CN103664925B - The Dihydropyrimidines of heteroaryl substitution and its application in medicine - Google Patents

The Dihydropyrimidines of heteroaryl substitution and its application in medicine Download PDF

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CN103664925B
CN103664925B CN201310404875.3A CN201310404875A CN103664925B CN 103664925 B CN103664925 B CN 103664925B CN 201310404875 A CN201310404875 A CN 201310404875A CN 103664925 B CN103664925 B CN 103664925B
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1h
alkyl
esi
thiadiazoles
compound
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CN201310404875.3A
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CN103664925A (en
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任青云
张英俊
刘辛昌
聂飚
王超磊
S·戈尔德曼
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广东东阳光药业有限公司
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Abstract

Purposes the present invention relates to a kind of Dihydropyrimidines of heteroaryl substitution and its as medicine, especially as the application of the medicine for treating and preventing hepatitis B.Specifically, the present invention relates to the compound shown in logical formula (I) or (Ia) or their enantiomter, diastereoisomer, hydrate, solvate or pharmaceutically acceptable salt, wherein each variable is defined as in the description.The invention further relates to the compound shown in logical formula (I) or (Ia) or the purposes of their enantiomter, diastereoisomer, hydrate, solvate or pharmaceutically acceptable salt or its pharmaceutical composition, especially as the purposes of the medicine for treating and preventing hepatitis B.

Description

The Dihydropyrimidines of heteroaryl substitution and its application in medicine

Invention field

Purposes the present invention relates to a kind of Dihydropyrimidines of heteroaryl substitution and its as medicine, especially makees For the application of the medicine for treating and preventing hepatitis B.The invention further relates to the dihydropyridine of these heteroaryls substitution Compound is with other antivirotics, and the medicine containing these compositions, in particular for treating and preventing hepatitis B (HBV) Infection.

Background of invention

Hepatitis type B virus belongs to hepatovirus section.It can cause acute and/or lasting/progressive chronic disease.Hepatitis B Virus also cause in pathomorphism many other Clinical signs --- especially the chronic inflammation of liver, hepatic sclerosis and liver are thin The canceration of born of the same parents.In addition, can have a negative impact during advancing of disease with the co-infection of hepatitis D.

The conventional dose for being licensed for treating chronic hepatitis treatment is interferon and Lamivudine (lamivudine).So And interferon only has medium activity, and there is higher toxicity;Although Lamivudine (lamivudine) has good Good activity, but amplification is rapid over the course for the treatment of for its drug resistance, and the effect that usually had a rebound after treatment is stopped, rummy Fixed (3-TC) > of husband IC50It is worth for 300nM (Science, 299 (2003), 893-896).

Deres etc. is reported using Bay41-4109, Bay39-5493 as the cyclosubstituted dihydropyridine of the heteroaryl of representative (HAP) compound, such compound can be by preventing the formation of normal nucleocapsid from having the function that to suppress hbv replication. Bay41-4109 is demonstrated by preferable drug metabolism parameter (Science, 299 (2003), 893-896) in clinical studies.It is right The research of its mechanism of action finds that the cyclosubstituted Dihydropyrimidines of heteroaryl pass through the 113-143 amino with core protein Sour residue effect, the angle between the dimer to form nucleocapsid is changed, result in unstable expansion nucleocapsid, accelerated The degraded (Biochem.Pharmacol.66 (2003), 2273-2279) of core protein.

Present need exist for the new compound that can effectively serve as antiviral drugs, especially as treatment and/ Or the medicine of prevention hepatitis B.

Abstract of invention

The present invention relates to the Dihydropyrimidines of heteroaryl substitution and treatment and the method for prevention HBV infection.

Especially, compound involved in the present invention, and its pharmaceutically acceptable composition, can effectively suppress HBV infection.On the one hand, the compound the present invention relates to one kind as shown in formula (I) or (Ia),

Or its enantiomter, diastereoisomer, dynamic isomer, hydrate, solvate or pharmaceutically acceptable Salt, wherein:

A is a key ,-O- ,-S- or-N (R5)-;

R is-X-Z;

X is-(CR7R7a)m- or-C (=O)-;

Z is heteroaryl, or Z is the subformula as shown in formula (II):

Wherein, B is a key ,-(CR7R7a)m- or-C (=O)-;

W is CR7Or N;

Y is-(CR7R7a)m- ,-O- ,-S- ,-S (=O)q- or-N (R6)-;

R1For aryl or heteroaryl;

R2For hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkanes Base alkyl, heterocyclic radical, cycloheteroalkylalkyl or alkoxy carbonyl group;

R3For thiadiazolyl group;Wherein described thiadiazolyl group can by one or more selected from hydrogen, fluorine, chlorine, bromine, iodine, alkyl, Alkoxy, alkylamino, haloalkyl, cyano group, hydroxyl, the substituent of nitro or amino are substituted;

R4For hydrogen, deuterium or C1-C4Alkyl;

R5For hydrogen, deuterium, alkyl ,-(CR7R7a)m- C (=O) O-R8, alkenyl or alkynyl;

R6For hydrogen, deuterium, alkyl ,-(CR7R7a)m- C (=O) O-R8、-(CR7R7a)m- C (=O) R8、-(CR7R7a)m- C (= O)-(CR7R7a)m-OR8、-(CR7R7a)m- C (=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m- C (=O)- (CR7R7a)m-N(R8R8a), alkenyl or alkynyl;

Each R7aAnd R7It independently is hydrogen, deuterium, F, Cl, Br, haloalkyl, alkyl or aryl;Or R7、R7aBe attached thereto C atoms form cycloalkyl together;

Each R8And R8aIndependently be hydrogen, deuterium, alkyl, haloalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, Cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or cycloheteroalkylalkyl;

Each R9Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylamino, haloalkyl, hydroxyl, nitro, Amino, trifluoromethoxy or cyano group;

Each n independently is 0,1,2 or 3;

Each m independently is 0,1,2,3 or 4;

Each q independently is 0,1 or 2;With

Wherein, described aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, aryl Alkyl, heteroaryl alkyl, heterocyclic radical and cycloheteroalkylalkyl can be optionally by hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkane Amino, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl are monosubstituted or identical or different It is polysubstituted.

Some embodiments wherein:

Z is the quinary heteroaryl containing 3 or 4 nitrogen-atoms, the heteroaryl can by one or more selected from hydrogen, deuterium, Fluorine, chlorine, bromine, iodine, C1-C4Alkyl, cyano group, hydroxyl, nitro, amino, the substituent of trifluoromethyl or trifluoromethoxy are substituted, Or Z is the subformula as shown in formula (III):

Wherein, B is a key ,-(CR7R7a)m- or-C (=O)-;

Y is-(CR7R7a)m- ,-O- ,-S- ,-S (=O)q- or-N (R6)-;

Each R6It independently is hydrogen, deuterium, C1-C4Alkyl, C2-C4Alkenyl ,-(CR7R7a)m- C (=O)-(CR7R7a)m-O- (CR7R7a)m-O-R8、-(CR7R7a)m- C (=O) O-R8、-(CR7R7a)m- C (=O) R8、-(CR7R7a)m- C (=O)-(CR7R7a)m- N(R8R8a)、-(CR7R7a)m- C (=O)-(CR7R7a)m-OR8Or C2-C4Alkynyl;

Each R7aAnd R7It independently is hydrogen, deuterium, F, Cl, Br, C1-C6Alkyl, C1-C4Haloalkyl or C6-C10Aryl;Or R7、 R7aC is formed together with the C atoms being attached thereto3-C8Cycloalkyl;

Each R8And R8aIt independently is hydrogen, deuterium, C1-C6Alkyl, C1-C4Haloalkyl, C6-C10Aryl, C6-C10Aryl C1-C4 Alkyl, C1-C9Heteroaryl, C1-C9Heteroaryl C1-C4Alkyl, C3-C10Cycloalkyl, C3-C10Cycloalkyl C1-C4Alkyl, C2-C10Heterocycle Base or C2-C10Heterocyclic radical C1-C4Alkyl;

Each R9It independently is hydrogen, deuterium, C1-C4Alkyl, fluorine, chlorine, bromine, iodine, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Halogen Substituted alkyl, hydroxyl, nitro, amino, trifluoromethoxy or cyano group;

Each n independently is 0,1,2 or 3;

Each m independently is 0,1,2,3 or 4;

Each q independently is 0,1 or 2.

In other embodiments, wherein:The subformula that Z is as follows:

Each R6It independently is hydrogen, deuterium, methyl, ethyl, propyl group ,-(CR7R7a)m- C (=O)-(CR7R7a)m-O-(CR7R7a)m- O-R8、-(CR7R7a)m- C (=O) O-R8、-(CR7R7a)m- C (=O) R8、-(CR7R7a)m- C (=O)-(CR7R7a)m-N(R8R8a) Or-(CR7R7a)m- C (=O)-(CR7R7a)m-OR8

Each R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls, 1- methyl-props Base or phenyl;

Each R8And R8aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls, phenyl or 1- Methyl-propyl;

Each R9And R9aIt independently is hydrogen, deuterium, amino, cyano group, methyl, ethyl or propyl group;

Each n independently is 0,1 or 2.

In some embodiments, R3For thiadiazolyl group, wherein the thiadiazolyl group can by one or more selected from hydrogen, Deuterium, fluorine, chlorine, bromine, iodine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Haloalkyl, cyano group, hydroxyl, nitro or The substituent of amino is substituted.

In other embodiment, R3For following subformula:

Each R10It independently is hydrogen, deuterium, fluorine, chlorine, bromine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Halo Alkyl, cyano group, hydroxyl, nitro or amino.

In other embodiments, R1For C6-C10Aryl, wherein the aryl can be taken by fluorine, deuterium, chlorine, nitro or bromine list In generation, is identical or different polysubstituted;

R2For hydrogen, deuterium or C1-C4Alkyl;

R5For hydrogen, deuterium or C1-C4Alkyl.

In some embodiments,

R1For phenyl, wherein the phenyl can by fluorine, deuterium, chlorine or bromine it is monosubstituted or identical or different polysubstituted.

In some embodiments, the present invention has the compound as shown in logical formula (IV) or (IVa),

Or its enantiomter, diastereoisomer, dynamic isomer, hydrate, solvate or pharmaceutically acceptable Salt, wherein:

Z is triazolyl, tetrazole radical, wherein the triazolyl or tetrazole radical can by one or more selected from hydrogen, deuterium, fluorine, Chlorine, bromine, iodine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Haloalkyl, cyano group, hydroxyl, nitro or amino Substituent is substituted;

Or Z is the subformula as shown in formula (V):

Y is-(CR7R7a)m- ,-O- ,-S- ,-S (=O)q- or-N (R6)-;

R2For hydrogen, deuterium or C1-C4Alkyl;

R3For thiadiazolyl group;Wherein described thiadiazolyl group can be by one or more selected from hydrogen, deuterium, chlorine, C1-C6Alkyl, cyanogen Base, hydroxyl, the substituent of nitro or amino are substituted;

Each R6It independently is hydrogen, deuterium, C1-C4Alkyl ,-(CR7R7a)m- C (=O) O-R8、-(CR7R7a)m- C (=O) R8、- (CR7R7a)m- C (=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m- C (=O)-(CR7R7a)m-N(R8R8a) or- (CR7R7a)m- C (=O)-(CR7R7a)m-OR8

Each R7aAnd R7It independently is hydrogen, deuterium, C1-C6Alkyl, C1-C4Haloalkyl or C6-C10Aryl;

Each R8And R8aIt independently is H, deuterium, C6-C10Aryl or C1-C6Alkyl;

Each R9It independently is hydrogen, deuterium, amino, cyano group or C1-C4Alkyl;

Each R11It independently is fluorine, deuterium, chlorine, nitro or bromine;

Each k independently is 1 or 2;

Each m independently is 0,1,2,3 or 4;

Each n independently is 0,1 or 2;

Each q independently is 0,1 or 2.

In some embodiments, Z is triazolyl, tetrazole radical, wherein the triazolyl or tetrazole radical can by one or It is multiple selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group, cyano group, hydroxyl, nitro or The substituent of amino is substituted;Or Z is the subformula as shown in formula (V):

Y is-(CR7R7a)m- ,-O- ,-S- ,-S (=O)q- or-N (R6)-;

Each R6It independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group ,-(CR7R7a)m- C (=O) O- R8、-(CR7R7a)m- C (=O) R8、-(CR7R7a)m- C (=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m- C (= O)-(CR7R7a)m-N(R8R8a) or-(CR7R7a)m- C (=O)-(CR7R7a)m-OR8

Each R7aAnd R7It independently is hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls, 2- Methyl-propyl or phenyl;

Each R8And R8aIt independently is H, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls, benzene Base or 2- methyl-propyls;

Each R9It independently is hydrogen, deuterium, amino, cyano group, methyl, ethyl, propyl group, isopropyl, butyl or the tert-butyl group;

Each q independently is 0,1 or 2;

Each n independently is 0,1 or 2;

Each m independently is 0,1,2,3 or 4.

In other embodiments, Z is independently selected from following subformula:

In other embodiments, R3Independently selected from following subformula:

On the one hand, the present invention relates to a kind of compound, or its enantiomter, diastereoisomer, dynamic isomer, medicine Acceptable salt on, the salt are acylate, inorganic acid salt or the salt obtained by alkali.

In certain embodiments, inorganic acid salt of the present invention is hydrochloride, hydrobromate, perchlorate, phosphate Or sulfate.

In certain embodiments, acylate of the present invention is carboxylate or sulphur hydrochlorate.

In certain embodiments, carboxylate of the present invention is acetate, oxalates, maleate, tartrate, lemon Lemon hydrochlorate, succinate or malonate.

In certain embodiments, sulphur hydrochlorate of the present invention is mesylate, esilate, benzene sulfonate, toluene Sulfonate or naphthalene sulfonate.

In certain embodiments, the salt of the present invention obtained by alkali is alkali metal, alkaline-earth metal, ammonium or N+ (R12)4Salt.

Wherein, in other embodiment, alkali metal or alkali salt of the present invention are sodium salt, lithium salts, potassium Salt, calcium salt or magnesium salts.

Wherein, in other embodiment, R of the present invention12It is H, C1-C4Alkyl, C6-C10Aryl, C6-C10Virtue Base C1-C4Alkyl etc..

On the one hand, the present invention relates to pharmaceutical composition, wherein pharmaceutical composition to include compound of the present invention, and its Pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or combinations thereof.

In certain embodiments, pharmaceutical composition of the present invention, it further includes Anti-HBV drugs.

In certain embodiments, pharmaceutical composition of the present invention, wherein Anti-HBV drugs are that HBV polymerize enzyme level Agent, immunomodulator or interferon.

