CN108947931A - A kind of thiazole amide compound, preparation method, pharmaceutical composition and application - Google Patents

A kind of thiazole amide compound, preparation method, pharmaceutical composition and application Download PDF

Info

Publication number
CN108947931A
CN108947931A CN201810463002.2A CN201810463002A CN108947931A CN 108947931 A CN108947931 A CN 108947931A CN 201810463002 A CN201810463002 A CN 201810463002A CN 108947931 A CN108947931 A CN 108947931A
Authority
CN
China
Prior art keywords
base
cyano
thiadiazoles
allyl
phenyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810463002.2A
Other languages
Chinese (zh)
Other versions
CN108947931B (en
Inventor
王任小
郭春
俞飚
李杨峰
李嫣
安然
徐耀春
周宓
李晴
孔文娜
李婕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Publication of CN108947931A publication Critical patent/CN108947931A/en
Application granted granted Critical
Publication of CN108947931B publication Critical patent/CN108947931B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/75—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention discloses a kind of thiazole amide compound, preparation method, pharmaceutical composition and applications.The present invention provides a kind of thiazole amide and its pharmaceutically acceptable salt shown in formula I, such compound can efficiently and selectively inhibit the key protein Bcl-X in apoptosis process on a molecular scaleL, Bcl-2 and Mcl-1.Meanwhile they are to cancer cell, especially people's acute lymphoblastic leukemia cell strain RS4；11 and people's promyelocytic leukemia cell line HL-60 there is apparent lethal effect and highly selective, there are the potentiality for being prepared into new type antineoplastic medicine, there is preferable market-oriented prospect.

