CN105175408B - Benzothiazole compound and its purposes as drug - Google Patents

Benzothiazole compound and its purposes as drug Download PDF

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CN105175408B
CN105175408B CN201410245448.XA CN201410245448A CN105175408B CN 105175408 B CN105175408 B CN 105175408B CN 201410245448 A CN201410245448 A CN 201410245448A CN 105175408 B CN105175408 B CN 105175408B
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benzothiazole
pyrroles
carbamyls
acid benzyl
benzyl esters
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CN105175408A (en
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盛春泉
袁正宏
朱仕平
张小楠
张万年
董国强
缪震元
姚建忠
刘娜
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SHANGHAI PUBLIC HEALTH CLINICAL CENTER
Second Military Medical University SMMU
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SHANGHAI PUBLIC HEALTH CLINICAL CENTER
Second Military Medical University SMMU
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Abstract

The present invention relates to pharmaceutical technology fields, and the present invention provides a kind of benzothiazole compounds, including its raceme, d types or l type isomers, shown in the general structure such as formula (I) of the compound.The compound of the present invention shows have good inhibiting effect to HCV through pharmacological evaluation, and acts on the non-structural protein NS5A target spots of HCV, has preferable external anti-HCV activity.The present invention also provides the preparation methods of above compound, and in the application for preparing HCV-Ab IgG inhibitor.

Description

Benzothiazole compound and its purposes as drug
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to benzothiazole class compound and preparation method thereof, and Purposes as drug.
Background technology
Hepatitis C Virus (Hepatitis C virus, HCV) infection seriously endangers human health, is post-transfusion hepatitis One of Etiological.Ribavirin and Peg-IFN alpha-2b combination therapy are clinically mainly used at present, but it can send out The genotype for waving effectiveness is limited, and effect is also bad, and easily causes drug resistance.There has been no safely and effectively vaccines so far can be pre- Anti- and thorough inhibition HCV, although the listing of Boceprevir, Telaprevir are considered as the new era for having started HCV therapy, But its price is very expensive, also cannot still cure HCV patient completely.
HCV belongs to Flavivirus, is a single-stranded positive RNA, there is 6 kinds of genotype and more than 50 kinds of hypotype.Viral gene overall length There are about 9600 nucleotide, are roughly divided into three 5 ' noncoding regions, open reading frame and 3 ' noncoding regions regions.It is non-positioned at 5 ' The internal ribosome entry site (internal ribosome entry site, IRES) of code area can start compilation facility, The gene for compiling open reading frame obtains the polyprotein of about 3000 amino acid composition.The albumen can be believed by host cell Number peptase and virus protease catalytic pyrolysis are 10 ripe amino acid peptide fragments.Wherein amino terminal is structural proteins, including Core protein, envelope protein E1 and E2, memebrane protein P7；Carboxyl terminal is non-structural protein, including NS2, NS3, NS4A, NS4B, NS5A and NS5B.
Wherein NS5A (Non-Structural5A protein) is a kind of non-structural protein (molecular weight of hyperphosphorylation For 58kDa), (AB036521.1) is formed by 447 amino acid, there are three different structural domains.Structural domain I (amino acid sequences： It 1-213) is made of highly conserved a both sexes ɑ-spiral and a hydrophobic side chain and the side chain of electrification, is NS5A and RNA In conjunction with important area.Its crystal structure (PDB code:A dimer 1ZH1) is held itself out to be, there are one include four and half Guangs The zinc calmodulin binding domain CaM of histidine residue (Cys39, Cys57, Cys59, Cys80), this region play important work to the stability of albumen With.Domain II (amino acid sequence：250-342) and Domain III (amino acid sequence：356-447) the also duplication to virus With assembling important role, but its specific crystal structure does not parse.Confirm there are many kinases to take part at present The Phosphorylation events of NS5A, and the phosphorylation level of NS5A also plays adjusting in the duplication of HCV genomes and translation process Effect.NS5A is the HCV-Ab IgG novel targets being concerned in recent years, and NS5A inhibitor has good patent medicine foreground (Zhu Bodyguard is flat, Zhang Wannian, Sheng Chunquan, anti hepatitis C virus drug action target and micromolecular inhibitor progress.Chinese drug The Chemicals, 2013:(23)312-320.).In addition, Chinese patent application CN200980155930.1, Publication No. CN102300461A, entitled " inhibitor of HCV NS5A " disclose it is a kind of for inhibit hepatitis C compound, The inhibitor of the HCV NS5A of pharmaceutical composition and combination treatment.
Invention content
The object of the present invention is to provide the compounds for finding a kind of efficient, low toxicity novel benzothiazoles HCV-Ab IgG NS5A； It is a further object of the present invention to provide the preparation methods of such benzothiazole compound；The third object of the present invention is to provide this The application of class benzothiazole compound.
The first aspect of the present invention, there is provided a kind of benzothiazole compounds, including its raceme, d- types or l- types Isomers, shown in the general structure such as formula (I) of the compound：
In formula (I)：
R1Indicate following groups：Hydrogen, benzyl, 3- hydrocinnamoyls, menaphthyl, 2- quinolylmethyls, benzyloxycarbonyl group；
R2Group indicates following groups：The pyrrolidines that pyridyl group, furyl, thienyl, indole methyl, benzyloxycarbonyl group are protected Base, methyl, ethyl, cyclopropane base, normal-butyl, benzyl, 2- naphthalenes, phenyl or substituted phenyl, substitution can be monosubstituted Can also be it is polysubstituted, substituent group have halogen, heterocycle or heterocyclic methyl, benzyloxycarbonyl group protection prolyl, low alkyl group, low Grade alkoxy, low-grade halogenated alkyl, nitro, cyano；
R3Group indicates following groups：Hydrogen or phenyl or substituted phenyl, it can also be take that substitution can be monosubstituted more Generation, substituent group have halogen, heterocycle or heterocyclic methyl, the prolyl of benzyloxycarbonyl group protection, low alkyl group, lower alkoxy, low Grade halogenated alkyl, nitro, cyano；
Y group indicates following groups：For sulfone, carbonyl, methylene；
Term " rudimentary " related with alkyl, halogenated alkyl and alkoxy refers to the straight chain containing 1 to 6 carbon atom herein Or branch saturated fat hydrocarbyl group；Naphthenic base refers to the ring containing 3 to 7 carbon；Aryl refers to mono-, di- or tricyclic hydrocarbon compound, wherein At least one ring is aromatic rings, and each ring contains most 7 carbon atoms.
The benzothiazole compound of the present invention, including its raceme, d- types or l- type isomers, and its can pharmaceutically connect The salt received, preferred compound are as follows：
2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- Nai Ji-formamido group)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzoylaminos)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- pyridylcarboxamides amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2,5- difluorobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (positive butyrylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (positive propionamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- furoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- chIorobenzoyIaminos)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- thenoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- indoles acetylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- bromobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- iodobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- methylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethylamino benzonitriles amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- methoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- nitrobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- cyano aminotoluenes base)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (cyclopropyl sulfonyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (methanesulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- chlorobenzenesulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- bromophenylsulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- iodobenzenes sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- cyano benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- biphenyl ylsulfonylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (N- benzenesulfonyls)-benzenesulfonamido-)]-benzothiazole -2- carbamyls }-pyrroles -1- acid benzyl esters,
2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (the fluoro- N- of 3- ((3- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (the fluoro- N- of 4- ((4- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (2- trifluoromethyls-N- ((2- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles -1- acid benzyl esters,
2- { [6- (3- trifluoromethyls-N- ((3- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles -1- acid benzyl esters,
2- { [6- (4- trifluoromethyls-N- ((4- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles -1- acid benzyl esters,
2- { [6- (the chloro- N- of 4- ((4- chlorphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (the bromo- N- of 4- ((4- bromophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters
2- { [6- (the iodo- N- of 4- ((4- iodophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (2- methyl-N- ((2- aminomethyl phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls Base }-pyrroles -1- acid benzyl esters,
2- { [6- (4- ethyls-N- ((4- ethylphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls Base }-pyrroles -1- acid benzyl esters,
2- { [6- (2- cyano-N- ((2- cyano-phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls Base }-pyrroles -1- acid benzyl esters,
2- { [6- (2- phenyl-N- ((2- xenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls } - Pyrroles -1- acid benzyl esters,
2- quinolyls-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiazole -2- Base } pyrrolidines -2- formamides,
1- how methyl-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiazole -2- Base } pyrrolidines -2- formamides, or
2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters.
The second aspect of the present invention, is to provide above-mentioned benzothiazole compound, including its raceme, d- types or l- types are different The preparation method of structure body.
The reaction process of the compound of the present invention is selected from the logical method one of reaction process or reaction process leads to method two：
Reaction process leads to method one：
Reaction process leads in method one：A.EDC.HCl, DMAP, THF, r.t., overnight, 92%；B.Fe, Hydrochloric acid, EtOH, 78 DEG C, 2h, 81.4%；c.R-COOH,EDC.HCl,DMAP,DCM,r.t., Overnight/R-COCl, DMAP, DCM, 0 DEG C-r.t., overnight, 36.11%-88.03%；d.RCHO,NaBH3CN, MeOH, r.t., overnight, 50.93%-95.07%；e.R-SO2Cl, pydine, r.t., overnight, 39.93%- 90.53%；f.R-SO2Cl, DMAP, r.t., overnight, 14.08%-92.03%.
Reaction step is as follows：
N- carbobenzyloxy-L-prolines (I) are dissolved in tetrahydrofuran (THF), and 1- ethyls-(3- dimethylaminos third are added Base) 30min is stirred at room temperature in phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl), add -6 nitrobenzene thiazole of 2- amino (II) With catalytic amount 4- lutidines (DMAP) and continue room temperature and be stirred to react, overnight, after reaction, solvent evaporated and dry method is mixed Sample, then column chromatography purify to obtain intermediate (III).
Intermediate (III) is dissolved in ethyl alcohol again, and iron powder is added, reaction solution is heated to 78 DEG C, then be added dropwise thereto Dilute hydrochloric acid maintains reflux state, and after 2h, the reaction was complete and is cooled to room temperature reaction solution, and solid residue is filtered through diatomite, It is evaporated ethyl alcohol, then is dissolved and is diluted with ethyl acetate, suitable quantity of water is added, then reconciles pH value of solution using saturated sodium bicarbonate solution It to neutrality, is again passed through diatomite and filters solid residue, take organic layer, after solvent evaporated, column chromatography purifies to obtain intermediate 2- [6- Aminobenzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters (IV).