In certain embodiments, pharmaceutical composition of the present invention, wherein Anti-HBV drugs have Lamivudine, for than husband It is fixed, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, grace His bent shore, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta- 1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a - A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol, or third Pa germanium.

On the other hand, the present invention relates to described compound or described pharmaceutical composition prepare be used to preventing, handle, Purposes in the medicine for the treatment of or mitigation patient's viral disease.

In certain embodiments, purposes of the present invention, wherein viral disease refer to hepatitis B infection or B-mode Disease caused by virus infection.

Wherein, in other embodiment, purposes of the present invention, wherein hepatitis B infection cause disease to refer to Hepatic sclerosis or canceration of hepatic cell.

In certain embodiments, purposes of the present invention, wherein viral disease refer to hepatitis B disease.

On the other hand, the present invention relates to described compound or pharmaceutical composition come prepare be used for prevent, handle, treat or Mitigate the purposes of the medicine of patient's hepatitis B disease, including give patient's compound as described in the present invention or of the present invention Pharmaceutical composition dose therapeutically effective.

Another aspect of the present invention is related to prevention, processing, treatment or the method for mitigating patient's HBV illnesss, and methods described includes Patient is administered using the compound pharmaceutically acceptable effective dose of the present invention.

Another aspect of the present invention is related to prevention, processing, treatment or the method for mitigating patient's HBV illnesss, and methods described includes Patient is administered using the pharmaceutically acceptable effective dose of the pharmaceutical composition of the compound containing the present invention.

Another aspect of the present invention is directed to use with a kind of compound of the invention and is used to preventing, handle or treating patient to produce HBV illnesss, and mitigate the purposes of the medicine of its order of severity.

Another aspect of the present invention is directed to use with a kind of pharmaceutical composition of the compound comprising the present invention and is used in advance to produce Anti-, processing or treatment patient's HBV illnesss, and mitigate the purposes of the medicine of its order of severity.

Some of embodiments are that the organism is mammal, and other embodiment is that the organism is people Class.Other embodiment is that methods described further includes kinases contact with HBV therapeutic agents.

Another aspect of the present invention is related to a kind of method for suppressing HBV infection, and this method includes cell and the chemical combination of the present invention Thing or composition can effectively suppress HBV dose of exposure.Other embodiment is that methods described further includes cell With the contact of HBV agent.

Another aspect of the present invention is related to the treatment to patient's HBV diseases, and this method, which includes patient, to be needed needed for effectively treatment The dosage of compound or its composition administration of the present invention.Other embodiment is that methods described further includes HBV Administration.

Another aspect of the present invention is related to a kind of method for suppressing patient's HBV infection, and this method, which includes patient, to be needed effectively to control Compound of the invention needed for treatment or the dosage of its composition administration.Other embodiment is that methods described is further Include the administration of HBV treatments.

Another aspect of the present invention is related to the method for preparation, separation and the purifying for the compound that formula (I) or formula (Ia) are included.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

Detailed description of the invention book

Definition and general terms

The present invention will in detail list the document corresponding to the content of the materialization of determination, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, and these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to Method and material described by this, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.There is many documents and similar material to distinguish or contradict with the present patent application, including but be not limited to term Definition, the usage of term, the technology of description, or the scope controlled as the present patent application.

The present invention will apply defined below unless other aspects show.According to the purpose of the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry, " Thomas Sorrell, University Science Books, Sausalito:1999, And " March ' s Advanced Organic Chemistry, " by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007, therefore all contents have all merged bibliography.

As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. In general, term " substituted ", represents that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless Other aspects show that an optional substituted radical can have a substituent to be taken in each commutable position of group Generation.When more than one position can be substituted by one or more substituents selected from specific group in given structural formula, that Substituent with identical or different can substitute in each position.Wherein described substituent can be, but be not limited to, hydroxyl Base, amino, halogen, cyano group, trifluoromethoxy, aryl alkyl, heteroaryl alkyl, haloalkyl, cycloheteroalkylalkyl, alkylamino, Trifyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl take Substituted alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, etc...

Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base with individually optional can be substituted by one or more substituents described in the invention.Some of embodiments are alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom.The further example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), 2- methyl-propyls or isobutyl group (i-Bu ,-CH2CH(CH3)2), 1- methyl-propyls or sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (-CH(CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3) CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH (CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- diformazans Base -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..Term " alkyl " and its prefix " alkane " make here With the saturated carbon chains all comprising straight chain and side chain.Term " alkylene " uses here, represents to hydrogenate from straight or branched saturated carbon Thing eliminates the saturation bivalent hydrocarbon radical that two hydrogen atoms obtain, and such example includes, but is not limited to, methylene, and ethylidine is secondary Isopropyl etc..

Either " haloalkyl " represents aliphatic group or alkyl by one to terminology used in the present invention " halogenated aliphatic " Individual or multiple identical or different halogen atoms are substituted, and wherein aliphatic group or alkyl have and contained as described in the present invention Justice, halogen atom are fluorine, chlorine, bromine or iodine, and such example includes, but is not limited to trifluoromethyl, trifluoroethyl etc..

Term " divalent group " used in the present invention represents to remove the base obtained by two hydrogen atoms from target molecule Group.Some of embodiments are to remove two hydrogen atoms from the same atom of target molecule;Other embodiment is, Get on two hydrogen atoms from the not homoatomic of target molecule.

Term " alkenyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is insatiable hunger And state, i.e. a C-C is sp2Double bond, the group of its alkenyl groups can be with individually optional by one or more institutes of the present invention The substituent of description is substituted, including group has negation " just " or " E " " Z " positioning, wherein specific example includes, but not It is limited to, vinyl (- CH=CH2), pi-allyl (- CH2CH=CH2), etc..

Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is insatiable hunger And state, i.e. a C-C is the keys of sp tri-, and wherein alkynyl group can be with individually optional by one or more described in the invention Substituent is substituted, and specific example includes, but is not limited to, acetenyl (CH of-C three), propargyl (- CH2The CH of C tri-), etc..

Term " annular aliphatic ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refers to monovalence or multivalence, non-aromatic, satisfies And/or part unsaturation ring, include monocyclic or 7-12 carbon atom two rings of 3-12 carbon atom.With 7-12 atom Bicyclic carbocyclic ring can be two rings [4,5], [5,5], [5,6] or [6,6] system, while have the bicyclic carbocyclic ring of 9 or 10 atoms can be with It is two rings [5,6] or [6,6] system.Suitable cyclic aliphatic group includes, but is not limited to, cycloalkyl, cycloalkenyl group and ring Alkynyl.The example of cyclic aliphatic group further comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta- 1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkene Base, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclododecane Base, etc..And " annular aliphatic ", carbocyclic ring ", " carbocylic radical " or " cycloalkyl " can be it is substituted or non-substituted, its Middle substituent can be, but be not limited to, hydroxyl, amino, halogen, cyano group, trifluoromethoxy, aryl alkyl, heteroaryl alkyl, Haloalkyl, cycloheteroalkylalkyl, alkylamino, trifyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl are miscellaneous Ring group, sulfydryl, nitro, aryloxy group, hydroxyl substituted alkyl group, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, etc..

Term " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably here, all referring to monocyclic, Bicyclic, or three-ring system, one or more atoms with individually optional can be substituted by hetero atom in its middle ring, and ring can be Full saturation or comprising one or more degrees of unsaturation, but the definitely not fragrant same clan, only a tie point are connected to other points Son gets on.One or more ring hydrogen atoms are taken by one or more substituents described in the invention individually optionally Generation.Some of embodiments are that " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " group are the monocyclic of 3-7 yuan of rings (1-6 carbon atom and selected from N, O, P, S 1,2 or 3 hetero atom, in this S or P optionally by one or more oxygen atom institutes Substitution is obtained as SO, SO2, PO, PO2Group, when described ring is three-membered ring, only one of which hetero atom), or 7-10 Bicyclic (the 4-9 carbon atom and optionally one or more in this S or P selected from N, O, P, S 1,2 or 3 hetero atom of member Oxygen atom substitutes to obtain as SO, SO2, PO, PO2Group).

Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocyclic fused formed group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, Azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxy amyl group, pyrazolinyl, Dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydroisoquinoline Base, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H- indyls Quinolizine base and N- pyridine radicals urea.The example of heterocyclic group also includes, two carbon on 1,1- dioxidothiomorpholinyl, and its middle ring Atom is substituted such as hybar X base by oxygen atom.And the heterocyclic radical can be substituted or non-substituted, wherein substituent It can be, but be not limited to, hydroxyl, amino, halogen, cyano group, trifluoromethoxy, aryl alkyl, heteroaryl alkyl, alkyl halide Base, cycloheteroalkylalkyl, alkylamino, trifyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic radical, mercapto Base, nitro, aryloxy group, hydroxyl substituted alkyl group, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, etc..

Term " cycloheteroalkylalkyl " includes the alkyl of heterocyclic radical substitution;Term " heterocyclylalkoxy " substitutes including heterocyclic radical Alkoxy, wherein oxygen atom is connected with the remainder of molecule;Term " heterocyclic radical alkylamino " includes the alkane of heterocyclic radical substitution Amino, wherein nitrogen-atoms are connected with the remainder of molecule;Wherein heterocyclic radical, alkyl, alkoxy and alkylamino radicals have such as Implication of the present invention.Such example includes, but is not limited to pyrroles's -2- methyl, morpholine -4- methyl, pyrroles's -2- methoxies Base, piperidines -2- ethyoxyls, piperazine -2- ethylaminos, morpholine -4- propoxyl group, morpholine -4- ethylaminos etc..

Term " hetero atom " represents one or more O, S, N, P and Si, including the form of N, S and any oxidation state of P;Primaryth, The form of secondary, tertiary amine and quaternary ammonium salt;Or the form that hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N (as 3,4- dihydros- N in 2H- pyrrole radicals), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).

Term " halogen " refers to F, Cl, Br or I.

Contain one or more degrees of unsaturation in " undersaturated " the expression part of term used in the present invention.

Term " alkoxy " used in the present invention, is related to alkyl, as defined in the present invention, passes through oxygen atom (" alkoxy ") is connected in main carbochain.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy can be by one The situation that individual or multiple halogen atoms are substituted.Wherein alkyl, alkenyl and alkoxy base have implication as described in the present invention, Such example includes, but is not limited to trifluoromethyl, trifluoromethoxy, and 2- is fluoride-based etc..

Term " aryl " can be used alone or the big portion as " aralkyl " " aralkoxy " or " aryloxy alkyl " Point, represent altogether containing the monocyclic of 6-14 yuan of rings, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are aromatic series , each of which member ring systems include 3-7 yuan of rings, and only an attachment point is connected with the remainder of molecule.Term " virtue Base " can be exchanged with term " aromatic rings " and used, as aromatic rings can include phenyl, naphthyl and anthracene.And the aryl can be with It is substituted or non-substituted, wherein substituent can be, but be not limited to, hydroxyl, amino, halogen, cyano group, trifluoromethoxy, Aryl alkyl, heteroaryl alkyl, haloalkyl, cycloheteroalkylalkyl, alkylamino, trifyl, aryl, heteroaryl, alcoxyl Base, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl substituted alkyl group, cycloalkyl, cycloalkyl-alkyl, alcoxyl Carbonyl, etc..

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Represent altogether containing the monocyclic of 5-14 yuan of rings, it is bicyclic, and three-ring system, wherein at least one member ring systems are aromatic, and at least One member ring systems includes one or more hetero atoms, and each of which member ring systems include 3-7 yuan of rings, and an only attachment point with Molecule remainder is connected.Term " heteroaryl " can exchange use with term " heteroaromatic " or " heteroaromatics ".And The heteroaryl can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydroxyl, amino, halogen, cyanogen Base, trifluoromethoxy, aryl alkyl, heteroaryl alkyl, haloalkyl, cycloheteroalkylalkyl, alkylamino, trifyl, virtue Base, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl substituted alkyl group, cycloalkyl, Cycloalkyl-alkyl, alkoxy carbonyl group, etc..

Other embodiment is, heteroaromatic includes following monocyclic, but it is monocyclic to be not limited to these:2- furyls, 3- Furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyrroles Piperidinyl, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazoles Base, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyranose, Pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2, 3- triazolyls, 1,2,3- thiadiazolyl group, 1,3,4- thiadiazolyl group, 1,2,5- thiadiazolyl group, pyrazinyl, 1,3,5-triazines base; Including following bicyclic, but it is bicyclic to be not limited to these:Benzimidazolyl, benzofuranyl, benzothienyl, indyl is (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls) etc..

Term " heteroaryl alkyl " represents that alkyl group is substituted by one or more heteroaryl groups, wherein alkyl group There is implication as described in the present invention with heteroaryl groups, such example includes, but is not limited to pyridine -2- ethyls, thiazole - 2- methyl, imidazoles -2- ethyls, pyrimidine -2- propyl group etc..

Term " sulfonyl ", no matter it is single use or is used in conjunction with other term pictures " alkyl sulphonyl ", respectively table Show the group-SO of divalence2-.Term " alkyl sulphonyl " refers to alkyl-substituted sulphonyl groups, formed alkyl sulphonyl (- SO2CH3)。

Term " sulfonamides ", " amino-sulfonyl " or " sulfamoyl " represent the sulphonyl groups of amino substitution, form ammonia Sulfonyl (- SO2NH2)。

Term " carboxyl ", no matter it is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H;Term " carbonyl ", no matter it is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.

Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of divalence, wherein alkyl group With implication as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level1-3Alkylthio group, such example Include, but is not limited to methyl mercapto (CH3S-), ethylmercapto group etc..

Term " aralkyl ", " aryl alkyl " include the alkyl group of aryl substitution, and wherein aryl and alkyl group has Implication as described in the present invention.Some of embodiments are that aromatic alkyl group or aromatic yl alkyl group refer to the " aralkyl of lower level Base " group, i.e. aromatic yl group are connected to C1-6Alkyl group on.Other embodiment is aromatic alkyl group or aryl alkyl Group refers to contain C1-3Alkyl " benzene alkylene ".Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..And virtue Aryl on alkyl can be further by hydroxyl, amino, halogen, cyano group, trifluoromethoxy, aryl alkyl, heteroaryl alkyl, halogen Substituted alkyl, cycloheteroalkylalkyl, alkylamino, trifyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocycle Base, sulfydryl, nitro, aryloxy group, hydroxyl substituted alkyl group, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, etc..

Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.Some of them are implemented Example is that alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Other Embodiment is that alkyl amino is C1-3Lower level alkylamino group.Suitable alkylamino group can be monoalkyl ammonia Base or dialkyl amido, such example include, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- Lignocaine etc..