Description

A kind of thiazole amide compound, preparation method, pharmaceutical composition and application
Technical field
The present invention relates to a kind of thiazole amide compound, preparation method, pharmaceutical composition and applications.
Background technique
Worldwide, the main reason for malignant tumour (i.e. cancer) is morbidity and is dead, there are about 14,000,000 within 2012 New cancer ratio.The estimated 20 years from now on neopathy number of cases of the World Health Organization will increase about 70%.Since current clinic makes Drug resistance, efficacy time dependence are showed with treating cancer drug and has the shortcomings that apparent toxic side effect, find structure The problem of novel, safe and efficient drug has become urgent need to resolve.
Apoptosis (can be described as apoptosis again in some cases) is a kind of removal senile cell or abnormal thin The natural death mechanism of born of the same parents, the disorder of the mechanism and a variety of diseases have direct relationship.Since the nineties in last century, People gradually have found that tumour is the proliferation and apoptosis unbalance caused (Okada, H. of cell；Mak, T.W.Nat.Rev.Cancer2004,4,592-603).Research shows that Apoptosis mechanism is suppressed in kinds of tumor cells, tumour Cell is thus able to hyperplasia；In addition, Apoptosis mechanism is suppressed but also tumour cell enhances the tolerance of chemotherapeutics (Igney,F.H.；Krammer,P.H.Nat.Rev.Cancer2002,2,277-288).Therefore, in apoptosis process Key regulator is molecular target, tries to restore the Apoptosis mechanism in tumour cell, carries out new type antineoplastic medicine research and development Strategy is in the attention and popularization for having obtained domestic and international the world of medicine during the last ten years recently.(Reed, J.C.Nat.Rev.Drug Discov.2002,1,111-121；Andersen,M.H.；Becker,J.C.；Straten, P.Nat.Rev.DrugDiscov.2005,4,399-409；Belmar,J.；Fesik, S.W.Pharmacol.Therapeut.2015,145,76-84；Pelz,N.F.；Bian,Z.et al.J.Med.Chem.2016,59,2054-2066.)。
WO2005072731A1 discloses a kind of thiazole amide compound, is estrogen receptor (estrogen Related receptor, ERR) regulator.Meanwhile existing literature (Xu Z, J Steroid Biochem Mol Biol.2016,158,22-30；CN102834392A；CN102770429A；WO2006047269A2 etc.) report, estrogen by The relevant disease of body (estrogen related receptor) includes tumour (such as breast cancer, endometrium that estrogen relies on Cancer, oophoroma etc.), non-estrogen rely on tumour (such as sdenocarcinoma of stomach, colorectal cancer, lung cancer, liver cancer) and other diseases (packet Include the relevant disease of bone, cardiovascular disease and Alzheimer's disease etc.).
However, the medicament categories of existing targeted apoptosis process are less, therefore, highly selective, high inhibitory activity is found New type antineoplastic medicine be current critical issue urgently to be solved.
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome in the prior art, anti-tumor drug selectivity is not high, inhibits The defects of activity is not high, and provide a kind of thiazole amide compound, preparation method, pharmaceutical composition and application.Such Compound can efficiently and selectively inhibit the key protein Bcl-X in apoptosis process on a molecular scaleL、Bcl-2 And Mcl-1.Meanwhile they are to cancer cell, especially people's acute lymphoblastic leukemia cell strain RS4；11 and people's original myelocyte Leukemia cell line HL-60 has apparent lethal effect and highly selective, has and is prepared into the latent of new type antineoplastic medicine Power has preferable market-oriented prospect.
The present invention provides a kind of thiazole amide compound or its pharmaceutically acceptable salt shown in formula I,
Wherein, X is CH or N；
R1For hydrogen, halogen (such as fluorine, chlorine, bromine or iodine, in another example fluorine, chlorine or bromine), C1~C4Alkoxy (such as methoxy Base), C1~C4Alkylthio group, C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " Such as methyl), hydroxyl, hydroxyl replace C1~C6(number of " hydroxyl " can be one or more to linear chain or branched chain alkyl Such as 1,2 or 3；" the C that hydroxyl replaces1~C6The C that linear chain or branched chain alkyl " such as hydroxyl replaces1~C4 Straight-chain alkyl；" the C that hydroxyl replaces1~C4Straight-chain alkyl " such as methylol), halogen replace C1~C4Alkyl is (described The number of " halogen " can be one or more such as 1,2,3,4 or 5；" halogen " can independently be Fluorine, chlorine or bromine；When there are multiple halogens, they be may be the same or different；" the C that halogen replaces1~C4Alkyl " such as three Methyl fluoride), halogen replace C1~C4(number of " halogen " can be one or more < such as 1,2,3 to alkoxy A, 4 or 5 >；" halogen " can independently be fluorine, chlorine or bromine；When there are multiple halogens, they can be identical or not Together；" the C that halogen replaces1~C4Alkoxy " such as trifluoromethoxy), halogen replace C1~C4Alkylthio group is (described The number of " halogen " can be one or more such as 1,2,3,4 or 5；" halogen " can independently be Fluorine, chlorine or bromine；When there are multiple halogens, they be may be the same or different), C3~C7Naphthenic base, C3~C7Cycloalkenyl, R1-1 Substituted or unsubstituted phenyl ring (the R1-1Number can be one or more such as 1,2,3,4 or 5；When There are multiple R1-1When, they may be the same or different；The R1-1Ortho position, the meta position or right of the phenyl ring can be independently in Position；" the R1-1Substituted phenyl ring " such as 4- methoxyl group-phenyl, 2- methoxyl group-phenyl or the chloro- phenyl of 2-), " hetero atom is N, one of O and S or a variety of, hetero atom number are 1~4,5~10 yuan of heteroaryl " (such as " in hetero atom N, O and S It is one or more, hetero atom number be 1~2,5~9 yuan of heteroaryl "；It is described " one of hetero atom N, O and S or A variety of, hetero atom number is 1~2,5~9 yuan of heteroaryl " such as thienyl or indyl；The thienyl such as thiophene- 2- base；The indyl such as indoles -2- base) or
R1-1It independently is halogen (such as fluorine, chlorine or bromine) or C1~C4Alkoxy (such as methoxyl group)；
R1-2For R1-2-1Substituted or unsubstituted C6~C10Aryl (the R1-2-1Number can be one or more < example Such as 1,2,3,4 or 5 >；When there are multiple R1-2-1When, they may be the same or different；" the C6~C10Aryl " Such as phenyl or naphthyl；Work as C6~C10When aryl is phenyl, the R1-2-1Ortho position, the meta position of the phenyl can be independently in Or contraposition；The naphthalene such as naphthalene -1- base；" the R1-2-1Substituted C6Aryl " such as 4- methylphenyl, 4- methoxy Base-phenyl, 4- fluoro-phenyl, 3- fluoro-phenyl or the chloro- phenyl of 4-)；R1-2-1For C1~C4Alkyl (such as methyl), C1~C4Alcoxyl Base (such as methoxyl group) or halogen (such as fluorine, chlorine or bromine)；
R3For hydrogen, nitro (such as 3- nitro or 4- nitro), halogen, trifluoromethyl, trifluoromethoxy, C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain hydrocarbons Base " such as methyl), C1~C4Alkoxy (such as methoxyl group), C3~C7Naphthenic base, C3~C7Cycloalkenyl, C3~C7Naphthenic base Substituted C1~C6Linear chain or branched chain alkyl or benzyl；(the R3It can be at ortho position, the meta or para position of the phenyl ring)
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or pyridyl group； The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl)；
R5It independently is hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, C1~C4Alkoxy (such as methoxyl group), C1 ~C4Alkylthio group, C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " such as first Base), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can for it is one or more < such as 1,2,3,4 or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1Can be independently in the phenyl ring ortho position, Position or contraposition；" the R5-1Substituted phenyl ring " such as chloro- phenyl of 4- methylphenyl, 4-, 4- fluoro-phenyl, 4- methoxyl group-benzene Base, 4- trifluoromethyl-phenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl, 2- nitro-phenyl or 4- Acetvlamino-phenvl) or R5-2It is substituted or unsubstituted that " one of hetero atom N, O and S or a variety of, hetero atom number are 1 ~4,5~6 yuan of heteroaryl " (the R5-2Number can for it is one or more < such as 1,2,3,4 or 5 >；When there are multiple R5-2When, they may be the same or different；The R5-2Ortho position, the meta position of the heteroaryl can be independently in Or contraposition；Described " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of the heteroaryl " example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or isoxazole Base；The thienyl such as thiophene -2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2What is replaced is miscellaneous Atom is one of N, O and S or a variety of, and hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- dimethyl-different Oxazole -4- base)；
All R5-1And R5-2It independently is nitro, trifluoromethyl, trifluoromethoxy, acetylamino, C1~C4Alkyl (example Such as methyl), halogen (such as fluorine, chlorine or bromine) or C1~C4Alkoxy (such as methoxyl group).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R1For C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " is for example Methyl), R1-1Substituted or unsubstituted phenyl ring (the R1-1Number can be one or more < such as 1,2,3,4 Or 5 >；When there are multiple R1-1When, they may be the same or different；The R1-1Can be independently in the phenyl ring ortho position, Meta or para position；" the R1-1Substituted phenyl ring " such as 4- methoxyl group-phenyl, 4- hydroxy-pheny, 2- methoxyl group-phenyl, 2- hydroxy-pheny or the chloro- phenyl of 2-), " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 The heteroaryl of member " (such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl Base "；" one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl " is for example Furyl, thienyl or indyl；The thienyl such as thiophene -2- base；The indyl such as indoles -2- base), Or
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R1For methyl, phenyl, 2- methoxyl group-phenyl, 4- methoxyl group-phenyl, the chloro- phenyl of 2-, 2- thienyl, 2- indoles Base, benzyl, 4- methoxy-benzyl, the fluoro- benzyl of 4-, the fluoro- benzyl of 3-, the chloro- benzyl of 4- or naphthalene -1- methyl.
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R3For nitro,(the R3Can be at the phenyl ring ortho position, Position or contraposition).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or pyridyl group； The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R5It independently is C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain hydrocarbons Base " such as methyl), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can for it is one or more < such as 1,2, 3,4 or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1The phenyl ring can be independently in Ortho position, meta or para position；" the R5-1Substituted phenyl ring " such as chloro- phenyl of 4- methylphenyl, 4-, 4- fluoro-phenyl, 4- Methoxyl group-phenyl, 4- trifluoromethyl-phenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl, 2- nitro- Phenyl or 4- Acetvlamino-phenvl) or R5-2Substituted or unsubstituted " one of hetero atom N, O and S or a variety of, miscellaneous original Subnumber is 1~4,5~6 yuan of heteroaryl " (the R5-2Number can be one or more < such as 1,2,3,4 A or 5 >；When there are multiple R5-2When, they may be the same or different；The R5-2The neighbour of the heteroaryl can be independently in Position, meta or para position；It is described that " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan miscellaneous Aryl " such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；It is described " one of hetero atom N, O and S or a variety of, hetero atom number be 1~2,5~6 yuan of heteroaryl " for example thienyl or Isoxazolyl；The thienyl such as thiophene -2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2It takes The hetero atom in generation is one of N, O and S or a variety of, and hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- diformazan Base-isoxazole -4- base).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R3For nitro,(the R3Can be at the phenyl ring ortho position, Position or contraposition).
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or pyridyl group； The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl)；
R5It independently is C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain hydrocarbons Base " such as methyl), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can for it is one or more < such as 1,2, 3,4 or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1The phenyl ring can be independently in Ortho position, meta or para position；" the R5-1Substituted phenyl ring " such as chloro- phenyl of 4- methylphenyl, 4-, 4- fluoro-phenyl, 4- Methoxyl group-phenyl, 4- trifluoromethyl-phenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl, 2- nitro- Phenyl or 4- Acetvlamino-phenvl) or R5-2Substituted or unsubstituted " one of hetero atom N, O and S or a variety of, miscellaneous original Subnumber is 1~4,5~6 yuan of heteroaryl " (the R5-2Number can be one or more < such as 1,2,3,4 A or 5 >；When there are multiple R5-2When, they may be the same or different；The R5-2The neighbour of the heteroaryl can be independently in Position, meta or para position；It is described that " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan miscellaneous Aryl " such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；It is described " one of hetero atom N, O and S or a variety of, hetero atom number be 1~2,5~6 yuan of heteroaryl " for example thienyl or Isoxazolyl；The thienyl such as thiophene -2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2It takes The hetero atom in generation is one of N, O and S or a variety of, and hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- diformazan Base-isoxazole -4- base).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R3It can ortho position in phenyl ring, meta or para position.
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R3It can be nitro, methylsulphur acidic group, 2- thiophene-sulfonic group, 3- pyridine-sulfonic group, 4- methyl-benzenesulfonic acid base, 4- first Oxygroup-benzene sulfonic acid base, 4- trifluoromethyl-benzene sulfonic acid base, 4- trifluoromethoxy-benzene sulfonic acid base, the fluoro- benzene sulfonic acid base of 4-, the chloro- benzene of 4- Sulfonic group, 4- nitro-benzene sulfonic acid base, 3- nitro-benzene sulfonic acid base, 2- nitro-benzene sulfonic acid base, 4- acetylaminohydroxyphenylarsonic acid benzene sulfonic acid base, 3, 5- dimethyl -4- oxazole-benzene sulfonic acid base, methanesulfonamido, 4- methyl-benzenesulfonyl amino, the chloro- benzenesulfonamido- of 4-, the fluoro- benzene of 4- Sulfonamido, 4- methoxy-benzenesulfonyl amino, 4- trifluoromethyl-benzene amino, 4- trifluoromethoxy-benzenesulfonamido-, 4- Nitro-benzenesulfonamido-, 3- nitro-benzenesulfonamido-, 2- thiophene-benzenesulfonamido- or 4- acetylaminohydroxyphenylarsonic acid benzenesulfonamido-.
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R1For C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " is for example Methyl), R1-1Substituted or unsubstituted phenyl ring (the R1-1Number can be one or more < such as 1,2,3,4 Or 5 >；When there are multiple R1-1When, they may be the same or different；The R1-1Can be independently in the phenyl ring ortho position, Meta or para position；" the R1-1Substituted phenyl ring " such as 4- methoxyl group-phenyl, 4- hydroxy-pheny, 2- methoxyl group-phenyl, 2- hydroxy-pheny or the chloro- phenyl of 2-), " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 The heteroaryl of member " (such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl Base "；" one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl " is for example Furyl, thienyl or indyl；The thienyl such as thiophene -2- base；The indyl such as indoles -2- base), Or
R3For nitro,(the R3Can be at the phenyl ring ortho position, Meta or para position)
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or pyridyl group； The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl)；
R5It independently is C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain hydrocarbons Base " such as methyl), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can for it is one or more < such as 1,2, 3,4 or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1The phenyl ring can be independently in Ortho position, meta or para position；" the R5-1Substituted phenyl ring " such as chloro- phenyl of 4- methylphenyl, 4-, 4- fluoro-phenyl, 4- Methoxyl group-phenyl, 4- trifluoromethyl-phenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl, 2- nitro- Phenyl or 4- Acetvlamino-phenvl) or R5-2Substituted or unsubstituted " one of hetero atom N, O and S or a variety of, miscellaneous original Subnumber is 1~4,5~6 yuan of heteroaryl " (the R5-2Number can be one or more < such as 1,2,3,4 A or 5 >；When there are multiple R5-2When, they may be the same or different；The R5-2The neighbour of the heteroaryl can be independently in Position, meta or para position；It is described that " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan miscellaneous Aryl " such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；It is described " one of hetero atom N, O and S or a variety of, hetero atom number be 1~2,5~6 yuan of heteroaryl " for example thienyl or Isoxazolyl；The thienyl such as thiophene -2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2It takes The hetero atom in generation is one of N, O and S or a variety of, and hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- diformazan Base-isoxazole -4- base).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R1It can be methyl, phenyl, 2- methoxyl group-phenyl, 4- methoxyl group-phenyl, the chloro- phenyl of 2-, 2- thienyl, 2- indoles Base, benzyl, 4- methoxy-benzyl, the fluoro- benzyl of 4-, the fluoro- benzyl of 3-, the chloro- benzyl of 4- or naphthalene -1- methyl；
R3Can ortho position in phenyl ring, meta or para position, such as nitro, methylsulphur acidic group, 2- thiophene-sulfonic group, 3- pyridine-sulphur Acidic group, 4- methyl-benzenesulfonic acid base, 4- methoxyl group-benzene sulfonic acid base, 4- trifluoromethyl-benzene sulfonic acid base, 4- trifluoromethoxy-benzene sulphur The fluoro- benzene sulfonic acid base of acidic group, 4-, the chloro- benzene sulfonic acid base of 4-, 4- nitro-benzene sulfonic acid base, 3- nitro-benzene sulfonic acid base, 2- nitro-benzene sulphur Acidic group, 4- acetylaminohydroxyphenylarsonic acid benzene sulfonic acid base, 3,5- dimethyl -4- oxazole-benzene sulfonic acid base, methanesulfonamido, 4- methyl-benzenesulfonyl The chloro- benzenesulfonamido- of amino, 4-, the fluoro- benzenesulfonamido- of 4-, 4- methoxy-benzenesulfonyl amino, 4- trifluoromethyl-benzene ammonia Base, 4- trifluoromethoxy-benzenesulfonamido-, 4- nitro-benzenesulfonamido-, 3- nitro-benzenesulfonamido-, 2- thiophene-benzene sulfonyl Amino or 4- acetylaminohydroxyphenylarsonic acid benzenesulfonamido-.
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
X is CH or N；
R1For hydrogen, halogen (such as fluorine, chlorine, bromine or iodine, in another example fluorine, chlorine or bromine), C1~C4Alkoxy (such as methoxy Base), C1~C4Alkylthio group, C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " Such as methyl), hydroxyl, hydroxyl replace C1~C6(number of " hydroxyl " can be one or more to linear chain or branched chain alkyl Such as 1,2 or 3；" the C that hydroxyl replaces1~C6The C that linear chain or branched chain alkyl " such as hydroxyl replaces1~C4 Straight-chain alkyl；" the C that hydroxyl replaces1~C4Straight-chain alkyl " such as methylol), halogen replace C1~C4Alkyl is (described The number of " halogen " can be one or more such as 1,2,3,4 or 5；" halogen " can independently be Fluorine, chlorine or bromine；When there are multiple halogens, they be may be the same or different；" the C that halogen replaces1~C4Alkyl " such as three Methyl fluoride), halogen replace C1~C4(number of " halogen " can be one or more < such as 1,2,3 to alkoxy A, 4 or 5 >；" halogen " can independently be fluorine, chlorine or bromine；When there are multiple halogens, they can be identical or not Together；" the C that halogen replaces1~C4Alkoxy " such as trifluoromethoxy), halogen replace C1~C4Alkylthio group is (described The number of " halogen " can be one or more such as 1,2,3,4 or 5；" halogen " can independently be Fluorine, chlorine or bromine；When there are multiple halogens, they be may be the same or different), C3~C7Naphthenic base, C3~C7Cycloalkenyl, R1-1 Substituted or unsubstituted phenyl ring (the R1-1Number can be one or more such as 1,2,3,4 or 5；When There are multiple R1-1When, they may be the same or different；The R1-1Ortho position, the meta position or right of the phenyl ring can be independently in Position；" the R1-1Substituted phenyl ring " such as 4- methoxyl group-phenyl, 2- methoxyl group-phenyl or the chloro- phenyl of 2-) or " miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~4,5~10 yuan of heteroaryl " (such as " hetero atom N, O and One of S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl "；Described " one in hetero atom N, O and S Kind is a variety of, and hetero atom number is 1~2,5~9 yuan of heteroaryl " such as thienyl or indyl；The thienyl is for example Thiophene -2- base；The indyl such as indoles -2- base)；
R1-1It independently is halogen (such as fluorine, chlorine or bromine) or C1~C4Alkoxy (such as methoxyl group)；
R3For hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy,C1 ~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " such as methyl), C3~C7's Naphthenic base, C3~C7Cycloalkenyl, C3~C7The C that naphthenic base replaces1~C6Linear chain or branched chain alkyl or benzyl；(the R3 It can be at ortho position, the meta or para position of the phenyl ring)
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (example Such as " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；" the miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or pyridyl group； The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl)；
R5It independently is hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, C1~C4Alkoxy (such as methoxyl group), C1 ~C4Alkylthio group, C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " such as first Base), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can for it is one or more < such as 1,2,3,4 or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1Can be independently in the phenyl ring ortho position, Position or contraposition；" the R5-1The chloro- phenyl of substituted phenyl ring " such as 4-, 4- fluoro-phenyl, 4- methoxyl group-phenyl, 4- fluoroform Base-phenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl or 4- Acetvlamino-phenvl) or R5-2It takes Generation or unsubstituted " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (institute The R stated5-2Number can be one or more such as 1,2,3,4 or 5；When there are multiple R5-2When, they can It is identical or different；The R5-2Ortho position, the meta or para position of the heteroaryl can be independently in；Described " hetero atom N, One of O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " such as " one in hetero atom N, O and S Kind is a variety of, and hetero atom number is 1~2,5~6 yuan of heteroaryl "；Described " one of hetero atom N, O and the S or more Kind, hetero atom number is 1~2,5~6 yuan of heteroaryl " such as thienyl or isoxazolyl；The thienyl such as thiophene- 2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2Substituted hetero atom is one of N, O and S or more Kind, hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- dimethyl-isoxazole -4- base)；
All R5-1And R5-2Independently be nitro, trifluoromethyl, trifluoromethoxy, acetylamino, halogen (such as fluorine, Chlorine or bromine) or C1~C4Alkoxy (such as methoxyl group).
In a certain technical solution, preferably (definition not annotated is such as follows for the definition of each group in the compound I It is preceding any described):
R1For C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " is for example Methyl), R1-1Substituted or unsubstituted phenyl ring (the R1-1Number can be one or more < such as 1,2,3,4 Or 5 >；When there are multiple R1-1When, they may be the same or different；The R1-1Can be independently in the phenyl ring ortho position, Meta or para position；" the R1-1Substituted phenyl ring " such as 4- methoxyl group-phenyl, 2- methoxyl group-phenyl or the chloro- phenyl of 2-), Or " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~10 yuan of heteroaryl " (such as " miscellaneous original Son is one of N, O and S or a variety of, and hetero atom number is 1~2,5~9 yuan of heteroaryl "；Described " hetero atom N, the O With one of S or a variety of, hetero atom number is 1~2,5~9 yuan of heteroaryl " such as thienyl or indyl；The thiophene Pheno base such as thiophene -2- base；The indyl such as indoles -2- base).