Step 1：Carboxylic acid reagents and DEC.HCl are dissolved in dichloromethane, at room temperature stir-activating 30min, and 2- (6- are added Aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and catalytic amount DMAP, maintenance is stirred at room temperature and overnight.It steams After dry solvent, column chromatography purifies to obtain target product (Va)
Step 2：2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and catalytic amount DMAP ice baths Under be dissolved in dichloromethane, keep reaction solution to maintain 0-5 DEG C, acyl chloride reagent be then slowly added dropwise into solution, it is then anti- It answers liquid temperature to be gradually warmed to room temperature, is stirred overnight.Solvent evaporated again, column chromatography purify to obtain target product (Va)
By 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and benzaldehyde, substituted benzene first Aldehyde or other aromatic aldehyde reagents are dissolved in methanol, and 2 drop acetic acid catalysis are added, and are stirred to react 30min at room temperature, cyano is then added Sodium borohydride is stirred overnight.Subsequent solvent evaporated, column chromatography purify to obtain target product (Vb)
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) are dissolved in pyridine, by solution temperature Degree is down to 0 DEG C, then sulfonic acid chloride class reagent is slowly added into solution, and subsequent solution temperature is gradually warmed to room temperature, is stirred overnight.With The dilute hydrochloric acid washing solution of 1mol/L is simultaneously extracted with dichloromethane, then with saturated common salt water washing 2 times, is taken organic layer, is evaporated molten Agent, column chromatography target product (Vc)
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) are dissolved in dichloromethane, and are added Solution temperature is down to 0 DEG C by catalytic amount DMAP simultaneously, then benzene sulfonyl chloride class reagent, subsequent solution temperature are slowly added into solution It is gradually warmed to room temperature, is stirred overnight.Solvent evaporated, column chromatography purify to obtain target product (Vd)
Reaction process leads to method two：
Reaction process leads in method two：A.EDC.HCl, DMAP, THF, r.t., overnight, 80.16%；b.Fe, Hydrochloric acid, EtOH, 78 DEG C, 2h, 75.23%；c.R-SO2Cl, DMAP, r.t., overnight, 60.85%； d.CF3COOH, DCM, r.t., 2h, 81.32%；e.RCHO,NaBH3CN, MeOH, r.t., overnight, 59.43%；f.R- COOH, EDC.HCl, DMAP, DCM, r.t., overnight, 82.37%.
Reaction step is as follows：
According to the synthetic method of intermediate (III), N- benzyloxycarbonyl groups-are substituted with N- tertbutyloxycarbonyls-L-PROLINE (VI) L-PROLINE (I) reacts to obtain intermediate (VII)
According to the synthetic method of intermediate (IV), intermediate (III) is substituted with intermediate (VII), reacts to obtain intermediate (Vd20)。
Intermediate (Vd20) be dissolved in 2 volumes methylene chlorides, 1 volume trifluoroacetic acid is added thereto, is stirred at room temperature 2h.Solvent evaporated, column chromatography purify to obtain target product (Vd15)
The third aspect of the present invention, is to provide above-mentioned benzothiazole compound, including its raceme, d- types or l- types are different Structure body, the application in preparing hepatitis C virus inhibitors, especially HCV NS5A inhibitor.
The present invention also provides above-mentioned benzothiazole compounds, including its raceme, d- types or l- type isomers, are making Application in standby anti-HCV medicament (or treatment HCV infection drug).
The compound of the present invention is through anti-HCV activity Inhibition test, it was demonstrated that majority of compounds inhibits with preferable HCV-Ab IgG Activity.
The present invention is that further investigation and exploitation new construction type anti-HCV medicament open new approach.
Specific implementation mode
In conjunction with embodiment, the present invention is described in detail, but the implementation of the present invention is not limited only to this.Examination used of the invention Agent and raw material are commercially available or can be prepared by literature method.
In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to manufacturer Proposed condition.
Embodiment 1：The conjunction of 2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
Step 1：The synthesis of 2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (III)
N- carbobenzyloxy-L-prolines (9.58g, 38.4mmol) and EDC.HCl (7.37g, 38.4mmol) are dissolved in dichloro Juxtaposition stirs 30min at room temperature in methane, then be added into solution 2- amino-6-nitrobenzothiazoles (5.00g, 25.6mmol), it while adding catalytic amount DMAP (0.31g, 2.54mmol) and continuing room temperature and be stirred to react, overnight.Reaction terminates Afterwards, solvent evaporated and dry method mix sample, then column chromatography purifies (hexane:EtOAc=3:1) yellow solid 10.05g, yield, are obtained 92.03%.
1H NMRδ(300MHz,CDCl3):11.33 (brs, 1H), 8.71 (s, 1H), 8.29 (d, J=8.73Hz, 1H), 7.82 (d, J=8.94Hz, 1H), 7.30-7.48 (m, 4H), 7.00-7.16 (m, 1H), 5.17-5.32 (m, 2H), 4.60- 7.77(m,1H),3.43-3.67(m,2H),2.42-2.64(m,1H),2.03-2.05(m,3H).MS(ESI)m/z:427.28 (M+1).
Step 2：The synthesis of 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV)
2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (2.00g, 4.69mmol, M03) are dissolved in second In alcohol (50mL), and iron powder (1.15g, 0.0188mol) is added, reaction solution is heated to 78 DEG C, then dilute hydrochloric acid is added dropwise thereto (7.50mL, 1mol/L) maintains reflux state.After 2h, the reaction was complete and is cooled to room temperature reaction solution, is filtered through diatomite Solid residue is evaporated ethyl alcohol, then is dissolved and diluted with ethyl acetate, and suitable quantity of water is added, and then uses saturated sodium bicarbonate solution PH value of solution is reconciled to neutrality, diatomite is again passed through and filters solid residue, take organic layer, after solvent evaporated, column chromatography purifies (DCM:MeOH=100:1) faint yellow solid 1.52g, yield 81.72%.
1H NMRδ(300MHz,DMSO-d6):12.21(brs,1H),7.37-7.42(m,3H),7.1-7.19(m,1H), 6.99-7.12(m,3H),6.69-6.73(m,1H),5.14-5.26(m,2H),4.91-5.10(m,2H),4.44-4.53(m, 1H),3.42-3.55(m,2H),2.16-2.37(m,1H),1.82-1.97(m,3H).MS(ESI)m/z:397.27(M+1).
The synthesis of 2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
Step 3a：
Ethylene-acetic acid (28.23mg, 0.328mmol) and DEC.HCl (62.86mg, 0.328mmol) are dissolved in 20mL dichloros In methane, stir-activating 30min, is added 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid benzyl esters at room temperature (100mg, 0.252mmol, M04) and catalytic amount DMAP (3.08mg, 0.0252mmol), is stirred overnight at room temperature.After solvent evaporated, Column chromatography purifies (DCM:MeOH=100:1) faint yellow solid 90.1mg, yield 76.97%.
Step 3b：
It 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (100mg, 0.252mmol, M04) and urges It is dissolved in 20mL dichloromethane under change amount DMAP (3.08mg, 0.0252mmol) ice bath, reaction solution is kept to maintain 0-5 DEG C, then Cyclopropyl carbonyl chloride (31.64mg, 0.303mmol) is slowly added dropwise into solution, following reaction liquid temperature is gradually warmed to room temperature, and is stirred Overnight.Solvent evaporated again, column chromatography purify to obtain product (DCM:MeOH=100:1) faint yellow solid 82.0mg, yield, are obtained 69.97%.
1H NMRδ(600MHz,DMSO-d6):12.45-12.48(br,1H),10.33-10.34(br,1H),8.33 (dd,J1=1.62Hz, J2=6.00Hz, 1H), 7.67 (dd, J1=4.50Hz, J2=8.70Hz, 1H), 7.50-7.53 (m, 1H), 7.37 (d, J=4.38Hz, 2H), 7.16 (d, J=7.01Hz, 1H), 7.03-7.10 (m, 2H), 4.91-5.11 (m, 2H),4.49-4.55(m,1H),3.42-3.56(m,2H),2.21-2.32(m,1H),1.84-1.99(m,3H),1.78-1.83 (m,1H),0.78-0.82(m,4H).MS(ESI)m/z:465.26(M+1).
Embodiment 2：The conjunction of 2- [6- (1- Nai Ji-formamido group)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with 1- naphthoic acids, obtains 2- [6- (1- Nai Ji-formyl ammonia Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 85.8mg, yield 61.77%.
1H NMRδ(300MHz,DMSO-d6):12.53(brs,1H),10.75(brs,1H),8.59(m,1H),8.21- 8.23 (m, 1H), 8.08 (d, J=8.19Hz, 1H), 8.00-8.03 (m, 1H), 7.74-7.79 (m, 3H), 7.58-7.64 (m, 3H),7.37-7.38(m,2H),7.03-7.19(m,3H),4.90-5.13(m,2H),4.51-4.58(m,1H),3.52-3.54 (m,2H),2.25-2.34(m,1H),1.85-1.92(m,3H).MS(ESI)m/z:551.17(M+1).
Embodiment 3：The conjunction of 2- [6- (4- fluorobenzoylaminos)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3b of embodiment 2- [6- (4- fluorobenzene first is obtained to substitute Cyclopropyl carbonyl chloride to fluorobenzoyl chloride Acylamino-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 90.7mg, yield 69.34%.
1H NMRδ(300MHz,DMSO-d6):12.54(brs,1H),10.43(brs,1H),8.40-8.54(m,1H), 8.06 (t, J=6.03Hz, 2H), 7.68-7.83 (m, 2H), 7.35-7.40 (m, 5H), 7.04-7.18 (m, 3H), 4.90- 5.13(m,2H),4.50-4.56(m,1H),3.56-3.58(m,2H),2.27-2.29(m,1H),1.87-1.92(m,3H).MS (ESI)m/z:519.31(M+1).
Embodiment 4：2- [6- (3- pyridylcarboxamides amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with niacin, obtains 2- [6- (3- pyridylcarboxamides amino)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 70.0mg, yield 46.11%.
1H NMRδ(300MHz,DMSO-d6):12.56(brs,1H),10.63(brs,1H),9.13(s,1H),8.76 (d, J=4.71Hz, 1H), 8.48 (d, J=3.96Hz, 1H), 8.31 (dd, J1=1.74Hz, J2=7.92Hz, 1H), 7.66- 7.89(m,2H),7.55-7.60(m,1H),7.36-7.38(m,2H),7.01-7.17(m,3H),4.89-5.12(m,2H), 4.49-4.57(m,1H),3.51-3.53(m,2H),2.25-2.33(m,1H),1.84-1.98(m,3H).MS(ESI)m/z: 502.26(M+1)
Embodiment 5：2- [6- (2,5- difluorobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
By the method for 1 step 3b of embodiment, Cyclopropyl carbonyl chloride is substituted with 2,5- difluoro benzoyl chlorides, obtains 2- [6- (2,5- Difluorobenzoyl amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 102.8mg, yield 75.98%.
1H NMRδ(300MHz,DMSO-d6):12.48(brs,1H),10.71(brs,1H),8.41-8.50(m,1H), 7.67-7.74(m,2H),7.52-7.60(m,1H),7.40-7.51(m,2H),7.37-7.38(m,2H),7.04-7.18(m, 3H),4.89-5.10(m,2H),4.51-4.57(m,1H), 3.56-3.58(m,2H),2.27-2.30(m,1H),1.87- 1.91(m,3H).MS(ESI)m/z:537.41(M+1).
Embodiment 6：The synthesis of 2- [6- (positive butyrylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By the method for 1 step 3b of embodiment, Cyclopropyl carbonyl chloride is substituted with n-butyryl chloride, obtains 2- [6- (positive butyrylamino)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are greenish yellow solid 42.5mg, yield 36.11%.