Term " aminoalkyl " includes the C substituted by one or more amino1-10Straight or branched alkyl group, wherein Alkyl group has implication as described in the present invention.Some of embodiments are that aminoalkyl is by one or more amino bases The substituted C of group1-6" aminoalkyl of lower level ", such example includes, but is not limited to, aminomethyl, aminoethyl, ammonia third Base, ammonia butyl and ammonia hexyl.

Term " alkoxy carbonyl group " expression alkyl-O-C (=O)-, wherein alkyl has implication as described in the present invention.Wherein one A little embodiments are that the alkyl group in alkoxy carbonyl group is C1-6The alkyl of lower level, such example include, but is not limited to, first Epoxide carbonyl, ethoxy carbonyl, and propoxycarbonyl.

Term " cycloalkyl-alkyl " represents that alkyl group can be substituted by one or more groups of naphthene base, wherein cycloalkanes Base and alkyl group have implication as described in the present invention.Such example includes, but is not limited to cyclohexyl methyl, cyclopropyl Ethyl etc..Described cycloalkyl further can be substituted by halogen, alkyl, alkoxy and hydroxyl.

As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as following formula institute Show) represent substituent any commutable position on ring and can substitute.For example, formula a is represented and any on ring may be substituted Position, as shown in formula b.

Unless otherwise indicated, structural formula described in the invention includes all isomeric forms, (such as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)):Such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and (Z), the rotamer of (E).Therefore, the single three-dimensional chemical isomer of compound of the invention or its is right Reflect isomers, diastereoisomer, or the mixture of geometric isomer (or rotamer) and belong to the scope of the present invention.

Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below:T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008,7,255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below:S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, the compound of 1994. present invention can include asymmetric center or chiral centre, therefore Different stereoisomers be present.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture, constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use To name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50:50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause do not have stereoselectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.

Term " dynamic isomer " or " tautomeric form " represent that the isomer of different-energy can be by relatively low The mutual inversion of phases of energy barrier.Such example includes, but is not limited to, and proton tautomer (i.e. prototropic change isomers) includes The change migrated by proton, such as the isomerization of keto-enol and imine-enamine.Valence dynamic isomer bag Include the restructuring change of some bonding electrons.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document:S.M.Berge et al., describe Pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malic acid, 2- hydroxyls Base propionic acid, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, Fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydroiodic acid Salt, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, Mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- Phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, Valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.This hair It is bright to be also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble or dispersion product It can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is pharmaceutically acceptable Salt further comprise appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydrogen-oxygen Compound, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document:TW.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons, New York, 1991;And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The description of the compounds of this invention

Compound involved in the present invention, and its pharmaceutically acceptable composition, can effectively suppress HBV infection.

On the one hand, the compound the present invention relates to one kind as shown in formula (I) or (Ia),

Or its enantiomter, diastereoisomer, dynamic isomer, hydrate, solvate or pharmaceutically acceptable Salt, wherein:

A is a key ,-O- ,-S- or-N (R5)-;

R is-X-Z;

X is-(CR7R7a)m- or-C (=O)-;

Z is heteroaryl, or Z is the subformula as shown in formula (II):

Wherein, B is a key ,-(CR7R7a)m- or-C (=O)-;

W is CR7Or N;

Y is-(CR7R7a)m-、-O-、-S-、-S(=O)q- or-N (R6)-;

R1For aryl or heteroaryl;

R2For hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkanes Base alkyl, heterocyclic radical, cycloheteroalkylalkyl or alkoxy carbonyl group;

R3For thiadiazolyl group;Wherein described thiadiazolyl group can by one or more selected from hydrogen, fluorine, chlorine, bromine, iodine, alkyl, Alkoxy, alkylamino, haloalkyl, cyano group, hydroxyl, the substituent of nitro or amino are substituted;

R4For hydrogen, deuterium or C1-C4Alkyl;

R5For hydrogen, deuterium, alkyl ,-(CR7R7a)m-C(=O)O-R8, alkenyl or alkynyl;

R6For hydrogen, deuterium, alkyl ,-(CR7R7a)m-C(=O)O-R8、-(CR7R7a)m-C(=O)R8、-(CR7R7a)m-C(=O)- (CR7R7a)m-OR8、-(CR7R7a)m-C(=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m-C(=O)-(CR7R7a)m-N (R8R8a), alkenyl or alkynyl;

Each R7aAnd R7It independently is hydrogen, deuterium, F, Cl, Br, haloalkyl, alkyl or aryl;Or R7、R7aBe attached thereto C atoms form cycloalkyl together;

Each R8And R8aIndependently be hydrogen, deuterium, alkyl, haloalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, Cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or cycloheteroalkylalkyl;

Each R9Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylamino, haloalkyl, hydroxyl, nitro, Amino, trifluoromethoxy or cyano group;

Each n independently is 0,1,2 or 3;

Each m independently is 0,1,2,3 or 4;

Each q independently is 0,1 or 2;With

Wherein, described aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, alkoxy carbonyl group, aryl Alkyl, heteroaryl alkyl, heterocyclic radical and cycloheteroalkylalkyl can be optionally by hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkane Amino, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl are monosubstituted or identical or different It is polysubstituted.

Some embodiments wherein:

Z is the quinary heteroaryl containing 3 or 4 nitrogen-atoms, the heteroaryl can by one or more selected from hydrogen, deuterium, Fluorine, chlorine, bromine, iodine, C1-C4Alkyl, cyano group, hydroxyl, nitro, amino, the substituent of trifluoromethyl or trifluoromethoxy are substituted, Or Z is the subformula as shown in formula (III):

Wherein, B is a key ,-(CR7R7a)m- or-C (=O)-;

Y is-(CR7R7a)m-、-O-、-S-、-S(=O)q- or-N (R6)-;

Each R6It independently is hydrogen, deuterium, C1-C4Alkyl, C2-C4Alkenyl ,-(CR7R7a)m-C(=O)-(CR7R7a)m-O- (CR7R7a)m-O-R8、-(CR7R7a)m-C(=O)O-R8、-(CR7R7a)m-C(=O)R8、-(CR7R7a)m-C(=O)-(CR7R7a)m-N (R8R8a)、-(CR7R7a)m-C(=O)-(CR7R7a)m-OR8Or C2-C4Alkynyl;

Each R7aAnd R7It independently is hydrogen, deuterium, F, Cl, Br, C1-C6Alkyl, C1-C4Haloalkyl or C6-C10Aryl;Or R7、 R7aC is formed together with the C atoms being attached thereto3-C8Cycloalkyl;

Each R8And R8aIt independently is hydrogen, deuterium, C1-C6Alkyl, C1-C4Haloalkyl, C6-C10Aryl, C6-C10Aryl C1-C4 Alkyl, C1-C9Heteroaryl, C1-C9Heteroaryl C1-C4Alkyl, C3-C10Cycloalkyl, C3-C10Cycloalkyl C1-C4Alkyl, C2-C10Heterocycle Base or C2-C10Heterocyclic radical C1-C4Alkyl;

Each R9It independently is hydrogen, deuterium, C1-C4Alkyl, fluorine, chlorine, bromine, iodine, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Halogen Substituted alkyl, hydroxyl, nitro, amino, trifluoromethoxy or cyano group;

Each n independently is 0,1,2 or 3;

Each m independently is 0,1,2,3 or 4;

Each q independently is 0,1 or 2.

In other embodiments, wherein:The subformula that Z is as follows:

Each R6It independently is hydrogen, deuterium, methyl, ethyl, propyl group ,-(CR7R7a)m-C(=O)-(CR7R7a)m-O-(CR7R7a)m- O-R8、-(CR7R7a)m-C(=O)O-R8、-(CR7R7a)m-C(=O)R8、-(CR7R7a)m-C(=O)-(CR7R7a)m-N(R8R8a) or- (CR7R7a)m-C(=O)-(CR7R7a)m-OR8

Each R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls, 1- methyl-props Base or phenyl;

Each R8And R8aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls, phenyl or 1- Methyl-propyl;

Each R9And R9aIt independently is hydrogen, deuterium, amino, cyano group, methyl, ethyl or propyl group;

Each n independently is 0,1 or 2.

In some embodiments, R3For thiadiazolyl group, wherein the thiadiazolyl group can by one or more selected from hydrogen, Deuterium, fluorine, chlorine, bromine, iodine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Haloalkyl, cyano group, hydroxyl, nitro or The substituent of amino is substituted.

In other embodiment, R3For following subformula:

Each R10It independently is hydrogen, deuterium, fluorine, chlorine, bromine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Halo Alkyl, cyano group, hydroxyl, nitro or amino.

In other embodiments, R1For C6-C10Aryl, wherein the aryl can be taken by fluorine, deuterium, chlorine, nitro or bromine list In generation, is identical or different polysubstituted;

R2For hydrogen, deuterium or C1-C4Alkyl;

R5For hydrogen, deuterium or C1-C4Alkyl.

In some embodiments,

R1For phenyl, wherein the phenyl can by fluorine, deuterium, chlorine or bromine it is monosubstituted or identical or different polysubstituted.

In some embodiments, the present invention has the compound as shown in logical formula (IV) or (IVa),

Or its enantiomter, diastereoisomer, dynamic isomer, hydrate, solvate or pharmaceutically acceptable Salt, wherein:

Z is triazolyl, tetrazole radical, wherein the triazolyl or tetrazole radical can by one or more selected from hydrogen, deuterium, fluorine, Chlorine, bromine, iodine, C1-C6Alkyl, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Haloalkyl, cyano group, hydroxyl, nitro or amino Substituent is substituted;

Or Z is the subformula as shown in formula (V):

Y is-(CR7R7a)m-、-O-、-S-、-S(=O)q- or-N (R6)-;

R2For hydrogen, deuterium or C1-C4Alkyl;

R3For thiadiazolyl group;Wherein described thiadiazolyl group can be by one or more selected from hydrogen, deuterium, chlorine, C1-C6Alkyl, cyanogen Base, hydroxyl, the substituent of nitro or amino are substituted;

Each R6It independently is hydrogen, deuterium, C1-C4Alkyl ,-(CR7R7a)m-C(=O)O-R8、-(CR7R7a)m-C(=O)R8、- (CR7R7a)m-C(=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m-C(=O)-(CR7R7a)m-N(R8R8a) or- (CR7R7a)m-C(=O)-(CR7R7a)m-OR8

Each R7aAnd R7It independently is hydrogen, deuterium, C1-C6Alkyl, C1-C4Haloalkyl or C6-C10Aryl;

Each R8And R8aIt independently is H, deuterium, C6-C10Aryl or C1-C6Alkyl;

Each R9It independently is hydrogen, deuterium, amino, cyano group or C1-C4Alkyl;

Each R11It independently is fluorine, deuterium, chlorine, nitro or bromine;

Each k independently is 1 or 2;

Each m independently is 0,1,2,3 or 4;

Each n independently is 0,1 or 2;

Each q independently is 0,1 or 2.

In some embodiments, Z is triazolyl, tetrazole radical, wherein the triazolyl or tetrazole radical can by one or It is multiple selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group, cyano group, hydroxyl, nitro or The substituent of amino is substituted;Or Z is the subformula as shown in formula (V):

Y is-(CR7R7a)m- ,-O- ,-S- ,-S (=O)q- or-N (R6)-;

Each R6It independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group ,-(CR7R7a)m- C (=O) O- R8、-(CR7R7a)m- C (=O) R8、-(CR7R7a)m- C (=O)-(CR7R7a)m-O-(CR7R7a)m-O-R8、-(CR7R7a)m- C (= O)-(CR7R7a)m-N(R8R8a) or-(CR7R7a)m- C (=O)-(CR7R7a)m-OR8

Each R7aAnd R7It independently is hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls, 2- Methyl-propyl or phenyl;

Each R8And R8aIt independently is H, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls, benzene Base or 2- methyl-propyls;

Each R9It independently is hydrogen, deuterium, amino, cyano group, methyl, ethyl, propyl group, isopropyl, butyl or the tert-butyl group;

Each q independently is 0,1 or 2;

Each n independently is 0,1 or 2;

Each m independently is 0,1,2,3 or 4.

In other embodiments, Z is independently selected from following subformula:

In other embodiments, R3Independently selected from following subformula:

The present invention relates to the compound of one of or its enantiomter, diastereoisomer, tautomerism Body, hydrate, solvate or pharmaceutically acceptable salt:

The application of compound and its pharmaceutically acceptable salt of the present invention also comprising the present invention, for producing medical product Effectively suppress HBV infection, including those are described in the invention.The compound of the present invention effectively suppresses HBV infection medicine in production Application in thing.The compound of the present invention is equally used for producing a kind of pharmaceuticals for mitigating, prevention, control or treatment patient's second The illness of type hepatitis.The present invention include pharmaceutical composition, the pharmaceutical composition include formula (I) or compound representated by (Ia) and Effective treatment dosage with reference to needed for of at least one pharmaceutically acceptable carrier, assistant agent or diluent.

The disease of the invention for equally including effectively suppression HBV infection, or the method sensitive to this illness, this method, which includes, to be made The therapeutically effective amount of compound is treated to patient representated by formula (I) or (Ia).

Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the model of the present invention Enclose.

Specifically, salt is pharmaceutically acceptable salt.Term is " pharmaceutically acceptable " must including material or composition Must be adapted to chemistry or toxicologically, with forming the other components of preparation and relevant for the mammal for the treatment of.

The present invention compound salt also include be used for prepare or purify the intermediate of compound shown in formula (I) or (Ia) or The salt of the enantiomter of compound separation shown in formula (I) or (Ia), but it is not necessarily pharmaceutically acceptable salt.

If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Pyruvic acid, oxalic acid, glycolic and salicylic acid;Pyrans saccharic acid, such as glucuronic acid and galacturonic acid;Alpha-hydroxy acid, such as citric acid And tartaric acid;Amino acid, such as asparatate and glutamic acid;Aromatic acid, such as benzoic acid and cinnamic acid;Sulfonic acid, such as to toluene Sulfonic acid, benzene sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.

If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R12)4Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R12)4Salt, such as R12It is H, C1-C4Alkyl, C6-C10Aryl, C6-C10Aryl C1-C4 Alkyl etc., and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain nothing from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Machine salt.Also appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide are included Thing, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

The composition of the compound of the present invention, preparation, administration and compound and the purposes of composition

According on the other hand, the characteristics of pharmaceutical composition of the invention including formula (I) or the compound of (Ia), institute of the present invention The compound listed, or embodiment 1-30 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.The present invention's Compound can effectively suppress hepatitis type B virus in composition, be held suitable for disease caused by virus is especially acute and chronic The treatment of continuous HBV virus infection, the chronic viral diseases that HBV triggers may cause morbid state to become serious, chronic HBV Infection can cause hepatic sclerosis and/or canceration of hepatic cell in many cases.

