CN108341810A - Epithio carbamide compounds and application thereof - Google Patents

Epithio carbamide compounds and application thereof Download PDF

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CN108341810A
CN108341810A CN201810053503.3A CN201810053503A CN108341810A CN 108341810 A CN108341810 A CN 108341810A CN 201810053503 A CN201810053503 A CN 201810053503A CN 108341810 A CN108341810 A CN 108341810A
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CN108341810B (en
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王喆
王晓光
范国钦
卢涔宾
杨赛
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Shanghai Longwood Pharmaceutical Co Ltd
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Abstract

The present invention relates to a kind of epithio carbamide compounds and application thereof.Specifically, the invention discloses a kind of compound with structure shown in chemical formula (A) for making hbv replication inhibitor or its stereoisomers or tautomer or its pharmaceutically acceptable salt, hydrate or solvate.Purposes the invention further relates to the pharmaceutical composition comprising above compound and its in treating hepatitis B.

Description

Epithio carbamide compounds and application thereof
Technical field
The invention belongs to field of medicaments, in particular it relates to the epithio carbamide compounds for treating hepatitis B And application thereof.
Background technology
Hepatitis type B virus (HBV) is a kind of tunicary, dsdna segment (dsDNA), Hepadna Virus DNA families The virus of (hepatovirus section (Hepadnaviridae)).Its genome includes 4 overlapping open reading frames：Pronucleus/karyogene, polymerization Enzyme gene, UM and S genes (they encode three envelope proteins) and X gene.When before infection, the dsdna segment base Because (open-circle DNA, rcDNA) is changed into covalently closed circular DNA (cccDNA) and virus mRNA to group in host cell nuclear It is transcribed.Once by encapsidate, which uses as template In reverse transcription, this reverse transcription regenerates part dsDNA genomes (rcDNA) in nucleocapsid.
The Spreading source of hepatitis type B virus has in serum efficient in being exposed to communicable blood or body fluid Viral DNA is detected in the saliva of the chronic carriers of valence DNA, tear and urine.The selection directly treated also limits at present In interferon and antiviral agent below；Tenofovir, Lamivudine, adefovirdipivoxil, Entecavir and Sebivo.
Press down as a kind of HBV in addition, heteroaryl dihydro-pyrimidin (HAPs) is authenticated in tissue cultures and animal model Preparation (weber (Weber) et al.,《Antiviral study》(Antiviral Res.)54:69-78).2013/006394 Hes of WO WO2013/096744 also discloses the sulfamoyl-aryl amides for being related to Anti-HBV effect.
However, variety of problems, such as toxicity, mutagenicity, shortage can be encountered in these above-mentioned direct HBV antiviral agents Selectivity, weak curative effect, poor bioavailability and synthesis difficulty etc..
Therefore, this field needs to develop the HBV inhibitor having the advantages that as potency is high, toxicity is more low.
Invention content
The purpose of the present invention is to provide the epithio carbamide compounds that one kind can be used as the structure novel of HBV inhibitor.
First aspect present invention, provide it is a kind of as compound shown in formula A or its stereoisomer or tautomer, Or its pharmaceutically acceptable salt, hydrate or solvate,
Wherein,
R1、R2It is each independently selected from the following group：Hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C10 Naphthenic base substituted or unsubstituted is selected from the group the heteroatomic 3-10 membered heterocycloalkyls of N, S and O, substitution or not with 1-3 Substituted C6-C10Aryl, halogen or the substituted or unsubstituted heteroatomic 5-10 members that N, S and O are selected from the group with 1-3 are miscellaneous Aryl, the R1、R2In, the substitution refers to be taken by one or more (such as 2,3,4 etc.) substituent groups selected from the group below Generation：- OH, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy ,=O ,-O-；
X is CR11R12Or-CR11=CR12-；Wherein, R11And R12It is each independently selected from the following group：H, halogen, substitution or not Substituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6It is alkynyl, substituted or unsubstituted C3-C10Naphthenic base substituted or unsubstituted there is 1-3 to be selected from the group the heteroatomic 3-10 membered heterocycloalkyls of N, S and O, take Generation or unsubstituted C6-C10Aryl, the substituted or unsubstituted heteroatomic 5-10 members that N, S and O are selected from the group with 1-3 are miscellaneous Aryl, substituted or unsubstituted C1-3Alkyl-R7,-C (=O) OC1-4Alkyl；The wherein described R7It is selected from the group：Halogen, C1-C3Alkane Base substituted or unsubstituted be selected from the group the heteroatomic 5-10 unit's heteroaryls of N, S and O with 1-2, have 1-3 choosing From the heteroatomic 3-7 membered heterocycloalkyls of the following group N, S and O ,-NR9R10, wherein the R9、R10It is each independently selected from：H、C1- C3Alkyl, halogenated C1-C3Alkyl；
Alternatively,
The R11And R12The heteroatomic substitution for being selected from the group N, S and O with 1-3 is collectively formed with adjacent C atoms Or unsubstituted 3-7 membered heterocycloalkyls, wherein the substitution of the 3-7 membered heterocycloalkyls refers to by one or more selected from the group below (such as 2,3,4 etc.) substituent group is replaced：- OH, halogen, methoxyl group ,-O- ,-C (=O) OC1-4Alkyl, benzyl, C1-4 Alkyl, halogenated C1-4Alkyl,
Also, the R11、R12In, the substitution refers to by one or more (such as 2,3,4 etc.) selected from the group below Substituent group is replaced：- OH, halogen, C1-C6Alkyl, halogenated C1-C6The C that alkyl ,-OH replace1-C6Alkyl, C1-C6Alkoxy ,- C (=O) OC1-4Alkyl；
Y is substituted or unsubstituted C1-C7Alkylidene or C2-C7Alkenylene, in the Y, the substitution, which refers to, to be selected from the group One or more (such as 2,3,4 etc.) substituent group replaced：C1-C4Alkyl, halogen ,-OH, preferably C1-C4Alkane Base or-OH；
Z is selected from the group：NH, O or a key；
Ring C is the substituted or unsubstituted heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O with 1-3, described In ring C, the substitution refers to be replaced by one or more (such as 2,3,4 etc.) substituent groups selected from the group below：C1-C3Alkane Base (preferably methyl), C3-C4Naphthenic base ,-CN or halogen；
Ring B is substituted or unsubstituted C6-C10Aryl substituted or unsubstituted there is 1-3 to be selected from the group N, S and O Heteroatomic 5-10 unit's heteroaryls；In the ring B, the substitution refer to by it is selected from the group below it is one or more (such as 2,3,4 It is a etc.) substituent group replaced：C1-C3Alkyl, C3-C4Naphthenic base ,-CN or halogen；
Ra、Rb、Rc、RdFor the substituent group of any position on ring B, it is each independently selected from the following group：H, halogen ,-CN, hydroxyl Base, amino, carboxyl ,-(C=O)-substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkyl, substitution or not Substituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C1-C8Alkylamino radical, substitution or unsubstituted C1-C8Alkoxy, substituted or unsubstituted C3-C10Naphthenic base substituted or unsubstituted there is 1-3 to be selected from the group N, S and O Heteroatomic 3-10 membered heterocycloalkyls, substituted or unsubstituted C6-C10Aryl is substituted or unsubstituted with 1-3 choosing From the heteroatomic 5-10 unit's heteroaryls of the following group N, S and O；The Ra、Rb、Rc、RdIn, " substitution " refers to being selected from the group One or more (such as 2,3,4 etc.) substituent group replaced：Halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1- C6Alkoxy, halogenated C1-C6Alkoxy, C3-C8Naphthenic base, halogenated C3-C8Naphthenic base, oxo ,-CN, hydroxyl, amino, carboxylic Base, C6-C10Aryl, halogenated C6-C10Aryl, heteroatomic 5-10 unit's heteroaryls, the halogen for being selected from the group N, S and O with 1-3 The heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O with 1-3 in generation.