R3For 3- nitro, 4- nitro,
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (institute " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " such as thienyl stated Or pyridyl group；The thienyl such as thiophene -2- base；The pyridyl group such as pyridin-3-yl).
R5For C1~C6Linear chain or branched chain alkyl (such as C1~C4Straight-chain alkyl；" the C1~C4Straight-chain alkyl " is for example Methyl), R5-1Substituted or unsubstituted phenyl ring (the R5-1Number can be one or more < such as 1,2,3,4 Or 5 >；When there are multiple R5-1When, they may be the same or different；The R5-1Can be independently in the phenyl ring ortho position, Meta or para position；" the R5-1The chloro- phenyl of substituted phenyl ring " such as 4-, 4- fluoro-phenyl, 4- methoxyl group-phenyl, 4- trifluoro Methylphenyl, 4- trifluoromethoxy-phenyl, 4- nitro-phenyl, 3- nitro-phenyl or 4- Acetvlamino-phenvl) or R5-2 Substituted or unsubstituted " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " (the R5-2Number can be one or more such as 1,2,3,4 or 5；When there are multiple R5-2When, they It may be the same or different；The R5-2Ortho position, the meta or para position of the heteroaryl can be independently in；It is described that " hetero atom is N, one of O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " such as thienyl or isoxazolyl；Institute The thienyl stated such as thiophene -2- base；The isoxazolyl such as isoxazole -4- base；" the R5-2Substituted hetero atom For one of N, O and S or a variety of, hetero atom number is 1~4,5~6 yuan of heteroaryl " such as 3,5- dimethyl-isoxazole- 4- yl).
In a certain technical solution, the definition of each group can (definition not annotated be such as described below in the compound I It is preceding any described):
R1Such as methyl, phenyl, 2- methoxyl group-phenyl, 4- methoxyl group-phenyl, the chloro- phenyl of 2-, 2- thienyl or 2- Yin Diindyl base.
R3Can ortho position in phenyl ring, meta or para position, such as nitro, methylsulphur acidic group, 2- thiophene-sulfonic group, 3- pyridine-sulphur Acidic group, 4- methyl-benzenesulfonic acid base, 4- methoxyl group-benzene sulfonic acid base, 4- trifluoromethyl-benzene sulfonic acid base, 4- trifluoromethoxy-benzene sulphur The fluoro- benzene sulfonic acid base of acidic group, 4-, the chloro- benzene sulfonic acid base of 4-, 4- nitro-benzene sulfonic acid base, 3- nitro-benzene sulfonic acid base, 4- acetylaminohydroxyphenylarsonic acid Benzene sulfonic acid base, 3,5- dimethyl -4- oxazole-benzene sulfonic acid base, methanesulfonamido, 4- methyl-benzenesulfonyl amino, the chloro- benzene sulfonyl of 4- Amino, 4- methoxy-benzenesulfonyl amino, 4- trifluoromethyl-benzene amino, 4- trifluoromethoxy-benzenesulfonamido-, 4- nitre Base-benzenesulfonamido-, 3- nitro-benzenesulfonamido-, 2- thiophene-benzenesulfonamido- or 4- acetylaminohydroxyphenylarsonic acid benzenesulfonamido-.
In the present invention, the thiazole amide compound shown in formula I can be following any compound:
(E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-1)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-2)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- Allyl) phenyl ester (I-3)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (4- methoxyphenyl) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-4)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- chlorphenyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester (I-5)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- methoxyphenyl) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-6)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- Allyl) phenyl ester (I-7)
(E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-8)
(E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- Allyl) phenyl ester (I-9)
(E) -4- trifluoromethyl benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) amino) -1- allyl) phenyl ester (I-10)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-11)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-12)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-13)
(E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-14)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-15)
(E) -3,5- dimethyl -4- oxazole sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) phenyl ester (I-16)
(E) -2- thiophene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-17)
(E) -2- thiophenic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-18)
(E)-acidum nicotinicum -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-19)
(E) -2- cyano -3- (3- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) allyl amide (I-20)
(E) -2- cyano -3- (4- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) allyl amide (I-21)
(E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester (I-22)
(E)-methanesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester (I-23)
(E)-methanesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- allyl Base) phenyl ester (I-24)
(E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) phenyl ester (I-25)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-26)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles - 2- yl) amino) -1- allyl) phenyl ester (I-27)
(E) -4- chlorobenzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-28)
(E) -4- fluorobenzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-29)
(E) -4- methoxy benzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-30)
(E) -4- trifluoromethoxy benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-31)
(E) -4- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-32)
(E) -4- acetylamino benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) amino) -1- allyl) phenyl ester (I-33)
(E) -2- thiophene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester (I-34)
(E) -3- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-35)
(E) -2- cyano -3- ((3- methanesulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Acrylamide (I-36)
(E) -2- cyano -3- ((3- tolysulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) acrylamide (I-37)
(E) -2- cyano -3- ((3- is to chlorobenzenesulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) acrylamide (I-38)
(E) -2- cyano -3- ((3- is to fluorobenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) acrylamide (I-39)
(E) -2- cyano -3- ((3- is to methoxybenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide (I-40)
(E) -2- cyano -3- ((3- is to trifluoromethoxy benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) acrylamide (I-41)
(E) -2- cyano -3- ((3- p-nitrophenyl sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide (I-42)
(E) -2- cyano -3- ((3- acetparaminosalol benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) acrylamide (I-43)
(E) -2- cyano -3- ((3- (thiophene -2- sulfonyl) amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) acrylamide (I-44)
(E) -2- cyano -3- ((3- m-nitro sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide (I-45)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) Phenyl ester (II-1)
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) Phenyl ester (II-2), and
(E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) phenyl ester (II-3)；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-46)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester (I-47)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-48)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-49)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-50)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-51)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-52)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-53)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-54)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-55)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-56)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-57)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester (I-58)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester (I-59)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester (I-60)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester (I-61)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5 benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- Allyl) phenyl ester (I-62)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- Allyl) phenyl ester (I-63)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- fluorophenyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-64)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-65)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-66)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-67)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-68)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-69)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-70)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-71)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-72)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-73)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-74)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-75)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-76)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-77)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-78)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-79)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-80)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester (I-81)
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-82)
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-83)
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-84)
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester (I-85)
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-86)
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester (I-87).
The present invention also provides the preparation methods of the compound I comprising following step: by compound II and chemical combination Object III carries out Knoevenagel reaction, obtains compound I；
The condition of the Knoevenagel reaction can be the condition of such reaction routine of this field, such as following conditions:
The Knoevenagel reaction can carry out in solvent (such as benzene or toluene).
The described Knoevenagel reaction can be in catalyst (such as NH4OAc and HOAc, the HOAc and described NH4The mass values of OAc can be 1.5~2) in the presence of carry out.
The molar ratio of the compound II and the compound III can be 1.0~1.5 (such as 1.2).
Routine monitoring method (such as TLC, HPLC in this field can be used in the process of the described Knoevenagel reaction Or NMR) be monitored, as reaction end when generally no longer being reacted using compound III, the reaction time can be 8h~10h.
The preparation method of the compound I can further comprise also following step: by compound IV and cyanoacetic acid second Ester carries out ammonolysis reaction, obtains the compound III；
The condition of the ammonolysis reaction can be the condition of such reaction routine of this field, such as following conditions:
The molar ratio of the cyan-acetic ester and the compound IV can be 1.5~2.0.
The ammonolysis reaction can carry out in solvent (such as methanol).
The ammonolysis reaction can carry out in the presence of sodium, the volume ratio of the mole of the sodium and the solvent It can be 10mmol:10mL.
The process of the ammonolysis reaction can be used the routine monitoring method (such as TLC, HPLC or NMR) in this field into Row monitoring, as reaction end when generally no longer being reacted using compound IV, the reaction time can be 5h~10h.
When the X is N, the preparation method of the compound I can further comprise also following step: by R1COOH Condensation reaction is carried out with thiosemicarbazides, obtains the compound IV.
The condition of the condensation reaction can be the condition of such reaction routine of this field, such as following conditions:
The R1The molar ratio of COOH and the thiosemicarbazides can be 1~1.2.
The condensation reaction can carry out in solvent (such as phosphorus oxychloride).
The temperature of the condensation reaction can be 60 DEG C~70 DEG C.
The process of the condensation reaction can be used the routine monitoring method (such as TLC, HPLC or NMR) in this field into Row monitoring, generally with R1It is reaction end when COOH no longer reacts, the reaction time can be 5h~10h.
Work as R3ForWhen, the preparation method of the compound I can further comprise also following step: by chemical combination Object V and R4C (=O) Cl carries out acylation reaction, obtains the compound II；
The condition of the acylation reaction can be the condition of such reaction routine of this field, such as following conditions:
The acylation reaction can be in solvent (such as CH2Cl2) in carry out.
The acylation reaction can carry out in the presence of alkali (such as DMAP and TEA).
Work as R3ForWhen, the preparation method of the compound I can further comprise also following step: by chemical combination Object V and R5S (=O)2Cl carries out acylation reaction, obtains the compound II；
The condition of the acylation reaction can be the condition of such reaction routine of this field, such as following conditions:
The acylation reaction can be in solvent (such as CH2Cl2) in carry out.
The acylation reaction can carry out in the presence of alkali (such as DMAP and TEA).
Work as R3ForWhen, the preparation method of the compound I can further comprise also following step: by chemical combination Object VI and R5S (=O)2Cl carries out acylation reaction, obtains the compound II；
The condition of the acylation reaction can be the condition of such reaction routine of this field, such as following conditions:
The acylation reaction can be in solvent (such as CH2Cl2) in carry out.
The acylation reaction can carry out in the presence of alkali (such as DMAP and TEA).
The present invention also provides a kind of such as Formula II or III compound represented,
Wherein, R1And R3It is as defined above any described.
The compound II can be following any compounds:
The compound III can be following any compounds:
The present invention also provides the application of above-mentioned compound I in medicine preparation, the drug for treating and/or Prevent disease relevant to Bcl anti-apoptotic proteins.Described " Bcl anti-apoptotic proteins " such as Bcl-XL, Bcl-2 and Mcl-1 egg It is one of white or a variety of.Described " disease relevant to Bcl anti-apoptotic proteins " such as tumour；For example white blood of the tumour Disease；The leukaemia such as people's acute lymphoblastic leukemia or people's promyelocytic leukemia.
The present invention also provides above-mentioned compound I to prepare the application in Bcl inhibitors of anti-apoptotic proteins.Described " Bcl anti-apoptotic proteins " such as Bcl-XL, one of Bcl-2 and Mcl-1 albumen or a variety of.
The present invention also provides the application of above-mentioned compound I in medicine preparation, the drug for treating and/or Pre- preventing leukemia.The leukaemia such as people's acute lymphoblastic leukemia or people's promyelocytic leukemia.
The present invention also provides a kind of pharmaceutical compositions comprising above-mentioned compound I and pharmaceutic adjuvant.
Term " halogen " refers to fluorine, chlorine, bromine, iodine.
Term " alkyl " (such as C1~C20Alkyl) indicate to include the branch for specifying the carbon atom of carbon number (such as 1~20) With the radical of saturated aliphatic alkyl of straight chain, specific example includes but is not limited to: methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), just Propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), 2- methyl-prop Base or isobutyl group (i-Bu ,-CH2CH(CH3)2), 1- methyl-propyl or sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t- Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl- 1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 4- methyl amyl (- CH2CH2CH2CH(CH3)CH3), 3- methyl amyl (- CH2CH2CH(CH3) CH2CH3), 2- methyl amyl (- CH2CH(CH3)CH2CH2CH3), 2- hexyl (- CH (CH3)CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3), 3,3- dimethylbutyl (- CH2CH2CH2(CH3)2CH3), 2,2- dimethylbutyl (- CH2C(CH3)2CH2CH3), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- Methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH(CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkoxy " (such as C1~C20Alkoxy) indicate the alkyl connected by oxygen bridge；The definition of the alkyl Ibid.
Term " alkane sulfydryl " (such as C1~C20Alkane sulfydryl) indicate the alkyl connected by sulphur bridge；The definition of the alkyl Ibid.
Term " naphthenic base " (such as C3~C12Naphthenic base) indicate that (such as 3-12) comprising respective number can form ring Carbon atom cyclic hydrocarbon groups, be saturated mode, and do not include hetero atom；Monocycle or 7-12 including 3-12 carbon atom Two rings or tricyclic (including spiro ring system, bridged-ring system and fused ring system) of a carbon atom；Its carbon atom can be oxidized.Have The bicyclic carbocyclic ring of 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, while have 9 or 10 atoms Bicyclic carbocyclic ring can be two rings [5,6] or [6,6] system.Suitable group of naphthene base includes but is not limited to: cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl.
Term " cycloalkenyl " (such as C3~C12Cycloalkenyl) indicate that (such as 3-12) comprising respective number can form ring Carbon atom cyclic hydrocarbon groups, part unsaturated (includes 1 or 2 double bond, but none ring has total conjugated Pi-electron system), and do not include hetero atom；Two rings or tricyclic (packet of monocycle or 7-12 carbon atom including 3-12 carbon atom Containing spiro ring system, bridged-ring system and fused ring system)；Its carbon atom can be oxidized.Bicyclic carbocyclic ring with 7-12 atom can be with It is two rings [4,5], [5,5], [5,6] or [6,6] system, while there is the bicyclic carbocyclic ring of 9 or 10 atoms can be two rings [5,6] Or [6,6] system.Suitable group of naphthene base includes but is not limited to: 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- Cyclopenta -3- alkenyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl.
Term " heteroaryl " indicate comprising 1-3 (such as 1,2,3 or 4) hetero atoms (selected from one of N, S and O or It is a variety of) and specified first number (such as 5~10 yuan) monocycle or polycyclic aroma system, wherein hetero-aromatic ring and aromatic ring, bicyclic heteroaryl Ring, tricyclic hetero-aromatic ring or Fourth Ring heteroaromatic ring systems are with condensed form cyclization, and N or S are optionally by one or more oxygen atoms It is replaced to obtain as NO, SO, SO2Group, N atom can be quaternized.Heteroaryl can be in any hetero atom or carbon atom On be connected in main structure to forming stable compound.Heteroaryl include but is not limited to be 3-7 former molecular monocycle, Or 7-10 former molecular bicyclic or 10-15 former molecular tricyclic.It can be two rings with 7-10 the bicyclic of atom [4,5], [5,5], [5,6] or [6,6] system can be tricyclic [5,5,6] with the tricyclic of 10-15 atom, [5,7,6] or [6,5,6] system.Heteroaryl includes but is not limited to: 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazoles Base, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- first Base isoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazinyl (such as 3- pyridazinyl) base, 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical is (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), Isothiazolyl, 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3-triazoles base, 1,2,3- is thio Di azoly, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, 1,3,4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyridine -6- base, benzimidazolyl, benzoxazolyl, quinoline Quinoline base, 1,8- phthalazinyl, benzofuranyl, benzothienyl, benzothiazolyl, indoles (such as 2- indyl) base are fast Purine base, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- Isoquinolyl), tetralyl, benzopyrene oxazolyl, acridinyl, benzimidazolyl, benzindole base, benzo isooxazine base, benzo [4,6] imidazo [1,2-a] pyridyl group, benzo [d] imidazoles [2,1-b] thiazolyl, benzofuranyl, benzo aphthofurans base, Diazosulfide base, benzothiazolyl, benzo thio-phenyl, benzotriazole base, benzo thiopyranyl, benzoxazinyl-, benzene And oxazolyl, benzothiazolyl, B-carboline base, carbazyl, cinnoline base, dibenzofuran group, imidazopyridyl, miaow Azoles benzothiazolyl, indazolyl, indolizine base, indyl, different benzo thienyl, iso-dihydro-indole-group, isoquinolyl, isothiazolidine Base, isothiazolyl, naphthyridines base, decahydro indyl, decahydro isoindolyl, oxazolidinedione base, oxazolidinyl, oxazole and pyridine Base, oxazolyl, Oxyranyle, embedding two pyridyl of tea, phenanthridinyl, phenanthroline base, phenarsazine base, phenazinyl, phenothiazinyl, pheno Oxazines base, phthalazinyl, pteridyl, pyridopyridine base, quinazolyl, quinoxaline base, thio-phenyl, triazine radical, 2H- pyrrolo- [3,4-c] pyridyl group, pyrazolo [2 ', 1 ': 2,3] oxazole simultaneously [4,5-c] pyridyl group, imidazo [2 ', 1 ': 2,3] thiazole simultaneously [4, 5-c] pyridyl group, imidazo [2 ', 1 ': 2,3] thiazole simultaneously [4,5-b] pyridyl group, imidazo [2 ', 1 ': 2,3] thiazole simultaneously [5,4- B] pyridyl group, pyrazolo [2 ', 1 ': 2,3] thiazole simultaneously [4,5-b] pyrazinyl, 1H- benzo [4,5] thieno [2,3-d] imidazoles Base, 1- methyl-1 H- benzo [4,5] thieno [2,3-d] imidazole radicals, imidazo [2', 1':2,3] thiazole simultaneously [4,5-b] pyrazine Base, imidazo [2', 1':2,3] thiazole simultaneously [5,4-b] pyridyl group, imidazo [2', 1':2,3] thiazole simultaneously [4,5-c] pyridyl group, 1H- benzo [f] imidazo [4,5-b] [1,4] sulphur azatropylidene base etc..
Term " pharmaceutically acceptable salt " is indicated by suitable non-toxic organic, inorganic acid, organic base or inorganic base The salt formed with compound I retains the bioactivity of compound I.The organic acid can for this field it is conventional can be at salt Various organic acids, preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzene methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid, succinic acid, Citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, phenylacetic acid, One of isethionic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, mandelic acid and salicylic acid are a variety of.The inorganic acid can be this Field it is conventional can be at the various inorganic acids of salt, preferably one of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid or a variety of.Described Organic base can for this field it is conventional can be at the various organic bases of salt, preferably pyridines, imidazoles, Pyrazine, indoles, fast quinoline One of class, tertiary amines and phenyl amines are a variety of.The preferred triethylamine of tertiary amines organic base and/or N, N- diisopropyl Ethamine.The preferred N of phenyl amines organic base, accelerine.The preferred pyridine of pyridines organic base, methyl pyrrole One of pyridine, 4-dimethylaminopyridine and 2- methyl -5- ethylpyridine are a variety of.The inorganic base can be conventional for this field Can be at the various inorganic bases of salt, preferred as alkali hydride, the hydroxide of alkali metal, the alkoxide of alkali metal, carbonic acid One of potassium, sodium carbonate, lithium carbonate, cesium carbonate, saleratus and sodium bicarbonate are a variety of.The alkali metal hydride is excellent Select sodium hydride and/or hydrofining.In the preferred sodium hydroxide of the hydroxide of the alkali metal, potassium hydroxide and lithium hydroxide It is one or more.One of the preferred sodium methoxide of the alkoxide of the alkali metal, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide Or it is a variety of.
Term " pharmaceutic adjuvant ", which refers to, those of is widely used auxiliary material in drug production field.Auxiliary material is mainly used for offer one A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is after so that subject is received administration with institute Expected rate dissolution, or promote subject to receive active constituent after composition is administered and effectively absorbed.The pharmaceutic adjuvant Can be inert filler, or certain function be provided, for example, stable the composition whole pH value or prevent composition active The degradation of ingredient.The pharmaceutic adjuvant may include one of following auxiliary material or a variety of: adhesive, suspending agent, emulsifier, Diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antitack agent, glidant, wetting agent, gelling agent, absorption Delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.