For the compound of the present invention, the indicating area that may be mentioned is, such as:Catarrhal jaundice may be caused The treatment of acute and chronic virus infection, for example, hepatitis B virus infection.The compound of the present invention is especially suitable for treatment chronic hepatitis B Infection and acute and chronic hepatitis B virus infection.

The present invention includes pharmaceutical preparation, except nontoxic, in inert pharmaceutics outside suitable carrier, also containing a kind of or more The compound (I) or (Ia) or composition of kind of the present invention or containing one or more active components (I) or (Ia) or the present invention Composition.

Said medicine preparation can also be beyond inclusion compound (I) or (Ia) other active pharmaceutical ingredients.

Free form be present in the compound of the present invention, or suitably, as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy Other any adducts or derivative being directly or indirectly administered according to the needs of patient, the present invention other aspect described by Compound, its metabolite or his residue.

As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load Body, assistant agent, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below:In Remington:The Science and Practice Of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show different Carrier can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition.Except any conventional carrier The incompatible scope of compound of medium and the present invention, such as caused any bad biological effect or with can pharmaceutically connect The caused interaction in harmful manner of any other component for the composition received, their purposes are also that the present invention is considered Scope.

It can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminium, aluminum oxide, it is stearic Sour aluminium, lecithin, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, satisfy With the partial glyceride mixtures of vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid hydrogen Potassium, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene- Block condensate, lanolin, sugar, such as lactose, dextrose and saccharose;Starch such as cornstarch and potato starch;Cellulose and it Derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate;Gum powder;Malt;Gelatin;Talcum powder;Auxiliary material Such as cocoa butter and suppository wax;Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil;Glycol Class compound, such as propane diols and polyethylene glycol;Esters such as ethyl oleate and ethyl laurate;Agar;Buffer such as hydrogen-oxygen Change magnesium and aluminium hydroxide;Alginic acid;Pyrogen-free water;Isotonic salt;Lin Ge (family name) solution;Ethanol, phosphate buffer solution, and other Nontoxic suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colouring agent, releasing agent, coating agents, sweetener, flavor enhancement And spices, preservative and antioxidant.For convenience, local anesthetic, preservative, buffer etc. can be directly dissolved in carrier In.

The pharmaceutical composition of the compounds of this invention, it can be granted with the any-mode of following aspect:It is administered orally, spraying is inhaled Enter method, local administration, per rectum administration, nose administration, local administration, vagina administration, parenterai administration is for example subcutaneous, vein, flesh It is interior, intraperitoneal, intrathecal, intra-ventricle, in breastbone, or intracranial injection or transfusion, or by a kind of reservoir medication of outer value.Preferably Mode is is administered orally, intramuscular injection, to Intraperitoneal medication or intravenous injection.

The compounds of this invention can be administered in a unit containing pharmaceutically acceptable composition.To medicament Type can be liquid dosage form, solid dosage forms.Liquid dosage form can be true solution class, colloidal type, particulate formulations, mixed suspension form.Its His formulation such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, suppository, lyophilized Powder-injection, inclusion compound, implants, patch, liniment etc..

Oral tablet and capsule can contain excipient such as adhesive, such as syrup, Arabic gum, sorbierite, tragacanth, or Polyvinylpyrrolidone, such as filler, lactose, sucrose, cornstarch, calcium phosphate, sorbierite, amion acetic acid, lubricant are such as hard Fatty acid magnesium, talcum, polyethylene glycol, tripoli, such as disintegrant, farina, or acceptable dibutyl phthalate such as bay sodium alkoxide sulfuric acid Salt.Tablet can be coated with known method in pharmaceutics.

The suspension of hydrous oil, solution, emulsion, syrup or elixir can be made in oral liquid, and dry product can also be made, and use Preceding supplement water or other suitable mediums.This liquid preparation can include conventional additive, such as suspending agent, sorbierite, fibre Tie up plain methyl ether, dextrose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, the edible oil of hydrogenation Fat, such as emulsifying agent, lecithin, the poly- candy list oleate of sorb, Arabic gum;Or nonaqueous carrier (edible oil may be included), such as Apricot kernel oil, grease such as glycerine, ethylene glycol, or ethanol;Preservative, such as methyl p-hydroxybenzoate or propyl ester, sorbic acid.If desired for Flavor enhancement or colouring agent can be added.

Suppository can include conventional suppository base, such as cocoa butter or other glyceride.

To being offerd medicine outside stomach, liquid forms are generally made up of compound and a kind of carrier of sterilization.Carrier first choice water.According to institute The difference of carrier and drug concentration is selected, compound both dissolved in and aaerosol solution is may be made as in carrier, and injection solution is being made When it is first that compound is soluble in water, filtering sterilization after be fitted into sealed bottle or ampoule.

When topical application, the form of appropriate ointment, lotion, or creme can be made in the compounds of this invention, its Middle active component is suspended or dissolved in the carrier of one or more, and the carrier that wherein ointment formulation can use includes but not office It is limited to:Mineral oil, Albolene, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water;Lotion Include but is not limited to carrier workable for creme:Mineral oil, sorbitan monostearate, polysorbate60, hexadecane ester Wax, hexadecene is fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.

In general, it has proved that advantageously no matter in human body medicine or in veterinary drug, active ingredient of the present invention Every 24 hours of the administration total amount of thing is about 0.5-500mg, preferably 1-100mg/kg body weight, if appropriate, single dose several times Amount administration, to reach required effect.The amount containing reactive compound is preferably from about 1-80mg, more preferably 1- in single dose 50mg/kg body weight, but can not also be according to above-mentioned dosage, i.e., species and body weight, the property of disease depending on treatment target With the administering mode of the order of severity, the type of preparation and medicine, and dosage period or time interval.

Pharmaceutical composition provided by the invention, also comprising Anti-HBV drugs.Wherein Anti-HBV drugs are that HBV polymerize enzyme level Agent, immunomodulator or interferon.

HBV medicines have a Lamivudine, Sebivo, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, emtricitabine, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α -1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol, or Propagermanium etc..

Another aspect of the present invention be related to a kind of compound of the invention or pharmaceutical composition prepare be used to preventing, handle, The purposes of the medicine for the treatment of or mitigation patient's hepatitis B disease, including the pharmaceutically acceptable effective dose of patient is given to suffering from Person is administered.Hepatitis B disease refers to cause caused liver diseases by hepatitis B virus infection or hepatitis B infection, wrapped Include oxyhepatitis, chronic hepatitis, hepatic sclerosis and stem cell cancer.Acute hepatitis b virus infection can be asymptomatic or show as Oxyhepatitis symptom.Chronic viral infection patient suffers from active disease, can develop into hepatic sclerosis and liver cancer.

Anti-HBV drugs can separately be administered with the composition of the compound comprising the present invention, and one as more dosage regimens Part.Or those medicines can be a part for one-pack type, mix to form single combination with the compound of the present invention Thing.If a part of the administration as more dosage regimens, two activating agents can be mutual simultaneously continuously or within a period of time Transmit, so as to obtain destination agent activity.

Can combine carrier mass produce one-pack type compound and the dosage of composition (those include a composition picture It is described in the invention) change depend on curing mainly and special mode of administration.Normally, the amount of composition of the invention will not surpass Cross composition and include the normal amount administered as unique activating agent.On the other hand, the scope of the amount of existing disclosed composition The 50%-100% of about existing composition normal amount, comprising reagent as sole active therapeutic agent.Included at those In composition, composition will play synergy with the compound of the present invention.

The compound of the present invention shows stronger antivirus action.This kind of compound has beyond expectation resist to HBV Virus activity, it is consequently adapted to for treating various diseases caused by virus, especially acute and chronic persistence HBV viruses infection Caused disease.The chronic viral diseases as caused by HBV can cause the symptom complex of the various different orders of severity, many institute's weeks Know, chronic hbv-infection can cause hepatic sclerosis and/or hepatocellular carcinoma.

The example for the indication that can be treated with the compounds of this invention has:Treatment can cause the acute and chronic of infectious hepatitis Virus infection, such as different in nature hepatites virus infections.The particularly preferably treatment of chronic hepatitis-B infection and acute The treatment of hepatites virus infections.

The invention further relates to compound of the invention and composition are used for preparation treatment and prevention viral disease and are particularly The purposes of the medicine of hepatitis B.

General synthetic method

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I) or (Ia).Following reaction scheme and embodiment are used to further illustrate Illustrate present disclosure.

Those skilled in the art will realize that:Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDCl3, d6- DMSO, CD3OD or d6- acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used:S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), q (quart, quartet), m (multiplet, multiplet), br (broadened, broad peak), Dd (doublet ofdoublets, double doublet), dt (doublet oftriplets, double triplets).Coupling constant, with conspicuous Hereby (Hz) is represented.

Algorithm (MS) data are by being equipped with G1312A binary pumps and a G1316ATCC (column temperature is maintained at 30 DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detector applications In analysis, ESI sources are applied to LC-MS spectrometers.

Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316ATCC (column temperature is maintained at 30 DEG C) Come what is determined, G1329A automatic samplers and G1315D DAD detectors are applied to Agilent6120 series LC-MS spectrometer Analysis, ESI sources are applied to LC-MS spectrometers.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration;Flow velocity is 0.6mL/min;HPLC peak value is by 210nm and 254nm UV-Vis wavelength records reading.The formic acid acetonitrile solution (phase A) and 0.1% formic acid that mobile phase is 0.1% are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatogram (HPLC), wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.

The use of brief word below is through the present invention:

MeCN, CH3CN acetonitriles

Boc tertiary butyl oxycarbonyls

DCM, CH2Cl2Dichloromethane

CHCl3Chloroform, chloroform

CDCl3Deuterochloroform

CCl4Carbon tetrachloride

DMSO dimethyl sulfoxide (DMSO)s

Morpholine morpholines

MeONa, CH3ONa sodium methoxides

HCl hydrochloric acid

NBS N-bromo-succinimides

H2O water

ML milliliters

Mmol mMs

G grams

RT.rt room temperatures

Rt retention times

The present invention can prepare intermediate by following methods:

Intermediate 1

The salt of intermediate 1, it can be prepared by above-mentioned method, wherein R3With implication as described in the present invention. Compound 1A reacts with cuprous cyanide, obtains compound 2A, then is reacted with sodium methoxide, ammonium chloride, then acidified, obtains chemical combination Thing 1.

Intermediate 8A

Compound 8A, it can be prepared by above-mentioned method, wherein R8’For alkyl-O-, alkyl-NH-, (alkyl)2- N-, alkyl-O- alkyl-O-, alkyl-O-C (=O)-or Trifluoromethylcarbonyl-O-.Compound 3A and compound 4A are in alkalescence condition Under, obtain compound 5A, then react with 6A, generation compound 7A is acidified, obtains product 8A.

Intermediate 11A

Compound 11A, it can be prepared by above-mentioned method.Wherein, R10’For halogen atom;R9’For alkyl;A is 0,1 or 2.Compound 9A and compound 10A reacts to obtain compound 11A.

Intermediate 13A

Compound 13A, it can be prepared by above-mentioned method.Compound 12A reacts to obtain chemical combination with trifluoroacetic acid Thing 13A.It can be prepared according to the logical formula (I) of the present invention or (Ia) compound by following methods:

Embodiment 1

Pyrimidines 6, it can be prepared by the method for reaction scheme 1, wherein R1, R2, R3, A, and Z is with such as Implication of the present invention.Amidine or its hydrochloric acid salt compounds 1, aldehyde compound 2 and compound 3 are in appropriate atent solvent In (such as alcohol reagent), cyclization obtains compound 4.

Compound 4 and bromating agent are reacted in atent solvent, obtain bromination product 5, then in the basic conditions, In appropriate atent solvent product 6 is obtained with ZH substitution reactions.

Embodiment 2

Pyrimidines 6a, it can be prepared by the method for reaction scheme 2, wherein Z isWherein Z ' isR6aFor-(CR7R7a)m-C(=O)O-R8b;R8bFor alkyl;R6a’For-(CR7R7a)m-C(=O)O-H;R7, R7aHave such as with m Implication of the present invention.Compound 6 obtains compound 6a by reaction.

The following examples can be so that the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright scope.

Embodiment

Embodiment 1:

4- (the chloro- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate

Step 1) 2- cyano group -1,3,4- thiadiazoles

Cuprous cyanide (7.2g, 80mmol), anhydrous acetonitrile (40mL), the tertiary fourth of nitrous acid are sequentially added in drying in three-necked bottle Ester (8.24g, 80mmol), 50 DEG C are heated under nitrogen protection.Be slowly added to 2- amido-1,3,4-thiadiazoles (4.05g, Anhydrous acetonitrile (20mL) solution 40mmol), controls and is added in 30min, drip off and be warming up to 60 DEG C, continues to react 3h, is down to 25 DEG C, filtering, washed with a small amount of acetonitrile, solvent, product crude product column chromatographic isolation and purification (petroleum ether/acetic acid is evaporated off in filtrate decompression Ethyl ester (V/V)=5/1), obtain red liquid (1.78g, 40%).

MS-ESI:(ESI, pos.ion) m/z:112.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.56 (s, 1H)

Step 2) 1,3,4- thiadiazoles -2- amitraz hydrochlorides

2- cyano group -1,3,4- thiadiazoles (1.11g, 10mmo1), sodium methoxide are sequentially added in 100mL eggplant type bottles (0.81g, 15mmol), absolute methanol (50mL), ammonium chloride (0.96g, 18mmol), stirring reaction 24h, mistake are sealed at 25 DEG C Filter, filtrate decompression are evaporated off solvent, the mashing of product crude acetone, filtering, a small amount of acetone rinse of product, obtain pale solid (1.15g, 70%).

MS-ESI:(ESI, pos.ion) m/z:129.0[M+1]+;

1H NMR (400MHz, D2O):δ 9.52 (s, 1H)

Step 3) 6- methyl -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate

Sequentially added in 25mL microwave reaction bottles 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.43g, 8.69mmo1), The chloro- 4- fluorobenzaldehydes (1.38g, 8.69mmol) of 2-, ethyl acetoacetate (1.36g, 10.5mmol), absolute ethyl alcohol (12mL), Microwave reaction 1h at 150 DEG C.Solvent, product crude product column chromatographic isolation and purification (petroleum ether/acetic acid second is evaporated off in filtering, filtrate decompression Ester (V/V)=5/1), obtain yellow solid (1.82g, 55%).MS-ESI:(ESI, pos.ion) m/z:381.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.36 (br.s, 1H), 9.71 (s, 1H), 7.62-7.40 (m, 3H), 6.03 (s, 1H), 3.99 (q, 2H), 2.52 (s, 3H), 1.10 (t, 3H)

Step 4) 6- bromomethyls -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins - 5- Ethyl formates

Sequentially added in dry reaction bottle 6- methyl -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.76g, 2mmol), CCl4(35mL), N255 DEG C are heated under protection, adds NBS (0.36g, 2mmol), stirring reaction 30min, stop reaction.Room temperature is cooled to, is filtered, solvent is evaporated off in filtrate decompression, and product is thick Product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=4/1), obtains yellow solid (0.46g, 50%).