In another preferred example, R1、R2It is each independently selected from the following group：Hydrogen, substituted or unsubstituted C1-C10Alkyl, substitution Or unsubstituted C3-C10Naphthenic base, the substituted or unsubstituted heteroatomic 3-10 members that N, S and O are selected from the group with 1-3 are miscellaneous Naphthenic base, substituted or unsubstituted C6-C10Aryl or the substituted or unsubstituted miscellaneous original for being selected from the group N, S and O with 1-3 The 5-10 unit's heteroaryls of son, the R1、R2In, the substitution refers to be replaced by one or more substituent groups selected from the group below：-OH、 Halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy ,-O-；
X is CR11R12Or-CR11=CR12-；Wherein, R11And R12It is each independently selected from the following group：H, halogen, substitution or not Substituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6It is alkynyl, substituted or unsubstituted C3-C10Naphthenic base substituted or unsubstituted there is 1-3 to be selected from the group the heteroatomic 3-10 membered heterocycloalkyls of N, S and O, take Generation or unsubstituted C6-C10Aryl, the substituted or unsubstituted heteroatomic 5-10 members that N, S and O are selected from the group with 1-3 are miscellaneous Aryl, C1-3Alkyl-R7Or-C (=O) OC1-4Alkyl；The wherein described R7It is selected from the group：Halogen, C1-C3Alkyl, substitution or not Substitution is selected from the group N, S and O with the 1-2 heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O, with 1-3 Heteroatomic 3-7 membered heterocycloalkyls ,-NR9R10, wherein the R9、R10It is each independently selected from：H、C1-C3It is alkyl, halogenated C1-C3Alkyl；
Alternatively,
The R11And R12The heteroatomic substitution for being selected from the group N, S and O with 1-3 is collectively formed with adjacent C atoms Or unsubstituted 3-7 membered heterocycloalkyls, wherein the substitution of the 3-7 membered heterocycloalkyls refers to by one or more selected from the group below Substituent group is replaced：- OH, halogen, methoxyl group ,-O- ,-C (=O) OC1-4Alkyl, benzyl, C1-4Alkyl, halogenated C1-4Alkyl,
Also, the R11、R12In, the substitution refers to be replaced by one or more substituent groups selected from the group below：- OH, halogen Element, C1-C6Alkyl, halogenated C1-C6The C that alkyl ,-OH replace1-C6Alkyl, C1-C6Alkoxy ,-C (=O) OC1-4Alkyl；
Ra、Rb、Rc、RdIt is defined as described above for the substituent group of any position on phenyl ring.
In another preferred example, R1For H, unsubstituted C1-C10Alkyl, C3-C10Naphthenic base, quilt-OH ,=O ,-O- or halogen The C of element substitution1-C10Alkyl.
In another preferred example, R11It is selected from the group：H, substituted or unsubstituted C1-C10Alkyl ,-C (=O) OC1-4Alkyl, C1-3Alkyl-R7, substituted or unsubstituted C2-4Alkynyl, the heteroatomic 3-7 circle heterocyclic rings alkane for being selected from the group N, S and O with 1-3 Base or the substituted or unsubstituted heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O with 1-3.
In another preferred example, R12It is selected from the group：H, substituted or unsubstituted C1-C10Alkyl, preferably H, substitution or Unsubstituted C1-C6Alkyl is more preferably H or methyl.
In another preferred example, ring C is substituted or unsubstituted 5 yuan or 6 unit's heteroaryls, and the substitution, which refers to, to be selected from the group One or more (such as 2,3,4 etc.) substituent group replaced：Methyl ,-CN or halogen.
In another preferred example, ring B is phenyl or substituted or unsubstituted 6 unit's heteroaryl, preferably phenyl or pyridine Base.
In another preferred example, the Ra、Rb、Rc、RdIt is each independently selected from the following group：H, halogen ,-CHF2、-CF2First Base ,-CH2F、-CF3、-OCF3、-CN、-C3-C4Naphthenic base or-C1-C4Alkyl.
In another preferred example, the ring C isOrWherein,
R4For H ,-C1-C3Alkyl (preferably methyl) ,-C3-C4Naphthenic base；
R5For H or halogen (preferably F)；
R6Selected from H, methyl ,-CN or halogen.
In another preferred example, the Z is O or key.
In another preferred example, the R7For the substituted or unsubstituted miscellaneous original for being selected from the group N, S and O with 1-2 The 5-10 unit's heteroaryls of son.
In another preferred example, the formula A compounds are selected from the group：
Second aspect of the present invention, provide it is a kind of prepare compound as described in the first aspect of the invention or its stereoisomer or The method of tautomer or its pharmaceutically acceptable salt, hydrate or solvate, shown formula A compounds are Formula VII -1 Compound represented, the method includes the steps (I)：
Alternatively,
Shown formula A compounds are -1 compound represented of Formula VIII, and the method includes the steps (II)：
In the step (I) or (II), R2、Ra、Rb、Rc、Rd, ring C, ring B it is as defined above described, m, n are respectively 1-5's Positive integer；
Wherein, R3It is selected from the group：H, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkene Base, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C10Naphthenic base, it is substituted or unsubstituted have 1-3 select From the heteroatomic 3-10 membered heterocycloalkyls of the following group N, S and O, substituted or unsubstituted C6-C10Aryl is substituted or unsubstituted Heteroatomic 5-10 unit's heteroaryls, the C for being selected from the group N, S and O with 1-31-3Alkyl-R7,-C (=O) OC1-4Alkyl；Wherein The R7It is selected from the group：Halogen, C1-C3Alkyl, the substituted or unsubstituted hetero atom for being selected from the group N, S and O with 1-2 5-10 unit's heteroaryls, be selected from the group with 1-3 heteroatomic 3-7 the membered heterocycloalkyls ,-NR of N, S and O9R10, wherein institute State R9、R10It is each independently selected from：H、C1-C3Alkyl, halogenated C1-C3Alkyl.
Third aspect present invention provides a kind of pharmaceutical composition, it includes described in (1) first aspect compound or its Stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate；(2) pharmaceutically acceptable Carrier.
In another preferred example, described pharmaceutical composition also includes other for preventing and/or treating hepatitis type B virus The drug of infection.
In another preferred example, described other to can be selected from for preventing and/or treat hepatitis b virus infected drug The following group：The stimulant of immunomodulator (such as interferon-' alpha ' (IFN-α), glycol interferon-α) or innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
In another preferred example, described other to can be selected from for preventing and/or treat hepatitis b virus infected drug The following group：Tenofovir, Lamivudine, adefovirdipivoxil, Entecavir, Sebivo, or combinations thereof.
Fourth aspect present invention provides the compound that is shown below：
Fifth aspect present invention provides compound or its stereoisomer as described in the first aspect of the invention or mutually makes a variation Pharmaceutical composition described in structure body or its pharmaceutically acceptable salt, hydrate or solvate or third aspect present invention Purposes is used to prepare prevention and/or treats hepatitis b virus infected drug.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific implementation mode
The present inventor is after extensive and in-depth study, it was found that a kind of to have excellent therapeutic effect to hepatitis B Novel ring thiourea.The compounds of this invention has novel parent nucleus, the especially structure with epithio urea in structure Therefore part not only has the activity of excellent Anti-HBV activity, but also cytotoxicity is lower (particularly with liver cell).In this base On plinth, inventor completes the present invention.