1H NMRδ(300MHz,DMSO-d6):12.44-12.46(br,1H),10.01(brs,1H),8.34(s,1H), 7.66 (d, J=8.70Hz, 1H), 7.48-7.52 (m, 1H), 7.37-7.38 (m, 2H), 7.16 (d, J=6.39Hz, 1H), 7.02-7.10(m,2H),4.90-5.13(m,2H),4.49-4.56(m,2H),3.40-3.53(m,2H),2.15-2.33(m, 3H), 1.85-1.99 (m, 3H), 1.57-1.69 (m, 2H), 0.923 (t, J=7.35Hz, 3H) .MS (ESI) m/z:467.25(M +1).
Embodiment 7：The synthesis of 2- [6- (positive propionamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By the method for 1 step 3b of embodiment, Cyclopropyl carbonyl chloride is substituted with positive propionyl chloride, obtains 2- [6- (positive propionamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are white solid 86.2mg, yield 75.55%.
1H NMRδ(300MHz,DMSO-d6):11.96-12.13(br,1H),10.00(brs,1H),8.32(s,1H), 7.65(dd,J1=1.83Hz, J2=8.40Hz, 1H), 7.48-7.52 (m, 1H), 7.37-7.38 (m, 2H), 7.16 (d, J= 6.51Hz,1H),7.02-7.09(m,2H),4.90-5.13(m,2H),4.49-4.54(m,1H),3.46-3.57(m,2H), 2.30-2.38 (m, 2H), 2.14-2.26 (m, 2H), 1.87-1.97 (m, 3H), 1.097 (t, J=7.41Hz, 3H) .MS (ESI) m/z:453.32(M+1).
Embodiment 8：The conjunction of 2- [6- (2- furoyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with furancarboxylic acid, obtains 2- [6- (2- furoyls amino)-benzene And thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters, it is faint yellow solid 105.5mg, yield 85.29%.
1H NMRδ(300MHz,DMSO-d6):12.53(brs,1H),10.37(brs,1H),8.40(s,1H),7.93 (s,1H),7.71(s,1H),7.35-7.37(m,3H),7.03-7.16(m,3H),6.63-6.78(m,1H),4.88-5.12 (m,2H),4.48-4.54(m,1H),3.58-3.77(m,2H),2.25-2.29(m,1H),1.76-2.03(m,3H).MS (ESI)m/z:491.22(M+1).
Embodiment 9：The conjunction of 2- [6- (4- chIorobenzoyIaminos)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3b of embodiment, Cyclopropyl carbonyl chloride is substituted with parachlorobenzoyl chloride, obtains 2- [6- (4- chlorobenzene first Acylamino-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 87.8mg, yield 65.04%.
1H NMRδ(300MHz,DMSO-d6):12.55 (brs, 1H), 10.49 (brs, 1H), 8.46 (d, J=3.84Hz, 1H),8.00(dd,J1=1.8Hz, J2=8.49Hz, 2H), 7.72 (s, 2H), 7.61 (d, J=8.31Hz, 2H), 7.37 (d, J =4.29Hz, 2H), 7.01-7.17 (m, 3H), 4.89-5.12 (m, 2H), 4.48-4.56 (m, 1H), 3.47-3.53 (m, 2H), 2.24-2.33(m,1H),1.84-2.00(m,3H).MS(ESI)m/z:535.26(M+1).
Embodiment 10：The conjunction of 2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with N- carbobenzyloxy-L-prolines, obtains 2- [6- (rings Propyl formamido group)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 92.5mg, yield 58.36%.
1H NMRδ(300MHz,DMSO-d6):12.45 (brs, 1H), 10.25 (brs, 1H), 8.31 (d, J= 22.39Hz, 1H), 7.68 (d, J=8.43Hz, 1H), 7.46-7.59 (m, 1H), 7.27-7.45 (m, 5H), 7.05-7.21 (m, 5H),4.88-5.07(m,4H),4.44-4.62(m,1H),4.28-4.44(m,1H),3.48-3.77(m,4H),2.11-2.40 (m,2H),1.78-2.11(m,6H).MS(ESI)m/z:628.29(M+1).
Embodiment 11：The conjunction of 2- [6- (2- thenoyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with thiophene-2-carboxylic acid, obtains 2- [6- (2- thenoyls Amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are light grey solid 112.5mg, yield 88.03%.
1H NMRδ(300MHz,DMSO-d6):12.55(brs,1H),10.40(brs,1H),8.31-8.47(m,1H), 7.96-8.14 (m, 1H) .7.86 (d, J=4.92Hz, 1H), 7.72-7.75 (m, 2H), 7.37-7.38 (m, 2H), 7.23 (t, J =4.71Hz, 1H), 7.01-7.17 (m, 3H), 4.89-5.10 (m, 2H), 4.49-4.55 (m, 1H), 3.48-3.53 (m, 2H), 2.26-2.33(m,1H),1.87-1.91(m,3H).MS(ESI)m/z:507.21(M+1).
Embodiment 12：The synthesis of 2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with benzoic acid, obtains 2- [6- (benzamido)-benzo Thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 71.3mg, yield 60.08%.
1H NMRδ(300MHz,DMSO-d6):12.55(brs,1H),10.44(brs,1H), 8.47-8.49(m,1H), 7.97(dd,J1=1.38Hz, J2=6.27Hz, 2H), 7.66-7.82 (m, 2H), 7.51-7.59 (m, 3H), 7.36-7.38 (m, 2H),7.01-7.18(m,2H),4.89-5.13(m,2H),4.49-4.57(m,1H),3.49-3.60(m,2H),2.24-2.33 (m,1H),1.82-2.00(m,3H).MS(ESI)m/z:501.28(M+1).
Embodiment 13：The conjunction of 2- [6- (3- indoles acetylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for 1 step 3a of embodiment, ethylene-acetic acid is substituted with 3-indolyl acetic acid hydrochloride, obtains 2- [6- (3- indoles Acetylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 121.5mg, yield 87.03%.
1H NMRδ(300MHz,DMSO-d6):12.45(brs,1H),10.90(brs,1H),10.24(brs,1H), 8.34(s,1H),7.63-7.69(m,2H),7.53-7.57(m,1H),7.28-7.37(m,5H),7.14-7.17(m,1H), 6.99-7.07(m,3H),4.89-5.10(m,2H),4.50-4.55(m,1H),3.77(s,2H),3.45-3.53(m,2H), 2.23-2.34(m,1H),1.83-1.93(m,3H).MS(ESI)m/z:554.30(M+1).
Embodiment 14：The synthesis of 2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By the method for 1 step 3b of embodiment, Cyclopropyl carbonyl chloride is substituted with phenyllacetyl chloride, obtains 2- [6- (benzamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 94.0mg, yield 72.42%.
1H NMRδ(300MHz,DMSO-d6):12.45-12.48(br,1H),10.32(brs,1H),8.32(s,1H), 7.67 (d, J=8.13Hz, 1H), 7.50-7.54 (m, 1H), 7.30-7.36 (m, 7H), 7.25 (d, J=6.42Hz, 1H), 7.16 (d, J=6.75Hz, 1H), 7.03-7.09 (m, 2H), 4.89-5.15 (m, 2H), 4.48-4.60 (m, 1H), 3.66 (s, 2H),3.45-3.53(m,2H),2.26-2.28(m,1H),1.86-1.91(m,3H).MS(ESI)m/z:515.21(M+1).
Embodiment 15：The synthesis of 2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (100mg, 0.252mmol) and benzene first Aldehyde (26.77mg, 0.252mmol) is dissolved in 20mL methanol, and 2 drop acetic acid catalysis are added, and is stirred to react 30min at room temperature, then Sodium cyanoborohydride (31.7mg, 0.504mmol) is added, is stirred overnight.Subsequent solvent evaporated, column chromatography purify (DCM: MeOH=100:1) 2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are obtained, are light grey solid 70.5mg, yield 57.46%.
1H NMRδ(600MHz,DMSO-d6):12.13-12.26(br,1H),7.43(dd,J1=3.60Hz, J2= 8.76Hz, 1H), 7.36-7.39 (m, 4H), 7.30-7.33 (m, 2H), 7.21-7.23 (m, 1H), 7.16 (d, J=7.20Hz, 1H),7.04-7.11(m,2H),7.00-7.03(m,1H),6.77-6.80(m,1H),6.35-6.38(br,1H),4.91- 5.10(m,2H),4.44-4.51(m,1H),4.29-4.31(m,2H), 3.40-3.52(m,2H),2.18-2.30(m,1H), 1.80-1.96(m,3H).MS(ESI)m/z:487.28(M+1)
Embodiment 16：The synthesis of 2- [6- (2- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
As described in Example 15, benzaldehyde is substituted with 2- fluorobenzaldehydes, obtains 2- [6- (2- fluorobenzene methylamino)-benzo thiophenes Azoles -2- carbamyls]-pyrroles's -1- acid benzyl esters are light grey solid 70.5mg, yield 57.46%.
1H NMRδ(300MHz,DMSO-d6):12.23 (brs, 1H), 7.44-7.47 (m, 2H), 7.36 (d, J= 4.41Hz,2H),7.29-7.31(m,1H),7.05-7.17(m,6H),6.80-6.82(m,1H),6.31(brs,1H),4.89- 5.07(m,2H),4.49-4.50(m,1H),4.25(s,2H),3.49-3.51(m,2H),2.20-2.24(m,1H),1.88- 1.90(m,3H).MS(ESI)m/z:505.36(M+1)
Embodiment 17：The synthesis of 2- [6- (3- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
As described in Example 15, benzaldehyde is substituted with 3- fluorobenzaldehydes, obtains 2- [6- (3- fluorobenzene methylamino)-benzo thiophenes Azoles -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 83.3mg, yield 65.44%.
1H NMRδ(600MHz,DMSO-d6):12.20(brs,1H),7.46(dd,J1=3.90Hz, J2=8.58Hz, 1H),7.35-7.38(m,3H),7.23-7.25(m,1H),7.17-7.21(m,2H),7.02-7.11(m,4H),6.78-6.81 (m,1H),6.42-6.43(br,1H),4.92-5.11(m,2H),4.46-4.52(m,1H),4.35(s,2H),3.42-3.56 (m,2H),2.17-2.31(m,1H),1.83-1.97(m,3H).MS(ESI)m/z:505.10(M+1).
Embodiment 18：The synthesis of 2- [6- (4- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
As described in Example 15, benzaldehyde is substituted with 4- fluorobenzaldehydes, obtains 2- [6- (4- fluorobenzene methylamino)-benzo thiophenes Azoles -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 83.3mg, yield 65.44%.
1H NMRδ(600MHz,DMSO-d6):12.13-12.25 (br, 1H), 7.40-7.45 (m, 3H), 7.37 (d, J= 4.44Hz, 2H), 7.09-7.17 (m, 4H), 7.05 (t, J=7.50Hz, 1H), 7.02 (dd, J1=2.22Hz, J2= 16.00Hz,1H),6.77-6.79(m,1H),6.33-6.36(br,1H),4.91-5.10(m,2H),4.45-4.51(m,1H), 4.28 (t, J=5.16Hz, 1H), 3.41-3.54 (m, 2H), 2.18-2.29 (m, 1H), 1.80-1.95 (m, 3H) .MS (ESI) m/z:505.28(M+1)
Embodiment 19：2- [6- (2- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
As described in Example 15, benzaldehyde is substituted with 2- trifluoromethylated benzaldehydes, obtains 2- [6- (2- trifluoromethylbenzene first Amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 132.8mg, yield 94.92%.