MS-ESI:(ESI, pos.ion) m/z:459.0[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.96 (br.s, 1H), 9.71 (s, 1H), 7.60-7.39 (m, 3H), 6.01 (s, 1H), 4.13 (q, 2H), 4.01 (q, 2H), 1.03 (t, 3H)

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates

By 6- bromomethyls -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.92g, 2mmo1), morpholine (0.7g, 8mmol), the lower 25 DEG C of stirrings 12h of nitrogen protection.Solvent is removed under reduced pressure, to residual Dichloromethane (100mL), organic layer saturated common salt water washing (80mL × 3), organic layer anhydrous sodium sulfate drying are added in excess. Product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=5/1), obtains yellow solid (0.42g, 45%).

MS-ESI:(ESI, pos.ion) m/z:466.1[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.80 (br.s, 1H), 9.69 (s, 1H), 7.57-7.35 (m, 3H), 6.06 (s, 1H), 3.98 (q, 2H), 3.90 (q, 2H), 3.66 (br.s, 4H), 2.54 (br.s, 4H), 1.05 (t, 3H)

Embodiment 2:

4- (the chloro- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (1,3,4- thiadiazoles -2- bases) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (the chloro- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (1,3,4- thiadiazoles - 2- yls)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

6- bromomethyls -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- are sequentially added in dry reaction bottle Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.92g, 2mmol), absolute ethyl alcohol (40mL), triethylamine (0.45g, 4.4mmol), thiomorpholine dioxide. HCl (0.42g, 2.4mmol), N2Protect lower 25 DEG C of stirrings 12h.Remove under reduced pressure molten Agent, the addition dichloromethane (100mL) into residue, organic layer saturated common salt water washing, organic layer anhydrous sodium sulfate drying, Product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=5/1), obtains yellow solid (0.41g, 40%).

MS-ESI:(ESI, pos.ion) m/z:514.1[M+1]+

1HNMR (4 () () MHz, DMSO-d6):δ 9.80 (br.s, 1H), 9.71 (s, 1H), 7.62-7.40 (m, 3H), 6.08 (s, 1H), 4.09 (q, 2H), 3.96 (q, 2H), 3.21 (br.s, 4H), 3.10 (br.s, 4H), 1.05 (t, 3H)

Embodiment 3:

4- (the chloro- 4- fluorophenyls of 2-) -6- ((1- epoxides thiomorpholine) methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates

By 6- bromomethyls -4- (the chloro- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.46g, 1mmol), thiomorpholine-oxide hydrochloride (0.31g, 2mmol) press the synthesis side of the step 1 of embodiment 2 Method obtains yellow solid (0.28g, 55%).

MS-ESI:(ESI, pos.ion) m/z:498.1[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.78 (br.s, 1H), 9.69 (s, 1H), 7.58-7.37 (m, 3H), 6.06 (s, 1H), 4.12-3.94 (m, 4H), 3.11 (br.s, 4H), 2.97 (br.s, 4H), 1.02 (t, 3H)

Embodiment 4:

4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases) -6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro Pyrimidine -5- Ethyl formates

Step 1) 5- ethyls -1,3,4- thiadiazoles -2- cyano group

By 5- ethyls -1,3,4- thiadiazoles -2- amino (12.9g, 100mmol), cuprous cyanide (17.9g, 200mmol) are pressed The synthetic method of the step 1 of embodiment 1 obtains white solid (3.2g, 23%).

MS-ESI:(ESI, pos.ion) m/z:140.0[M+1]+

1HNMR (4 () () MHz, DMSO-d6):δ 3.12 (q, 2H), 1.28 (t, 3H)

Step 2) 5- ethyls -1,3,4- thiadiazoles -2- amitraz hydrochlorides

By 5- ethyls -1,3,4- thiadiazoles -2- cyano group (1.39g, 10mmol), sodium methoxide (0.54g, 10mmol), chlorination Ammonium (0.64g, 12mmol) obtains micro white solid (1.41g, 73%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:157.1[M+I]+

1H NMR (400MHz, DMSO-d6):δ 7.14 (s, 1H), 6.95 (s, 2H), 3.06 (q, 2H), 1.31 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases) -6- methyl isophthalic acids, 4- dihydros Pyrimidine -5- Ethyl formates

By 5- ethyls -1,3, the chloro- 4- fluorobenzaldehydes of 4- thiadiazoles -2- amitraz hydrochlorides (1.93g, 10mmol), 2- (1.59g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.47g, 36%).

MS-ESI:(ESI, pos.ion) m/z:409.1[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.62 (s, 1H), 7.71 (dd, 1H), 7.33 (dd, 1H), 7.07 (m, 1H), 5.99 (s, 1H), 4.06 (q, 2H), 3.01 (q, 2H), 2.46 (s, 3H), 1.30 (t, 3H), 1.12 (t, 3H)

Step 4) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases) -6- methyl isophthalic acids, 4- dihydro-pyrimidins - 5- Ethyl formates (0.41g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow solid by the synthetic method of the step 4 of embodiment 1 (0.29g, 59%).

MS-ESI:(ESI, pos.ion) m/z:487.0[M+1]+

1HNMR (400MHz, DMSO-d6):δ 10.22 (s, 1H), 7.78 (dd, 1H), 7.36 (dd, 1H), 7.04 (m, 1H), 6.27 (s, 1H), 4.74 (dd, 2H), 4.08 (q, 2H), 3.04 (q, 2H), 1.33 (t, 3H), 1.16 (t, 3H)

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases) -6- (morpholine methyl) -1, 4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (5- ethyls -1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro Pyrimidine -5- Ethyl formates (0.49g, 1mmol), morpholine (0.35g, 4mmo1) obtain yellow by the synthetic method of the step 5 of embodiment 1 Solid (0.3g, 60%).

MS-ESI:(ESI, pos.ion) m/z:494.1[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 7.68 (dd, 1H), 7.42 (dd, 1H), 7.12 (m, 1H), 5.83 (s, 1H), 4.12 (q, 2H), 4.03-3.98 (m, 2H), 3.68 (br.s, 4H), 3.14 (q, 2H), 2.47 (br.s, 4H), 1.35 (t, 3H), 1.12 (t, 3H)

Embodiment 5:

4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate

By 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.65g, 10mmol), the bromo- 4- fluorobenzaldehydes of 2- (2.03g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.45g, 34%).

MS-ESI:(ESI, pos.ion) m/z:425.0[M+1]+

1H NMR (400MHz, DMSO- (d6):δ 9.76 (s, 1H), 9.68 (s, 1H), 7.49-7.23 (m, 3H), 6.07 (s, 1H), 4.05 (q, 2H), 2.51 (s, 3H), 1.05 (t, 3H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid Ethyl ester (0.43g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.27g, 53%).

MS-ESI:(ESI, pos.ion) m/z:502.9[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 9.64 (s, 1H), 7.51-7.25 (m, 3H), 6.04 (s, 1H), 4.52 (dd, 2H), 4.01 (q, 2H), 1.07 (t, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.33g, 65%).

MS-ESI:(ESI, pos.ion) m/z:510.1[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.78 (s, 1H), 9.73 (s, 1H), 7.59-7.21 (m, 3H), 6.08 (s, 1H), 3.96 (q, 2H), 3.91 (d, 2H), 3.68 (t, 4H), 2.51 (t, 4H), 1.07 (t, 3H)

Embodiment 6:

6- ((1H- tetrazole -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 1H- tetrazoles (0.14g, 2mmol) obtain yellow solid by the synthetic method of the step 1 of embodiment 2 (0.25g, 51%).

MS-ESI:(ESI, pos.ion) m/z:493.0[M+1]+

1H-NMR (400MHz, DMSO-d6):δ 10.12 (s, 1H), 9.74 (s, 1H), 9.00 (s, 1H), 7.35-7.28 (m, 2H), 7.19-6.93 (m, 1H), 6.39 (s, 1H), 5.73 (s, 1H), 4.47 (s, 1H), 4.08 (q, 2H), 1.16 (t, 3H)

Embodiment 7:

6- ((5- amino -1H- tetrazole -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 1H- tetrazole -5- amino (0.17g, 2mmol) are obtained by the synthetic method of the step 1 of embodiment 2 Yellow solid (0.21g, 42%).

MS-ESI:(ESI, pos.ion) m/z:508.0[M+1]+

1H-NMR (400MHz, DMSO-d6):δ 10.10 (s, 1H), 9.08 (s, 1H), 7.32-7.27 (m, 2H), 7.21- 6.93 (m, 1H), 6.54 (br.s, 2H), 5.86 (s, 1H), 5.62 (s, 1H), 4.61 (s, 1H), 4.02 (q, 2H), 1.12 (t, 3H).

Embodiment 8:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((3- cyano group -1H-1,2,4- triazole -1- bases) methyl) -2- (1,3,4- thiophenes two Azoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 1H-1,2,4- triazole -3- cyano group (0.19g, 2mmol) press the synthesis of the step 1 of embodiment 2 Method obtains yellow solid (0.23g, 45%).

MS-ESI:(ESI, pos.ion) m/z:517.0[M+1]+

1H-NMR (400MHz, DMSO-d6):δ 9.93 (s, 1H), 8.92 (s, 1H), 8.73 (s, 1H), 7.33-7.24 (m, 2H), 7.18-6.93 (m, 1H), 6.11 (s, 1H), 6.03 (s, 1H), 4.76 (s, 1H), 4.05 (q, 2H), 1.14 (t, 3H)

Embodiment 9:

6- ((4- Acetylpiperazine -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,2,4- thiadiazoles -5- bases) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 1,2,4- thiadiazoles -5- cyano group

1,2,4- thiadiazoles -5- amino (10.1g, 100mmol), cuprous cyanide (17.9g, 200mmol) are pressed into embodiment 1 The synthetic method of step 1 obtains brownish oil shape thing (2.78g, 25%).

MS-ESI:(ESI, pos.ion) m/z:112.0[M+1]+

1HNMR (400MHz, DMSO-d6):δ 6.51 (s, 1H)

Step 2) 1,2,4- thiadiazoles -5- amitraz hydrochlorides

By 1,2,4- thiadiazoles -5- cyano group (1.11g, 10mmol), sodium methoxide (0.54g, 10mmol), ammonium chloride (0.64g, 12mmol) obtains gray solid (1.19g, 72%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:129.0[M+1]+

1HNMR (400MHz, DMSO-d6):δ 7.08 (s, 1H), 6.86 (br.s, 2H), 6.30 (s, 1H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,2,4- thiadiazoles -5- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate

By 1,2,4- thiadiazoles -5- amitraz hydrochlorides (1.65g, 10mmol), the bromo- 4- fluorobenzaldehydes of 2- (2.03g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.19g, 28%).

MS-ESI:(ESI, pos.ion) m/z:425.0[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.62 (s, 1H), 7.33-7.25 (m, 2H), 7.13-7.04 (m, 1H), 6.12 (s, 1H), 5.77 (s, 1H), 4.01 (q, 2H), 2.44 (s, 3H), 1.16 (t, 3H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,2,4- thiadiazoles -5- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,2,4- thiadiazoles -5- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid Ethyl ester (0.43g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.26g, 52%).

MS-ESI:(ESI, pos.ion) m/z:502.9[M+1]+

1HNMR (400MHz, DMSO-d6):δ 9.59 (s, 1H), 7.35-7.27 (m, 2H), 7.15-7.07 (m, 1H), 6.10 (s, 1H), 5.87 (s, 1H), 4.67 (dd, 2H), 4.09 (q, 2H), 1.12 (t, 3H)

Step 5) 6- ((4- Acetylpiperazine -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,2,4- thiadiazoles - 5- yls)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,2,4- thiadiazoles -5- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 4- Acetylpiperazines (0.26g, 2mmol) obtain yellow by the synthetic method of the step 1 of embodiment 2 Solid (0.29g, 53%).

MS-ESI:(ESI, pos.ion) m/z:551.1[M+1]+

1H-NMR (400MHz, DMSO-d6):δ 10.24 (s, 1H), 7.32-7.25 (m, 2H), 7.11-6.97 (m, 1H), 6.14 (s, 1H), 5.78 (s, 1H), 4.02 (q, 2H), 3.91-3.83 (m, 2H), 3.43 (t, 4H), 2.44 (t, 4H), 2.10 (s, 3H), 1.13 (t, 3H)

Embodiment 10:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (tertbutyloxycarbonyl) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles - 2- yls) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (tertbutyloxycarbonyl) piperazine -1- bases) methyl) -2- (1,3,4- thiophenes Diazole -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 4-Boc- piperazines (0.37g, 2mmol) obtain yellow by the synthetic method of the step 1 of embodiment 2 and consolidated Body (0.36g, 59%).

MS-ESI:(ESI, pos.ion) m/z:609.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 10.17 (s, 1H), 9.00 (s, 1H), 7.41-7.29 (m, 2H), 7.21- 6.99 (m, 1H), 5.93 (s, 1H), 4.02 (q, 2H), 3.90-3.86 (m, 2H), 3.19 (t, 4H), 2.48 (t, 4H), 1.42 (s, 9H), 1.11 (t, 3H)

Embodiment 11:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (carbethoxyl group) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles -2- Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) piperazine -1- Ethyl formates

Piperazine (2g, 23.2mmol), water (10mL) are sequentially added in dry reaction bottle, 25 DEG C of stirring and dissolvings are complete, cold But to 0 DEG C, ethyl chloroformate (1.26g, 11.6mmol) methanol (20mL) solution is slowly added dropwise.Drop finishes, and 4h is stirred at 25 DEG C, Stop stirring.Saturated sodium-chloride water solution (30mL), dichloromethane (200mL) are added into reaction solution successively, extracting and demixing, is had Machine layer anhydrous sodium sulfate drying.Remove solvent, crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=40/ under reduced pressure 1) white solid (0.62g, 33.7%), is obtained.

MS-ESI:(ESI, pos.ion) m/z:159.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 4.14 (q, 2H), 3.44 (t, 4H), 2.82 (t, 4H), 1.82 (br.s, 1H), 1.26 (t, 3H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (carbethoxyl group) piperazine -1- bases) methyl) -2- (1,3,4- thiophenes two Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), piperazine -1- Ethyl formates (0.32g, 2mmol) are obtained yellow by the synthetic method of the step 1 of embodiment 2 Color solid (0.28g, 49%).

