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WO2008067711A1 - Compounds having substituted 4-members ring structure and their medicine uses - Google Patents

Compounds having substituted 4-members ring structure and their medicine uses Download PDF

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Publication number
WO2008067711A1
WO2008067711A1 PCT/CN2007/002959 CN2007002959W WO2008067711A1 WO 2008067711 A1 WO2008067711 A1 WO 2008067711A1 CN 2007002959 W CN2007002959 W CN 2007002959W WO 2008067711 A1 WO2008067711 A1 WO 2008067711A1
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Prior art keywords
group
substituted
halogen atom
alkoxy
amide
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PCT/CN2007/002959
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French (fr)
Chinese (zh)
Inventor
Mingwei Wang
Desu Chen
Na Li
Qing Liu
Jiayu Liao
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2008067711A1 publication Critical patent/WO2008067711A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

Definitions

  • the present invention relates to a class of compounds having a substituted four-membered ring structure as a modulator of Glucagon like peptide-1 receptor (GLP-1R) in the prevention and/or treatment of metabolic disorders (including Not limited to medical use such as diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • metabolic disorders including Not limited to medical use such as diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
  • Type 1 diabetes Disorders of glucose metabolism, especially diabetes, have become a major disease in modern society that seriously threatens human health and life. 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.
  • 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.
  • the potassium ion channel When the sulfonylurea-type hypoglycemic agent binds to the receptor of the pancreatic ⁇ -cell membrane, the potassium ion channel is closed, and the potassium ion efflux is blocked, resulting in depolarization of the cell membrane, causing the Ca 2+ channel to open, causing extracellular calcium influx, intracellular. When 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. Mainly there are metformin, phenformin and butyl bismuth.
  • hypoglycemic agents mainly include Thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, etc.), ⁇ 3-adrenergic receptor modulators, glucagon receptor antagonists, and fatty acids.
  • Thiazolidinediones such as troglitazone, rosiglitazone, pioglitazone, etc.
  • ⁇ 3-adrenergic receptor modulators such as glucagon receptor antagonists
  • glucagon receptor antagonists such as glucagon receptor antagonists
  • Metabolic interference drugs such as acarbose, voglibose, miglitol, etc.
  • aldose reductase inhibitors such as acarbose, voglibose, miglitol, etc.
  • GLP-1R Glucagon like peptide-1 receptor
  • GPCR G protein-coupled receptor
  • GLP-1 In vitro, GLP-1 promotes differentiation of embryonic stem cells into insulin Secreted beta-like cells (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' Treatment of s disease (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.
  • GLP-1R has the effect of lowering blood pressure and dilating blood vessels.
  • Acute injection of GLP-1 can improve left ventricular systolic function in cardiac hypertrophy experiments. 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.
  • GLP-1 innovative drugs such as the GLP-1 derivative developed by Danovo Nordisk in Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Lilly in the United States.
  • the company's joint development of the GLP-1 analogue Exendin-4 (trade name Exenatide; has been approved for listing in April last year, this year's sales are expected to exceed $1 billion).
  • 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. Summary of the invention
  • the object of the present invention is to provide a compound having a substituted four-membered ring structure represented by the following formula I or II, and a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological action.
  • a prodrug another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the following formula I or hydrazine or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof;
  • a further object of the present invention is to provide a compound represented by the following Formula I or II or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof as a glucagon-like peptide-1 receptor modulator in the prevention And/or for medical use in the treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases 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 having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
  • the compounds include all stereo and optical isomers thereof.
  • n is 0-2; 0; S or NH.
  • R t and R 2 are each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; thiol; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; a substituted or unsubstituted thienyl group; or a substituted or unsubstituted pyrrolyl group.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; decyloxy; amine; amine alkyl; amide; carboxamide; thiol; 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 5 is any of the following substituent groups: H; C t - (6 groups of embankment; one, two or three substituents include a halogen atom contain any, dC ⁇ alkoxy or hydroxy embankment, including the dC An alkyl group of 6 ; ( 2 : 6 alkenyl; any one, two or three substituted C 2 -alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; C 2 - ⁇ alkynyl; comprising any one, two or three substituents a C 2 -C 6 alkynyl group include a halogen atom, a hydroxyl group or a C 6 embankment of including; C 3 - C 6 cycloalkyl group; and includes any containing halogen, C "C e is a hydroxyl group or embankment, including one, two or three substituents of C 3 - C 6 cycloalky
  • R 3 and ⁇ are respectively:
  • substituents H; C 6 alkyl; or any one, two or three substituted d-C 6 including a halogen atom, d-( 6 alkoxy group or hydroxyl group) alkyl; C 2 - C 6 alkenyl; containing optionally include halogen atoms, C "embankment.
  • C 6 is alkoxy or hydroxy, including a C, two or three substituents of C 2 - C s alkenyl;
  • R 7 and R 8 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group.
  • a fluorenyl group of CrC 6 a C 2 -C 6 alkenyl group; an alkenyl group containing any one, two or three substituted C 2 C s including a halogen atom, an alkoxy group of d- or a hydroxyl group; 2 - (: 6 alkynyl; any one, two or three substituted c 2 - () 6 alkynyl group including a halogen atom, d-C 6 alkoxy group or a hydroxyl group; c 3 - a cycloalkyl group of 6 6; a cycloalkyl group of any one, two or three substituted c 3 - c 6 having a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a benzyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group;
  • CrC ⁇ alkyl nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, any one, two or three substituted furans group; include a halogen atom-containing, - any (alkyl, nitro, carboxyl, acyloxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including a 4 , two or three substituted pyranyl groups; containing a halogen atom, d-C 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing an alkyl group including a
  • H is any one of the following substituents: H; C alkyl; any one, two or three substituted d ⁇ C 6 alkyl groups including a halogen atom, an alkoxy group of C "0" or a hydroxy group ; (: 2 -( 6 alkenyl; containing halogen Any one, two or three substituted c 2 c (i alkenyl group; c 2 - c 6 alkynyl group of the atom, c, -c 6 alkoxy group or hydroxy group; containing a halogen atom, Ci Any one, two or three substituted C 2 -C 6 alkynyl groups of -Ce alkoxy or hydroxy; C 3 - C e cyclodecyl; containing a halogen atom including a halogen atom, d-Ce Any one, two or three substituted c 3 -c 6 cycloalkyl groups, such as aryl; benzyl; furyl;
  • a three-substituted aryl group containing a halogen atom, an alkyl group of ( ⁇ - ⁇ , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group, a thio, including any one, two or three substituted pyridyl; include a halogen atom-containing, c 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; containing a halogen atom include, dc 4 Any one, two or three substituted pyrans of alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, s
  • Each of which is independently a substituent of any of the following: H; an alkyl group of Cr C 6 ; an alkyl group containing any one, two or three substituents including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 2 -alkenyl group; any one, two or three substituted ( 2- ( 6 alkenyl; C 2 -C B 1 ⁇ 2 alkyne) containing a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Any one, two or three substituted C 2 -C e alkynyl groups including a halogen atom, an alkoxy group of d-Ce 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 a halogen atom, a d-C 6 alkoxy group or a hydroxy
  • R, and R 2 are each independently:
  • R 12, R 13 are each independently any of the following substituent groups: H; C (group 6 of the embankment; contain any halogen atom include, CrC 6 alkoxy or hydroxy, including one, two or three substituents An alkyl group of (2); C 2 - ( 8 alkenyl; an optionally, two or three substituted C 2 - C e alkenyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group ; C 2 -C fi alkynyl; any one, two or three substituted C 2 - (: 6 alkynyl group; C 3 - C containing a halogen atom, a decyloxy group of C s or a hydroxyl group; 6 cycloalkyl; includes any halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C e cycloalkyl; aryl; benzyl; fu
  • a substituted thienyl group contains include halogen atoms, - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyrrolyl groups; dC 6 decanoyl group; any one, two or three substituted Ci-Ce containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group the embankment acyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, - embankment any alkoxy or hydroxy (6, including one, two or three substituents of c 2 -c 6 alkenyl group; a C An alkynyl group of 2 - C 6 ; a acetylene group of any one, two or three substituted c 2 - c 6 containing a halogen
  • any one of the following substituents H; - ( 6 fluorenyl; any one, two or three substituted Cr ( 6 alkyl group) including a halogen atom, a Cr ⁇ decyloxy group or a hydroxyl group
  • C 2 - C 6 Alkynyl any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C e cycloalkyl group
  • halogen atom Containing any one including a halogen atom, (-, fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, an alkyl group of 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group , carboxamide, sulfhydryl
  • R 3 and R 4 are -
  • R 7 and R 8 are each independently one of the following substituents: H; dC fluorenyl; any one, two or three substituted CrCe containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; An alkyl group; a C 2 -C e alkenyl group; any one, two or three substituted C 2 - ( ⁇ alkenyl groups) containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C s ; (alkynyl group of 2 6 ; alkynyl group having any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; ; include a halogen atom-containing, C, - C e of any embankment or a hydroxyl group, including one, two or three substituents
  • R 3 is any one of the following substituents: H; c, a fluorenyl group; any one, two or three substituted (including 6 fluorenyl groups including a halogen atom, (a alkoxy group or a hydroxyl group)
  • An alkenyl group of c 2 - c e any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group
  • One, two or three substituents pyrrolyl; of Cr alkanoyl; contains include halogen atoms, - alkoxy or hydroxy arbitrary, including one, two or three C embankment substituted acyl group "of the C 6; a C 2 -C 6 alkenoyl group; any one, two or three substituted C 2 -C 6 alkenoyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; C 2 - C e Alkynyl group; any one, two or three substituted C 2 -C 6 alky
  • R tl are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three substituted dCs including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Alkenyl group; C 2 -C e alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of Cr; C 2 - an alkynyl group; any one, two or three substituted C 2 - ( 6 alkynyl groups; C 3 - C 6 containing an alkoxy group including a halogen atom, C, -C 6 or a hydroxyl group; a cycloalkyl group; any one, two or three substituted C 3 - C s cycloalkyl groups including a halogen atom, an alkoxy group of
  • R 2 is each independently:
  • RM is any one of the following substituents: H; an alkyl group of CrCe; any one, two or three substituted ( 6 alkyl groups) including a halogen atom, a decyloxy group of d-C 6 or a hydroxyl group C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - (; 6 ) containing a halogen atom, an alkoxy group or a hydroxyl group; An alkynyl group; any one, two or three substituted C 2 -C B alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cyclodecyl groups such as a halogen atom, an alkoxy group of a CrC 6 or a hydroxyl group;
  • H is any one of the following substituents: H; ("( 6 fluorenyl; any one, two or three substituted d- including a lii atom, C" (a alkoxy group or a hydroxyl group)
  • two or three substituted pyranyl groups containing a halogen atom, a fluorenyl group of d-c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, a mercapto group of ( 4 ), a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, Amido, carboxamide, sulfhydryl, methylthio, B Group, including any one, two or three substituents pyrrolyl; c, - C B of alkanoyl; contain any halogen atoms include, dC 6 alkoxy,
  • R 7 each independently is any one of the following substituents: H; d- ( 6 alkyl; any one, two or three substituted including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group) a fluorenyl group; a C 2 -CJ alkenyl group; any one, two or three substituted C 2 - ( 6 alkenyl groups; C 2 containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; Alkynyl group of -C 6 ; alkynyl group of any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 3 - C 6 naphthenic group; Any one, two or three substituted C 3 -C e cyclodecyl groups including a halogen atom, an alkoxy group of d-C
  • R 3 is any one of the following substituents: H; C" thiol group of C e ; any one, two or three substituted groups including a halogen atom, a d-C alkoxy group or a hydroxyl group - ( 6 ⁇ group; c 2 - alkenyl; optionally include a halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - (alkenyl; C 2 - (6 alkynyl Any one, two or three substituted C 2 -C B alkynyl group including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a cycloalkyl group of c 3 - C s ; containing a halogen atom any alkoxy or hydroxy dC e inner one, two or three substituents of ⁇ - c 6 cycloalkyl; and aryl
  • each of Ru and Ru is independently any one of the following substituents: H; dC fluorenyl; any one, two or three substituted dGs including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; An alkyl group; a C 2 -C cramp alkenyl group; any one, two or three substituted C 2 - C (; alkenyl group; C containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; 2 - (6 alkynyl; contain optional atoms including vegetarian, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkynyl group; C 3 - C 6 a cycloalkyl group; any one, two or three substituted C 3 -C e cycloalkyl groups including a halogen atom, an alkoxy group of d-C 6 or
  • Two or three substituted pyranyl groups containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio Any one, two or three substituted thienyl groups, including a halogen atom; (-(: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, Any one, two or three substituted pyrrolyl groups such as an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group; a decanoyl group of dC 6 ; an alkoxy group containing a halogen atom, C "C 6 " Any one, two or three substitutions, including a hydroxy group Cr C e alkanoyl; C 2 -C 6 alkenyl group; a halogen
  • R and R 2 are each independently:
  • R 15 and R 16 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; An alkyl group of c!-; an alkenyl group of c 2 -c 6 ; an alkenyl group containing any one, two or three substituted c 2 -c 6 groups including a halogen atom, an alkoxy group of c 6 or a hydroxyl group; C 2 - (alkynyl group of 6 ; alkynyl group containing any one, two or three substituted C 2 - C s including a halogen atom, (alkoxy group of Ce or a hydroxyl group); C 3 -C 6 cycloalkyl; contain any halogen atoms include, d-Ce alkoxy or hydroxy the embankment, including one, two or three substituent
  • a three-substituted furyl group containing an alkyl group including a halogen atom, Cr C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethyl sulfide Arbitrarily One, two or three substituted pyranyl groups; containing a halogen atom, d-( ⁇ , alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, d-c, a nitro group, a carboxyl group, an acid group, an alkoxy group, an
  • alkanoyl alkanoyl group containing any one, two or three substituted C e including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a C 2 - C 6 alkenoyl group; containing a 13 ⁇ 4 atom any alkoxy or hydroxy c 'c E inner one, two or three substituents of c 2 - C 6 alkenyl group of; C 2 - C s alkynyl group; contains include halogen atoms, the oxygen embankment Any one, two or three substituted c 2 -c 6 alkynyl groups, or a hydroxyl group; c 3 -c s cycloalkanoyl group; containing a halogen atom, d- alkoxy group or hydroxyl group Any one, two or three substituted c 3 - ⁇ cyclodecanoyl; adamantyl formyl, substituted adamantyl formyl;
  • any one of the following substituent groups H; alkyl C "6, C; include a halogen atom-containing, any alkoxy or hydroxy (6, including one, two or three substituents of C 6 D- Alkyl; C 2 _C S alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; (6 alkynyl group; a halogen atom includes any containing, G-Ce alkoxy or hydroxy group including one, two or three substituents of C 2 -C e alkynyl group; C 3 - C 6 cycloalkyl firing of Any one, two or three substituted ( 3 -C e cycloalkyl groups; aryl; benzyl; furyl; pyran) containing a halogen atom, an alkoxy group of d-Ce or a
  • R 7 is each independently a substituent of any of the following: H; a fluorenyl group of C 6 ; any one, two or three substituted C's including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group.
  • H is any one of the following substituents: H; d- (: 6 alkyl; any one, two or three substituted d-containing a halogen atom or a hydroxyl group including a halogen atom, d-C e ( 6 : an alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted ( 2- ( 6- ) alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of dC e
  • R u are each independently any of the following substituent groups: H; CrC 6 alkyl; one, two or three substituents include a halogen atom-containing arbitrary, C, -C 3 alkoxy or hydroxy embankment inner of D- ⁇ alkyl; C 2 -C e alkenyl; any one, two or three substituted ( 2- ( 6 olefin) containing a halogen atom, a decyloxy group or a hydroxyl group of d-Cs a C 2 - (alkynyl group; any one or two containing an alkoxy group including a halogen atom, C, or C 6 or a hydroxyl group; 2007/002959 three substituted c 2 -C e alkynyl groups; C 3 -C 6 cycloalkyl groups; containing any one or two including a halogen atom, an alkoxy group of d-c 6 or a hydroxyl group or Three substituted
  • 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 invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's) Ill).
  • the invention relates to methods of preventing and/or treating metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • the method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound which 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.
  • a compound having a substituted four-membered ring structure represented by II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action The compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted aryl Substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the present invention relates to a combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • This compound has the structure of the following formula I or II -
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; ; carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Or an unsubstituted thiophenyl group; or a substituted or unsubstituted pyrrolyl group.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the present invention provides a kit comprising the above combined preparation.
  • the present invention still further provides the use of the above combined preparation for the prevention and/or treatment of metabolic disorders (including sputum not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). ), to achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life.
  • metabolic disorders including sputum not limited to diabetes, insulin resistance and obesity
  • cardiovascular diseases such as Alzheimer's disease.
  • neurodegenerative diseases such as Alzheimer's disease.
  • metabolic disorder refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes.
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by insulin secretion and/or dysfunction.
  • 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 tissues surrounding the body to insulin, and target tissues such as muscles and fats are resistant to insulin-induced glucose uptake. Insulin resistance is prevalent in type 2 diabetes, accounting for more than 90%, and is one of the main factors in the development of type 2 diabetes.
  • obesity refers to an excess of body fat, a male weighing more than 25% of the ideal body weight, or a woman weighing more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overeating and too little activity are all causes of obesity.
  • AD Alzheimer's Disease
  • AD Alzheimer's dementia
  • 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 refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods. The compounds thus derived and produced can be administered to animals and humans without toxic effects. The compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant application.
  • substantially pure means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis, and High performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the 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.
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted into a biologically, pharmaceutically or therapeutically active form.
  • 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 to transport precursors of properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • substantially is the same or uniform or similar, and the understanding of the related art by those skilled in the art can vary from context to context and is generally at least 70%, preferably at least 80%, more preferably at least 90%. , optimally at least 95% identical.
  • composition refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • object as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • metabolic disorders including but not limited to diabetes, insulin resistance and obesity
  • cardiovascular disease including but not limited to diabetes, insulin resistance and obesity
  • neurodegenerative diseases such as Alzheimer's disease
  • B-glucagon-like peptide-1 receptor modulator The present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and Neurodegenerative diseases (such as
  • the present invention relates to a compound having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action -
  • the compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; oxiran; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • R 4 are each independently one of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • the compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • the compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain different amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method.
  • the compound is prepared by the synthetic method cited in Section F below.
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • suitable acid for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.;
  • a sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the present invention relates to methods for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
  • the method comprises administering to a subject in need or willingness 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-mentioned disease is by administering an effective amount of a compound having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological agent
  • a compound having a substituted four-membered ring structure represented by the following formula I or II or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological agent
  • the compounds include all stereo and optical isomers thereof.
  • X and Y are respectively (CH 2 ) march, n is 0-2; 0; S or NH.
  • R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
  • Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted aryl Substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • Any subject can be controlled by this method, preferably a mammal, more preferably a human.
  • the method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease).
  • a preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • 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.
  • Administration of the compounds of the invention alone or in combination with other suitable diabetes therapeutics including insulin sensitizers can be by any suitable method. 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.
  • the method further comprises performing a diagnosis and prognosis 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 related symptoms.
  • a diagnostic or prognostic method disclosed in International Patent No. WO 01/44815 and U.S. Patent No. 5,571,674 can be used.
  • the present invention also relates to a combination preparation comprising a compound which selectively modulates the function of the glucagon-like peptide-1 receptor, or a pharmacologically Acceptable salts, and one or more therapeutic agents for metabolic disorders include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutic agent for one or more metabolic disorders including an insulin sensitizer, which is represented by the following formula I or II:
  • X and Y are respectively (CH, n is 0-2; 0; S or NH.
  • each independently is any one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Amido; thiol; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted thienyl; or substituted or unsubstituted pyrrolyl.
  • R 3 each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
  • any suitable therapeutic agent for diabetes can be used in the combination formulations of the invention.
  • one or more of the above-described diabetes therapeutic agents including insulin sensitizers may be included in the combined preparation of the present invention.
  • a 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.
  • kits 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, for example, intraluminal, subcutaneous, intravenous, intramuscular Injection, intradermal injection, oral or topical medication.
  • the method can be administered by injection in a single dose in an ampoule, or in a multi-dose container with an added 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 a powder form with a suitable vehicle, sterile non-pyrogenic water or other solvent before use.
  • the topical preparation of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • compositions and methods for administration that may be used in the present invention include, but are not limited to, U.S. Patents 5,736,154, 6,197, 801 Bl, 5,741,511, 5, 886, 039 5, 941, 868, 6, 258, 374B1 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 dose and frequency of administration will vary with age, weight, health status, and individual patient response.
  • Dosage forms include tablets, lozenges, lenticular capsules, 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-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 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 preferably a sterile solution
  • Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the compound represented by the formula I or II of the present invention is produced by the method described below, wherein the starting materials are synthesized by the synthesis method described in the Chinese Patent Application (Application No.: 200310109331. 0).
  • the preparation method of the compound represented by the formula I or II of the present invention is as follows:
  • the compound 1 and the compound 2 are dissolved in a suitable amount of a mixed solvent of dichloromethane, water, dichloroethane, DMSO, dioxane or the above solvent, optionally with a catalytic amount of benzophenone, and the reaction temperature is controlled at 0. Between C and 60 ° C, placed in a 150W high-pressure mercury lamp or natural light for 1 day to 2 months, during the period by HPLC detection of the reaction, lyophilization to remove the solvent, the residue was separated by reverse-phase silica gel column chromatography to obtain the present invention Compound.
  • a mixed solvent of dichloromethane water, dichloroethane, DMSO, dioxane or the above solvent
  • a catalytic amount of benzophenone optionally with a catalytic amount of benzophenone
  • Figure 1 illustrates in vitro pharmacodynamic test results of compounds S4P and Boc5 a.
  • HEK293/GLP1R+Luc was induced with different concentrations of GLP-1, S4P and Boc5, respectively, and compounds were evaluated by detecting the expression of CRE-driven luciferase reporter gene.
  • Boc5 of compound S4P and GLP- 1R agonistic activity is dose-dependent average, and both the EC 5.
  • the values are similar (S4P is 1. 2 ⁇ ⁇ , Boc5 is 3.1 ⁇ ⁇ ), but the reaction intensity of S4P at 10 ⁇ is 37.3% of GLP-1 ( ⁇ ), and Boc5 is GLP-1R Full agonist.
  • Exendin (9-39) was used to verify the receptor specificity of the compound for GLP-1R agonistic activity. When added to 0.05 nM GLP-1, 10 4M S4P and Boc5, Exendin (9-39) dose-dependently inhibited the expression of the reporter gene induced by it, IC 5 . The values were 68.22, 14.69 and 33.38 nM, respectively, indicating that the biological activities of S4P and Boc5 and GLP-1 are mediated by GLP-1R. c. Using the 125 1 labeled GLP-1 as a ligand, the affinity of the compound for the receptor is tested by a competitive binding assay.
  • Intraperitoneal injection of Boc5 to suppress appetite ED 6 rendervalue is 1.57 ⁇ 0. 09 mg ⁇ 80 mg / kg.
  • Boc5 intraperitoneal injection of appetite inhibition can be induced by prophylactic intraperitoneal injection of exendin (9-39 Antagonism d.
  • Boc5 oral administration ED 5 for feeding inhibition The value is 0. 53 soil 0. 08 mg.
  • the appetite suppressing effect of oral administration of Boc5 can be antagonized by prophylactic intraperitoneal injection of exendin (9-39).
  • Figure 3 shows the pharmacokinetic parameters of Boc5 in normal C57BL/6 mice. Normal C57BL/6 mice were injected intraperitoneally with Boc5 2mg/20g body weight (3 per time point). The pharmacokinetic parameters were determined by HPLC. analysis. The final elimination half-life is 7.5 ⁇ 1. 2 hours.
  • FIG. 4 illustrates the long-term pharmacodynamic study of compounds S4P and Boc5 a.
  • Each group of mice was randomly divided into blank control group, S4P treatment group and wild type control group according to HbAlc level. The results showed that HbAlc was significantly down-regulated after S4P administration; b.
  • Each group of mice were randomly divided into a free feeding control group, a feeding restriction control group, a Boc5 1 mg group, a Boc5 2 mg group, and a wild type control group according to HbAlc levels.
  • HbAlc was gradually decreased in the intraperitoneal injection of Boc5 1 mg or 2 mg diabetic mice, which reached normal levels at 4-6 weeks of treatment, and was not significantly different from wild-type mice, but significantly lower than the free-feeding control group and the feeding restriction control.
  • Group; c. The fasting blood glucose changes in mice were unstable, but the response trend of each group was related to HbAlc;
  • d. The food intake of the mice in the free feeding control group increased by 23%, and the average body weight increased by 12 g;
  • the body weight changes of Boc5 1 mg and 2 mg treatment groups were not significantly different from wild-type mice, and the weight gain was significantly lower than that of the free-feeding control group.
  • mice were randomly selected for abdominal cavity.
  • the injection glucose tolerance test (IPGTT) showed that the area under the curve (AUC) of the B 0 c5 2 mg treatment group was significantly lower than that of the free feeding control group and the feeding restriction control group ( ). 0006 and). 0006), and the wild There was no significant difference between the mice, suggesting that the glucose tolerance of the Boc5 2 mg treatment group has returned to normal; f.
  • the fasting insulin level of the free feeding control group and the feeding restriction control group is significantly higher than that of the wild type mice. Tip a decrease in insulin sensitivity, and limit food intake compared to the control group, Boc5 1 mg and 2 mg treatment group had some degree of downward trend.
  • 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 65:35, the flow rate was 0. 2 ml/min, and the detection wavelength was 254 nm.
  • the enthalpy was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 0D or DMSO-cU; ESI-MS was measured by AB Mariner mass spectrometer EI was measured by a Finnigan MAT95 mass spectrometer.
  • the materials used in the synthesis were all commercially available except for the specific source. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
  • the compound Wang516 (1 g) was dissolved in an appropriate amount of DMSO, placed under a 150 W high-pressure mercury lamp for 3 days, and 1 ml of water was added thereto for further 7-10 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound S4P was obtained.
  • 13 CN R (75MHz, DMS0-d 6 ) 174.7, 172.8, 166.8, 159.4, 150.1, 142.1, 137.7, 135.2, 133.6, 131.6, 129.1, 128.7, 128.1, 122.5, 122.1, 118.1, 112.5, 63.2, 54.9, 48.4 , 45.3, 30.0, 25.7.
  • the compound Wan g 520 (10 g) was dissolved in an appropriate amount of DMS0, placed under a 150 W high pressure mercury lamp for 3 days, and 1 ml of water was added thereto, and the irradiation was continued for 25-30 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound Boc5 was obtained.
  • GLP-1R is a G protein-coupled receptor.
  • the Get subunit of G protein is activated to stimulate adenylate cyclase, resulting in elevated intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the proinsulin 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).
  • HEK 293 human embryonic kidney cell strain stably transfected with a GLP-1R receptor gene expression vector and a luciferase reporter gene expression vector regulated by a cAMP response element was used to detect its response to a test compound (Cell). 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 screened for a compound is considered to have GLP-1R agonistic activity.
  • DMEM medium (GIBC0 company) Steady-GloTM Luciferase Assay System (Promega)
  • HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 ⁇ /well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 ⁇ M/ml G418.
  • the GLP-1 standard and the test compounds S4P and Boc5 were each diluted to a certain concentration gradient, and then added to the above 96-well microplate in ⁇ /well.
  • cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor2 reader was used for reading.
  • HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 ⁇ /well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. Dilute Exendin (9-39) to a certain concentration gradient, then add 1 ⁇ /well to the above 96-well microplate, incubate at 37 ° C, 5% CO 2 for 10 minutes, then add 10 ⁇ M S4P, Boc5 and 0. 05 nMGLP-1, at 37. C, cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay Kit, and the Victor2 reader was used for reading.
  • HEK 293/GLP1R+Luc cells in 10 5 logarithmic growth phase were incubated with 125 1 GLP-1 positive peptide (final concentration 40 ⁇ ) for 4 hours at 200 ° C in 200 ⁇ l assay buffer.
  • 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.
  • Boc5 compound S4P and capable of specifically 12,511 standard competitive binding with GLP- (Table 3, FIG LC. At a concentration of 30 ⁇ M, 34? Inhibition rate of 8005 and 80.6%, respectively 63. The IC 5 value of the two is 286. 6 nM 1. 5 ⁇ M. Under the same experimental conditions, the IC 5 of the GLP-1 has a value of 0.66 nM.
  • GLP-1 analogues produces inhibition of food intake, delayed gastric emptying, stimulation of insulin secretion, inhibition of glucagon secretion, and repair of insulin first phase secretion (Regul Pept, 2004, Vol. 117 : 77 88 ).
  • Boc5 solution was intraperitoneally injected overnight after fasting to observe the inhibitory effect of acute administration of the compound on appetite.
  • mice female, 6 weeks old, 18-20 g, purchased from Shanghai Slack Laboratory Animal Co., Ltd.
  • Test compound Boc5 with different dose gradients were dissolved in 1% DMS0 and 20% PEG400 saline (abdominal Cavity injection test) or 2% DMS0 and 20% PEG400 saline (oral administration test)
  • mice After overnight fasting, the mice were housed in single cages and then divided into blank control group, exendin- 4 1 g group, Boc5 0. 1 mg group, Boc5 0. 3 rag group, Boc5 1 mg group and Boc5 2 mg group.