Definition
As used herein, term " alkyl " includes the alkyl of linear chain or branched chain.Such as C1-C8Alkyl indicates there is 1-8 carbon Alkyl of the linear chain or branched chain of atom, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl etc..
As used herein, term " alkenyl " includes the alkenyl of linear chain or branched chain.Such as C2-C6Alkenyl refers to former with 2-6 carbon Son linear chain or branched chain alkenyl, such as vinyl, allyl, 1- acrylic, isopropenyl, 1- cyclobutenyls, 2- cyclobutenyls or Similar group.
As used herein, term " alkynyl " includes the alkynyl of linear chain or branched chain.Such as C2-C6Alkynyl refers to 2-6 carbon The alkynyl of the linear chain or branched chain of atom, such as acetenyl, propinyl, butynyl or similar group.
As used herein, term " C3-C10Naphthenic base " refers to the naphthenic base with 3-10 carbon atom.It can be monocycle, Such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or similar group.Can also be bi-cyclic form, such as bridged ring or loop coil shape Formula.
As used herein, term " C1-C8Alkylamino radical " refers to by C1-C8The amido that alkyl is replaced, can be it is monosubstituted or It is disubstituted；For example, methylamino, ethylamino-, Propylamino, isopropylamine base, butylamine base, isobutyl amine, tert-butylamine base, dimethylamine Base, diethylin, dipropyl amido, diisopropylamino, dibutyl amino, di-iso-butylmanice base, two tert-butylamine bases etc..
As used herein, term " C1-C8Alkoxy " refers to the alkoxy of the linear chain or branched chain with 1-8 carbon atom；Example Such as, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy etc..
As used herein, term " the heteroatomic 3-10 membered heterocycloalkyls for being selected from the group N, S and O with 1-3 " refers to Ring-type with 3-10 atom and that wherein 1-3 atom is the heteroatomic saturation or fractional saturation that are selected from the group N, S and O Group.It can be monocycle, can also be bi-cyclic form, such as bridged ring or loop coil form.Specific example can be oxa- ring Butane, azetidine, tetrahydrochysene -2H- pyranoses, piperidyl, tetrahydrofuran base, morpholinyl and pyrrolidinyl etc..
As used herein, term " C6-C10Aryl " refers to the aryl for having 6-10 carbon atom, for example, phenyl or naphthyl Deng similar group.
As used herein, term " the heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O with 1-3 " refers to and has 5-10 atom and wherein 1-3 atom be the heteroatomic cyclic aromatic groups for being selected from the group N, S and O.It can be single Ring can also be condensed ring form.Specific example can be pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, pyrroles Base, pyrazolyl, imidazole radicals, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazole radical, furyl, thienyl, isoxazole Base, thiazolyl, oxazolyl etc..
Group of the present invention is " substituted or unsubstituted " unless stated otherwise, otherwise group of the invention Replaced by substituent group selected from the group below：Halogen, itrile group, nitro, hydroxyl, amino, C1-C6Alkyl-amino, C1-C6Alkyl, C2- C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, halogenated C2-C6Alkenyl, halogenated C2-C6Alkynyl, halogenated C1-C6 Alkoxy, allyl, benzyl, C6-C12Aryl, C1-C6Alkoxy -C1-C6Alkyl, C1-C6Alkoxy-carbonyl, carbobenzoxy, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl base etc..
As used herein, " halogen " or " halogen atom " refers to F, Cl, Br and I.More preferably, halogen or halogen atom are selected from F, Cl And Br." halogenated " refers to being replaced by the atom selected from F, Cl, Br and I.
Unless stated otherwise, structural formula described in the invention is intended to include that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometric isomer (or rotamer))：Such as R, S configuration containing asymmetric center, double bond (Z), (E) isomers etc..Therefore, the single three-dimensional chemical isomer of the compounds of this invention or its enantiomter, diastereomeric are different The mixture of structure body or geometric isomer (or rotamer) belongs to the scope of the present invention.
As used herein, term " tautomer " indicates that with different energy structural isomer can be more than low Energy barrier, to mutual inversion of phases.For example, proton tautomer (i.e. prototropic change) includes carrying out change by proton transfer, such as 1H- indazoles and 2H- indazoles.Valence tautomers include carrying out change by some bonding electrons recombinate.
As used herein, term " solvate " refers to that the compounds of this invention is coordinated to form special ratios with solvent molecule Complex.
As used herein, term " hydrate " refers to the complex that the compounds of this invention carries out coordination formation with water.
Active constituent
As used herein, " the compounds of this invention " refers to formula (A) compound represented, and further includes and formula (A) compound Various crystalline forms, pharmaceutically acceptable salt, hydrate or solvate.
As used herein, " pharmaceutically acceptable salt " refers to the compounds of this invention and is formed by with acid or alkali and is suitable as medicine The salt of object.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is that the compounds of this invention is formed with acid Salt.The acid for suitably forming salt includes but is not limited to：The inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, hardship Sour, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Pharmaceutical composition and method of administration
Since the compounds of this invention has the inhibitory activity of excellent hepatitis type B virus (HBV), chemical combination of the present invention Object and its various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain chemical combination of the present invention Object is that the pharmaceutical composition of main active can be used for preventing and/or treat and (stablize, mitigate or cure) hepatitis type B virus Infection or for prevent and/or treat (stablize, mitigate or cure) hepatitis type B virus relevant disease (for example, hepatitis B, into Malleability liver fibrosis, the inflammation for leading to hepatic sclerosis and necrosis, end-stage liver disease, ethyl liver cancer).
The present invention pharmaceutical composition include safe and effective amount within the scope of the compounds of this invention and can pharmaceutically receive Excipient or carrier.Wherein " safe and effective amount " refers to：The amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate Serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contain 10-200mg sheets Invention compound/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition Middle each component energy and the compounds of this invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmaceutically Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose Acetic acid esters etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as ), profit Humectant (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to)：Oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral medication includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mix：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can be used coating and shell material and prepare, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene The mixture etc. of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances.
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compounds (such as anti-HBV agent) Administering drug combinations.
When administering drug combinations, described pharmaceutical composition further include with it is one or more (2 kinds, 3 kinds, 4 kinds, or more) other Pharmaceutically acceptable compound (such as anti-HBV agent).In other pharmaceutically acceptable compounds (such as anti-HBV agent) It is one or more (2 kinds, 3 kinds, 4 kinds, or more) can with the compound of the present invention simultaneously, separate or be sequentially used for preventing And/or treat HBV infection or HBV relevant diseases.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000mg, preferably 20~500mg.Certainly, specific dosage is also contemplated that administration route, patient health situation etc. Factor, within the scope of these are all skilled practitioners technical ability.
The compounds of this invention：
Main advantages of the present invention include：
1. the compound of the present invention structure novel and having the function of excellent anti-hepatitis virus infection.
2. the compound of the present invention is very low to the toxicity of normal cell.
3. the compounds of this invention and containing the compounds of this invention be main active pharmaceutical composition can be used for it is pre- Prevent and/or treats hepatitis b virus infected.
4. the compounds of this invention and containing the compounds of this invention be main active pharmaceutical composition can be used for it is pre- Anti- and/or treatment hepatitis type B virus relevant disease is (for example, hepatitis B, progressivity liver fibrosis, the inflammation for leading to hepatic sclerosis With necrosis, end-stage liver disease, ethyl liver cancer).