MS-ESI:(ESI, pos.ion) m/z:581.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 9.65 (s, 1H), 7.51-7.21 (m, 3H), 6.03 (s, 1H), 4.17 (q, 2H), 4.07 (q, 2H), 4.01-3.97 (m, 2H), 3.49 (t, 4H), 2.85 (t, 4H), 1.22 (t, 3H), 1.07 (t, 3H)

Embodiment 12:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- (tertiary fourth amino) acetyl group) piperazine -1- bases) methyl) -2- (1,3,4- Thiadiazoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2- chloracetyls) piperazine -1- t-butyl formates

Sequentially added in 250mL dry reaction bottles N-Boc- piperazines (3.94g, 21.2mmol), triethylamine (2.15g, 21.2mmol), dichloromethane (80mL), 0 DEG C is cooled to, chloracetyl chloride (2.63g, 23.3mmol) dichloromethane is slowly added dropwise (30mL) solution.Drop finishes, and reaction solution stirs 1.5h at 25 DEG C.Saturated aqueous common salt (80mL), two are sequentially added into reaction solution Chloromethanes (200mL), extracting and demixing, organic layer anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product crude product column chromatography for separation is pure Change (petrol ether/ethyl acetate (V/V)=3/1), obtain white solid (5.3g, 95%).

MS-ESI:(ESI, pos.ion) m/z:207.1[M+I-56]+

1H NMR (400MHz, CDCl3):δ 4.10 (s, 2H), 3.60 (t, 2H), 3.51 (s, 4H), 3.44 (t, 2H), 1.48 (s, 9H)

Step 2) 4- (2- (tert-butylamine base) acetyl group) piperazine -1- t-butyl formates

4- (2- chloracetyls) piperazine -1- t-butyl formates (1g, 3.81mmol), uncle are sequentially added in dry reaction bottle Butylamine (1.11g, 15mmol), acetonitrile (45mL), 70 DEG C of reaction 5h, are cooled to 25 DEG C.Solvent is evaporated off in filtering, filtrate decompression, to Dichloromethane (150mL), saturated aqueous common salt (80mL), extracting and demixing are sequentially added in residue.Organic layer anhydrous sodium sulfate is done It is dry, remove solvent under reduced pressure, crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=40/1), obtain white solid (0.9g, 79%).

MS-ESI:(ESI, pos.ion) m/z:300.2[M+l]+

1H NMR (400MHz, CDCl3):δ 3.60 (br.s, 2H), 3.45 (br.s, 2H), 3.41 (br.s, 6H), 1.47 (s, 9H), 1.11 (s, 9H)

Step 3) 2- (tert-butylamine base) -1- (piperazine -1- bases) acetyl group trifluoroacetate

Sequentially added in dry reaction bottle 4- (2- (tert-butylamine base) acetyl group) piperazine -1- t-butyl formates (0.6g, 2mmol), dichloromethane (8mL), trifluoroacetic acid (8mL), 12h is stirred at 25 DEG C.Remove solvent under reduced pressure, obtain brownish oil shape thing (0.55g, 87%).

MS-ESI:(ESI, pos.ion) m/z:200.2[M+l]+

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- (tertiary fourth amino) acetyl group) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, l mmol), 2- (tert-butylamine base) -1- (piperazine -1- bases) acetyl group trifluoroacetate (0.63g, 2mmol) Yellow solid (0.29g, 46%) is obtained by the synthetic method of the step 1 of embodiment 2.

MS-ESI:(ESI, pos.ion) m/z:622.2[M+I]+

1H NMR (400MHz, DMSO-d6):δ 9.76 (s, 1H), 9.58 (s, 1H), 7.53-7.25 (m, 3H), 6.07 (s, 1H), 4.11 (q, 2H), 3.99-3.88 (m, 2H), 3.63 (br.s, 2H), 3.52 (br.s, 2H), 3.47 (br.s, 4H), 3.41 (br.s, 2H), 1.15 (s, 9H), 1.03 (t, 3H)

Embodiment 13:

2- (4- ((6- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -2- (1,3,4- thiadiazoles -2- bases) -3,6- dihydros Pyrimidine-4-yl) methyl) piperazine -1- bases) acetic acid

Step 1) 2- (piperazine -1- bases) tert-butyl acetate

Piperazine anhydrous (2g, 23.2mmol), acetonitrile (40mL) are sequentially added in dry reaction bottle, 25 DEG C of stirring and dissolvings are complete Quan Hou, bromo-acetic acid tert-butyl (2.26g, 11.6mmol) acetonitrile (20mL) solution is slowly added dropwise.Drop finishes, and 25 DEG C are continued to stir 4h.Filtering, filtrate decompression are evaporated off solvent, dichloromethane (100mL), saturated aqueous common salt (50mL) are sequentially added into residue, Extracting and demixing, organic layer anhydrous sodium sulfate drying.Remove solvent, crude product column chromatographic isolation and purification (methylene chloride/methanol under reduced pressure (V/V) colorless oil (0.4g, 17%)=60/1), is obtained.

MS-ESI:(ESI, pos.ion) m/z:201.2[M+l]+

1H NMR (400MHz, CDCl3):δ 3.10 (s, 2H), 2.93 (t, 4H), 2.55 (t, 4H), 2.27 (s, 1H), 1.47 (s, 9H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- (tert-butoxy) -2- oxoethyls) piperazine -1- bases) first Base) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 2- (piperazine-l- bases) tert-butyl acetate (0.4g, 2mmol) press the synthesis of the step 1 of embodiment 2 Method obtains yellow solid (0.16g, 25%).

MS-ESI:(ESI, pos.ion) m/z:623.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 9.52 (s, 1H), 7.47-7.21 (m, 3H), 6.01 (s, 1H), 4.13 (q, 2H), 3.95-3.86 (m, 2H), 3.15 (s, 2H), 2.98 (t, 4H), 2.61 (t, 4H), 1.48 (s, 9H), 1.06 (t, 3H)

Step 3) 2- (4- ((6- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -2- (1,3,4- thiadiazoles -2- bases) -3, 6- dihydro-pyrimidin -4- bases) methyl) piperazine -1- bases) acetic acid

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- (tert-butoxy) -2- oxo second is sequentially added in dry reaction bottle Base) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.62g, 1mmol), aqueous hydrochloric acid solution (6mol/L, 10mL), 40 DEG C of reaction 1h, is cooled to 25 DEG C, and ammoniacal liquor adjusts pH to 5-6, and the aqueous solution is with two Chloromethanes (60mL × 3) extracts, organic layer anhydrous sodium sulfate drying.Remove solvent under reduced pressure and obtain yellow solid (0.4g, 70%).

MS-ESI:(ESI, pos.ion) m/z:567.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 9.65 (s, 1H), 9.47 (s, 1H), 7.57-7.19 (m, 3H), 6.03 (s, 1H), 3.98-3.84 (m, 4H), 3.16 (s, 2H), 2.71 (br.s, 4H), 2.59 (br.s, 4H), 1.04 (t, 3H)

Embodiment 14:

4- (the bromo- 4- fluorophenyls of 2-) -64 (4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- t-butyl formates

NaH (0.17g, 7.13mmol), glycol monoethyl ether (30mL), 4- (2- chlorine are sequentially added in dry reaction bottle Acetyl group) piperazine -1- t-butyl formates (1g, 3.81mmol), KI (40mg, 0.24mmol), 80 DEG C reaction 2h.To reaction Ethyl acetate (120mL), saturated aqueous common salt (80mL), extracting and demixing, organic layer anhydrous sodium sulfate drying are sequentially added in liquid.Subtract Solvent is evaporated off in pressure, crude product column chromatographic isolation and purification (petrol ether/ethyl acetate/dichloromethane (V/V/V)=2/1/1), obtains colorless oil Shape thing (0.5g, 43%).

MS-ESI:(ESI, pos.ion) m/z:303.2[M+l]+

1H NMR (400MHz, DMSO-d6):δ 4.22 (s, 2H), 3.69-3.67 (m, 2H), 3.57-3.53 (m, 4H), 3.52-3.49 (m, 2H), 3.48-3.42 (m, 4H), 3.39 (s, 3H), 1.47 (s, 9H)

Step 2) 2- (2- methoxy ethoxies) -1- (piperazine -1- bases) acetyl group trifluoroacetate

By 4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- t-butyl formates (0.57g, 1.88mmol), trifluoro Acetic acid (5.6mL) obtains brownish oil shape thing (0.55g, 93%) by the synthetic method of the step 3 of embodiment 12.

MS-ESI:(ESI, pos.ion) m/z:203.2[M+l]+.

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- bases) first Base) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 2- (2- methoxy ethoxies) -1- (piperazine -1- bases) acetyl group trifluoroacetate (0.63g, 2mmol) yellow is obtained by the synthetic method of the step 1 of embodiment 2 glue shape solid (0.34g, 55%).

MS-ESI:(ESI, pos.ion) m/z:625.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 9.73 (s, 1H), 9.41 (s, 1H), 7.52-7.23 (m, 3H), 6.09 (s, 1H), 4.28 (s, 2H), 4.12-3.91 (m, 4H), 3.71-3.67 (m, 2H), 3.61-3.55 (m, 4H), 3.53-3.48 (m, 2H), 3.45-3.41 (m, 4H), 3.37 (s, 3H), 1.10 (t, 3H)

Embodiment 15:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- benzene oxygen acetyl group) piperazine -1- bases) methyl) -2- (1,3,4- thiophenes two Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2- benzene oxygen acetyl group) piperazine -1- t-butyl formates

Phenol (0.16g, 1.7mmol), potassium carbonate (0.23g, 1.7mmol), CH are sequentially added in dry reaction bottle3CN (20mL), 4- (2- chloracetyls) piperazine -1- t-butyl formates (0.3g, 1.13mmol), 70 DEG C of reaction 6h.Filtering, filtrate subtract Solvent is evaporated off in pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=5/1), obtains colorless oil (0.2g, 55%).

MS-ESI:(ESI, pos.ion) m/z:265.1[M+l-56]+

1H NMR (400MHz, DMSO-d6):δ 7.32-7.26 (m, 2H), 7.01-6.93 (m, 3H), 4.70 (s, 2H), 3.58 (br.s, 4H), 3.44-3.39 (m, 4H), 1.46 (s, 9H)

Step 2) 2- phenoxy groups -1- (piperazine -1- bases) ethyl ketone trifluoroacetate

By 4- (2- benzene oxygen acetyl group) piperazine -1- t-butyl formates (0.41g, 1.28mmol), trifluoroacetic acid (3.82mL) Brownish oil shape thing (0.39g, 90%) is obtained by the synthetic method of the step 3 of embodiment 12.

MS-ESI:(ESI, pos.ion) m/z:221.1[M+l]+.

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- benzene oxygen acetyl group) piperazine -1- bases) methyl) -2- (1,3,4- Thiadiazoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 2- phenoxy groups -1- (piperazine -1- bases) ethyl ketone trifluoroacetate (0.67g, 2mmol) are by implementation The synthetic method of the step 1 of example 2 obtains yellow solid (0.37g, 57%).

MS-ESI:(ESI, pos.ion) m/z:643.1[M+l]+

1H NMR (400MHz, DMSO-d6):δ 9.66 (s, 1H), 9.38 (s, 1H), 7.55-7.22 (m, 5H), 7.07- 6.98 (m, 3H), 6.01 (s, 1H), 4.67 (s, 2H), 4.09-3.83 (m, 4H), 3.49 (br.s, 4H), 3.46-3.34 (m, 4H), 1.08 (t, 3H)

Embodiment 16:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- glycolyls) piperazine -1- bases) methyl) -2- (1,3,4- thiadiazoles - 2- yls) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2- (tert-butoxy) acetyl group) piperazine -1- t-butyl formates

Potassium tert-butoxide (0.53g, 4.7mmol), the tert-butyl alcohol (45mL), 4- (2- chloroethenes are sequentially added in dry reaction bottle Acyl group) piperazine -1- t-butyl formates (1g, 3.81mmol), 80 DEG C of reaction 1.5h, are filtered, solvent, crude product post is evaporated off in filtrate decompression Chromatography purifies (petrol ether/ethyl acetate/dichloromethane (V/V/V)=5/1/1), obtains colorless oil (0.44g, 38%).

MS-ESI:(ESI, pos.ion) m/z:301.2[M+1]+

1H NMR (400MHz, DMSO-d6):δ 4.07 (s, 2H), 3.58-3.55 (m, 4H), 3.46-3.42 (m, 4H), 1.47 (s, 9H), 1.23 (s, 9H)

Step 2) 2- oxos -2- (piperazine -1- bases) ethyl trifluoro-acetate trifluoroacetate

By 4- (2- (tert-butoxy) acetyl group) piperazine -1- t-butyl formates (0.41g, 1.37mmol), trifluoroacetic acid (4mL) obtains brownish oil shape thing (0.44g, 90%) by the synthetic method of the step 3 of embodiment 11.

MS-ESI:(ESI, pos.ion) m/z:241.1[M+1]+.

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((4- (2- glycolyls) piperazine -1- bases) methyl) -2- (1,3,4- thiophenes Diazole -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formate (0.5g, 1mmol), 2- oxos -2- (piperazine -1- bases) ethyl trifluoro-acetate trifluoroacetate (0.71g, 2mmol) yellow solid (0.12g, 22%) is obtained by the synthetic method of the step 1 of embodiment 2.

MS-ESI:(ESI, pos.ion) m/z:567.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.81 (s, 1H), 9.45 (s, 1H), 7.52-7.19 (m, 3H), 6.05 (s, 1H), 4.13-3.85 (m, 6H), 3.63-3.57 (m, 4H), 3.43-3.38 (m, 4H), 1.04 (t, 3H)

Embodiment 17:

4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin - 5- isopropyl formates

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Isopropyl formate

By 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.65g, 10mmol), the bromo- 4- fluorobenzaldehydes of 2- (2.03g, 10mmol), isopropyl acetoacetate (1.73g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.23g, 28%).

MS-ESI:(ESI, pos.ion) m/z:439.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.76 (s, 1H), 9.62 (s, 1H), 7.39-7.28 (m, 2H), 7.19- 7.05 (m, 1H), 6.01 (s, 1H), 4.85-4.79 (m, 1H), 2.47 (s, 3H), 1.11 (d, 6H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- isopropyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid Isopropyl ester (0.44g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow solid by the synthetic method of the step 4 of embodiment 1 (0.25g, 48%).

MS-ESI:(ESI, pos.ion) m/z:516.9[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 9.55 (s, 1H), 7.46-7.29 (m, 2H), 7.17- 7.02 (m, 1H), 6.04 (s, 1H), 4.82-4.75 (m, 1H), 4.64 (dd, 2H), 1.07 (d, 6H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydros Pyrimidine -5- isopropyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) 6- (bromomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Isopropyl propionate (0.52g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.31g, 60%).