  • the mode of administration is intraperitoneal injection. Each group of mice was fed ad libitum, and the remaining feed was observed at intervals of 15-30 minutes before and after administration, and the observation data for 12 hours was used to calculate the cumulative food intake.
  • a blank control group, Boc5 0.3 mg group, Boc5 1 rag group, Boc5 3 mg group, and Boc5 10 mg group were set, the intragastric volume was 1 ml, and the observation period was 6 hours.
  • GLP-1R agonists can reduce body weight in obese animal models, reducing HbAlc and blood lipids, restoring beta cell function, increasing insulin sensitivity, and inducing beta cell proliferation and differentiation in an animal model of type 2 diabetes (Regul P. T, 2004, Vol. 117: 77-88).
  • type 2 diabetes model 578176]-111+/+ 1 ⁇ ) * ( /3 ⁇ 43 ⁇ 4) mice a pharmacodynamic study of intraperitoneal injections of Boc5 and S4P was performed.
  • CS BL/ej-m+Z+ Lepr 1 * Mice Male and female, 8 weeks old, purchased from the Model Animal Research Center of Nanjing University (identified by the center to meet the characteristics of type 2 diabetes).
  • Test compound Boc5 or S4P with different dose gradients dissolved in 1% DMS0 and 20% PEG400 saline
  • mice Each group of mice was randomly divided into 4 groups (14-15/group) according to HbAlc levels, and the mode of administration was intraperitoneal injection.
  • the Boc5 1 mg group, and the Boc5 2 mg group a feeding restriction control group was set, and the daily food intake of the group was equal to the Boc5 2 mg group of the previous day to detect changes in blood glucose characteristics caused by feeding inhibition.
  • a group of wild-type non-diabetic C57BL/6 mice were set up to observe the normal range of values of each indicator. Observed indicators are as follows: HbAlc once a week, fasting blood glucose twice a week, body weight and food intake observed once a day.
  • mice in each group After 6 weeks of treatment, half of each group (7 - 8) were fasted overnight, fasting insulin levels were measured, and 2 g kg-1 D-glucose was injected intraperitoneally. The animals were sacrificed and blood samples were taken for total cholesterol and triglycerides. , high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase. The remaining mice in each group after stopping the drug continued to observe for 6 weeks.
  • HbAlc was significantly down-regulated (Fig. 4a), so HbAlc was used as the main evaluation index for Boc5-related studies.
  • the db/db mice were randomly grouped according to the HbAlc value. Prior to dosing, HbAlc was significantly higher in each group of db/db mice than in wild-type mice, which maintained a lower level of HbAlc throughout the course of the experiment.
  • the experimental results showed that the HbAlc of the db/db mice in the free feeding control group and the feeding restriction group continued to be higher.
  • HbAlc in the intraperitoneal injection of Boc5 1 mg or 2 mg in diabetic mice gradually decreased, reaching normal levels at 4-6 weeks of treatment, with no significant difference from wild-type mice, but significantly lower than the free-feeding control.
  • Group and feeding restriction control group db/db mice (0. 0001; Tukey-Kramer test).
  • HbAlc in both treatment groups remained at normal levels (Fig. 4b).
  • mice showed little change in body weight, compared with 23% for food intake and 12 g for the free-feeding control group (Fig. 4d); There was no significant difference in body weight between the control group, Boc5 1 rag and 2 mg treatment groups. The weight gain was significantly lower than the free feeding control group R0. 0001).
  • each group of mice was randomly selected for intraperitoneal injection of glucose tolerance test (IPGTT).
  • the remaining mice in each group also underwent IPGTT test 15 weeks after discontinuation of the drug.
  • the blood glucose response of the mice was measured as the area under the curve (AUC) within 120 minutes after the glucose load of 2 g/kg (Fig. 4e).
  • AUC area under the curve
  • the AUC of the Boc5 2 mg-treated group was significantly lower than that of the free-feeding control group and the food-feeding control group (X 0006 and ). 0006), but there was no significant difference compared with the wild type mice ( ). 64). Therefore, the glucose tolerance of the Boc5 2 mg treatment group has returned to normal.
  • the glucose tolerance of the Boc5 1 mg treatment group was partially improved. After 15 weeks of drug withdrawal, the glucose tolerance of the mice in the treatment group rebounded, and there was no significant difference in the glucose tolerance status of each group of diabetic mice (AO. 05), which was significantly higher than that of the wild type mice (free feeding control group 0026). , feeding restriction control group 0153, Boc5 2 mg / ). 0072, Boc5 1 mg ). 0052).
  • triglycerides in the Boc5-treated group showed a downward trend, while total cholesterol decreased significantly ( ⁇ 0.0054 compared with the food-inhibited control group, 0002 compared with the free-feeding control group), due to low-density lipoprotein A slight decrease in cholesterol (3.0045) and a significant decrease in high-density lipoprotein cholesterol ( ).0005).

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Abstract

Disclosed are compounds having substituted 4-members ring structure represented by general formula I or general formula II, or pharmaceutically acceptable salts, esters, solvates, metal complexes thereof, or prodrugs having same pharmacological action. And disclosed is the use as a kind of glucagons-1 acceptor regulators for preventing and/or treating metabolic disorder disease (including but not limited by diabetes, insuline resistance and adiposis), angiocardiopathy and nerve regression diseases (such as Alzheimer's disease).

Description

一类具有取代四元环结构的化合物及其医学用途 技术领域  Compounds with substituted four-membered ring structure and their medical use
本发明涉及一类具有取代四元环结构的化合物作为胰高血糖样肽一 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）、 心血管疾病和神经退行性疾病 （如 Alzheimer' s 病）等的医学用途。 背景技术  The present invention relates to a class of compounds having a substituted four-membered ring structure as a modulator of Glucagon like peptide-1 receptor (GLP-1R) in the prevention and/or treatment of metabolic disorders (including Not limited to medical use such as diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease. Background technique
糖代谢紊乱， 特别是糖尿病， 已成为现代社会严重烕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， 第一代如甲苯磺丙脲， 第二代包括格列本脲 （优降糖）、 格列齐特 （达美 康）， 格列吡嗪 （美吡哒） 和格列喹酮 （糖适平） 等。 双胍类降糖药物能抑制食欲， 增加 胰岛素与受体的结合， 促进细胞对葡萄糖的无氧酵解， 抑制组织呼吸， 抑制肝糖元异生。 主要有二甲双胍、 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。 Disorders of glucose metabolism, especially diabetes, have become a major disease in modern society that seriously threatens human health and life. 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. When the sulfonylurea-type hypoglycemic agent binds to the receptor of the pancreatic β-cell membrane, the potassium ion channel is closed, and the potassium ion efflux is blocked, resulting in depolarization of the cell membrane, causing the Ca 2+ channel to open, causing 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 toluene propyl propyl urea, the second generation including glibenclamide (glibenclamide), gliclazide (Damecon), glipizide (mepyrazin) ) and gliclazide (sugar leveling) and the like. 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. Mainly there are metformin, 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.
胰高血糖素样肽- 1受体 （Glucagon like peptide- 1 receptor, GLP-1R) 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一胰高血糖素样肽- 1 (Glucagon like peptide-1 , GLP-1 ), 通过与 GLP- 1R高度特异性地结合使其活化， 刺激胰岛素分泌， 抑制胰高血糖素的产生， 使餐后血糖降低并维持在恒定水平。 生理条件下， GLP- 1 剌激胰岛素分泌的作用依赖于血 糖浓度， 不会因持续分泌而发生低血糖。 GLP-1还具有促进 β细胞的增殖和分化， 以及神经 调节功能， 延迟胃排空， 降低食欲。 在体外， GLP- 1 能促进胚胎干细胞分化为具有胰岛素 分泌功能的类 β细胞（J Endocrinol. 2005, 186 : 343-52) 。 GLP-l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 的收縮功能。 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。 Glucagon like peptide-1 receptor (GLP-1R) belongs to type B G protein-coupled receptor (GPCR). When the body ingests nutrients, the gutagonal peptide-1 (GLP-1) released by the enteroendocrine cells is activated by highly specific binding to GLP-1R. It stimulates insulin secretion, inhibits the production of glucagon, and lowers postprandial blood glucose and maintains it at a constant level. Under physiological conditions, the effect of GLP-1 on insulin secretion is dependent on blood glucose levels, and hypoglycemia does not occur due to continued 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 differentiation of embryonic stem cells into insulin Secreted beta-like cells (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' Treatment of s disease (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 improve left ventricular systolic function in cardiac hypertrophy experiments. 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.
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 Nor disk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  A number of internationally renowned multinational pharmaceutical companies are developing GLP-1 innovative drugs, such as the GLP-1 derivative developed by Danovo Nordisk in Denmark (trade name Liraglutide; entering Phase III clinical trials) and Amylin Pharmaceuticals and Lilly in the United States. The company's joint development of the GLP-1 analogue Exendin-4 (trade name Exenatide; has been approved for listing in April last year, this year's sales are expected to exceed $1 billion). 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. Summary of the invention
本发明的目的在于提供了一类由以下通式 I或 II表示的具有取代四元环结构的化合 物及其药学上可以接受的盐、酯、溶剂化物、金属配合物、或者具有相同药理作用的前药; 本发明的另一目的在于提供了一种含有由以下通式 I或 Π表示的化合物或其药学上 可以接受的盐、 酯、 溶剂化物或金属配合物的药物组合物；  The object of the present invention is to provide a compound having a substituted four-membered ring structure represented by the following formula I or II, and a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological action. a prodrug; another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the following formula I or hydrazine or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof;
本发明的又一目的在于提供了由以下通式 I或 II表示的化合物或其药学上可以接受 的盐、 酯、 溶剂化物或金属配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 Alzheimer' s病）等的医学用途。  A further object of the present invention is to provide a compound represented by the following Formula I or II or a pharmaceutically acceptable salt, ester, solvate or metal complex thereof as a glucagon-like peptide-1 receptor modulator in the prevention And/or for medical use in the treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease.
本发明提供胰高血糖样肽一 1受体调节剂，增加了预防和 /或治疗代谢紊乱性疾病（包 括但不局限于糖尿病、 胰岛素抵抗和肥胖症）、 心血管疾病和神经退行性疾病 （如 Alzheimer' s病）等药物的成员。本发明涉及由以下通式 I或 II表示的具有取代四元环结 构的化合物， 或其药物学上可接受的盐、 酯、 溶剂化物、 金属配合物或者具有相同药理作 用的前药：
Figure imgf000005_0001
所述化合物包括其所有的立体和光学异构体。 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 having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
Figure imgf000005_0001
The compounds include all stereo and optical isomers thereof.
其中 X和 Y 分别为（C )„, n为 0- 2; 0； S或者 NH。  Where X and Y are respectively (C)„, n is 0-2; 0; S or NH.
其中 Rt、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环烷基； 羟基； 硝 基； 羧基； 醛基； 烷氧基； 胺基； 胺烧基； 酰胺基； 碳酰胺基； 巯基； 烧硫基； 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； 或者， 取代或未取代的吡咯基。 Wherein R t and R 2 are each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; thiol; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; a substituted or unsubstituted thienyl group; or a substituted or unsubstituted pyrrolyl group.
R3、 各自独立地为下列任意一种取代基： 氢； 烷基； 环烷基； 垸氧基； 胺基； 胺烷 基； 酰胺基； 碳酰胺基； 垸硫基； 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 3 , each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; decyloxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
优选地，对于上述通式 I或 II的化合物， 其特征在于： X、 Y 分别是 (C¾)„, n为 0-2; 0； S或者 NH， R2分别各自独立为:
Figure imgf000005_0002
Preferably, for the compound of the above formula I or II, characterized in that X and Y are respectively (C3⁄4) „, n is 0-2; 0; S or NH, R 2 are each independently:
Figure imgf000005_0002
其中 R5为下列任意一种取代基： H; Ct- ( 6的垸基； 含有包括卤素原子、 d-C^垸氧基 或羟基在内的任意一个、 两个或者三个取代的 d- C6的烷基； （：2 ( 6的烯基； 含有包括卤素 原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- 的烯基； C2- ^的 炔基;含有包括卤素原子、 C6的垸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「Ce的垸氧基或羟基在内的任意一个、 两个 或者三个取代的 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 C, -^的綜基、 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、 CrCj垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 C ( 4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 （ C4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、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基; 含有包括卤素原子、 d- c4的烷基、 硝基、 羧基、 酸基、 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咯基； c「 c6的烷酰基； 含 有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrCB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- Cs的烯酰基； C2- CB的炔酰基； 含有包括卤素原子、 ( 的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 C2-Ce的炔酰基； C3- C6的环垸酰基； 含有包括卤素 原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（(¾)„, n为 0- 2; 0； S或者 NH时; Wherein R 5 is any of the following substituent groups: H; C t - (6 groups of embankment; one, two or three substituents include a halogen atom contain any, dC ^ alkoxy or hydroxy embankment, including the dC An alkyl group of 6 ; ( 2 : 6 alkenyl; any one, two or three substituted C 2 -alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; C 2 - ^ alkynyl; comprising any one, two or three substituents a C 2 -C 6 alkynyl group include a halogen atom, a hydroxyl group or a C 6 embankment of including; C 3 - C 6 cycloalkyl group; and includes any containing halogen, C "C e is a hydroxyl group or embankment, including one, two or three substituents of C 3 - C 6 cycloalkyl group; and an aryl group; a benzyl group; furanyl; pyranyl ; thienyl; pyrrolyl; pyridyl; containing a hetero atom including a halogen atom, C, -^, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio Any one, two or three substituted aryl groups including an ethylthio group; containing a halogen atom, a CrCj fluorenyl group, a nitro group, a carboxy group , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, C ( Any one, two or three substituted furans of 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio Any one containing a halogen atom, (C 4 alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, d-C 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; Any one containing a halogen atom, an alkyl group of d-c 4 , a nitro group, a carboxyl group, an acid group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, Two or three substituted pyrrolyl groups; c "c 6 alkanoyl group; alkanoyl group containing any one, two or three substituted CrC B including a halogen atom, - alkoxy group or a hydroxyl group; An alkenoyl group of 2 - C 6 ; an enoyl group containing any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 2 - C B alkyne An acyl group containing any one, two or three substituted C 2 -C e including a halogen atom, a decyloxy group or a hydroxyl group; a C 3 -C 6 cyclodecanoyl group; Any one, two or three substituted C 3 -C 6 cycloalkanoyl groups of dC 6 having a decyloxy group or a hydroxyl group; adamantyl formyl group, substituted adamantyl formyl group; aroyl group; benzyl group; furan Formyl; pyranoyl; thiophene; pyrroyl; (3⁄4)„, n is 0– 2; 0; S or NH;
R3、 ^分别为：
Figure imgf000006_0001
R 3 and ^ are respectively:
Figure imgf000006_0001
其中 为下列任意一种取代基： H; C6的烷基； 含有包括卤素原子、 d- (6的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 d- C6的烷基； C2- C6的烯基； 含有包括卤素 原子、 C「C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- Cs的烯基； C2- (^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、 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的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 （ C4的烷基、 硝 基、 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呋喃基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 Cr 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、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- C6的烷酰基； 含 有包括卤素原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d- C6的烷 酰基； C2_C6的烯酰基； 含有包括卤素原子、 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- ( 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-Cfi的炔酰基； C3- C6的环烷酰基； 含有包括卤素 原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3- C3的环垸酰基； 金 刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基; 为（C ) n, n为 0- 2; 0； S或者 NH; Wherein is any one of the following substituents: H; C 6 alkyl; or any one, two or three substituted d-C 6 including a halogen atom, d-( 6 alkoxy group or hydroxyl group) alkyl; C 2 - C 6 alkenyl; containing optionally include halogen atoms, C "embankment. 6 is alkoxy or hydroxy, including a C, two or three substituents of C 2 - C s alkenyl; C An alkynyl group of 2 - (^; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of CC 6 or a hydroxyl group; a ring of C 3 - C 6 Any one, two or three substituted C 3 -C 6 cyclodecyl groups containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group any thio, ethylthio, including one, two or three aryl group substituents; containing a halogen atom include, CrC alkyl with 4-nitro, 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 methylthio group, an ethylthio group; Any one, two or three substituted alkyl, nitro, carboxyl, aldehyde, anthracene, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio group of C 4 a furan group; containing an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and the like. Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, Cr 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, methylthio, ethylthio, including any one, two or three substituents thienyl; include a halogen atom-containing, D- (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amino , amide group, carboxamide group, thiol group, methylthio group, B Group, including any one, two or three substituents pyrrolyl; d- C 6 alkanoyl; includes optionally containing a halogen atom, a hydroxyl group or an alkoxy group including one, two or three substituents of d - C 6 alkoxy group; a C 2 _C 6 alkenyl group; a comprises containing any halogen atoms, C "C6 alkoxy or hydroxy inner one, two or three substituents of C 2 - C 6 alkenyl group of a C 2 -C 6 alkynyl group; a acetylene group containing any one, two or three substituted C 2 -C fi groups including a halogen atom, d-( 6 alkoxy group or hydroxyl group; C 3 - a cycloalkanoyl group of C 6 ; any one, two or three substituted C 3 -C 3 cyclodecanoyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; adamantyl group, substituted gold Benzoyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene a pyrroyl group; (C) n , n is 0-2; 0; S or NH;
或者 、 分别为-
Figure imgf000007_0001
Or, respectively -
Figure imgf000007_0001
其中 R7、 R8各自独立为下列任意一种取代基： H; d- 的烷基； 含有包括卤素原子、 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的垸基； 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 Cs的 烯基； C2- (：6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- (]6的炔基； c3-c6的环烷基； 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； 含有包括卤素原子、 0>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、 c4的垸基、 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、Wherein R 7 and R 8 are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group. a fluorenyl group of CrC 6 ; a C 2 -C 6 alkenyl group; an alkenyl group containing any one, two or three substituted C 2 C s including a halogen atom, an alkoxy group of d- or a hydroxyl group; 2 - (: 6 alkynyl; any one, two or three substituted c 2 - () 6 alkynyl group including a halogen atom, d-C 6 alkoxy group or a hydroxyl group; c 3 - a cycloalkyl group of 6 6; a cycloalkyl group of any one, two or three substituted c 3 - c 6 having a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a benzyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, 0>, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted aryl groups including a methylthio group and an ethylthio group; a fluorenyl group containing a halogen atom and c 4 Any one, two or three substituted pyridyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Halogen atom,
CrC^ 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呋喃基； 含有包括卤素原子、 -( 4的烷基、 硝 基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的吡喃基； 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、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基; CrC6的烷酰基； 含有包括卤素原子、 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- 的烯酰基； 含有包括卤素原子、 -( 6的垸氧基或羟基在内的 任意一个、两个或者三个取代的 C2- Ce的烯酰基； C2_Ce的炔酰基； 含有包括卤素原子、（^ C6 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c2-c6的炔酰基； c3- 的环烷酰基; 含有包括卤素原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- ( 6的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X^ (C ) n, n为 0- 2; 0； S或者 NH; ¾为（(¾)„, n为 0- 2; 0; S或者 NH; CrC^ alkyl, nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, any one, two or three substituted furans group; include a halogen atom-containing, - any (alkyl, nitro, carboxyl, acyloxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including a 4 , two or three substituted pyranyl groups; containing a halogen atom, d-C 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, d-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 such as an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkanoyl group of CrC 6 ; an alkoxy group including a halogen atom, d- or Any one, two or three substituted d-alkanes including a hydroxyl group Group; c 2 - enoyl; include a halogen atom-containing, - or any embankment hydroxyl group (6, including one, two or three substituents of C 2 - C e alkylene group; C 2 _Ce alkynyl acyl; contain any include halogen atoms, alkoxy or hydroxy (^ C 6 inner one, two or three substituents c-alkynyl group of 2 -c 6; c 3 - a cycloalkyl group; a halogen-containing comprising Any one, two or three substituted C 3 -( 6 cycloalkanoyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl acyl group, an atom, a decyloxy group or a hydroxy group of d-Ce ; furoyl; pyranoyl; thiophene; pyrroyl; X^ (C) n , n is 0-2; 0; S or NH; 3⁄4 is ((3⁄4)„, n is 0-2 ; 0; S or NH;
或者 R3、 分别为：
Figure imgf000007_0002
Or R 3 , respectively:
Figure imgf000007_0002
其中 为下列任意一种取代基： H; C 烷基； 含有包括卤素原子、 C「 0>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； （：2-( 6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 c(i的烯基； c2- c6的 炔基;含有包括卤素原子、 Ci-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 的炔基； C3- Ce的环垸基； 含有包括卤素原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个 或者三个取代的 c3-c6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- c4的垸基、 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芳基； 含有包括卤素原子、 (^-^的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 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、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d-c4的烷基、硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的噻吩基； 含有包括卤素原子、 c4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 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； c,-ce的烷酰基； 含 有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-Ce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、 （^-(]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的炔酰基； c3 c6的环烷酰基； 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 c3- ce的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（C ) n, n为 0- 2; 0； S或者 NH; Wherein is any one of the following substituents: H; C alkyl; any one, two or three substituted d~C 6 alkyl groups including a halogen atom, an alkoxy group of C "0" or a hydroxy group ; (: 2 -( 6 alkenyl; containing halogen Any one, two or three substituted c 2 c (i alkenyl group; c 2 - c 6 alkynyl group of the atom, c, -c 6 alkoxy group or hydroxy group; containing a halogen atom, Ci Any one, two or three substituted C 2 -C 6 alkynyl groups of -Ce alkoxy or hydroxy; C 3 - C e cyclodecyl; containing a halogen atom including a halogen atom, d-Ce Any one, two or three substituted c 3 -c 6 cycloalkyl groups, such as aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; Any one or two of a halogen atom, a fluorenyl group of d-c 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Or a three-substituted aryl group; containing a halogen atom, an alkyl group of (^-^, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group, a thio, including any one, two or three substituted pyridyl; include a halogen atom-containing, c 4 alkyl, nitro, carboxamide , Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; containing a halogen atom include, dc 4 Any one, two or three substituted pyrans of alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) one, two or three substituents thienyl; include a halogen atom-containing, C-alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio 4 Any one, two or three substituted pyrrolyl groups such as an ethylthio group; an alkanoyl group of c, -c e ; or any one or two containing an alkoxy group including a halogen atom, dC 6 or a hydroxyl group; Or an alkanoyl group of three substituted d-Ce; an enoyl group of c 2 - C 6 Any one, two or three substituted c 2 -c 6 enoyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 2 C 6 alkynyl group; containing a halogen atom, Any one, two or three substituted c 2 - c 6 alkynyl groups of (^-( 6 ) alkoxy or hydroxy; c 3 c 6 cycloalkanoyl; containing a halogen atom, d- Any one, two or three substituted c 3 - c e cycloalkanoyl groups of alkoxy or hydroxy groups of Cs; adamantyl formyl, substituted adamantyl formyl; aroyl; benzoyl; furoyl ; pyranoyl; thiophene; pyrrolyl; (C) n , n is 0-2; 0; S or NH;
或者 、 ¾分别为：
Figure imgf000008_0001
Or, 3⁄4 are:
Figure imgf000008_0001
其中 。、 各自独立为下列任意一种取代基： H; Cr 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 - 的烷基； C2- 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 （2-( 6的 烯基； C2-CB ½炔基； 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-Ce的炔基； C3-C6的环烷基； 含有包括卤素原子、 d- C6的烷氧基或羟基在内 的任意一个、两个或者三个取代的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基; 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的垸基、 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芳基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 -^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、 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、 Ct- G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、 (^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；among them. Each of which is independently a substituent of any of the following: H; an alkyl group of Cr C 6 ; an alkyl group containing any one, two or three substituents including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 2 -alkenyl group; any one, two or three substituted ( 2- ( 6 alkenyl; C 2 -C B 1⁄2 alkyne) containing a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Any one, two or three substituted C 2 -C e alkynyl groups including a halogen atom, an alkoxy group of d-Ce 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 a halogen atom, a d-C 6 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 fluorenyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and a thio, including any one, two or three aryl group substituents; containing a halogen atom include, D- (4 alkyl group, a nitro group Carboxyl, aldehyde, alkoxy, amine, amide group, carbonamide group, Any one, two or three substituted pyridyl groups including a fluorenyl group, a methylthio group, an ethylthio group; containing an alkyl group including a halogen atom, -^, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group Any one, two or three substituted furanyl groups, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde any, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; include a halogen atom-containing, C t - Any one, two or three substituted thiophenes of alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamido, decyl, methylthio, ethylthio Any one containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Two or three substituted pyrrolyl groups;
CrCs的烷酰基； 含有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个 取代的 d Ce的烷酰基； C2-C6的烯酰基； 含有包括卤素原子、 d- ( 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、 C,-^ 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3_C6的环烷酰基； 含有包括卤素原子、 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 （：3-( 6的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾)„， n为 0-2; 0； S或者 NH; 为（CH2)„, n为 0-2; 0； S或者 NH。 An alkanoyl group of CrC s; an alkanoyl group having any one, two or three substituted d Ce groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; a C 2 -C 6 alkenoyl group; Any one, two or three substituted C 2 -C 6 alkenoyl groups of an atom, d-( 6 alkoxy group or a hydroxyl group; a C 2 -C 6 alkynyl group; containing a halogen atom, C, - any of ^ alkoxy or hydroxy, including one, two or three substituents of C 2 -C 6 alkynyl group; a cycloalkyl group of C 3 _C 6; include a halogen atom-containing, C, -C 6 of Any one, two or three substituted alkoxy groups or hydroxy groups (: 3 -( 6 cycloalkanoyl; adamantyl form, substituted adamantyl form; aroyl group; benzyl group; furoyl group; Pyranoyl; thiophene; pyrrolyl; ((3⁄4) „, n is 0-2; 0; S or NH; (CH 2 ) „, n is 0-2; 0; S or NH .
