 6 alkyl groups of a C atom, a C alkoxy group or a hydroxyl group; a C 2 -C 6 alkenyl group; containing a halogen atom, C, -C any of the 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, d- alkoxy or Any one, two or three substituted C 2 -C 6 alkynyl groups including a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group or a hydroxyl group including a halogen atom, C r C 6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one or two of a 3⁄4 atom, an alkyl group of -C4, 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 aryl 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 ethylthio group Any one, two or three substituted pyridyl groups; containing an alkyl group including a halogen atom, dC; 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 furanyl groups including a thiol group or an ethylthio 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 Any one, two or three substituted pyranyl groups including a carbaryl group, a fluorenyl group, a thiol group, an ethylthio group; an alkyl group including a halogen atom, C C4, a nitro group, a carboxyl group, and a phenyl group , alkoxy, amine, amide, carbon amide , A mercapto group, a sulfur Yue Any one, two or three substituted thienyl groups including a thiol group; an alkyl group including a halogen atom, d-Ct, 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, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; a C,-C 6 alkanoyl group; and an alkane including a ?3⁄4 atom, dC 6 Any one, two or three substituted dC^ alkanoyl groups such as an oxy group or a hydroxyl group; a c 2 -c 6 alkenoyl group; or any one containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group , two or three substituted c 2 -c 6 enoyl groups; c 2 -c 6 alkynyl group; any one or two containing an alkoxy group including a halogen atom, c r c 6 or a hydroxyl group or a three-substituted C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkanoyl group; any one, two or three groups including a ? 3⁄4 atom, an -C 6 alkoxy group or a hydroxyl group; c substituted cycloalkyl group of 3 -c 6; Yue group adamantane, substituted adamantane Yue group; an aryl group; a benzyl group; Yue acyl furans; Yue-pyran group; Yue thienyl group; Yue-pyrrolo acyl; 1 (0¾) 11, n is 0-2, 0, S or NH; X 2 is (CH 2) n, n is 0- 2, 0, S or NH; when RR 2 , R 3 are:
Figure imgf000087_0001
 其中 R17 , R18各自独立为下列任意一种取代基： H; d-C6的烷基； 含有包括面素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者 三个取代的 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的烯基； C2-C6的炔基； 含有包括 1¾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 CrC6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括鹵素原子、 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、 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、 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- 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； 含有包括面素原子、 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！ ¾素原子、 d-Ce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 C2-C6的炔酰基； CrC6的环烷酰基； 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 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； 吡咯曱酰基； |为（( )11, n为 0-2， 0, S或 者 NH时； X2为（CH2)n， n为 0-2， 0, S或者 NH时， R4, R5, 分别为:
Figure imgf000089_0001
Wherein R 17 and R 18 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three substitutions including a surface atom, an alkoxy group of d- or a hydroxyl 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; Alkenyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group containing a 13⁄4 atom, d-alkoxy or hydroxy; 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 group; containing any one of a halogen atom, an alkyl group of C4, 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; atoms containing pigment include, CrC 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue, b Any one, two or three substituted pyridyl groups including a thio group; 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 Any one, two or three substituted furanyl groups including a mercapto group, an anthracenethio group, 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 Any one, two or three substituted pyranyl groups, an amine group, an amide group, a carboxamide group, a fluorenyl group, a thiol group, an ethylthio group; and an alkane including a [ 3⁄4 atom, d-C 