MS-ESI:(ESI, pos.ion) m/z:524.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.68 (s, 1H), 9.52 (s, 1H), 7.49-7.26 (m, 2H), 7.18- 7.05 (m, 1H), 6.06 (s, 1H), 4.80-4.74 (m, 1H), 3.93-3.81 (m, 2H), 3.52 (br.s, 4H), 2.63 (br.s, 4H), 1.07 (d, 6H)

Embodiment 18:

4- (the bromo- 4- fluorophenyls of 2-) -2- (the chloro- 1,3,4- thiadiazoles -2- bases of 5-) -6- (morpholinomethyl) -1,4- dihydros Pyrimidine -5- Ethyl formates

The chloro- 1,3,4- thiadiazoles -2- cyano group of step 1) 5-

By the thiadiazoles -2- amino (13.6g, 100mmol) of 5- chloro- 1,3,4-, cuprous cyanide (17.9g, 200mmol) by real The synthetic method for applying the step 1 of example 1 obtains micro- brown liquid (3.49g, 24%).

MS-ESI:(ESI, pos.ion) m/z:146.0[M+1]+.

The chloro- 1,3,4- thiadiazoles -2- amitraz hydrochlorides of step 2) 5-

By the thiadiazoles -2- cyano group (1.46g, 10mmol) of 5- chloro- 1,3,4-, sodium methoxide (0.54g, 10mmol), ammonium chloride (0.64g, 12mmol) obtains light yellow solid (1.29g, 65%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:163.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 7.16 (s, 1H), 6.87 (br.s, 2H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (the chloro- 1,3,4- thiadiazoles -2- bases of 5-) -6- methyl isophthalic acids, 4- dihydros are phonetic Pyridine -5- Ethyl formates

By the thiadiazoles -2- amitraz hydrochlorides (1.99g, 10mmol) of 5- chloro- 1,3,4-, the bromo- 4- fluorobenzaldehydes of 2- (2.03g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.38g, 30%).

MS-ESI:(ESI, pos.ion) m/z:459.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 7.38-7.28 (m, 2H), 7.18-7.05 (m, 1H), 6.21 (s, 1H), 4.06 (q, 2H), 2.46 (s, 3H), 1.13 (t, 3H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (the chloro- 1,3,4- thiadiazoles -2- bases of 5-) -1,4- two Hydrogen pyrimidine -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (thiadiazoles -2- bases of 5- chloro- 1,3,4-) -6- methyl isophthalic acids, 4- dihydro-pyrimidins -5- Ethyl formate (0.46g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow solid by the synthetic method of the step 4 of embodiment 1 (0.23g, 43%).

MS-ESI:(ESI, pos.ion) m/z:536.9[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.68 (s, 1H), 7.41-7.29 (m, 2H), 7.17-7.03 (m, 1H), 6.17 (s, 1H), 4.59 (dd, 2H), 4.11 (q, 2H), 1.10 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (the chloro- 1,3,4- thiadiazoles -2- bases of 5-) -6- (morpholinomethyl) -1, 4- dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (thiadiazoles -2- bases of 5- chloro- 1,3,4-)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates (0.54g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow by the synthetic method of the step 5 of embodiment 1 and consolidated Body (0.33g, 60%).

MS-ESI:(ESI, pos.ion) m/z:544.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.62 (s, 1H), 7.44-7.27 (m, 2H), 7.15-7.02 (m, 1H), 6.13 (s, 1H), 4.14 (q, 2H), 4.02-3.91 (m, 2H), 3.51 (br.s, 4H), 2.65 (br.s, 4H), 1.10 (t, 3H)

Embodiment 19:

4- (the bromo- 4- fluorophenyls of 2-) -2- (3- isopropyl -1,2,4- thiadiazoles -5- bases) -6- (morpholinomethyl) -1,4- Dihydro-pyrimidin -5- Ethyl formates

Step 1) 3- isopropyl -1,2,4- thiadiazoles -5- cyano group

By 3- isopropyls -1,2,4- thiadiazoles -5- amino (14.3g, 100mmol), cuprous cyanide (17.9g, 200mmol) Brownish oil shape thing (4.14g, 27%) is obtained by the synthetic method of the step 1 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:154.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 3.25-3.14 (m, 1H), 1.23 (d, 6H)

Step 2) 3- isopropyl -1,2,4- thiadiazoles -5- amitraz hydrochlorides

By 3- isopropyls -1,2,4- thiadiazoles -5- cyano group (1.53g, 10mmol), sodium methoxide (0.54g, 10mmol), chlorine Change ammonium (0.64g, 12mmol) and obtain light yellow solid (1.41g, 68%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:171.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 7.01 (s, 1H), 6.83 (br.s, 2H), 3.27-3.16 (m, 1H), 1.19 (d, 6H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (3- isopropyl -1,2,4- thiadiazoles -5- bases) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates

By 3- isopropyls -1,2, the bromo- 4- fluorobenzaldehydes of 4- thiadiazoles -5- amitraz hydrochlorides (2.07g, 10mmol), 2- (2.03g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.26g, 27%).

MS-ESI:(ESI, pos.ion) m/z:46701[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 7.47-7.24 (m, 2H), 7.15-6.99 (m, 1H), 6.17 (s, 1H), 4.06 (q, 2H), 3.22-3.15 (m, 1H), 2.48 (s, 3H), 1.26 (d, 6H), 1.13 (t, 3H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (3- isopropyl -1,2,4- triazole -5- bases) -1, 4- dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -2- (3- isopropyls -1,2,4- thiadiazoles -5- bases) -6- methyl isophthalic acids, 4- dihydros is phonetic Pyridine -5- Ethyl formates (0.47g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow by the synthetic method of the step 4 of embodiment 1 and consolidated Body (0.28g, 51%).

MS-ESI:(ESI, pos.ion) m/z:545.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.67 (s, 1H), 7.48-7.06 (m, 3H), 6.13 (s, 1H), 4.63 (dd, 2H), 4.11 (q, 2H), 3.25-3.16 (m, 1H), 1.22 (d, 6H), 1.10 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (3- isopropyl -1,2,4- thiadiazoles -5- bases) -6- (morpholino first Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (3- isopropyls -1,2,4- triazole -5- bases)-Isosorbide-5-Nitrae-two Hydrogen pyrimidine -5- Ethyl formates (0.55g, 1mmol), morpholine (0.35g, 4mmol) are obtained yellow by the synthetic method of the step 5 of embodiment 1 Color solid (0.3g, 55%).

MS-ESI:(ESI, pos.ion) m/z:552.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.67 (s, 1H), 7.48-7.06 (m, 3H), 6.13 (s, 1H), 4.14 (q, 2H), 4.01-3.93 (m, 2H), 3.63 (br.s, 4H), 3.22-3.14 (m, 1H), 2.52 (br.s, 4H), 1.18 (d, 6H), 1.07 (t, 3H)

Embodiment 20:

4- (the bromo- 4- fluorophenyls of 2-) -6- (3- ethyl morpholines) methyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydros Pyrimidine -5- Ethyl formates

By 6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (1.01g, 2mmol), 3- ethyl morpholines (0.46g, 4mmol) obtain yellow solid by the synthetic method of the step 1 of embodiment 2 (0.6g, 56%).

MS-ESI:(ESI, pos.ion) m/z:538.1[M+1]+

1H NMR (400MHz, CDCl3):δ 9.82 (br.s, 1H), 9.71 (s, 1H), 7.32-6.92 (m, 3H), 6.17 (s, 1H), 4.31-4.27 (m, 1H), 4.16-4.11 (m, 1H), 4.08-4.00 (m, 2H), 3.91-3.83 (m, 2H), 3.80-3.76 (m, 2H), 3.56-3.51 (m, 1H), 2.75-2.71 (m, 1H), 2.64-2.47 (m, 2H), 2.33-2.22 (m, 1H), 1.15- 1.11 (m, 6H)

Embodiment 21:

4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins -5- Methyl formate

Step 1) 6- methyl -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Methyl formate

By 2- carbonamidines -1,3, the bromo- 4- fluorobenzaldehydes of 4- thiadiazoles hydrochloride (1.65g, 10mmol), 2- (2.03g, 10mmol), methyl acetoacetate (1.4g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.23g, 30%).

MS-ESI:(ESI, pos.ion) m/z:411.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.37 (br.s, 1H), 9.67 (s, 1H), 7.56-7.21 (m, 3H), 5.98 (s, 1H), 3.53 (s, 3H), 2.46 (s, 3H)

Step 2) 6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins - 5- methyl formates

By 6- methyl -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid Methyl esters (0.82g, 2mmol), NBS (0.36g, 2mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.55g, 55%).

MS-ESI:(ESI, pos.ion) m/z:489.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.86 (br.s, 1H), 9.69 (s, 1H), 7.57-7.28 (m, 3H), 6.02 (s, 1H), 3.91 (dd, 2H), 3.65 (s, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholine methyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- methyl formates

By 6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Sour methyl esters (0.98g, 2mmol), morpholine (0.7g, 8mmol) by the synthetic method of the step 5 of embodiment 1 obtain yellow solid (0.69g, 70%).

MS-ESI:(ESI, pos.ion) m/z:496.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.82 (br.s, 1H), 9.71 (s, 1H), 7.58-7.23 (m, 3H), 6.05 (s, 1H), 3.91 (dd, 2H), 3.67 (br.s, 4H), 3.52 (s, 3H), 2.56 (br.s, 4H)

Embodiment 22:

4- (the bromo- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (5- methyl isophthalic acids, 3,4- thiophenes two Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- cyano group -5- methyl thiadiazoles

By 2- amino -5- methyl isophthalic acids, 3,4- thiadiazoles (11.5g, 100mmol), cuprous cyanide (17.9g, 200mmol) are pressed The synthetic method of the step 1 of embodiment 1 obtains white solid (3.13g, 25%).

MS-ESI:(ESI, pos.ion) m/z:126.0[M+1]+

1H NMR (400MHz, CDCl3):δ 2.93 (s, 3H)

Step 2) 5- methyl isophthalic acids, 3,4- thiadiazoles -2- amitraz hydrochlorides

By 2- cyano group -5- methyl isophthalic acids, 3,4- thiadiazoles (1.25g, 10mmol), sodium methoxide (0.54g, 10mmol), chlorination Ammonium (0.64g, 12mmol) obtains light yellow solid (1.25g, 70%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:143.0[M+1]+

1H NMR (400MHz, D20):δ 2.91 (s, 3H)

Step 3) 6- methyl -4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro Pyrimidine -5- Ethyl formates

By 5- methyl isophthalic acids, 3,4- thiadiazoles -2- amitraz hydrochlorides (1.8g, 10mmol), the bromo- 4- fluorobenzaldehydes of 2- (2.03g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.01g, 23%).

MS-ESI:(ESI, pos.ion) m/z:439.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.24 (br.s, 1H), 7.56-7.21 (m, 3H), 5.98 (s, 1H), 3.93 (q, 2H), 2.72 (s, 3H), 2.46 (s, 3H), 1.10 (t, 3H)

Step 4) 6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-two Hydrogen pyrimidine -5- Ethyl formates

By 6- methyl -4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin - 5- Ethyl formates (0.88g, 2mmol), NBS (0.36g, 2mmol) obtain yellow solid by the synthetic method of the step 4 of embodiment 1 (0.57g, 55%).

MS-ESI:(ESI, pos.ion) m/z:516.9[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.19 (br.s, 1H), 7.52-7.20 (m, 3H), 6.02 (s, 1H), 4.56 (dd, 2H), 4.04 (q, 2H), 2.69 (s, 3H), 1.13 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (5- methyl isophthalic acids, 3,4- Thiadiazoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates (1.04g, 2mmol), thiomorpholine dioxide. HCl (0.42g, 2.4mmol) press the step of embodiment 2 L synthetic method obtains yellow solid (0.6g, 52%).

MS-ESI:(ESI, pos.ion) m/z:572.0[M+1]+

1H-NMR (400MHz, CDCl3):δ 9.26 (br.s, 1H), 7.34-6.95 (m, 3H), 6.19 (s, 1H), 4.31 (d, 1H), 4.03 (q, 2H), 3.98 (d, 1H), 3.19 (br.s, 4H), 3.13 (br.s, 4H), 2.78 (s, 3H), 1.12 (t, 3H)

Embodiment 23:

4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) -6- (morpholine methyl) -1,4- dihydros Pyrimidine -5- Ethyl formates

6- bromomethyls -4- (the bromo- 4- fluorophenyls of 2-) -2- (5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro is phonetic Pyridine -5- Ethyl formates (1.04g, 2mmol), morpholine (0.7g, 8mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.65g, 62%).

MS-ESI:(ESI, pos.ion) m/z:524.1[M+1]+

1H NMR (400MHz, CDCl3):δ 9.64 (br.s, 1H), 7.33-6.94 (m, 3H), 6.19 (s, 1H), 4.03 (q, 2H), 3.99 (dd, 2H), 3.83 (t, 4H), 2.77 (s, 3H), 2.61 (t, 4H), 1.12 (t, 3H)

Embodiment 24:

4- (2,4 dichloro benzene base) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins -5- Ethyl formate

Step 1) 4- (2,4- dichlorophenyl) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester

By 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.65g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.03g, 26%).

MS-ESI:(ESI, pos.ion) m/z:397.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.72 (s, 1H), 9.27 (s, 1H), 7.46-7.38 (m, 1H), 7.32- 7.28 (m, 1H), 7.23-7.16 (m, 1H), 6.21 (s, 1H), 4.07 (q, 2H), 2.52 (s, 3H), 1.08 (t, 3H)

Step 2) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin - 5- Ethyl formates

By 4- (2,4- dichlorophenyl) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid second Ester (0.4g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.26g, 55%).

MS-ESI:(ESI, pos.ion) m/z:475.0 [M+1 ]+

1H NMR (400MHz, DMSO-d6):δ 9.69 (s, 1H), 9.24 (s, 1H), 7.43-7.39 (m, 1H), 7.34- 7.29 (m, 1H), 7.22-7.13 (m, 1H), 6.18 (s, 1H), 4.68 (dd, 2H), 4.03 (q, 2H), 1.04 (t, 3H)

Step 3) 4- (2,4- dichlorophenyl) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro Pyrimidine -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.48g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.31g, 65%).