The positive effect of the present invention is that: such compound can efficiently and selectively press down on a molecular scale Key protein Bcl-X in apoptosis process processedL, Bcl-2 and Mcl-1.Meanwhile they are acute to cancer cell, especially people Lymphoblastic leukemia cell lines RS4；11 and people's promyelocytic leukemia cell line HL-60 have apparent lethal effect and height Selectivity has the potentiality for being prepared into new type antineoplastic medicine, has preferable market-oriented prospect.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
Unless otherwise specified, the explanation in following all examples is all to be previously mentioned with quality (gram) for unit Room temperature refers to 20 DEG C~30 DEG C.
The preparation of 1 2- cyano-N- of embodiment (5- methylthiazol -2- base) acetamide
Sodium block (0.23g, 10mmol) is dissolved in dry anhydrous methanol (10mL), 5mmol 2- amino -5- first is added Base thiazole (0.57g, 5mmol), is stirred at room temperature 20min, adds cyan-acetic ester (0.8mL, 7.5mmol), back flow reaction 5h, until contact plate discovery raw material disappears.When post-processing, first most methanol are removed in rotation, add 20mL distilled water, are finally added dropwise Glacial acetic acid is until precipitating is formed.It filters, is recrystallized to give target product with EtOH-dioxane system.1H NMR(400MHz, DMSO-d6):δ7.24(s,1H),4.12(s,2H),2.31(s,3H)；MS(ESI)(m/z):182(M+H+)；
The preparation of 2 2- cyano-N- of embodiment (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino -5- (thiophene -2- base) -1,3,4- thiadiazoles, the original needed for remaining Material, reagent and the preparation method is the same as that of Example 1, obtain product 2- cyano-N- (- 1,3,4- thiadiazoles -2- base of 5- (thiophene -2- base)) Acetamide.1H NMR(400MHz,DMSO-d6): δ 7.75-7.74 (dd, J=4.0Hz, 1H), 7.70-7.7.67 (dd, J= 2.4Hz, 1H), 7.20-7.7.18 (t, J=4Hz, 1H), 4.04 (s, 2H)；MS(ESI)(m/z):251(M+H+)；
The preparation of 3 2- cyano-N- of embodiment (5- phenyl -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino-5-phenyl -1,34- thiadiazoles, the raw material, reagent needed for remaining And the preparation method is the same as that of Example 1, obtains product 2- cyano-N- (5- phenyl -1,3,4- thiadiazoles -2- base) acetamide.1H NMR (400MHz,DMSO-d6):δ8.10-8.08(m,2H),7.44-7.43(m,3H),4.62(s,2H)；MS(ESI)(m/z):245 (M+H+)；
The preparation of 4 2- cyano-N- of embodiment (5- (4- methoxyphenyl) -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino -5- (4- methoxyphenyl) -1,3,4- thiadiazoles, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1, obtain product 2- cyano-N- (- 1,3,4- thiophene two of 5- (4- methoxyphenyl) Azoles -2- base) acetamide.1H NMR(400MHz,DMSO-d6):δ7.77-7.76(d,2H),7.08-7.06(d,2H),4.64(s, 2H), 3.87 (s, 3H)；MS(ESI)(m/z):275(M+H+)；
The preparation of 5 2- cyano-N- of embodiment (5- (2- chlorphenyl) -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino -5- (2- chlorphenyl) -1,3,4- thiadiazoles, the original needed for remaining Material, reagent and the preparation method is the same as that of Example 1, obtain product 2- cyano-N- (- 1,3,4- thiadiazoles -2- base of 5- (2- chlorphenyl)) Acetamide.1H NMR(400MHz,DMSO-d6):δ8.37-8.34(m,1H),7.55-7.51(m,1H),7.43-7.41(m, 2H),4.64(s,2H)；MS(ESI)(m/z):279(M+H+)；
The preparation of 6 2- cyano-N- of embodiment (5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino -5- (1H- indoles -2- base) -1,3,4- thiadiazoles, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1, obtain product 2- cyano-N- (5- (1H- indoles -2- base) -1,3,4- thiophenes two Azoles -2- base) acetamide.1H NMR(400MHz,DMSO-d6):δ7.58-7.56(d,1H),7.43-7.41(d,1H),7.21- 7.18(t,1H),7.07-7.04(m,1H),6.81(s,1H),4.09(s,2H)；MS(ESI)(m/z):284(M+H+)；
The preparation of 7 2- cyano-N- of embodiment (5- (2- methoxyphenyl) -1,3,4- thiadiazoles -2- base) acetamide
Change 2- amino -5- methylthiazol into 2- amino -5- (2- methoxyphenyl) -1,3,4- thiadiazoles, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1, obtain product 2- cyano-N- (- 1,3,4- thiophene two of 5- (2- methoxyphenyl) Azoles -2- base) acetamide.1H NMR(400MHz,DMSO-d6):δ7.74(d,1H),7.47-7.43(m,1H),7.28-7.24(m, 2H),7.17-7.11(m,1H),4.12(s,3H),3.82(m,2H)；MS(ESI)(m/z):275(M+H+)；
The preparation of 8 4- toluenesulfonic acid -2- aldehyde radical phenyl ester of embodiment
Benzaldehyde,2-hydroxy and 4- toluene sulfonyl chloride are in DMAP/TEA/CH2Cl2Under the conditions of reaction generate 2- aldehyde radical-benzene Base -4- oluene sulfonic acides ester, 95% or more yield.Post-processing: CH2Cl2Extraction, after the washing of 1M HCl solution, successively with saturation NaHCO3With saturated common salt water washing, flash column chromatography after solvent, pure CH are removed in rotation2Cl2Cross column.1H NMR(400MHz, CDCl3):δ9.99(s,1H),7.87(d,1H),7.72-7.70(d,2H),7.41-7.37(m,1H),7.34-7.32(m, 2H),7.23-7.21(d,1H),2.46(s,3H)；MS(ESI)(m/z):277(M+H+)；
The preparation of 9 benzene sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into benzene sulfonyl chloride, the raw material, reagent and preparation method needed for remaining with embodiment 8, Obtain product benzene sulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ9.99(s,1H),7.87-7.83(m,3H), 7.73-7.69(m,1H),7.60-7.53(m,3H),7.42-7.38(t,1H),7.21-7.19(d,1H)；MS(ESI)(m/z): 263(M+H+)；
The preparation of 10 4- toluenesulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change Benzaldehyde,2-hydroxy into 3- hydroxy benzaldehyde, raw material, reagent and the same embodiment of preparation method needed for remaining 8, obtain product 4- toluenesulfonic acid -3- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ9.92(s,1H),7.79-7.77 (m,1H),7.72(s,1H),7.71(s,1H),7.51-7.47(m,2H),7.33-7.31(m,3H),2.45(s,3H)；MS (ESI)(m/z):277(M+H+)；
The preparation of 11 4- toluenesulfonic acid -4- aldehyde radical phenyl ester of embodiment
Change Benzaldehyde,2-hydroxy into 4- hydroxy benzaldehyde, raw material, reagent and the same embodiment of preparation method needed for remaining 8, obtain product 4- toluenesulfonic acid -4- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ9.97(s,1H),7.84-7.82 (d,2H),7.73-7.71(d,2H),7.34-7.32(d,2H),7.18-7.16(d,2H),2.45(s,3H)；MS(ESI)(m/ z):277(M+H+)；
The preparation of 12 4- trifluoromethyl benzene sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- trifluoromethyl benzene sulfonyl chloride, raw material, reagent and preparation method needed for remaining With embodiment 8, product 4- trifluoromethyl benzene sulfonic acid -2- aldehyde radical phenyl ester is obtained.1H NMR(400MHz,CDCl3):δ10.08(s, 1H),8.04-8.02(d,2H),7.92-7.90(d,1H),7.85-7.83(m,2H),7.61(t,1H),7.47-7.45(t, 1H),7.19-7.17(d,1H)；MS(ESI)(m/z):331(M+H+)；
The preparation of 13 4- chlorobenzenesulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- chlorobenzene sulfonyl chloride, the raw material, reagent and preparation method needed for remaining are the same as implementation Example 8 obtains product 4- chlorobenzenesulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.06(s,1H),7.90-7.88 (m,1H),7.80-7.78(d,2H),7.61-7.57(m,1H),7.57-7.52(m,2H),7.44-7.42(t,1H),7.19- 7.17(d,1H)；MS(ESI)(m/z):297(M+H+)；
The preparation of 14 4- fluorobenzene sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- fluorophenylsulfonyl chloride, the raw material, reagent and preparation method needed for remaining are the same as implementation Example 8 obtains product 4- fluorobenzene sulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.04(s,1H),7.89-7.86 (m,3H),7.62-7.58(m,1H),7.44-7.40(t,1H),7.26-7.18(m,3H)；MS(ESI)(m/z):281(M+H+)；
The preparation of 15 4- methoxy benzenesulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- Methoxybenzenesulfonyl chloride, the raw material, reagent and preparation method needed for remaining are same Embodiment 8 obtains product 4- methoxy benzenesulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.02(s,1H), 7.87-7.85(m,1H),7.74-7.72(d,2H),7.59-7.55(m,1H),7.40-7.36(t,1H),7.20-7.18(d, 1H),6.98-6.96(d,2H),3.88(s,3H)；MS(ESI)(m/z):293(M+H+)；
The preparation of 16 4- trifluoromethoxy benzene sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- trifluoromethoxy benzene sulfonyl chloride, raw material, reagent and preparation side needed for remaining Method obtains product 4- trifluoromethoxy benzene sulfonic acid -2- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ10.06 (s,1H),7.94-7.89(m,3H),7.60-7.58(m,1H),7.45-7.42(m,1H),7.39-7.37(d,2H),7.21- 7.19(d,1H)；MS(ESI)(m/z):347(M+H+)；
The preparation of 17 4- nitrobenzene-sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- nitrobenzene sulfonyl chloride, the raw material, reagent and preparation method needed for remaining are the same as real Example 8 is applied, product 4- nitrobenzene-sulfonic acid -2- aldehyde radical phenyl ester is obtained.1H NMR(400MHz,CDCl3):δ10.07(s,1H),8.42- 8.40(d,2H),8.11-8.09(d,2H),7.92-7.90(m,1H),7.63-7.61(m,1H),7.49-7.47(t,1H), 7.21-7.19(d,1H)；MS(ESI)(m/z):308(M+H+)；
The preparation of 18 4- acetylamino benzene sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- acetamidobenzenesulfonyl chloride, raw material, reagent and preparation method needed for remaining Together
Embodiment 8 obtains product 4- acetylamino benzene sulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ 10.01(s,1H),7.87-7.85(d,1H),7.76-7.69(m,4H),7.65(s,1H),7.59(t,1H),7.40(t,1H), 7.22-7.20(d,1H),2.22(s,3H)；MS(ESI)(m/z):320(M+H+)；
The preparation of 19 3,5- dimethyl oxazoline -4- sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 3,5- dimethyl oxazoline -4- sulfonic acid chloride, raw material, reagent and preparation needed for remaining Method obtains product 3,5- dimethyl oxazoline -4- sulfonic acid -2- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ 10.19(s,1H),7.97-7.95(m,1H),7.63(m,1H),7.51-7.49(t,1H),7.16-7.14(d,1H),2.44 (s,3H),2.32(s,3H)；MS(ESI)(m/z):282(M+H+)；
The preparation of 20 thiophene -2- sulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into thiophene -2- sulfonic acid chloride, the raw material, reagent and preparation method needed for remaining are the same as implementation Example 8 obtains product thiophene -2- sulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.03(s,1H),7.90-7.88 (m,1H),7.78-7.76(m,1H),7.64-7.60(m,2H),7.45-7.41(t,1H),7.30-7.26(d,1H),7.15- 7.13(t,1H)；MS(ESI)(m/z):269(M+H+)；
The preparation of 21 methanesulfonic acid -2- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into mesyl chloride, the raw material, reagent and preparation method needed for remaining with embodiment 8, Obtain product methanesulfonic acid -2- aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.29(s,1H),7.98-7.96(s,1H), 7.68-7.65(m,1H),7.50-7.44(m,1H),3.30(s,3H)；MS(ESI)(m/z):201(M+H+)；
The preparation of 22 methanesulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into mesyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, needed for remaining Raw material, reagent and preparation method obtain product methanesulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ 10.02(s,1H),7.87-7.85(m,1H),7.78(s,1H),7.63-7.56(m,2H),3.21(s,3H)；MS(ESI)(m/ z):201(M+H+)；
The preparation of 23 methanesulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into mesyl chloride, Benzaldehyde,2-hydroxy changes 4- hydroxy benzaldehyde into, needed for remaining Raw material, reagent and preparation method obtain product methanesulfonic acid -4- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ 10.02(s,1H),7.97-7.95(m,1H),7.47-7.45(d,1H),3.21(s,3H)；MS(ESI)(m/z):201(M+H+)；
The preparation of 24 4- trifluoromethyl benzene sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Changing 4- toluene sulfonyl chloride into 4- trifluoromethyl benzene sulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, Raw material, reagent and preparation method needed for remaining obtain product 4- trifluoromethyl benzene sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ9.98(s,1H),8.04-8.02(d,2H),7.92-7.90(d,1H),7.85-7.83(m, 2H),7.61(t,1H),7.47-7.45(t,1H),7.19-7.17(d,1H)；MS(ESI)(m/z):331(M+H+)；
The preparation of 25 4- chlorobenzenesulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- chlorobenzene sulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining institute Raw material, reagent and the preparation method needed obtains product 4- chlorobenzenesulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz, CDCl3):δ9.95(s,1H),7.81-7.77(m,3H),7.53-7.49(m,4H),7.30-7.28(d,1H)；MS(ESI)(m/ z):297(M+H+)；
The preparation of 26 4- fluorobenzene sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- fluorophenylsulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining institute Raw material, reagent and the preparation method needed obtains product 4- fluorobenzene sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz, CDCl3):δ9.92(s,1H),7.86-7.84(m,2H),7.79-7.77(d,1H),7.51-7.47(m,2H),7.29-7.27 (d,1H),7.24-7.18(m,2H)；MS(ESI)(m/z):281(M+H+)；
The preparation of 27 4- methoxy benzenesulfonic acid -3- aldehyde radical phenyl ester of embodiment
Changing 4- toluene sulfonyl chloride into 4- Methoxybenzenesulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, Remaining required raw material, reagent and preparation method obtain product 4- methoxy benzenesulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz,CDCl3):δ9.93(s,1H),7.78-7.74(m,3H),7.50-7.46(m,2H),7.30-7.28(m,1H), 6.98-9.96(d,2H),3.88(s,3H)；MS(ESI)(m/z):293(M+H+)；
The preparation of 28 4- trifluoromethoxy benzene sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 4- trifluoromethoxy benzene sulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzenes first into Aldehyde, raw material, reagent and preparation method needed for remaining obtain product 4- trifluoromethoxy benzene sulfonic acid -3- aldehyde radical benzene with embodiment 8 Ester.1H NMR(400MHz,CDCl3):δ9.96(s,1H),7.94-7.90(m,2H),7.79(m,1H),7.60-7.58(m, 1H),7.45-7.42(m,1H),7.39-7.37(d,2H),7.21-7.19(d,1H)；MS(ESI)(m/z):347(M+H+)；
The preparation of 29 4- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Changing 4- toluene sulfonyl chloride into 4- nitrobenzene sulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining Required raw material, reagent and preparation method obtains product 4- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz,CDCl3):δ9.97(s,1H),8.56-8.54(m,2H),8.20-8.18(d,1H),7.84-7.79(m,2H), 7.63-7.61(m,1H),7.49-7.47(t,1H),7.21-7.19(d,1H)；MS(ESI)(m/z):308(M+H+)；
The preparation of 30 4- acetylamino benzene sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Changing 4- toluene sulfonyl chloride into 4- acetamidobenzenesulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, Raw material, reagent and preparation method needed for remaining obtain product 4- acetylamino benzene sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR(400MHz,CDCl3):δ9.92(s,1H),7.91(s,1H),7.79-7.71(m,5H),7.50-7.48(m,2H), 7.30-7.26(m,1H),2.23(s,3H)；MS(ESI)(m/z):320(M+H+)；
The preparation of 31 3,5- dimethyl oxazoline -4- sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into 3,5- dimethyl oxazoline -4- sulfonic acid chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzenes into Formaldehyde, raw material, reagent and preparation method needed for remaining obtain product 3,5- dimethyl oxazoline -4- sulfonic acid -3- with embodiment 8 Aldehyde radical phenyl ester.1H NMR(400MHz,CDCl3):δ10.09(s,1H),7.97-7.95(m,1H),7.63(m,1H),7.51- 7.49(t,1H),7.16-7.14(d,1H),2.44(s,3H),2.32(s,3H)；MS(ESI)(m/z):282(M+H+)；
The preparation of 32 thiophene -2- sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into thiophene -2- sulfonic acid chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining institute Raw material, reagent and the preparation method needed obtains product thiophene -2- sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz,CDCl3):δ9.93(s,1H),7.90-7.88(m,1H),7.78-7.76(m,1H),7.64-7.60(m,2H), 7.45-7.41(t,1H),7.30-7.26(d,1H),7.15-7.13(t,1H)；MS(ESI)(m/z):269(M+H+)；
The preparation of 33 3- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester of embodiment
Changing 4- toluene sulfonyl chloride into 3- nitrobenzene sulfonyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining Required raw material, reagent and preparation method obtains product 3- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz,CDCl3):δ9.95(s,1H),8.71(s,1H),8.556-8.54(d,1H),8.20-8.18(d,1H),7.84- 7.79(m,2H),7.57-7.52(m,2H),7.36-7.34(d,1H)；MS(ESI)(m/z):308(M+H+)；
The preparation of 34 thiophene -2-carboxylic acid -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into thiophene -2- formyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining institute Raw material, reagent and the preparation method needed obtains product thiophene -2-carboxylic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz,CDCl3): δ 10.13 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H),7.34(s,1H),7.32(m,2H)；MS(ESI)(m/z):233(M+H+)；
The preparation of 35 Nicotinicum Acidum -3- aldehyde radical phenyl ester of embodiment
Change 4- toluene sulfonyl chloride into pyridine -3- formyl chloride, Benzaldehyde,2-hydroxy changes 3- hydroxy benzaldehyde into, remaining institute Raw material, reagent and the preparation method needed obtains product pyridine -3- formic acid -3- aldehyde radical phenyl ester with embodiment 8.1H NMR (400MHz, CDCl3): δ 10.04 (s, 1H), 9.41-9.40 (d, 1H), 8.89-8.87 (dd, J=2.0Hz, J=3.2Hz, 1H), 8.47-8.45 (m, 1H), 7.84-7.82 (dd, J=2Hz, J=1.6Hz, 1H), 7.78-7.77 (t, 1H), 7.65- 7.61(t,1H),7.53-7.48(m,2H)；MS(ESI)(m/z):228(M+H+)；
Embodiment 36 (E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-1)
By 0.5mmol 1,3,4- thiadiazoles amides midbody compound 2- cyano-N- (5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) acetamide (0.5mmol) and the corresponding aldehyde raw material 4- toluenesulfonic acid -2- of 0.6mmol (1.2equiv.) Aldehyde radical phenyl ester is in NH4Heating reflux reaction 8h under the conditions of OAc/HOAc/PhMe (144mg/0.2mL/10mL), until raw material is complete It disappears.When post-processing, CH2Cl2Extraction, then successively with saturation NaHCO3With saturated common salt water washing, flash column after solvent is removed in rotation Analysis purifying, first CH2Cl2CH is used in elution again2Cl2: MeOH=100:1 crosses column, obtains product (E) -4- toluenesulfonic acid -2- (2- cyanogen Base -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR (400MHz,DMSO-d6)δ8.58(s,1H),8.33-8.31(d,1H),7.83-7.81(d,2H),7.73(d,1H),7.70 (d,1H),7.61-7.58(m,2H),7.53-7.49(t,1H),7.38-7.34(t,1H),7.23-7.18(m,2H),2.21 (s,3H)；13C NMR(100MHz,DMSO-d6):δ154.66,147.67,146.73,144.77,133.94,131.94, 131.37,130.96,130.89,130.58,129.92,129.79,129.69,129.08,128.75,128.54,128.28, 128.15,125.92,124.44,115.04,110.27,21.19；MS(ESI)(m/z):509.2(M+H+)；HRMS(MALDI) (m/z):Calcd for C23H17N4O4S3(M+H+):509.0406,Found:509.0392；
Meanwhile in conjunction with following documents for describing the similar reaction of the present embodiment, it is able to conclude that the double bond of the product is E structure Type.Later embodiment herewith, no longer illustrates:
1.Identification of a Selective InverseAgonist for the Orphan Nuclear ReceptorEstrogen-Related ReceptorαJ.Med.Chem.2004,47,5593.
2.One pot,three-component synthesis of novel 3,4-dihydrophthalazin-2 (1H)-yl-4-phenyl-4H-pyrans Tetrahedron Lett.2014,55,2177.
3.Uses of Cyanoacetylhydrazine in Heterocyclic Synthesis: NovelSynthesis of Pyrazole Derivatives with Anti-tumor Activities Molecules, 2012,17,8449.
Embodiment 37 (E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) - 1- allyl) phenyl ester preparation (II-1)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- first Base thiazol-2-yl) acetamide, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methyl with embodiment 36 Benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) phenyl ester.1H NMR (400MHz,DMSO-d6)δ8.50(s,1H),8.23-8.22(d,2H),7.69-7.67(t,3H),7.60-7.58(m,3H), 7.24(s,1H),2.35(s,3H),2.31(s,3H)；MS(ESI)(m/z):438.2(M-H+)；HRMS(MALDI)(m/z): Calcd for C21H18N3O4S2(M+H+):440.0733,Found:440.0733；
Embodiment 38 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-2)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -3- aldehyde radical phenyl ester, raw material needed for remaining, Reagent and preparation method obtain product (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methyl with embodiment 36 Thiazol-2-yl) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.00-7.98(d, 1H),7.89-7.88(m,2H),7.84-7.81(t,1H),7.75-7.71(m,1H),7.59-7.53(m,2H),7.48-7.46 (d,1H),7.27-7.24(m,3H),2.31(s,3H)；13C NMR(100MHz,DMSO-d6):δ150.56,149.27, 146.10,133.56,131.90,131.06,130.38,129.84,129.60,129.39,128.49,128.21,127.52, 126.05,123.39,115.66,108.79,21.18；MS(ESI)(m/z):509.4(M+H+)；HRMS(MALDI)(m/z): Calcd for C23H17N4O4S3(M+H+):509.0406,Found:509.0414；
Embodiment 39 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester preparation (I-3)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzene Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -3- aldehyde radical Phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- toluenesulfonic acid -3- (2- cyanogen with embodiment 36 Base -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO- d6)δ8.43(s,1H),7.96-7.93(m,3H),7.78-7.76(m,3H),7.63-7.59(m,1H),7.56-7.55(m, 3H),7.49-7.47(m,2H),7.25-7.23(m,1H),2.42(s,3H)；MS(ESI)(m/z):503.2(M+H+)；HRMS (MALDI)(m/z):Calcd for C25H19N4O4S2(M+H+):503.0842,Found:503.0839；
Embodiment 40 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (4- methoxyphenyl) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-4)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxyphenyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methylbenzene sulphur Acid -3- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methylbenzene sulphur with embodiment 36 Acid -3- (2- cyano -3- oxo-((5- (4- methoxyphenyl) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester 。1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.96-7.94(d,1H),7.88-7.86(d,2H),7.78-7.75 (m,3H),7.62-7.58(m,1H),7.49-7.47(m,2H),7.25-7.22(m,1H),7.10-7.08(d,2H),3.83 (s,3H),2.42(s,3H)；13C NMR(100MHz,DMSO-d6):δ161.39,159.56,150.20,149.26,146.09, 133.68,131.09,131.00,130.37,129.39,128.29,128.23,125.90,123.34,122.20,115.95, 114.78,109.48,55.41,21.18；MS(ESI)(m/z):531.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C26H21N4O5S2(M+H+):533.0948,Found:533.0941；
Embodiment 41 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- chlorphenyl) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-5)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (2- Chlorphenyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -3- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- toluenesulfonic acid -3- with embodiment 36 (2- cyano -3- oxo-((5- (2- chlorphenyl) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR (400MHz,DMSO-d6)δ8.47(s,1H),8.15-8.13(m,2H),7.96-7.94(m,1H),7.76-7.68(m,5H), 7.63-7.47(m,3H),7.26-7.24(m,1H),2.42(s,3H)；13C NMR(100MHz,DMSO-d6):δ165.08, 162.33,159.94,158.29,150.80,149.92,148.73,133.67,133.49,132.32,132.16,131.90, 131.20,131.08,130.93,130.84,130.69,130.60,130.47,130.39,129.90,129.70,129.42, 128.23,127.94,127.29,123.44,21.20；MS(ESI)(m/z):535.1(M-H+)；HRMS(MALDI)(m/z): Calcd for C25H18ClN4O4S2(M+H+):537.0453,Found:537.0452；
Embodiment 42 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- methoxyphenyl) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-6)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (2- Methoxyphenyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methylbenzene sulphur Acid -3- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methylbenzene sulphur with embodiment 36 Acid -3- (2- cyano -3- oxo-((5- (2- methoxyphenyl) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester 。1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.30-8.28(m,2H),7.96-7.94(m,1H),7.83-7.76 (m,2H),7.63-7.47(m,3H),7.26-7.21(m,2H),7.14-7.10(m,2H),4.25-4.23(q,3H),2.42 (s,3H)；MS(ESI)(m/z):531.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C26H21N4O5S2(M+H+): 533.0948,Found:533.0947；
Embodiment 43 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- methyl-1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester preparation (I-7)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- first Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -3- aldehyde radical Phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- toluenesulfonic acid -3- (2- cyanogen with embodiment 36 Base -3- oxo-((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO- d6)δ8.27(s,1H),7.94-7.92(d,1H),7.77-7.74(m,3H),7.60-7.56(m,1H),7.48-7.46(d, 2H),7.23-7.21(m,1H),2.58(s,3H),2.41(s,3H)；MS(ESI)(m/z):439.2(M-H+)；HRMS (MALDI)(m/z):Calcd for C20H17N4O4S2(M+H+):441.0686,Found:441.0687；