4 Base, nitro, carboxyl, aldehyde, alkoxy, amine Any one, two or three substituted thienyl groups, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde Any one, two or three substituted pyrrolyl groups including a group, 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 dC 6 ; Any one, two or three substituted dC 6 alkanoyl groups, such as alkoxy, dC 6 alkoxy or hydroxy; c 2 -c 6 enoyl; Any one, two or three substituted C 2 -C 6 alkenoyl groups of a 3 atomic atom, a d-Ce alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; containing a halogen atom, d Any one, two or three substituted C 2 -C 6 alkynyl groups including alkoxy or hydroxy; C r C 6 cycloalkanoyl; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, a d-alkoxy group or a hydroxyl group; an adamantyl decanoyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; | is (( ) 11 , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH, R 4 , R 5 , are:
Figure imgf000089_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- 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 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的烯基； C2-C6的炔基； 含有包括面素原子、 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、 （ 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！ ¾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 [¾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啶基； 含有包括 [¾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 素原子、 d-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 者三个取代的吡喃基； 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噻吩基；含有包括 素原子、 c,-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； -C6的烷酰基； 含有包括 1¾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! 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的烯酰基； C2-C6的炔酰基； 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的炔酰 基； CrC6的环烷酰基； 含有包括面素原子、 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， 0， S或者 NH; 或者 R4， R5, R6分别为：
Figure imgf000090_0001
Wherein R 8 is any of the following substituent groups: H; C r C 6 alkyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy group including one, two or three alkoxy substituted C a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl groups including a prime atom, an alkoxy group of CC 6 or a hydroxyl group; C 2 -C 6 alkynyl group; contain any pigment surface comprising atom, d- alkoxy or hydroxy group including one, two or three substituents of C 2 -C 6 alkynyl group; a C 3 -C 6 cycloalkyl group of Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, (C6 alkoxy group or hydroxyl group; aryl group; benzyl group; furyl group; pyranyl group; a thiophenyl group; a pyrrolyl 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, a thiol group, an ethyl sulfide Any one, two or three substituted aryl groups, including [3⁄4 atom, (C4 alkyl, nitro, carboxyl) Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including one, two, three or substituted pyridyl; comprising comprising [¾ prime atoms, dC Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, sulfonyl, ethylthio Any one containing a single atom, a d-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, a thiol group, or an ethylthio group. Two or three substituted pyranyl groups; containing an alkyl group, a d-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, Any one, two or three substituted thienyl groups including an ethylthio group; an alkyl group including a pertinar atom, c, -c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Any one of a carboxamide group, a sulfhydryl group, a sulfonium group, and an ethylthio group. , Two or three substituents pyrrolyl; -C 6 alkanoyl; optionally containing pigment comprising 1¾ 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 ;! ¾ comprise any pigment containing atoms, -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 ! ¾ atom, R & lt any C C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a C cycloalkyl group C 6 R < a pigment-containing surface comprising atom Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of d-alkoxy or hydroxy; adamantyl decanoyl, substituted adamantyl decanoyl; aroyl; benzyl; furan Decanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 4 , R 5 , R 6 are:
Figure imgf000090_0001