1H NMRδ(300MHz,DMSO-d6):12.22 (brs, 1H), 7.74 (d, J=7.80Hz, 1H), 7.61-7.62 (m, 2H), 7.46 (d, J=8.58Hz, 2H), 7.35-7.37 (m, 2H), 7.16 (d, J=6.81 Hz, 1H), 7.05-7.10 (m, 2H), 6.97 (d, J=8.70Hz, 1H), 6.74 (d, J=8.46Hz, 1H), 6.50 (brs, 1H), 4.89-5.07 (m, 2H),4.39-4.57(m,3H),3.48-3.50(m,2H),2.24-2.26(m,1H),1.84-1.95(m,3H).MS(ESI)m/ z:555.29(M+1).
Embodiment 20：2- [6- (3- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
As described in Example 15, benzaldehyde is substituted with 3- trifluoromethylated benzaldehydes, obtains 2- [6- (3- trifluoromethylbenzene first Amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 129.9mg, yield 92.85%.
1H NMRδ(300MHz,DMSO-d6):12.21(brs,1H),7.68-7.73(m,2H),7.54-7.62(m, 2H), 7.45 (d, J=8.19Hz, 1H), 7.36-7.37 (m, 2H), 7.14-7.16 (m, 1H), 7.03-7.05 (m, 3H), 6.79 (d, J=7.62Hz, 1H), 6.49 (brs, 1H), 4.88-5.07 (m, 2H), 4.41-4.47 (m, 3H), 3.46-3.48 (m, 2H),2.23-2.26(m,1H),1.89-1.97(m,3H).MS(ESI)m/z:555.49(M+1).
Embodiment 21：2- [6- (4- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
As described in Example 15, benzaldehyde is substituted with 4- trifluoromethylated benzaldehydes, obtains 2- [6- (4- trifluoromethylbenzene first Amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 71.2mg, yield 50.93%.
1H NMRδ(300MHz,DMSO-d6):12.22 (brs, 1H), 7.58-7.69 (m, 4H), 7.45 (d, J= 8.31Hz, 1H), 7.29-7.40 (m, 2H), 7.16 (d, J=6.06Hz, 1H), 7.01-7.06 (m, 3H), 6.78 (d, J= 8.70Hz,1H),6.52(brs,1H),4.89-5.11(m,2H),4.42-4.48(m,3H),3.44-3.51(m,2H),2.23- 2.25(m,1H),1.88-1.90(m,3H).MS(ESI)m/z:555.11(M+1).
Embodiment 22：The synthesis of 2- [6- (2- bromobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
As described in Example 15, benzaldehyde is substituted with 2- bromobenzaldehydes, obtains 2- [6- (2- bromobenzenes methylamino)-benzo thiophenes Azoles -2- carbamyls]-pyrroles's -1- acid benzyl esters are white solid 76.0mg, yield 53.30%.
1H NMRδ(300MHz,DMSO-d6):12.22 (brs, 1H), 7.62 (d, J=7.83Hz, 1H), 6.98-7.48 (m,10H),6.68-6.79(m,1H),6.42(brs,1H),4.82-5.12(m,2H),4.40-4.52(m,1H),4.33(s, 2H),3.46-3.51(m,2H),2.21-2.26(m,1H),1.82-1.91(m,3H).MS(ESI)m/z:567.03(M+1).
Embodiment 23：The synthesis of 2- [6- (4- iodobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
As described in Example 15, benzaldehyde is substituted with 4- benzaldehyde iodines, obtains 2- [6- (4- iodobenzenes methylamino)-benzo thiophenes Azoles -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 141.2mg, yield 91.39%.
1H NMRδ(300MHz,DMSO-d6):12.21 (brs, 1H), 7.66 (d, J=5.82Hz, 2H), 7.44 (d, J= 8.04Hz, 1H), 7.32-7.36 (m, 2H), 7.18-7.20 (m, 3H), 6.98-7.07 (m, 3H), 6.77 (d, J=6.51Hz, 1H),6.41(brs,1H),4.89-5.07(m,2H),4.39-4.60(m,1H),4.26(s,2H),3.43-3.65(m,2H), 2.12-2.36(m,1H),1.90-1.98(m,3H).MS(ESI)m/z:613.14(M+1).
Embodiment 24：The conjunction of 2- [6- (2- methylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
As described in Example 15, benzaldehyde is substituted with 2- tolyl aldehydes, obtains 2- [6- (2- methylbenzenes methylamino)-benzene And thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters, it is faint yellow solid 106.2mg, yield 84.09%.
1H NMRδ(300MHz,DMSO-d6):12.20 (brs, 1H), 7.45 (d, J=8.61Hz, 1H), 7.29-7.37 (m, 3H), 7.02-7.16 (m, 7H), 6.82 (d, J=8.43Hz, 1H), 6.16 (brs, 1H), 4.90-5.12 (m, 2H), 4.46-4.51(m,1H),4.24(s,1H),3.44-3.51(m,2H),2.33(s,3H),2.24-2.26(m,1H),1.87- 1.97(m,3H).MS(ESI)m/z:501.64(M+1).
Embodiment 25：The conjunction of 2- [6- (4- ethylamino benzonitriles amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
As described in Example 15, benzaldehyde is substituted with 4- ethylo benzene formaldehyde, obtains 2- [6- (4- ethylamino benzonitriles amino)-benzene And thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters, it is faint yellow solid 122.6mg, yield 94.44%.
1H NMRδ(300MHz,DMSO-d6):12.16-12.18 (br, 1H), 7.42 (d, J=8.82Hz, 1H), 7.28- 7.37 (m, 5H), 7.13-7.16 (m, 3H), 7.00-7.07 (m, 2H), 6.78 (d, J=8.82Hz, 1H), 6.29 (brs, 1H), 4.89-5.11(m,2H),4.44-4.50(m,1H),4.24(s,2H),3.44-3.51(m,2H),2.52-2.59(m,2H), 2.21-2.26(m,1H),1.84-2.00(m,3H),1.11-1.17(m,3H).MS(ESI)m/z:515.79(M+1).
Embodiment 26：2- [6- (4- methoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
As described in Example 15, benzaldehyde is substituted with 4-methoxybenzaldehyde, obtains 2- [6- (4- methoxyl group aminotoluenes Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 123.3mg, yield 94.63%.
1H NMRδ(300MHz,DMSO-d6):12.20 (brs, 1H), 7.44 (d, J=8.58Hz, 1H), 7.36-7.37 (m, 2H), 7.30 (d, J=6.63Hz, 2H), 7.17 (d, J=6.54Hz, 1H), 7.01-7.10 (m, 3H), 6.87 (d, J= 8.07Hz, 2H), 6.79 (d, J=8.70Hz, 1H), 6.28 (brs, 1H), 4.90-5.08 (m, 2H), 4.46-4.52 (m, 1H),4.22(s,2H),3.70(s,3H),3.46-3.51(m,2H),2.14-2.26(m,1H),1.86-1.90(m,3H).MS (ESI)m/z:517.72(M+1).
Embodiment 27：2- [6- (4- ethoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
As described in Example 15, benzaldehyde is substituted with 4- ethoxy-benzaldehydes, obtains 2- [6- (4- ethoxy benzonitrile ammonia Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 127.2mg, yield 95.07%.
1H NMRδ(300MHz,DMSO-d6):12.21 (brs, 1H), 7.44 (d, J=8.61Hz, 1H), 7.34-7.39 (m, 2H), 7.29 (d, J=8.16Hz, 2H), 7.17 (d, J=7.05Hz, 1H), 7.00-7.07 (m, 3H), 6.85 (d, J= 8.04Hz, 2H), 6.80 (d, J=8.94Hz, 1H), 6.26 (brs, 1H), 4.90-5.12 (m, 2H), 4.46-4.51 (m, 1H), 4.21(s,2H),3.92-3.98(m,2H),3.49-3.51(m,2H),2.20-2.25(m,1H),1.86-1.90(m,3H), 1.27-1.30(m,3H).MS(ESI)m/z:531.41(M+1).
Embodiment 28：The conjunction of 2- [6- (3- nitrobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
As described in Example 15, benzaldehyde is substituted with 3- nitrobenzaldehydes, obtains 2- [6- (3- nitrobenzoyls amino)-benzene And thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters, it is Chinese red solid 107.4mg, yield 80.09%.
1H NMRδ(300MHz,DMSO-d6):12.23 (brs, 1H), 8.24 (s, 1H), 8.08 (d, J=8.07Hz, 1H), 7.84 (d, J=6.84Hz, 1H), 7.58-7.64 (m, 1H), 7.46 (dd, J1=1.59Hz, J2=8.70Hz, 1H), 7.35-7.36 (m, 2H), 7.15 (d, J=6.12Hz, 1H), 7.01-7.06 (m, 3H), 6.81 (dd, J1=2.19Hz, J2= 8.67Hz,1H),6.60(brs,1H),4.88-5.11(m,2H),4.37-4.58(m,3H),3.43-3.50(m,2H),2.20- 2.25(m,1H),1.84-1.90(m,3H).MS(ESI)m/z:532.07(M+1).
Embodiment 29：The conjunction of 2- [6- (4- cyano aminotoluenes base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
As described in Example 15, benzaldehyde is substituted with 4- cyanobenzaldehydes, obtains 2- [6- (4- cyano aminotoluenes base)-benzene And thiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters, it is yellow solid 107.9mg, yield 83.64%.
1H NMRδ(300MHz,DMSO-d6):12.20 (brs, 1H), 7.78 (d, J=6.93Hz, 1H), 7.56 (d, J= 5.79Hz, 1H), 7.45 (d, J=8.58Hz, 1H), 7.32-7.41 (m, 2H), 7.12-7.24 (m, 1H), 6.99-7.06 (m, 3H), 6.77 (d, J=8.22Hz, 1H), 6.53 (brs, 1H), 4.89-5.07 (m, 2H), 4.41-4.57 (m, 3H), 3.44- 3.76(m,2H),2.23-2.25(m,1H),1.90-1.97(m, 3H).MS(ESI)m/z:512.08(M+1).
Embodiment 30：2- { 6- [4- (1H- imidazoles -1- bases) aminotoluene base]-benzothiazole -2- carbamyls }-pyrroles -1- The synthesis of acid benzyl ester
As described in Example 15, benzaldehyde is substituted with 4- (1H- imidazoles -1- bases) benzaldehyde, obtains 2- { 6- [4- (1H- miaows Azoles -1- bases) aminotoluene base]-benzothiazole -2- carbamyls }-pyrroles's -1- acid benzyl esters are gray solid 106.8mg, yield 76.61%.
1H NMRδ(300MHz,DMSO-d6):12.22(brs,1H),8.10-8.42(m,1H),7.64-7.70(m, 1H), 7.45-7.58 (m, 5H), 7.24-7.40 (m, 3H), 7.05-7.15 (m, 4H), 6.81 (d, J=8.25Hz, 1H), 6.45 (brs,1H),4.90-5.06(m,2H),4.42-4.61(m,1H),4.36(s,2H),3.43-3.63(m,2H),2.08-2.37 (m,1H),1.87-1.90(m,3H).MS(ESI)m/z:553.32(M+1).