或者， 当 R,、 R2分别各自独立为：
Figure imgf000009_0001
Or, when R, and R 2 are each independently:
Figure imgf000009_0001
其中 R12、 R13各自独立为下列任意一种取代基： H; C ( 6的垸基； 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 (^的烷基； C2- ( 8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- Ce的 烯基； C2-Cfi的炔基； 含有包括卤素原子、 Cs的垸氧基或羟基在内的任意一个、 两个或者 三个取代的 C2- (：6的炔基； C3- C6的环烷基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内 的任意一个、两个或者三个取代的 C3- Ce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、 （ - 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的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 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呋喃基； 含有包括卤素原子、 C,- C4的垸基、 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、 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、 -( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的垸酰基； 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 Ci-Ce的垸酰基； C2-C6的烯酰基； 含有包括卤素原子、 -( 6的垸氧基或羟基在内的 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 Ce 的垸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-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- ( (的 环垸酰基； 金刚垸甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾ ， n为 0- 2; 0； S或者 NH; 为（(¾)„， n为 0 - 2; 0； S或者 NH时； Wherein R 12, R 13 are each independently any of the following substituent groups: H; C (group 6 of the embankment; contain any halogen atom include, CrC 6 alkoxy or hydroxy, including one, two or three substituents An alkyl group of (2); C 2 - ( 8 alkenyl; an optionally, two or three substituted C 2 - C e alkenyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group ; C 2 -C fi alkynyl; any one, two or three substituted C 2 - (: 6 alkynyl group; C 3 - C containing a halogen atom, a decyloxy group of C s or a hydroxyl group; 6 cycloalkyl; includes any halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C e cycloalkyl; aryl; benzyl; furyl ; pyranyl; thienyl; pyrrolyl; pyridyl; containing halogen atom, (-C 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl Any one, two or three substituted aryl groups including a methylthio group and an ethylthio group; alkyl with arbitrary d- C 4, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three a substituted pyridyl group; containing an alkyl group including a halogen atom, CrC 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and the like. Any one, two or three substituted furanyl groups; a fluorenyl group containing 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 pyranyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three of an amide group, a carboxamide group, a thiol group, a methylthio group or an ethylthio group. A substituted thienyl group; contains include halogen atoms, - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted pyrrolyl groups; dC 6 decanoyl group; any one, two or three substituted Ci-Ce containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group the embankment acyl; C 2 -C 6 alkenyl group; a halogen atom-containing include, - embankment any alkoxy or hydroxy (6, including one, two or three substituents of c 2 -c 6 alkenyl group; a C An alkynyl group of 2 - C 6 ; a acetylene group of any one, two or three substituted c 2 - c 6 containing a halogen atom, a decyloxy group or a hydroxyl group of C Ce; a ring of c 3 -c 6 alkanoyl; contains include halogen atoms, alkoxy or hydroxy dC any e inner one, two or three substituents of C 3 - ((cyclic acyl embankment; adamantyl embankment formyl, substituted adamantane formyl; Aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyr Formyl; is ((¾, n is 0- 2; 0; S, or NH; is ((¾) ", n is 0--2; 0; S, or NH;
、 分别为-
Figure imgf000010_0001
, respectively -
Figure imgf000010_0001
其中 为下列任意一种取代基： H; -( 6的垸基； 含有包括卤素原子、 Cr ^的垸氧基 或羟基在内的任意一个、 两个或者三个取代的 Cr ( 6的烷基； C2- ( 6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- Ce的烯基； C2- C6的 炔基;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 的炔基； C3- Ce的环烷基； 含有包括卤素原子、 CrC6的垸氧基或羟基在内的任意一个、 两个 或者三个取代 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 Cr (：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 (^-(：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 ^的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、（,-( 的垸基、 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- (^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、 ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- C6的垸酰基； 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- Ce的烷 酰基； C2- Ce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- (]«的烯酰基； C2- C(i的炔酰基； 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- Cs的炔酰基； C3- Ce的环烷酰基； 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 C3- CB的环烷酰基； 金 刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； ¾为（CH2) n， n为 0- 2 ; 0； S或者 NH; Wherein any one of the following substituents: H; - ( 6 fluorenyl; any one, two or three substituted Cr ( 6 alkyl group) including a halogen atom, a Cr ^ decyloxy group or a hydroxyl group C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - C e alkenyl group including a halogen atom, d-alkoxy group or hydroxyl group; C 2 - C 6 Alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C e cycloalkyl group; Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, a decyloxy group or a hydroxyl group of CrC 6 ; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; Pyrrolyl; pyridyl; containing a halogen atom, Cr (: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio including any one, two or three aryl group substituents; include a halogen atom-containing, (^ - (: 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 methylthio group, an ethylthio group; 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. Containing any one including a halogen atom, (-, fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, d-(^, alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, an alkyl group of 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group , carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituents pyrrolyl group; a C 6 acyl D- embankment; includes any halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of d- C Alkanoyl group of e ; C 2 -C e enoyl group; any one, two or three substituted C 2 - (]« enoyl group containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; C 2 - C (i, alkynyl group; atoms containing pigment comprising, - one, two or three substituents at any of the C 2 alkoxy or hydroxy (including 6 - C s alkynyl group; C 3 - C a cycloalkanoyl group of e ; containing halogen Any one, two or three substituted C 3 - C B cycloalkanoyl groups of an atom, an alkoxy group of d-Ce or a hydroxyl group; an adamantyl formyl group, a substituted adamantyl group; an aroyl group; ; furoyl; pyranoyl; thiophene; pyrrolyl; 3⁄4 is (CH 2 ) n , n is 0-2; 0; S or NH;
或者 R3、 R4分别为-
Figure imgf000011_0001
Or R 3 and R 4 are -
Figure imgf000011_0001
其中 R7、 R8各自独立为下列任意一种取代基： H; d-C 垸基； 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 CrCe的烷基； C2-Ce的烯基； 含有包括卤素原子、 C,- 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- (^的 烯基； （2 6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- Cs的炔基； C3-C6的环烷基； 含有包括卤素原子、 C,- Ce的垸氧基或羟基在内 的任意一个、两个或者三个取代的 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 （ ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括 素原子、 C「 ( 4的垸基、 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、 (^-( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- ( 4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 ^-(：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的垸酰基； 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 C「Ce的烷酰基； C2- C6的烯酰基； 含有包括卤素原子、 d- ( 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-Gi 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- C6的炔酰基； C3-C6的环烷酰基; 含有包括卤素原子、 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- 的 环烷酰基； 金刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾)„， ri为 0- 2 ; 0； S或者 NH; 为（CH2) n， n为 0-2; 0； S或者 NH; Wherein R 7 and R 8 are each independently one of the following substituents: H; dC fluorenyl; any one, two or three substituted CrCe containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; An alkyl group; a C 2 -C e alkenyl group; any one, two or three substituted C 2 - (^ alkenyl groups) containing an alkoxy group or a hydroxyl group including a halogen atom, C, -C s ; (alkynyl group of 2 6 ; alkynyl group having any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group or a hydroxyl group; a C 3 -C 6 cycloalkyl group; ; include a halogen atom-containing, C, - C e of any embankment or a hydroxyl group, including one, two or three substituents of C 3 - C 6 cycloalkyl group; and an aryl group; a benzyl group; furanyl; pyrazol Thienyl; thiophenyl; pyrrolyl; pyridyl; containing halogen atom, ( 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methyl sulfide group, ethylthio, including any one, two or three aryl group substituents; including vegetarian containing atoms, C "(4 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 methylthio group, an ethylthio group; They include a halogen atom, (^ - (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including any one of 4, Two or three substituted furanyl groups; containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group) Any one, two or three substituted pyranyl groups including an ethylthio group; containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide) Any one, two or three substituted thienyl groups including a carbaryl group, a fluorenyl group, a methylthio group, an ethylthio group; a halogen atom, a ^-(: 4 alkyl group, a nitro group, a carboxyl group, Aldehyde, alkoxy, amine, amide, carboxamide, hydrazine , Methylthio, ethylthio, including any one, two or three substituents pyrrolyl; dC embankment 6 acyl; includes any halogen atom-containing, alkoxy or hydroxy dC 6 including a two a substituted or three C 'C E alkanoyl; C 2 - C 6 alkenyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy (6, including one, two or three substituents C 2 -C 6 alkenoyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 - C containing a halogen atom, a decyloxy group or a hydroxyl group of d-Gi 6 alkynyl group; C 3 -C 6 cycloalkyl group; or a hydroxyl group optionally containing embankment include a halogen atom, the inner one, two or three substituents of C 3 - a cycloalkyl group; an adamantyl carboxylic embankment Acyl, substituted adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; ((3⁄4), ri is 0-2; 0; S or NH; Is (CH 2 ) n , n is 0-2; 0; S or NH;
或者 R3、 分别为-
Figure imgf000011_0002
其中 为下列任意一种取代基： H; c,- 的垸基； 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 (：6的垸基； c2- ce的烯基； 含有包括卤素 原子、 d-C6的垸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- (^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-Ce 的炔基; c3- C6的环烷基； 含有包括卤素原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个 或者三个取代的( 3-( 6的环垸基； 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、 Cr ^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芳基； 含有包括卤素原子、 C, - ( 的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 C4的垸基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的呋喃基； 含有包括卤素原子、 的垸基、 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 个取代的吡喃基； 含有包括卤素原子、 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噻吩基； 含有包括卤素原子、 （ 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； Cr 的烷酰基； 含 有包括卤素原子、 - 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C「 C6的垸 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- Ce的炔酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基 在内的任意一个、 两个或者三个取代的 C2-C6的炔酰基； C3-C6的环烷酰基； 含有包括卤素 原子、 d-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_Ce的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（C ) n， n为 0- 2; 0； S或者 NH; Or R 3 , respectively -
Figure imgf000011_0002
Wherein is any one of the following substituents: H; c, a fluorenyl group; any one, two or three substituted (including 6 fluorenyl groups including a halogen atom, (a alkoxy group or a hydroxyl group) An alkenyl group of c 2 - c e ; any one, two or three substituted C 2 -C 6 alkenyl groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; C 2 - (^ Alkynyl group; any one, two or three substituted C 2 -C e alkynyl groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a c 3 -C 6 cycloalkyl group; Any one, two or three substituted groups including a halogen atom, a decyloxy group of dC e or a hydroxyl group ( 3- ( 6 -cycloalkyl; aryl; benzyl; furyl; pyranyl; thienyl) ; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, Cr ^, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted aryl groups; containing a halogen atom, C, - (indenyl group, nitro group, carboxyl group) Any aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, C 4 to Any one, two or three substituted furanyl groups including a mercapto group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Any one, two or three containing a halogen atom, a mercapto group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group a substituted pyranyl group; containing an alkyl group including a halogen atom, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and the like. Any one, two or three substituted thienyl groups; containing a halogen atom, ( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, methyl sulfide) Any of the base and ethylthio group One, two or three substituents pyrrolyl; of Cr alkanoyl; contains include halogen atoms, - alkoxy or hydroxy arbitrary, including one, two or three C embankment substituted acyl group "of the C 6; a C 2 -C 6 alkenoyl group; any one, two or three substituted C 2 -C 6 alkenoyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; C 2 - C e 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; Any one, two or three substituted C 3 _C e cycloalkanoyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; an adamantyl formyl group, a substituted adamantyl form group; an aroyl group; Acyl; furoyl; pyranoyl; thiophene; pyrrolyl; (C) n , n is 0-2; 0; S or NH;
或者 R3、 分别为:
Figure imgf000012_0001
Or R 3 , respectively:
Figure imgf000012_0001
其中 。、 Rtl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、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-C^的烷基； C2- Ce的烯基； 含有包括卤素原子、 Cr 的垸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- ( 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- ( 6的炔基； C3- C6的环垸基； 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 C3- Cs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「 ( 4的垸基、 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芳基； 含有包括卤素原子、 c4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 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、 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、 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、（^-( 4的浣基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 d- ( 4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 d-CB的垸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- (^的烯酰基； 含有包括卤素原子、 （^-( 6的垸氧基或羟基在内的 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的环垸酰基； 含有包括卤素原子、 Cr" Ce的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C:i- ^的 环烷酰基； 金刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X, ¾ (CH2) n, n为 0-2 ; 0； S或者 NH; 为（。¾)„， n为 0-2 ; 0； S或者簡。 among them. And R tl are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three substituted dCs including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; Alkenyl group; C 2 -C e alkenyl group; any one, two or three substituted C 2 -C 6 alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of Cr; C 2 - an alkynyl group; any one, two or three substituted C 2 - ( 6 alkynyl groups; C 3 - C 6 containing an alkoxy group including a halogen atom, C, -C 6 or a hydroxyl group; a cycloalkyl group; any one, two or three substituted C 3 - C s cycloalkyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; containing a halogen atom, C" ( 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, c 4 , a nitro group, a carboxyl group, and an aldehyde group Any one, two or three substituted pyridyl groups, an anthracene group, an amino group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-, Any one, two or three substituted furanyl groups including a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of an atom, d-(alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) a substituted pyranyl group; containing a halogen atom, (^-( 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group, methylthio group, B Any one, two or three substitutions including a thio group a thiophenyl group; containing a halogen atom, d- ( 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) Any one, two or three substituted pyrrolyl groups; dC 6 alkanoyl group; any one, two or three substituted alkanoyl groups containing a halogen atom, a decyloxy group or a hydroxyl group of dC B ; C 2 - (^ enoyl; include a halogen atom-containing, (^ - alkoxy or hydroxy arbitrary embankment (6, including one, two or three substituents of C 2 - C 6 alkenyl group of; C 2 - An alkynyl group of C 6 ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; a ring of C 3 -C 6 Decanoyl; any one, two or three substituted C :i- ^cycloalkanoyl groups including a halogen atom, an alkoxy group of Cr"C e or a hydroxyl group; adamantyl group, substituted Donkey Kong armor Acyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrole Acyl; X, 3⁄4 (CH 2 ) n , n is 0-2; 0; S or NH; is (.3⁄4) „, n is 0-2; 0; S or Jane.
此外更优选地， 当 、 R2分别各自独立为：
Figure imgf000013_0001
Further preferably, when R 2 is each independently:
Figure imgf000013_0001
其中 RM为下列任意一种取代基： H; CrCe的烷基； 含有包括卤素原子、 d- C6的垸氧基 或羟基在内的任意一个、 两个或者三个取代的 ( 6的烷基； C2- (6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- ( 6的烯基； C2- (；6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-CB 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 C3- C6的环垸基； 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、 Cr (4的垸基、 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芳基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 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、 0>的垸基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d -( 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 （ ^的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括卤素原子、 d-c4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- c6的烷酰基； 含 有包括卤素原子、 d- 的垸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-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； 含有包括卤素原子、 d- ( 6的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 c2-c6的炔酰基； c3- ce的环烷酰基； 含有包括卤素 原子、 c,-ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 c3_ce的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； X, ¾ (CH2)„, n为 0-2; 0； S或者 NH时; Wherein RM is any one of the following substituents: H; an alkyl group of CrCe; any one, two or three substituted ( 6 alkyl groups) including a halogen atom, a decyloxy group of d-C 6 or a hydroxyl group C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - (; 6 ) containing a halogen atom, an alkoxy group or a hydroxyl group; An alkynyl group; any one, two or three substituted C 2 -C B alkynyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted C 3 -C 6 cyclodecyl groups such as a halogen atom, an alkoxy group of a CrC 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; group; a pyridyl group; include a halogen atom-containing, Cr (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy embankment, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including Any one, two or three substituted aryl groups; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, Any one, two or three substituted pyridyl groups including an aldehyde group, a decyloxy 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 furanyl groups including a mercapto group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Any one or two containing a halogen atom, d-(alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group, and the like Or three a substituted pyranyl group; containing a halogen atom, (^, thiol, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted thienyl groups; containing a halogen atom, a fluorenyl group of dc 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, Any one, two or three substituted pyrrolyl groups such as a methylthio group or an ethylthio group; an alkanoyl group of d-c 6 ; or a fluorenyl group containing a halogen atom, d- or a hydroxyl group; a two or three substituted alkanoyl group; a C 2 -C 6 alkenoyl group; any one, two or three substituted C 2 - including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group. An alkenoyl group of C 6 ; a C 2 -C 6 alkynyl group; an alkyne containing any one, two or three substituted c 2 -c 6 including a halogen atom, d-( 6 fluorenyloxy group or hydroxyl group) acyl; c 3 - c e cycloalkyl group; a halogen atom include an oxygen-containing embankment, c, -c e of Including a hydroxyl group or any two or three substituted cycloalkyl group c 3 _c e; a formyl adamantane, substituted adamantane formyl; aryl group; a benzyl group; furoyl; formyl pyran; Thioyl group; pyrroyl group; X, 3⁄4 (CH 2 ) „, n is 0-2; 0; S or NH;
R3、 分别为：
Figure imgf000014_0001
R 3 , respectively:
Figure imgf000014_0001
其中 为下列任意一种取代基： H; (「( 6的垸基； 含有包括 lii素原子、 C「 (^的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 d- 的烷基； C2- C6的烯基； 含有包括卤素 原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- (：6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- Ce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的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- ( 的烷基、 硝基、 羧基、 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、 -( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 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、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的呋喃基； 含有包括卤素原子、 d-c4的烷基、硝基、 羧基、醛基、 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、 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、 （ (]4的垸基、 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咯基； c,- CB的烷酰基； 含 有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-c6的垸 酰基； c2- c6的烯酰基； 含有包括卤素原子、 的垸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- (]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-cs的炔酰基； c3- ce的环烷酰基； 含有包括卤素 原子、 C ;e的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c3- c6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； ¾为（CH2)„， n为 0-2 ; 0； S或者 NH; Wherein is any one of the following substituents: H; ("( 6 fluorenyl; any one, two or three substituted d- including a lii atom, C" (a alkoxy group or a hydroxyl group) An alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted C 2 - (: 6 alkenyl groups) containing a halogen atom, a decyloxy group of d-Ce or a hydroxyl group; (: 2 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, a C-C 6 alkoxy group or a hydroxyl group; C 3 - C e a cycloalkyl group; any one, two or three substituted c 3 - c 6 cyclodecyl groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; Pyranyl; thienyl; pyrrolyl; pyridyl; containing halogen atom, d-(alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, A any thio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, - (4 alkyl, nitro Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; any c 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents of a furan group; containing any one of a halogen atom, an alkyl group of dc 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group. , two or three substituted pyranyl groups; containing a halogen atom, a fluorenyl group of d-c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a group Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing a halogen atom, a mercapto group of ( 4 ), a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, Amido, carboxamide, sulfhydryl, methylthio, B Group, including any one, two or three substituents pyrrolyl; c, - C B of alkanoyl; contain any halogen atoms include, dC 6 alkoxy or hydroxy, including one, two or three substituted acyl dc embankment 6; c 2 - c 6 alkenoyl; embankment optionally containing a hydroxyl group include a halogen atom, or, the inner one, two or three substituents of c 2 -c 6 alkenyl group; and An alkynyl group of c 2 -c 6 ; a acetylene group of any one, two or three substituted c 2 -c s including a halogen atom, an alkoxy group of d-(] 6 or a hydroxyl group; c 3 - a cycloalkanoyl group of c e ; containing halogen Atom, C; e any of alkoxy or hydroxy, including one, two or three substituents of c 3 - c 6 cycloalkyl group; a formyl adamantane, substituted adamantane formyl; aroyl; benzoyl ; furoyl; pyranoyl; thiophene; pyrrolyl; 3⁄4 (CH 2 ), n is 0-2; 0; S or NH;
或者 、 分别为：
Figure imgf000015_0001
Or, respectively:
Figure imgf000015_0001
其中 R7、 各自独立为下列任意一种取代基： H; d- ( 6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 ^的垸基； C2-CJ烯基； 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- ( 6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- Cs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- Ce的环垸基； 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、 ^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、 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、 ^-( 4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- C4'的烷基、 硝 基、 羧基、 醛基、 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喃基； 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 d-C6的垸酰基； 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- Cs的烯酰基； C2-Ce的炔酰基； 含有包括卤素原子、 d-C6 的垸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； C:i-Ce的环烷酰基; 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 （3-(：6的 环垸酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（。¾)„, n为 0- 2 ; 0； S或者 NH; 为（CH2) n, n为 0 - 2 ; 0； S或者 NH; Wherein R 7 , each independently is any one of the following substituents: H; d- ( 6 alkyl; any one, two or three substituted including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group) a fluorenyl group; a C 2 -CJ alkenyl group; any one, two or three substituted C 2 - ( 6 alkenyl groups; C 2 containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; Alkynyl group of -C 6 ; alkynyl group of any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group of d- or a hydroxyl group; a C 3 - C 6 naphthenic group; Any one, two or three substituted C 3 -C e cyclodecyl groups including a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, Any one, two or three substituted aryl groups including an ethylthio group; containing a halogen atom, an 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 methylthio group, an ethylthio group; - any (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents a furanyl group; an alkyl group including a halogen atom, d-C 4 ', a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, a decyloxy 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 and 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, Amido, carboxamide, sulfhydryl, methylthio, ethylthio Including any one, two or three substituents pyrrolyl; dC 6 alkanoyl; contain any halogen atom include, dC 6 alkoxy or hydroxy, including one, two or three substituents of dC 6 Decanoyl; C 2 -C 6 alkenoyl; acyl having any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group or a hydroxyl group; C 2 -C Alkynyl group of e ; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; a cycloalkanoyl group of C :i -C e Any one, two or three substituted ( 3 -(: 6 cyclodecanoyl; adamantyl form, substituted adamantyl formyl group) including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; Aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; 3⁄4)„, n is 0- 2; 0; S or NH; is (CH 2 ) n , n is 0 - 2 ; 0; S or NH;
或者 R3、 分别为：
Figure imgf000015_0002
其中 为下列任意一种取代基： H; C「 Ce的垸基； 含有包括卤素原子、 d- C 烷氧基 或羟基在内的任意一个、 两个或者三个取代的 -( 6的垸基； c2- 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- ( 的烯基； C2- ( 6的 炔基;含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、两个或者三个取代的 C2-CB 的炔基； c3- Cs的环烷基； 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^- c6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- ( 的烷基、 硝基、 羧基、 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、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝 基、 羧基、 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呋喃基； 含有包括卤素原子、 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、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括卤素原子、 c4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 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； c,- ce的垸酰基； 含 有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或者三个取代的 CrC6的烷 酰基； c2-c6的烯酰基； 含有包括卤素原子、 d-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、 ^-(^的烷氧基或羟基 在内的任意一个、 两个或者三个取代的 c2-c6的炔酰基； c3- c«的环烷酰基； 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 C3- C6的环垸酰基； 金 刚垸甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH ， ri为 0- 2; 0； S或者 NH; Or R 3 , respectively:
Figure imgf000015_0002
Wherein is any one of the following substituents: H; C" thiol group of C e ; any one, two or three substituted groups including a halogen atom, a d-C alkoxy group or a hydroxyl group - ( 6垸group; c 2 - alkenyl; optionally include a halogen atom-containing, CrC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - (alkenyl; C 2 - (6 alkynyl Any one, two or three substituted C 2 -C B alkynyl group including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a cycloalkyl group of c 3 - C s ; containing a halogen atom any alkoxy or hydroxy dC e inner one, two or three substituents of ^ - c 6 cycloalkyl; and aryl; benzyl; furyl; tetrahydropyranyl; thienyl; pyrrolyl; Pyridyl; containing any of a halogen atom, d-(alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, thiol, methylthio, ethylthio one, two or three aryl group substituents; containing a halogen atom include, dC 4 alkyl group, a nitro group, a carboxyl group, Any, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, d- C 4 Any one, two or three substituted furanyl groups such as an alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Any one or two containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or a three-substituted pyranyl group; a fluorenyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and a Any one, two or three substituted thienyl groups including a thio group; containing an alkyl group including a halogen atom, c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group Any of thiol, methylthio, ethylthio One, two or three substituents pyrrolyl; c, - c e of embankment acyl; CrC contain any halogen atoms include, dC 6 alkoxy or hydroxy, including one, two or three substituents 6 Alkanoyl; c 2 -c 6 alkenoyl; any one, two or three substituted C 2 -C 6 alkenoyl group including a halogen atom, an alkoxy group of dc or a hydroxyl group; C 2 - C An alkynyl group of 6; a acetylenic group having any one, two or three substituted c 2 -c 6 groups including a halogen atom, an alkoxy group or a hydroxyl group; a cycloalkane of c 3 - c«; Any one, two or three substituted C 3 -C 6 cyclodecanoyl groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; adamantyl group, substituted adamantyl form; Aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH, ri is 0-2; 0; S or NH;
或者 R3、 ！^分别为：
Figure imgf000016_0001
Or R 3 , ! ^ are respectively:
Figure imgf000016_0001
其中^、 Ru各自独立为下列任意一种取代基： H; d-C 垸基； 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 d-G;的烷基； C2-C„的烯基； 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 - C(;的 烯基； C2- ( 6的炔基； 含有包括 素原子、 C「C6的垸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-Ce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、 Cr C4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芳基； 含有包括卤素原子、 d-c4的垸基、 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、Wherein, each of Ru and Ru is independently any one of the following substituents: H; dC fluorenyl; any one, two or three substituted dGs including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; An alkyl group; a C 2 -C„ alkenyl group; any one, two or three substituted C 2 - C (; alkenyl group; C containing an alkoxy group including a halogen atom, d-Ce or a hydroxyl group; 2 - (6 alkynyl; contain optional atoms including vegetarian, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkynyl group; C 3 - C 6 a cycloalkyl group; any one, two or three substituted C 3 -C e cycloalkyl groups including a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; an aryl group; a benzyl group; a pyranyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, Cr C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; a thiol 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 a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group;
CrC4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 ( 的垸基、 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- (^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、 （ -(：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的垸酰基； 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 Cr Ce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_Cr，的烯酰基； C2- Cs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- Ce的炔酰基； C3-C6的环垸酰基； 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 C:i- ( 6的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； ！为 ！! ， n为 0-2; 0； S或者 NH; X2为（CH2)„， n为 0 - 2; 0； S或者簡。 Any one, two or three substituted groups of a sulfhydryl 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 or an ethylthio group of CrC 4 a furan group; containing any one of a halogen atom, a sulfhydryl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethylthio group. Two or three substituted pyranyl groups; containing a halogen atom, d-(^, alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio Any one, two or three substituted thienyl groups, including a halogen atom; (-(: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, Any one, two or three substituted pyrrolyl groups such as an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group; a decanoyl group of dC 6 ; an alkoxy group containing a halogen atom, C "C 6 " Any one, two or three substitutions, including a hydroxy group Cr C e alkanoyl; C 2 -C 6 alkenyl group; a halogen atom-containing optionally include, d- C 6 alkoxy or hydroxy, including one, two or three substituents of C 2 _C r, a Alkenoyl; C 2 -C s acetylene; acetylene acyl group containing any one, two or three substituted C 2 - C e including a halogen atom, C "C 6 alkoxy group" or a hydroxyl group; 3- C6 cyclodecanoyl; any one, two or three substituted C :i- ( 6 -cycloalkanoyl; adamantane-containing group including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; Acyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; ! is !!, n is 0-2; 0; S or NH ; X 2 Is (CH 2 )„, n is 0 - 2; 0; S or Jane.