 其中 R9， R1()各自独立为下列任意一种取代基： H; d-Cs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、 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! 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、 -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、 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、 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、 -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、 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、 C 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； 含有包括面素原子、 - 的烷氧基或 羟基在内的任意一个、 两个或者三个取代的 d- 的烷酰基； C2-C6的 烯酰基； 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 C2-C6的烯酰基； C2-C6的炔酰基； 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； CrC6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； 1为（( ¾)11, n为 0-2, O, S或 者 NH时； X2为（CH2)n, n为 0-2, 0, S或者 NH; 或者 R4, R5， R6分别为：
Figure imgf000091_0001
Wherein R 9 and R 1() are each independently a substituent of any of the following: H; an alkyl group of d-Cs; any one, two or three containing an alkoxy group including a prime atom, d- or a hydroxyl group. a substituted C r C 6 alkyl; C 2 -C 6 alkenyl group; a, any two or three substituents include a halogen atom-containing, C r C 6 alkoxy or hydroxy C 2, including the -C 6 thiol; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 containing a 3⁄4 atom, an CrC 6 alkoxy group or a hydroxyl group Alkynyl; C 3 -C 6 cycloalkyl; 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; Aryl; benzyl; furanyl; pyranyl; thioxyl; pyrrolyl; pyridyl; containing alkyl, nitro, carboxyl, aldehyde, alkoxy, amino group including a prime atom, C r C 4 , amide groups, carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three aryl group substituents; containing a halogen atom include, dC 4 of , Nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, thio Yue, Any one, two or three substituted pyridyl groups including an alkyl group; an alkyl group including a halogen atom, -C4, 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 furanyl groups including a thiol group, a thiol group, 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 any group, an amine group, an amide group, a carbonamide group, a mercapto group, Yue thio, ethylthio, including one, two or three of the substituents pyranyl; comprising pigment containing atoms, CC 4 alkyl, nitro Any one, two or three substituted thienyl 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; , c r c any alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three a substituted pyrrolyl; CrC 6 alkanoyl; comprising Surface comprising atom, - alkoxy or hydroxy arbitrary, including one, two or three of d- substituted alkanoyl; C 2 -C 6 alkenyl group; a comprises an alkoxy-containing atom, a d- Any one, two or three substituted C 2 -C 6 alkenoyl groups, or a C 2 -C 6 alkynyl group; or an alkoxy group including a halogen atom, d-Cs or a hydroxyl group any one, two or three substituents of C 2 -C 6 alkynyl group; a C cycloalkyl group C 6 R < a pigment contain any atoms including, d- alkoxy or hydroxy group including one, two, three or 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; Yue thienyl group; Yue-pyrrolo acyl; 1 Is (( 3⁄4) 11 , n is 0-2, O, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or NH; or R 4 , R 5 , R 6 They are:
Figure imgf000091_0001
 其中 Ru为下列任意一种取代基： H; d- 的烷基； 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 (^-( 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! 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 三个取代的芳基； 含有包括 (¾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! ¾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呋喃基； 含有包括！ ¾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 者三个取代的吡喃基； 含有包括 [¾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、 琉基、 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、 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-Ce的烷酰基； 含有包括 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 d- 的烷酰基； C2-C6的烯酰基； 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 C2-C6的烯酰基； C2-C6的炔酰基； 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的炔酰 基； C3-C6的环烷酰基； 含有包括！ ¾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 R4， R5， R6分别为：
Figure imgf000093_0001