Embodiment 31：The conjunction of 2- [6- (cyclopropyl sulfonyl amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with cyclopropyl mesyl chloride, obtains 2- [6- (cyclopropyl sulfonyl ammonia Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 77.2mg, yield 61.12%.
1H NMRδ(300MHz,DMSO-d6):12.52(brs,1H),9.76(br,1H),7.82(dd,J1=1.74Hz, J2=6.87Hz, 1H), 7.69 (dd, J1=2.52Hz, J2=8.58Hz, 1H), 7.37-7.38 (m, 2H), 7.32 (dd, J1= 1.74,J2=8.61Hz, 1H), 7.16 (d, J=6.39Hz, 1H), 7.04-7.09 (m, 2H), 4.90-5.13 (m, 2H), 4.50-4.55(m,1H),3.46-3.53(m,2H),2.60-2.61(m,1H),2.16-2.33(m,1H),1.87-1.97(m, 3H),0.89-0.90(m,4H).MS(ESI)m/z:501.16(M+1).
Embodiment 32：The synthesis of 2- [6- (methanesulfonamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
By the method for embodiment 33, benzene sulfonyl chloride is substituted with mesyl chloride, obtains 2- [6- (methanesulfonamido)-benzothiazole- 2- carbamyls]-pyrroles's -1- acid benzyl esters are light grey solid 70.0mg, yield 58.48%.
1H NMRδ(300MHz,DMSO-d6):12.51(brs,1H),9.82(brs,1H),7.80(dd,J1=1.59Hz, J2=6.99Hz, 1H), 7.70 (dd, J1=2.31Hz, J2=.58Hz, 1H), 7.36-7.37 (m, 2H), 7.29 (d, J= 8.49Hz,1H),7.04-7.17(m,3H),4.90-5.12(m,2H),4.50-4.56(m,1H),3.48-3.53(m,2H), 2.99-3.00(m,3H),2.26-2.33(m,1H),1.86-1.97(m,3H).MS(ESI)m/z:475.17(M+1).
Embodiment 33：The synthesis of 2- [6- (benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (100mg, 0.252mmol) are dissolved in In 20mL pyridines, solution temperature is down to 0 DEG C, then is slowly added benzene sulfonyl chloride (53.46mg, 0.303mmol) into solution, Subsequent solution temperature is gradually warmed to room temperature, and is stirred overnight.Solution is washed with the dilute hydrochloric acid of 1mol/L and is extracted with dichloromethane, then is used Saturated common salt water washing 2 times takes organic layer, solvent evaporated, column chromatography to purify (DCM:MeOH=100:5) 2- [6- (benzene sulfonyls are obtained Amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid (98.8mg, yield 54.08%).1H NMRδ(300MHz,DMSO-d6):12.17-12.60(br,1H),10.17-10.54(br,1H),7.71-7.75(m,2H), 7.66-7.68(m,1H),7.49-7.61(m,4H),7.36-7.38(m,2H),7.13-7.15(m,2H),6.98-7.01(m, 2H),4.88-5.08(m,2H),4.47-4.52(m,1H),3.47-3.52(m,2H),2.12-2.38(m,1H),1.85-1.99 (m,3H).MS(ESI)m/z:537.19(M+1).
Embodiment 34：The conjunction of 2- [6- (2- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 2- fluorophenylsulfonyl chlorides, obtains 2- [6- (2- fluorobenzene sulfonamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 83.0mg, yield 59.33%.
1H NMRδ(600MHz,DMSO-d6):12.49(brs,1H),10.63(brs,1H),7.79-7.83(m,1H), 7.70(dd,J1=1.98Hz, J2=11.82Hz, 1H), 7.64-7.68 (m, 1H), 7.60 (t, J=8.70Hz, 1H), 7.41 (d, J=9.36Hz, 1H), 7.37-7.38 (m, 2H), 7.31-7.33 (m, 1H), 7.16-7.19 (m, 1H), 7.14 (d, J= 6.72Hz,1H),6.97-7.03(m,2H),4.89-5.11(m,2H),4.48-4.53(m,1H),3.42-3.56(m,2H), 2.21-2.31(m,1H),1.83-1.97(m,3H).MS(ESI)m/z:555.14(M+1).
Embodiment 35：The conjunction of 2- [6- (3- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 3- fluorophenylsulfonyl chlorides, obtains 2- [6- (3- fluorobenzene sulfonamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 85.9mg, yield 61.40%.
1H NMRδ(600MHz,DMSO-d6):12.51(brs,1H),10.41(brs,1H),7.71(dd,J1= 1.98Hz,J2=10.86Hz, 1H), 7.52-7.63 (m, 4H), 7.46-7.50 (m, 1H), 7.37-7.38 (m, 2H), 7.14 (d, J=6.60Hz, 2H), 6.98-7.03 (m, 2H), 4.90-5.11 (m, 2H), 4.48-4.54 (m, 1H), 3.42-3.55 (m, 2H),2.21-2.32(m,1H),1.85-2.00(m,3H).MS(ESI)m/z:555.35(M+1).
Embodiment 36：The conjunction of 2- [6- (4- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- fluorophenylsulfonyl chlorides, obtains 2- [6- (4- fluorobenzene sulfonamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 113.7mg, yield 81.27%.
1H NMRδ(300MHz,DMSO-d6):12.51(brs,1H),10.33(brs,1H),7.74-7.81(m,2H), 7.68(s,1H),7.60(dd,J1=3.51Hz, J2=8.46Hz, 1H), 7.35-7.37 (m, 4H), 7.12-7.14 (m, 2H), 6.97-6.99(m,2H),4.87-5.11(m,2H),4.49-4.52(m,1H),3.44-3.51(m,2H),2.24-2.26(m, 1H),1.85-1.90(m,3H).MS(ESI)m/z:555.33(M+1).
Embodiment 37：2- [6- (2- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyls The synthesis of ester
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 2- trifluoromethyl benzene sulfonyl chlorides, obtains 2- [6- (2- trifluoromethyls Benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 100mg, yield 65.60%.
1H NMRδ(300MHz,DMSO-d6):12.52(brs,1H),10.66(brs,1H),8.06-8.10(m,1H), 7.95-8.00 (m, 1H), 7.79-7.81 (m, 2H), 7.71 (d, J=4.17Hz, 1H), 7.59-7.63 (m, 1H), 7.36- 7.37(m,2H),7.11-7.16(m,2H),6.97-7.01(m,2H),4.86-5.11(m,2H),4.46-4.51(m,1H), 3.44-3.51(m,2H),2.24-2.29(m,1H),1.88-1.98(m,3H).MS(ESI)m/z:605.19(M+1).
Embodiment 38：2- [6- (3- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyls The synthesis of ester
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 3- trifluoromethyl benzene sulfonyl chlorides, obtains 2- [6- (3- trifluoromethyls Benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 100.2mg, yield 65.70%.
1H NMRδ(600MHz,DMSO-d6):12.51-12.52(br,1H),10.46(brs,1H),7.97-8.02(m, 3H),7.71(dd,J1=2.16Hz, J2=11.82Hz, 1H), 7.62 (t, J=8.16Hz, 1H), 7.37-7.38 (m, 2H), 7.10-7.14(m,2H),6.97-7.02(m,2H),4.89-5.11(m,2H),4.48-4.53(m,1H),3.42-3.54(m, 2H),2.23-2.31(m,1H),1.85-1.98(m,3H).MS(ESI)m/z:605.15(M+1).
Embodiment 39：2- [6- (4- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyls The synthesis of ester
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- trifluoromethyl benzene sulfonyl chlorides, obtains 2- [6- (4- trifluoromethyls Benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 135.4mg, yield 88.79%.
1H NMRδ(300MHz,DMSO-d6):12.5(brs,1H),10.56(brs,1H),7.91-7.93(m,4H), 7.66-7.74(m,1H),7.61(dd,J1=3.84Hz, J2=8.64Hz, 1H), 7.35-7.36 (m, 2H), 7.11-7.16 (m,2H),6.96-6.98(m,2H),4.87-5.11(m,2H),4.47-4.52(m,1H),3.41-3.52(m,2H),2.24- 2.27(m,1H),1.84-1.88(m,3H).MS(ESI)m/z:605.57(M+1).
Embodiment 40：The conjunction of 2- [6- (4- chlorobenzenesulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- chlorobenzene sulfonyl chlorides, obtains 2- [6- (4- chlorobenzenesulfonyls amino)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 57.5mg, yield 39.93%.
1H NMRδ(300MHz,DMSO-d6):12.52(brs,1H),10.40(brs,1H),7.70-7.75(m,3H), 7.56-7.62(m,3H),7.35-7.36(m,2H),7.12-7.15(m,2H),6.97-6.99(m,2H),4.87-5.11(m, 2H),4.48-4.54(m,1H),3.44-3.52(m,2H),2.24-2.26(m,1H),1.84-2.01(m,3H).MS(ESI)m/ z:571.41(M+1).
Embodiment 41：The conjunction of 2- [6- (4- bromophenylsulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- bromobenzene sulfonyl chlorides, obtains 2- [6- (4- bromophenylsulfonyls amino)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 138.6mg, yield 89.28%.
1H NMRδ(300MHz,DMSO-d6):12.52(brs,1H),10.40(brs,1H),7.58-7.74(m,6H), 7.35-7.37(m,2H),7.12-7.16(m,2H),6.97-6.99(m,2H),4.87-5.11(m,2H),4.49-4.52(m, 1H),3.46-3.51(m,2H),2.24-2.27(m,1H),1.77-2.07(m,3H).MS(ESI)m/z:617.16(M+1).
Embodiment 42：The conjunction of 2- [6- (4- iodobenzenes sulfonamido)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters At
By the method for embodiment 33, benzene sulfonyl chloride is substituted with Pipsyl Chloride, obtains 2- [6- (4- iodobenzenes sulfonamido)- Benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 121.4mg, yield 72.65%.
1H NMRδ(300MHz,DMSO-d6):12.52 (brs, 1H), 10.39 (brs, 1H), 7.89 (d, J=8.43Hz, 2H),7.64-7.73(m,1H),7.60(dd,J1=3.72Hz, J2=8.67Hz, 1H), 7.45-7.50 (m, 2H), 7.35- 7.36(m,2H),7.12-7.16(m,2H),6.97-7.01(m,2H),4.87-5.11(m,2H),4.47-4.54(m,1H), 3.41-3.55(m,2H),2.17-2.30(m,1H),1.82-1.97(m,3H).MS(ESI)m/z:663.22(M+1).
Embodiment 43：2- [6- (4- ethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- ethyl benzene sulfonyl chlorides, obtains 2- [6- (4- ethyl benzene fulfonic amides Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 103.8mg, yield 72.89%.