Embodiment 44 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) - 1- allyl) phenyl ester preparation (II-2)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- first Base thiazol-2-yl) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -3- aldehyde radical phenyl ester, remaining Required raw material, reagent and preparation method obtains product (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxygen with embodiment 36 Generation -3- ((5- methylthiazol -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ13.12(w,s, 1H),8.30(s,1H),7.93-7.91(d,1H),7.77-7.73(m,3H),7.58-7.54(m,1H),7.47-7.45(m, 2H),7.22-7.18(m,2H),2.50(s,3H),2.30(s,3H)；13C NMR(100MHz,DMSO-d6):δ149.27, 149.13,146.09,134.02,131.09,130.93,130.38,129.30,128.26,125.54,124.59,123.18, 116.49,110.68,21.21,11.86；MS(ESI)(m/z):438.2(M-H+)；HRMS(MALDI)(m/z):Calcd for C21H18N3O4S2(M+H+):440.0733,Found:440.0730；
Embodiment 45 (E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-8)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -4- aldehyde radical phenyl ester, raw material needed for remaining, Reagent and preparation method obtain product (E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.46(s, 1H),8.03-8.01(d,2H),7.82-7.77(m,3H),7.51-7.49(m,3H),7.30-7.28(d,2H),7.23-7.21 (m,1H),2.43(s,3H)；13C NMR(100MHz,DMSO-d6):δ164.63,154.55,151.18,149.45,146.15, 132.96,132.10,131.24,130.39,128.96,128.62,128.35,128.26,122.88,116.52,109.72, 21.20；MS(ESI)(m/z):509.4(M+H+)；HRMS(MALDI)(m/z):Calcd for C23H17N4O4S3(M+H+): 509.0407,Found:509.0416；
Embodiment 46 (E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester preparation (I-9)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzene Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- toluenesulfonic acid -4- aldehyde radical Phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- toluenesulfonic acid -4- (2- cyanogen with embodiment 36 Base -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO- d6)δ8.46(s,1H),8.04-8.02(d,2H),7.95-7.92(m,2H),7.81-7.79(d,2H),7.56-7.54(m, 3H),7.51-7.49(d,2H),7.29-7.27(d,2H),2.43(s,3H)；13CNMR(100MHz,DMSO-d6):δ147.7, 146.7,146.0,144.9,144.6,134.0,130.6,129.8,129.1,128.3,128.2,125.9,124.5, 115.0,112.8,111.9,21.2；MS(ESI)(m/z):501.3(M-H+)；HRMS(MALDI)(m/z):Calcd for C25H19N4O4S2(M+H+):503.0842,Found:503.0831；
Embodiment 47 (E) -4- trifluoromethyl benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-10)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- trifluoromethyl benzene sulfonic acid -2- aldehyde radical phenyl ester, the original needed for remaining Material, reagent and preparation method obtain product (E) -4- trifluoromethyl benzene sulfonic acid -2- (2- cyano -3- oxo -3- with embodiment 36 ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ 8.15(s,1H),8.06-8.04(d,1H),7.99-7.9(m,2H),7.91-7.89(m,2H),7.84-7.83(d,1H), 7.79(m,1H),7.76-7.22(m,1H),7.61-7.58(t,1H),7.50-7.48(d,1H),7.25-7.23(t,1H)；13C NMR(100MHz,DMSO-d6):δ147.35,144.69,137.10,134.93,134.60,134.10,131.90,129.99, 129.63,129.46,129.30,128.57,128.51,127.20,125.76,124.23,121.54,115.06；MS(ESI) (m/z):563.6(M+H+)；HRMS(MALDI)(m/z):Calcd for C23H14F3N4O4S3(M+H+):563.0124, Found:563.0130；
Embodiment 48 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-11)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.15(s,1H), 8.06-8.04(d,1H),7.82-7.81(d,1H),7.76-7.74(m,3H),7.71-7.69(m,1H),7.59-7.56(m, 3H),7.45-7.43(d,1H),7.25-7.23(t,1H)；13C NMR(100MHz,DMSO-d6):δ147.42,144.45, 140.93,133.87,132.24,131.98,130.28,130.15,129.69,129.37,129.26,128.51,128.34, 125.99,124.17,115.34；MS(ESI)(m/z):529.3(M+H+)；HRMS(MALDI)(m/z):Calcd for C22H14ClN4O4S3(M+H+):528.9860,Found:528.9855；
Embodiment 49 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-12)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.17(s,1H), 8.05-8.03(d,1H),7.84-7.81(m,3H),7.78-7.77(d,1H),7.73-7.69(t,1H),7.60-7.59(t, 1H),7.44-7.42(d,1H),7.38-7.34(t,2H),7.25-7.23(t,1H)；13C NMR(100MHz,DMSO-d6):δ 167.23,164.68,147.46,144.61,133.90,132.17,131.81,131.70,129.76,129.45,129.22, 128.52,128.32,125.98,124.13,117.58,117.35,115.33；MS(ESI)(m/z):513.2(M+H+)； HRMS(MALDI)(m/z):Calcd for C22H14FN4O4S3(M+H+):513.0156,Found:513.0162；
Embodiment 50 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-13)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid -2- aldehyde radical phenyl ester, the original needed for remaining Material, reagent and preparation method obtain product (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- oxo -3- with embodiment 36 ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ 8.12(s,1H),8.02-8.00(d,1H),7.82-7.81(d,1H),7.78-7.77(d,1H),7.71-7.69(t,1H), 7.60-7.56(m,3H),7.46-7.44(d,1H),7.25-7.23(t,1H),6.98-6.96(d,2H),3.77(s,3H)；13C NMR(100MHz,DMSO-d6):δ164.54,147.71,144.56,133.81,132.23,130.72,129.69,129.39, 129.04,128.51,128.09,126.08,124.41,123.90,115.25,55.84；MS(ESI)(m/z):525.3(M+H+)；HRMS(MALDI)(m/z):Calcd for C23H17N4O5S3(M+H+):525.0356,Found:525.0372；
Embodiment 51 (E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1, 3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-14)
4- toluenesulfonic acid -2- aldehyde radical phenyl ester is changed into 4- trifluoromethoxy benzene sulfonic acid -2- aldehyde radical phenyl ester, needed for remaining Raw material, reagent and preparation method obtain product (E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxygen with embodiment 36 Generation -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz, DMSO-d6)δ8.18(s,1H),8.08-8.06(d,1H),7.92-7.90(d,2H),7.83-7.81(d,1H),7.77-7.70 (m,2H),7.60-7.57(t,1H),7.50-7.45(m,3H),7.25-7.23(m,1H)；13C NMR(100MHz,DMSO- d6):δ152.96,147.44,144.47,133.99,132.08,131.74,131.26,129.82,129.44,129.20, 128.53,128.40,125.84,124.14,121.53,120.91,118.33,115.25；MS(ESI)(m/z):579.3(M+ H+)；HRMS(MALDI)(m/z):Calcd for C23H14F3N4O5S3(M+H+):579.0073,Found:579.0073；
Embodiment 52 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) phenyl ester (I-15)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -2- aldehyde radical phenyl ester, raw material needed for remaining, Reagent and preparation method obtain product (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.32- 8.30(d,2H),8.06-8.04(m,4H),7.85-7.84(d,1H),7.79-7.78(d,1H),7.75-7.72(t,1H), 7.62-7.58(t,1H),7.51-7.49(d,1H),7.27-7.25(t,1H)；MS(ESI)(m/z):540.3(M+H+)；HRMS (MALDI)(m/z):Calcd for C22H14N5O6S3(M+H+):540.0101,Found:540.0112；
Embodiment 53 (E) -3,5- dimethyl -4- oxazole sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) - 1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-16)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3,5- dimethyl -4- oxazole sulfonic acid -2- aldehyde radical phenyl ester, remaining institute Raw material, reagent and the preparation method needed obtains product (E) -3,5- dimethyl -4- oxazole sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR (400MHz,DMSO-d6)δ8.13-8.09(m,2H),7.68-7.63(m,1H),7.63-7.60(m,2H),7.52-7.50(d, 1H),7.48-7.47(d,1H),7.15-7.11(w,1H),2.43(s,3H),2.00(s,3H)；MS(ESI)(m/z):514.3 (M+H+)；HRMS(MALDI)(m/z):Calcd for C21H16N5O5S3(M+H+):514.0308,Found:514.0319；
Embodiment 54 (E) -2- thiophene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-17)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- thiophene-sulfonic acid -2- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -2- thiophene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- bases) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.16-8.10(m, 2H),7.74-7.64(m,4H),7.38-7.36(d,1H),7.17-7.16(w,4H)；MS(ESI)(m/z):501.2(M+H+)； HRMS(MALDI)(m/z):Calcd for C20H13N4O4S4(M+H+):500.9814,Found:500.9821；
Embodiment 55 (E) -2- thiophenic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-18)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- thiophenic acid -3- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -2- thiophenic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.51(s,1H), 8.13-8.08(m,2H),7.98-7.92(m,2H),7.81-7.69(m,3H),7.60-7.58(m,1H),7.34-7.22(m, 2H)；13C NMR(100MHz,DMSO-d6):δ159.87,151.22,150.47,135.71,135.56,133.28,131.93, 131.39,130.63,129.80,129.55,128.83,128.48,128.16,126.32,123.36,115.98,108.42； MS(ESI)(m/z):463.0(M-H+)；HRMS(MALDI)(m/z):Calcd for C21H13N4O3S3(M+H+):465.0144, Found:465.0153；
Embodiment 56 (E)-acidum nicotinicum -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester (I-19)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into acidum nicotinicum -3- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E)-acidum nicotinicum -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.18(d,1H), 7.82(d,1H),7.81-7.74(m,3H),7.49-7.47(m,3H),7.41(t,1H),7.27(m,1H),7.24-7.21(m, 2H)；MS(ESI)(m/z):458.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C22H14N5O3S2(M+H+): 460.0533,Found:460.0536；
Embodiment 57 (E) -2- cyano -3- (3- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Allyl amide (I-20)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- nitrobenzaldehyde, the raw material, reagent and preparation side needed for remaining Method obtains product (E) -2- cyano -3- (3- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles-with embodiment 36 2- yl) allyl amide.1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.36-8.32(m,3H),7.85-7.81(t, 1H),7.59-7.58(d,1H),7.43-7.42(d,1H),7.14-7.12(m,2H)；13C NMR(100MHz,DMSO-d6):δ 169.09,164.84,153.65,148.11,145.10,136.11,135.51,134.63,130.62,127.98,126.83, 126.24,125.22,123.54,117.74,115.96；MS(ESI)(m/z):382.1(M-H+)；HRMS(MALDI)(m/z): Calcd for C16H10N5O3S2(M+H+):384.0219,Found:384.0223；
Embodiment 58 (E) -2- cyano -3- (4- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Allyl amide (I-21)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzaldehyde, the raw material, reagent and preparation side needed for remaining Method obtains product (E) -2- cyano -3- (4- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles-with embodiment 36 2- yl) allyl amide.1H NMR(400MHz,DMSO-d6)δ8.37-8.33(m,2H),8.20-8.18(m,2H),7.59(d, 1H),7.43(d,1H),7.13(m,2H)；13C NMR(100MHz,DMSO-d6):δ169.07,164.74,153.69, 148.10,144.98,139.37,135.52,130.71,127.98,126.83,126.24,124.04,117.60,117.21； MS(ESI)(m/z):382.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C16H10N5O3S2(M+H+):384.0219, Found:384.0231；
Embodiment 59 (E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-22)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into methanesulfonic acid -2- aldehyde radical phenyl ester, raw material, reagent needed for remaining and Preparation method with embodiment 36, obtain product (E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.04-8.02 (m, 1H), 7.95 (s, 1H), 7.83-7.82 (d, J=4.8Hz, 1H), 7.79-7.78 (m, 1H), 7.75-7.71 (t, J= 8Hz,1H),7.63(m,1H),7.22(t,1H)3.47(s,3H)；13C NMR(100MHz,DMSO-d6):δ151.07, 149.30,133.72,131.79,131.20,129.96,129.74,128.95,128.53,126.39,123.79,115.82, 37.61；MS(ESI)(m/z):431.0(M-H+)；HRMS(MALDI)(m/z):Calcd for C17H13N4O4S3(M+H+): 433.0094,Found:433.0091；
Embodiment 60 (E)-methanesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester (I-23)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into methanesulfonic acid -4- aldehyde radical phenyl ester, raw material, reagent needed for remaining and Preparation method with embodiment 36, obtain product (E)-methanesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.07-8.05 (m,1H),7.95(s,1H),7.83-7.82(m,1H),7.79-7.78(m,2H),7.75-7.71(m,2H),3.47(s,3H) ；13C NMR(100MHz,DMSO-d6):δ151.58,150.78,132.40,132.10,130.85,129.67,129.55, 129.42,128.40,123.34,123.13,121.80,116.11,108.21,37.86；MS(ESI)(m/z):431.0(M-H+)；HRMS(MALDI)(m/z):Calcd for C17H13N4O4S3(M+H+):433.0094,Found:433.0095；
Embodiment 61 (E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl Base) phenyl ester (II-3)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- first Base thiazol-2-yl) acetamide, 4- toluenesulfonic acid -2- aldehyde radical phenyl ester is changed into methanesulfonic acid -2- aldehyde radical phenyl ester, needed for remaining Raw material, reagent and preparation method obtain product (E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methyl with embodiment 36 Thiazol-2-yl) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),8.50(s,1H), 8.23-8.22(d,1H),7.69-7.67(t,1H),7.60-7.58(m,2H),7.24(s,1H),3.54(s,3H),2.31(s, 3H)；13C NMR(100MHz,DMSO-d6):δ147.73,144.40,133.59,129.26,127.83,126.65,124.33, 123.34,116.55,113.01,38.26,11.96；MS(ESI)(m/z):362.2(M-H+)；HRMS(MALDI)(m/z): Calcd for C15H14N3O4S2(M+H+):364.0420,Found:364.0422；
Embodiment 62 (E)-methanesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methyl-1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester (I-24)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- first Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into methanesulfonic acid -3- aldehyde radical phenyl ester, Remaining required raw material, reagent and preparation method obtain product (E)-methanesulfonic acid -3- (2- cyano -3- oxo -3- with embodiment 36 ((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.48(s, 1H),8.03-8.01(d,1H),7.96(s,1H),7.73-7.69(t,1H),7.60-7.58(m,1H),3.46(s,3H), 2.59(s,3H)；MS(ESI)(m/z):363.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C14H13N4O4S2(M+H+):365.0373,Found:365.0379。
Embodiment 63 (E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) - 1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-25)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluoroform Oxygroup benzene sulfonic acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- with embodiment 36 Trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.20(s,1H),8.09-8.01(d, 1H),7.93-7.91(d,2H),7.74-7.72(t,1H),7.65-7.60(m,2H),7.51-7.45(m,4H),7.25-7.21 (t,1H),7.18(s,1H),7.10-7.08(t,1H)；MS(ESI)(m/z):612.5(M+H+)；HRMS(MALDI)(m/z): Calcd for C27H17F3N5O5S2(M+H+):612.0618,Found:612.0620；
Embodiment 64 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) phenyl ester (I-26)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid-with embodiment 36 2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.20(s,1H),8.06-8.05(m,1H),7.84(m,1H),7.73 (m,1H),7.65-7.59(m,2H),7.45-7.37(m,3H),7.23-7.19(m,1H),7.08(m,1H),6.86(m,2H), 6.63(s,1H)；MS(ESI)(m/z):546.4(M+H+)；HRMS(MALDI)(m/z):Calcd for C26H17FN5O4S2(M+H+):546.0701,Found:546.0712；
Embodiment 65 (E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- Thiadiazoles -2- base) amino) -1- allyl) phenyl ester (I-27)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methylbenzene Sulfonic acid -3- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methylbenzene with embodiment 36 Sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) Phenyl ester.1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.44(s,1H),7.97-7.95(d,1H),7.79-7.76 (m,3H),7.63-7.59(m,2H),7.50-7.48(d,1H),7.45-7.43(d,1H),7.26-7.19(m,2H),7.14 (s,1H),7.14-7.06(t,1H),2.34(s,3H)；MS(ESI)(m/z):540.5(M-H+)；HRMS(MALDI)(m/z): Calcd for C27H20N5O4S2(M+H+):542.0951,Found:542.0965；
Embodiment 66 (E) -4- chlorobenzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-28)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -3- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -4- chlorobenzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.44(s,1H), 7.98-7.96(d,1H),7.92-7.90(m,2H),7.82-7.81(d,1H),7.77-7.75(m,4H),7.66-7.62(m, 1H),7.32-7.29(m,1H),7.24-7.21(m,1H)；MS(ESI)(m/z):527.1(M-H+)；HRMS(MALDI)(m/ z):Calcd for C22H14ClN4O4S3(M+H+):528.9860,Found:528.9850；
Embodiment 67 (E) -4- fluorobenzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-29)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -3- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -4- fluorobenzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H), 8.00-7.94(s,3H),7.83-7.79(m,2H),7.74(s,1H),7.66-7.62(m,1H),7.55-7.49(m,2H), 7.32-7.29(m,1H),7.24-7.22(m,1H)；MS(ESI)(m/z):511.2(M-H+)；HRMS(MALDI)(m/z): Calcd for C22H14FN4O4S3(M+H+):513.0156,Found:513.0140；
Embodiment 68 (E) -4- methoxy benzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-30)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid -3- aldehyde radical phenyl ester, the original needed for remaining Material, reagent and preparation method obtain product (E) -4- methoxy benzenesulfonic acid -3- (2- cyano -3- oxo -3- with embodiment 36 ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ 8.15 (s, 1H), 7.90-7.89 (d, J=4Hz, 1H), 7.81-7.79 (d, J=8Hz, 2H), 7.65 (s, 1H), 7.59 (m, 1H),7.55(m,1H),7.44(m,1H),7.18-7.16(m,3H),7.15-7.13(m,1H),3.86(s,3H)；MS(ESI) (m/z):523.3(M-H+)；HRMS(MALDI)(m/z):Calcd for C23H17N4O5S3(M+H+):525.0356,Found: 525.0348；
Embodiment 69 (E) -4- trifluoromethoxy benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1, 3,4- thiadiazoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-31)
4- toluenesulfonic acid -2- aldehyde radical phenyl ester is changed into 4- trifluoromethoxy benzene sulfonic acid -3- aldehyde radical phenyl ester, needed for remaining Raw material, reagent and preparation method obtain product (E) -4- trifluoromethoxy benzene sulfonic acid -3- (2- cyano -3- oxygen with embodiment 36 Generation -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz, DMSO-d6)δ8.43(s,1H),8.06-8.02(m,2H),7.97-7.95(m,1H),7.82-7.81(m,1H),7.76-7.75 (m,2H),7.67-7.65(m,3H),7.34-7.32(m,1H),7.23-7.21(m,1H)；MS(ESI)(m/z):577.2(M-H+)；HRMS(MALDI)(m/z):Calcd for C23H14F3N4O5S3(M+H+):579.0073,Found:579.0065；
Embodiment 70 (E) -4- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I-32)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester, raw material needed for remaining, Reagent and preparation method obtain product (E) -4- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.47- 8.45 (d, J=8Hz, 2H), 8.41 (s, 1H), 8.20-8.18 (d, J=8Hz, 2H), 7.97-7.95 (d, J=8Hz, 1H), 7.81-7.80(m,1H),7.75-7.72(m,2H),7.677.63(m,1H),7.37-7.35(m,1H),7.23-7.21(m, 1H)；MS(ESI)(m/z):540.3(M+H+)；HRMS(MALDI)(m/z):Calcd for C22H14N5O6S3(M+H+): 540.0101,Found:540.0106；
Embodiment 71 (E) -4- acetylamino benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-33)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- acetylamino benzene sulfonic acid -3- aldehyde radical phenyl ester, the original needed for remaining Material, reagent and preparation method obtain product (E) -4- acetylamino benzene sulfonic acid -3- (2- cyano -3- oxo -3- with embodiment 36 ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),8.36(s,1H),7.95-7.93(m,1H),7.83-7.80(m,3H),7.80-7.73(m,3H),7.69- 7.68(m,1H),7.59(m,1H),7.21-7.19(m,2H),2.09(s,3H)；MS(ESI)(m/z):550.3(M-H+)； HRMS(MALDI)(m/z):Calcd for C24H18N5O5S3(M+H+):552.0465,Found:552.0455；
Embodiment 72 (E) -2- thiophene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) and phenyl ester preparation (I-34)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- thiophene-sulfonic acid -3- aldehyde radical phenyl ester, raw material, examination needed for remaining Agent and preparation method obtain product (E) -2- thiophene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H), 8.25-8.23 (m, 1H), 8.00-7.98 (s, J=8Hz, 1H), 7.84-7.82 (m, 2H), 7.78-7.76 (m, 2H), 7.67- 7.63(m,1H),7.33-7.28(m,2H),7.24-7.22(m,1H)；MS(ESI)(m/z):499.1(M-H+)；HRMS (MALDI)(m/z):Calcd for C20H13N4O4S4(M+H+):500.9814,Found:500.9807；
Embodiment 73 (E) -3- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene Diazole -2- base) amino) -1- allyl) and phenyl ester preparation (I35)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- nitrobenzene-sulfonic acid -3- aldehyde radical phenyl ester, raw material needed for remaining, Reagent and preparation method obtain product (E) -3- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- allyl) phenyl ester.1H NMR(400MHz,DMSO-d6)δ8.67- 8.65 (d, J=8Hz, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.30-8.28 (d, J=8Hz, 1H), 7.99-7.95 (m, 2H), 7.80-7.79 (m, 1H), 7.73 (s, 1H), 7.67-7.63 (t, J=8Hz, 1H), 7.42-7.40 (m, 1H), 7.23- 7.21(m,1H),7.04(m,1H)；MS(ESI)(m/z):538.1(M-H+)；HRMS(MALDI)(m/z):Calcd for C22H14N5O6S3(M+H+)540.0100,Found:540.0084；
Embodiment 74 (E) -2- cyano -3- ((3- methanesulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide preparation (I-36)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- methanesulfonamido benzaldehyde, raw material, reagent needed for remaining and Preparation method obtains product (E) -2- cyano -3- ((3- methanesulfonamido) phenyl)-N- (5- (thiophene -2- with embodiment 36 Base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.39(s,1H), 7.82-7.81(d,1H),7.78-7.75(m,2H),7.72-7.67(m,2H),7.36-7.34(m,1H),2.92(s,3H)；MS (ESI)(m/z):430.2(M-H+)；HRMS(MALDI)(m/z):Calcd for C17H14N5O3S3(M+H+):432.0253, Found:432.0267；
Embodiment 75 (E) -2- cyano -3- ((3- tolysulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) acrylamide preparation (I-37)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- tolysulfonyl aminobenzaldehyde, raw material, examination needed for remaining Agent and preparation method obtain product (E) -2- cyano -3- ((3- tolysulfonyl amino) phenyl)-N- (5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.39(s, 1H),7.82-7.81(d,1H),7.78-7.75(m,2H),7.72-7.67(m,3H),7.47-7.43(t,1H),7.36-7.34 (d,2H),7.30-7.28(d,1H),7.24-7.21(t,1H),2.33(s,3H)；MS(ESI)(m/z):508.3(M+H+)； HRMS(MALDI)(m/z):Calcd for C23H18N5O3S3(M+H+):508.0566,Found:508.0574；
Embodiment 76 (E) -2- cyano -3- ((3- is to chlorobenzenesulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) acrylamide preparation (I38)
The raw material, examination for 4- toluenesulfonic acid -2- aldehyde radical phenyl ester being changed into 3- to chlorobenzenesulfonyl aminobenzaldehyde, needed for remaining Agent and preparation method obtain product (E) -2- cyano -3- ((3- is to chlorobenzenesulfonyl amino) phenyl)-N- (5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.82- 7.77(m,3H),7.76-7.74(m,2H),7.72-7.68(m,1H),7.65-7.61(m,3H),7.50-7.45(m,1H), 7.31-7.27(m,1H),7.24-7.21(t,1H)；MS(ESI)(m/z):526.2(M-H+)；HRMS(MALDI)(m/z): Calcd for C22H15ClN5O3S3(M+H+):528.0020,Found:528.0031
Embodiment 77 (E) -2- cyano -3- ((3- is to fluorobenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- Thiadiazoles -2- base) acrylamide preparation (I-39)
The raw material, examination for 4- toluenesulfonic acid -2- aldehyde radical phenyl ester being changed into 3- to fluorobenzene sulfonamido benzaldehyde, needed for remaining Agent and preparation method obtain product (E) -2- cyano -3- ((3- is to fluorobenzene sulfonamido) phenyl)-N- (5- (thiophene with embodiment 36 Pheno -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),7.89- 7.86(m,2H),7.82-7.81(d,1H),7.78-7.76(m,2H),7.71-7.69(d,1H),7.48(s,1H),7.43- 7.38(m,3H),7.31-7.29(d,1H),7.24-7.21(t,1H)；13C NMR(100MHz,DMSO-d6):δ165.70, 163.20,151.88,138.50,135.57,132.69,131.91,130.33,129.87,129.77,129.62,128.52, 127.95,127.55,126.11,124.19,121.26,116.74,116.52；MS(ESI)(m/z):510.3(M-H+)； HRMS(MALDI)(m/z):Calcd for C22H15FN5O3S3(M+H+):512.0315,Found:512.0324；
Embodiment 78 (E) -2- cyano -3- ((3- is to methoxybenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1, 3,4- thiadiazoles -2- base) acrylamide preparation (I-40)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester original of the 3- to methoxybenzene sulfonamido benzaldehyde, needed for remaining into Material, reagent and preparation method obtain product (E) -2- cyano -3- ((3- is to methoxybenzene sulfonamido) benzene with embodiment 36 Base)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.55 (s,1H),8.40(s,1H),7.82(d,1H),7.78-7.75(m,4H),7.71-7.69(t,1H),7.48-7.44(t,1H), 7.30-7.28(d,1H),7.24-7.18(m,1H),7.07-7.05(d,2H),3.79(s,3H)；13C NMR(100MHz, DMSO-d6):δ162.60,157.63,152.04,138.96,132.57,131.87,130.83,130.24,129.82, 129.65,129.10,128.99,128.53,128.37,125.54,123.73,120.94,114.50,55.63；MS(ESI) (m/z):522.3(M-H+)；HRMS(MALDI)(m/z):Calcd for C23H18N5O4S3(M+H+):524.0504,Found: 524.0515；
Embodiment 79 (E) -2- cyano -3- ((3- is to trifluoromethoxy benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- Base) -1,3,4- thiadiazoles -2- base) acrylamide preparation (I-41)
4- toluenesulfonic acid -2- aldehyde radical phenyl ester is changed into 3- to trifluoromethoxy benzenesulfonamido- benzaldehyde, needed for remaining Raw material, reagent and preparation method with embodiment 36, obtaining product (E) -2- cyano -3-, ((3- is to trifluoromethoxy benzene sulfonyl ammonia Base) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),8.26(s,1H),7.95-7.84(m,1H),7.72-7.67(m,2H),7.61(s,1H),7.57-7.53 (m,1H),7.46-7.42(m,2H),7.28-7.26(m,2H),7.19-7.17(m,1H),7.07(m,1H)；13C NMR (100MHz,DMSO-d6):δ151.20,149.53,138.21,133.33,130.22,129.89,129.09,128.42, 128.26,128.05,126.00,123.52,121.51,121.12,118.51,116.56；MS(ESI)(m/z):576.2(M- H+)；HRMS(MALDI)(m/z):Calcd for C23H15F3N5O4S3(M+H+):578.0232,Found:578.0235；