Term explanation
Unless otherwise defined, otherwise whole technologies used herein all have with scientific terminology such as fields of the present invention The normally understood identical meanings of those of ordinary skill.
As used herein, in use, term " about " means that the value can be from enumerating in mentioning the numerical value specifically enumerated Value changes not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).
As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.
Experiment material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
It is the synthesis of 10 class compounds below：
Embodiment 1：The synthesis of compound 10a
Step 1:
Compound 1 (1.5g) is dissolved in acetic acid (20mL), reaction system then is added in iron powder (1.9g), temperature is risen to Ethyl acetate (30mL) is added in 50 degree of reaction 2h, reaction system, adds water 30 (mL), ethyl acetate (3*20mL) extraction, anhydrous sulphur Sour sodium drying, organic phase is spin-dried for, crude product column chromatography obtains compound 2 (1g).ESI-MS, (M+H=189.04)
Step 2：
Chlorosulfonic acid isocyanate (200mg) is dissolved in dichloromethane (5mL), system temperature is down to 0 degree, then by tertiary fourth Reaction system is added in alcohol (105mg), stirs 30min, and triethylamine (214mg) and compound 2 (266mg) are added instead under 0 degree System is answered, it is warming up to after adding and reaction 2h is stirred at room temperature, by reaction system plus water (20mL), dichloromethane (3*20mL) extracts, Anhydrous sodium sulfate is dried, and organic phase is spin-dried for, crude product column chromatography obtains compound 3 (150mg), ESI-MS, (M+H=368.06)
Step 3:
Compound 3 (100mg) and Isosorbide-5-Nitrae-dibromobutane (58.8mg) are dissolved in acetone (10mL), by cesium carbonate (266mg) Reaction system is added, reaction system, ethyl acetate (3*20mL) extraction, anhydrous slufuric acid is added for 24 hours, by water (15mL) in 60 degree of reactions Sodium is dried, and organic phase is spin-dried for, and crude product obtains yellow solid 80mg, ESI-MS, (M+H=422.11) through column chromatography for separation
Step 4：
Compound 4 (80mg) is dissolved in tetrahydrofuran (2mL), water (0.5mL), methanol (0.5mL), then at room temperature by one Reaction system is added in hydronium(ion) lithia (80mg), then system pH is adjusted to 3-4, second by 40 degree of lower reaction 5h with 1N hydrochloric acid Acetoacetic ester (3*15mL) extracts, and anhydrous sodium sulfate drying, organic phase is spin-dried for obtaining yellow solid (50mg) ESI-MS, (M+H= 408.09)
Step 5：
By compound 5 (50mg), triethylamine (70mg), the fluoro- 3- acetonitriles -1- aniline (22mg) of 4- are dissolved in dichloromethane In (3mL), 5 degree or so are then cooled the temperature to, reaction system then is added in TBTU (70mg), 12h is reacted at room temperature, adds water Organic phase is spin-dried for, crude product column chromatography obtains compound 6 by (15mL), dichloromethane (3*20mL) extraction, anhydrous sodium sulfate drying (40mg) ESI-MS, (M+H=526.13)
Step 6：
Compound 6 (40mg) is dissolved in dichloromethane (2mL) and then reaction system is added in 4NHCl (1mL), it is anti-under 30 degree 2h is answered, reaction solution is spin-dried for, saturated sodium bicarbonate solution tune pH value to 7-8, ethyl acetate (3*10mL) extraction, anhydrous sodium sulfate It is dry, it is spin-dried for organic phase, crude product obtains compound 10a (8mg) through column chromatography for separation
Embodiment 2：The synthesis of compound 10b
With reference to the step 1-5 of embodiment 1, difference was in step 3 with 1,3- dibromopropane generations the preparation method of compound 6b For Isosorbide-5-Nitrae-dibromobutane.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6b, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=1：1) target product 10b (11mg).
Embodiment 3：The synthesis of compound 10c
With reference to the step 1-5 of embodiment 1, difference is in step 3 with 1 for the preparation method of compound 6c, pentamethylene bromide generation For Isosorbide-5-Nitrae-dibromobutane.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6c, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=2：1) target product 10c (6mg).
Embodiment 4：The synthesis of compound 10d
With reference to the step 1-5 of embodiment 1, difference is in step 3 with 2 for the preparation method of compound 6d, pentamethylene bromide generation For Isosorbide-5-Nitrae-dibromobutane.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6d, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=2：1) target product 10d (7mg).
Embodiment 5：The synthesis of compound 10e
With reference to the step 1-5 of embodiment 1, difference is to use 2- difluoromethyl -5- bromines in step 3 preparation method of compound 6e Propane replaces Isosorbide-5-Nitrae-dibromobutane.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6e, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=2：1) target product 10e (11mg).
Embodiment 6：The synthesis of compound 10f
With reference to the step 1-5 of embodiment 1, difference is to use 2- methylisoxazole benzyls in step 3 preparation method of compound 6f Base -2,5- dibromo-hexane replaces Isosorbide-5-Nitrae-dibromobutane.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6f, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=1：1) target product 10f (8mg).
Embodiment 7：The synthesis of compound 10g
With reference to the step 1-5 of embodiment 1, difference is to use 1- isopropyls-Isosorbide-5-Nitrae-two in step 3 preparation method of compound 6g Bromohexane replaces Isosorbide-5-Nitrae-dibromobutane, with 3,4- difluoro-anilines instead of the fluoro- 3- cyano-anilines of 4- in step 5.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6g, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=1：1) target product 10g (4mg).
Embodiment 8：The synthesis of compound 10h
With reference to the step 1-5 of embodiment 1, difference is to use 1- isopropyls-Isosorbide-5-Nitrae-two in step 3 preparation method of compound 6h Bromohexane replaces Isosorbide-5-Nitrae-dibromobutane, replaces the fluoro- 3- cyano-anilines of 4- with the fluoro- 3- difluoromethyls aniline of 4- in step 5.
According to the step 6 of embodiment 1, compound 6 only need to be replaced with compound 6h, other conditions are constant, (just through column chromatography Heptane：Ethyl acetate=1：1) target product 10h (9mg).