1H NMRδ(600MHz,DMSO-d6):12.48(brs,1H),10.27(brs,1H),7.64-7.69(m,3H), 7.58-7.61 (m, 1H), 7.37-7.38 (m, 2H), 7.35 (d, J=8.28Hz, 2H), 7.14-7.17 (m, 2H), 6.98- 7.03(m,2H),4.90-5.11(m,2H),4.47-4.53(m,1H),3.42-3.54(m,2H),2.59-2.64(m,2H), 2.21-2.31(m,1H),1.83-1.98(m,3H),1.11-1.15(m,3H).MS(ESI)m/z:565.08(M+1).
Embodiment 44：2- [6- (2- cyano benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 2- cyanobenzenesulfonyl chlorides, obtains 2- [6- (2- cyano benzene fulfonic amides Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are yellow solid 113.2mg, yield 79.89%.
1H NMRδ(300MHz,DMSO-d6):12.54(brs,1H),10.78(brs,1H),7.99-8.04(m,2H), 7.84-7.88 (m, 1H), 7.79 (d, J=7.50Hz, 1H), 7.71 (dd, J1=2.10Hz, J2=6.66Hz, 1H), 7.61 (dd,J1=3.24Hz, J2=8.64Hz, 1H), 7.35-7.38 (m, 2H), 7.09-7.14 (m, 2H), 6.95-7.03 (m, 2H), 4.87-5.09(m,2H),4.46-4.60(m,1H),3.44-3.52(m,2H),2.17-2.31(m,1H),1.85-1.95(m, 3H).MS(ESI)m/z:562.79(M+1).
Embodiment 45：2- [6- (4- biphenyl ylsulfonylamino)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters Synthesis
By the method for embodiment 33, benzene sulfonyl chloride is substituted with 4- biphenylsulfonyl chlorides, obtains 2- [6- (4- xenyl sulphonyl ammonia Base)-benzothiazole -2- carbamyls]-pyrroles's -1- acid benzyl esters are faint yellow solid 139.9mg, yield 90.53%.
1H NMRδ(300MHz,DMSO-d6):12.51(brs,1H),10.42(brs,1H),7.78-7.82(m,4H), 7.74(s,1H),7.59-7.66(m,3H),7.35-7.43(m,5H),7.18-7.23(m,1H),7.06-7.16(m,1H), 6.95-6.96(m,2H),4.86-5.11(m,2H),4.49-4.50(m,1H),3.42-3.51(m,2H),2.23-2.25(m, 1H),1.83-1.88(m,3H).MS(ESI)m/z:613.50(M+1).
Embodiment 46：2- [6- (N- benzenesulfonyls)-benzenesulfonamido-)]-benzothiazole -2- carbamyls }-pyrroles -1- The synthesis of acid benzyl ester
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (100mg, 0.252mmol) are dissolved in 20mL In dichloromethane, and catalytic amount DMAP (3.08mg, 0.0252mmol) is added while solution temperature is down to 0 DEG C, then to solution In be slowly added benzene sulfonyl chloride (98.01mg, 0.555mmol), subsequent solution temperature is gradually warmed to room temperature, is stirred overnight.It is evaporated molten Agent, column chromatography purify (DCM:MeOH=100:5) 2- { [6- (N- benzenesulfonyls)-benzenesulfonamido-)]-benzothiazole -2- Carbamyl }-pyrroles's -1- acid benzyl esters are light grey solid 120mg, yield 88.63%.
1H NMRδ(600MHz,DMSO-d6):12.58-12.96(br,1H),7.79-7.85(m,6H),7.73-7.77 (m, 1H), 7.66-7.70 (m, 5H), 7.37 (d, J=4.38Hz, 2H), 7.16 (d, J=7.08Hz, 1H), 7.03-7.10 (m, 2H),6.94-6.96(m,1H),4.91-5.11(m,2H),4.49-4.54(m,1H),3.42-3.57(m,2H),2.22-2.32 (m,1H),1.82-2.00(m,3H).MS(ESI)m/z:677.32(M+1).
Embodiment 47：2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 2- fluorophenylsulfonyl chlorides, obtains 2- { [6- (2- fluoro- N- ((2- fluorobenzene Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is faint yellow solid 149.6mg yield 83.2%.
1H NMRδ(600MHz,DMSO-d6):12.73-12.76(br,1H),7.93(dd,J1=2.22Hz, J2= 21.54Hz,1H),7.82-7.90(m,4H),7.74-7.77(m,1H),7.51-7.54(m,2H),7.45-7.47(m,1H), 7.43-7.45 (m, 1H), 7.38 (d, J=4.44Hz, 2H), 7.18-7.21 (m, 1H), 7.14-7.15 (m, 1H), 6.98- 7.07(m,2H),4.89-5.12(m,2H),4.51-4.56(m,1H),3.45-3.56(m,2H),2.23-2.34(m,1H), 1.84-2.00(m,3H).MS(ESI)m/z:713.20(M+1).
Embodiment 48：2- { [6- (the fluoro- N- of 3- ((3- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 3- fluorophenylsulfonyl chlorides, obtains 2- { [6- (3- fluoro- N- ((- fluorobenzene Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is white solid 141.5mg, Yield 78.70%.
1H NMRδ(300MHz,DMSO-d6):12.78(brs,1H),7.93(dd,J1=1.95Hz, J2=7.95Hz, 1H), 7.62-7.75 (m, 9H), 7.36-7.37 (m, 2H), 7.15 (d, J=6.03Hz, 1H), 7.02-7.09 (m, 3H), 4.89-5.13(m,2H),4.52-4.58(m,1H),3.43-3.54(m,2H),2.18-2.34(m,1H),1.87-2.00(m, 3H).MS(ESI)m/z:713.44(M+1).
Embodiment 49：2- { [6- (the fluoro- N- of 4- ((4- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 4- fluorophenylsulfonyl chlorides, obtains 2- { [6- (4- fluoro- N- ((4- fluorobenzene Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is white solid 143.1mg, Yield 79.59%.
1H NMRδ(600MHz,DMSO-d6):12.75(brs,1H),7.89-7.94(m,4H),7.85(dd,J1= 2.04Hz,J2=19.56Hz, 1H), 7.74-7.77 (m, 1H), 7.54 (t, J=8.46Hz, 4H), 7.38 (d, J=4.26Hz, 2H), 7.17 (d, J=7.26Hz, 1H), 7.02-7.10 (m, 3H), 4.93-5.12 (m, 2H), 4.53-4.58 (m, 1H), 3.44-3.58(m,2H),2.25-2.35(m,1H),1.84-2.03(m,3H).MS(ESI)m/z:713.01(M+1).
Embodiment 50：2- { [6- (2- trifluoromethyls-N- ((2- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzene And thiazole -2- carbamyls-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 2- trifluoromethyl benzene sulfonyl chlorides, obtains 2- { [6- (2- fluoroforms Base-N- ((2- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles's -1- acid benzyl esters, For faint yellow solid 60.7mg, yield 29.61%.
1H NMRδ(300MHz,DMSO-d6):12.77(brs,1H),8.33-8.39(m,1H),7.93-8.03(m, 7H),7.65-7.70(m,1H),7.36-7.37(m,2H),6.92-7.13(m,4H),4.85-5.11(m,2H),4.49-4.52 (m,1H),3.48-3.61(m,2H),2.25-2.32(m,1H),1.86-2.00(m,3H).MS(ESI)m/z:813.45(M+ 1).
Embodiment 51：2- { [6- (3- trifluoromethyls-N- ((3- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzene And thiazole -2- carbamyls-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 3- trifluoromethyl benzene sulfonyl chlorides, obtains 2- { [6- (3- fluoroforms Base-N- ((3- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles's -1- acid benzyl esters, For yellow solid 88.4mg, yield 43.12%.
1H NMRδ(300MHz,DMSO-d6):12.80 (brs, 1H), 8.28 (d, J=7.47Hz, 2H), 8.11-8.13 (m,2H),7.75-8.03(m,6H),7.37-7.38(m,2H),7.14-7.16(m,1H),7.03-7.05(m,3H),4.88- 5.08(m,2H),4.48-4.56(m,1H),3.47-3.49(m,2H),2.26-2.34(m,1H),1.85-1.91(m,3H).MS (ESI)m/z:813.44(M+1).
Embodiment 52：2- { [6- (4- trifluoromethyls-N- ((4- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzene And thiazole -2- carbamyls-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 4- trifluoromethyl benzene sulfonyl chlorides, obtains 2- { [6- (4- fluoroforms Base-N- ((4- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles's -1- acid benzyl esters, For faint yellow solid 96.1mg, yield 46.88%.
1H NMRδ(600MHz,DMSO-d6):12.79(brs,1H),8.09-8.12(m,8H),7.96(dd,J1= 2.10Hz,J2=19.38Hz, 1H), 7.78-7.81 (m, 1H), 7.38 (d, J=4.20Hz, 2H), 7.18 (d, J=6.84Hz, 1H),7.10-7.13(m,1H),7.05-7.09(m,2H),4.94-5.13(m,2H),4.53-4.59(m,1H),3.45-3.59 (m,2H),2.25-2.36(m,1H),1.84-2.03(m, 3H).MS(ESI)m/z:813.01(M+1).
Embodiment 53：2- { [6- (the chloro- N- of 4- ((4- chlorphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 4- chlorobenzene sulfonyl chlorides, obtains 2- { [6- (4- chloro- N- ((4- chlorobenzenes Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is faint yellow solid 158.2mg yield 84.11%.
1H NMRδ(600MHz,DMSO-d6):12.77(brs,1H),7.94-7.91(m,5H),7.76-7.81(m, 5H), 7.39 (d, J=4.20Hz, 2H), 7.18 (d, J=7.02Hz, 1H), 7.04-7.11 (m, 3H), 4.93-5.13 (m, 2H),4.53-4.59(m,1H),3.45-3.59(m,2H),2.25-2.39(m,1H),1.85-2.03(m,3H).MS(ESI)m/ z:746.97(M+1).
Embodiment 54：2- { [6- (the bromo- N- of 4- ((4- bromophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 4- bromobenzene sulfonyl chlorides, obtains 2- { [6- (4- bromo- N- ((4- bromobenzenes Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is faint yellow solid 143.6mg yield 68.22%.
1H NMRδ(600MHz,DMSO-d6):12.76 (brs, 1H), 7.93 (d, J=8.34Hz, 4H), 7.89 (dd, J1 =2.16Hz, J2=15.60Hz, 1H), 7.76-7.79 (m, 5H), 7.39 (d, J=4.32Hz, 2H), 7.17 (d, J= 6.96Hz,1H),7.04-7.11(m,3H),4.93-5.13(m,2H),4.53-4.58(m,1H),3.45-3.59(m,2H), 2.25-2.36(m,1H),1.84-2.03(m,3H).MS(ESI)m/z:834.80(M+1).
Embodiment 55：2- { [6- (the iodo- N- of 4- ((4- iodophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with Pipsyl Chloride, obtains 2- { [6- (4- iodo- N- ((4- iodobenzenes Base) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is white solid 202.9mg, Yield 86.64%.
1H NMRδ(300MHz,DMSO-d6):12.78 (brs, 1H), 8.08 (d, J=7.92Hz, 4H), 7.88 (d, J= 6.09Hz, 1H), 7.73-7.77 (m, 1H), 7.56-7.58 (m, 4H), 7.36 (m, 2H), 7.16 (d, J=6.57Hz, 1H), 7.04-7.06(m,3H),4.90-5.08(m,2H),4.46-4.63(m,1H),3.46-3.54(m,2H),2.23-2.30(m, 1H),1.89-1.91(m,3H).HRMS calcd for C32H27I2N4O7S3(M+1)927.9053,found928.9112.