Embodiment 80 (E) -2- cyano -3- ((3- p-nitrophenyl sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) acrylamide preparation (I-42)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- p-nitrophenyl sulfonamido benzaldehyde, raw material needed for remaining, Reagent and preparation method obtain product (E) -2- cyano -3- ((3- p-nitrophenyl sulfonamido) phenyl)-N- with embodiment 36 (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.75(s,1H), 8.25(s,1H),7.95-7.89(m,2H),7.72-7.67(m,2H),7.60-7.53(m,3H),7.47-7.42(m,1H), 7.28-7.26(m,1H),7.19-7.18(m,1H),7.07(m,1H)；MS(ESI)(m/z):537.2(M-H+)；HRMS (MALDI)(m/z):Calcd for C22H15N6O5S3(M+H+):539.0260,Found:539.0267；
Embodiment 81 (E) -2- cyano -3- ((3- acetparaminosalol benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- base) - 1,3,4- thiadiazoles -2- base) acrylamide preparation (I-43)
4- toluenesulfonic acid -2- aldehyde radical phenyl ester is changed into 3- acetparaminosalol benzenesulfonamido- benzaldehyde, needed for remaining Raw material, reagent and preparation method obtain product (E) -2- cyano -3- ((3- acetparaminosalol benzenesulfonamido-) with embodiment 36 Phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.56 (s,1H),10.29(s,1H),8.39(s,1H),7.82-7.81(m,1H),7.78-7.76(m,2H),7.74-7.67(m, 4H),7.46-7.44(m,1H),7.29-7.28(m,1H),7.24-7.22(m,1H),2.02(s,3H)；MS(ESI)(m/z): 549.3(M-H+)；HRMS(MALDI)(m/z):Calcd for C24H19N6O4S3(M+H+):551.0624,Found: 551.0628；
Embodiment 82 (E) -2- cyano -3- ((3- (thiophene -2- sulfonyl) amino) phenyl)-N- (5- (thiophene -2- base) - 1,3,4- thiadiazoles -2- base) acrylamide preparation (I-44)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- (thiophene -2- sulfonyl) aminobenzaldehyde, the original needed for remaining Material, reagent and preparation method obtain product (E) -2- cyano -3- ((3- (thiophene -2- sulfonyl) amino) benzene with embodiment 36 Base)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.81 (s,1H),8.43(s,1H),7.93-7.91(m,1H),7.82-7.81(m,1H),7.78-7.74(m,1H),7.71-7.70 (d,1H),7.64-7.63(m,1H),7.51-7.49(m,1H),7.36-7.34(m,1H),7.24-7.18(m,2H),7.14- 7.12(m,1H)；MS(ESI)(m/z):498.2(M-H+)；HRMS(MALDI)(m/z):Calcd for C20H14N5O3S4(M+H+):499.9974,Found:499.9987；
Embodiment 83 (E) -2- cyano -3- ((3- m-nitro sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3, 4- thiadiazoles -2- base) acrylamide preparation (I-45)
Change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 3- m-nitro sulfonamido benzaldehyde, raw material needed for remaining, Reagent and preparation method obtain product (E) -2- cyano -3- ((3- m-nitro sulfonamido) phenyl)-N- with embodiment 36 (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acrylamide.1H NMR(400MHz,DMSO-d6)δ10.93(s,1H), 8.57(s,1H),8.47-8.45(m,2H),8.40(s,1H),8.18-8.16(m,1H),7.87-7.69(m,4H),7.53- 7.49(m,1H),7.35-7.33(m,1H),7.24-7.20(m,1H)；MS(ESI)(m/z):537.2(M-H+)；HRMS (MALDI)(m/z):Calcd for C22H15N6O5S3(M+H+):539.0260,Found:539.0271；
Embodiment 84 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-46)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining with embodiment 36, Obtain product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.02(s,1H),7.99-7.97(d,1H), 7.72-7.69(t,1H),7.56(s,1H),7.52(s,1H),7.45-7.43(d,1H),7.32-7.30(d,2H),7.22- 7.21(d,2H),6.96-6.94(d,2H),4.28(s,2H),3.76(s,3H),2.26(s,3H)；ESI-HRMS(m/z): 569.09([M+Na]+)；
Embodiment 85 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiophene two Azoles -2- base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-47)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxybenzene Sulfonic acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxyl group with embodiment 36 Benzene sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl Base) phenyl ester.1H NMR(600MHz,DMSO-d6):8.06(s,1H),8.00-7.99(d,1H),7.72-7.69(t,1H), 7.58-7.53(m,3H),7.44-7.43(d,1H),7.32-7.30(d,2H),6.96-6.91(m,4H),4.28(s,2H), 3.76(s,3H),3.71(s,3H)；ESI-HRMS(m/z):563.1([M+H]+),585.1([M+Na]+)；
Embodiment 86 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-48)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.26-8.25(m,2H),8.04-8.02(t,2H),7.99-7.98(d,2H), 7.72-7.71(t,1H),7.60-7.57(t,1H),7.49-7.47(d,1H),7.32-7.31(d,2H),6.97-6.94(m, 2H),4.29(s,2H),3.76(s,3H)；ESI-HRMS(m/z):578.1([M+H]+),600.1([M+Na]+)；
Embodiment 87 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-49)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.29(s,1H),8.07-8.06(m,1H),7.97-7.92(m,2H),7.87-7.85 (m,1H),7.80-7.78(m,1H),7.73-7.70(m,1H),7.62-7.59(t,1H),7.44-7.43(m,1H),7.32- 7.29(m,2H),6.96-6.93(m,2H),4.27(s,2H),3.74(s,3H)；ESI-HRMS(m/z):578.1([M+H]+), 600.1([M+Na]+)；
Embodiment 88 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-50)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.07(s,1H),8.04-8.02(m,1H),7.73-7.70(m,3H),7.58-7.56(t, 1H),7.53-7.52(d,2H),7.44-7.43(d,1H),7.32-7.30(m,2H),6.96-6.94(m,2H),4.27(s, 2H),3.76(s,3H)；ESI(m/z):567.2([M+H]+)；
Embodiment 89 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-51)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methoxy-benzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.11(s,1H),8.03-8.02(m,1H),7.82-7.79(m,2H),7.72-7.69(m, 1H),7.58-7.55(m,1H),7.43-7.41(d,1H),7.33-7.30(m,4H),6.96-6.94(m,2H),4.28(s, 2H),3.76(s,3H)；ESI(m/z):551.2([M+H]+)；
Embodiment 90 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-52)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining with embodiment 36, Obtain product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.16-8.14(d,1H),8.00-7.94(m, 4H),7.82-7.79(m,2H),7.62-7.50(m,6H),7.44-7.43(m,1H),7.15-7.14(d,2H),4.85(s, 2H),2.17(s,3H)；ESI(m/z):566.5([M+H]+),588.5([M+Na]+)；
Embodiment 91 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiophene two Azoles -2- base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-53)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxybenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxybenzene with embodiment 36 Sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.15-8.14(d,1H),8.02(s,1H),7.99-7.97(m,2H),7.94-7.93 (d,1H),7.71-7.68(m,1H),7.65-7.64(m,1H),7.62-7.52(m,6H),7.44-7.42(t,1H),6.88- 6.86(d,2H),4.84(s,2H),3.63(s,3H)；ESI(m/z):583.2([M+H]+)；
Embodiment 92 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-54)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.24-8.22(m,2H),8.15-8.14(d,1H),8.03-7.94(m,6H), 7.72-7.70(m,1H),7.65-7.64(m,1H),7.62-7.54(m,4H),7.47-7.46(m,1H),4.85(s,2H)； ESI(m/z):598.2([M+H]+)；
Embodiment 93 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-55)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.27(s,1H),8.14-8.13(d,1H),8.06-8.04(m,1H),8.00-7.98 (m,1H),7.95-7.83(m,4H),7.77-7.75(m,1H),7.72-7.69(m,1H),7.62-7.54(d,4H),7.43- 7.42(m,1H),4.83(s,2H)；ESI(m/z):598.1([M+H]+)；
Embodiment 94 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-56)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.15-8.13(d,1H),8.03-7.98(m,3H),7.95-7.93(m,1H),7.72-7.69 (m,3H),7.65-7.64(m,1H),7.62-7.54(m,4H),7.49-7.46(m,2H),7.44-7.42(d,1H),4.84 (s,2H)；ESI(m/z):587.1([M+H]+)；
Embodiment 95 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-57)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (naphthalene Base -1- methyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.15-8.14(d,1H),8.08(s,1H),8.01-7.99(m,2H),7.95-7.93(d, 1H),7.80-7.77(m,2H),7.71-7.68(m,1H),7.65-7.64(d,1H),7.62-7.59(m,1H),7.58-7.54 (m,3H),7.42-7.40(d,1H),7.30-7.26(m,2H),4.84(s,2H)；ESI(m/z):571.2([M+H]+)；
Embodiment 96 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester preparation (I-58)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, raw material, reagent and preparation method needed for remaining obtain product with embodiment 36 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl Base) phenyl ester.1H NMR(600MHz,DMSO-d6):8.03(s,1H),7.99-7.97(m,1H),7.72-7.69(t,1H), 7.56-7.52(m,3H),7.45-7.44(d,1H),7.40-7.37(d,4H),7.33-7.31(m,1H),7.21-7.20(d, 2H),4.37(s,2H),2.25(s,3H)；ESI-HRMS(m/z):517.1([M+H]+),539.1([M+Na]+)；
Embodiment 97 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester preparation (I-59)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- toluenesulfonic acid -2- (2- with embodiment 36 Cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz, DMSO-d6):8.06(s,1H),8.00-7.99(m,1H),7.72-7.69(t,1H),7.58-7.54(m,3H),7.45-7.43 (d,1H),7.40-7.37(d,4H),7.34-7.30(m,1H),6.93-6.91(m,2H),4.36(s,2H),3.71(s,3H)； ESI-HRMS(m/z):533.1([M+H]+),555.1([M+Na]+)；
Embodiment 98 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester preparation (I-60)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -2- aldehyde radical Phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene-sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz, DMSO-d6):8.27-8.25(t,2H),8.04-7.98(m,4H),7.74-7.71(m,1H),7.60-7.58(t,1H), 7.49-7.48(m,1H),7.40-7.39(t,4H),7.34-7.31(m,1H),4.37(s,2H)。ESI-HRMS(m/z): 548.06([M+H]+)
Embodiment 99 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester preparation (I-61)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene-sulfonic acid -2- aldehyde radical Phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene-sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz, DMSO-d6):8.30(s,1H),8.07-8.06(m,1H),7.98-7.96(t,1H),7.95-7.92(t,1H),7.86-7.85 (m,1H),7.80-7.78(m,1H),7.73-7.70(m,1H),7.62-7.59(t,1H),7.45-7.43(m,1H),7.41- 7.37(m,4H),7.34-7.30(m,1H),4.35(s,2H)。SI-HRMS(m/z):548.06([M+H]+)
Embodiment 100 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester preparation (I-62)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- aldehyde radical benzene Ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- cyano-with embodiment 36 3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO- d6):8.08(s,1H),8.04-8.02(m,1H),7.91-7.70(m,3H),7.59-7.55(m,1H),7.53-7.51(m, 2H),7.45-7.43(d,1H),7.41-7.22(m,5H),4.37(s,2H)；ESI(m/z):537.2([M+H]+)；
Embodiment 101 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester preparation (I-63)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- benzyl Base -1,3,4- thiadiazoles -2- base) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- aldehyde radical benzene Ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- cyano-with embodiment 36 3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO- d6):8.12(s,1H),8.03-8.02(m,1H),7.82-7.80(m,2H),7.72-7.69(m,1H),7.58-7.56(m, 1H),7.43-7.38(m,5H),7.34-7.30(m,3H),4.36(s,2H)；ESI(m/z):521.2([M+H]+)；
Embodiment 102 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-64)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining are obtained with embodiment 36 Product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.04(s,1H),7.99-7.98(m,1H),7.72-7.70 (t,1H),7.57-7.53(m,3H),7.46-7.43(m,3H),7.24-7.21(m,4H),4.37(s,2H),2.26(s,3H)； ESI(m/z):535.2([M+H]+)；
Embodiment 103 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-65)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxybenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.07(s,1H),8.01-7.99(m,1H),7.72-7.69(m,1H),7.62-7.54(m, 3H),7.45-7.43(m,3H),7.23-7.20(t,2H),6.93-6.92(m,2H),4.36(s,2H),3.72(s,3H)；ESI (m/z):551.2([M+H]+)；
Embodiment 104 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-66)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.32-8.31(d,2H),8.11-8.09(d,2H),8.03-8.01(t,1H),7.97(s,1H), 7.66-7.63(m,1H),7.57-7.54(t,1H),7.40-7.38(m,3H),7.20-7.17(t,2H),4.28(s,2H)； ESI(m/z):589.2([M+Na]+)；
Embodiment 105 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-67)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.31(s,1H),8.06-8.05(d,1H),8.00-7.93(m,2H),7.87-7.85(m,1H), 7.81-7.78(m,1H),7.73-7.68(m,1H),7.62-7.58(m,1H),7.45-7.41(m,3H),7.23-7.20(m, 2H),4.35(s,2H)；ESI(m/z):566.2([M+H]+)；
Embodiment 106 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-68)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.08(s,1H),8.04-8.02(m,1H),7.74-7.70(m,3H),7.59-7.56(m,1H), 7.54-7.52(m,2H),7.45-7.42(m,3H),7.24-7.21(m,2H),4.37(s,2H)。ESI(m/z):555.1([M+ H]+)；
Embodiment 107 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-69)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.12(s,1H),8.04-8.02(d,1H),7.82-7.80(m,2H),7.72-7.69(m,1H), 7.58-7.56(m,1H),7.45-7.42(m,3H),7.34-7.30(m,2H),7.24-7.21(m,2H),4.37(s,2H)； ESI(m/z):539.1([M+H]+)；
Embodiment 108 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-70)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining are obtained with embodiment 36 Product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.04(s,1H),7.99-7.98(d,1H),7.73-7.70 (t,1H),7.57-7.53(m,3H),7.46-7.42(m,2H),7.28-7.21(m,4H),7.17-7.14(m,1H),4.41 (s,2H),2.26(s,3H)；ESI(m/z):535.2([M+H]+)；
Embodiment 109 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-71)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxybenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.10(s,1H),8.02-8.01(d,1H),7.73-7.71(t,1H),7.60-7.55(m, 3H),7.46-7.43(m,2H),7.29-7.25(t,2H),7.17-7.15(m,1H),6.95-6.93(d,2H),4.42(s, 2H),3.74(s,3H)；ESI(m/z):551.2([M+H]+)；
Embodiment 110 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-72)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.26-8.25(d,2H),8.04-7.98(m,4H),7.74-7.72(t,1H),7.61-7.58(t, 1H),7.50-7.43(m,2H),7.27-7.24(t,2H),7.18-7.15(m,1H),4.41(s,2H)；ESI(m/z):588.4 ([M+Na]+)；
Embodiment 111 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-73)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.32(s,1H),8.08-8.07(d,1H),7.99-7.94(m,2H),7.87-7.86(t,1H), 7.82-7.79(m,1H),7.74-7.71(m,1H),7.63-7.60(t,1H),7.46-7.42(m,2H),7.27-7.24(m, 2H),7.17-7.14(m,1H),4.40(s,2H)；ESI(m/z):566.2([M+H]+)；
Embodiment 112 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-74)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.09(s,1H),8.04-8.03(d,1H),7.74-7.71(m,3H),7.59-7.56(t,1H), 7.54-7.52(m,2H),7.46-7.42(m,2H),7.27-7.24(m,2H),7.17-7.14(m,1H),4.40(s,2H)； ESI(m/z):555.0([M+H]+),577.1([M+Na]+)；
Embodiment 113 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-75)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (3- Luorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.13(s,1H),8.04-8.03(d,1H),7.84-7.81(m,2H),7.73-7.70(m,1H), 7.59-7.56(t,1H),7.46-7.43(m,2H),7.34-7.31(m,2H),7.28-7.24(m,2H),7.17-7.14(m, 1H),4.41(s,2H)；ESI(m/z):539.1([M+H]+),561.1([M+Na]+)；
Embodiment 114 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-76)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining are obtained with embodiment 36 Product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.04(s,1H),7.99-7.98(m,1H),7.72-7.70 (t,1H),7.57-7.53(m,3H),7.47-7.42(m,5H),7.22-7.21(d,2H),4.39(s,2H),2.26(s,3H)； ESI(m/z):551.1([M+H]+)；
Embodiment 115 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-77)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxy benzenesulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxybenzene sulphur with embodiment 36 Acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.07(s,1H),8.01-7.99(m,1H),7.72-7.70(t,1H),7.58-7.54(m, 3H),7.46-7.42(m,5H),6.93-6.92(d,2H),4.38(s,2H),3.72(s,3H)；ESI(m/z):567.1([M+ H]+),589.4([M+Na]+)；
Embodiment 116 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-78)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.26-8.24(m,2H),8.04-7.98(m,4H),7.74-7.71(m,1H),7.60-7.58(t, 1H),7.49-7.42(m,5H),4.38(s,2H)；ESI(m/z):582.1([M+H]+)；
Embodiment 117 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-79)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene-sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene-sulfonic acid -2- with embodiment 36 (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.31(s,1H),8.08-8.06(d,1H),7.99-7.93(m,2H),7.87-7.85(t,1H), 7.81-7.78(t,1H),7.73-7.71(t,1H),7.62-7.60(t,1H),7.46-7.41(m,5H),4.36(s,2H)； ESI(m/z):582.2([M+H]+)；
Embodiment 118 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-80)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.09(s,1H),8.04-8.02(m,1H),7.74-7.70(m,3H),7.59-7.52(m,3H), 7.46-7.41(m,5H),4.37(s,2H)；ESI(m/z):571.0([M+H]+)；
Embodiment 119 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) Amino) -3- oxo -1- allyl) phenyl ester preparation (I-81)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Chlorobenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- aldehyde Base phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- cyanogen with embodiment 36 Base -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.12(s,1H),8.03-8.02(m,1H),7.82-7.80(m,2H),7.72-7.69(m,1H), 7.58-7.56(t,1H),7.45-7.41(m,5H),7.33-7.31(m,2H),4.37(s,2H)；ESI(m/z):555.1([M+ H]+)；
Embodiment 120 (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-82)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, raw material, reagent and preparation method needed for remaining are obtained with embodiment 36 To product (E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.02(s,1H),7.99-7.97(d,1H),7.72- 7.70(t,1H),7.56-7.52(m,3H),7.45-7.44(d,1H),7.28-7.24(m,2H),7.22-7.14(m,4H), 4.31(s,2H),2.30(s,3H),2.26(s,3H)；ESI(m/z):531.2([M+H]+)；
Embodiment 121 (E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiophene two Azoles -2- base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-83)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- methoxybenzene sulphur Acid -2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- methoxybenzene with embodiment 36 Sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) benzene Ester.1H NMR(600MHz,DMSO-d6):8.00(s,1H),7.99(s,1H),7.71(s,1H),7.58-7.55(m,3H), 7.44-7.43(d,1H),7.28-7.25(t,2H),7.20-7.18(t,2H),6.92-6.91(d,2H),4.30(s,2H), 3.71(s,3H),2.30(s,3H)；ESI(m/z):547.2([M+H]+)；
Embodiment 122 (E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-84)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- nitrobenzene-sulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- nitrobenzene-sulfonic acid-with embodiment 36 2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.26-8.24(d,2H),8.04-8.02(d,2H),7.99-7.98(d,2H),7.74-7.71 (t,1H),7.60-7.58(t,1H),7.49-7.48(d,1H),7.28-7.27(d,2H),7.21-7.20(d,2H),4.31 (s,2H),2.31(s,3H)；ESI(m/z):561.2([M+H]+)；
Embodiment 123 (E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles - 2- yl) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-85)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 2- nitrobenzene-sulfonic acid - 2- aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -2- nitrobenzene-sulfonic acid-with embodiment 36 2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR(600MHz,DMSO-d6):8.29(s,1H),8.07-8.06(d,1H),7.98-7.93(m,2H),7.87-7.85(m, 1H),7.81-7.79(m,1H),7.73-7.70(m,1H),7.62-7.60(m,1H),7.44-7.43(d,1H),7.27-7.26 (d,2H),7.20-7.19(d,2H),4.29(s,2H),2.30(s,3H)；ESI(m/z):562.2([M+H]+)；
Embodiment 124 (E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-86)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- chlorobenzenesulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- chlorobenzenesulfonic acid -2- (2- with embodiment 36 Cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.07(s,1H),8.04-8.02(d,1H),7.75-7.74(d,2H),7.69-7.68(d,1H), 7.57-7.53(m,3H),7.42-7.40(d,1H),7.26-7.25(d,2H),7.19-7.18(d,2H),4.28(s,2H), 2.30(s,3H)；ESI(m/z):551.1([M+H]+)；
Embodiment 125 (E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- Base) amino) -3- oxo -1- allyl) and phenyl ester preparation (I-87)
Change 2- cyano-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) acetamide into 2- cyano-N- (5- (4- Methylbenzyl) -1,3,4- thiadiazoles -2- bases) acetamide, change 4- toluenesulfonic acid -2- aldehyde radical phenyl ester into 4- fluorobenzene sulfonic acid -2- Aldehyde radical phenyl ester, raw material, reagent and preparation method needed for remaining obtain product (E) -4- fluorobenzene sulfonic acid -2- (2- with embodiment 36 Cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl) phenyl ester.1H NMR (600MHz,DMSO-d6):8.11(s,1H),8.03-8.02(d,1H),7.82-7.79(m,2H),7.72-7.69(t,1H), 7.58-7.55(t,1H),7.43-7.41(d,1H),7.33-7.30(t,2H),7.27-7.25(t,2H),7.20-7.19(d, 2H),4.30(s,2H),2.30(s,3H)；ESI(m/z):535.2([M+H]+)；
Effect example 1 passes through the Reverse transcriptase constant K of fluorescence polarization molecule process detection compoundi
Synthesis one with 26 amino acid residues Bid BH3 polypeptide (amino acid 79-104: QEDIIRNIARHLAQVGDSMDRSIPPG), and in N-terminal mark upper 6- Fluoresceincarboxylic acid succinimide ester (FAM) as glimmering Optical label (FAM-Bid).By His-Bcl-XLAlbumen or His-Bcl-2 albumen or His-Mcl-1 albumen and small molecule to be measured It closes object to be dissolved in phosphate buffered saline solution, incubation 30 minutes is protected from light at 37 degree, FAM-Bid polypeptide is then added, 37 after mixing Degree is protected from light incubation 20 minutes.His-Bcl-XLAlbumen, His-Bcl-2 albumen, the end of His-Mcl-1 albumen and FAM-Bid polypeptide Concentration is respectively 230nM, 425nM, 200nM and 10nM.Final concentration of the compound in system is respectively 1nM, 10nM, 100nM, 1 μM, 10 μM, 50 μM and 100 μM.60 μ l are respectively taken to be added in 384 orifice plates (parallel three groups) the above reaction solution, immediately in enzyme mark The detection of fluorescence polarization is carried out on instrument.Fluorescence polarization value (mP) is surveyed under the 535nm launch wavelength generated by the excitation of 485nm wavelength Amount.Two control groups are set up simultaneously, and a control group is to contain only Bcl-X in reaction systemLOr Bcl-2 or Mcl-1 and FAM- Bid (is equivalent to 0% inhibiting rate), and another control group is to contain only FAM-Bid polypeptide in reaction system.According to control group and by The measurement result for surveying compound polarization value calculates albumen inhibiting rate.The logarithm mapping of compound concentration is found out with albumen inhibiting rate IC50Value.According to formula Ki=[I]50/([L]50/Kd+[P]0/Kd+ 1) Competitive assays that compound and albumen is calculated are derived Constant KiValue.In formula [I]50Compound concentration when for albumen inhibiting rate being 50%, [L]50When for albumen inhibiting rate being 50% Free FAM-Bid concentration, KdFor the dissociation constant of target protein and FAM-Bid polypeptide, [P]0When for albumen inhibiting rate being 0% Floating preteins concentration.
The Competitive assays constant of other compounds and three albumen, concrete outcome are detected according to above-mentioned identical experimental method As shown in table 1.
1 the compounds of this invention of table is to Bcl-XL, the Competitive assays constant K of Bcl-2 and Mcl-1 albumeni
Table 1 is the results show that all compounds at least show have micromole to sub-micromolar a kind of anti-apoptotic proteins Affinity.Wherein compound I-1, I-2, I-10~I-17, I-28~I-35, I-38~I-40, I-42 and I-45 are to three Anti-apoptotic proteins all have the affinity of micromole to sub-micromolar.Compound I-11~I-13, I-15~I-17, I-20 and I- 21 show to Bcl-XLThe selectivity of albumen, compound I8, I9, I22, I25-I27 are shown to Bcl-2 and Mcl-1 albumen Selectivity.These are the result shows that thiadiazoles amide and thiazole amide compound involved in the present invention being capable of efficient, selections Act on anti-apoptotic proteins Bcl-X to propertyL, Bcl-2 and Mcl-1.
Effect example 2 is using MTT experiment detection compound to the cytotoxicity of multiple cell lines
The people's acute lymphoblastic leukemia cell RS4 that will be detected；11 and people promyelocytic leukemia cell HL-60 is used RPMI1640 culture solution culture containing 10% fetal calf serum, human embryonic kidney cells 293T cell use the DMEM containing 10% fetal calf serum to train Nutrient solution culture.Cell, RS4 are planted in 96 well culture plates；The cell concentration of 11 and HL-60 is 2 × 104/ hole, 293T cell concentration For 5000 cells/wells；Zeroing group only adds culture medium.Be separately added into 96 orifice plates compound (setting five 40 μM of various concentration, 20 μM, 10 μM, 5 μM and 2.5 μM, parallel three groups under each concentration), then it is placed on CO2It is incubated for 48 hours in incubator.To every hole 10 μ LCCK-8 solution are added and are incubated for 1 hour, measure each hole absorbance value at 450nm wavelength using microplate reader.Calculate cell Survival rate=(experimental group absorbance value-zeroing group absorbance value)/(control group absorbance value-zeroing group absorbance value).With thin Born of the same parents' survival rate finds out IC to the mapping of compound concentration logarithm50Value.
2 the compounds of this invention of table is in RS4；Cytotoxicity test results in 11, HL-60 and 293T cell line
Table 2 the result shows that, majority of compounds of the invention shows as > 50 μM of IC to normal cell 293T50Value, substantially There is no lethality.Confirm that compound of the present invention being capable of specifically killing tumor cell.