Embodiment 9：The synthesis of compound 20a
Step 11：
Allyl bromide, bromoallylene (1.4g) is added drop-wise in acetonitrile (30mL) solution of compound 2 (2g) and potassium carbonate (2.3g), it will System temperature rises to 85 degree, reacts 1h, adds water to reaction system, ethyl acetate (3*20mL) extraction, and anhydrous sodium sulfate is dried, Organic phase is spin-dried for, crude product column chromatography obtains compound 12 (2.1g) ESI-MS, (M+H=229.07)
Step 12：
Chlorosulfonic acid isocyanate (2g) is dissolved in dichloromethane (40mL), system temperature is down to 0 degree, then by the tert-butyl alcohol Reaction system is added in (1.3g), stirs 30min, reactant is added under 0 degree in triethylamine (3g) and compound 12 (2.0g) System, it is warming up to after adding and reaction 2h is stirred at room temperature, by reaction system plus water (50mL), dichloromethane (3*50mL) extraction is anhydrous Sodium sulphate is dried, and organic phase is spin-dried for, crude product column chromatography obtains compound 13 (1.4g), ESI-MS, (M+H=408.10)
Step 13：
Compound 13 (1.2g) and allyl bromide, bromoallylene (1.1g) are dissolved in acetonitrile, reaction system then is added in cesium carbonate, 80 degree are warming up to, 2h is reacted, reaction system, ethyl acetate (3*20mL) extraction is added in water (20mL), anhydrous sodium sulfate is dried, Organic phase is spin-dried for obtaining compound 14 (1g) ESI-MS, (M+H=448.12)
Step 14：
Compound 14 (400mg) is dissolved in dichloromethane (400mL), formula catalyst CatB (42mg) additions then will be praised Reaction system addition silica gel is spin-dried for white powder by reaction system, 30 degree of reaction 12h, and column chromatography obtains compound 15 (130mg) ESI-MS, (M+H=420.09)
Step 15：
Compound 15 (80mg) is dissolved in tetrahydrofuran (2mL), water (0.5mL), methanol (0.5mL) then at room temperature will Reaction system is added in one hydronium(ion) lithia (80mg), then system pH is adjusted to 3-4 by 40 degree of lower reaction 5h with 1N hydrochloric acid, Ethyl acetate (3*15mL) extracts, and anhydrous sodium sulfate drying, organic phase is spin-dried for obtaining yellow solid 16 (40mg) ESI-MS, (M+H= 406.07)
Step 16：
By compound 16 (40mg), triethylamine (60mg), the fluoro- 3- acetonitriles -1- aniline (22mg) of 4- are dissolved in dichloromethane In (3mL), 5 degree or so are then cooled the temperature to, reaction system then is added in TBTU (70mg), 12h is reacted at room temperature, adds water Organic phase is spin-dried for, crude product column chromatography obtains compound 17 by (15mL), dichloromethane (3*20mL) extraction, anhydrous sodium sulfate drying (40mg) ESI-MS, (M+H=524.11)
Step 17：
Compound 17 (40mg) is dissolved in dichloromethane (2mL) and then reaction system is added in 4NHCl (1mL), under 30 degree 2h is reacted, reaction solution is spin-dried for, saturated sodium bicarbonate solution tune pH value to 7-8, ethyl acetate (3*10mL) extraction, anhydrous slufuric acid Sodium is dried, and is spin-dried for organic phase, crude product obtains compound 20a (12mg) through column chromatography for separation
Embodiment 10：The synthesis of compound 20b
With reference to the step 11-16 of embodiment 9, difference is to use the bromo- 1- butylene of 4- in step 13 preparation method of compound 17b Instead of propylene bromine.
According to the step 17 of embodiment 9, compound 17 only need to be replaced with compound 17b, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=2：1) target product 20b (6mg).
Embodiment 11：The synthesis of compound 20c
With reference to the step 11-16 of embodiment 9, difference is to use the bromo- 1- butylene of 3- in step 13 preparation method of compound 17c Instead of propylene bromine.
According to the step 17 of embodiment 9, compound 17 only need to be replaced with compound 17c, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=2：1) target product 20c (13mg).
Embodiment 12：The synthesis of compound 20d
With reference to the step 11-16 of embodiment 9, difference is to use the different evil of 4- methyl in step 13 preparation method of compound 17d Azoles benzyl -1- amylenes replace propylene bromine.
According to the step 17 of embodiment 9, compound 17 only need to be replaced with compound 17d, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=2：1) target product 20d (22mg).
Embodiment 13：The synthesis of compound 20e
With reference to the step 11-16 of embodiment 9, difference is to use 1- isopropyls -1- in step 13 preparation method of compound 17e Propylene replaces propylene bromine, with 3,4- difluoro-anilines instead of the fluoro- 3- cyano-anilines of 4- in step 16.
According to the step 17 of embodiment 9, compound 17 only need to be replaced with compound 17e, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=1：1) target product 20e (14mg).
Embodiment 14：The synthesis of compound 20f
With reference to the step 11-16 of embodiment 9, difference is to use 1- isopropyls -1- in step 13 preparation method of compound 17f Propylene replaces propylene bromine, replaces the fluoro- 3- cyano-anilines of 4- with the fluoro- 3- difluoromethyls base aniline of 4- in step 16.
According to the step 17 of embodiment 9, compound 17 only need to be replaced with compound 17f, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=1：1) target product 20f (8mg).
Embodiment 15：The synthesis of compound 30a
Step 21:
Compound 21 (1.5g) is dissolved in acetic acid (20mL), reaction system then is added in iron powder (1.9g), by temperature liter To 50 degree of reaction 2h, ethyl acetate (30mL) is added in reaction system, adds water 30 (mL), ethyl acetate (3*20mL) extraction anhydrous Sodium sulphate is dried, and organic phase is spin-dried for, crude product column chromatography obtains compound 22 (1g).ESI-MS, (M+H=190.03)
Step 22：
Chlorosulfonic acid isocyanate (200mg) is dissolved in dichloromethane (5mL), system temperature is down to 0 degree, then by tertiary fourth Reaction system is added in alcohol (105mg), stirs 30min, and triethylamine (214mg) and compound 22 (266mg) are added instead under 0 degree System is answered, it is warming up to after adding and reaction 2h is stirred at room temperature, by reaction system plus water (20mL), dichloromethane (3*20mL) extracts, Anhydrous sodium sulfate is dried, and organic phase is spin-dried for, crude product column chromatography obtains compound 23 (150mg), ESI-MS, (M+H=369.06)
Step 23:
Compound 23 (100mg) and Isosorbide-5-Nitrae-dibromobutane (58.8mg) are dissolved in acetone (10mL), by cesium carbonate (266mg) Reaction system is added, reaction system, ethyl acetate (3*20mL) extraction, anhydrous slufuric acid is added for 24 hours, by water (15mL) in 60 degree of reactions Sodium is dried, and organic phase is spin-dried for, crude product obtains yellow solid compound 24 (80mg), ESI-MS, (M+H=through column chromatography for separation 422.11)
Step 24：
Compound 24 (80mg) is dissolved in tetrahydrofuran (2mL), water (0.5mL), methanol (0.5mL) then at room temperature will Reaction system is added in one hydronium(ion) lithia (80mg), then system pH is adjusted to 3-4 by 40 degree of lower reaction 5h with 1N hydrochloric acid, Ethyl acetate (3*15mL) extracts, and anhydrous sodium sulfate drying, organic phase is spin-dried for obtaining yellow solid 25 (50mg) ESI-MS, (M+H= 408.09)
Step 25：
By compound 25 (50mg), triethylamine (70mg), the fluoro- 3- acetonitriles -1- aniline (22mg) of 4- are dissolved in dichloromethane In (3mL), 5 degree or so are then cooled the temperature to, reaction system then is added in TBTU (70mg), 12h is reacted at room temperature, adds water Organic phase is spin-dried for, crude product column chromatography obtains compound 26 by (15mL), dichloromethane (3*20mL) extraction, anhydrous sodium sulfate drying (40mg) ESI-MS, (M+H=526.13)
Step 26：
Compound 26 (40mg) is dissolved in dichloromethane (2mL) and then reaction system is added in 4NHCl (1mL), under 30 degree 2h is reacted, reaction solution is spin-dried for, saturated sodium bicarbonate solution tune pH value to 7-8, ethyl acetate (3*10mL) extraction, anhydrous slufuric acid Sodium is dried, and is spin-dried for organic phase, crude product obtains compound 30a (8mg) through column chromatography for separation
Embodiment 16：The synthesis of compound 30b
With reference to the step 21-25 of embodiment 15, difference is in step 23 with 2,4- dibromos penta preparation method of compound 26b Alkane replaces Isosorbide-5-Nitrae-dibromobutane.