Embodiment 56：2- { [6- (2- methyl-N- ((2- aminomethyl phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 2- toluene sulfonyl chlorides, obtains 2- { [6- (2- methyl-N- ((2- Aminomethyl phenyl) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is faint yellow solid 163.6mg yield 92.03%.
1H NMRδ(300MHz,DMSO-d6):12.76(brs,1H),7.88-7.90(m,2H),7.61-7.73(m, 4H),7.40-7.45(m,4H),7.36-7.37(m,2H),6.95-7.15(m,4H),4.86-5.13(m,2H),4.46-4.61 (m,1H),3.45-3.53(m,2H),2.28-2.43(m,7H),1.84-2.00(m,3H).MS(ESI)m/z:705.54(M+ 1).
Embodiment 57：2- { [6- (4- ethyls-N- ((4- ethylphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 4- ethyl benzene sulfonyl chlorides, obtains 2- { [6- (4- ethyl-N- ((4- Ethylphenyl) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is white solid 161.0mg yield 87.17%.
1H NMRδ(300MHz,DMSO-d6):12.77 (brs, 1H), 7.71-7.79 (m, 6H), 7.49 (d, J= 7.92Hz, 4H), 7.36-7.37 (m, 2H), 7.16 (d, J=6.51Hz, 1H), 7.00-7.05 (m, 3H), 4.90-5.09 (m, 2H),4.45-4.64(m,1H),3.46-3.54(m,2H),2.69-2.76(m,4H),2.17-2.40(m,1H),1.88-1.91 (m,3H),1.19-1.23(m,6H).MS(ESI)m/z:733.59(M+1).
Embodiment 58：2- { [6- (2- cyano-N- ((2- cyano-phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- Carbamyl }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 2- cyanobenzenesulfonyl chlorides, obtains 2- { [6- (2- cyano-N- ((2- Cyano-phenyl) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is yellow solid 25.8mg, yield 14.08%.
1H NMRδ(600MHz,DMSO-d6):12.79(brs,1H),8.17-8.26(m,4H),8.04-8.09(m, 4H), 7.92-7.98 (m, 1H), 7.79-7.82 (m, 1H), 7.39 (d, J=4.44Hz, 2H), 7.21-7.24 (m, 1H), 7.16 (d, J=6.96Hz, 1H), 7.04-7.11 (m, 2H), 4.91-5.13 (m, 2H), 4.53-4.59 (m, 1H), 3.44-3.61 (m, 2H),2.25-2.35(m,1H),1.86-2.03(m,3H).MS(ESI)m/z:727.01(M+1).
Embodiment 59：2- { [6- (2- phenyl-N- ((2- xenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia Formoxyl }-pyrroles's -1- acid benzyl esters synthesis
By the method for embodiment 46, benzene sulfonyl chloride is substituted with 2- phenylbenzene sulfonyl chlorides, obtains 2- { [6- (2- phenyl-N- ((2- Xenyl) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is yellow solid 108.3mg yield 51.79%.
1H NMRδ(600MHz,DMSO-d6):12.76 (brs, 1H), 7.99 (d, J=8.16Hz, 4H), 7.91-7.95 (m, 5H), 7.77-7.81 (m, 5H), 7.55 (t, J=7.68Hz, 4H), 7.48 (t, J=7.38 Hz, 2H), 7.37-7.38 (m,2H),7.16-7.17(m,1H),7.09-7.12(m,1H),7.03-7.08(m,2H),4.92-5.12(m,2H),4.53- 4.58(m,1H),3.44-3.58(m,2H),2.24-2.34(m,1H),1.83-2.03(m,3H).MS(ESI)m/z:829.11 (M+1).
Embodiment 60：Step 1：2- quinolyls-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] Benzo [d] thiazol-2-yl } pyrrolidines -2- formamides synthesis
Step 1：The synthesis of 2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles's -1- acid isobutyl (VII)
By the method for 1 step 1 of embodiment, N- carbobenzyloxy-L-prolines are replaced with N- tertbutyloxycarbonyls-L-PROLINE, Obtain 2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles's -1- acid isobutyls
Step 2：The synthesis of 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid isobutyl (VIII)
By the method for 1 step 2 of embodiment, with 2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles's -1- acid isobutyl groups Ester replaces 2- (6- nitrobenzene thiazole -2- carbamyls)-pyrroles's -1- acid benzyl esters, obtains 2- (6- aminobenzothiazole -2- ammonia first Acyl group)-pyrroles's -1- acid isobutyls
Step 3：2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls Base }-pyrroles's -1- acid isobutyls (Vd20) synthesis
By the method for 1 step 3b of embodiment, with 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid isobutyl groups Ester replaces 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid benzyl esters, and cyclopropyl first is replaced with 2- fluorophenylsulfonyl chlorides Acyl chlorides obtains 2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid isobutyls
Step 4：N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiazol-2-yl } pyrrole Cough up alkane -2- formamides (Vd15) synthesis
2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole It coughs up -1- acid isobutyl (M08) to be dissolved in 20mL dichloromethane, 10mL trifluoroacetic acids is added thereto, 2h. is stirred at room temperature and is evaporated Solvent, column chromatography purify (DCM:MeOH=100:1) product.
Step 5：2- quinolyls-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiophenes Azoles -2- bases } pyrrolidines -2- formamides synthesis
As described in Example 15, with N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzos [d] thiazol-2-yl } pyrrolidines -2- formamides replacement 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid benzyl esters, Benzaldehyde is substituted with 2- quinoline aldehyde, obtains 2- quinolyls-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] Benzo [d] thiazol-2-yl } pyrrolidines -2- formamides, be
Faint yellow solid 62.3mg, yield 50.26%.1H NMRδ(300MHz,DMSO-d6):12.87(brs,1H), 8.37(dd,J1=8.28Hz, J2=19.60Hz, 1H), 7.80-7.93 (m, 6H), 7.73-7.78 (m, 1H), 7.62 (d, J= 8.37Hz, 1H), 7.52-7.57 (m, 2H), 7.41-7.49 (m, 2H), 7.37 (d, J=7.50Hz, 1H), 7.24-7.28 (m, 1H), 7.19 (d, J=8.91Hz, 1H), 6.89 (d, J=5.22Hz, 1H), 4.29 (d, J=14.92Hz, 1H), 4.06 (d, J =14.65Hz, 1H), 3.76-3.81 (m, 1H), 3.38-3.51 (m, 2H), 2.15-2.20 (m, 1H), 1.82-2.00 (m, 3H).
Embodiment 61：1- how methyl-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzos [d] Thiazol-2-yl } pyrrolidines -2- formamides synthesis
As described in Example 15, with N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzos [d] thiazol-2-yl } pyrrolidines -2- formamides replacement 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid benzyl esters, With 1- naphthaldehydes substitute benzaldehyde, obtain 1- how methyl-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzene And [d] thiazol-2-yl pyrrolidines -2- formamides, it is faint yellow solid 77.4mg, yield 72.42%.
1H NMRδ(300MHz,DMSO-d6):12.01 (brs, 1H), 8.41 (d, J=8.40Hz, 1H), 7.80-7.91 (m, 6H), 7.76 (d, J=8.25Hz, 1H), 7.70 (d, J=8.67Hz, 1H), 7.34-7.56 (m, 8H), 7.15 (dd, J1= 2.16Hz,J2=8.46Hz, 1H), 4.29 (d, J=12.70Hz, 1H), 3.99 (d, J=12.61Hz, 1H), 3.53-3.58 (m,1H),3.37-3.41(m,2H),2.14-2.18(m,1H),1.75-1.91(m,3H).
Embodiment 62：2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles -1- acid benzyl esters (D19) synthesis
By the method for 1 step 3a of embodiment, with N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] Benzo [d] thiazol-2-yl } pyrrolidines -2- formamides replacement 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles's -1- acid benzyls Ester substitutes ethylene-acetic acid with 3- benzenpropanoic acids, obtains 2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzene And thiazole -2- carbamyls-pyrroles's -1- acid benzyl esters, it is faint yellow solid 94.0mg, yield 72.42%.
1H NMRδ(300MHz,DMSO-d6):12.63 (br, 1H), 7.79-7.90 (m, 5H), 7.75 (d, J= 8.67Hz,1H),7.41-7.55(m,4H),7.21-7.28(m,4H),7.13-7.18(m,2H),4.53-4.56(m,1H), 3.47-3.68(m,2H),2.76-2.81(m,2H),2.59-2.64(m,2H),2.13-2.20(m,1H),1.88-1.98(m, 3H).
The structural formula of target compound 1-62 is as shown in table 1, and number 1-62 corresponds to target compound in following table 1, table 2 1-62 and embodiment 1-62.
1. preferred compound structural formula in part of the present invention of table
Embodiment 63：Antiviral Effect activity and cytotoxicity：
1) material：
Human liver cancer cell Huh-7.5 cell lines (this cell is used for the infection of Jc1 recombinant viruses) are incubated at common DMEM trainings Base is supported (containing 10% fetal calf serum, 105U/L penicillin, 0.1g/L streptomysins, nonessential amino acid), and it is every according to cell density Passage in 48 to 72 hours is primary.
HCV recombinant viruses：Jc1FLAG2 (p7-nsGluc2A) is presented by Rockerfeller universities Charles professors Rice It gives.This viral genome include can Gaussian luciferase (Gluc) gene of secreting, expressing (be inserted in NS2 the 29th After codon [Leu]), thus can be quantitative to virus replication situation by bioluminescent detection.(Cell culture- produced hepatitis C virus does not infect peripheral blood mononuclear cells.Marukian S,Jones CT,Andrus L,Evans MJ,Ritola KD,Charles ED,Rice CM, Dustin LB.Hepatology.2008,48(6):1843-1850.)
CCK-8 cytoactive detection kits are purchased from Dojindo Laboratories.Gluc detection kits, (Renilla luciferase assay system E2820) is purchased from Promega companies.
2) method：
The cell toxicity test of drug：
The previous day is tested, Huh-7.5 is inoculated in (2X10 in 96 porocyte culture plates4/ hole), next day cell confluency degree reaches 90% or more.The experiment same day by diluted chemical compound in DMEM complete mediums (50 μM or 100 μM of maximum concentration), and does again Than dilution (total 5-6 dilution), only the complete medium of DMSO solvents will be added as blank control, each dilution at least three A multiple holes.96 orifice plate inner cell culture mediums are sucked, the culture medium of the compound containing respective concentration is changed to.Cell is put back into culture Case carries out CCK-8 cytoactive detections after continuing culture 72 hours.
CCK-8 cytoactive detections：
By CCK-8 reagents with 1:10 dilution proportions are in DMEM complete mediums.Cells and supernatant is exhausted, is changed to and contains The culture solution of CCK-8 reagents, puts back to cell incubator and is incubated 1-2 hours, and observation culture solution color change (becoming yellow) works as face After color depth reaches requirement, 96 orifice plates are positioned in microplate reader, detect 450nM absorbances.Made with the blank well of non-refinement born of the same parents For negative control.