Wherein R u is any one of the following substituents: H; d-alkyl; Any one, two or three substituted (^-( 6 alkyl; C 2 -C 6 alkenyl; containing halogen atom, C r C) including a halogen atom or a hydroxyl group of dC 6 Any one, two or three substituted C 2 -C 6 alkenyl groups of 6 alkoxy groups or hydroxyl groups; C 2 -C 6 alkynyl groups; alkoxy groups containing a halogen atom, C r C 6 Any one, two or three substituted C 2 -C 6 alkynyl groups including a hydroxyl group; a C 3 -C 6 cycloalkyl group; an alkoxy group or a hydroxyl group including a halogen atom, -C 6 Any one, two or three substituted C 3 -C 6 cycloalkyl groups; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; , any of a C r C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, Yue thio, ethylthio, including 4, two or three Substituted aryl; containing (3⁄4 atom, d-C4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, hydrazine Any one, two or three substituted pyridyl groups including a thiol group or an ethylthio group; containing an alkyl group including a ?3⁄4 atom, -C4, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted furanyl groups, an amide group, a carboxamide group, a fluorenyl group, a sulfonium group, an ethylthio group; an alkyl group including a ? 3⁄4 atom, an alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyranyl 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; 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 dC 4 a thienyl 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, a carboxamide group, a fluorenyl group, a thiol group, an ethyl thio group Any one, two or three substituted pyrrolyl groups; d-Ce alkanoyl Any one, two or three substituted d-alkanoyl groups including a pertinar atom, an alkoxy group of C C6 or a hydroxyl group; a C 2 -C 6 alkenoyl group; containing a [3⁄4 atom, Any one, two or three substituted C 2 -C 6 alkenoyl groups of C,-C 6 alkoxy or hydroxy; C 2 -C 6 alkynyl; containing a acene atom, 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 cycloalkanoyl; ¾ atom, an alkoxy or hydroxy dC any of 6, including one, two or three substituents of C 3 -C 6 cycloalkyl group; Yue group adamantane, substituted adamantane Yue group; an aryl group; benzyl Acyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl hydrazide; X 2 is (CH 2 ) n , n is 0-2, O, S or NH; or R 4 , R 5 , R 6 respectively for:
Figure imgf000093_0001
 其中 R12， R13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、 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-C6的烯基； 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 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、 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! ¾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、 0(：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； 含有包括卤素原子、 C 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^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； 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、 -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,-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！ 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 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； 吡咯曱酰基； ，为^！！ ， n为 0-2, 0, S或 者 NH时； X2为（CH2)n， n为 0-2， 0， S或者丽。 Wherein R 12 and R 13 are each independently a substituent of any of the following: H; an alkyl group of dC 6 ; any one, two or three substituted groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C r C 6 alkyl; C 2 -C 6 alkenyl group; and one, two or three substituents include a halogen atom-containing arbitrary, C r C 6 alkoxy or hydroxy, including a C 2 -C 6 alkenyl; C 6 alkynyl, C R < includes any containing a halogen atom, d- alkoxy or hydroxy group 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 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; a pyridyl group; 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 Any one, two or three substituted aryl groups including a fluorenyl group, an anthracenethio group, an ethylthio group; containing a 3⁄4 atom, dC 4 Any one, two or three substituted pyridyl groups including 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, and an ethylthio group. Containing any one including a halogen atom, an alkyl group of 0 (: 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) , two or three substituted furanyl groups; containing an alkyl group including a halogen atom, CrC4, a nitro group, a carboxyl group, an aldehyde group, an alkane Any one, two or