当 R、 R2分别各自独立为： When R and R 2 are each independently:
X2R16 X 2 R 16
其中 R15、 R16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!- 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- ( 6的炔基； 含有包括卤素原子、 （ 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- Cs的炔基； C3-C6的环烷基； 含有包括卤素原子、 d-Ce的垸氧基或羟基在内 的任意一个、两个或者三个取代的 c3- cs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、 的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 -(]4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 Cr C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的吡喃基； 含有包括卤素原子、 d- (^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- c的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基；Wherein R 15 and R 16 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; An alkyl group of c!-; an alkenyl group of c 2 -c 6 ; an alkenyl group containing any one, two or three substituted c 2 -c 6 groups including a halogen atom, an alkoxy group of c 6 or a hydroxyl group; C 2 - (alkynyl group of 6 ; alkynyl group containing any one, two or three substituted C 2 - C s including a halogen atom, (alkoxy group of Ce or a hydroxyl group); C 3 -C 6 cycloalkyl; contain any halogen atoms include, d-Ce alkoxy or hydroxy the embankment, including one, two or three substituents of c 3 - c s cycloalkyl; aryl; benzyl; furyl ; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom, a fluorenyl 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 methyl group Any one, two or three substituted aryl groups including an ethylthio group; an alkyl group containing a halogen atom, CrC 4 Any one, two or three substituted pyridyl groups including a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Any one or two of a halogen atom, an alkyl group of -(] 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Or a three-substituted furyl group; containing an alkyl group including a halogen atom, Cr C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethyl sulfide Arbitrarily One, two or three substituted pyranyl groups; containing a halogen atom, d-(^, alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, d-c, a nitro group, a carboxyl group, an acid group, an alkoxy group, an amine group, Any one, two or three substituted pyrrolyl groups such as an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group;
( 的烷酰基； 含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 Ce的烷酰基； C2- C6的烯酰基； 含有包括 1¾素原子、 c「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- Cs的炔酰基； 含有包括卤素原子、 的垸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-cs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 -^的 环垸酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X (CH ' n为 0- 2; 0; S或者 NH; 为（C )„, n为 0- 2; 0; S或者 NH时， (alkanoyl; alkanoyl group containing any one, two or three substituted C e including a halogen atom, an alkoxy group or a hydroxyl group of CrCe; a C 2 - C 6 alkenoyl group; containing a 13⁄4 atom any alkoxy or hydroxy c 'c E inner one, two or three substituents of c 2 - C 6 alkenyl group of; C 2 - C s alkynyl group; contains include halogen atoms, the oxygen embankment Any one, two or three substituted c 2 -c 6 alkynyl groups, or a hydroxyl group; c 3 -c s cycloalkanoyl group; containing a halogen atom, d- alkoxy group or hydroxyl group Any one, two or three substituted c 3 -^cyclodecanoyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanyl; pyranoyl; thiophene; Pyrroloyl; X (CH ' n is 0-2; 0; S or NH; is (C) „, n is 0-2; 0; S or NH,
R:i、 分别为：
Figure imgf000018_0001
R :i , respectively:
Figure imgf000018_0001
其中 为下列任意一种取代基： H; C「 C6的烷基； 含有包括卤素原子、 ( 6的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 d- C6的烷基； C2_CS的烯基； 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- ( 6的烯基； C2- ( 6的 炔基;含有包括卤素原子、 G-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-Ce 的炔基； C3- C6的环焼基； 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( 3- Ce的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 d- (^的垸基、 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、 CrC^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呋喃基； 含有包括卤素原子、 d- (^的垸基、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、 Cr 的垸基、 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- (：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- Cs的烧酰基； 含 有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 Cfi的烷 酰基； C2-C6的烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或 者三个取代的 C2- Cs的烯酰基； C2 的炔酰基； 含有包括卤素原子、 d- ( 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的炔酰基； c3- c6的环烷酰基； 含有包括卤素 原子、 CrC6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3-Cfi的环烷酰基； 金 刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2)„， n为 0- 2; 0； S或者 NH; Wherein any one of the following substituent groups: H; alkyl C "6, C; include a halogen atom-containing, any alkoxy or hydroxy (6, including one, two or three substituents of C 6 D- Alkyl; C 2 _C S alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; (6 alkynyl group; a halogen atom includes any containing, G-Ce alkoxy or hydroxy group including one, two or three substituents of C 2 -C e alkynyl group; C 3 - C 6 cycloalkyl firing of Any one, two or three substituted ( 3 -C e cycloalkyl groups; aryl; benzyl; furyl; pyran) containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; a thiophenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, d-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 sulfide group; Any one, two or three substituted aryl groups including a thiol group, a halogen atom, a fluorenyl group, a nitro 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 decyl group, a methylthio group, an ethylthio group; Any one, two or three substituted furans of alkyl, nitro, carboxy, aldehyde, decyloxy, amino, amido, carboxamido, decyl, methylthio, ethylthio Any one containing a halogen atom, d-(^, sulfonyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio One, two or three substituted pyranyl groups; containing a halogen atom, a sulfhydryl 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 Any one, two or three substituted thienyl groups including an ethylthio group; containing a halogen atom, d- (: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide) Base, carboxamide, sulfhydryl, methylthio, ethylthio Within any one, two or three substituents pyrrolyl; dC s burned group; a halogen atom-containing optionally include, a hydroxyl group or a dC embankment 6 of the inner one, two or three substituents of C fi alkanoyl; C 2 -C 6 alkenyl group; and one, two or three substituents containing a C 2 optionally include a halogen atom, alkoxy or hydroxy CrC 6 including - C s alkylene group; C Alkynyl group of 2 ; containing an alkoxy group or a hydroxyl group including a halogen atom, d- ( 6 ) Any one, two or three substituted c 2 - c 6 alkynyl groups; c 3 - c 6 cycloalkanoyl group; any one containing a halogen atom, a decyloxy group of CrC 6 or a hydroxyl group , two or three substituted C 3 -C fi cycloalkanoyl; adamantyl formyl, substituted adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrole Acyl; (CH 2 ), n is 0-2; 0; S or NH;
或者 、 分别为：
Figure imgf000019_0001
Or, respectively:
Figure imgf000019_0001
其中 R7、 各自独立为下列任意一种取代基： H; C6的垸基； 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 C「 C6的垸基； C2- ( 6的烯基； 含有包括卤素原子、 -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- ^的 烯基； C2- ( 6的炔基； 含有包括卤素原子、 CrCs的垸氧基或羟基在内的任意一个、 两个或者 三个取代的（2-( 6的炔基； C3- Ce的环烷基； 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 ( 的环垸基； 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、 （ (：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 (^-( 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呋喃基； 含有包括卤素原子、 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 —个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 C「 ( 的燒基、 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、 ( 4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基; d- 的烷酰基； 含有包括卤素原子、 - 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的垸酰基； C2-C6的烯酰基； 含有包括卤素原子、 Ct-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-cs的炔酰基； 含有包括卤素原子、 c,-cs 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 c2- ce的炔酰基； c3- c6的环垸酰基; 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 C:,- ( 6的 环烷酰基； 金刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X^ (CH , n为 0- 2; 0； S或者 NH; X2为（CH2) n, n为 0 - 2; 0； S或者 NH; Wherein R 7 is each independently a substituent of any of the following: H; a fluorenyl group of C 6 ; any one, two or three substituted C's including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group. alkyl with C 6; C 2 - (6 alkenyl group; a halogen atom-containing optionally include, -Cs alkoxy or hydroxy group including one, two or three substituents of C 2 - ^ alkenyl; C 2- ( 6 alkynyl; any one, two or three substituted ( 2- ( 6 alkynyl; C 3 - C e ring) containing a halogen atom, a decyloxy group or a hydroxyl group of CrC s Any one, two or three substituted (cycloalkyl; aryl; benzyl; furyl; pyranyl; a thiophenyl group; a pyrrolyl group; a pyridyl group; containing a halogen atom, ((: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, Any one, two or three substituted aryl groups including an ethylthio group; containing an alkyl group including a halogen atom and d-( 4 ) 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 methylthio group, an ethylthio group; They include a halogen atom, (^ - (alkyl, nitro, carboxyl, aldehyde, alkoxy embankment, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including any one of 4, Two or three substituted furanyl groups; including halogen atom, alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, C" (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide) , any mercapto, methylthio, ethylthio, including one, two or three substituents thienyl; include halogen atom-containing, (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine Base, amide group, carboxamide group, sulfhydryl group, methylthio group, Any one, two or three substituted pyrrolyl groups including an ethylthio group; an alkanoyl group of d-; any one, two or three substituted groups including a halogen atom, an alkoxy group or a hydroxyl group a decanoyl group of dC 6 ; an enoyl group of C 2 -C 6 ; an acyl group of any one, two or three substituted c 2 -c 6 containing an alkoxy group including a halogen atom, Ct-Ce or a hydroxyl group; Alkynyl group of c 2 -c s ; acetylene group of any one, two or three substituted c 2 - c e containing a halogen atom or a hydroxyl group including a halogen atom, c, -c s ; c 3 - a cyclic acyl group of c 6 ; any one, two or three substituted C:, - ( 6 cycloalkanoyl; adamantyl group) having a halogen atom, a C, or an alkoxy group or a hydroxyl group , substituted adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; X^ (CH, n is 0-2; 0; S or NH; X 2 is (CH 2 ) n , n is 0 - 2; 0; S or NH;
或者 、 ^分别为：
Figure imgf000020_0001
Or, ^ are:
Figure imgf000020_0001
其中 为下列任意一种取代基： H; d- (：6的烷基； 含有包括卤素原子、 d- Ce的垸氧基 或羟基在内的任意一个、 两个或者三个取代的 d- (：6的烷基； C2-C6的烯基； 含有包括卤素 原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的（2-( 6的烯基； C2- Ce的 炔基;含有包括卤素原子、 c - 的垸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- ，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- ce的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- ^的烷基、 硝基、 羧基、 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- ( 的垸基、 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的垸基、 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、 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 素原子、 c「 (4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基； 含有包括卤素原子、 d- c4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- ce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- 的烷 酰基； C2- C6的烯酰基； 含有包括卤素原子、 d-C3的烷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- cs的炔酰基； c3- c6的环烷酰基； 含有包括卤素 原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- C6的环垸酰基； 金 刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH ， n为 0- 2; 0； S或者 NH; Wherein is any one of the following substituents: H; d- (: 6 alkyl; any one, two or three substituted d-containing a halogen atom or a hydroxyl group including a halogen atom, d-C e ( 6 : an alkyl group; a C 2 -C 6 alkenyl group; any one, two or three substituted ( 2- ( 6- ) alkenyl group including a halogen atom, a decyloxy group or a hydroxyl group of dC e An alkynyl group of C 2 -C e ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, a decyloxy group or a hydroxy group; c 3 - , a cycloalkyl group; any one, two or three substituted c 3 - c e cycloalkyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl 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, a carboxamide group, a fluorenyl group, a methyl sulfide Any one, two or three substituted aryl groups including a thiol group, including a halogen atom, a fluorenyl group, a nitro group Any carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two, three or substituted pyridyl; include a halogen atom-containing, CrC any alkyl with 4, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furan Any one containing a halogen atom, (C4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group, two or three substituted pyran group; comprising pigment containing atoms, C "(4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio Any one, two or three substituted thienyl groups including a thiol group; an alkyl group including a halogen atom, d-c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group Base, carboxamide, sulfhydryl, methylthio, Thio, including any one, two or three substituents pyrrolyl; d- c e alkanoyl; contain any halogen atoms include, CrC 6 alkoxy or hydroxy, including one, two or three Substituted d-alkanoyl; C 2 -C 6 enoyl; any one, two or three substituted c 2 - c 6 olefins including a halogen atom, an alkoxy group of dC 3 or a hydroxyl group Acyl group; c 2 - c 6 alkynyl group; alkynyl group containing any one, two or three substituted c 2 - c s including a halogen atom, c "c 6 alkoxy group" or a hydroxyl group; c 3 a cycloalkanoyl group of c 6 ; any one, two or three substituted C 3 -C 6 cyclodecanoyl groups including a halogen atom, a decyloxy group or a hydroxyl group of dC e ; an adamantyl formyl group, a substitution Adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH, n is 0-2; 0; S or NH;
或者 R3、 分别为:
Figure imgf000020_0002
Or R 3 , respectively:
Figure imgf000020_0002
其中 Ri。、 Ru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,-C3的垸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- Ce 烯基； 含有包括卤素原子、 d-Cs的垸氧基或羟基在内的任意一个、 两个或者三个取代的 （2-(：6的 烯基； C2- ( 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 2007/002959 三个取代的 c2- Ce的炔基； C3- C6的环烷基； 含有包括卤素原子、 d- c6的烷氧基或羟基在内 的任意一个、两个或者三个取代的 c3-c6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 0>的烧基、 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、 ( 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、Where Ri. , R u are each independently any of the following substituent groups: H; CrC 6 alkyl; one, two or three substituents include a halogen atom-containing arbitrary, C, -C 3 alkoxy or hydroxy embankment inner of D-^ alkyl; C 2 -C e alkenyl; any one, two or three substituted ( 2- ( 6 olefin) containing a halogen atom, a decyloxy group or a hydroxyl group of d-Cs a C 2 - (alkynyl group; any one or two containing an alkoxy group including a halogen atom, C, or C 6 or a hydroxyl group; 2007/002959 three substituted c 2 -C e alkynyl groups; C 3 -C 6 cycloalkyl groups; containing any one or two including a halogen atom, an alkoxy group of d-c 6 or a hydroxyl group or Three substituted c 3 -c 6 cycloalkyl; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing a halogen atom, Any one, two or three substituted aryl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substituted pyridines of 4 , alkyl, nitro, carboxyl, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Containing a halogen atom,
Cr ( 的烷基、 硝基、 羧基、 酸基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- 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- ( 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 个取代的噻吩基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、碳酰胺基、巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡咯基； d-Ce的烷酰基； 含有包括卤素原子、 CrCs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-Ce的烯酰基； 含有包括卤素原子、 -(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、 C「C6 的垸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- Cs的环烷酰基； 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 （3-^的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X,为（C )„, n为 0-2; 0； S或者 NH; 为（CH2)„, n为 0- 2; 0； S或者 NH。 Any one, two or three substituted groups of Cr (alkyl, nitro, carboxyl, acid, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) a furan group; any one containing a halogen atom, an alkyl group of a 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 methylthio group, an ethylthio group , two or three substituted pyranyl groups; containing a halogen atom, d-( 4 alkyl, nitro, carboxyl, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, A Any one, two or three substituted thienyl groups including a thio group or an ethylthio group; containing an alkyl group including a halogen atom, dC 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group Any one, two or three substituted pyrrolyl groups, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkanoyl group of dC e ; an alkoxy group or a hydroxyl group including a halogen atom, CrCs Any one, two or three substituted (alkanoyl) a C 2 -C e alkenoyl group; an enoyl group containing any one, two or three substituted C 2 -C 6 groups including a halogen atom, -( 6 alkoxy group or a hydroxyl group; C 2 - C 6 alkynyl group; one, two or three of the substituents include halogen atoms contain any C, C 'C 6 alkoxy or hydroxy embankment, including 2 - C 6 alkynyl group; C 3 - C s cyclic alkanoyl; (3 contain any include halogen atoms, alkoxy or hydroxy C 6 inner one, two or three substituents of - ^ cycloalkyl group; formyl adamantane, substituted adamantane formyl; aryl Acyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; X, (C) „, n is 0-2; 0; S or NH; (CH 2 ) „, n Is 0-2; 0; S or 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。  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 invention also provides a medicament comprising the above compound for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (eg Alzheimer's) Ill).
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 样肽一 1受体的化合物或其药物学上可接受的盐， 以预防或治疗上述疾病或症状。优选地， 上述代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛素抵抗和肥胖症）、 心血管疾病和神 经退行性疾病 （如 Alzheimer' s病） 等通过给予有效量的由以下通式 I或 II表示的具有 取代四元环结构的化合物、 或其药物学上可接受的盐、 酯、 溶剂化物、 金属配合物或者具 有相同药理作用的前药：
Figure imgf000022_0001
所述化合物包括其所有的立体和光学异构体。 In a further aspect, the invention relates to methods of preventing and/or treating metabolic disorders, including but not limited to diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease. The method comprises administering to a subject in need or willing to receive treatment or prevention an effective amount of a compound which 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 the following Formula I or a compound having a substituted four-membered ring structure represented by II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action:
Figure imgf000022_0001
The compounds include all stereo and optical isomers thereof.
其中 X和 Y分别为 (CH2)„, n为 0-2; 0； S或者 NH。 Wherein X and Y are respectively (CH 2 ) „, n is 0-2; 0; S or NH.
其中 、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环烷基； 羟基； 硝 基； 羧基； 醛基； 烷氧基； 胺基； 胺垸基； 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； 或者， 取代或未取代的吡咯基。 Wherein R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
、 各自独立地为下列任意一种取代基： 氢； 烷基； 环垸基； 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。  Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; 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.
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 肽一 1 受体， 尤其是激活该受体功能的化合物， 或其药物学上可接受的盐， 或单独， 或与 药物学上可接受的载体或赋形剂组合存在。 该化合物具有以下通式 I或 II的结构-  In another aspect, the present invention relates to a combination preparation comprising a compound having a selective modulation of a glucagon-like peptide-1 receptor, particularly a function of activating the receptor, or a pharmaceutically acceptable salt thereof Or alone or in combination with a pharmaceutically acceptable carrier or excipient. This compound has the structure of the following formula I or II -
Figure imgf000022_0002
及其所有的立体和光学异构体， 或者与其具有相同药理作用的前药、 其酯、 其溶剂化物或 其金属配合物。
Figure imgf000022_0002
And all of its stereo and optical isomers, or prodrugs having the same pharmacological effects, esters thereof, solvates thereof or metal complexes thereof.
其中 X和 Y分别为 (CH2)„, n为 0-2; 0； S或者 NH。 Wherein X and Y are respectively (CH 2 ) „, n is 0-2; 0; S or NH.
_ 其中 、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环烷基； 羟基； 硝 基； 羧基； 醛基； 烷氧基； 胺基； 胺垸基； 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； 或者， 取代或未取代的吡咯基。 Wherein R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine sulfhydryl; ; carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Or an unsubstituted thiophenyl group; or a substituted or unsubstituted pyrrolyl group.
R3、 各自独立地为下列任意一种取代基： 氢； 烷基； 环烷基； 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 （包括伹不局限于糖尿病、 胰岛素抵抗和肥胖症)、 心血 管疾病和神经退行性疾病 （如 Alzheimer' s病）等， 达到选择性地激动胰高血糖素样肽一 1受体的药效， 改善患者的症状和生命质量。 R 3 , each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl. ' The present invention provides a kit comprising the above combined preparation. The present invention still further provides the use of the above combined preparation for the prevention and/or treatment of metabolic disorders (including sputum not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). ), to achieve selective stimulation of the glucagon-like peptide-1 receptor, improve the patient's symptoms and quality of life.
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。  In order to clarify the contents of the invention and not to be limited thereto, the invention will be described in detail in the following subsections.
A定义 除非另有定义， 本发明所用的技术和科学上的术语， 与本发明所属领域的通用技术的 一般理解具有相同意义。 本处提到的来源于基因库和其他数据库的所有专利， 申请， 公布 的申请和其他出版物和序列被全面收入引用作为参考。 如果本节阐明的定义与本专利参用 的来源于基因库和其他数据库的所有专利， 申请， 公布的申请和其他出版物和序列被收入 和引用的定义阐述相反， 或不一致时， 以本节阐明的定义为准。  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.
本文所用， "一"或 "一个"指 "至少一个" 或 "一个或多个"。  As used herein, "a" or "an" refers to "at least one" or "one or more."
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。  As used herein, "metabolic disorder" refers to a related symptom and/or disease caused by metabolic disorders such as sugar, fat or protein caused by various causes.
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。  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 insulin secretion and/or dysfunction. 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.
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。  As used herein, "insulin resistance" refers to a decrease in the sensitivity of tissues surrounding the body 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.
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。  As used herein, "obesity" refers to an excess of body fat, a male weighing more than 25% of the ideal body weight, or a woman weighing more than 30% of the ideal body weight. Genetic factors, hypothalamic disease, endocrine disorders, overeating and too little activity are all causes of obesity.
本文所用， "阿尔茨海默病（Alzheimer' s Disease, AD, 又称早老性痴呆 Alzheimer' s dementia) 是一种神经系统的进行性蜕变性疾病， 临床上表现为智力水平的慢性削弱及记 忆的慢性丢失。  As used herein, "Alzheimer's Disease (AD), also known as Alzheimer's dementia) is a progressive degenerative disease of the nervous system, clinically characterized by chronic impairment of intelligence and memory. Chronic loss.
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。  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".
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。 An "effective amount" of a compound for treating a particular disease as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease. This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable. As used herein, "pharmaceutically acceptable salts, esters or other derivatives" include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods. The compounds thus derived and produced can be administered to animals and humans without toxic effects. The compound is either pharmaceutically active or a prodrug.
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。  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.
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。  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.
本文所用， "基本上纯" 是指足够均匀， 通过本领域技术人员为评价纯度使用的标 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。  As used herein, "substantially pure" means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis, and High performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the 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.
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 Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392]。  As used herein, "prodrug" refers to a compound that is administered in vivo and which can be metabolized or converted into 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 to transport precursors of properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties. By virtue of pharmacokinetics and knowledge of the 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"相同或均匀或相似， 按照本 4页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。  The term "substantially" is the same or uniform or similar, and the understanding of the related art by those skilled in the art can vary from context to context and is generally at least 70%, preferably at least 80%, more preferably at least 90%. , optimally at least 95% identical.
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。  As used herein, "composition" refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
这里所用的 "联合"指两种或多种之间的任何联合。  As used herein, "union" refers to any association between two or more.
这里使用的术语 "对象"包括人和动物， 例如， 狗， 猫， 牛， 猪， 啮齿动物等。 有经 验的实施者应可理解对象为适于并愿意对代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛 素抵抗和肥胖症）、 心血管疾病和神经退行性疾病 （如 Alzheimer' s病）等进行治疗和预 防。  The term "object" as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like. Experienced practitioners should understand that the subject is suitable and willing to be resistant to metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular disease and neurodegenerative diseases (such as Alzheimer's disease). Treatment and prevention.
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。  Any of the protective groups, abbreviations for amino acids and other compounds used herein, are consistent with their general, recognized abbreviations or the Biochemical Nomenclature issued by the IUPAC-IUB Committee, unless otherwise stated.
B胰髙血糖素样肽一 1受体调节剂 本发明提供胰高血糖素样肽一 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（包括但不局限于糠尿病、胰岛素抵抗和肥胖症)、心血管疾病和神经退行性疾病（如B-glucagon-like peptide-1 receptor modulator The present invention provides a modulator of glucagon-like peptide-1 receptor function, which increases prevention and/or treatment of metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and Neurodegenerative diseases (such as
Alzheimer' s病）等药物的成员。本发明涉及由以下通式 I或 II表示的具有取代四元环结 构的化合物， 或其药物学上可接受的盐、 酯、 溶剂化物、 金属配合物或者具有相同药理作 用的前药- Member of the drug such as Alzheimer's disease. The present invention relates to a compound having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or prodrug having the same pharmacological action -
Figure imgf000025_0001
所述化合物包括其所有的立体和光学异构体。
Figure imgf000025_0001
The compounds include all stereo and optical isomers thereof.
其中 X和 Y分别为 (CH2)„, n为 0-2; 0； S或者 NH。 Wherein X and Y are respectively (CH 2 ) „, n is 0-2; 0; S or NH.
其中 、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环垸基； 羟基； 硝 基； 羧基； 醛基； 垸氧基； 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； 或者， 取代或未取代的吡咯基。 Wherein R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; oxiran; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
、 R4各自独立地为下列任意一种取代基： 氢； 烷基； 环烷基； 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。 And R 4 are each independently one of the following substituents: hydrogen; alkyl; cycloalkyl; 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.
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。  The compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture. The compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain different amounts of bound water molecules.
本发明的化合物可按照任何合适的方法来制备或合成。 优选地， 用以下面 F节中引证 的合成法制备该化合物。  The compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compound is prepared by the synthetic method cited in Section F below.
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^：可接受的载体或赋形剂结合。  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.
本发明的化合物可用任何合适的酸以其药物学上可接受的盐的形式来制备。 例如， 无 机酸如盐酸、 氢溴酸、 硝酸、 硫酸、 磷酸等； 有机酸诸如甲酸、 乙酸、 丙酸、 苯甲酸、 马 来酸、 富马酸、 琥珀酸、 酒石酸、 柠檬酸等； 烷基磺酸如甲基磺酸、 乙基磺酸等； 芳基磺 酸如苯磺酸、 对甲苯磺酸等均可使用。  The compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; A sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
C治疗和预防方法 本发明涉及用于预防和 /或治疗代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛素抵 抗和肥胖症）、 心血管疾病和神经退行性疾病 （如 Alzheimer' s病）等的方法。 该方法包 括对需要或愿意接受治疗或预防的对象， 给予有效量的、 选择性地激动胰高血糖素样肽一 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。 C treatment and prevention methods The present invention relates to methods for preventing and/or treating metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease. The method comprises administering to a subject in need or willingness 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.
优选地， 上述疾病通过给予有效量的由以下通式 I或 II表示的具有取代四元环结构 的化合物、 或其药物学上可接受的盐、 酯、 溶剂化物、 金属配合物或者具有相同药理作用 的前药来治疗或预防：  Preferably, the above-mentioned disease is by administering an effective amount of a compound having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof or the same pharmacological agent The prodrug of action to treat or prevent:
Figure imgf000026_0001
所述化合物包括其所有的立体和光学异构体。
Figure imgf000026_0001
The compounds include all stereo and optical isomers thereof.
其中 X和 Y分别为 (CH2)„， n为 0-2; 0； S或者 NH。 Wherein X and Y are respectively (CH 2 ) „, n is 0-2; 0; S or NH.
其中 、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环垸基； 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； 或者， 取代或未取代的吡咯基。 Wherein R 2 is each independently one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl.
、 各自独立地为下列任意一种取代基： 氢； 烷基； 环烷基； 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。  Each of which is independently a substituent of any of the following: hydrogen; alkyl; cycloalkyl; 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.
可以用本方法防治任何对象， 优选哺乳动物， 更优选人。  Any subject can be controlled by this method, preferably a mammal, more preferably a human.
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。  The method can be used to control metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease). A preferred disease or condition is any disease or condition caused or accompanied by insulin secretion and/or dysfunction.
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。  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.
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。 可以通过任何合适的方法单独以本发明的化合物给药， 或与其他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。 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. Administration of the compounds of the invention alone or in combination with other suitable diabetes therapeutics including insulin sensitizers can be by any suitable method. 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.
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 W0 01/44815和美 国专利 5， 571， 674揭示的诊断或预后方法。  In a specific embodiment, the method further comprises performing a diagnosis and prognosis 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 related symptoms. For example, a diagnostic or prognostic method disclosed in International Patent No. WO 01/44815 and U.S. Patent No. 5,571,674 can be used.
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一 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。 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.
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 I或 II表示：  Preferably, such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutic agent for one or more metabolic disorders including an insulin sensitizer, which is represented by the following formula I or II:
Figure imgf000027_0001
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。
Figure imgf000027_0001
And all of its stereo and optical isomers, or prodrugs having the same pharmacological effects, esters thereof, solvates thereof or metal complexes thereof.
其中 X和 Y分别为（CH ， n为 0-2; 0； S或者 NH。  Wherein X and Y are respectively (CH, n is 0-2; 0; S or NH.
. 其中 、 各自独立地为下列任意一种取代基： 氢； 卤素； 烷基； 环烷基； 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； 或者， 取代或未取代的吡咯基。 Wherein each independently is any one of the following substituents: hydrogen; halogen; alkyl; cycloalkyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Amido; thiol; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Substituted thienyl; or substituted or unsubstituted pyrrolyl.
R3、 各自独立地为下列任意一种取代基： 氢； 烷基； 环烷基； 烷氧基； 胺基； 胺烷 基； 酰胺基； 碳酰胺基； 垸硫基； 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 3 , each independently of any of the following substituents: hydrogen; alkyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; thiol; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
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。 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.
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。  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.
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。  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、 肌内注射、 真皮内注射、 口服或局部用药。 本方法可以使用注射给药制剂， 以单剂量的形式在安瓿， 或多剂量容器 中与添加的缓冲剂注射给药。 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 采用泡沬， 凝胶， 软膏， 油膏， 转皮膜片， 或膏状物。  Formulations and Dosages According to the invention, the compounds of the invention, alone or in combination with other agents, carriers or excipients, are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular Injection, intradermal injection, oral or topical medication. The method can be administered by injection in a single dose in an ampoule, or in a multi-dose container with an added 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, the active ingredient may be in a powder form with a suitable vehicle, sterile non-pyrogenic water or other solvent before use. The topical preparation of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
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 Bl、 5， 741, 511、 5， 886, 039、 5, 941， 868、 6, 258, 374B1和 5, 686， 102 所阐述的内容。  Pharmaceutical compositions and methods for administration that may be used in the present invention include, but are not limited to, U.S. Patents 5,736,154, 6,197, 801 Bl, 5,741,511, 5, 886, 039 5, 941, 868, 6, 258, 374B1 and 5, 686, 102.
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。  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 dose and frequency of administration will vary with age, weight, health status, and individual patient response.
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。  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 to increase the dose.
任何合适的给药途径均可被采用。剂型包括片剂， 锭剂， 豆状胶囊， 分散剂， 悬浮剂， 溶液， 胶囊， 膜片及类似物等。  Any suitable route of administration can be employed. Dosage forms include tablets, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
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—羟基一丙基一 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，缓冲剂，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， 缓冲溶液， 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。 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-hydroxypropyl-β-cyclodextrin. Finely mixed. Depending on the needs of the administration, a special carrier, a local or parenteral route, may be employed. For the preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion, similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. . Examples of such parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions. The total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 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.
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。  In another embodiment, the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.
F制备方法 本发明的通式 I或 II表示的化合物按如下所述的方法制备， 其中所用原料参照中国 专利申请（申请号： 200310109331. 0) 中所描述的合成方法合成。 本发明的通式 I 或 II 表示的化合物制备方法如下：
Figure imgf000029_0001
F Preparation method The compound represented by the formula I or II of the present invention is produced by the method described below, wherein the starting materials are synthesized by the synthesis method described in the Chinese Patent Application (Application No.: 200310109331. 0). The preparation method of the compound represented by the formula I or II of the present invention is as follows:
Figure imgf000029_0001
化合物 1和化合物 2溶于适量的二氯甲烷、 水、 二氯乙烷、 DMS0、 二氧六环或上述溶 剂的混合溶剂中， 任选加入催化量的二苯酮， 反应温度控制在 0。C〜60°C间， 置于 150W高 压汞灯或自然光下光照 1天到 2个月， 期间用 HPLC检测跟踪反应， 冷冻干燥除去溶剂， 剩余物用反相硅胶柱层析分离得到本发明的化合物。 附图说明  The compound 1 and the compound 2 are dissolved in a suitable amount of a mixed solvent of dichloromethane, water, dichloroethane, DMSO, dioxane or the above solvent, optionally with a catalytic amount of benzophenone, and the reaction temperature is controlled at 0. Between C and 60 ° C, placed in a 150W high-pressure mercury lamp or natural light for 1 day to 2 months, during the period by HPLC detection of the reaction, lyophilization to remove the solvent, the residue was separated by reverse-phase silica gel column chromatography to obtain the present invention Compound. DRAWINGS
图 1说明 化合物 S4P和 Boc5的体外药效学试验结果 a. 分别用不同浓度的 GLP - 1、 S4P和 Boc5诱导 HEK293/GLP1R+Luc， 通过检测 CRE驱动的荧光素酶报告基因的表达评估 化合物的相对 （100 %， 10 nM的 GLP- 1 )激动活性。 化合物 S4P和 Boc5对 GLP- 1R的激动 活性均具剂量依赖性， 且两者的 EC5。数值相近（S4P为 1. 2 μ Μ， Boc5为 3. 1 μ Μ)， 但 S4P 在 10 μΜ时的反应强度为 GLP- 1 ( ΙΟ ηΜ)的 37. 3%， 而 Boc5为 GLP- 1R的全激动剂。 b. 应 用 Exendin (9- 39)验证化合物对 GLP- 1R激动活性的受体特异性。 当分别加入 0. 05 nM GLP- 1、 10 4M S4P和 Boc5时， Exendin (9-39)均可剂量依赖性地抑制其所诱导的报告基因 表达， IC5。值分别为 68. 22、 14. 69及 33. 38 nM, 表明 S4P和 Boc5的生物活性和 GLP- 1— 样， 是通过 GLP-1R介导的。 c. 以 1251标记的 GLP— 1作为配基， 通过竞争性结合试验方法 检测化合物对受体的亲合力。 当不同浓度梯度的 GLP- 1、 S4P和 Boc5与1251标 GLP- 1及从 HEK293/GLP1R+LUC细胞提取的 GLP1R共同孵育时， S4P和 Boc5均能特异性地与 1MI标 GLP-1 竞争性结合，其在 30 μ M时的抑制率分别达到 80. 6%和 63. 7 % ,两者的 IC5。值分别为 286. 6 nM和 1. 5 μ Μ。 同样实验条件下， GLP-1的 IC5。值为 0. 66 nM。 图 2说明 化合物 Boc5的摄食抑制试验结果 应用 C57BL/6小鼠， 隔夜禁食后腹腔注 射 Boc5溶液和阳性对照 （或者拮抗剂）， 每间隔 15- 30分钟观察摄食量。 a. Boc5腹腔注 射剂量依赖地抑制食欲， 在 Boc5 2 mg/20g体重的剂量下， 12小时的摄食抑制率为 54土 13% ( 0. 0034)。 b. 腹腔注射 Boc5抑制食欲的 ED6„值为 1. 57士 0. 09 mg Γ80 mg/kg)。 c. Boc5腹腔注射给药产生的食欲抑制作用可以被预防性腹腔注射 exendin (9-39)所拮抗。 d.与空白对照组相比， 口服给药 1 ml/20g体重时， 2 小时的摄食抑制作用具有剂量依赖 性，提示口服给药能够产生生物活性。 e. Boc5口服给药产生摄食抑制作用的 ED5。值为 0. 53 土 0. 08 mg。 f. Boc5口服给药产生的食欲抑制作用可以被预防性腹腔注射 exendin (9-39) 所拮抗。 Figure 1 illustrates in vitro pharmacodynamic test results of compounds S4P and Boc5 a. HEK293/GLP1R+Luc was induced with different concentrations of GLP-1, S4P and Boc5, respectively, and compounds were evaluated by detecting the expression of CRE-driven luciferase reporter gene. Relative (100%, 10 nM GLP-1) agonistic activity. Boc5 of compound S4P and GLP- 1R agonistic activity is dose-dependent average, and both the EC 5. The values are similar (S4P is 1. 2 μ Μ, Boc5 is 3.1 μ Μ), but the reaction intensity of S4P at 10 μΜ is 37.3% of GLP-1 (ΙΟηΜ), and Boc5 is GLP-1R Full agonist. b. Exendin (9-39) was used to verify the receptor specificity of the compound for GLP-1R agonistic activity. When added to 0.05 nM GLP-1, 10 4M S4P and Boc5, Exendin (9-39) dose-dependently inhibited the expression of the reporter gene induced by it, IC 5 . The values were 68.22, 14.69 and 33.38 nM, respectively, indicating that the biological activities of S4P and Boc5 and GLP-1 are mediated by GLP-1R. c. Using the 125 1 labeled GLP-1 as a ligand, the affinity of the compound for the receptor is tested by a competitive binding assay. When different concentrations of GLP-1, S4P and Boc5 were incubated with 125 1 GLP-1 and GLP1R extracted from HEK293/GLP1R+LUC cells, both S4P and Boc5 could specifically compete with 1M I-targeted GLP-1. Sexual binding, its inhibition rate at 30 μM reached 80.6% and 63.7 %, respectively, of IC 5 . The values are 286. 6 nM and 1.5 μμ. Under the same experimental conditions, GLP-1 IC 5 . The value is 0. 66 nM. Figure 2 illustrates the results of the feeding inhibition test of the compound Boc5. C57BL/6 mice were administered intraperitoneally with Boc5 solution and a positive control (or antagonist) after overnight fasting, and the food intake was observed every 15 to 30 minutes. a. Boc5 intraperitoneal dose-dependently suppresses appetite. At a dose of Boc5 2 mg/20 g body weight, the 12-hour food intake inhibition rate was 54% 13% (0.0034). b. Intraperitoneal injection of Boc5 to suppress appetite ED 6 „value is 1.57 ± 0. 09 mg Γ 80 mg / kg. c. Boc5 intraperitoneal injection of appetite inhibition can be induced by prophylactic intraperitoneal injection of exendin (9-39 Antagonism d. Compared with the blank control group, the oral administration of 1 ml/20 g body weight, the 2-hour feeding inhibition was dose-dependent, suggesting that oral administration can produce biological activity. e. Boc5 oral administration ED 5 for feeding inhibition. The value is 0. 53 soil 0. 08 mg. f. The appetite suppressing effect of oral administration of Boc5 can be antagonized by prophylactic intraperitoneal injection of exendin (9-39).