Antiviral Effect Activity determination：
The previous day is tested, by Huh-7.5 inoculations and (2X10 in 96 porocyte culture plates4/ hole), next day cell confluency degree reaches 90% or more.On the experiment same day, Jc1FLAG2 (p7-nsGluc2A) recombinant virus supernatant is diluted in DMEM complete mediums (5-10 times).Cell conditioned medium is sucked, the culture solution (100 holes μ l/) containing recombinant virus is changed to and is adsorbed, infected, cell is put It returns in incubator and is incubated 6-8 hours.Complete viruses adsorption after, by diluted chemical compound in DMEM complete mediums (maximum concentration Adjusted according to preliminary result, usually 50 μM, 10 μM, 2 μM), and doubling dilution (total 5-6 dilution) is done, will only it add The complete medium of DMSO solvents is as blank control, at least three multiple holes of each dilution.By 96 orifice plate inner cell culture mediums It sucks, is changed to the culture medium of the compound containing respective concentration.Cell is put back into incubator, Gluc inspections are carried out after continuing culture 72 hours It surveys.
Gaussia luciferase (Gluc) Activity determination:
Using 8 townhouse pipettors, cell conditioned medium (20 holes μ l/) is transferred in the luminous detection plate in 96 hole of black transparent bottom, Using Renilla luciferase substrates (20 holes μ l/), detected in the automatic luminous detector of the holes Glomax96.Using every hole Automatically it detects immediately plus after substrate, per 5 seconds hole signal acquisition time, to reduce the error that signal decaying introduces.
3) data analysis：
Drug CC50And IC50The calculating of value and its 95% confidence interval is non-linear using Prism5 (Graphpa) software Fitting algorithm (inhibibor, variable slope) obtains.
Half-inhibition concentration IC of 2 compound of table to human liver cancer cell Huh-7.5 cell lines50With cytotoxicity (unit：μ mol·L-1)
Most compounds show good external HCV inhibitory activity, and are superior to lead compound GL100953,2 A compound activity reaches nM grades, the especially IC of compound D1950Value has reached 0.19 μm of olL-1, cytotoxicity CC50Value More than 50 μm olL-1, it is 141 times of advantage compound object GL110509.
The pharmacological activity of the compounds of this invention makes it can be used for preparing anti-HCV medicament.The pharmaceutical composition can be solid Body form or liquid form.
The preferred embodiment of the invention is illustrated above, but the invention be not limited to it is described Embodiment, those skilled in the art can also make various equivalent under the premise of without prejudice to the invention spirit Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.

Claims (6)

1. a kind of benzothiazole compound, shown in the general structure such as formula (I) of the compound：
In formula (I)：
R1Indicate following groups：Hydrogen, benzyl, 3- hydrocinnamoyls, menaphthyl, 2- quinolylmethyls, benzyloxycarbonyl group；
R2Group indicates following groups：Hydrogen, halogen, nitro, cyano, phenyl, low alkyl group, low-grade cycloalkyl, lower alkoxy, Low-grade halogenated alkyl, substituted or unsubstituted aralkyl or aryl, substitution can be monosubstituted or polysubstituted, and wherein substituent group is Halogen, heterocycle or heterocyclic methyl, benzyloxycarbonyl group protection prolyl, low alkyl group, lower alkoxy, low-grade halogenated alkyl, Nitro, cyano；
R3Group indicates following groups：Hydrogen, halogen, nitro, cyano, phenyl, low alkyl group, low-grade cycloalkyl, lower alkoxy, Low-grade halogenated alkyl, substituted or unsubstituted aralkyl or aryl, substitution can be monosubstituted or polysubstituted, and wherein substituent group is Halogen, heterocycle or heterocyclic methyl, benzyloxycarbonyl group protection prolyl, low alkyl group, lower alkoxy, low-grade halogenated alkyl, Nitro, cyano；
Y group indicates following groups：For sulfone, carbonyl, methylene；
Term " rudimentary " related with alkyl, halogenated alkyl and alkoxy refers to the linear chain or branched chain containing 1 to 6 carbon atom herein Saturated fat hydrocarbyl group；Naphthenic base refers to the ring containing 3 to 7 carbon；Aryl refers to mono-, di- or tricyclic hydrocarbon compound, and wherein at least one A ring is aromatic rings, and each ring contains most 7 carbon atoms.
2. a kind of benzothiazole compound according to claim 1, which is characterized in that the compound is：
2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- Nai Ji-formamido group)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzoylaminos)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- pyridylcarboxamides amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2,5- difluorobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (positive butyrylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (positive propionamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- furoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- chIorobenzoyIaminos)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (cyclopropylcarboxamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- thenoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- indoles acetylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzene methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- trifluoromethylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- bromobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- iodobenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- methylbenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethylamino benzonitriles amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- methoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethoxybenzenes methylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- nitrobenzoyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- cyano aminotoluenes base)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (cyclopropyl sulfonyl amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (methanesulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- fluorobenzene sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (3- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- trifluoromethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- chlorobenzenesulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- bromophenylsulfonyls amino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- iodobenzenes sulfonamido)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- ethyls benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (2- cyano benzenesulfonamido-)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (4- biphenyl ylsulfonylamino)-benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters,
2- [6- (N- benzenesulfonyls)-benzenesulfonamido-)]-benzothiazole -2- carbamyls }-pyrroles -1- acid benzyl esters,
2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester,
2- { [6- (the fluoro- N- of 3- ((3- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester,
2- { [6- (the fluoro- N- of 4- ((4- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester,
2- { [6- (2- trifluoromethyls-N- ((2- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles -1- acid benzyl esters,
2- { [6- (3- trifluoromethyls-N- ((3- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles -1- acid benzyl esters,
2- { [6- (4- trifluoromethyls-N- ((4- trifluoromethyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- ammonia first Acyl group }-pyrroles -1- acid benzyl esters,
2- { [6- (the chloro- N- of 4- ((4- chlorphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester,
2- { [6- (the bromo- N- of 4- ((4- bromophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester
2- { [6- (the iodo- N- of 4- ((4- iodophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester,
2- { [6- (2- methyl-N- ((2- aminomethyl phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (4- ethyls-N- ((4- ethylphenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (2- cyano-N- ((2- cyano-phenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrrole Cough up -1- acid benzyl esters,
2- { [6- (2- phenyl-N- ((2- xenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles - 1- acid benzyl esters,
2- quinolyls-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiazol-2-yl } pyrrole Cough up alkane -2- formamides,
1- how methyl-N- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)] benzo [d] thiazol-2-yl } pyrrole Alkane -2- formamides are coughed up, or
2- { [6- (the fluoro- N- of 2- ((2- fluorophenyls) sulfonyl) benzene sulfonamido)]-benzothiazole -2- carbamyls }-pyrroles -1- Acid benzyl ester.
3. a kind of preparation method of benzothiazole compound as described in claim 1, this method is selected from reaction process and leads to method One or reaction process lead to method two：
Reaction process leads to method one：
It is as follows that reaction process leads to the step of method one：
N- carbobenzyloxy-L-prolines (I) are dissolved in tetrahydrofuran (THF), and 1- ethyls-(3- dimethylaminopropyls) carbon is added 30min is stirred at room temperature in acyl diimmonium salt hydrochlorate (EDC.HCl), adds -6 nitrobenzene thiazole of 2- amino (II) and catalysis It measures 4- lutidines (DMAP) and continues room temperature and be stirred to react, overnight, after reaction, simultaneously dry method mixes sample to solvent evaporated, then Column chromatography purifies to obtain intermediate (III)；
Intermediate (III) is dissolved in ethyl alcohol again, and iron powder is added, reaction solution is heated to 78 DEG C, then dilute salt is added dropwise thereto Acid maintains reflux state, and after 2h, the reaction was complete and is cooled to room temperature reaction solution, filters solid residue through diatomite, is evaporated Ethyl alcohol, then dissolved and diluted with ethyl acetate, suitable quantity of water is added, then reconciles pH value of solution into using saturated sodium bicarbonate solution Property, is again passed through diatomite and filters solid residue, takes organic layer, and after solvent evaporated, column chromatography purifies to obtain intermediate 2- [6- amino Benzothiazole -2- carbamyls]-pyrroles -1- acid benzyl esters (IV)；
Step 1：Carboxylic acid reagents and DEC.HCl are dissolved in dichloromethane, at room temperature stir-activating 30min, and 2- (6- amino is added Benzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and catalytic amount DMAP, maintenance is stirred at room temperature and overnight.It is evaporated molten After agent, column chromatography purifies to obtain target product (Va)；
Step 2：It is molten under 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and catalytic amount DMAP ice baths In dichloromethane, reaction solution is kept to maintain 0-5 DEG C, acyl chloride reagent, following reaction liquid are then slowly added dropwise into solution Temperature is gradually warmed to room temperature, and is stirred overnight, then solvent evaporated, and column chromatography purifies to obtain target product (Va)；
By 2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) and benzaldehyde, substituted benzaldehyde or Other aromatic aldehyde reagents are dissolved in methanol, and 2 drop acetic acid catalysis are added, and are stirred to react 30min at room temperature, cyano boron hydrogen is then added Change sodium, is stirred overnight, subsequent solvent evaporated, column chromatography purifies to obtain target product (Vb)；
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) are dissolved in pyridine, solution temperature is dropped To 0 DEG C, then sulfonic acid chloride class reagent is slowly added into solution, subsequent solution temperature is gradually warmed to room temperature, is stirred overnight, and uses 1mol/L Dilute hydrochloric acid washing solution and extracted with dichloromethane, then with saturated common salt water washing 2 times, take organic layer, solvent evaporated, column layer Analyse target product (Vc)；
2- (6- aminobenzothiazole -2- carbamyls)-pyrroles -1- acid benzyl esters (IV) are dissolved in dichloromethane, and catalysis are added Solution temperature is down to 0 DEG C by amount DMAP simultaneously, then benzene sulfonyl chloride class reagent is slowly added into solution, and subsequent solution temperature edges up It to room temperature, is stirred overnight, solvent evaporated, column chromatography purifies to obtain target product (Vd)；
Reaction process leads to method two：
It is as follows that reaction process leads to the step of method two：
According to the synthetic method of intermediate (III), N- benzyloxycarbonyl group-L- dried meat is substituted with N- tertbutyloxycarbonyls-L-PROLINE (VI) Propylhomoserin (I) reacts to obtain intermediate (VII)；
According to the synthetic method of intermediate (IV), intermediate (III) is substituted with intermediate (VII), reacts to obtain intermediate (Vd20)；
Intermediate (Vd20) be dissolved in 2 volumes methylene chlorides, 1 volume trifluoroacetic acid is added thereto, 2h is stirred at room temperature, steams Dry solvent, column chromatography purify to obtain target product (Vd15)。
4. a kind of application of benzothiazole compound as described in claim 1 in preparing hepatitis C virus inhibitors.
5. a kind of application of benzothiazole compound as described in claim 1 in preparing HCV NS5A inhibitor.
6. a kind of application of benzothiazole compound as described in claim 1 in preparing anti-HCV medicament.
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