three substituted pyranyl 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, CC 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, two or three of an atom, an alkyl group of a dC^, 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 pyrrolyl; D- alkanoyl; includes any containing [¾ prime atoms, C r C 6 alkoxy or hydroxy inner one, two or three substituents of C r C 6 alkanoyl; C 2- C6 alkenoyl; any one, two or three substituted C 2 -C 6 alkenoyl group including a halogen atom, a C 6 alkoxy group or a hydroxyl group; C 2 -C 6 An alkynyl group; an alkoxy group including a halogen atom, C, or 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 substituted C 3 -C 6 cycloalkanoyl groups of a 3 atomic atom, a d-alkoxy group or a hydroxyl group; an adamantyl decanoyl group, a substituted adamantyl decanoyl group; an aroyl group; Acyl; furanoyl; pyranoyl; thiophene acyl; pyrrolyl acyl; ! , n is 0-2, 0, S or NH; X 2 is (CH 2 ) n , n is 0-2, 0, S or Li. 3、 根据权利要求 1或 2任意一项所述的具有取代环戊烷结构的化 合物， 其特征在于当分子中存在几何异构体时， 所述化合物为各种单 独的几何异构体或者其混合物。 The compound having a substituted cyclopentane structure according to any one of claims 1 to 2, wherein when a geometric isomer is present in the molecule, the compound is a single geometric isomer or mixture. 4、 根据权利要求 1至 3任意一项所述的具有取代环戊烷结构的化 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 cyclopentane structure according to any one of claims 1 to 3, characterized in that when a chiral carbon is present in the molecule, the compound is a racemate or an optically active substance. 5、 椐权利要求 1至 4任意一项所述的具有取代环戊烷结构的化合 物的制备方法是通过如下步骤实施的: 5. A compound having a substituted cyclopentane structure according to any one of claims 1 to 4. The preparation method of the object is carried out by the following steps:
Figure imgf000095_0001
取氰化钠 （leq) 溶于适量的水中， 加入氯化铵 ( l.leq), 室温下 搅拌， 当氯化铵完全溶解后， 加入上述酮（leq) 的曱醇溶液。 反应温 度迅速上升， 继续搅拌 2 小时， 加水稀释， 用苯提取， 苯层用水洗， 用 6N盐酸提取氨基腈； 合并酸液， 回流 2 小时， 加水稀释， 减压蒸馏， 去除酮和其他的 挥发性物质； 加氨水调节 PH至弱碱性，冷却至室温，有黄色的晶体出现，过滤， 滤饼用少量的水洗， 然后用乙醚和 95%的热乙醇洗， 干燥得到氨基酸; 取上述氨基酸（ leq)溶于氢氧化钠溶液（ 1.25eq), 冷却至 30°C 以下， 同时滴加酰氯（ l.leq)和氢氧化钠溶液（2eq)， 始终维持反应 液呈弱碱性，滴加结束后继续搅拌 0.5小时，加浓盐酸调节 PH至酸性， 冷却， 过滤得到粗品， 用乙醇重结晶得到产物；
Figure imgf000095_0001
Sodium cyanide (leq) is dissolved in an appropriate amount of water, ammonium chloride (l.leq) is added, and stirred at room temperature. When ammonium chloride is completely dissolved, the above ketone (leq) sterol solution is added. The reaction temperature rises rapidly, stirring is continued for 2 hours, diluted with water, extracted with benzene, washed with benzene, washed with 6N hydrochloric acid, combined with acid solution, refluxed for 2 hours, diluted with water, distilled under reduced pressure, and ketone and other volatiles are removed. Adding ammonia to adjust the pH to weakly alkaline, cooling to room temperature, yellow crystals appear, filtering, filter cake washed with a small amount of water, then washed with ether and 95% hot ethanol, dried to obtain amino acids; Leq) dissolved in sodium hydroxide solution (1.25eq), cooled to below 30 °C, while adding acid chloride (l.leq) and sodium hydroxide solution (2eq), always keep the reaction solution weakly alkaline, the end of the addition After stirring for 0.5 hour, the pH was adjusted to be acidic by adding concentrated hydrochloric acid, cooled, and filtered to obtain a crude product which was recrystallized from ethanol to give a product;
Figure imgf000095_0002
取酮（0.67eq)溶于适量的乙醚和水中， 冰盐浴冷却； 加入氰化钠 ( 1.67eq), 剧烈搅拌； 当大部分的氰化钠全部溶解后且反应液温度降 至 5 °C以下，慢慢滴加适量的浓盐酸，维持反应温度在 5 °C到 10 °C之间； 滴加结束后， 移去冰浴， 同时剧烈搅拌 2 小时； 静置， 分离乙醚层， 将水层倒入反应瓶中， 加水溶解盐； 水层再用乙醚提取， 合并乙醚层， 蒸去乙醚； 将残余物倒入浓盐酸中， 并用氯化氢气体饱和， 放置过夜； 然后先用空气带走部分氯化氢气体， 再慢慢滴加 50 %氢氧化钠溶液调 节至碱性； 冰浴冷却， 用机械搅拌， 加入氢氧化钠固体（0.6eq )， 水蒸 汽蒸镏直至无多余的氨和酮； 加水稀释， 乙醚提取（弃去）； 水层用浓 盐酸酸化， 冷却， 过滤得到 α -羟基酸； 取 α -羟基酸（ 0.69eq )加入酰氯（ 0.69eq ), 水浴加热反应 , 冷却 析晶， 得产物；
Figure imgf000096_0001
Figure imgf000095_0002