图 3说明 Boc5在正常 C57BL/6小鼠的药代动力学参数分析 正常 C57BL/6小鼠腹腔 注射 Boc5 2mg/20g体重后 （每时间点 3只）， 应用 HPLC检测方法进行药代动力学参数分 析。 最终消除半衰期为 7. 5 士 1. 2小时。  Figure 3 shows the pharmacokinetic parameters of Boc5 in normal C57BL/6 mice. Normal C57BL/6 mice were injected intraperitoneally with Boc5 2mg/20g body weight (3 per time point). The pharmacokinetic parameters were determined by HPLC. analysis. The final elimination half-life is 7.5 ± 1. 2 hours.
图 4说明 化合物 S4P和 Boc5的长期药效学研究 a. 将各组小鼠依据 HbAlc水平随 机分为空白对照组、 S4P治疗组和野生型对照组， 结果表明 S4P给药后， HbAlc明显下调； b. 将各组小鼠依据 HbAlc水平随机分为自由摄食对照组、摄食限制对照组、 Boc5 1 mg组、 Boc5 2 mg组和野生型对照组。 腹腔注射 Boc5 1 mg或者 2 mg的糖尿病小鼠的 HbAlc逐渐 降低， 在治疗 4- 6周时达到正常水平， 与野生型小鼠无显著性差异， 但是显著低于自由摄 食对照组和摄食限制对照组； c. 小鼠的空腹血糖变化不稳定， 但是各组的反应趋势与 HbAlc—致； d. 自由摄食对照组小鼠摄食量增加 23%， 平均体重增加了 12 g; 摄食限制对 照组、 Boc5 1 mg及 2 mg治疗组的体重变化与野生型小鼠无显著性差异， 体重增加均明显 低于自由摄食对照组； e. 6周的治疗结束时， 各组小鼠随机抽取半数进行腹腔注射糖耐量 试验 （IPGTT), 结果表明， B0c5 2 mg治疗组的曲线下面积 （AUC)显著低于自由摄食对照 组和摄食限制对照组 （ ). 0006和 ). 0006)， 而与野生型小鼠相比无显著性差异， 提 示 Boc5 2 mg治疗组的糖耐量已经恢复正常； f. 自由摄食对照组和摄食限制对照组的空 腹胰岛素水平显著高于野生型小鼠，提示了胰岛素敏感性的降低，与摄食限制对照组相比， Boc5 1 mg和 2 mg治疗组有一定程度的下调趋势。 具体实施方式 实验仪器及试剂 Figure 4 illustrates the long-term pharmacodynamic study of compounds S4P and Boc5 a. Each group of mice was randomly divided into blank control group, S4P treatment group and wild type control group according to HbAlc level. The results showed that HbAlc was significantly down-regulated after S4P administration; b. Each group of mice were randomly divided into a free feeding control group, a feeding restriction control group, a Boc5 1 mg group, a Boc5 2 mg group, and a wild type control group according to HbAlc levels. HbAlc was gradually decreased in the intraperitoneal injection of Boc5 1 mg or 2 mg diabetic mice, which reached normal levels at 4-6 weeks of treatment, and was not significantly different from wild-type mice, but significantly lower than the free-feeding control group and the feeding restriction control. Group; c. The fasting blood glucose changes in mice were unstable, but the response trend of each group was related to HbAlc; d. The food intake of the mice in the free feeding control group increased by 23%, and the average body weight increased by 12 g; The body weight changes of Boc5 1 mg and 2 mg treatment groups were not significantly different from wild-type mice, and the weight gain was significantly lower than that of the free-feeding control group. e. At the end of 6 weeks of treatment, each group of mice was randomly selected for abdominal cavity. The injection glucose tolerance test (IPGTT) showed that the area under the curve (AUC) of the B 0 c5 2 mg treatment group was significantly lower than that of the free feeding control group and the feeding restriction control group ( ). 0006 and). 0006), and the wild There was no significant difference between the mice, suggesting that the glucose tolerance of the Boc5 2 mg treatment group has returned to normal; f. The fasting insulin level of the free feeding control group and the feeding restriction control group is significantly higher than that of the wild type mice. Tip a decrease in insulin sensitivity, and limit food intake compared to the control group, Boc5 1 mg and 2 mg treatment group had some degree of downward trend. 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 65 : 35， 流速为 0. 2 ml/min, 检测波长为 254 nm。 瑢点采用 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， CD30D或 DMSO- cU ; ESI-MS由 AB Mariner型质谱仪测得， 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。 下面的具体实施例对本发明作进一步阐述， 但不限制本发明。 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 65:35, the flow rate was 0. 2 ml/min, and the detection wavelength was 254 nm. The enthalpy was measured using an IA6304 melting point apparatus; NMR was measured by Varian Mercury-300 and Varian Mercury Plus 400 nuclear magnetic resonance spectrometer (solvent was CDC1 3 , CD 3 0D or DMSO-cU; ESI-MS was measured by AB Mariner mass spectrometer EI was measured by a Finnigan MAT95 mass spectrometer. The materials used in the synthesis were all commercially available except for the specific source. The following specific examples are intended to further illustrate the invention but are not intended to limit the invention.
实施例 1: 化合物 S4P的制备  Example 1: Preparation of Compound S4P
NMR定标： 5H/C 7.26/77.0 ppm (CDC13); δ H/C 2.50/39.51 ppm (DMSO - d6)。 NMR calibration: 5H/C 7.26/77.0 ppm (CDC1 3 ); δ H/C 2.50/39.51 ppm (DMSO - d 6 ).
Figure imgf000031_0001
Figure imgf000031_0001
将化合物 Wang516 (1 g)溶于适量的 DMSO中， 置于 150W高压汞灯下照射 3天， 加入 1 ml 水， 继续照射 7-10天， 期间用 HPLC检测跟踪反应。 反应完毕， 冷干除去溶剂， 剩余物用 柱层析分离。 得到浅黄色粉状固体化合物 S4P。 The compound Wang516 (1 g) was dissolved in an appropriate amount of DMSO, placed under a 150 W high-pressure mercury lamp for 3 days, and 1 ml of water was added thereto for further 7-10 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound S4P was obtained.
lHNMR (300MHz, DMS0-dB) 10.053 (2H, br. s), 8.630 (2H, br. s), 8.090 (2H, dd, Ji=4.8 Hz, J2=l.2 Hz), 8.029 (2H, dd, J;=3.6 Hz, /2-1.2 Hz), 7.605 (4H, d, J =8.4 Hz), 7.395 (4H, d, J=8.1 Hz), 7.31 (2H， m)， 7.280 (2H, br. s), 7.260 (2H, m), 7.206 (2H, br. d, J=8.1 Hz), 4.987 (2H， br.s), 3.244 (6H, s)， 2.740 (2H, m), 1.815 (4H, m), 1.703 (4H， m) , 1.652 (4H， m)， 1.526 (4H, m)。 lHNMR (300MHz, DMS0-d B ) 10.053 (2H, br. s), 8.630 (2H, br. s), 8.090 (2H, dd, Ji=4.8 Hz, J 2 =l.2 Hz), 8.029 (2H , dd, J;=3.6 Hz, / 2 -1.2 Hz), 7.605 (4H, d, J = 8.4 Hz), 7.395 (4H, d, J=8.1 Hz), 7.31 (2H, m), 7.280 (2H , br. s), 7.260 (2H, m), 7.206 (2H, br. d, J=8.1 Hz), 4.987 (2H, br.s), 3.244 (6H, s), 2.740 (2H, m), 1.815 (4H, m), 1.703 (4H, m), 1.652 (4H, m), 1.526 (4H, m).
13CN R (75MHz， DMS0-d6) 174.7, 172.8, 166.8， 159.4, 150.1, 142.1, 137.7, 135.2, 133.6, 131.6, 129.1, 128.7, 128.1, 122.5， 122.1, 118.1, 112.5, 63.2, 54.9, 48.4, 45.3， 30.0， 25.7。 13 CN R (75MHz, DMS0-d 6 ) 174.7, 172.8, 166.8, 159.4, 150.1, 142.1, 137.7, 135.2, 133.6, 131.6, 129.1, 128.7, 128.1, 122.5, 122.1, 118.1, 112.5, 63.2, 54.9, 48.4 , 45.3, 30.0, 25.7.
实施例 2: 化合物 S4P及其异构体的制备  Example 2: Preparation of Compound S4P and Its Isomers
Figure imgf000031_0002
将化合物 Wang516 (10 g)溶于适量的 DMSO中， 置于室温自然光下照射 30- 90天， 冷干除 去溶剂， 剩余物用 HPLC分离， 可以得到很少量浅黄色粉状固体化合物 S4P的区域异构体 和 S4P。
Figure imgf000031_0002
The compound Wang516 (10 g) was dissolved in an appropriate amount of DMSO, and exposed to natural light at room temperature for 30-90 days. The solvent was removed by cold drying, and the residue was separated by HPLC to obtain a small amount of a pale yellow powdery solid compound S4P. Isomer and S4P.
1讓 R (300MHz, DMSO— d6) 10.125 (2H, br. s)， 8.025 (2H， d, J=4.8 Hz) , 7.921 (2H， d， J=2.9 Hz) , 7.667 (4H, br. s) , 7.251 (2H, m), 7.220 (2H, br. s), 6.983 (2H， d, J=7.7 Hz) , 6.908 (2H, d， J=7.7 Hz) , 5.269 (2H, br. s), 3.335 (6H， s)， 2.779 (2H， m), 1.832 (4H， ra), 1.715 (4H, m)， 1.677 (4H, m), 1.527 (4H， m)。 1 Let R (300MHz, DMSO-d 6 ) 10.125 (2H, br. s), 8.025 (2H, d, J=4.8 Hz), 7.921 (2H, d, J=2.9 Hz), 7.667 (4H, br. s) , 7.251 (2H, m), 7.220 (2H, br. s), 6.983 (2H, d, J=7.7 Hz), 6.908 (2H, d, J=7.7 Hz) , 5.269 (2H, br. s ), 3.335 (6H, s), 2.779 (2H, m), 1.832 (4H, ra), 1.715 (4H, m), 1.677 (4H, m), 1.527 (4H, m).
13CNMR (75MHz, DMSO— de) 174.8, 174.7, 164.7, 159.5, 149.9, 142.1， 136.5， 135.0, 131.7， 129.3, 128.7, 127.6， 121.8, 120.1, 118.4， 112.0, 64.7, 55.1， 51.8, 45.3, 30.1, 25.7。 13 C NMR (75 MHz, DMSO-d e ) 174.8, 174.7, 164.7, 159.5, 149.9, 142.1, 136.5, 135.0, 131.7, 129.3, 128.7, 127.6, 121.8, 120.1, 118.4, 112.0, 64.7, 55.1, 51.8, 45.3, 30.1, 25.7.
S4P的核磁共振数据同实例 1。  The NMR data of S4P is the same as in Example 1.
实施例 3: 应用催化剂的情况下化合物 S4P的制备  Example 3: Preparation of Compound S4P in the Case of Application of Catalyst
Figure imgf000032_0001
Figure imgf000032_0001
将化合物 Wang516 (20 mg)溶于适量的 DMS0中， 加入 25 mg二苯酮， 置于 150w高 压汞灯下照射 1天， 冷干除去溶剂， 剩余物用柱层分离， 得到浅黄色粉状固体化合物 S4P。  The compound Wang516 (20 mg) was dissolved in an appropriate amount of DMS0, 25 mg of benzophenone was added, and the mixture was irradiated for 1 day under a 150-W high-pressure mercury lamp, and the solvent was removed by cold drying, and the residue was separated by a column to obtain a pale yellow powdery solid. Compound S4P.
实施例 4: 化合物 Boc5的制备  Example 4: Preparation of Compound Boc5
NMR定标： δΗ/C 7.26/77.0 ppm (CDC13); δ H/C 2.50/39.51 ppm (DMSO d6)。 NMR calibration: δ Η / C 7.26 / 77.0 ppm (CDC1 3 ); δ H / C 2.50 / 39.51 ppm (DMSO d 6 ).
Figure imgf000033_0001
Figure imgf000033_0001
将化合物 Wang520 (10 g)溶于适量的 DMS0中， 置于 150W高压汞灯下照射 3天， 加 入 1 ml水， 继续照射 25-30天， 期间用 HPLC检测跟踪反应。 反应完毕， 冷干除去溶剂， 剩余物用柱层析分离。 得到浅黄色粉状固体化合物 Boc5。 The compound Wan g 520 (10 g) was dissolved in an appropriate amount of DMS0, placed under a 150 W high pressure mercury lamp for 3 days, and 1 ml of water was added thereto, and the irradiation was continued for 25-30 days, during which time the reaction was followed by HPLC. After completion of the reaction, the solvent was removed by cold drying, and the residue was separated by column chromatography. The pale yellow powdery solid compound Boc5 was obtained.
¾NMR (300MHz, DMSO— d6) 9.571 (2H, br. s)， 8.607 (2H， br. s)， 8.078 (2H, d, /=4.8 Hz) , 8.035 (2H, d， J=3.3 Hz) , 7.464 (4H， d， J=8.4 Hz) , 7.363 (4H， d， J=S.1 Hz), 7.31 (2H, m), 7.30 (2H, m), 7.260 (2H， m), 7.216 (2H， br. d, J=8.1 Hz), 4.991 (2H, br. s)， 3.270 (6H, s)， 1.444 (18H, s)。 3⁄4 NMR (300MHz, DMSO—d 6 ) 9.571 (2H, br. s), 8.607 (2H, br. s), 8.078 (2H, d, /=4.8 Hz), 8.035 (2H, d, J=3.3 Hz) , 7.464 (4H, d, J=8.4 Hz), 7.363 (4H, d, J=S.1 Hz), 7.31 (2H, m), 7.30 (2H, m), 7.260 (2H, m), 7.216 ( 2H, br. d, J=8.1 Hz), 4.991 (2H, br. s), 3.270 (6H, s), 1.444 (18H, s).
13CNMR (75MHz, DMSO— d6) 172.8, 166.9, 159.5， 152.6， 150.2, 1 2.4, 137.8, 135.2, 133.6, 131.1, 128.8, 128.4， 128.2, 122, 117.1, 112， 79.6, 63.2, 54.9, 48, 28.1。 13 CNMR (75MHz, DMSO—d 6 ) 172.8, 166.9, 159.5, 152.6, 150.2, 1 2.4, 137.8, 135.2, 133.6, 131.1, 128.8, 128.4, 128.2, 122, 117.1, 112, 79.6, 63.2, 54.9, 48 , 28.1.
实施例 5: 体外药效学试验  Example 5: In vitro pharmacodynamic test
1. 报告基因表达检测  Reporter gene expression detection
GLP-1R为 G蛋白偶联受体， 当 GLP- 1R与激动剂结合后， G蛋白的 Get 亚单位被活化， 刺激腺苷酸环化酶， 导致细胞内 cAMP水平升高。 因前胰岛素基因的启动子区域存在 cAMP 反应元件， cAMP与该反应元件结合后， 启动前胰岛素基因的转录， 从而刺激胰岛素的表达 和分泌 (Diabetes, 2000, Vol. 49:1156-1164)。 本实验方法采用稳定转染 GLP-1R受体 基因表达载体和受 cAMP反应元件调节的荧光素酶报告基因表达载体的人胚肾细胞株（HEK 293),检测其对被测化合物的反应（Cell Biology, 1992， Vol. 89:8641-8645； Proc. Natl. Acad. Sci. U.S.A. 1987, Vol. 84:3434-3438)。 在对化合物进行筛选时， 可诱导荧光素 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 Get subunit of G protein is activated to stimulate adenylate cyclase, resulting in elevated intracellular cAMP levels. Since the cAMP response element exists in the promoter region of the proinsulin 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). In this experimental method, a human embryonic kidney cell strain (HEK 293) stably transfected with a GLP-1R receptor gene expression vector and a luciferase reporter gene expression vector regulated by a cAMP response element was used to detect its response to a test compound (Cell). 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 screened for a compound is considered to have GLP-1R agonistic activity.
1.1 试验材料与仪器  1.1 Test materials and instruments
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）  Cell line: HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (National New Drug Screening Center self-built)
胎牛血清 （GIBC0公司）  Fetal bovine serum (GIBC0)
DMEM培养基 （GIBC0公司） Steady- GloTM荧光素酶分析系统 （Promega公司） DMEM medium (GIBC0 company) 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 Carbon Dioxide Incubator (Forma);
Victor2读板机 （Wallac公司）；  Victor2 plate reader (Wallac);
待测化合物： S4P、 Boc5  Test compound: S4P, Boc5
1. 2 试验方法  1. 2 Test methods
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 μΕ/ml G418的 DMEM培养基于 37°C培养过夜。 将 GLP- 1标准品与待测化合物 S4P 和 Boc5分别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- GloTM荧光素酶分析系统试剂盒说明检测荧光素酶活 性， Victor2读板机进行读数。  HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 μΐ/well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 μM/ml G418. The GLP-1 standard and the test compounds S4P and Boc5 were each diluted to a certain concentration gradient, and then added to the above 96-well microplate in Ιμΐ/well. At 37. C, cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay System Kit and the Victor2 reader was used for reading.
1. 3 试验结果  1. 3 test results
研究结果表明（表 1，图 la) ,化合物 S4P和 Boc5均剂量依赖性地诱导 HEK293/GLP1R+Luc 细胞内荧光素酶的表达。 两者的 EC5。数值相近（S4P为 1. 2 μ Μ， Boc5为 3. 1 μ Μ)， 但 S4P 在 10 MM时的反应强度为 GLP- 1 ( 10 nM) 的 37. 3%, 而 Boc5为 GLP- 1R的全激动剂。 The results showed that (Table 1, panel la), compounds S4P and Boc5 all dose-dependently induced luciferase expression in HEK293/GLP1R+Luc cells. Both EC 5 . The values are similar (S4P is 1. 2 μ Μ, Boc5 is 3. 1 μ Μ), but the reaction intensity of S4P at 10 MM is 37.3% of GLP-1 (10 nM), while Boc5 is GLP-1R Full agonist.
表 1. 报告基因表达检测化合物的相对活性  Table 1. Reporting gene expression assay for relative activity of compounds
(%反应， 以 10 nM GLP-1的反应为 100%)  (% reaction, 100% reaction with 10 nM GLP-1)
~~终浓度 （nM) 相对 GLP- 1的激动活性 ( )  ~~ final concentration (nM) relative to GLP-1 agonistic activity ( )
S4P Boc5  S4P Boc5
100000 22. 6 113. 0  100000 22. 6 113. 0
30000 29. 6 107. 2  30000 29. 6 107. 2
10000 37. 3 92. 8  10000 37. 3 92. 8
3000 30. 3 62. 9  3000 30. 3 62. 9
1000 19. 9 26. 4  1000 19. 9 26. 4
300 7. 8 5. 3  300 7. 8 5. 3
100 2. 0 0. 7  100 2. 0 0. 7
30 0. 5 0. 1  30 0. 5 0. 1
2. Exendin (9- 39)拮抗试验 2. Exendin (9- 39) Antagonistic Test
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 Exendin (9-39) (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。  To confirm the receptor specificity of the active compound for the activation of the reporter gene, we used the specific antagonist of GLP-1R, Exendin (9-39) (Eur. J. Pharmacol. 1994, 269: 183-191; Metabolism 2004, 53 : 252-259. ) to verify whether it can antagonize the agonistic activity of the above representative compounds on GLP-1R.
2. 1 试验材料与仪器：  2. 1 Test materials and instruments:
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）  Cell line: HEK 293/GLP-lR+Luc cell line stably expressed by GLP-1R and luciferase (National New Drug Screening Center self-built)
胎牛血清 （GIBC0公司） DMEM培养基 （GIBCO公司） Fetal bovine serum (GIBC0 company) 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-GloTM 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）；  Victor2 plate reader (Wallac);
待测化合物： S4P、 Boc5  Test compound: S4P, Boc5
2. 2 试验方法  2. 2 Test methods
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 Exendin (9-39)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， 然后分别加入 10 μΜ S4P、 Boc5和 0. 05 nMGLP- 1 , 在 37。C， 5%C02条件下培养 6小时。 按 Steady- GloTM荧光素酶分析系统试剂盒说明检测荧光素酶活性， Victor2读板机进行读 数。  HEK293/GLP1R+Luc cells were inserted into 96-well culture plates at 20,000/100 μΐ/well, and cultured overnight at 37 ° C in DMEM medium containing 10% fetal bovine serum and 500 g/ml G418. Dilute Exendin (9-39) to a certain concentration gradient, then add 1 μΐ/well to the above 96-well microplate, incubate at 37 ° C, 5% CO 2 for 10 minutes, then add 10 μM S4P, Boc5 and 0. 05 nMGLP-1, at 37. C, cultured for 6 hours under 5% CO 2 conditions. Luciferase activity was measured by the Steady-GloTM Luciferase Assay Kit, and the Victor2 reader was used for reading.
2. 3 试验结果  2. 3 test results
Exendin (9-39)能剂量依赖性地抑制由 GLP-1、 S4P和 Boc5诱导的报告基因表达（表 2, 图 lb ), 其 IC5。值分别为 68. 22、 14. 69及 33. 38 nM， 表明 S4P和 Boc5的生物活性是通过 GLP- 1R介导的。 Exendin (9-39) dose-dependently inhibited reporter gene expression induced by GLP-1, S4P and Boc5 (Table 2, Figure lb), IC 5 . The values were 68.22, 14.69 and 33.38 nM, respectively, indicating that the biological activities of S4P and Boc5 are mediated by GLP-1R.
表 2. Exendin (9-39)对 GLP - 1、 S4P和 Boc5的拮抗作用  Table 2. Antagonism of Exendin (9-39) on GLP-1, S4P and Boc5
(%反应， 以 0. 05 nM GLP- 1的反应为 100%)  (% reaction, with 0. 05 nM GLP-1 reaction is 100%)
相对活性 （％)  Relative activity (%)
Exendin (9-39)  Exendin (9-39)
0. 05 nM 10 μ M S4P 10 μ Μ  0. 05 nM 10 μ M S4P 10 μ Μ
(nM)  (nM)
GLP— 1 Boc5  GLP-1 Boc5
10000 2 6 4  10000 2 6 4
1000 3 5 3  1000 3 5 3
100 39 11 18  100 39 11 18
10 91 59 84  10 91 59 84
1 97 100 99  1 97 100 99
0. 1 101 104 102  0. 1 101 104 102
0 100 105 101  0 100 105 101
3. 受体结合活力测试 3. Receptor binding viability test
为确定活性化合物对受体的结合能力， 制备大量表达 GLP-1R的细胞， 以 1251标记的 GLP-1作为配基， 同时加入待检测化合物。 当待测化合物与 1251标 GLP-1进行竞争性结合 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)。 To determine the ability of the active compound to bind to the receptor, a large number of cells expressing GLP-1R were prepared, and 125 1 labeled GLP-1 was used as a ligand while the compound to be detected was added. When the test compound is competitively bound to 125 1 labeled GLP-1, the isotope labeling on the cell membrane is reduced. 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).
3. 1 试验材料与仪器： HEK 293/GLPlR+Luc 细胞株 （国家新药筛选中心自建） 3. 1 Test materials and instruments: HEK 293/GLP1R+Luc cell line (self-built by National New Drug Screening Center)
标记化合物： 1251标记的 GLP- 1 (Amersham Biosciences 公司） Labeled 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）  TomTech Cell Collector (TomTec)
闪烁液 （Wallac 公司）  Scintillation fluid (Wallac)
待测化合物： S4P、 Boc5  Test compound: S4P, Boc5
3. 2试验方法  3. 2 test methods
取 105对数生长期的 HEK 293/GLPlR+Luc细胞， 于 25° C条件下， 200μ1 测试缓冲液 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。 HEK 293/GLP1R+Luc cells in 10 5 logarithmic growth phase were incubated with 125 1 GLP-1 positive peptide (final concentration 40 ρΜ) for 4 hours at 200 ° C in 200 μl assay buffer. Add a non-labeled positive peptide or a drug to be screened. The cells were washed three times with a washing solution using a cell harvester. Scintillation fluid was added and each well reading was read on a Microbata counter.
3. 3试验结果  3. 3 test results
化合物 S4P和 Boc5能特异性地与 1251标 GLP- 1竞争性结合 （表 3， 图 lc。 在 30 μ M 浓度下， 34?和8005的抑制率分别达到80. 6%和63. 7%， 两者的 IC5。值分别为 286. 6 nM 1. 5 μ M。 同样实验条件下， GLP- 1的 IC5。值为 0. 66 nM。 Boc5 compound S4P and capable of specifically 12,511 standard competitive binding with GLP- (Table 3, FIG LC. At a concentration of 30 μ M, 34? Inhibition rate of 8005 and 80.6%, respectively 63. The IC 5 value of the two is 286. 6 nM 1. 5 μ M. Under the same experimental conditions, the IC 5 of the GLP-1 has a value of 0.66 nM.
表 3. S4P和 Boc5对 1251标记 GLP- 1的结合活力测试 终浓度 （nM) 1251结合百分比 （％) Table 3. Binding viability of S1P and Boc5 to 125 1 labeled GLP-1. Final concentration (nM) 125 1 percent binding (%)
S4P Boc5  S4P Boc5
30000 19. 4 36. 3  30000 19. 4 36. 3
6000 16. 3 44. 2  6000 16. 3 44. 2
1200 35. 2 71. 0  1200 35. 2 71. 0
240 60. 3 90. 8  240 60. 3 90. 8
48 86. 3 99. 2  48 86. 3 99. 2
10 86. 8 93. 0  10 86. 8 93. 0
0 100. 0 100. 0 实施例 6: 体内药效学试验  0 100. 0 100. 0 Example 6: In vivo pharmacodynamic test
1. 急性体内试验  Acute in vivo test
急性注射 GLP-1类似物能够产生抑制摄食、 延迟胃排空、 剌激胰岛素分泌、 抑制胰高 血糖素分泌和修复胰岛素第一时相分泌的作用 （Regul Pept, 2004， Vol. 117 : 77 88 )。 本试验应用 C57BL/6小鼠， 隔夜禁食后腹腔注射 Boc5溶液， 观察化合物的急性给药对食 欲的抑制作用。  Acute injection of GLP-1 analogues produces inhibition of food intake, delayed gastric emptying, stimulation of insulin secretion, inhibition of glucagon secretion, and repair of insulin first phase secretion (Regul Pept, 2004, Vol. 117 : 77 88 ). In this study, C57BL/6 mice were used, and Boc5 solution was intraperitoneally injected overnight after fasting to observe the inhibitory effect of acute administration of the compound on appetite.
1. 1 试验材料和仪器 '  1. 1 Test materials and instruments '
C57BL/6小鼠： 雌性， 6周龄， 18- 20g， 购自上海斯莱克实验动物有限公司  C57BL/6 mice: female, 6 weeks old, 18-20 g, purchased from Shanghai Slack Laboratory Animal Co., Ltd.