Claims (16)

1. a kind of thiazole amide compound or its pharmaceutically acceptable salt shown in formula I, which is characterized in that
Wherein, X is CH or N；
R1For hydrogen, halogen, C1~C4Alkoxy, C1~C4Alkylthio group, C1~C6The C that linear chain or branched chain alkyl, hydroxyl, hydroxyl replace1 ~C6The C that linear chain or branched chain alkyl, halogen replace1~C4The C that alkyl, halogen replace1~C4The C that alkoxy, halogen replace1~C4 Alkylthio group, C3~C7Naphthenic base, C3~C7Cycloalkenyl, R1-1Substituted or unsubstituted phenyl ring, " in hetero atom N, O and S One or more, hetero atom number is 1~4,5~10 yuan of heteroaryl " or
R1-1It independently is halogen or C1~C4Alkoxy；
R1-2For R1-2-1Substituted or unsubstituted C6~C10Aryl；R1-2-1For C1~C4Alkyl, C1~C4Alkoxy or halogen；
R3For hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy,C1~C6 Linear chain or branched chain alkyl, C1~C4Alkoxy, C3~C7Naphthenic base, C3~C7Cycloalkenyl, C3~C7The C that naphthenic base replaces1~ C6Linear chain or branched chain alkyl or benzyl；
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
R5It independently is hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, C1~C4Alkoxy, C1~C4Alkylthio group, C1~C6 Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2It is substituted or unsubstituted " in hetero atom N, O and S One or more, hetero atom number is 1~4,5~6 yuan of heteroaryl "；
All R5-1And R5-2It independently is nitro, trifluoromethyl, trifluoromethoxy, acetylamino, C1~C4Alkyl, halogen, Or C1~C4Alkoxy.
2. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R1In Halogen is fluorine, chlorine, bromine or iodine；
And/or R1In C1~C4Alkoxy is methoxyl group；
And/or R1In C1~C6Linear chain or branched chain alkyl is C1~C4Straight-chain alkyl；
And/or as the R1For " the C that hydroxyl replaces1~C6When linear chain or branched chain alkyl ", the number of the hydroxyl is one It is a or multiple；
And/or as the R1For " the C that hydroxyl replaces1~C6When linear chain or branched chain alkyl ", " C that hydroxyl replaces1~ C6Linear chain or branched chain alkyl " is " C that hydroxyl replaces1~C4Straight-chain alkyl "；
And/or as the R1For " the C that halogen replaces1~C4When alkyl ", the number of " halogen " is one or more, When there are multiple halogens, they are identical or different；
And/or as the R1For " the C that halogen replaces1~C4When alkyl ", " halogen " independently is fluorine, chlorine or bromine；
And/or as the R1For " the C that halogen replaces1~C4When alkoxy ", the number of " halogen " is one or more A, when there are multiple halogens, they are identical or different；
And/or as the R1For " the C that halogen replaces1~C4When alkoxy ", " halogen " independently be fluorine, chlorine or Bromine；
And/or as the R1For " the C that halogen replaces1~C4When alkylthio group ", the number of " halogen " is one or more It is a；
And/or as the R1For " the C that halogen replaces1~C4When alkylthio group ", " halogen " independently be fluorine, chlorine or Bromine；
And/or as the R1For " R1-1When substituted or unsubstituted phenyl ring ", the R1-1Number be one or more, when There are multiple R1-1When, they are identical or different；
And/or as the R1For " R1-1When substituted or unsubstituted phenyl ring ", the R1-1To be independently in the phenyl ring WithThe ortho position of connection site, meta or para position；
And/or R1In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 yuan of heteroaryl Base " is " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~9 yuan of heteroaryl "；
And/or as the R1-1When for halogen, the halogen is fluorine, chlorine or bromine；
And/or as the R1-1For C1~C4When alkoxy, the C1~C4Alkoxy is methoxyl group；
And/or as the R1-2For R1-2-1Substituted or unsubstituted C6~C10When aryl, the R1-2-1Number be one Or it is multiple, when there are multiple R1-2-1When, they are identical or different；
And/or as the R1-2For R1-2-1Substituted or unsubstituted C6~C10When aryl, " the C6~C10Aryl " is benzene Base or naphthalene；
And/or as the R1-2-1For C1~C4When alkyl, the C1~C4Alkyl is methyl；
And/or as the R1-2-1For C1~C4When alkoxy, the C1~C4Alkoxy is methoxyl group；
And/or as the R1-2-1When for halogen, the halogen is fluorine, chlorine or bromine；
And/or R3In " C1~C6Linear chain or branched chain alkyl " is C1~C4Straight-chain alkyl；
And/or R3In " C1~C4Alkoxy " is methoxyl group；
And/or R3Ortho position, meta or para position in the phenyl ring and double bond connection site；
And/or R4In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~6 yuan of heteroaryl " For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan of heteroaryl "；
And/or R5In " C1~C4Alkoxy " is methoxyl group；
And/or R5In " C1~C6Linear chain or branched chain alkyl " is C1~C4Straight-chain alkyl；
And/or as the R5For " R5-1When substituted or unsubstituted phenyl ring ", the R5-1Number be one or more, when There are multiple R5-1When, they are identical or different；
And/or as the R5For " R5-1When substituted or unsubstituted phenyl ring ", the R5-1Be independently in the phenyl ring with The ortho position of sulfuryl connection site, meta or para position；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number It is 1~4,5~6 yuan of heteroaryl " when, the R5-2Number be one or more, when there are multiple R5-2When, their phases It is same or different；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number It is 1~4,5~6 yuan of heteroaryl " when, the R5-2Be independently in the heteroaryl and sulfuryl connection site ortho position, Meta or para position；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number When be 1~4,5~6 yuan of heteroaryl ", described " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4 A, 5~6 yuan of heteroaryl " is that " one of hetero atom N, O and S or a variety of, hetero atom number are 1~2,5~6 yuan miscellaneous Aryl "；
And/or as the R5-1When for halogen, the halogen is fluorine, chlorine or bromine；
And/or as the R5-1For C1~C4When alkoxy, the C1~C4Alkoxy is methoxyl group；
And/or as the R5-1For C1~C4When alkyl, the C1~C4Alkyl is methyl；
And/or as the R5-2When for halogen, the halogen is fluorine, chlorine or bromine；
And/or as the R5-2For C1~C4When alkoxy, the C1~C4Alkoxy is methoxyl group；
And/or as the R5-2For C1~C4When alkyl, the C1~C4Alkyl is methyl.
3. thiazole amide compound I as claimed in claim 2 or its pharmaceutically acceptable salt, which is characterized in that R1In C1~C6Linear chain or branched chain alkyl is methyl；
And/or as the R1For " the C that hydroxyl replaces1~C6When linear chain or branched chain alkyl ", the number of the hydroxyl is 1 It is a, 2 or 3；
And/or as the R1For " the C that halogen replaces1~C4When alkyl ", the number of " halogen " is 1,2,3 It is a, 4 or 5, when there are multiple halogens, they are identical or different；
And/or as the R1For " the C that halogen replaces1~C4When alkoxy ", the number of " halogen " is 1,2,3 It is a, 4 or 5, when there are multiple halogens, they are identical or different；
And/or as the R1For " the C that halogen replaces1~C4When alkylthio group ", the number of " halogen " is 1,2,3 It is a, 4 or 5；
And/or as the R1For " R1-1When substituted or unsubstituted phenyl ring ", the R1-1Number be 1,2,3,4 It is a or 5, when there are multiple R1-1When, they are identical or different；
And/or R1In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 yuan of heteroaryl Base " is thienyl or indyl；
And/or as the R1-2For R1-2-1Substituted or unsubstituted C6~C10When aryl, the R1-2-1Number be 1,2 A, 3,4 or 5, when there are multiple R1-2-1When, they are identical or different；
And/or as the R1-2When for phenyl, the R1-2-1It is independently in the neighbour of the phenyl Yu methyl connection site Position, meta or para position；
And/or R3In " C1~C6Linear chain or branched chain alkyl " is methyl；
And/or R4In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~6 yuan of heteroaryl " For thienyl or pyridyl group；
And/or R5In " C1~C6Linear chain or branched chain alkyl " is methyl；
And/or as the R5For " R5-1When substituted or unsubstituted phenyl ring ", the R5-1Number be 1,2,3,4 It is a or 5, when there are multiple R5-1When, they are identical or different；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number It is 1~4,5~6 yuan of heteroaryl " when, the R5-2Number be 1,2,3,4 or 5, when there are multiple R5 -2When, they are identical or different；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number When be 1~4,5~6 yuan of heteroaryl ", described " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4 It is a, 5~6 yuan of heteroaryl " it is thienyl or isoxazolyl.
4. thiazole amide compound I as claimed in claim 3 or its pharmaceutically acceptable salt, which is characterized in that work as institute The R stated1For " the C that hydroxyl replaces1~C6When linear chain or branched chain alkyl ", " C that hydroxyl replaces1~C4Straight-chain alkyl " is hydroxyl Methyl；
And/or as the R1For " the C that halogen replaces1~C4When alkyl ", " C that halogen replaces1~C4Alkyl " is three Methyl fluoride；
And/or as the R1For " the C that halogen replaces1~C4When alkoxy ", " C that halogen replaces1~C4Alkoxy " For trifluoromethoxy；
And/or as the R1For " R1-1When substituted or unsubstituted phenyl ring ", " R1-1Substituted phenyl ring " is 4- methoxy Base-phenyl, 2- methoxyl group-phenyl or the chloro- phenyl of 2-；
And/or work as R1In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 yuan of heteroaryl When base " is thienyl, the thienyl is thiophene -2- base；
And/or work as R1In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~10 yuan of heteroaryl When base " is indyl, the indyl is indoles -2- base；
And/or as the R1-2For R1-2-1Substituted or unsubstituted C6~C10When aryl, " the R1-2-1Substituted C6Virtue Base " is 4- methylphenyl, 4- methoxyl group-phenyl, 4- fluoro-phenyl, 3- fluoro-phenyl or the chloro- phenyl of 4-；
And/or work as R4In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~6 yuan of heteroaryl When base " is thienyl, the thienyl is thiophene -2- base；
And/or work as R4In " one of hetero atom N, O and S or a variety of, hetero atom number be 1~4,5~6 yuan of heteroaryl When base " is pyridyl group, the pyridyl group is pyridin-3-yl；
And/or as the R5For " R5-1When substituted or unsubstituted phenyl ring ", " R5-1Substituted phenyl ring " is 4- methyl- The chloro- phenyl of phenyl, 4-, 4- fluoro-phenyl, 4- methoxyl group-phenyl, 4- trifluoromethyl-phenyl, 4- trifluoromethoxy-phenyl, 4- nitre Base-phenyl, 3- nitro-phenyl, 2- nitro-phenyl or 4- Acetvlamino-phenvl；
And/or as the R5For " R5-2Substituted or unsubstituted hetero atom is one of N, O and S or a variety of, hetero atom number It is 1~4,5~6 yuan of heteroaryl " when, " the R5-2Substituted hetero atom is one of N, O and S or a variety of, miscellaneous original Subnumber is 1~4,5~6 yuan of heteroaryl " it is 3,5- dimethyl-isoxazole -4- base.
5. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R1For first Base, phenyl, 2- methoxyl group-phenyl, 4- methoxyl group-phenyl, the chloro- phenyl of 2-, 2- thienyl, 2- indyl, benzyl, 4- methoxyl group The fluoro- benzyl of benzyl, 4-, the fluoro- benzyl of 3-, the chloro- benzyl of 4- or naphthalene -1- methyl；
And/or R3For nitro, methylsulphur acidic group, 2- thiophene-sulfonic group, 3- pyridine-sulfonic group, 4- methyl-benzenesulfonic acid base, 4- methoxy Base-benzene sulfonic acid base, 4- trifluoromethyl-benzene sulfonic acid base, 4- trifluoromethoxy-benzene sulfonic acid base, the fluoro- benzene sulfonic acid base of 4-, the chloro- benzene sulphur of 4- Acidic group, 4- nitro-benzene sulfonic acid base, 3- nitro-benzene sulfonic acid base, 2- nitro-benzene sulfonic acid base, 4- acetylaminohydroxyphenylarsonic acid benzene sulfonic acid base, 3,5- Dimethyl -4- oxazole-benzene sulfonic acid base, methanesulfonamido, 4- methyl-benzenesulfonyl amino, the chloro- benzenesulfonamido- of 4-, the fluoro- benzene sulphur of 4- Acylamino-, 4- methoxy-benzenesulfonyl amino, 4- trifluoromethyl-benzene amino, 4- trifluoromethoxy-benzenesulfonamido-, 4- nitre Base-benzenesulfonamido-, 3- nitro-benzenesulfonamido-, 2- thiophene-benzenesulfonamido- or 4- acetylaminohydroxyphenylarsonic acid benzenesulfonamido-.
6. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R1For C1 ~C6Linear chain or branched chain alkyl, R1-1Substituted or unsubstituted phenyl ring, " one of hetero atom N, O and S or a variety of, hetero atom Number is 1~4,5~10 yuan of heteroaryl " or
And/or R3For nitro,
And/or R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
And/or R5It independently is C1~C6Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2Replace or not " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl " replaced.
7. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R3For nitre Base,
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
R5It independently is C1~C6Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2It is substituted or unsubstituted " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl ".
8. thiazole amide compound I as claimed in claim 6 or its pharmaceutically acceptable salt, which is characterized in that R1For C1 ~C6Linear chain or branched chain alkyl, R1-1Substituted or unsubstituted phenyl ring, " one of hetero atom N, O and S or a variety of, hetero atom Number is 1~4,5~10 yuan of heteroaryl " or
R3For nitro,
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
R5It independently is C1~C6Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2It is substituted or unsubstituted " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl ".
9. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that
Wherein, X is CH or N；
R1For hydrogen, halogen, C1~C4Alkoxy, C1~C4Alkylthio group, C1~C6The C that linear chain or branched chain alkyl, hydroxyl, hydroxyl replace1 ~C6The C that linear chain or branched chain alkyl, halogen replace1~C4The C that alkyl, halogen replace1~C4The C that alkoxy, halogen replace1~C4 Alkylthio group, C3~C7Naphthenic base, C3~C7Cycloalkenyl, R1-1Substituted or unsubstituted phenyl ring or " hetero atom N, O and S One of or it is a variety of, hetero atom number be 1~4,5~10 yuan of heteroaryl "；
R1-1It independently is halogen or C1~C4Alkoxy；
R3For hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy,C1~C6Directly Chain or branched hydrocarbyl, C3~C7Naphthenic base, C3~C7Cycloalkenyl, C3~C7The C that naphthenic base replaces1~C6Linear chain or branched chain hydrocarbon Base or benzyl；
R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
R5It independently is hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, C1~C4Alkoxy, C1~C4Alkylthio group, C1~C6 Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2It is substituted or unsubstituted " in hetero atom N, O and S One or more, hetero atom number is 1~4,5~6 yuan of heteroaryl "；
All R5-1And R5-2It independently is nitro, trifluoromethyl, trifluoromethoxy, acetylamino, halogen or C1~C4Alcoxyl Base.
10. thiazole amide compound I as claimed in claim 9 or its pharmaceutically acceptable salt, which is characterized in that R1For C1~C6Linear chain or branched chain alkyl, R1-1Substituted or unsubstituted phenyl ring or " one of hetero atom N, O and S or a variety of, it is miscellaneous Atomicity is 1~4,5~10 yuan of heteroaryl "；
And/or R3For 3- nitro, 4- nitro,
And/or R4For " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl "；
And/or R5For C1~C6Linear chain or branched chain alkyl, R5-1Substituted or unsubstituted phenyl ring or R5-2It is substituted or unsubstituted " one of hetero atom N, O and S or a variety of, hetero atom number are 1~4,5~6 yuan of heteroaryl ".
11. thiazole amide compound I as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that described Thiazole amide compound I be following any compound:
(E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- allyl Base) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (4- methoxyphenyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- chlorphenyl) -1,3,4- thiadiazoles -2- base) amino) - 1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- (2- methoxyphenyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo-((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- allyl Base) phenyl ester；
(E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -4- (2- cyano -3- oxo-((5- phenyl -1,3,4- thiadiazoles -2- base) amino) -1- allyl Base) phenyl ester；
(E) -4- trifluoromethyl benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester；
(E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -3,5- dimethyl -4- oxazole sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester；
(E) -2- thiophene-sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -2- thiophenic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E)-acidum nicotinicum -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -2- cyano -3- (3- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) allyl amide (I- 20)
(E) -2- cyano -3- (4- nitrobenzophenone)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) allyl amide；
(E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- Allyl) phenyl ester；
(E)-methanesulfonic acid -4- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) amino) -1- Allyl) phenyl ester；
(E)-methanesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methyl-1,3,4- thiadiazoles -2- base) amino) -1- allyl) Phenyl ester；
(E) -4- trifluoromethoxy benzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiophene two Azoles -2- base) amino) -1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (1H- indoles -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Amino) -1- allyl) phenyl ester；
(E) -4- trifluoromethoxy benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -4- acetylamino benzene sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) amino) -1- allyl) phenyl ester；
(E) -2- thiophene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -3- nitrobenzene-sulfonic acid -3- (2- cyano -3- oxo -3- ((5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) ammonia Base) -1- allyl) phenyl ester；
(E) -2- cyano -3- ((3- methanesulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) propylene Amide；
(E) -2- cyano -3- ((3- tolysulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Acrylamide；
(E) -2- cyano -3- ((3- is to chlorobenzenesulfonyl amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Acrylamide；
(E) -2- cyano -3- ((3- is to fluorobenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- base) Acrylamide；
(E) -2- cyano -3- ((3- is to methoxybenzene sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) acrylamide；
(E) -2- cyano -3- ((3- is to trifluoromethoxy benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide；
(E) -2- cyano -3- ((3- p-nitrophenyl sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) acrylamide；
(E) -2- cyano -3- ((3- acetparaminosalol benzenesulfonamido-) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiophene two Azoles -2- base) acrylamide；
(E) -2- cyano -3- ((3- (thiophene -2- sulfonyl) amino) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles - 2- yl) acrylamide；
(E) -2- cyano -3- ((3- m-nitro sulfonamido) phenyl)-N- (5- (thiophene -2- base) -1,3,4- thiadiazoles -2- Base) acrylamide；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) benzene Ester；
(E) -4- toluenesulfonic acid -3- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) benzene Ester；
(E)-methanesulfonic acid -2- (2- cyano -3- oxo -3- ((5- methylthiazol -2- base) amino) -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) ammonia Base) -3- oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methoxy-benzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (naphthalene -1- methyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- alkene Propyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- Allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- alkene Propyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- alkene Propyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5 benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl Base) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- benzyl -1,3,4- thiadiazoles -2- base) amino) -3- oxo -1- allyl Base) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- fluorophenyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (3- luorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- chlorobenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxo - 1- allyl) phenyl ester；
(E) -4- toluenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- methoxy benzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) - 3- oxo -1- allyl) phenyl ester；
(E) -4- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -2- nitrobenzene-sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- Oxo -1- allyl) phenyl ester；
(E) -4- chlorobenzenesulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester；With
(E) -4- fluorobenzene sulfonic acid -2- (2- cyano -3- ((5- (4- methylbenzyl) -1,3,4- thiadiazoles -2- base) amino) -3- oxygen Generation -1- allyl) phenyl ester.
12. the preparation method of the thiazole amide compound I as described in any one of claim 1~11, which is characterized in that its Include the following steps: that compound II, which is carried out Knoevenagel with compound III, to react, and obtains compound I；
13. a kind of such as Formula II or III compound represented, which is characterized in that
Wherein, R1And R3Definition as described in any one of claim 1~11.
14. compound II or III as claimed in claim 13, which is characterized in that the compound II is following anyization Close object:
And/or the compound III is following any compounds:
15. the thiazole amide compound I or its pharmaceutically acceptable salt as described in any one of claim 1~11 are making Application in standby drug or Bcl inhibitors of anti-apoptotic proteins, the drug is for treating and/or preventing and Bcl anti-apoptotic egg White relevant disease.
16. a kind of pharmaceutical composition comprising thiazole amide compound I as described in any one of claim 1~11 or Its pharmaceutically acceptable salt and pharmaceutic adjuvant.
CN201810463002.2A 2017-05-27 2018-05-15 Thiazole amide compound, preparation method thereof, pharmaceutical composition and application Active CN108947931B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2017103922673 2017-05-27
CN201710392267 2017-05-27