The ketone (0.67 eq) was dissolved in an appropriate amount of diethyl ether and water, and cooled in an ice salt bath; sodium cyanide (1.67 eq) was added and stirred vigorously; when most of the sodium cyanide was dissolved and the temperature of the reaction solution was lowered To the temperature below 5 °C, slowly add appropriate amount of concentrated hydrochloric acid to maintain the reaction temperature between 5 °C and 10 °C. After the dropwise addition, remove the ice bath and vigorously stir for 2 hours. Allow to stand and separate the ether. Layer, the water layer is poured into the reaction flask, water is added to dissolve the salt; the aqueous layer is extracted with diethyl ether, and the ether layer is combined, and the ether is evaporated; the residue is poured into concentrated hydrochloric acid and saturated with hydrogen chloride gas, and left overnight; The air is taken away from part of the hydrogen chloride gas, and then slowly added with 50% sodium hydroxide solution to adjust to alkaline; cooled in an ice bath, mechanically stirred, added with sodium hydroxide solid (0.6 eq), steam evaporated until no excess ammonia And ketone; diluted with water, extracted with ether (discarded); aqueous layer was acidified with concentrated hydrochloric acid, cooled, filtered to give α-hydroxy acid; α-hydroxy acid (0.69 eq) was added to acid chloride (0.69 eq), heated in a water bath, cooled Crystallization, resulting in a product;
Figure imgf000096_0001
 在氮气保护下， 取 LDA ( 1.2mmol )溶于适量的四氢呋喃中， 冷却 至- 50°C , 慢慢滴加羧酸（ 0.5mmol ), 维持该温度继续搅拌 30分钟， 50°C继续搅拌 2小时； 用液氮 /曱醇浴冷却至 - 100°C , 滴加硝基取代的 玲烃 ( 1.5mmol ), 反应 5个小时， 反应液温度慢慢升至 0 - 10°C ; 加入 适量的 17 %稀盐酸， 水浴中搅拌过夜； 加水， 二氯曱烷提取， 依次用 水和饱和食盐水洗涤， 干燥； 蒸去溶剂上柱分离。  Under nitrogen protection, take LDA (1.2mmol) in an appropriate amount of tetrahydrofuran, cool to -50 ° C, slowly add carboxylic acid (0.5mmol), continue to stir at this temperature for 30 minutes, continue stirring at 50 °C 2 Hour; cool to -100 ° C with a liquid nitrogen / methanol bath, add nitro-substituted alkane (1.5 mmol), react for 5 hours, slowly raise the temperature of the reaction to 0 - 10 ° C; add appropriate amount 17% diluted hydrochloric acid, stirred in a water bath overnight; water was added, dichloromethane was extracted, washed successively with water and saturated brine, dried; 6、 根据权利要求 1至 4中任意一项所述具有取代环戊烷结构的化 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The compound having a substituted cyclopentane structure or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for use in the preparation of a preventive and/or therapeutic metabolic disorder (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。 Uses (including but not limited to diabetes, insulin resistance, and obesity), cardiovascular disease, and neurodegenerative diseases (such as Alzheimer's disease). 7、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 4中任一项所述的具有取代环戊烷结构的化合物以及这类化 合物药物学上可接受的盐及其与其它分子或载体的连结物。 7. A method for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg A pharmaceutical composition of Alzheimer's disease or the like, which comprises, as an active ingredient, a compound having a substituted cyclopentane structure according to any one of claims 1 to 4, and a pharmaceutically acceptable salt of such a compound, and A linker to other molecules or carriers. 8、 根据权利要求 7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。 8. A pharmaceutical composition according to claim 7 further comprising a pharmaceutically acceptable carrier and excipient. 9、 如权利要求 7所述药物组合物， 其特征在于所述疾病或症状可 以因对已经上市的药物产生耐药性或毒副反应而引起。 9. A pharmaceutical composition according to claim 7, characterized in that the disease or condition can be caused by resistance or toxic side effects to the already marketed drug. 10、一种联合制剂， 包括如权利要求 1至 4中任意一项所述具有取 代环戊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 combined preparation comprising a compound having a cyclopentane structure as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and other therapeutic agents. 11、一种药盒， 其包括权利要求 1至 4中任意一项所述的具有取代 环戊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 ί氐抗和肥胖症）、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 cyclopentane structure according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and the use of the compound or a pharmaceutically acceptable compound thereof Accepted salts prevent and/or treat metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases, and neurodegenerative diseases (such as Alzheimer's disease). 12、 一种药盒， 其包括权利要求 10所述的联合制剂， 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。 12. A kit comprising the combination of claim 10, and using the 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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