MS-ESI:(ESI, pos.ion) m/z:482.1 [M+1 ]+

1H NMR (400MHz, DMSO-d6):δ 9.59 (s, 1H), 9.27 (s, 1H), 7.48-7.41 (m, 1H), 7.36- 7.27 (m, 1H), 7.25-7.14 (m, 1H), 6.15 (s, 1H), 4.11 (q, 2H), 4.01-3.89 (m, 2H), 3.48 (br.s, 4H), 2.52 (br.s, 4H), 1.10 (t, 3H)

Embodiment 25:

4- (2,4 dichloro benzene base) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (1,3,4- thiadiazoles -2- bases) - 1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.48g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) press the synthesis side of the step 1 of embodiment 2 Method obtains yellow solid (0.29g, 54%).

MS-ESI:(ESI, pos.ion) m/z:530.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.63 (s, 1H), 9.31 (s, 1H), 7.45-7.38 (m, 1H), 7.34- 7.25 (m, 1H), 7.22-7.13 (m, 1H), 6.12 (s, 1H), 4.06 (q, 2H), 3.97-3.84 (m, 2H), 3.24 (br.s, 4H), 2.92 (br.s, 4H), 1.09 (t, 3H)

Embodiment 26:

4- (2,4 dichloro benzene base) -2- (1,3,4- thiadiazoles -2- bases) -6- (thiomorpholine methyl) -1,4- dihydro-pyrimidins - 5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.48g, 1mmol), thiomorpholine (0.41g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.25g, 51%).

MS-ESI:(ESI, pos.ion) m/z:498.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.71 (s, 1H), 9.25 (s, 1H), 7.47-7.39 (m, 1H), 7.35- 7.27 (m, 1H), 7.24-7.15 (m, 1H), 6.14 (s, 1H), 4.03 (q, 2H), 3.99-3.82 (m, 2H), 2.91-2.65 (m, 4H), 2.61-2.52 (m, 4H), 1.05 (t, 3H)

Embodiment 27:

2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4- dichlorophenyl) -6- (morpholinomethyl)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates

Step 1) 5- (tert-butyl group) -1,3,4- thiadiazoles -2- cyano group

By 5- (tert-butyl group) -1,3,4- thiadiazoles -2- amino (15.7g, 100mmol), cuprous cyanide (17.9g, 200mmol) brownish oil shape thing (4.18g, 25%) is obtained by the synthetic method of the step 1 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:168.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 1.43 (s, 9H)

Step 2) 5- (tert-butyl group) -1,3,4- thiadiazoles -2- amitraz hydrochlorides

By 5- (tert-butyl group) -1,3,4- thiadiazoles -2- cyano group (1.67g, 10mmol), sodium methoxide (0.54g, 10mmol), Ammonium chloride (0.64g, 12mmol) obtains light yellow solid (1.5g, 68%) by the synthetic method of the step 2 of embodiment 1.

MS-ESI:(ESI, pos.ion) m/z:185.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 7.18 (s, 1H), 6.89 (br.s, 2H), 1.46 (s, 9H)

Step 3) 2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4 dichloro benzene base) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates

By 5- (tert-butyl group) -1,3,4- thiadiazoles -2- amitraz hydrochlorides (2.2g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.22g, 27%).

MS-ESI:(ESI, pos.ion) m/z:453.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.42 (s, 1H), 7.56-7.43 (m, 1H), 7.33-7.26 (m, 1H), 7.24-7.13 (m, 1H), 6.10 (s, 1H), 4.05 (q, 2H), 2.49 (s, 3H), 1.42 (s, 9H), 1.13 (t, 3H)

Step 4) 6- (bromomethyl) -2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4- dichlorophenyl) -1, 4- dihydro-pyrimidin -5- Ethyl formates

2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4- dichlorophenyl) -6- methyl isophthalic acids, 4- dihydros is phonetic Pyridine -5- Ethyl formates (0.45g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow by the synthetic method of the step 4 of embodiment 1 and consolidated Body (0.25g, 47%).

MS-ESI:(ESI, pos.ion) m/z:531.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.63 (s, 1H), 7.52-7.41 (m, 1H), 7.35-7.27 (m, 1H), 7.22-7.11 (m, 1H), 6.13 (s, 1H), 4.67 (dd, 2H), 4.08 (q, 2H), 1.43 (s, 9H), 1.11 (t, 3H)

Step 5) 2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4 dichloro benzene base) -6- (morpholino first Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -2- (5- (tert-butyl group) -1,3,4- thiadiazoles -2- bases) -4- (2,4- dichlorophenyl)-Isosorbide-5-Nitrae-two Hydrogen pyrimidine -5- Ethyl formates (0.53g, 1mmol), morpholine (0.35g, 4mmol) are obtained yellow by the synthetic method of the step 5 of embodiment 1 Color solid (0.3g, 55%).

MS-ESI:(ESI, pos.ion) m/z:538.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.68 (s, 1H), 7.49-7.40 (m, 1H), 7.37-7.28 (m, 1H), 7.24-7.13 (m, 1H), 6.07 (s, 1H), 4.12 (q, 2H), 4.02-3.91 (m, 2H), 3.63 (br.s, 4H), 2.45 (br.s, 4H), 1.41 (s, 9H), 1.12 (t, 3H)

Embodiment 28:

4- (2,4- dichlorophenyl) -6- (morpholinomethyl) -2- (base of 1,3,4- thiadiazoles -2)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Methyl formate

Step 1) 4- (2,4- dichlorophenyl) -6- methyl -2- (1,3,4 thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Sour methyl esters

By 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.65g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol), methyl acetoacetate (1.39g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.25g, 25%).

MS-ESI:(ESI, pos.ion) m/z:499.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.56 (br.s, 1H), 9.45 (s, 1H), 7.51-7.45 (m, 1H), 7.36-7.31 (m, 1H), 7.26-7.18 (m, 1H), 6.03 (s, 1H), 3.59 (s, 3H), 2.48 (s, 3H)

Step 2) 6- (bromomethyl) -4- (2,4 dichloro benzene base) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins - 5- methyl formates

By 4- (2,4- dichlorophenyl) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid first Ester (0.38g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.21g, 45%).

MS-ESI:(ESI, pos.ion) m/z:461.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.49 (br.s, 1H), 9.41 (s, 1H), 7.52-7.47 (m, 1H), 7.38-7.32 (m, 1H), 7.28-7.19 (m, 1H), 6.06 (s, 1H), 4.65 (dd, 2H), 3.61 (s, 3H)

Step 3) 4- (2,4 dichloro benzene base) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydros Pyrimidine -5- methyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Sour methyl esters (0.46g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.22g, 47%).

MS-ESI:(ESI, pos.ion) m/z:468.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.55 (br.s, 1H), 9.43 (s, 1H), 7.49-7.44 (m, 1H), 7.39-7.32 (m, 1H), 7.29-7.18 (m, 1H), 6.05 (s, 1H), 3.97-3.83 (m, 2H), 3.66 (br.s, 4H), 3.58 (s, 3H), 2.49 (br.s, 4H)

Embodiment 29:

4- (2,4 dichloro benzene base) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (1,3,4- thiadiazoles -2- bases) - 1,4- dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Sour methyl esters (0.46g, 1mmol), thiomorpholine dioxide. HCl (0.42g, 2.4mmol) press the synthesis of the step 1 of embodiment 2 Method obtains yellow solid (0.26g, 50%).

MS-ESI:(ESI, pos.ion) m/z:516.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 10.58 (br.s, 1H), 9.40 (s, 1H), 7.53-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.28-7.16 (m, 1H), 6.06 (s, 1H), 4.02-3.84 (m, 2H), 3.63 (s, 3H), 3.29 (br.s, 4H), 2.97 (br.s, 4H)

Embodiment 30:

4- (2,4 difluorobenzene base) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases) -1,4- dihydro-pyrimidins -5- Ethyl formate

Step 1) 4- (2,4- difluorophenyl) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester

By 1,3,4- thiadiazoles -2- amitraz hydrochlorides (1.65g, 10mmol), 2,4- difluorobenzaldehydes (1.42g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (0.87g, 24%).

MS-ESI:(ESI, pos.ion) m/z:365.1[M+1]+

1H NMR (400MHz, CDCl3):δ 9.15 (s, 1H), 7.82 (s, 1H), 7.32-7.26 (m, 1H), 6.82-6.79 (m, 2H), 6.06 (s, 1H), 4.08 (q, 2H), 2.48 (s, 3H), 1.17 (t, 3H)

Step 2) 6- (bromomethyl) -4- (2,4- difluorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin - 5- Ethyl formates

By 4- (2,4- difluorophenyl) -6- methyl -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- formic acid second Ester (0.36g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of the step 4 of embodiment 1 obtain yellow solid (0.19g, 43%).

MS-ESI:(ESI, pos.ion) m/z:443.0[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.25 (s, 1H), 7.88 (s, 1H), 7.39-7.29 (m, 1H), 6.97- 6.82 (m, 2H), 6.02 (s, 1H), 4.68 (dd, 2H), 4.11 (q, 2H), 1.14 (t, 3H)

Step 3) 4- (2,4- difluorophenyl) -6- (morpholinomethyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro Pyrimidine -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- difluorophenyl) -2- (1,3,4- thiadiazoles -2- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- first Acetoacetic ester (0.44g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow solid by the synthetic method of the step 5 of embodiment 1 (0.27g, 59%).

MS-ESI:(ESI, pos.ion) m/z:450.1[M+1]+

1H NMR (400MHz, DMSO-d6):δ 9.56 (s, 1H), 7.93 (s, 1H), 7.35-7.28 (m, 1H), 6.95- 6.81 (m, 2H), 6.10 (s, 1H), 4.09 (q, 2H), 3.99-3.84 (m, 2H), 3.68 (br.s, 4H), 2.45 (br.s, 4H), 1.07 (t, 3H)

Embodiment 31:

External Anti-HBV activity drug activity determination experiment is carried out with HBV HepG2.2.15 cell lines

I. experimental method:

QPCR detects cell culture fluid viral DNA content and calculates the suppression percentage (%Inh) of compounds on viral, has Body experimental method is as follows:

Inoculation HepG2.2.15 cells contain chemical combination to be tested to 96 hole microwell plates (40,000 cells/well), addition in second day The cell culture fluid processing cell of thing, the compound for surveying suppression percentage are two-pack hole, final compound concentration 500nmol.The Five days nutrient solutions for changing drug containing, collect culture supernatant within the 8th day and extract the DNA in supernatant.

Viral DNA extracts:With reference to QIAamp96DNABlood Kit (QIAGEN51161).

Quantitative PCR:Reaction mixture is configured according to PCR system;It is (quantitative special that mixed liquor is added into 384 hole PCR reaction plates With);Add the standard items template diluted in proportion;Add sample form;384 orifice plates are sealed up with shrouding film;According to program Run quantitative PCR apparatus.

Compound suppresses percentage to hbv replication and calculated:%Inh.=【1- adds compound processing HBV amount of DNA/DMSO pairs According to processing HBV amount of DNA】×100.

II. experimental result:

The suppression percentage (%Inh) of the external suppression hbv replication of the compound of the present invention is determined according to the above method, as a result It see the table below 2:

Table 2

III. conclusion:

As a result show, embodiment 1,5,21,24,28,30 suppresses hbv replication percentage and is more than 80%, shows the present invention Described compound has the function that stronger Anti-HBV activity replicates.This kind of compound has antiviral work beyond expectation to HBV Property, therefore suitable for treatment various diseases caused by HBV virus infection.

Although above oneself to the present invention through with generality explanation, embodiment and experiment, having made to retouch in detail State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art 's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed Scope.

Claims (19)

1. one kind has the compound as shown in formula (IV) or (IVa),
Or its pharmaceutically acceptable salt, wherein:
Z is the subformula as shown in formula (V):
Y is-O- or-S-;
R2For C1-C4Alkyl;
R3For thiadiazolyl group;Wherein described thiadiazolyl group can be selected from hydrogen, deuterium, chlorine or C by one1-C6The substituent of alkyl is taken Generation;
R9For hydrogen, deuterium, methyl or ethyl;
Each R11It independently is fluorine, deuterium, chlorine or bromine;
Each k independently is 1 or 2;
N is 0 or 1.
2. compound according to claim 1, wherein:
Z is independently selected from following subformula:
3. compound according to claim 1, wherein:
R3Independently selected from following subformula:
4. compound according to claim 1, the structure comprising one of:
Or its pharmaceutically acceptable salt.
5. according to the compound described in claim 1-4 any one, or its pharmaceutically acceptable salt, wherein the salt is that have Machine hydrochlorate, inorganic acid salt or the salt obtained by alkali.
6. compound according to claim 5, or its pharmaceutically acceptable salt, wherein, inorganic acid salt is hydrochloride, hydrogen Bromate, perchlorate, phosphate or sulfate.
7. compound according to claim 5, or its pharmaceutically acceptable salt, wherein, acylate be carboxylate or Person's sulphur hydrochlorate.
8. compound according to claim 7, or its pharmaceutically acceptable salt, wherein, carboxylate is acetate, oxalic acid Salt, maleate, tartrate, citrate, succinate or malonate.
9. compound according to claim 7, or its pharmaceutically acceptable salt, wherein, sulphur hydrochlorate be mesylate, Esilate, benzene sulfonate, toluene fulfonate or naphthalene sulfonate.
10. compound according to claim 5, or its pharmaceutically acceptable salt, wherein, the salt obtained by alkali is alkali Metal, alkaline-earth metal, ammonium or N+(R12)4Salt, wherein, R12It is H, deuterium, C1-C4Alkyl, C6-C10Aryl or C6-C10Aryl C1- C4Alkyl.
11. compound according to claim 10, or its pharmaceutically acceptable salt, wherein, alkali metal or alkaline-earth metal Salt is sodium salt, lithium salts, sylvite, calcium salt or magnesium salts.
12. a kind of pharmaceutical composition, include the compound described in claim 1, and its pharmaceutically acceptable carrier, figuration Agent, diluent, assistant agent, medium or combinations thereof.
13. pharmaceutical composition according to claim 12, it further includes Anti-HBV drugs.
14. pharmaceutical composition according to claim 13, wherein Anti-HBV drugs are HBV AG14361s, immunological regulation Agent or interferon.
15. pharmaceutical composition according to claim 14, wherein Anti-HBV drugs have Lamivudine, Sebivo, for promise good fortune Wei ester, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, emtricitabine, method Pu Luowei, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta-1a, interferon α-2, in vain Cytokine -2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol, or Propagermanium.
16. usage right requires that any described compounds of 1-4 or any described pharmaceutical compositions of claim 12-15 are being made Purposes in standby prevention, the medicine for handling, treating or mitigating patient's viral disease.
17. purposes according to claim 16, wherein viral disease refer to hepatitis B infection or hepatitis B infection Caused disease.
18. purposes according to claim 17, wherein hepatitis B infection cause disease to refer to hepatic sclerosis or hepatocellular carcinoma Become.
19. purposes according to claim 16, wherein viral disease refer to hepatitis B disease.
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