According to the step 26 of embodiment 15, compound 26 only need to be replaced with compound 26b, other conditions are constant, through column layer Analyse (normal heptane：Ethyl acetate=1：1) target product 30b (11mg).
Embodiment 17：The synthesis of compound 30c
With reference to the step 21-25 of embodiment 15, difference is to use the different evil of 2- methyl in step 23 preparation method of compound 26c Azoles benzyl -2,5- dibromo-hexane replaces Isosorbide-5-Nitrae-dibromobutane.
According to the step 26 of embodiment 15, compound 26 only need to be replaced with compound 26c, other conditions are constant, through column layer Analyse (normal heptane：Ethyl acetate=2：1) target product 30c (8mg).
Embodiment 18：The synthesis of 30d
With reference to the step 21-25 of embodiment 15, difference is to use 1- isopropyls-in step 23 preparation method of compound 26d Isosorbide-5-Nitrae-dibromo-hexane replaces Isosorbide-5-Nitrae-dibromobutane.In step 25 the fluoro- 3- cyano-anilines of 4- are replaced with 3,4- difluoro-anilines.According to The step 26 of embodiment 15 only need to replace compound 26 with compound 26d, and other conditions are constant, through column chromatography (normal heptane：Second Acetoacetic ester=2：1) target product 30d (9mg).
Embodiment 19：The synthesis of compound 30e
With reference to the step 21-25 of embodiment 15, difference is to use 1- isopropyls in step 23 preparation method of compound 26e Base-Isosorbide-5-Nitrae-dibromo-hexane replaces Isosorbide-5-Nitrae-dibromobutane.In step 25 the fluoro- 3- cyano of 4- is replaced with the fluoro- aniline of 3- difluoromethyls -4- Aniline.According to the step 26 of embodiment 15, compound 26 only need to be replaced with compound 26e, other conditions are constant, through column chromatography (normal heptane：Ethyl acetate=2：1) target product 30e (11mg).
Embodiment 20：The synthesis of compound 40a
Step 31：
Allyl bromide, bromoallylene (1.4g) is added drop-wise in acetonitrile (30mL) solution of compound 31 (2g) and potassium carbonate (2.3g), it will System temperature rises to 85 degree, reacts 1h, adds water to reaction system, ethyl acetate (3*20mL) extraction, and anhydrous sodium sulfate is dried, Organic phase is spin-dried for, crude product column chromatography obtains compound 32 (2.1g) ESI-MS, (M+H=230.07)
Step 32：
Chlorosulfonic acid isocyanate (2g) is dissolved in dichloromethane (40mL), system temperature is down to 0 degree, then by the tert-butyl alcohol Reaction system is added in (1.3g), stirs 30min, reactant is added under 0 degree in triethylamine (3g) and compound 32 (2.0g) System, it is warming up to after adding and reaction 2h is stirred at room temperature, by reaction system plus water (50mL), dichloromethane (3*50mL) extraction is anhydrous Sodium sulphate is dried, and organic phase is spin-dried for, crude product column chromatography obtains compound 33 (1.4g), ESI-MS, (M+H=409.11)
Step 33：
Compound 33 (1.2g) and allyl bromide, bromoallylene (1.1g) are dissolved in acetonitrile, reaction system then is added in cesium carbonate, 80 degree are warming up to, 2h is reacted, reaction system, ethyl acetate (3*20mL) extraction is added in water (20mL), anhydrous sodium sulfate is dried, Organic phase is spin-dried for obtaining compound 34 (1g) ESI-MS, (M+H=449.13)
Step 34：
Compound 34 (400mg) is dissolved in dichloromethane (400mL), formula catalyst CatB (42mg) additions then will be praised Reaction system addition silica gel is spin-dried for white powder by reaction system, 30 degree of reaction 12h, and column chromatography obtains compound 35 (130mg) ESI-MS, (M+H=421.10)
Step 35：
Compound 35 (80mg) is dissolved in tetrahydrofuran (2mL), water (0.5mL), methanol (0.5mL) then at room temperature will Reaction system is added in one hydronium(ion) lithia (80mg), then system pH is adjusted to 3-4 by 40 degree of lower reaction 5h with 1N hydrochloric acid, Ethyl acetate (3*15mL) extracts, and anhydrous sodium sulfate drying, organic phase is spin-dried for obtaining yellow solid 36 (40mg) ESI-MS, (M+H= 407.08)
Step 36：
By compound 36 (40mg), triethylamine (60mg), the fluoro- 3- acetonitriles -1- aniline (22mg) of 4- are dissolved in dichloromethane In (3mL), 5 degree or so are then cooled the temperature to, reaction system then is added in TBTU (70mg), 12h is reacted at room temperature, adds water Organic phase is spin-dried for, crude product column chromatography obtains compound 37 by (15mL), dichloromethane (3*20mL) extraction, anhydrous sodium sulfate drying (40mg) ESI-MS, (M+H=525.11)
Step 37：
Compound 37 (40mg) is dissolved in dichloromethane (2mL) and then reaction system is added in 4NHCl (1mL), under 30 degree 2h is reacted, reaction solution is spin-dried for, saturated sodium bicarbonate solution tune pH value to 7-8, ethyl acetate (3*10mL) extraction, anhydrous slufuric acid Sodium is dried, and is spin-dried for organic phase, crude product obtains compound 40a (12mg) through column chromatography for separation
Embodiment 21：The synthesis of compound 40b
With reference to the step 31-36 of embodiment 20, difference is to use the bromo- 1- fourths of 3- in step 32 preparation method of compound 37b Alkene replaces propylene bromine.
According to the step 37 of embodiment 20, compound 37 only need to be replaced with compound 37b, other conditions are constant, through column layer Analyse (normal heptane：Ethyl acetate=2：1) target product 40b (6mg).
Embodiment 22：The synthesis of compound 40c
With reference to the step 31-36 of embodiment 20, difference is to use the different evil of 4- methyl in step 32 preparation method of compound 37c Azoles benzyl -1- amylenes replace propylene bromine according to the step 37 of embodiment 20, and compound 37 only need to be replaced with compound 37c, other Condition is constant, through column chromatography (normal heptane：Ethyl acetate=2：1) target product 40c (13mg).
Embodiment 23：The synthesis of compound 40d
With reference to the step 31-36 of embodiment 20, difference is to use 1- isopropyls-in step 32 preparation method of compound 37d 1- propylene replaces propylene bromine, with 3,4- difluoro-anilines instead of the fluoro- 3- cyano-anilines of 4- in step 35.
According to the step 37 of embodiment 20, compound 37 only need to be replaced with compound 37d, other conditions are constant, through column layer Analyse (normal heptane：Ethyl acetate=2：1) target product 40d (12mg).
Embodiment 24：The synthesis of compound 40e
With reference to the step 31-36 of embodiment 20, difference is to use 1- isopropyls-in step 32 preparation method of compound 37e 1- propylene replaces propylene bromine, replaces the fluoro- 3- cyano-anilines of 4- with the fluoro- aniline of 3- difluoromethyls -4- in step 35.
According to the step 37 of embodiment 20, compound 37 only need to be replaced with compound 37e, other conditions are constant, through column layer Analyse (normal heptane：Ethyl acetate=2：1) target product 40e (13mg).
Biological examples -- anti-HBV activity is tested
Experiment one：Effect on hepatitics B virus in vitro nucleocapsid assembling activity test method
Main agents and raw material：
C150 albumen is that Yao Ming Kants company expresses and purifies；
Purchased from Thermo Fischer Scient Inc..
Protein fluorescence marks：
150 μ L 2%w/v skim milks are added per hole to 96 orifice plates, are incubated at room temperature 2 hours.Skim milk is sopped up, is spent It is dried after ionized water cleaning, room temperature preservation.By C150 albumen (often 3 milligrams of pipe) 5ml Hitrap desalting column desalinations.To every pipe 50mM is added in C150 albumen after desalination20 μ l of fluorescent dye are uniformly mixed, and 4 DEG C are protected from light overnight incubation.With Sephadex G-25 gel filtrations remove the fluorescent dye not combined with C150.The fluorescent label efficiency of C150 is calculated, formula is such as Under：
Wherein,
Indicate the concentration of fluorescent marker；
[C150Bo] indicates the concentration of fluorescent marker protein；
A504 indicates the light absorption value of wavelength 504nM；
A280 indicates the light absorption value of wavelength 280nM；
M-1Indicate the inverse of molar concentration.
Diluted chemical compound：
Compound stock solutions are diluted to 6mM with DMSO, then 600 μM are diluted to 50mM HEPES, then use 10%DMSO/ Further 3 times of 50mM HEPES are serially diluted 8 concentration.
C150Bo is diluted to 2 μM with 50mM HEPES.Take the compound of 37.5 μ L C150Bo and the 2.5 each concentration of μ L It is added to mixing in 96 hole reaction plates, is incubated at room temperature 15 minutes.The 750mM NaCl/50mM HEPES of 10 μ l are taken to be added to reaction The final concentration of 150mM of Kong Zhong, NaCl.
0% albumen assembles control wells, and the final concentration of 0mM of the 50mM HEPES, NaCl of 10 μ L is added.
100% albumen assembles control wells, and the final concentration of 1M of 5M the NaCl/50mM HEPES, NaCl of 10 μ L is added.
DMSO final concentration of 0.5%, final concentration of 30 μM of compound highest, final concentration of 1.5 μM of C150Bo.Incubation at room temperature 1 hour.Measure fluorescence signal (exciting light 485nm；Emit light 535nm).
Data analysis
% albumen assembling=[1- (sample fluorescence value -1M NaCl fluorescent values)/(0M NaCl fluorescent value -1M NaCl fluorescence Value)] × 100.
IC50Value is calculated by prism softwares, and equation is as follows：
Y=Bottom+ (Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
Wherein, X indicates that the logarithm of concentration, Y indicate that effect value, Y originate from bottom and be fitted to top with S types；
Bottom indicates the bottom of curve；Top indicates the top of curve；
HillSlope is indicated：The absolute value of the greatest gradient of curve.
Experiment two：It is measured in the anti-hepatitis B activity of HepG2.2.15 cells
Main agents：
QIAamp 96DNA Blood Kits (12) (Qiagen, article No. 51162)；
FastStart Universal Probe Master (Roche, article No. 04914058001)；
Cell-titer Glo detection reagents (Promega, article No. G7573).
Diluted chemical compound：External Anti-HBV effect experiment and equal 3 times of all compounds of cytotoxicity experiment are serially diluted, 8 Concentration.The final initial concentration of test-compound is 30 μM, and the final initial concentrations of reference compound GLS4 are 1 μM, DMSO final concentrations It is 0.5%.
It is inoculated with HepG2.2.15 cells (4 × 104Cells/well) to 96 orifice plates, at 37 DEG C, 5%CO2Overnight incubation.Second It, is added in the fresh medium to culture hole of the compound containing various concentration.5th day, culture solution old in culture hole is absorbed, The fresh medium of the compound containing various concentration is added.
8th day, the supernatant in culture hole is collected, the HBV DNA, qPCR for extracting in supernatant detect HepG2.2.15 HBV DNA contents in supernatant.After collecting supernatant, then supplemented medium and Cell-titer Glo reagents into culture hole, enzyme Mark instrument detects the values of chemiluminescence in each hole.
Active calculation formula is as follows:
Y=Bottom+ (Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
Wherein, X indicates that the logarithm of concentration, Y indicate that effect value, Y originate from bottom and be fitted to top with S types；
Bottom indicates the bottom of curve；Top indicates the top of curve；
HillSlope is indicated：The absolute value of the greatest gradient of curve.
Experiment three：Cytotoxicity assay
The cytotoxicity of untested compound is tested using HepG2 cells, by these cells in untested compound In the presence of be incubated 4 days.Cell viability is assessed using resazurin measurement.
In table：
A1 indicates that IC50 (μM) exists<1；
A2 indicates IC50 (μM) between 1~100；
A3 indicates that IC50 (μM) exists>100；
B1 indicates that EC50 (μM) exists<Between 1；
B2 indicates EC50 (μM) between 1~100；
B3 indicates that EC50 (μM) exists>100；
Wherein, control compound is：
(referring to WO2014184350A1)
The result shows that：The effect on hepatitics B virus in vitro nucleocapsid assembling activity and anti-hepatitis B activity of the compound of the present invention It is excellent, and cytotoxicity is lower.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. it is a kind of as compound shown in formula A or its stereoisomer or tautomer or its pharmaceutically acceptable salt, Hydrate or solvate,
Wherein,
R1、R2It is each independently selected from the following group：Hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C10Cycloalkanes Base, substituted or unsubstituted heteroatomic 3-10 membered heterocycloalkyls, the substitution or unsubstituted for being selected from the group N, S and O with 1-3 C6-C10Aryl, halogen or the substituted or unsubstituted heteroatomic 5-10 members heteroaryl for being selected from the group N, S and O with 1-3 Base, the R1、R2In, the substitution refers to be replaced by one or more substituent groups selected from the group below：- OH, halogen, C1-C6Alkane Base, halogenated C1-C6Alkyl, C1-C6Alkoxy ,=O ,-O-；
X is CR11R12Or-CR11=CR12-；Wherein, R11And R12It is each independently selected from the following group：H, halogen, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3- C10Naphthenic base, it is substituted or unsubstituted with 1-3 be selected from the group the heteroatomic 3-10 membered heterocycloalkyls of N, S and O, substitution or Unsubstituted C6-C10Aryl, the substituted or unsubstituted heteroatomic 5-10 members heteroaryl for being selected from the group N, S and O with 1-3 Base, substituted or unsubstituted C1-3Alkyl-R7Or-C (=O) OC1-4Alkyl；The wherein described R7It is selected from the group：Halogen, C1-C3Alkane Base substituted or unsubstituted be selected from the group the heteroatomic 5-10 unit's heteroaryls of N, S and O with 1-2, have 1-3 choosing From the heteroatomic 3-7 membered heterocycloalkyls of the following group N, S and O ,-NR9R10, wherein the R9、R10It is each independently selected from：H、C1- C3Alkyl, halogenated C1-C3Alkyl；
Alternatively,
The R11And R12The heteroatomic substitution or not that N, S and O are selected from the group with 1-3 is collectively formed with adjacent C atoms Substituted 3-7 membered heterocycloalkyls, wherein the substitution of the 3-7 membered heterocycloalkyls refers to by one or more substitutions selected from the group below Base is replaced：- OH, halogen, methoxyl group ,-O- ,-C (=O) OC1-4Alkyl, benzyl, C1-4Alkyl, halogenated C1-4Alkyl,
Also, the R11、R12In, the substitution refers to be replaced by one or more substituent groups selected from the group below：- OH, halogen, C1-C6Alkyl, halogenated C1-C6The C that alkyl ,-OH replace1-C6Alkyl, C1-C6Alkoxy ,-C (=O) OC1-4Alkyl；
Y is substituted or unsubstituted C1-C7Alkylidene or C2-C7Alkenylene, in the Y, the substitution refers to by selected from the group below one A or multiple substituent groups are replaced：C1-C4Alkyl, halogen ,-OH, preferably C1-C4Alkyl or-OH；
Z is selected from the group：NH, O or a key；
Ring C is the substituted or unsubstituted heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O with 1-3, the ring C In, the substitution refers to be replaced by one or more substituent groups selected from the group below：C1-C3Alkyl, C3-C4Naphthenic base ,-CN or halogen Element；
Ring B is substituted or unsubstituted C6-C10Aryl, the substituted or unsubstituted miscellaneous original for being selected from the group N, S and O with 1-3 The 5-10 unit's heteroaryls of son；In the ring B, the substitution refers to be replaced by one or more substituent groups selected from the group below：C1-C3 Alkyl, C3-C4Naphthenic base ,-CN or halogen；
Ra、Rb、Rc、RdFor the substituent group of any position on ring B, it is each independently selected from the following group：H, halogen ,-CN, hydroxyl, ammonia Base, carboxyl ,-(C=O)-substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8It is alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C1-C8Alkylamino radical, substituted or unsubstituted C1-C8 Alkoxy, substituted or unsubstituted C3-C10Naphthenic base, the substituted or unsubstituted miscellaneous original for being selected from the group N, S and O with 1-3 The 3-10 membered heterocycloalkyls of son, substituted or unsubstituted C6-C10Aryl substituted or unsubstituted there is 1-3 to be selected from the group N, the heteroatomic 5-10 unit's heteroaryls of S and O；The Ra、Rb、Rc、RdIn, " substitution " refers to by one selected from the group below Or multiple substituent groups are replaced：Halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkoxy, C3-C8Naphthenic base, halogenated C3-C8Naphthenic base, oxo ,-CN, hydroxyl, amino, carboxyl, C6-C10Aryl, halogenated C6-C10Virtue Base, the heteroatomic 5-10 unit's heteroaryls that N, S and O are selected from the group with 1-3, it is halogenated have 1-3 it is a be selected from the group N, S and The heteroatomic 5-10 unit's heteroaryls of O.
2. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable Salt, hydrate or solvate, which is characterized in that R1、R2It is each independently selected from the following group：Hydrogen, substituted or unsubstituted C1-C10 Alkyl, substituted or unsubstituted C3-C10Naphthenic base, the substituted or unsubstituted hetero atom for being selected from the group N, S and O with 1-3 3-10 membered heterocycloalkyls, substituted or unsubstituted C6-C10Aryl substituted or unsubstituted there is 1-3 to be selected from the group N, S With the heteroatomic 5-10 unit's heteroaryls of O, the R1、R2In, the substitution refers to by one or more substituent groups institute selected from the group below Substitution：- OH, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy ,-O-；
X is CR11R12Or-CR11=CR12-；Wherein, R11And R12It is each independently selected from the following group：H, halogen, substitution or unsubstituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3- C10Naphthenic base, it is substituted or unsubstituted with 1-3 be selected from the group the heteroatomic 3-10 membered heterocycloalkyls of N, S and O, substitution or Unsubstituted C6-C10Aryl, the substituted or unsubstituted heteroatomic 5-10 members heteroaryl for being selected from the group N, S and O with 1-3 Base, C1-3Alkyl-R7Or-C (=O) OC1-4Alkyl；The wherein described R7It is selected from the group：Halogen, C1-C3Alkyl, substitution or do not take In generation, is selected from the group the miscellaneous of N, S and O with the 1-2 heteroatomic 5-10 unit's heteroaryls for being selected from the group N, S and O, with 1-3 The 3-7 membered heterocycloalkyls of atom ,-NR9R10, wherein the R9、R10It is each independently selected from：H、C1-C3Alkyl, halogenated C1- C3Alkyl；
Alternatively,
The R11And R12The heteroatomic substitution or not that N, S and O are selected from the group with 1-3 is collectively formed with adjacent C atoms Substituted 3-7 membered heterocycloalkyls, wherein the substitution of the 3-7 membered heterocycloalkyls refers to by one or more substitutions selected from the group below Base is replaced：- OH, halogen, methoxyl group ,-O- ,-C (=O) OC1-4Alkyl, benzyl, C1-4Alkyl, halogenated C1-4Alkyl,
Also, the R11、R12In, the substitution refers to be replaced by one or more substituent groups selected from the group below：- OH, halogen, C1-C6Alkyl, halogenated C1-C6The C that alkyl ,-OH replace1-C6Alkyl, C1-C6Alkoxy ,-C (=O) OC1-4Alkyl；
Ra、Rb、Rc、RdFor the substituent group of any position on phenyl ring, definition is as described in claim 1.
3. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable Salt, hydrate or solvate, which is characterized in that R1For H, unsubstituted C1-C10Alkyl, C3-C10Naphthenic base or by-OH ,= O ,-O- or the C of halogen substitution1-C10Alkyl.
4. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable Salt, hydrate or solvate, which is characterized in that ring C be substituted or unsubstituted 5 yuan or 6 unit's heteroaryls, it is described substitution refer to by One or more substituent group selected from the group below is replaced：Methyl ,-CN or halogen.
5. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable Salt, hydrate or solvate, which is characterized in that the Ra、Rb、Rc、RdIt is each independently selected from the following group：H, halogen ,-CHF2、- CF2Methyl ,-CH2F、-CF3、-OCF3、-CN、-C3-C4Naphthenic base or-C1-C4Alkyl.
6. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable Salt, hydrate or solvate, which is characterized in that the formula A compounds are selected from the group：
7. a kind of compound as described in claim 1 or its stereoisomer or tautomer or its of preparing can pharmaceutically connect The method of salt, hydrate or the solvate received, shown formula A compounds are -1 compound represented of Formula VII, the method includes Step (I)：
Alternatively,
Shown formula A compounds are -1 compound represented of Formula VIII, and the method includes the steps (II)：
In the step (I) or (II), R2、Ra、Rb、Rc、Rd, ring C, ring B definition with described in claim 1, m, n are respectively 1- 5 positive integer；
Wherein, R3It is selected from the group：H, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl takes Generation or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C10Naphthenic base substituted or unsubstituted there is 1-3 to be selected from down The heteroatomic 3-10 membered heterocycloalkyls of group N, S and O, substituted or unsubstituted C6-C10Aryl substituted or unsubstituted has 1-3 heteroatomic 5-10 unit's heteroaryls, the C for being selected from the group N, S and O1-3Alkyl-R7,-C (=O) OC1-4Alkyl；It is wherein described R7It is selected from the group：Halogen, C1-C3Alkyl, the substituted or unsubstituted heteroatomic 5- for being selected from the group N, S and O with 1-2 10 unit's heteroaryls, heteroatomic 3-7 the membered heterocycloalkyls ,-NR for being selected from the group N, S and O with 1-39R10, wherein the R9、 R10It is each independently selected from：H、C1-C3Alkyl, halogenated C1-C3Alkyl.
8. a kind of pharmaceutical composition, it includes (1) compound described in claim 1 or its stereoisomers or tautomerism Body or its pharmaceutically acceptable salt, hydrate or solvate；(2) pharmaceutically acceptable carrier.
9. compound as follows：
10. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable The purposes of salt, hydrate or solvate or pharmaceutical composition according to any one of claims 8 is used to prepare prevention and/or treatment second The drug of Hepatitis virus infection.
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