Exendin-4 (Sigma公司)  Exendin-4 (Sigma)
HPLC (Agilent公司）  HPLC (Agilent)
待测化合物： 不同剂量梯度的 Boc5均溶解于 1% DMS0和 20% PEG400的生理盐水 （腹 腔注射试验） 或者 2% DMS0和 20% PEG400的生理盐水 （口服给药试验） Test compound: Boc5 with different dose gradients were dissolved in 1% DMS0 and 20% PEG400 saline (abdominal Cavity injection test) or 2% DMS0 and 20% PEG400 saline (oral administration test)
1. 2试验方法  1. 2 test methods
小鼠经隔夜禁食后， 单笼饲养， 随即分为空白对照组、 exendin- 4 1 g组、 Boc5 0. 1 mg组、 Boc5 0. 3 rag组、 Boc5 1 mg组和 Boc5 2 mg组， 给药方式为腹腔注射。 各组小鼠 自由摄食， 给药前及给药后每间隔 15- 30分钟观察剩余饲料， 连续 12小时的观察资料用 于计算累积摄食量。 在口服试验中， 设置空白对照组、 Boc5 0. 3 mg组、 Boc5 1 rag组、 Boc5 3 mg组和 Boc5 10 mg组， 灌胃体积为 1 ml， 观察周期为 6小时。  After overnight fasting, the mice were housed in single cages and then divided into blank control group, exendin- 4 1 g group, Boc5 0. 1 mg group, Boc5 0. 3 rag group, Boc5 1 mg group and Boc5 2 mg group. The mode of administration is intraperitoneal injection. Each group of mice was fed ad libitum, and the remaining feed was observed at intervals of 15-30 minutes before and after administration, and the observation data for 12 hours was used to calculate the cumulative food intake. In the oral test, a blank control group, Boc5 0.3 mg group, Boc5 1 rag group, Boc5 3 mg group, and Boc5 10 mg group were set, the intragastric volume was 1 ml, and the observation period was 6 hours.
1. 3试验结果  1. 3 test results
研究结果表明 Boc5剂量依赖地抑制食欲， 作用时间长达 12小时以上。 与空白对照鼠 相比， 在 Boc5 2 mg/20g体重的剂量下， 12小时的摄食抑制率为 54 士 13% (P-0. 0034) , ED5„为 1. 57土 0. 09 mg 80 mg/kg) (图 2a, 2b)。与空白对照组相比， 口服给药 1 ml/20g 体重时， 2小时的摄食抑制作用具有剂量依赖性，提示口服给药能够产生生物活性（图 2d)， ED5。为 0. 53 士 0. 08 mg (图 2e)。 腹腔注射给药和口服给药产生的食欲抑制作用均可以被 预防性腹腔注射 eXendin (9- 39)所拮抗（图 2c， 2f )。 Studies have shown that Boc5 dose-dependently suppresses appetite for up to 12 hours. Compared with the control mice, at doses Boc5 2 mg / 20g of body weight, food intake inhibition rate for 12 hours Disabled 54 13% (P-0. 0034 ), ED 5 " to 1.57 Soil 0. 09 mg 80 Mg/kg) (Fig. 2a, 2b). The 2 hour feeding inhibition was dose-dependent when administered orally at 1 ml/20 g body weight compared with the blank control group, suggesting that oral administration can produce biological activity (Fig. 2d). ), ED 5 is 0. 53 ± 0. 08 mg (Fig. 2e). Appetite suppression by intraperitoneal administration and oral administration can be antagonized by prophylactic intraperitoneal injection of e X endin (9-39) ( Figure 2c, 2f).
正常 C57BL/6小鼠腹腔注射 Boc5 2mg/20g体重后 （每时间点 3只）， 应用 HPLC检测 方法进行药代动力学参数分析。最终消除半衰期为 7. 5 ± 1. 2小时（图 3)。 Boc5 10 rag/20g 体重口服给药的生物活性经 HPLC分析发现明显的血药峰得到确 1λ。  Normal C57BL/6 mice were injected intraperitoneally with Boc5 2mg/20g body weight (3 at each time point), and the pharmacokinetic parameters were analyzed by HPLC. The final elimination half-life was 7. 5 ± 1. 2 hours (Figure 3). The biological activity of Boc5 10 rag/20g orally administered by HPLC was analyzed by HPLC to find that the peak of the blood drug was confirmed to be 1λ.
2. 长期体内试验  2. Long-term in vivo testing
GLP-1R激动剂的长期外周给药能够减轻肥胖症动物模型的体重，在 2型糖尿病动物模 型能够降低 HbAlc和血脂、 恢复 β细胞功能、 提高胰岛素敏感性以及诱导 β细胞的增值和分 化（Regul P印 t， 2004, Vol. 117 : 77-88)。应用2型糖尿病模型 578176】-111+/+ 1^) * ( /¾¾) 小鼠， 开展了腹腔注射 Boc5和 S4P的药效学研究。  Long-term peripheral administration of GLP-1R agonists can reduce body weight in obese animal models, reducing HbAlc and blood lipids, restoring beta cell function, increasing insulin sensitivity, and inducing beta cell proliferation and differentiation in an animal model of type 2 diabetes (Regul P. T, 2004, Vol. 117: 77-88). Using a type 2 diabetes model 578176]-111+/+ 1^) * ( /3⁄43⁄4) mice, a pharmacodynamic study of intraperitoneal injections of Boc5 and S4P was performed.
2. 1试验材料和仪器  2. 1 test materials and instruments
CS BL/ej-m+Z+ Lepr1* 小鼠： 雌雄各半， 8周龄， 购自南京大学模式动物研究 中心 （经该中心确认符合 2型糖尿病发病特征）。 CS BL/ej-m+Z+ Lepr 1 * Mice: Male and female, 8 weeks old, purchased from the Model Animal Research Center of Nanjing University (identified by the center to meet the characteristics of type 2 diabetes).
DS1 Glycosal HbAlc Analyzer (Drew Scientific公司）  DS1 Glycosal HbAlc Analyzer (Drew Scientific)
Glycosal HbAlc kit (Pr oval is Diagnostics公司)  Glycosal HbAlc kit (Pr oval is Diagnostics)
Freestyle Mini™自动血糖仪 /试纸 （TheraSense 公司）  Freestyle MiniTM Automatic Blood Glucose Meter / Test Strip (TheraSense)
D- glucose (Sigma公司)  D-glucose (Sigma)
总胆固醇、 甘油三酯、 高密度脂蛋白、 低密度脂蛋白、 谷丙转氨酶和谷草转氨酶测定 试剂盒 （Roche公司）  Total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, alanine aminotransferase, and aspartate aminotransferase assay kits (Roche)
全自动生化分析仪 7060 (Hitachi公司）  Automatic Biochemical Analyzer 7060 (Hitachi Corporation)
待测化合物： 不同剂量梯度的 Boc5或者 S4P均溶解于 1% DMS0和 20% PEG400的生理 盐水  Test compound: Boc5 or S4P with different dose gradients dissolved in 1% DMS0 and 20% PEG400 saline
2. 2试验方法 各组小鼠依据 HbAlc水平随机分为 4组 （14- 15只 /组）， 给药方式为腹腔注射。 除了 自由摄食对照组、 Boc5 1 mg组和 Boc5 2 mg组以外， 设置摄食限制对照组， 该组的日摄 食量等于前一日的 Boc5 2 mg组， 以检测摄食抑制引起的血糖特征改变。 另外设置一组野 生型非糖尿病 C57BL/6小鼠， 用以观察各项指标的正常值范围。 观察指标如下： HbAlc每 周一次，空腹血糖每周两次，体重和摄食量每日观察一次。治疗 6周后，每组抽取半数（7 - 8 只） 隔夜禁食， 检测空腹胰岛素水平， 进行 2g kg- 1 D- glucose腹腔注射糖耐量试验， 处 死动物， 采集血样检测总胆固醇、甘油三酯、 高密度脂蛋白胆固醇、 低密度脂蛋白胆固醇、 谷丙转氨酶和谷草转氨酶。 停药后的各组剩余小鼠继续观察 6周。 2. 2 test methods Each group of mice was randomly divided into 4 groups (14-15/group) according to HbAlc levels, and the mode of administration was intraperitoneal injection. In addition to the free feeding control group, the Boc5 1 mg group, and the Boc5 2 mg group, a feeding restriction control group was set, and the daily food intake of the group was equal to the Boc5 2 mg group of the previous day to detect changes in blood glucose characteristics caused by feeding inhibition. In addition, a group of wild-type non-diabetic C57BL/6 mice were set up to observe the normal range of values of each indicator. Observed indicators are as follows: HbAlc once a week, fasting blood glucose twice a week, body weight and food intake observed once a day. After 6 weeks of treatment, half of each group (7 - 8) were fasted overnight, fasting insulin levels were measured, and 2 g kg-1 D-glucose was injected intraperitoneally. The animals were sacrificed and blood samples were taken for total cholesterol and triglycerides. , high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase. The remaining mice in each group after stopping the drug continued to observe for 6 weeks.
2. 3 试验结果  2. 3 test results
S4P给药后， HbAlc明显下调 （图 4a)， 因此将 HbAlc作为 Boc5相关研究的主要评价 指标。 根据 HbAlc值， 将 db/db小鼠进行随机分组。 给药前， 各组 db/db小鼠的 HbAlc显 著高于野生型小鼠， 后者在整个实验进程中均保持较低水平的 HbAlc。 实验结果表明， 自 由摄食对照组和摄食限制对照组 db/db小鼠的 HbAlc均持续较高。相比之下，腹腔注射 Boc5 1 mg或者 2 mg的糖尿病小鼠的 HbAlc逐渐降低， 在治疗 4- 6周时达到正常水平， 与野生 型小鼠无显著性差异， 但是显著低于自由摄食对照组和摄食限制对照组 db/db 小鼠 ( 0. 0001； Tukey-Kramer检验）。 停药的 6周内， 两个治疗组的 HbAlc仍然保持在正常水 平 （图 4b)。  After S4P administration, HbAlc was significantly down-regulated (Fig. 4a), so HbAlc was used as the main evaluation index for Boc5-related studies. The db/db mice were randomly grouped according to the HbAlc value. Prior to dosing, HbAlc was significantly higher in each group of db/db mice than in wild-type mice, which maintained a lower level of HbAlc throughout the course of the experiment. The experimental results showed that the HbAlc of the db/db mice in the free feeding control group and the feeding restriction group continued to be higher. In contrast, HbAlc in the intraperitoneal injection of Boc5 1 mg or 2 mg in diabetic mice gradually decreased, reaching normal levels at 4-6 weeks of treatment, with no significant difference from wild-type mice, but significantly lower than the free-feeding control. Group and feeding restriction control group db/db mice (0. 0001; Tukey-Kramer test). Within 6 weeks of discontinuation, HbAlc in both treatment groups remained at normal levels (Fig. 4b).
与 HbAlc相比而言， 小鼠的空腹血糖变化不稳定， 但是各组的反应趋势与 HbAlc—致 (图 4c)。 空腹血糖和 HbAlc所反映的体内血糖状况在 Boc5 1 mg 及 2 mg治疗组均达到 正常范围。  Compared with HbAlc, the fasting blood glucose changes in mice were unstable, but the response trend of each group was related to HbAlc (Fig. 4c). The blood glucose status reflected by fasting blood glucose and HbAlc reached the normal range in the Boc5 1 mg and 2 mg treatment groups.
在 6周的给药试验期内， 野生型小鼠的体重变化很小， 与之相比， 自由摄食对照组小 鼠摄食量增加 23%， 平均体重增加了 12 g (图 4d); 摄食限制对照组、 Boc5 1 rag及 2 mg 治疗组的体重变化与野生型小鼠无显著性差异。 体重增加均明显低于自由摄食对照组 R0. 0001 )。  In the 6-week dosing trial period, the wild-type mice showed little change in body weight, compared with 23% for food intake and 12 g for the free-feeding control group (Fig. 4d); There was no significant difference in body weight between the control group, Boc5 1 rag and 2 mg treatment groups. The weight gain was significantly lower than the free feeding control group R0. 0001).
6 周的治疗结束时， 各组小鼠随机抽取半数进行腹腔注射糖耐量试验 （IPGTT), 各组 余下的小鼠在停药观察 15周后也进行了 IPGTT试验。 小鼠的血糖反应以 2 g/kg的葡萄糖 负荷后 120分钟内的曲线下面积（AUC)来衡量（图 4e)。 在治疗 6周后， 自由摄食对照组 和摄食限制对照组的 AUC显著高于野生型小鼠 （^=0. 0075 和 ^=0. 0043 )。 Boc5 2 mg治疗 组的 AUC 显著低于自由摄食对照组和摄食限制对照组 （ X 0006 和 ). 0006)， 而与野 生型小鼠相比无显著性差异 （ ). 64)。 因此， Boc5 2 mg治疗组的糖耐量已经恢复正常。  At the end of 6 weeks of treatment, each group of mice was randomly selected for intraperitoneal injection of glucose tolerance test (IPGTT). The remaining mice in each group also underwent IPGTT test 15 weeks after discontinuation of the drug. The blood glucose response of the mice was measured as the area under the curve (AUC) within 120 minutes after the glucose load of 2 g/kg (Fig. 4e). After 6 weeks of treatment, the AUC of the free feeding control group and the feeding restriction group were significantly higher than those of the wild type mice (^=0. 0075 and ^=0. 0043). The AUC of the Boc5 2 mg-treated group was significantly lower than that of the free-feeding control group and the food-feeding control group (X 0006 and ). 0006), but there was no significant difference compared with the wild type mice ( ). 64). Therefore, the glucose tolerance of the Boc5 2 mg treatment group has returned to normal.
Boc5 1 mg治疗组的糖耐量得到部分改善。 停药观察 15周后， 治疗组小鼠的糖耐量反弹， 使得各组糖尿病小鼠的糖耐量状况无显著性差异 （AO. 05)， 均显著高于野生型小鼠 （自 由摄食对照组 0026， 摄食限制对照组 0153， Boc5 2 mg / ). 0072， Boc5 1 mg ). 0052)。 The glucose tolerance of the Boc5 1 mg treatment group was partially improved. After 15 weeks of drug withdrawal, the glucose tolerance of the mice in the treatment group rebounded, and there was no significant difference in the glucose tolerance status of each group of diabetic mice (AO. 05), which was significantly higher than that of the wild type mice (free feeding control group 0026). , feeding restriction control group 0153, Boc5 2 mg / ). 0072, Boc5 1 mg ). 0052).
自由摄食对照组和摄食限制对照组的空腹胰岛素水平显著高于野生型小鼠 (尸〈0.0001)， 提示了胰岛素敏感性的降低。 与摄食限制对照组相比， Boc5 1 mg 和 2 mg 治疗组有一定程度的下调趋势 （ O.0054和 O.0653) (图 4f )。 Fasting insulin levels were significantly higher in the free-feeding control group and the food-feeding-restricted control group than in wild-type mice (People <0.0001), suggesting a decrease in insulin sensitivity. Boc5 1 mg and 2 mg treatment groups had a certain degree of down-regulation (O.0054 and O.0653) compared with the food-restricted control group (Fig. 4f).
6周治疗结束时， Boc5治疗组的甘油三酯有下降趋势，而总胆固醇显著降低（ ^0.0054 与摄食限制对照组相比， 0002 与自由摄食对照组相比）， 归因于低密度脂蛋白胆固醇 的轻微降低 （ 3.0045) 和高密度脂蛋白胆固醇的大幅度下调 （ ).0005)。  At the end of the 6-week treatment, triglycerides in the Boc5-treated group showed a downward trend, while total cholesterol decreased significantly (^0.0054 compared with the food-inhibited control group, 0002 compared with the free-feeding control group), due to low-density lipoprotein A slight decrease in cholesterol (3.0045) and a significant decrease in high-density lipoprotein cholesterol ( ).0005).

Claims

权利要求书 Claim
1、 一类由以下通式 I或 II表示的具有取代四元环结构的化合物或其药物学上可接受 的盐、 酯、 溶剂化物、 金属配合物、 或者与其具有相同药理作用的前药： A class of compounds having a substituted four-membered ring structure represented by the following formula I or II, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof, or a prodrug having the same pharmacological action thereto:
Figure imgf000040_0001
其中 X和 Y分别为 (CH2)„, n为 0-2; 0； S或者 NH;
Figure imgf000040_0001
Wherein X and Y are respectively (CH 2 ) „, n is 0-2; 0; S or NH ;
其中 、 R2各自独立地为下列任意一种取代基： 氢； 卤素； 垸基； 环垸基； 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； 或者， 取代或未取代的吡咯基； Wherein R 2 is each independently one of the following substituents: hydrogen; halogen; fluorenyl; cyclodecyl; hydroxy; nitro; carboxy; aldehyde; alkoxy; amine; amine alkyl; Carboxamide; mercapto; alkylthio; ether; thioether; substituted or unsubstituted aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; Unsubstituted thienyl; or substituted or unsubstituted pyrrolyl;
R3、 各自独立地为下列任意一种取代基： 氢； 垸基； 环垸基； 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 3 , each independently of any of the following substituents: hydrogen; fluorenyl; cycloalkyl; alkoxy; amine; amine alkyl; amide; carboxamide; alkylthio; substituted or unsubstituted Aryl; substituted or unsubstituted pyridyl; substituted or unsubstituted furyl; substituted or unsubstituted pyranyl; substituted or unsubstituted thienyl; substituted or unsubstituted pyrrolyl.
2、 根据权利要求 1 所述的具有取代四元环结构的化合物或其药物学上可接受的盐、 酯、 溶剂化物、 金属配合物、 或者与其具有相同药理作用的前药， 其特征在于：  2. A compound having a substituted four-membered ring structure according to claim 1, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof, or a prodrug having the same pharmacological action therewith, characterized in that:
X、 Y分别是 (CH2)„, n为 0- 2; 0； S或者 NH时; R,, R2分别各自独立为:
Figure imgf000040_0002
X, Y are (CH 2 ) „, n is 0- 2; 0; S or NH; R, R 2 are each independently:
Figure imgf000040_0002
其中 R5为下列任意一种取代基： H; CrC6的烷基； 含有包括卤素原子、 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- 的垸基； C2-；6的烯基； 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- 6的烯基； C2- ( 的 炔基;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-Ce 的炔基； C3-C6的环烷基； 含有包括卤素原子、 d-CB的烷氧基或羟基在内的任意一个、 两个 或者三个取代的^- Ce的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基; 含有包括卤素原子、 C,-^的烷基、硝基、羧基、 醛基、烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 Cr 的院基、 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、 （^-(]4的垸基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 ( 4的垸基、 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- 4的垸基、 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咯基； c6的垸酰基； 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 Cr Ce的烷 酰基； C2-Ce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- 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-Ce的环烷酰基； 含有包括卤素 原子、 CrCe的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3- Cs的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2) n， n为 0- 2; 0； S或者 NH时； Wherein R 5 is any one of the following substituents: H; an alkyl group of CrC 6 ; a fluorene of any one, two or three substituted d- groups including a halogen atom, an alkoxy group of d-^ or a hydroxyl group; groups; C 2 -; 6 alkenyl group; a halogen atom-containing optionally include, d-Ce alkoxy or hydroxy group including one, two or three substituents of C 2 - 6 alkenyl group; a C 2 - ( Alkynyl; any one, two or three substituted C 2 -C e alkynyl group including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C 6 cycloalkyl group; Any one, two or three substituted cyclo-C e cycloalkyl groups including a halogen atom, an alkoxy group of dC B or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; Pyrrolyl; pyridyl; containing alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted aryl groups; containing a halogen atom, a Gr, a nitro group, a carboxy group, 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 methylthio group, an ethylthio group; containing a halogen atom, (^-(] 4 Sulfhydryl Any one, two or three substituted furanyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of d-( 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) a substituted pyranyl; include a halogen atom-containing, (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted thienyl groups; containing a halogen atom, a fluorenyl group of d- 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group Any one, two or three substituted pyrrolyl groups such as a methylthio group or an ethylthio group; a decanoyl group of c 6 ; or any one or two groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; Or three substituted Cr C e alkanoyl groups; C 2 - An alkenoyl group of C e ; an optionally, a two or three substituted C 2 -C 6 alkenoyl group including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; a C 3 -C e cycloalkanoyl group; Any one, two or three substituted C 3 - C s cycloalkanoyl groups of an atom, an alkoxy group of a CrCe or a hydroxyl group; an adamantyl form, a substituted adamantyl form; an aroyl group; a benzyl group; Formyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2; 0; S or NH;
、 分别为：
Figure imgf000041_0001
, respectively:
Figure imgf000041_0001
其中 为下列任意一种取代基： H; CrCe的烷基； 含有包括卤素原子、 d- ( 6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- ^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- (：6的 炔基;含有包括卤素原子、 Ci-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- Cs 的炔基； C3- Ce的环垸基； 含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、 两个 或者三个取代的( 3- 的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基; 含有包括卤素原子、 d- 的烷基、 硝基、 羧基、 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、 - 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- (^的垸基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的呋喃基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 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、 Cr ( 4的垸基、 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- ( 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咯基； Cr C6的垸酰基； 含 有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C,- C6的烷 酰基； C2- Ce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- (：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- 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 刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（C¾) n， n为 0- 2; 0； S或者 NH; Wherein any one of the following substituent groups: H; C r C e alkyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy (6, including one, two or three substituents of d- ( Alkyl; C 2 - ^ alkenyl; any one, two or three substituted C 2 -C6 alkenyl group including a halogen atom, C "C 6 alkoxy group or a hydroxyl group; C 2 - (: 6 alkynyl; alkynyl group containing any one, two or three substituted C 2 - C s including a halogen atom, an alkoxy group of Ci-Ce or a hydroxyl group; C 3 - C e Any one, two or three substituted ( 3 -cycloalkyl; aryl; benzyl; furyl; pyranyl) containing a halogen atom, an alkoxy group of CrCe or a hydroxyl group; ; thienyl; pyrrolyl; pyridyl; 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 decyl group, a methyl group, a Any one, two or three substituted aryl groups including a thio group; containing an alkyl group including a halogen atom, - a nitro group, a carboxy group Any one, two or three substituted pyridyl groups, 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- Any one, two or three substituted thiol, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio a furan group; containing an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and the like. any one, two or three of the substituents pyranyl; include a halogen atom-containing, Cr (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group, a mercapto group, Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing a halogen atom, d-(alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, Amido, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituents pyrrolyl group; a C 6 acyl group of Cr embankment; C optionally include a halogen atom-containing, d- alkoxy or hydroxy group including one, two or three substituents of - C 6 alkane Acyl group; C 2 -C e enoyl group; any one, two or three substituted c 2 -c 6 enoyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; C 2 - C An alkynyl group of 6; a acetylene group containing any one, two or three substituted C 2 - groups including a halogen atom, d- (: 6 alkoxy group or hydroxyl group); 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 CrC 6 or a hydroxyl group; an adamantyl group, a substituted adamantyl group; an aroyl group; Benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; (C3⁄4) n , n is 0-2; 0; S or NH;
或者 R3、 分别为：
Figure imgf000042_0001
Or R 3 , respectively:
Figure imgf000042_0001
其中 R7、 各自独立为下列任意一种取代基： H; d- C6的垸基； 含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、 两个或者三个取代的 烷基； C2- Cs的烯基； 含有包括卤素原子、 Cr" 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- Cs的炔基； 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的炔基； C3-C6的环烷基； 含有包括卤素原子、 Cr 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的环焼基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d-C4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 C C4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、 d-C4的焼基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- 0>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喃基； 含有包括卤素原子、（ (：4的烷基、 硝基、 羧基、醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； C CS的烷酰基； 含有包括卤素原子、 CrCs的垸氧基或羟基在内的任意一个、 两个或者三个 取代的 CrCe的烷酰基； C2-C6的烯酰基； 含有包括卤素原子、 d- ( 6的烷氧基或羟基在内的 任意一个、两个或者三个取代的 C2- C6的烯酰基； C2- C6的炔酰基； 含有包括卤素原子、 CrC6 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- C6的炔酰基； C3- C6的环烷酰基; 含有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- ( 的 环烷酰基； 金刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾ , n为 0-2; 0; S或者 NH; 为（(¾)„， n为 0 - 2; 0; S或者 NH; 或者 R3、 分别为:
Figure imgf000043_0001
Wherein R 7 is each independently a substituent of any of the following: H; a fluorenyl group of d-C 6 ; any one, two or three substituted alkanes including a halogen atom, an alkoxy group of CrCe or a hydroxyl group; groups; C 2 - C s alkylene group; a halogen atom-containing optionally include, Cr "C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 - C 6 alkenyl; C 2 - an alkynyl group of C s ; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C 6 cycloalkane Any one, two or three substituted C 3 -C 6 cyclodecyl groups including a halogen atom, an alkoxy group of Cr C 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a thiophenyl group; a pyrrolyl group; a pyridyl group; a fluorenyl 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 decyl group, a methyl group, ethylthio, including any one, two or three aryl group substituents; comprising, the CC of the alkyl group include a halogen atom 4 Any one, two or three substituted pyridyl groups including a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of an atom, a thiol 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 methylthio group, an ethylthio group Substituted furanyl; containing an alkyl group including a halogen atom, d- 0>, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyranyl groups; containing a halogen atom, ((: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group) Any one, two or three substituted thienyl groups including a mercapto group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, Amido, carboxamide, sulfhydryl, methylthio Ethylthio, including any one, two or three substituents pyrrolyl; alkanoyl CC S; and one, two or three substituents include a halogen atom contain any, the CRCS embankment including a hydroxyl group or a An alkanoyl group of CrC e ; a C 2 -C 6 alkenoyl group; an alkyl group containing any one, two or three substituted C 2 - C 6 groups including a halogen atom, d-( 6 alkoxy group or hydroxyl group) Acyl; C 2 -C 6 alkynyl; any one, two or three substituted C 2 -C 6 alkynyl group including a halogen atom, a decyloxy group of CrC 6 or a hydroxyl group; C 3 - C 6 cycloalkyl group; comprising any one, two or three of the substituents include halogen atoms C 3, d-C6 alkoxy or hydroxy, including the embankment of - (cycloalkyl group; formyl embankment adamantyl, substituted adamantyl embankment Formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; ((3⁄4, n is 0-2; 0; S or NH; is ((3⁄4)), n is 0 - 2; 0; S or NH; Or R 3 , respectively:
Figure imgf000043_0001
其中 R9为下列任意一种取代基： H; Cr C6的烷基； 含有包括卤素原子、 d- 6的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 d- ( 6的垸基； C2-Ce的烯基； 含有包括卤素 原子、 CrCe的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- ( 6的烯基； C2-CB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-Ce 的炔基； C3- Cs的环烷基； 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 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的垸基、 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-C^的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝 基、 羧基、 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、（ ( 4的垸基、 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- (^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- (：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咯基； d-Cs的烷酰基； 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 d- Ce的烷 酰基； C2- Ce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、 的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 c2- ce的炔酰基； c3- c8的环垸酰基； 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 c3- cs的环垸酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH , n为 0- 2; 0； S或者 NH; Wherein R 9 is any one of the following substituents: H; an alkyl group of Cr C 6 ; any one, two or three substituted d- (including a halogen atom, an alkoxy group of d- 6 or a hydroxyl group) alkyl with 6; C 2 -C e alkenyl group; a halogen atom-containing optionally include, CRCE the embankment or a hydroxyl group, including one, two or three substituents of C 2 - (6 alkenyl; C 2 Alkynyl group of -C B ; any one, two or three substituted C 2 -C e alkynyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a cycloalkane of C 3 - C s Any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; ; thienyl; pyrrolyl; pyridyl; containing fluorenyl group including a halogen atom, d-C 4 , nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group Any one, two or three substituted aryl groups including an ethylthio group; a fluorenyl group containing a halogen atom, dC^, a nitro group, a carboxy group Any one, two or three substituted pyridyl groups including an alkyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; - any one, two or three substitutions of an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group or an ethylthio group of C 4 a furanyl group; containing a halogen atom, ( 4 , fluorenyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) Any one, two or three substituted pyranyl groups; containing a halogen atom, d-(^, alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, fluorenyl Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing a halogen atom, d-(: 4 alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, Amine, amide, carboxamide, sulfhydryl, methylthio, B Any one, two or three substituted pyrrolyl groups; d-Cs alkanoyl group; any one, two or three substitutions including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group Alkanoyl group of d-C e ; enoyl group of C 2 - C e ; enoyl group of any one, two or three substituted c 2 - c 6 containing a halogen atom, an alkoxy group or a hydroxyl group a c 2 - c 6 alkynyl group; a acetylenyl group having any one, two or three substituted c 2 - c e groups including a halogen atom, a decyloxy group or a hydroxyl group; a c 3 - c 8 ring a decanoyl group; a cyclodecanoyl group containing any one, two or three substituted c 3 - c s including a halogen atom, an alkoxy group of dC e ; an adamantyl formyl group, a substituted adamantyl form group; Aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH, n is 0-2; 0; S or NH;
或者 、 分别为-
Figure imgf000043_0002
Or, respectively -
Figure imgf000043_0002
其中 R1()、 Ru各自独立为下列任意一种取代基： H; d- (6的垸基； 含有包括卤素原子、 d-C8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的垸基； C2-C6的烯基； 含有包括卤素原子、 -Cs的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- ( 6的 烯基； c2_cfi 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- (6的炔基； C3- Ce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的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- c4的垸基、 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、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 疏基、 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、 CrC 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、 CrQi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、 （,-( 4的焼基、 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； 的垸酰基； 含有包括卤素原子、 6的烷氧基或羟基在内的任意一个、 两个或者三个 取代的 d- Ce的烷酰基； C2- C6的烯酰基； 含有包括卤素原子、 d- (6的垸氧基或羟基在内的 任意一个、两个或者三个取代的 C2- Ce的烯酰基； C2- Cs的炔酰基； 含有包括卤素原子、 d- 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- Ce的炔酰基； C3- C6的环烷酰基; 含有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 （3-( 6的 环垸酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾)„， n为 0- 2; 0； S或者 NH; X2为（C¾) n， n为 0 - 2; 0; S或者 NH; Wherein R 1 ( ) and Ru are each independently a substituent of any of the following: H ; d- ( 6 fluorenyl; any one, two or three containing a halogen atom, an alkoxy group of dC 8 or a hydroxyl group) Substituted d-C 6 fluorenyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 - (including a halogen atom, a decyloxy group of -Cs or a hydroxy group) 6 Alkenyl; c 2 _c fi alkynyl; any one, two or three substituted C 2 - ( 6 alkynyl group; C 3 - C e containing a halogen atom, (alkoxy group or hydroxyl group) a cycloalkyl group; any one, two or three substituted c 3 - c 6 cyclodecyl groups including a halogen atom, an alkoxy group of d-c 6 or a hydroxyl group; an aryl group; a benzyl group; a furyl group ; pyranyl; thienyl; pyrrolyl; pyridyl; containing fluorenyl group including a halogen atom, d-c 4 , nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group Any one, two or three substituted aryl groups including a methylthio group or an ethylthio group; an alkyl group including a halogen atom, d-c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group Any one, two or three substituted pyridyl groups including a amide group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, a nitro group, a carboxyl group, and an aldehyde group , alkoxy, amino, amide, carboxamide, sulfhydryl, methylthio, ethanesulfide Any one, two or three substituted furanyl groups; containing an alkyl group including a halogen atom, CrC, 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 pyranyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, CrQi, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group group, any carbon amide group, a mercapto group, methylthio, ethylthio, including one, two or three substituents thienyl; include a halogen atom-containing, (, - (4 firing group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a decanoyl group; Any one, two or three substituted d-C e alkanoyl groups of 6 alkoxy or hydroxy; C 2 - C 6 enoyl; containing a halogen atom, d- ( 6 oxime) Any one, two or three bases or hydroxyl groups Substituted C 2 - C e alkylene group; C 2 - C s alkynyl group; a halogen atom-containing optionally include, d- or hydroxyl group of the embankment, including one, two or three substituents of C 2 - C Alkynyl group of e ; C 3 -C 6 cycloalkanoyl; any one, two or three substituted ( 3 -( 6 -cyclodecanoyl) containing a halogen atom, a decyloxy group of dC 6 or a hydroxyl group ; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; ((3⁄4) „, n is 0-2; S or NH ; X 2 is (C3⁄4) n , n is 0 - 2; 0; S or NH;
或者， 当 、 R2分别各自独立为：
Figure imgf000044_0001
Or, when, R 2 are each independently:
Figure imgf000044_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、 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-Cs的烷基； C2- (^的烯基； 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- ^的 烯基； ^-08的炔基； 含有包括卤素原子、 CrC6的垸氧基或羟基在内的任意一个、 两个或者 三个取代的 C2- (：6的炔基； C3- C6的环烷基； 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 C3- Ce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、 （^-( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 （^- 的垸基、 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、 -(：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- ( 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喃基； 含有包括卤素原子、 CrG的垸基、 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- (^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咯基； CrCs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- Ce的烯酰基； 含有包括卤素原子、 -( 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- Ce的烯酰基； C2- C6的炔酰基； 含有包括卤素原子、 C「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- Ce的炔酰基； C3_C6的环烷酰基; 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 C3- ( 的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X, ¾ (C¾)„, n为 0- 2; 0； S或者 NH; 为（CH ， n为 0-2; 0; S或者 NH时； Wherein R 12 and R 13 are each independently a substituent of any of the following: H; an alkyl group of d-C 6 ; any one, two or three containing an alkoxy group including a halogen atom, CrC 6 or a hydroxyl group; a substituted alkyl group of d-Cs; an alkenyl group of C 2 - (^; any one, two or three substituted C 2 - ^ containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; Alkenyl; ^-0 8 alkynyl; any one, two or three substituted C 2 - (: 6 alkynyl group; C 3 - containing a halogen atom, a decyloxy group of CrC 6 or a hydroxyl group; a cycloalkyl group of C 6 ; a cycloalkyl group having any one, two or three substituted C 3 - C e groups including a halogen atom, an alkoxy group of d-Ce; an aryl group; a benzyl group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; pyridyl; include a halogen atom-containing, (^ - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide Any one, two or three substituted aryl groups including a thiol group, a thiol group, a methylthio group, and an ethylthio group; Sulfhydryl, nitro, carboxyl, aldehyde, decyloxy, amine, amide, carboxamide, Any one, two or three substituted pyridyl groups including a fluorenyl group, a methylthio group, an ethylthio group; containing a halogen atom, -(: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, Any one, two or three substituted furanyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a halogen atom, a d-( 4 alkyl group, a nitro group) Any one, two or three substituted pyranyl groups such as a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group; Any one, two or three substituted groups of a sulfhydryl 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 or an ethylthio group. a thiophenyl group; containing a halogen atom, d-(^, alkyl, nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio any one, two or three substituents pyrrolyl; CrC s Alkanoyl; containing optionally include a halogen atom, d- alkoxy or hydroxy group including one, two or three substituents of (- to C 6 alkanoyl; C 2 - C e alkylene group; include a halogen atom-containing , - any alkoxy or hydroxy (6, including one, two or three substituents of C 2 - C e alkylene group; C 2 - C 6 alkynyl group; a comprises containing a halogen atom, C "C e Any one, two or three substituted C 2 -C e alkynyl groups such as alkoxy or hydroxy; C 3 _C 6 cycloalkanoyl; containing alkoxy groups including a halogen atom, d-Cs or Any one, two or three substituted C 3 -(cycloalkanoyl; adamantyl, substituted adamantyl form; aroyl; benzyl; furanoyl; pyranoyl; thiophene Formyl; pyrroyl group; X, 3⁄4 (C3⁄4) „, n is 0- 2; 0; S or NH; is (CH, n is 0-2; 0; S or NH;
、 分别为：
Figure imgf000045_0001
, respectively:
Figure imgf000045_0001
其中 Re为下列任意一种取代基： H; d- ^的烷基； 含有包括卤素原子、 Cr ( 6的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 ( 6的烷基； C2-C6的烯基； 含有包括卤素 原子、 （ Ce的垸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、 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 (VC6 的炔基； C3-C3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- Cs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、 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、 C C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 C,- ( 的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的呋喃基； 含有包括卤素原子、（ (^的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的噻吩基; 含有包括卤素原子、 （ -θ!的焼基、 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； c,- ce的垸酰基； 含 有包括卤素原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 d- C6的烷 酰基； c2- C6的烯酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、 两个或 者三个取代的 C2- C6的烯酰基； C2- C6的炔酰基； 含有包括卤素原子、 ( 6的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 c2- ce的炔酰基； c3-ce的环垸酰基； 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- ce的环烷酰基； 金 刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2)„， n为 0- 2 ; 0； S或者 NH; Wherein R e is any of the following substituent groups: H; d- ^ alkyl group; one, two or three substituents include a halogen atom contain any, Cr alkoxy or hydroxy (including a 6 (6 An alkyl group; a C 2 -C6 alkenyl group; an alkenyl group containing any one, two or three substituted C 2 -C 6 groups including a halogen atom, (decyloxy group or hydroxy group of Ce; 2 - ( 6 Alkynyl; any one, two or three substituted (VC 6 alkynyl group; C 3 -C 3 cycloalkyl group containing a halogen atom, d-C 6 alkoxy group or a hydroxyl group; Any one, two or three substituted C 3 - C s cycloalkyl groups including a halogen atom, (C6 alkoxy group or a hydroxyl group; aryl; benzyl; furyl; pyranyl; thienyl) ; pyrrolyl; pyridyl; containing a halogen 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 thiol group, a methylthio group, an ethylthio group in any one, two or three aryl group substituents; containing a halogen atom include, CC 4 alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted pyridyl groups including a fluorenyl group, a fluorenyl group, an amide group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; 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. Containing any one of a halogen atom, ((alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) Two or three substituted pyranyl groups; containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, methyl sulfide Any one, two or three substituted thienyl groups including a thiol group; a halogen atom, a sulfhydryl group, a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group Base, carboxamide group, Any one, two or three substituted pyrrolyl groups including a mercapto group, a methylthio group, an ethylthio group; a cyanyl group of c, - c e ; a decyloxy group or a hydroxyl group including a halogen atom, d-Ce Any one, two or three substituted d-C 6 alkanoyl groups; c 2 - C 6 alkenoyl groups; any one or two containing a halogen atom, an alkoxy group of dC 6 or a hydroxyl group three substituted C 2 - C 6 alkenyl group; a C 2 - C 6 alkynyl group; and one, two or three substituents contain any include halogen atoms, hydroxyl group, or embankment (6 c 2 of the inner - c e alkynyl group; c 3 -c e embankment cycloalkyl group; a halogen atom-containing optionally include, c "c 6 alkoxy or hydroxy, including one, two or three substituents of c 3 - c e Cycloalkanoyl; adamantyl formyl, substituted adamantyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ), n is 0- 2; 0; S or NH;
或者 R3、 分别为：
Figure imgf000046_0001
Or R 3 , respectively:
Figure imgf000046_0001
其中 R7、 R8各自独立为下列任意一种取代基： H; d- (：6的烷基； 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（^-( 6的烷基； （2-( 6的烯基； 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 C2- C6的 烯基； （2-(：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- ( 6的炔基； C3- C6的环烷基； 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 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- (：4的垸基、 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芳基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4的浣基、 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呋喃基； 含有包括卤素原子、 d- 的垸基、 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,- 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的垸基、 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; 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 c「 ce的烷酰基； c2-c6的烯酰基； 含有包括卤素原子、 d- ce ½垸氧基或羟基在内的 任意一个、两个或者三个取代的 c2- ce的烯酰基； c2- ce的炔酰基； 含有包括卤素原子、 c「 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的炔酰基； c3- c6的环烷酰基; 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 C:i- (^的 环垸酰基； 金刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（012)„， n为 0-2 ; 0； S或者丽； 为（CH ， n为 0- 2 ; 0； S或者 NH; Wherein R 7 and R 8 are each independently a substituent of any of the following: H; d- (: 6 alkyl; any one or two containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group or substituted three (^ - (6 alkyl group; (2 - (6 alkenyl; contain any include halogen atoms, alkoxy or hydroxy Ci- C 6 inner one, two or three substituents of C 2 - C 6 alkenyl group; (2 - (: alkynyl; optionally include a halogen atom-containing, dC 6 alkoxy or hydroxy, including one, two or three substituents of C 2 - (6 Alkynyl; C 3 -C 6 cycloalkyl; any one, two or three substituted C 3 -C 6 cycloalkyl group including a halogen atom, an alkoxy group of dC e or a hydroxyl group; Benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing halogen atom, d- (: 4 fluorenyl, nitro, carboxyl, aldehyde, decyloxy, amine, Any one, two or three substituted aryl groups including an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any atom, d- C alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio 4 including one, two, or three substituted pyridyl; include a halogen atom-containing, CrC 4 Huan group, a nitro group, a carboxyl group, an aldehyde group, embankment group, amine, amide, carboxamide, mercapto, methylthio, ethylthio in Any one, two or three substituted furan groups; containing a halogen atom, a fluorenyl 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, Any one, two or three substituted pyranyl groups including a methylthio group and an ethylthio group; containing an alkyl group including a halogen atom, c, -, 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 methylthio group, an ethylthio group; a thiol group including a halogen atom, C, -C 4 , a nitro group, Carboxyl, aldehyde, alkoxy, amine, amide, carbonyl Any one, two or three substituted pyrrolyl groups including an amine group, a fluorenyl group, a methylthio group, an ethylthio group; an alkanoyl group; an alkoxy group including a halogen atom, c, -C6 or a hydroxyl group; any one, two or three substituents of c 'c E alkanoyl; 2 -c 6 c alkenoyl; a halogen atom-containing optionally include, d- c e ½ embankment including a hydroxyl group or, two Or an enoyl group of three substituted c 2 - c e ; an alkynyl group of c 2 - c e ; any one, two or three substitutions including a halogen atom, an alkoxy group of c " c e or a hydroxyl group a c 2 - c 6 alkynyl group; a c 3 - c 6 cycloalkanoyl group; any one, two or three substituted C :i groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; - (cyclohexanoyl; adamantyl, substituted adamantyl; aroyl; benzyl; furanoyl; pyranoyl a thiophene acyl group; a pyrrolyl group; a (01 2 ) „, n is 0-2; 0; S or 丽; is (CH, n is 0-2; 0; S or NH;
或者 、 ^分别为-
Figure imgf000047_0001
Or, ^ respectively -
Figure imgf000047_0001
其中 为下列任意一种取代基： H; (^-( 6的垸基； 含有包括卤素原子、 Cr (：6的垸氧基 或羟基在内的任意一个、 两个或者三个取代的 C6的烷基； C2- ^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- ( 6的烯基； C2- (6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的环垸基； 含有包括卤素原子、 Ct-Cs的烷氧基或羟基在内的任意一个、两个 或者三个取代的( 3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 ^的垸基、 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、 的嫁基、 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、 d- ( 的垸基、 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呋喃基； 含有包括卤素原子、 ( 的垸基、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- (：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的噻吩基； 含有包括卤素原子、 d- ( 4的烷基、硝基、羧基、醛基、烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； CrC6的垸酰基； 含 有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个取代的 d- CB的烷 酰基； C2- C6的烯酰基； 含有包括卤素原子、 C「C6的垸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、 ( 8的烷氧基或羟基 在内的任意一个、 两个或者三个取代的 C2- C6的炔酰基； C3- C6的环烷酰基； 含有包括卤素 原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3- C6的环垸酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2) n, n为 0-2; 0； S或者 NH; Wherein is any one of the following substituents: H; (^-( 6 fluorenyl; any one, two or three substituted C 6 including a halogen atom, Cr (: 6 decyloxy group or hydroxyl group) Alkyl; C 2 - ^ alkenyl; any one, two or three substituted C 2 - ( 6 alkenyl; C 2 - containing a halogen atom, d-alkoxy or hydroxy group (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 of; C 3 - C 6 cycloalkyl group embankment ; contain any halogen atoms include, Ct-Cs alkoxy or hydroxy group including one, two or three substituents of (3 - C 6 cycloalkyl group; an aryl group; a benzyl group; furanyl; pyranyl ; thienyl; pyrrolyl; pyridyl; containing a halogen atom, a sulfhydryl 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 ethyl sulfide Any one, two or three substituted aryl groups, including a halogen atom, a nitro group, a carboxyl group, an aldehyde group Any one, two or three substituted pyridyl groups including a methoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a fluorenyl group containing a halogen atom, d- Any one, two or three substituted furanyl groups including a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethylthio group; Any one, two or three of a halogen atom, a sulfhydryl 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 or an ethylthio group. Substituted pyranyl group; containing a halogen atom, d- (: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, mercapto group, methylthio group, ethyl sulfide Any one, two or three substituted thienyl groups, including a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide) Any one of a group, a thiol group, a methylthio group, and an ethylthio group, a two or three substituted pyrrolyl group; a decanoyl group of CrC 6 ; an alkanoyl group having any one, two or three substituted d-C B groups including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group; C 2 - C 6 alkenyl group; a comprises containing any halogen atoms, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - C 6 alkenyl group of; C 2 - C An alkynyl group of 6; a acetylenedoyl group containing any one, two or three substituted C 2 -C 6 groups including a halogen atom, an alkoxy group of 8 ; a C 3 -C 6 cycloalkanoyl group; Any one, two or three substituted C 3 -C 6 cyclodecanoyl groups including a halogen atom, an alkoxy group or a hydroxyl group; an adamantyl form group, a substituted adamantyl form group; an aroyl group; ; furoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2; 0; S or NH;
或者 、 分别为-
Figure imgf000047_0002
Or, respectively -
Figure imgf000047_0002
其中 R1Q、 Ru各自独立为下列任意一种取代基： H; d- ( 6的烷基； 含有包括卤素原子、 Ct-Ce的烷氧基或羟基在内的任意一个、 两个或者三个取代的 烷基； C2- C6的烯基； 含有包括卤素原子、 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- (：6的 烯基； C2-C6 炔基； 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- (]6的炔基； C3-C6的环垸基； 含有包括卤素原子、 d- C6的烷氧基或羟基在内 的任意一个、两个或者三个取代的 C3-C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 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芳基； 含有包括卤素原子、 C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 -( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 C,- (^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喃基； 含有包括卤素原子、 院基、 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- ( 4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-C6的垸酰基； 含有包括卤素原子、 d-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； 含有包括卤素原子、 C「 ( 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-C^ 的垸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- (：6的环烷酰基; 含有包括卤素原子、 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； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X^ (C )„, n为 0- 2; 0； S或者 NH; 为（CH2)„， n为 0-2; 0； S或者 NH; Wherein R 1Q and Ru are each independently a substituent of any of the following: H; d- ( 6 alkyl; containing a halogen atom, Any one, two or three substituted alkyl groups including an alkoxy group or a hydroxyl group of Ct-Ce; a C 2 -C 6 alkenyl group; containing an alkoxy group including a halogen atom, C e or a hydroxyl group Any one, two or three substituted C 2 - (: 6 alkenyl; C 2 - C 6 alkynyl; any one or two containing an alkoxy group including a halogen atom, dC e or a hydroxyl group or a three-substituted C 2 - (] 6 alkynyl group; a C 3 - C 6 cycloalkyl group; any one, two or three containing a halogen atom, an alkoxy group of d-C 6 or a hydroxyl group; Substituted C 3 -C 6 cycloalkyl; aryl; benzyl; furyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing alkyl group including halogen atom, d-C 4 , nitro group, Any one, two or three substituted aryl groups including a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group, a mercapto group, a methylthio group, b Group, including any one, two or three substituted pyridyl; contains include halogen atoms, - (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group 4 Any one, two or three substituted furanyl groups including a fluorenyl group, a methylthio group, an ethylthio group; containing an alkyl group including a halogen atom, C, - (^, a nitro group, a carboxyl group, an aldehyde group, an anthracene 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 methylthio group, an ethylthio group, and the like, including a halogen atom, a hospital group, a nitro group, and a carboxyl group. Any one, two or three substituted thienyl groups, 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- any (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents of pyrrolyl; dC embankment 6 acyl; include halogen-containing Promoter, any dC ^ alkoxy or hydroxy group including one, two or three substituents of C "C 6 alkanoyl; C 2 - C 6 alkenyl group; a halogen atom include containing, C '(6 Any one, two or three substituted C 2 -C 6 enoyl groups such as alkoxy or hydroxy; C 2 -C 6 alkynyl; containing a halogen atom or a hydroxyl group including a halogen atom, Any one, two or three substituted c 2 -C 6 alkynyl groups; C 3 - (: 6 cycloalkanoyl group; containing any one including a halogen atom, an alkoxy group of Ce, or a hydroxyl group; Two or three substituted C 3 -C 6 cycloalkanoyl; adamantyl formyl, substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrole X^ (C )„, n is 0- 2; 0; S or NH; is (CH 2 )„, n is 0-2; 0; S or NH;
或者， 当 、 R2分别各自独立为-
Figure imgf000048_0001
Or, when, R 2 are each independently -
Figure imgf000048_0001
其中 R14为下列任意一种取代基： H; _(：6的烷基； 含有包括卤素原子、 d- ( 6的烷氧基 或羟基在内的任意一个、 两个或者三个取代的 C「 ( 6的烷基； C2- ( 的烯基； 含有包括卤素 原子、 -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- 的烯基； C2- ( 6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- C(i 的炔基； C3- C6的环垸基； 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 O Ce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、 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的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- ( 的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的呋喃基； 含有包括卤素原子、 ^的烷基、 硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 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、 ( 4的烷基、硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d- c6的烷酰基； 含 有包括卤素原子、 d-C3的烷氧基或羟基在内的任意一个、 两个或者三个取代的 Cr Cs的烷 酰基； C2- C6的烯酰基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或 者三个取代的 C2- C6的烯酰基； C2- C6的炔酰基； 含有包括卤素原子、 d-C^的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 C2-C3的炔酰基； C3- C6的环烷酰基； 含有包括卤素 原子、 d- 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3 C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（(¾)„， n为 0- 2; 0； S或者 NH时； Wherein R 14 is any one of the following substituents: H; _(: 6 alkyl; any one, two or three substituted Cs including a halogen atom, d-( 6 alkoxy group or hydroxyl group) "( 6 alkyl; C 2 - (alkenyl; any one, two or three substituted C 2 -alkenyl group including a halogen atom, -Ce alkoxy group or a hydroxyl group; C 2 - (6 alkynyl; comprising any one, two or three substituents of a halogen atom include C 2, d- C 6 alkoxy or hydroxy, including - C (i, alkynyl group; C 3 - C 6 cyclic alkyl with; contain optional atoms including vegetarian, C "C 6 alkoxy or hydroxy, including one, two or three cycloalkyl, substituted OC e; the aryl group; a benzyl group; furanyl; pyrazol a thiol group; a pyrrolyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, Any one, two or three substituted aryl groups including a mercapto group, a methylthio group, an ethylthio group; a mercapto 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 pyridyl groups, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a halogen atom, a d-alkyl group, a nitro group, a carboxyl group, Any one, two or three substituted furanyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; and an alkane including a halogen atom; Any one, two or three substituted pyranyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one containing a halogen atom, an alkyl group of d-c 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, Two or three substituted thienyl groups; Any atom, (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including, two or three a substituted pyrrolyl group; an alkanoyl group of d-c 6 ; an alkanoyl group containing any one, two or three substituted Cr C s including a halogen atom, an alkoxy group of dC 3 or a hydroxyl group; C 2 - An alkenoyl group of C 6 ; an optionally, a two or three substituted C 2 -C 6 alkenoyl group including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a C 2 -C 6 alkynyl group; Any one, two or three substituted C 2 -C 3 alkynyl groups including a halogen atom, a decyloxy 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 d- alkoxy or hydroxy; adamantyl formyl, substituted adamantyl form; aroyl; benzoyl; furoyl ; pyranoyl; thiophene; pyrrolyl; ((3⁄4) „, n is 0- 2; 0; S or NH;
、 分别为：
Figure imgf000049_0001
, respectively:
Figure imgf000049_0001
其中 Rs为下列任意一种取代基： H; C「 C6的烷基； 含有包括卤素原子、 C「 ( 的垸氧基 或羟基在内的任意一个、 两个或者三个取代的 d- (：6的烷基； C2- (：6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- 的烯基； C2- (：6的 炔基;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 的炔基； C3- C6的环烷基； 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 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基; 含有包括卤素原子、 Cr ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 d-C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- ( 4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 （^-( 的垸基、 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 素原子、 d- C4的垸基、 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噻吩基; 含有包括卤素原子、 c,- 的烧基、 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咯基； d- c6的垸酰基； 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- 的垸 酰基； C2-C6的烯酰基； 含有包括卤素原子、 C「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- Ce的烯酰基； C2- Cfi的炔酰基； 含有包括卤素原子、 d- 的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 C2- C6的炔酰基； C3- Cs的环垸酰基； 含有包括卤素 原子、 C「C6的垸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 刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； X2为（CH ， n为 0- 2; 0； S或者 NH; Wherein R s is any one of the following substituents: H ; C "C 6 alkyl group; any one, two or three substituted d- including a halogen atom, a C ( methoxy group or a hydroxy group. ( 6 : alkyl group; C 2 - (: 6 alkenyl group; any one, two or three substituted C 2 - alkenyl groups including a halogen atom, an alkoxy group or a hydroxyl group; C 2 ; - (: 6 alkynyl group; a halogen atom-containing optionally include, d-Ce alkoxy or hydroxy group including one, two or three substituents of C 2 - C 6 alkynyl group; C 3 - C 6 of a cycloalkyl group; any one, two or three substituted C 3 -C 6 cycloalkyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; an aryl group; a benzyl group; a furyl group; tetrahydrothiopyranyl; thienyl; pyrrolyl; pyridyl; include a halogen atom-containing, Cr (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio Any one, two or three substituted aryl groups including a thiol group; an alkyl group including a halogen atom, dC 4 , and a nitrate Any one, two or three substituted pyridyl groups including a carboxy group, a carboxy group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three of d-( 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) a substituted furanyl group; containing a halogen atom, (^-(indenyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio) Any one, two or three substituted pyranyl groups; containing a sulfhydryl group including a aryl group, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thienyl groups including a thiol group, a thiol group, a methylthio group, and an ethylthio group; Any one or two containing a halogen atom, a c-alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Or a substituted triazole group; a decanoyl group of d-c 6 ; a decanoyl group containing any one, two or three substituted d- groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; a 2- C6 alkenoyl group; an enoyl group containing any one, two or three substituted C 2 - C e including a halogen atom, an alkyl group of C "C e " or a hydroxyl group; C 2 - C fi Any one, two or three substituted C 2 -C 6 alkynyl groups containing a halogen atom, a decyloxy group or a hydroxyl group of d-; a cyclodecanoyl group of C 3 - C s ; include a halogen atom, "a hydroxyl group or a C 6 embankment, including any of a C, two or three substituents of the cycloalkyl group of C 6. 3 C; formyl embankment adamantyl, substituted adamantyl embankment formyl; aroyl; Benzyl; furanoyl; pyranoyl; thiophene; pyrroyl; X 2 Is (CH, n is 0-2; 0; S or NH;
或者 R3、 分别为：
Figure imgf000050_0001
Or R 3 , respectively:
Figure imgf000050_0001
其中 R7、 R8各自独立为下列任意一种取代基： H; d- Cs的烷基； 含有包括 [if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 d- ( 6的烷基； O ( 6的烯基； 含有包括卤素原子、 d-CB的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- ( 6的 烯基； （2-( 6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- (：6的炔基； C3- C6的环垸基； 含有包括卤素原子、 d- 的烷氧基或羟基在内 的任意一个、两个或者三个取代的 C3- C6的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括 素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 C「C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 Cr ( 4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、两个或者三个取代的吡喃基； 含有包括卤素原子、 C4的垸基、 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 个取代的噻吩基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡咯基； d-C6的烷酰基； 含有包括卤素原子、 d-C3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-ce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-ce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-ca的炔酰基； c3-ce的环烷酰基; 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 （3-(：6的 环垸酰基； 金刚垸甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； X【为 (CH2)„, n为 0- 2; 0； S或者 NH; 为（CH2)„， n为 0 - 2; 0； S或者丽； Wherein R 7 and R 8 are each independently a substituent of any of the following: H; an alkyl group of d-C s ; or any one or two including an alkoxy group or a hydroxyl group of [if a atom, d-Ce] Or three substituted d-( 6 alkyl; O ( 6 alkenyl; any one, two or three substituted C 2 - containing a halogen atom, a decyloxy group of dC B or a hydroxyl group) 6 alkenyl; ( 2- ( 6 alkynyl; any one, two or three substituted C 2 - (: 6 alkynyl group) including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group; a C 3 -C 6 cyclodecyl group; any one, two or three substituted C 3 -C 6 cyclodecyl groups including a halogen atom, an alkoxy group of d- or a hydroxyl group; an aryl group; a furanyl group; a pyrenyl group; a pyrenyl group; a pyrrolyl group; a pyridyl group; an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carbon group; amide groups, mercapto, methylthio, ethylthio, including one, two or three aryl group substituents; including vegetarian containing atoms, d- C 4 Any one, two or three substituted pyridyl groups of an alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Containing any one of a halogen atom, a C "C 4 alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, two or three substituents furanyl; containing a halogen atom include, Cr (alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio 4 Any one, two or three substituted pyranyl groups including an ethylthio group; a halogen group including a halogen atom, a C 4 group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, and a carbon group Any one, two or three substituted thienyl groups including an amide group, a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, and an anthracene Oxyl, amine, amide, carboxamide, sulfhydryl Methylthio, ethylthio, including any one, two or three substituents pyrrolyl; dC 6 alkanoyl; contain any halogen atom include, dC 3 alkoxy or hydroxy, including one, two, Or a substituted acyl alkanoyl group; an alkenoyl group of c 2 -c e ; any one, two or three substituted c 2 -c containing a halogen atom, an alkoxy group of d- or a hydroxyl group e enoyl; C 2 - C 6 alkynyl group; a halogen atom-containing optionally include, d- alkoxy or hydroxy group including one, two or three of c 2 -c a substituted alkynyl group; C a cycloalkanoyl group of 3 - c e ; any one, two or three substituted groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group ( 3 - (: 6 ) Cyclodecanoyl; adamantyl, substituted adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrroyl; X [(CH 2 ) „, n is 0 - 2; 0; S or NH; is (CH 2 ) „, n is 0 - 2; 0; S or 丽;
或者 、 分别为：
Figure imgf000051_0001
Or, respectively:
Figure imgf000051_0001
其中 为下列任意一种取代基： H; 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- ( 6的烯基； 含有包括卤素 原子、 d- 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- (^的烯基； C2- ( 的 炔基;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 的炔基； C3- Cs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- Ce的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 -^的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 CrC4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- (：4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 d- 的垸基、 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噻吩基; 含有包括卤素原子、 （^-( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； C,- C6的烷酰基； 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 Ct-Ce的烷 酰基； C2- C6的烯酰基； 含有包括卤素原子、 C,- CB的烷氧基或轻基在内的任意一个、 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、 （广 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- 的炔酰基； c3- c6的环烷酰基； 含有包括卤素 原子、 CrCs的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C3- C6的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH , n为 0- 2; 0； S或者 NH; Wherein any one of the following substituents: H; an alkyl group; any one, two or three substituted (-C 6 alkyl groups) including a halogen atom, d- (a alkoxy group or a hydroxyl group) C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - (^ alkenyl; C 2 - (containing) including a halogen atom, a decyloxy group or a hydroxyl group of d- An alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, an alkoxy group of dC e or a hydroxyl group; a C 3 -C s cycloalkyl group; Any one, two or three substituted C 3 -C e cycloalkyl groups such as alkoxy, C, or C 6 alkoxy or hydroxy; aryl; benzyl; furyl; pyranyl; a thiophenyl group; a pyrrolyl group; a pyridyl group; containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, Any one, two or three substituted aryl groups including an ethylthio group; containing an alkyl group including a halogen atom, -^, a nitro group, a carboxyl group, Any one, two or three substituted pyridyl groups including an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; containing a halogen atom, CrC 4 Any one, two or three substituted furanyl 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 decyl group, a methylthio group, an ethylthio group; Any one containing a halogen atom, d- (: 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) , two or three substituted pyranyl groups; containing a halogen atom, a fluorenyl group, a nitro group, a carboxy group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group , ethylthio, including any one, two or three substituents thienyl; include a halogen atom-containing, (^ - (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide Base, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted pyrrolyl groups; C, -C 6 alkanoyl group; any one, two or three substituted groups including a halogen atom, an alkoxy group of d-Ce or a hydroxyl group Alkanoyl group of Ct-Ce; enoyl group of C 2 - C 6 ; any one, two or three substituted C 2 - C6 containing an alkoxy group or a light group including a halogen atom, C, - C B enoyl; C 2 - C 6 alkynyl group; a halogen atom-containing include any (alkoxy or hydroxy C e wide inner one, two or three substituents of c 2 - alkynyl acyl; c 3 a cycloalkanoyl group of c 6 ; any one, two or three substituted C 3 -C 6 cycloalkanoyl groups including a halogen atom, an alkoxy group of CrC s or a hydroxyl group; adamantyl formyl group, substituted Adamantyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; (CH, n is 0-2; 0; S or NH;
或者 R3、 分别为:
Figure imgf000051_0002
其中 。、 各自独立为下列任意一种取代基： H; d- (：6的垸基； 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 ^-(：6的垸基； C2- (^，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- ( 的 烯基； C2- ( 6的炔基； 含有包括 素原子、 C「C6的垸氧基或羟基在内的任意一个、 两个或者 三个取代的 C2- ( 6的炔基； C3-C6的环垸基； 含有包括卤素原子、 C「C6的垸氧基或羟基在内 的任意一个、两个或者三个取代的 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- C4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 d- C4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 (^的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 Cr C4的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 ^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 素原子、 C「C4的垸基、 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 个取代的噻吩基； 含有包括卤素原子、 d- C4的垸基、 硝基、 羧基、 酸基、 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咯基； d-C6的烷酰基； 含有包括卤素原子、 d-C6的垸氧基或羟基在内的任意一个、 两个或者三个 取代的 C,- Cs的烷酰基； C2- Ce的烯酰基； 含有包括 素原子、 d- ( 6的垸氧基或羟基在内的 任意一个、 两个或者三个取代的 C2- Ce的烯酰基； C2-Ce的炔酰基； 含有包括卤素原子、 Ci- 的烷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-Cs的烷氧基或羟基在内的任意一个、 两个或者三个取代的 c3-cf)的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； Xi为 (CH2) n， n为 0- 2; 0； S或者 NH; ¾为 (CH2)„, n为 0 2 ; 0； S或者 NH; Or R 3 , respectively:
Figure imgf000051_0002
among them. And each independently is any one of the following substituents: H; d- (: 6 fluorenyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of dC 6 or a hydroxyl group) (: 6 fluorenyl; C 2 - (^, alkenyl; any one, two or three substituted C 2 - (alkenyl groups) including a halogen atom, an alkoxy group or a hydroxyl group; C 2 - (6 alkynyl; contain optional atoms including vegetarian, C "C 6 alkoxy or hydroxy embankment inner one, two or three substituents of C 2 - (6 alkynyl; C 3 -C embankment 6 cycloalkyl group; a halogen atom include containing, "hydroxyl group or a C 6 embankment, including any of a C, two or three substituents of C 3 - C 6 cycloalkyl group; an aryl group; a benzyl group; Furanyl; pyranyl; thienyl; pyrrolyl; pyridyl; containing an alkyl group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group , any mercapto, methylthio, ethylthio, including one, two or three aryl group substituents; include a halogen atom-containing, d- C 4 Any one, two or three substituted pyridyl groups including a mercapto group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Any one or two containing a halogen atom, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group or an ethylthio group. Or a three-substituted furyl group; containing an alkyl group including a halogen atom, Cr C 4 , a nitro group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a group, a methyl group, a thio, including any one, two or three of the substituents pyranyl; comprising pigment containing atoms, C "C 4 alkyl with a nitro group, a carboxyl group, an aldehyde group, embankment 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; a thiol group including a halogen atom, d-C 4 , a nitro group, a carboxyl group, an acid group, Oxime, amine, amide, carboxamide, sulfhydryl, a Any one, two or three substituted pyrrolyl groups such as a thio group or an ethylthio group; an alkanoyl group of dC 6 ; or any one or two containing a halogen atom, a decyloxy group of dC 6 or a hydroxyl group a three-substituted C,-C s alkanoyl group; a C 2 -C e enoyl group; containing any one, two or three substitutions including a prime atom, d- ( 6 oxime oxy group or hydroxy group) C 2 - C e alkylene group; C 2 -C e alkynyl group; a halogen atom includes contain any, of the CI-alkoxy or hydroxy, including one, two or three substituents of c 2 - c 6 of Alkanoyl; c 3 - c 6 cycloalkanoyl; cycloalkanoyl group containing any one, two or three substituted c 3 -c f) including a halogen atom, an alkoxy group of d-Cs or a hydroxyl group ; adamantyl formyl, substituted adamantyl formyl; aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; Xi is (CH 2 ) n , n is 0-2; ; S or NH; 3⁄4 is (CH 2 ) „, n is 0 2 ; 0; S or NH;
或者， 当 、 分别各自独立为-
Figure imgf000052_0001
Or, when, each independently -
Figure imgf000052_0001
其中 R15、 R1S各自独立为下列任意一种取代基： H; d- 的烷基； 含有包括卤素原子、 CrC6的烷氧基或羟基在内的任意一个、 两个或者三个取代的（^-( 6的垸基； C2- ( 6的烯基； 含有包括卤素原子、 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- (^的 烯基； C2- ( 的炔基； 含有包括卤素原子、 d-Ce的垸氧基或羟基在内的任意一个、 两个或者 三个取代的 C2- ( 6的炔基； C:「C6的环垸基； 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- Ce的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基; 吡咯基； 吡啶基； 含有包括卤素原子、 d- ( 的垸基、 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芳基； 含有包括卤素原子、 d- ( 4的垸基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 -^的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- 的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的吡喃基； 含有包括卤素原子、 c4的烷基、硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 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、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基; d-Ce的烷酰基； 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 d- C6的烷酰基； C2- C6的烯酰基； 含有包括卤素原子、 ( 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- Ce的炔酰基； 含有包括卤素原子、 C「C6 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C2- Ce的炔酰基； C3- CB的环烷酰基; 含有包括卤素原子、 C 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- (：6的 环烷酰基； 金刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（(¾)„， n为 0-2; 0； S或者 NH; 为（CH , n为 0- 2; 0; S或者 NH时， Wherein R 15 and R 1S are each independently a substituent of any of the following: H; d-alkyl; any one, two or three substituted groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group. (^-( 6 fluorenyl; C 2 - ( 6 alkenyl; any one, two or three substituted C 2 - (^ alkenyl) containing a halogen atom, a decyloxy group or a hydroxyl group) C 2 - (alkynyl; any one, two or three substituted C 2 - ( 6 alkynyl group) including a halogen atom, a decyloxy group or a hydroxyl group of d-Ce; C : "C 6 cyclic alkyl with; containing optionally include halogen atoms, C "C 6 alkoxy or hydroxy, including one, two or three substituents of C 3 - C e embankment cycloalkyl group; an aryl group; a benzyl group; furan a pyranyl group; a thienyl group; Pyrrolyl; pyridyl; containing a halogen atom, d-(indenyl, nitro, carboxy, aldehyde, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted aryl groups; containing a halogen atom, d- ( 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, Any one, two or three substituted pyridyl groups including a fluorenyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, -^, 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 decyl group, a methylthio group, an ethylthio group; an alkyl group including a halogen atom, d-, a nitro group, a carboxyl group, an aldehyde group, any of alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; include a halogen atom-containing, c 4 of Alkyl, nitro, carboxyl, aldehyde, alkoxy Any one, two or three substituted thienyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a sulfhydryl group containing a halogen atom, d-C 4 , and a nitrate Any one, two or three substituted pyrrolyl groups including a carboxy group, a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Alkanoyl; any one, two or three substituted d-C 6 alkanoyl group including a halogen atom, an alkoxy group of d Ce or a hydroxyl group; a C 2 - C 6 alkenoyl group; Any one, two or three substituted C 2 -C 6 alkenoyl groups of ( 6 alkoxy or hydroxy group; C 2 -C e alkynyl group; containing a halogen atom, C "C 6 Any one, two or three substituted C 2 -C e alkynyl groups such as a decyloxy group or a hydroxyl group; a C 3 - C B cycloalkanoyl group; an alkoxy group or a hydroxyl group including a halogen atom, CC e including any one, two or three substituents of C 3 - (: 6 cycloalkyl group; adamantane formyl , substituted adamantyl formyl; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; ((3⁄4) „, n is 0-2; 0; S or NH; (CH, n is 0-2; 0; S or NH,
、 分别为：
Figure imgf000053_0001
, respectively:
Figure imgf000053_0001
其中 为下列任意一种取代基： H; Ce的烷基； 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 d- C6的烷基； C2- C6的烯基； 含有包括卤素 原子、 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 C2 - 的烯基； C2-CB的 炔基；含有包括卤素原子、 C -Ca的烷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- ce的环烷基； 含有包括卤素原子、 的垸氧基或羟基在内的任意一个、 两个 或者三个取代的 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 C「 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 CrC^ 烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的吡啶基； 含有包括卤素原子、 d- [ 的烷基、 硝 基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意 一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 C,- 的烷基、 硝基、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 个取代的吡喃基； 含有包括卤素原子、 （^( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的噻吩基; 含有包括卤素原子、 d- ( 4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的吡咯基； d-Ce的垸酰基； 含 有包括卤素原子、 d- 的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d-Ce的烷 酰基； c2-ce的烯酰基； 含有包括卤素原子、 d-C6的垸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-G的垸氧基或羟基 在内的任意一个、 两个或者三个取代的 c2- c6的炔酰基； c3- ce的环垸酰基； 含有包括卤素 原子、 d-CB的垸氧基或羟基在内的任意一个、 两个或者三个取代的 c3- 的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2) n， n为 0-2; 0； S或者 NH; Wherein is any one of the following substituents: H ; alkyl of C e ; any one, two or three substituted d-C 6 containing an alkoxy group or a hydroxyl group including a halogen atom, d-C s Alkyl; C 2 -C 6 alkenyl; any one, two or three substituted C 2 -alkenyl group including a halogen atom, an alkoxy group or a hydroxyl group; C 2 -C B alkyne Any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, a C-Ca alkoxy group or a hydroxyl group; a c 3 - c e cycloalkyl group; Any one, two or three substituted C 3 -C 6 cycloalkyl groups such as a halogen atom, a decyloxy group or a hydroxyl group; an aryl group; a benzyl group; a furyl group; a pyranyl group; a thienyl group; ; pyridyl; containing any halogen atom, C" alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio One, two or three substituted aryl groups; containing halogen atom, CrC^ alkyl group, nitro group, carboxyl group, aldehyde 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 methylthio group, an ethylthio group; and an alkane including a halogen atom, d-[ Any one, two or three substituted furyl groups including a nitro group, a carboxy group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one or two including a halogen atom, a C, an alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group. Or three A substituted pyranyl; include halogen atom-containing, (^ (4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio Any one, two or three substituted thienyl groups, including a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide) Any one, two or three substituted pyrrolyl groups including a thiol group, a thiol group, a methylthio group, an ethylthio group; a decanoyl group of d-Ce; an alkoxy group or a hydroxyl group including a halogen atom, d- Any one, two or three substituted alkanoyl groups of dC e ; an alkenoyl group of c 2 -c e ; any one, two or three substitutions including a halogen atom, a decyloxy group of dC 6 or a hydroxyl group a C 2 -C 6 alkenoyl group; a C 2 -C 6 alkynyl group; any one, two or three substituted c 2 - c 6 containing a halogen atom, a decyloxy group or a hydroxyl group of dG alkynyl group; c 3 - c e embankment cycloalkyl group; embankment containing group include a halogen atom, dC B of A hydroxyl group, including any one, two or three substituents of c 3 - a cycloalkyl group; formyl adamantane, substituted adamantane formyl; aryl group; a benzyl group; furoyl; formyl pyran; thiophenecarboxamide Acyl; pyrroyl group; (CH 2 ) n , n is 0-2 ; 0; S or NH;
或者 R3、 R4分别为：
Figure imgf000054_0001
Or R 3 and R 4 are:
Figure imgf000054_0001
其中 R7、 R8各自独立为下列任意一种取代基： H; d- (^的烷基； 含有包括卤素原子、 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 垸基； C2- ( 6的烯基； 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- ( 的 烯基； C2- ( 6的块基； 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- ( 6的炔基； C:i-C6的环烷基； 含有包括卤素原子、 C「 Cs的烷氧基或羟基在内 的任意一个、两个或者三个取代的 C3- Ce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、 (：4的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三个取代的芳基； 含有包括卤素原子、 d- C4 ½烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 d- ( 的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 d- ( 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喃基； 含有包括卤素原子、 d- (；4的烷基、 硝基、羧基、醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的噻吩基； 含有包括卤素原子、 C「C4 垸基、 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咯基; d- C6的烷酰基； 含有包括卤素原子、 d-Cs的垸氧基或羟基在内的任意一个、 两个或者三个 取代的（ - 的垸酰基； c2-ce的烯酰基； 含有包括卤素原子、 d-c s垸氧基或羟基在内的 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广 CB 的垸氧基或羟基在内的任意一个、 两个或者三个取代的 c2- cs的炔酰基； c3- c6的环烷酰基; 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 C3- ( 6的 环烷酰基； 金刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； 为（。 )„， n为 0- 2; 0; S或者 NH; 为（CH2)„, n为 0-2; 0； S或者 NH; Wherein R 7 and R 8 each independently are any one of the following substituents: H; d-(^ alkyl; any one, two or three containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group a substituted fluorenyl group; a C 2 - ( 6 alkenyl group; any one, two or three substituted C 2 - (alkenyl groups) containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group; C 2 - (6 block group; a halogen atom-containing optionally include, dC e alkoxy or hydroxy group including one, two or three substituents of C 2 - (6 alkynyl; C: i -C 6 cycloalkyl; containing optionally include a halogen atom, C "C s alkoxy or hydroxy group including one, two or three substituents of C 3 - C e cycloalkyl; aryl; benzyl; furan Pyridyl; pyrenyl; pyrrolyl; pyridyl; containing halogen atom, (: 4 alkyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, fluorenyl , methylthio, ethylthio, including any one, two or three aryl group substituents; include a halogen atom-containing, d- C 4 ½ 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 methylthio group, an ethylthio group; Any one or two including a halogen atom, d-(alkyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, ethylthio group) Or a three-substituted furan group; containing a halogen atom, d-( 4 alkyl group, nitro group, carboxyl group, aldehyde group, decyloxy group, amine group, amide group, carboxamide group, thiol group, methylthio group, B Any one, two or three substituted pyranyl groups including a thio group; containing a halogen atom, d- (; 4 alkyl group, nitro group, 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 methylthio group and an ethylthio group; containing a halogen atom, a C "C 4 fluorenyl group, a nitro group, a carboxyl group, an aldehyde group, Alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted pyrrolyl groups including a methylthio group or an ethylthio group; an alkanoyl group of d-C 6 ; or any one containing a halogen atom, a decyloxy group of d-Cs or a hydroxyl group , two or three substituted (-decanoyl; c 2 -c e acyl; any one, two or three substituted c 2 including a halogen atom, dc s methoxy or hydroxy group - c 6 alkenyl group; a C 2 -C 6 alkynyl group; a halogen atom include containing, C C B wide Any one, two or three substituted c 2 - c s acetylene groups of a decyloxy group or a hydroxyl group; a c 3 - c 6 cycloalkanoyl group; an alkoxy group including a halogen atom, d Ce or Any one, two or three substituted C 3 -( 6 cycloalkanoyl; adamantyl form, substituted adamantyl group; aroyl group; benzyl group; furoyl group; pyroyl group; a thiophene acyl group; a pyrrolyl group; a (.) „, n is 0-2; 0; S or NH; is (CH 2 ) „, n is 0-2; 0; S or NH;
或者 、 分别为-
Figure imgf000055_0001
Or, respectively -
Figure imgf000055_0001
其中 为下列任意一种取代基： H; d- (]6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- (：6的烯基； 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- ( 的烯基； C2-Ce的 炔基;含有包括卤素原子、 d-Ce的垸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- Cs的环烷基； 含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、 两个 或者三个取代的 C3- C6的环烷基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d- ( 4的垸基、 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- 的垸基、 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、 d- C4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呋喃基； 含有包括卤素原子、 CrC4的烷基、硝基、羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、 两个或者三 个取代的吡喃基； 含有包括卤素原子、 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、 Cr (：4的垸基、 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咯基； C,- Cs的垸酰基； 含 有包括卤素原子、 CrC6的浣氧基或羟基在内的任意一个、 两个或者三个取代的 d- CB的烷 酰基； C2- C6的烯酰基； 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 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-C3的环浣職基； 含有包括卤素 原子、 Ce的垸氧基或羟基在内的任意一个、 两个或者三个取代的 C3- Ce的环烷酰基； 金 刚烷甲酰基、 取代金刚烷甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰基； 噻吩甲酰 基； 吡咯甲酰基； 为（CH2) n, n为 0- 2; 0； S或者 NH; Wherein any of the following substituents: H; d-(] 6 alkyl; containing any one, two or three substituted C's including a halogen atom, d- («alkoxy or hydroxy group) C 6 alkyl; C 2 - (: 6 alkenyl; any one, two or three substituted C 2 - (alkenyl) containing a halogen atom, an alkoxy group of d-Ce or a hydroxyl group a C 2 -C e alkynyl group; any one, two or three substituted C 2 -C 6 alkynyl groups including a halogen atom, a decyloxy group or a hydroxyl group of d-Ce; C 3 - C s cycloalkyl; contain any halogen atoms include, CRCE of alkoxy or hydroxy, including one, two or three substituents of C 3 - C 6 cycloalkyl group; and an aryl group; a benzyl group; furanyl; Pyranyl; thienyl; pyrrolyl; pyridyl; containing halogen atom, d-( 4 fluorenyl, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted aryl groups including a methylthio group and an ethylthio group; a fluorenyl group containing a halogen atom, d-, a nitro group Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; - any one, two or three substitutions of an alkyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group of C 4 a furanyl group; optionally containing 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 methylthio group, an ethylthio group, and the like. One, two or three substituted pyranyl groups; containing an alkyl group including a halogen atom, d-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 and an ethylthio group; containing a halogen atom, a Cr (: 4 fluorenyl group, a nitro group, a carboxyl group, an aldehyde group, a decyloxy group, an amine group) , amide group, carboxamide group, thiol group, methylthio group, B Any one, two or three substituted pyrrolyl groups including a thio group; a decanoyl group of C, -C s ; any one, two or three containing a halogen atom, a decyloxy group of CrC 6 or a hydroxyl group a substituted alkanoyl group of d- C B; C 2 - C 6 alkenyl group; includes any pigment containing C atoms, C "C 6 alkoxy or hydroxy, including one, two or three substituents 2 alkenyl group of C 6 -; C 2 C 6 alkynyl group; a halogen atom include optionally containing, (a ^ alkoxy or hydroxy, including one, two or three substituents of C 2 - C 6 alkynyl group; and a C 3 -C 3 cyclopentyl group; a cycloalkanoyl group having any one, two or three substituted C 3 - C e groups including a halogen atom, a decyloxy group of Ce or a hydroxyl group; an adamantyl group , substituted adamantyl form; aroyl; benzyl; furanoyl; pyranoyl; thiophene; pyrrolyl; (CH 2 ) n , n is 0-2; 0; S or NH;
或者 R3、 分别为:
Figure imgf000056_0001
Or R 3 , respectively:
Figure imgf000056_0001
其中 。、 Ru各自独立为下列任意一种取代基： H; 的烷基； 含有包括卤素原子、 CrCe的烷氧基或羟基在内的任意一个、 两个或者三个取代的 d- ( 6的垸基； 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- 勺 烯基； C2_Ce 炔基； 含有包括卤素原子、 C「C6的垸氧基或羟基在内的任意一个、 两个或者 三个取代的 C2- 的炔基； C3 C6的环烷基； 含有包括卤素原子、 Cr Ce的垸氧基或羟基在内 的任意一个、两个或者三个取代的 C3- Ce的环垸基； 芳基； 苄基； 呋喃基； 吡喃基； 噻吩基； 吡咯基； 吡啶基； 含有包括卤素原子、 d 的垸基、 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芳基； 含有包括卤素原子、 d- ( 4的烷基、硝基、羧基、醛基、烷氧基、 胺基、酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡啶基； 含有包括卤素原子、 ^-^的烷基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙 硫基在内的任意一个、 两个或者三个取代的呋喃基； 含有包括卤素原子、 C,- C4的垸基、 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、 ( 4的垸基、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- ( 4的焼基、 硝基、 羧基、 醛基、 烷氧基、 胺基、 酰胺基、碳酰胺基、巯基、 甲硫基、 乙硫基在内的任意一个、两个或者三个取代的吡咯基； d-Cs的烷酰基； 含有包括卤素原子、 d-C6的烷氧基或羟基在内的任意一个、两个或者三个 取代的 d- C6的垸酰基； C2-C6的烯酰基； 含有包括卤素原子、 C「 (：6的垸氧基或羟基在内的 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- Ce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； 金刚烷甲酰基、 取代金刚垸甲酰基； 芳酰基； 苄酰基； 呋喃甲酰基； 吡喃甲酰 基； 噻吩甲酰基； 吡咯甲酰基； ¾为（CH2) n， n为 0-2; 0； S或者 NH; ¾为（CH2)„， n为 0-2; 0； S或者 。 among them. And Ru each independently of any one of the following substituents: H; an alkyl group; any one, two or three substituted d- ( 6 fluorenes including a halogen atom, an alkoxy group of CrC e or a hydroxyl group) groups; C 2 - C 6 alkenyl group; a halogen atom include containing, C, - any C 6 alkoxy or hydroxy inner one, two or three substituents of C 2 - tablespoons alkenyl; C 2 _C e alkynyl; optionally include a halogen atom-containing C, C 'C 6 alkoxy or hydroxy embankment inner one, two or three substituents of 2 - alkynyl; C. 3 C 6 cycloalkyl group; a comprises containing any of halogen atom, C r C e of the embankment or a hydroxyl group, including one, two or three substituents of C 3 - C e embankment cycloalkyl group; an aryl group; a benzyl group; furyl; tetrahydropyranyl; thienyl a pyrrolyl group; a pyridyl group; a thiol group including a halogen atom, d, a nitro group, a carboxy group, an aldehyde group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group within any one, two or three aryl group substituents; containing a halogen atom include, d- (4 alkyl group, a nitro group Any one, two or three substituted pyridyl groups including a carboxyl group, an aldehyde group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one, two or three substituted alkyl, nitro, carboxy, aldehyde, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio a furanyl group; a fluorenyl 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 methylthio group, an ethylthio group any one, two or three of the substituents pyranyl; include halogen atom-containing, (group 4 of the embankment, nitro, carboxyl, aldehyde, alkoxy, amine, amide, carboxamide group, a mercapto group, Any one, two or three substituted thienyl groups including a methylthio group and an ethylthio group; containing a halogen atom, d-( 4 fluorenyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group) , amide group, carboxamide group, sulfhydryl group, methylthio group, ethyl thio group Any one, two or three substituents pyrrolyl; d-Cs alkanoyl; containing optionally include a halogen atom, an alkoxy group or a hydroxyl dC 6, including one, two or three substituents of dC 6 the embankment acyl; C 2 -C 6 alkenyl group; a comprises containing a halogen atom, C "(: C 6 alkoxy or hydroxy embankment any inner one, two or three substituents 2 -C 6 alkenyl group of a C 2 -C 6 alkynyl group; a acetylenyl group having any one, two or three substituted C 2 - C e groups including a halogen atom, an alkoxy group of CrC 6 or a hydroxyl group; C 3 - C 6 a 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; an adamantyl formyl group, a substituted adamantyl group Aroyl; benzoyl; furoyl; pyranoyl; thiophene; pyrrolyl; 3⁄4 is (CH 2 ) n , n is 0-2; 0; S or NH; 3⁄4 is (CH 2 ) „, n is 0-2; 0; S or.
3、 裉据权利要求 1至 2任意一项所述的具有取代四元环结构的化合物或其药物学上 可接受的盐、 酯、 溶剂化物、 金属配合物、 或者与其具有相同药理作用的前药， 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。  3. A compound having a substituted four-membered ring structure according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof, or the same pharmacological action therewith The drug is characterized in that, when geometric isomers are present in the molecule, the compounds are various individual geometric isomers or mixtures thereof.
4、 根据权利要求 1至 3任意一项所述的具有取代四元环结构的化合物或其药物学上 可接受的盐、 酯、 溶剂化物、 金属配合物、 或者与其具有相同药理作用的前药， 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 four-membered ring structure according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, solvate, metal complex thereof, or prodrug having the same pharmacological action thereto It is characterized in that, when chiral carbon is present in the molecule, the compound is a racemate or an optically active body.
5、 根据权利要求 1至 4中任意一项所述具有取代四元环结构的化合物或其药物学上 可接受的盐、 酯、 溶剂化物、 金属配合物、 或者与其具有相同药理作用的前药用于制备预 防和 /或治疗代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛素抵抗和肥胖症）、 心血管疾 病和神经退行性疾病 （如 Alzheimer' s病） 的用途。 5. A compound having a substituted four-membered ring structure according to any one of claims 1 to 4 or a pharmacologically acceptable compound thereof Acceptable salts, esters, solvates, metal complexes, or prodrugs having the same pharmacological effects therewith for use in the preparation of prophylactic and/or therapeutic metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, Use of cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
6、 一种用于预防和 /或治疗代谢紊乱性疾病 （包括但不局限于糖尿病、 胰岛素抵抗和 肥胖症）、 心血管疾病和神经退行性疾病（如 Alzheimer' s 病）等的药物组合物， 该组合 物含有作为活性成分的权利要求 1至 4中任一项所述的化合物以及这类化合物在治疗上可 接受的盐类及其与其它分子或载体的连结物。  6. A pharmaceutical composition for preventing and/or treating metabolic disorders (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as Alzheimer's disease) The composition contains, as an active ingredient, a compound according to any one of claims 1 to 4 and a therapeutically acceptable salt of such a compound and a linker with other molecules or carriers.
7、 根据权利要求 6所述的药物组合物， 其特征在于进一步含有药物学上可接受的载 体和赋形剂。  7. A pharmaceutical composition according to claim 6 further comprising a pharmaceutically acceptable carrier and excipient.
8、 根据权利要求 6所述的药物组合物， 其特征在于所述疾病或症状可以因对已经上 市的治疗药物产生耐药性或毒副反应而引起。 .  8. A pharmaceutical composition according to claim 6 wherein the disease or condition can be caused by resistance or toxic side effects to a therapeutic agent already on the market. .
9、 一种联合制剂， 包括如权利要求 1至 4中任意一项所述化合物或其药物学上可接 受的盐和其他治疗药物。  A combination preparation comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and other therapeutic agents.
10、 一种药盒， 其包括权利要求 1至 4中任意一项所述的化合物或其药物学上可接受 的盐， 以及使用所述化合物或其药物学上可接受的盐预防和 /或治疗代谢紊乱性疾病 （包 括但不局限于糖尿病、 胰岛素抵抗和肥胖症）、 心血管疾病和神经退行性疾病 （如 Alzheimer' s病） 的说明。  A kit comprising the compound 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 salt thereof for prevention and/or prevention Description of the treatment of metabolic disorders including, but not limited to, diabetes, insulin resistance and obesity, cardiovascular disease and neurodegenerative diseases such as Alzheimer's disease.
11、 一种药盒， 其包括权利要求 9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） 的说明。  11. A kit comprising the combination of claim 9, 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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