Publications (2)

Publication Number Publication Date
CN108947931A true CN108947931A (en) 2018-12-07
CN108947931B CN108947931B (en) 2023-07-07

Family

ID=64499151

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810463002.2A Active CN108947931B (en) 2017-05-27 2018-05-15 Thiazole amide compound, preparation method thereof, pharmaceutical composition and application

Country Status (1)

Country Link
CN (1) CN108947931B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021521235A (en) * 2018-04-17 2021-08-26 マサリコヴァ ユニヴェルジタ Substitution aminothiazole as an inhibitor of nuclease

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005072731A1 (en) * 2004-01-29 2005-08-11 X-Ceptor Therapeutics, Inc. 3-phenyl-n- ((1, 3, 4) thiadiazol-2-yl) -acrylamide derivatives and related compounds as modulators of estrogen-related receptors for the treatment of e.g. cancer, rheumatoid arthritis or neurological disorders
CN101096363A (en) * 2006-06-27 2008-01-02 中国人民解放军军事医学科学院毒物药物研究所 2,4,5-three-substituted thiazole compound, preparation method, medicament composition and pharmacy use thereof
CN101827832A (en) * 2007-10-08 2010-09-08 阿德维纳斯治疗私人有限公司 Acetamide derivatives as glucokinase activators, their process and medicinal applications
WO2013032907A1 (en) * 2011-08-26 2013-03-07 The Broad Institute, Inc. Compounds and methods for the treatment of cancer stem cells

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005072731A1 (en) * 2004-01-29 2005-08-11 X-Ceptor Therapeutics, Inc. 3-phenyl-n- ((1, 3, 4) thiadiazol-2-yl) -acrylamide derivatives and related compounds as modulators of estrogen-related receptors for the treatment of e.g. cancer, rheumatoid arthritis or neurological disorders
CN101096363A (en) * 2006-06-27 2008-01-02 中国人民解放军军事医学科学院毒物药物研究所 2,4,5-three-substituted thiazole compound, preparation method, medicament composition and pharmacy use thereof
CN101827832A (en) * 2007-10-08 2010-09-08 阿德维纳斯治疗私人有限公司 Acetamide derivatives as glucokinase activators, their process and medicinal applications
WO2013032907A1 (en) * 2011-08-26 2013-03-07 The Broad Institute, Inc. Compounds and methods for the treatment of cancer stem cells

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
COLUMBUS, OHIO, US REGISTRY[ONLINE]: "STN检索报告", 《STN REGISTRY》 *
EMILY M.CHEN ET AL.: "Synthesis and Antiproliferative Evaluation of 2"-Arenesulfonyloxy-5-benzylidene-thiazolidine-2,4-diones", 《J.HETEROCYCLIC CHEM》 *
GERD KAUPP ET AL.: "Versatile 2-aminothiazoles, building blocks for highly functionalised heterocycles", 《J.HETEROCYCLIC CHEM.》 *
STEPHEN L. GWALTNEY ET AL.: "Novel Sulfonate Derivatives: Potent Antimitotic Agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
刘志强 等: "雌激素受体与恶性肿瘤关系的研究进展", 《实验与检验医学》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021521235A (en) * 2018-04-17 2021-08-26 マサリコヴァ ユニヴェルジタ Substitution aminothiazole as an inhibitor of nuclease
JP7175031B2 (en) 2018-04-17 2022-11-18 マサリコヴァ ユニヴェルジタ Substituted aminothiazoles as inhibitors of nucleases

Also Published As

Publication number Publication date
CN108947931B (en) 2023-07-07

Similar Documents

Publication Publication Date Title
JP7293560B2 (en) Aromatic vinyl or aromatic ethyl derivative, its production method, intermediate, drug composition and use
CN103958500B (en) Kinases inhibitor
KR102081444B1 (en) Novel viral replication inhibitors
AU2013305475B2 (en) Perforin inhibiting benzenesulfonamide compounds, preparation and uses thereof
CA2631732C (en) Pyrrolotriazine derivatives useful for treating cancer through inhibition of aurora kinase
CN111138301A (en) Biphenyl compound, intermediate thereof, preparation method, pharmaceutical composition and application
CN105283443B (en) Hete rocyclic derivatives and application thereof
US10174047B2 (en) Thienodiazepine derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical composition including the same as an active ingredient
KR100963644B1 (en) Novel pyrazolopyrimidinone derivatives and preparation thereof
JP2009525350A (en) Pyrrolo [2,3, B] pyridine derivatives useful as RAF kinase inhibitors
BRPI0709680B1 (en) PIRROL, THIOPHENE AND FURAN DERIVATIVES REPLACED BY PYRIDIL AND PYRIDIMIL AS KINASE INHIBITORS
TW201504233A (en) Benzimidazolone derivatives as bromodomain inhibitors
TW200407112A (en) Immunity-related protein kinase inhibitors
TW201132640A (en) Substituted imidazopyridinyl-aminopyridine compounds
CA2940144C (en) Substituted indazol-3-yl derivatives and pharmaceutical compositions thereof useful as inhibitor of fascin
JP6630844B2 (en) 5-membered heterocyclic amide WNT pathway inhibitor
JP6612857B2 (en) Benzimidazole analogs and related methods
Ma et al. Discovery of potent inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl) phenoxy) pyridine analogue
Jin et al. 4-([1, 2, 4] Triazolo [1, 5-a] pyridin-6-yl)-5 (3)-(6-methylpyridin-2-yl) imidazole and-pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type I receptor kinase
US20130116243A1 (en) Inhibitors of akt activity
WO2021032004A9 (en) Azaheteroaryl compound and application thereof
CN108947931A (en) A kind of thiazole amide compound, preparation method, pharmaceutical composition and application
WO2022095904A1 (en) Pyrazolopyridazinone compound, and pharmaceutical composition and use thereof
CN106535894A (en) MCL-1 modulating compounds for cancer treatment
JP2020506172A (en) Compounds and their use in the treatment of schistosomiasis

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant