CN103664899A

CN103664899A - Heteroaryl-substituted dihydropyrimidine compounds and application thereof in medicines

Info

Publication number: CN103664899A
Application number: CN201310410130.8A
Authority: CN
Inventors: 张英俊; 刘辛昌; 任青云; 王超磊; S·戈尔德曼
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2012-09-11
Filing date: 2013-09-10
Publication date: 2014-03-26
Anticipated expiration: 2033-09-10
Also published as: CN103664899B

Abstract

The invention relates to heteroaryl-substituted dihydropyrimidine compounds and application thereof in medicines, particularly application in medicines for treating and preventing hepatitis B. Particularly, the invention relates to compounds disclosed as general formula (I) or (Ia), or enantiomers, diastereoisomers, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein the variables are defined in the specification. The invention also relates to application of the compounds disclosed as general formula (I) or (Ia), or enantiomers, diastereoisomers, hydrates, solvates or pharmaceutically acceptable salts thereof, especially application in medicines for treating and preventing hepatitis B.

Description

The Dihydropyrimidines that heteroaryl replaces and the application in medicine thereof

Invention field

The present invention relates to Dihydropyrimidines that a kind of heteroaryl replaces and as the purposes of medicine, especially as the application that is used for the treatment of and prevents the medicine of hepatitis B.The invention still further relates to the Dihydropyrimidines of these heteroaryls replacements with other antiviral agents, and the medicine that contains these compositions, in particular for treatment and prevention hepatitis B (HBV), infect.

Background of invention

Hepatitis B virus belongs to hepatovirus section.It can cause acute and or continue/progressive chronic disease.Hepatitis B virus also causes many other clinical sign---especially chronic inflammatory diseases, liver cirrhosis and the hepatocellular cancerations of liver in pathomorphism.In addition, can have a negative impact in advancing of disease process with the common infection of hepatitis D.

The conventional dose that is licensed for treatment chronic hepatitis treatment is Interferon, rabbit and lamivudine (lamivudine).Yet Interferon, rabbit only has medium activity, and there is higher toxic side effects; Although lamivudine (lamivudine) has good activity, its resistance amplification in therapeutic process is rapid, and the effect that usually has a rebound after stopping treatment, the IC of lamivudine (3-TC) > ₅₀value is 300nM(Science, 299(2003), 893-896).

Deres etc. have reported take dihydropyridine (HAP) compound that hetero-aromatic ring that Bay41-4109, Bay39-5493 be representative replaces, and this compounds can be by stoping the formation of normal nucleocapsid to reach the effect of inhibition HBV replication.Bay41-4109 has showed good drug metabolism parameter (Science, 299(2003) in clinical study, 893-896).The research of its mechanism of action is found, the Dihydropyrimidines that hetero-aromatic ring replaces is by the 113-143 amino-acid residue effect with core protein, changed the angle between the dimer that forms nucleocapsid, cause forming unsettled expansion nucleocapsid, accelerate the degraded (Biochem.Pharmacol.66(2003) of core protein, 2273-2279).

Still need at present to have new can be effectively as the compound of antiviral, especially as the medicine that treats and/or prevents hepatitis B.

Abstract of invention

The present invention relates to Dihydropyrimidines and treatment and the method for preventing HBV to infect that heteroaryl replaces.

Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can effectively suppress HBV and infect.

On the one hand, the present invention relates to a kind of suc as formula (I) or the compound (Ia),

Or its enantiomer, diastereomer, tautomer, hydrate, solvate or pharmacy acceptable salt, wherein:

A be a key ,-O-,-S-or-N (R ⁵)-;

R is-X-Z;

X is-(CR ⁷r ^7a) _m-or-C (=O)-;

Z is minor structure formula as shown in the formula (II):

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

W is CR ⁷, or N;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ¹for aryl or heteroaryl;

R ²for hydrogen, deuterium, alkyl, thiazolinyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical, heterocyclic radical alkyl or carbalkoxy;

R ³for containing 5 yuan of heteroaryls of 3 or 4 nitrogen-atoms, wherein said 5 yuan of heteroaryls that contain 3 or 4 nitrogen-atoms can be optionally by monosubstituted or identical or different polysubstituted of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxyl group, alkylamino, arylalkyl, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl; Wherein, R ³be not

R ⁴for hydrogen, deuterium or C ₁-C ₄alkyl;

R ⁵for hydrogen, deuterium, alkyl ,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸, alkenyl or alkynyl;

R ⁶for hydrogen, deuterium, alkyl ,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a), alkenyl or alkynyl;

Each R ^7aand R ⁷be hydrogen, deuterium, F, Cl, Br, alkyl, haloalkyl or aryl independently; Or R ⁷, R ^7aform cycloalkyl together with the C atom being attached thereto;

Each R ⁸and R ^8abe hydrogen, deuterium, alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical or heterocyclic radical alkyl independently;

Each R ⁹be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxyl group, alkylamino, haloalkyl, cyano group, hydroxyl, nitro, amino ,-(CR independently ⁷r ^7a) _m-N (R ⁷r ^7a) or trifluoromethoxy;

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

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

Each q is 0,1 or 2 independently; With

Wherein, described aryl, heteroaryl, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, carbalkoxy, arylalkyl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl can be optionally by monosubstituted or identical or different polysubstituted of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxyl group, alkylamino, arylalkyl, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl.

Some embodiments therein:

Z is the minor structure formula as shown in formula III:

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ⁶for hydrogen, deuterium, C ₁-C ₄alkyl, C ₁-C ₄thiazolinyl ,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) ,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸, or C ₁-C ₄alkynyl;

Each R ^7aand R ⁷be hydrogen, deuterium, F, Cl, Br, C independently ₁-C ₆haloalkyl, C ₁-C ₆alkyl or C ₆-C ₁₀aryl; Or R ⁷, R ^7aform C together with the C atom being attached thereto ₃-C ₈cycloalkyl;

Each R ⁸and R ^8abe hydrogen, deuterium, C independently ₁-C ₆alkyl, C ₁-C ₄haloalkyl, C ₆-C ₁₀aryl, C ₆-C ₁₀aryl C ₁-C ₄alkyl, C ₁-C ₉heteroaryl, C ₁-C ₉heteroaryl C ₁-C ₄alkyl, C ₃-C ₁₀cycloalkyl, C ₃-C ₁₀cycloalkyl C ₁-C ₄alkyl, C ₂-C ₁₀heterocyclic radical or C ₂-C ₁₀heterocyclic radical C ₁-C ₄alkyl;

Each R ⁹be hydrogen, deuterium, C independently ₁-C ₄alkyl, fluorine, chlorine, bromine, iodine, C ₁-C ₄alkoxyl group, C ₁-C ₄alkylamino, C ₁-C ₄haloalkyl, cyano group, hydroxyl, nitro, amino ,-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) or trifluoromethoxy;

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

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

Each q is 0,1 or 2 independently.

In other embodiments, wherein: Z is minor structure formula as follows:

Each R ⁶be hydrogen, deuterium, methyl, ethyl, propyl group ,-(CR independently ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) or-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸;

Each R ⁷, and R ^7abe hydrogen, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-methyl-propyl, 1-methyl-propyl or phenyl independently;

Each R ⁸and R ^8abe hydrogen, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-methyl-propyl, phenyl, trifluoromethyl, cyclopropyl or 1-methyl-propyl independently;

Each R ⁹be independently hydrogen, deuterium, amino, cyano group, methyl, ethyl, propyl group, sec.-propyl, fluorine or-(CR ⁷r ^7a) _m-N (R ⁸r ^8a);

Each n is 0,1 or 2 independently;

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

At some embodiments, R ³for 5 yuan of heteroaryls containing 3 or 4 nitrogen-atoms, wherein said 5 yuan of heteroaryls that contain 3 or 4 nitrogen-atoms can be by one or more hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C of being selected from ₁-C ₄alkyl, C ₁-C ₄alkoxyl group, C ₁-C ₄alkylamino, C ₆-C ₁₀aryl C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, cyano group, hydroxyl, nitro or amino substituting group replace; Wherein, R ³be not

At other embodiment, R ³for following minor structure formula:

Each R ¹⁰be hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl group, methoxyl group, oxyethyl group, propoxy-, phenyl methyl, phenylethyl, cyano group, hydroxyl, nitro or amino independently;

Wherein, R ³be not

Each p is 0 or 1 independently.

At other embodiments, R ¹for C ₆-C ₁₀aryl, wherein said aryl can be by monosubstituted or identical or different polysubstituted of fluorine, deuterium, chlorine, nitro or bromine;

R ²for hydrogen, deuterium or C ₁-C ₄alkyl;

R ⁵for hydrogen, deuterium or C ₁-C ₄alkyl.

In some embodiments,

R ¹for phenyl, wherein said phenyl can be by monosubstituted or identical or different polysubstituted of fluorine, deuterium, chlorine or bromine.

In some embodiments, the present invention have as logical formula IV or (structure of IV as shown in a),

Z is suc as formula the minor structure formula shown in (V):

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ²for hydrogen, deuterium or C ₁-C ₄alkyl;

R ³for triazolyl or tetrazyl, wherein said triazolyl or tetrazyl can be by one or more hydrogen, deuterium, C of being selected from ₁-C ₄alkyl, C ₆-C ₁₀aryl C ₁-C ₄alkyl, cyano group, hydroxyl, nitro or amino substituting group replace; Wherein, R ³be not

R ⁶for hydrogen, deuterium, C ₁-C ₄alkyl ,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) or-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸;

Each R ^7aand R ⁷be hydrogen, deuterium, C independently ₁-C ₄haloalkyl, C ₁-C ₄alkyl or C ₆-C ₁₀aryl;

Each R ⁸and R ^8abe H, C independently ₃-C ₈cycloalkyl, C ₁-C ₄haloalkyl or C ₁-C ₆alkyl;

Each R ⁹be hydrogen, deuterium, amino, cyano group, C independently ₁-C ₄alkyl, fluorine or-(CR ⁷r ^7a) _m-N (R ⁸r ^8a);

Each R ¹¹be fluorine, deuterium, chlorine, nitro or bromine independently;

Each k is 1 or 2 independently;

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

Each n is 0,1 or 2 independently;

Each q is 0,1 or 2 independently.

In some embodiments, Z is suc as formula the minor structure formula shown in (V):

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ⁶for hydrogen, deuterium, methyl, ethyl, propyl group, butyl, sec.-propyl, the tertiary butyl ,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) or-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸;

Each R ^7aand R ⁷be hydrogen, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 1-methyl-propyl, 2-methyl-propyl, phenyl independently;

Each R ⁸and R ^8abe hydrogen, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-methyl-propyl, trifluoromethyl, cyclopropyl or 1-methyl-propyl independently;

Each q is 0,1 or 2 independently;

Each n is 0,1 or 2 independently;

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

In other embodiments, Z is independently selected from following minor structure formula:

At other embodiments, R ³for triazolyl or tetrazyl, wherein said triazolyl or tetrazyl can be replaced by one or more hydrogen, deuterium, methyl, ethyl, propyl group, phenyl methyl, 1-phenylethyl, 2-phenylethyl, cyano group, hydroxyl, nitro or amino substituting groups of being selected from; Wherein,

R ³be not

At other embodiments, R ³independently selected from following minor structure formula:

On the one hand, the present invention relates to a kind of compound, or its enantiomer, diastereomer, pharmacy acceptable salt, described salt is organic acid salt, inorganic acid salt or the salt that obtains by alkali.

In certain embodiments, inorganic acid salt of the present invention is hydrochloride, hydrobromate, perchlorate, phosphoric acid salt or vitriol.

In certain embodiments, organic acid salt of the present invention is carboxylate salt or sulphur hydrochlorate.

In certain embodiments, carboxylate salt of the present invention is acetate, oxalate, maleate, tartrate, Citrate trianion, succinate or malonate.

In certain embodiments, sulphur hydrochlorate of the present invention is mesylate, esilate, benzene sulfonate, tosylate or naphthalenesulfonate.

In certain embodiments, the salt obtaining by alkali of the present invention is basic metal, alkaline-earth metal, ammonium or N ⁺(R ¹²) ₄salt.

Wherein, in other embodiment, basic metal of the present invention or alkaline earth salt are sodium salt, lithium salts, sylvite, calcium salt or magnesium salts.

Wherein, in other embodiment, R of the present invention ¹²h, deuterium, C ₁-C ₄alkyl, C ₆-C ₁₀aryl, C ₆-C ₁₀aryl C ₁-C ₄alkyl etc.

On the one hand, the present invention relates to composition, wherein composition comprises compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

In certain embodiments, pharmaceutical composition of the present invention, it further comprises anti-HBV medicine.

In certain embodiments, pharmaceutical composition of the present invention, wherein anti-HBV medicine is HBV AG14361, immunomodulator or Interferon, rabbit.

In certain embodiments, pharmaceutical composition of the present invention, wherein anti-HBV medicine has lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, Alfacon-1 b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, polyoxyethylene glycol Intederon Alpha-2a, virazole, Wellferon-A, sizofiran, Euforavac, Veldona, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, LEVAMISOLE HCL, or propagermanium.

On the other hand, the present invention relates to described compound or described pharmaceutical composition and prevent, process, treat or alleviate the purposes in the medicine of disease viral disease in preparation.

In certain embodiments, purposes of the present invention, wherein virus disease refers to the disease that hepatitis B infection or hepatitis B infection cause.

Wherein, in other embodiment, purposes of the present invention, wherein hepatitis B infection causes that disease refers to liver cirrhosis or canceration of hepatic cell.

In certain embodiments, purposes of the present invention, wherein virus disease refers to hepatitis B disease.

On the other hand, the present invention relates to described compound or pharmaceutical composition for the preparation of the purposes of preventing, process, treat or alleviate the medicine of patient's hepatitis B disease, comprise and give patient the dose therapeutically effective of compound or pharmaceutical composition of the present invention as described in the present invention.

The present invention relates to prevention, processes, treats or alleviates the method for patient HBV illness on the other hand, and described method comprises uses the pharmaceutically acceptable effective dose of compound of the present invention to carry out administration to patient.

The present invention relates to prevention, processes, treats or alleviates the method for patient HBV illness on the other hand, and described method comprises uses the pharmaceutically acceptable effective dose of the pharmaceutical composition that contains compound of the present invention to carry out administration to patient.

The present invention relates on the other hand with a kind of compound of the present invention and produces for prevention, processes or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.

The present invention relates on the other hand with a kind of pharmaceutical composition that comprises compound of the present invention and produces for prevention, processes or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.

Some of them embodiment is, described organism is Mammals, and other embodiment is that described organism is the mankind.Other embodiment is, described method further comprises contacting of kinases and HBV therapeutical agent.

The present invention relates to a kind of method that HBV of inhibition infects on the other hand, and the method comprises cell and contacts with the dosage that compound of the present invention or composition can effectively suppress HBV.Other embodiment is, described method further comprises contacting of cell and HBV agent.

The present invention relates to the treatment to patient HBV disease on the other hand, and the method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.Other embodiment is that described method further comprises the administration of HBV.

The present invention relates to a kind of method that the patient of inhibition HBV infects on the other hand, and the method comprises needs of patients and effectively treats the dosage of required compound of the present invention or its composition administration.Other embodiment is that described method further comprises the administration of HBV treatment.

The present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) or formula (Ia) comprise on the other hand.

Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.

Circumstantial letter of the present invention

Definition and general terms

The present invention will list the corresponding document of specific content of determining in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim is defined.Those skilled in the art is many similar or be equal to method described herein and material by identification, and these can be applied to go in practice of the present invention.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but be never limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.

Unless the present invention shows other aspects of the following definition of application.According to object of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 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 reference.

Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Generally speaking, term " replacement ", represents that the one or more hydrogen atoms of give in structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting group that position can be selected from concrete group in given structural formula replaces, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to hydroxyl, amino, halogen; cyano group, trifluoromethoxy, arylalkyl, heteroarylalkyl, haloalkyl; heterocyclic radical alkyl, alkylamino, trifyl, aryl, heteroaryl; alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical; sulfydryl, nitro, aryloxy, hydroxyl substituted alkyl; cycloalkyl, cycloalkylalkyl, carbalkoxy, etc.

The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, and wherein alkyl can independently optionally be replaced by one or more substituting groups described in the invention.Some of them embodiment is, alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is that alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is that alkyl group contains 1-3 carbon atom.Alkyl group further example comprises, but is not limited to methyl (Me ,-CH ₃), ethyl (Et ,-CH ₂cH ₃), n-propyl (n-Pr ,-CH ₂cH ₂cH ₃), sec.-propyl (i-Pr ,-CH (CH ₃) ₂), normal-butyl (n-Bu ,-CH ₂cH ₂cH ₂cH ₃), 2-methyl-propyl or isobutyl-(i-Bu ,-CH ₂cH (CH ₃) ₂), 1-methyl-propyl or sec-butyl (s-Bu ,-CH (CH ₃) CH ₂cH ₃), the tertiary butyl (t-Bu ,-C (CH ₃) ₃), n-pentyl (CH ₂cH ₂cH ₂cH ₂cH ₃), 2-amyl group (CH (CH ₃) CH ₂cH ₂cH ₃), 3-amyl group (CH (CH ₂cH ₃) ₂), 2-methyl-2-butyl (C (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butyl (CH (CH ₃) CH (CH ₃) ₂), 3-methyl isophthalic acid-butyl (CH ₂cH ₂cH (CH ₃) ₂), 2-methyl-1-butene base (CH ₂cH (CH ₃) CH ₂cH ₃), n-hexyl (CH ₂cH ₂cH ₂cH ₂cH ₂cH ₃), 2-hexyl (CH (CH ₃) CH ₂cH ₂cH ₂cH ₃), 3-hexyl (CH (CH ₂cH ₃) (CH ₂cH ₂cH ₃)), 2-methyl-2-amyl group (C (CH ₃) ₂cH ₂cH ₂cH ₃), 3-methyl-2-amyl group (CH (CH ₃) CH (CH ₃) CH ₂cH ₃), 4-methyl-2-amyl group (CH (CH ₃) CH ₂cH (CH ₃) ₂), 3-methyl-3-amyl group (C (CH ₃) (CH ₂cH ₃) ₂), 2-methyl-3-amyl group (CH (CH ₂cH ₃) CH (CH ₃) ₂), 2,3-dimethyl-2-butyl (C (CH ₃) ₂cH (CH ₃) ₂), 3,3-dimethyl-2-butyl (CH (CH ₃) C (CH ₃) ₃), n-heptyl, n-octyl, etc.Term " alkyl " and its prefix " alkane " are used herein, all comprise the saturated carbon chains of straight chain and side chain.Term " alkylene " is used herein, the saturated bivalent hydrocarbon radical that expression obtains from two hydrogen atoms of straight or branched saturated carbon hydride cancellation, and such example comprises, but is not limited to methylene radical, ethylidine, inferior sec.-propyl etc.

The term " halogenated aliphatic " that the present invention uses or " haloalkyl " represent that aliphatic group or alkyl are replaced by one or more identical or different halogen atoms, wherein aliphatic group or alkyl have implication as described in the present invention, halogen atom is fluorine, chlorine, bromine or iodine, such example comprises, but be not limited to trifluoromethyl, trifluoroethyl etc.

Term used in the present invention " divalent group " represents to remove two resulting groups of hydrogen atom from target molecule.Some of them embodiment is to remove two hydrogen atoms from the same atom of target molecule; Other embodiment is, from the not homoatomic of target molecule two hydrogen atoms that get on to fall.

Term " thiazolinyl " represents the monovalence alkyl of 2-12 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and a C-C is sp ²two keys, wherein the group of alkenyl can independently optionally be replaced by one or more substituting groups described in the invention, comprises that group has the location of negation " just " or " E " " Z ", and wherein concrete example comprises, but is not limited to, vinyl (CH=CH ₂), allyl group (CH ₂cH=CH ₂), etc.

Term " alkynyl " represents the monovalence alkyl of 2-12 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, a C-C is sp triple bond, wherein alkynyl group can independently optionally be replaced by one or more substituting groups described in the invention, concrete example comprises, but be not limited to ethynyl (C tri-CH), propargyl (CH ₂c tri-CH), etc.

Term " annular aliphatic ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refer to monovalence or multivalence, non-aromatic, and the unsaturated ring of saturated or part, comprises the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable cyclic aliphatic group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is never limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.And described " annular aliphatic ", carbocyclic ring ", " carbocylic radical " or " cycloalkyl " can be substituted or non-substituted, wherein substituting group can be, but is not limited to, hydroxyl, amino; halogen, cyano group, trifluoromethoxy, arylalkyl, heteroarylalkyl; haloalkyl, heterocyclic radical alkyl, alkylamino, trifyl, aryl; heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl; heterocyclic radical, sulfydryl, nitro, aryloxy; hydroxyl substituted alkyl, cycloalkyl, cycloalkylalkyl, carbalkoxy.

Term " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein the upper one or more atoms of ring can independently optionally be replaced by heteroatoms, ring can be completely saturated or comprise one or more degrees of unsaturation, but is never the fragrant same clan, only has a tie point to be connected to other molecules and gets on.One or more ring hydrogen atoms are independent optionally to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom be selected from N, O, P, 1,2 or 3 heteroatoms of S, at this S or P, optionally by one or more Sauerstoffatom, replaced and obtain picture SO, SO ₂, PO, PO ₂group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, O, P, 1,2 or 3 heteroatoms of S, is optionally replaced and obtains picture SO, SO by one or more Sauerstoffatom at this S or P ₂, PO, PO ₂group).

Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and saturated or the unsaturated ring of part or heterocyclic fused formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, nitrogen heterocyclic heptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indyl quinolizinyl and N-pyridyl urea.The example of heterocyclic group also comprises, 1,1-dioxy thio-morpholinyl, and wherein encircle two carbon atoms by Sauerstoffatom replacement as pyrimidine dione base.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino; halogen, cyano group, trifluoromethoxy, arylalkyl, heteroarylalkyl; haloalkyl, heterocyclic radical alkyl, alkylamino, trifyl, aryl; heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl; heterocyclic radical, sulfydryl, nitro, aryloxy; hydroxyl substituted alkyl, cycloalkyl, cycloalkylalkyl, carbalkoxy etc.

Term " heterocyclic radical alkyl " comprises the alkyl that heterocyclic radical replaces; Term " heterocyclic radical alkoxyl group " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule; Wherein heterocyclic radical, alkyl, alkoxyl group and alkylamino group have implication as described in the present invention.Such example comprises, but is not limited to pyrroles-2-methyl, morpholine-4-methyl, pyrroles-2-methoxyl group, piperidines-2-oxyethyl group, piperazine-2-ethylamino, morpholine-4-propoxy-, morpholine-4-ethylamino etc.

Term " heteroatoms " represents one or more O, S, and N, P and Si, comprise N, the form of S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the substituted form of the hydrogen in heterocycle on nitrogen-atoms, for example, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).

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

Term used in the present invention " undersaturated " represents that part contains one or more degrees of unsaturation.

The term using in the present invention " alkoxyl group ", relates to alkyl, defined as the present invention, by Sauerstoffatom (" alkoxyl group "), is connected in main carbochain.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxyl group can be by the situations that one or more halogen atom replaced.Wherein alkyl, thiazolinyl and alkoxy base have implication as described in the present invention, and such example comprises, but are not limited to trifluoromethyl, trifluoromethoxy, and 2-is fluoride-based etc.

Term " aryl " can be used separately or as most of " aralkyl " " aralkoxy " or " aryloxy alkyl ", represent to contain altogether the monocycle of 6-14 ring, dicyclo, carbocyclic ring system with three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, as aromatic nucleus can comprise phenyl, naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino; halogen, cyano group, trifluoromethoxy, arylalkyl, heteroarylalkyl; haloalkyl, heterocyclic radical alkyl, alkylamino, trifyl, aryl; heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl; heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl substituted alkyl; cycloalkyl, cycloalkylalkyl, carbalkoxy, etc.

Term " heteroaryl " can be used separately or as most of " heteroarylalkyl " or " heteroaryl alkoxyl group ", represent to contain altogether the monocycle of 5-14 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can be used with term " fragrant heterocycle " or " heteroaromatics " exchange.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino; halogen, cyano group, trifluoromethoxy, arylalkyl, heteroarylalkyl; haloalkyl, heterocyclic radical alkyl, alkylamino, trifyl, aryl; heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl; heterocyclic radical, sulfydryl, nitro, aryloxy; hydroxyl substituted alkyl, cycloalkyl, cycloalkylalkyl, carbalkoxy etc.

Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyranyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl group, 1, 3, 4-thiadiazolyl group, 1, 2, 5-thiadiazolyl group, pyrazinyl, 1, 3, 5-triazinyl, also comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) etc.

Term " heteroarylalkyl " represents that alkyl group is replaced by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.

No matter term " alkylsulfonyl ", be to use separately or be used in conjunction with other term picture " alkyl sulphonyl ", represents respectively the group-SO of divalence ₂-.Term " alkyl sulphonyl " refers to the alkylsulfonyl group that alkyl replaces, and forms alkyl sulphonyl (SO ₂cH ₃).

Term " sulphonamide ", " amino-sulfonyl " or " sulfamyl " represents the amino alkylsulfonyl group replacing, and forms sulfamyl (SO ₂nH ₂).

No matter term " carboxyl " is to use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO ₂h; No matter term " carbonyl ", be to use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.

Term " alkylthio " comprises C _1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is that alkylthio is more rudimentary C _1-3alkylthio, such example comprises, but is not limited to methylthio group (CH ₃s-), ethylmercapto group etc.

Term " halogenated alkylthio " comprises C _1-10haloalkyl be connected on bivalent sulfur atom, wherein haloalkyl has implication as described in the present invention.Some of them embodiment is that halogenated alkylthio is more rudimentary C _1-3halogenated alkylthio, such example comprises, but is not limited to trifluoromethylthio.

Term " aralkyl ", " arylalkyl " comprises the alkyl group that aryl replaces, wherein aryl and alkyl group have implication as described in the present invention.Some of them embodiment is, aromatic alkyl group or aromatic yl alkyl group refer to " more rudimentary aralkyl " group, and aromatic yl group is connected to C _1-6alkyl group on.Other embodiment is that aromatic alkyl group or aromatic yl alkyl group refer to containing C _1-3" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.And the aryl on aralkyl can be further by hydroxyl, amino, halogen, cyano group, trifluoromethoxy; arylalkyl, heteroarylalkyl, haloalkyl, heterocyclic radical alkyl, alkylamino; trifyl, aryl, heteroaryl, alkoxyl group; alkyl, thiazolinyl, alkynyl, heterocyclic radical; sulfydryl, nitro, aryloxy, hydroxyl substituted alkyl; cycloalkyl, cycloalkylalkyl, carbalkoxy, etc.

Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is that alkylamino is one or two C _1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is that alkylamino is C _1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.

Term " aminoalkyl group " comprises the C being replaced by one or more amino _1-10straight or branched alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced _1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

Term " carbalkoxy " expression alkyl-O-C (=O)-, wherein alkyl has implication as described in the present invention.Some of them embodiment is, the alkyl group in carbalkoxy is the more rudimentary alkyl of C1-6, and such example comprises, but is not limited to methoxycarbonyl, ethoxy carbonyl, and propoxycarbonyl.

Term " alkyl amino alkyl " comprises the alkyl group being replaced by alkylamino, and wherein alkylamino and alkyl group have implication as described in the present invention.Some of them embodiment is that alkylamino alkyl is C _1-6more rudimentary alkyl amino alkyl.Other embodiment is that alkylamino alkyl is C _1-3more rudimentary alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group replace, and such example comprises, but is not limited to N-methylamino methyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc.

Term " cycloalkylalkyl " represents that alkyl group can be replaced by one or more group of naphthene base, and wherein cycloalkyl and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to cyclohexyl methyl, cyclopropyl ethyl etc.Described cycloalkyl can be further by halogen, alkyl, and alkoxyl group and hydroxyl replace.

Picture is described in the invention, and key of substituting group picture is connected to the member ring systems (being shown below) forming on the ring at center and represents that substituting group can replace any commutable position on ring.For example, the substituted position of the upper any possibility of formula a representative ring, shown in b.

Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.

Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C _1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be with reference to Publication about Document about the complete discussion of prodrug: 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 other aspects show, within all tautomeric forms of compound of the present invention are included in scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.

" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can be by adopting the method for test to characterize as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.

The definition of neutral body chemistry of the present invention and the use of convention be conventionally with reference to Publication about Document: 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, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, and enantiomer, atropisomer, and their mixture, as racemic mixture, formed a part of the present invention.A lot of organic compound all exist with optical activity form, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause in chemical reaction process, there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.

Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can transform mutually by lower energy barrier.Such example comprises, but is not limited to, and proton tautomerism body (being prototropy isomer) comprises the change by proton shifting, for example isomerization of keto-acid-enol form and imines-enamine.Valence tautomer comprises the restructuring change of some bonding electronss.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19,1977. record.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method recorded on books document as ion exchange method.Other pharmacy acceptable salts comprise adipate, oxysuccinic acid, 2 hydroxy propanoic acid, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N ⁺(C _1-4alkyl) ₄salt.The present invention also intends having conceived the formed quaternary ammonium salt of compound of the group of any comprised N.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the formed associated complex of water.

When term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), the sub-methoxycarbonyl (Fmoc) of carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group ₂cH ₂sO ₂ph, cyano ethyl, 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl; 2-(diphenylphosphino) ethyl, nitro-ethyl, etc.Can reference for the general description of blocking group: T W.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 pharmaceutically acceptable composition, can effectively suppress HBV and infect.

A be a key ,-O-,-S-or-N (R ⁵)-;

R is-X-Z;

X is-(CR ⁷r ^7a) _m-or-C (=O)-;

Z is minor structure formula as shown in the formula (II):

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

W is CR ⁷, or N;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ¹for aryl or heteroaryl;

R ⁴for hydrogen, deuterium or C ₁-C ₄alkyl;

Each R ⁸and R ^8abe hydrogen, deuterium, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical or heterocyclic radical alkyl independently;

Each R ⁹be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxyl group, alkylamino, haloalkyl, cyano group, hydroxyl, nitro, amino ,-(CR independently ⁷r ^7a) _m-N (R ⁸r ^8a) or trifluoromethoxy;

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

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

Each q is 0,1 or 2 independently; With

The above aryl, heteroaryl, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, carbalkoxy, arylalkyl, heteroarylalkyl, heterocyclic radical and heterocyclic radical alkyl can be optionally by monosubstituted or identical or different polysubstituted of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxyl group, alkylamino, arylalkyl, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl;

Wherein, some embodiments are:

Z is the minor structure formula as shown in formula III:

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

Each R ^7aand R ⁷be hydrogen, deuterium, F, Cl, Br, C independently ₁-C ₆alkyl, C ₁-C ₆haloalkyl or C ₆-C ₁₀aryl; Or R ⁷, R ^7aform C together with the C atom being attached thereto ₃-C ₈cycloalkyl;

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

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

Each q is 0,1 or 2 independently;

In some embodiments,

Z is minor structure formula as follows:

Each n is 0,1 or 2 independently;

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

In some embodiments, R ³for 5 yuan of heteroaryls containing 3 or 4 nitrogen-atoms, wherein said 5 yuan of heteroaryls that contain 3 or 4 nitrogen-atoms can be by one or more hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C of being selected from ₁-C ₄alkyl, C ₁-C ₄alkoxyl group, C ₁-C ₄alkylamino, C ₆-C ₁₀aryl C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, cyano group, hydroxyl, nitro or amino substituting group replace; Wherein, R ³be not

In some embodiments, R ³for following minor structure formula:

Wherein, R ³be not

Each p is 0 or 1 independently.

In some embodiments,

R ¹for C ₆-C ₁₀aryl, wherein said aryl can be by monosubstituted or identical or different polysubstituted of fluorine, deuterium, chlorine, nitro or bromine;

R ₂for hydrogen, deuterium or C ₁-C ₄alkyl;

R ⁵for hydrogen, deuterium or C ₁-C ₄alkyl;

In other embodiment,

R ¹for phenyl, wherein said phenyl can be by monosubstituted or identical or different polysubstituted of fluorine, deuterium, chlorine or bromine;

In other embodiment, the present invention have as logical formula IV or (structure of IV as shown in a),

Z is suc as formula the minor structure formula shown in (V):

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ²for hydrogen, deuterium or C ₁-C ₄alkyl;

Each R ⁸and R ^8abe H, deuterium, C independently ₃-C ₈cycloalkyl, C ₁-C ₄haloalkyl or C ₁-C ₆alkyl;

Each R ¹¹be fluorine, deuterium, chlorine, nitro or bromine independently;

Each k is 1 or 2 independently;

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

Each n is 0,1 or 2 independently;

Each q is 0,1 or 2 independently.

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

Each q is 0,1 or 2 independently;

Each n is 0,1 or 2 independently;

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

At other embodiments, R ³for triazolyl or tetrazyl, wherein said triazolyl or tetrazyl can be replaced by one or more hydrogen, deuterium, methyl, ethyl, propyl group, phenyl methyl, 1-phenylethyl, 2-phenylethyl, cyano group, hydroxyl, nitro or amino substituting groups of being selected from; Wherein, R ³be not

The present invention relates to following one of them compound or its enantiomer, diastereomer, tautomer, hydrate, solvate or pharmacy acceptable salt:

The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, effectively suppresses HBV infect for the production of pharmaceutical prod, comprises that those are described in the invention.The application of compound of the present invention in producing the effective HBV of inhibition infection medicine.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treat the illness of patient's hepatitis B.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises formula (I) or (Ia) compound and at least one pharmaceutically acceptable carrier of representative, the required effective treatment consumption of combination of assistant agent or thinner.

The present invention comprises the disease that effective inhibition HBV infects equally, or the method to this illness sensitivity, the method comprise use formula (I) or (Ia) the treatment significant quantity of representative compound patient is treated.

Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be applicable to chemistry or toxicologically, relevant with the Mammals that forms other components of preparation and be used for the treatment of.

The salt of compound of the present invention also comprise for the preparation of purifying formula (I) or (Ia) shown in the intermediate of compound or formula (I) or (Ia) shown in the salt of enantiomer of compound separation, but pharmacy acceptable salt not necessarily.

If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method providing on document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, Lactic acid Citric Acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or their combination.

If compound of the present invention is acid, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N ⁺(R ¹²) ₄salt and alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, the organic salt obtaining from amino acid, and as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, N ⁺(R ¹²) ₄salt, as R ¹²h, deuterium, C ₁-C ₄alkyl, C ₆-C ₁₀aryl, C ₆-C ₁₀aryl C ₁-C ₄alkyl etc., and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.Also comprise suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

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

According on the other hand, the feature of pharmaceutical composition of the present invention comprises formula (I) or compound (Ia), the compound that the present invention is listed, or the compound of embodiment 1-23, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, compound can effectively suppress hepatitis B virus, be applicable to the treatment of the HBV virus infection of the especially acute and chronic sustained of disease that virus causes, the chronic disease viral disease that HBV causes may cause morbid state to become serious, and chronic HBV infection can cause liver cirrhosis and/or canceration of hepatic cell in many cases.

Concerning compound of the present invention, the indicating area that may be mentioned is, for example: may cause the treatment of the acute and chronic viral infection of infectious hepatitis, and for example, hepatitis B virus infection.Compound of the present invention is especially applicable to treatment chronic viral hepatitis B to be infected and acute and chronic hbv-infection.

The present invention includes pharmaceutical preparation, except nontoxic, suitable outside system in the pharmacopedics of inertia, also contain one or more compounds of the present invention (I) or (Ia) or composition or contain one or more activeconstituentss (I) or (Ia) or composition of the present invention.

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

There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can be directly or indirectly according to other any adducts or derivatives of needing administration of patient, the described compound in other aspects of the present invention, its meta-bolites or his residue.

Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As described with Publication about Document: 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 comprehensive content of document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produced or the interaction producing in the mode being harmful to any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.

The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, the derivative of Mierocrystalline cellulose and it is as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycols compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleic acid ester and ethyl laurate, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in carrier.

The compounds of this invention pharmaceutical composition, any-mode that can following aspect is granted: oral administration, spraying inhalation, topical, per rectum administration, nose administration, topical, vagina administration, parenterai administration is as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone, or intracranial injection or transfusion, or by a kind of reservoir medication of outer value.Preferred mode is oral administration, and intramuscular injection, to intraperitoneal administration or intravenous injection.

The compounds of this invention or to contain pharmaceutically acceptable composition can be with unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, mixed suspension form.Other formulations such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc.

Oral tablet and capsule can contain vehicle as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent, as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate is as bay sodium alkoxide vitriol.Tablet can be with known method dressing in pharmacopedics.

Oral liquid can be made the suspension of hydrous oil, solution, and emulsion, syrup or elixir, also can make dry product, with front make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, gum arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease is as glycerine, ethylene glycol, or ethanol; Sanitas, as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.As needs can add seasonings or tinting material.

Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.

Stomach is offerd medicine outward, and liquid formulation is made by the carrier of compound and a kind of sterilization conventionally.The first-selected water of carrier.According to the difference of selected carrier and drug level, compound had both dissolved in carrier and also can be made into aaerosol solution, first that compound is soluble in water when making injection solution, packed in sealed bottle or ampoule after filter-sterilized.

When topical application, the compounds of this invention can be made suitable ointment, lotion, or the form of creme, wherein activeconstituents suspends or is dissolved in one or more carrier, wherein ointment formulation operable carrier is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.

Generally speaking, verified advantageously no matter at human body medicine or in veterinary drug, the administration total amount of active compound of the present invention is about 0.5-500mg in every 24 hours, preferred 1-100mg/kg body weight, if suitable, single dose administration several times, to reach desired effect.Amount containing active compound in single dose is preferably about 1-80mg, 1-50mg/kg body weight more preferably, but also can be not according to above-mentioned dosage, the character and severity, the type of preparation and the administering mode of medicine that depend on the kind for the treatment of target and body weight, disease, and administration cycle or the timed interval.

Pharmaceutical composition of the present invention comprises arbitrary compound of the present invention and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.Wherein, described pharmaceutical composition, it further comprises anti-HBV medicine.Wherein anti-HBV medicine is HBV AG14361, immunomodulator or Interferon, rabbit.

HBV medicine has lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, Alfacon-1 b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, polyoxyethylene glycol Intederon Alpha-2a, virazole, Wellferon-A, sizofiran, Euforavac, Veldona, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, LEVAMISOLE HCL, or propagermanium etc.

The present invention relates to a kind of compound of the present invention or pharmaceutical composition on the other hand for the preparation of the purposes of preventing, process, treat or alleviate the medicine of patient's hepatitis B disease, comprises that giving the pharmaceutically acceptable effective dose of patient carries out administration to patient.

Anti-HBV medicine can separate administration with the composition that comprises compound of the present invention, as a part for many dosage regimens.Or those medicines can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thereby obtain destination agent activity.

The change that can produce the compound of one-pack type and the consumption of composition (those comprise a composition as described in the invention) in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition of the present invention comprises as the amount of the normal administration of unique promoting agent being no more than composition.On the other hand, the scope of the amount of existing disclosed composition is approximately the 50%-100% of existing composition normal amount, and the reagent comprising is as unique active therapeutic agent.In the composition comprising at those, composition will play synergy with compound of the present invention.

Compound of the present invention demonstrates stronger antivirus action.This compounds has antiviral activity beyond expectation to HBV, is therefore suitable for for the viral various diseases causing for the treatment of, the disease that especially acute and chronic persistence HBV virus infection causes.The chronic viral disease being caused by HBV can cause the syndrome of various different severity, and well-known, chronic hbv-infection can cause liver cirrhosis and/or hepatocellular carcinoma.

The example of the indication of available the compounds of this invention treatment has: treatment can cause the acute and chronic viral infection of infectious hepatitis, for example different in nature hepatites virus infections.Particularly preferably be the treatment of chronic hepatitis B infection and the treatment of acute hepatitis b virus infection.

The invention still further relates to, compound of the present invention and composition are for the preparation for the treatment of and the prophylaxis of viral diseases purposes of the medicine of hepatitis B particularly.

General synthetic method

Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula (I) or (Ia).Reaction scheme below and embodiment are for further illustrating content of the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and be all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; as suitable protection, disturb group, by utilizing other known reagent except described in the invention, or reaction conditions is made to the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.

The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company does not have during use through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, and Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buys and obtains.

Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5, to reflux to be dried to obtain.Anhydrous methylene chloride and chloroform are through hydrolith, to reflux to be dried to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.

Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), and reaction flask is suitable soft rubber ball beyond the Great Wall all, and substrate is squeezed into by syringe.Glassware was all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 ₃, d ₆-DMSO, CD ₃oD or d ₆-acetone is solvent (report YippmWei unit), uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.When there is multiplet, by the abbreviation of using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quart, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).

Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS of outfit G1312A binary pump and a G1316A TCC (column temperature remains on 30 ℃), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS of outfit G1311A quaternary pump and G1316A TCC (column temperature remains on 30 ℃), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Above two kinds of spectrographs have all been equipped with Agilent Zorbax SB-C18 post, and specification is 2.1 * 30mm, 5 μ m.Volume injected is to determine by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC is to be recorded and read by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (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 chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 * 30mm, 4 μ m, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature remains on 40 ℃.

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

CHCl ₃chloroform, trichloromethane

CDC1 ₃deuterochloroform

CCl ₄tetracol phenixin

DMSO dimethyl sulfoxide (DMSO)

NBS N-bromo-succinimide

D ₂o heavy water

ML milliliter

Mmol mmole

G gram

RT, rt room temperature

Rt retention time

The synthetic method of intermediate:

Intermediate 1

The salt of intermediate 1, can prepare by above-mentioned method, wherein R ³there is implication as described in the present invention.Compound 1A reacts with cuprous cyanide, obtains compound 2A, then reacts with sodium methylate, ammonium chloride, and by acidifying, obtains compound 1.

Intermediate 5A

Compound 5A, can prepare by above-mentioned method.Compound 3A and compound 4A, under alkaline condition, obtain compound 5A.

Intermediate 8A

Compound 8A, can prepare by above-mentioned method.Compound 6A and compound 7A reaction obtain compound 8A.Wherein, R is alkyl or benzyl; X is F, Cl or Br.

According to general formula of the present invention (I) or (Ia) compound can prepare by following method:

Embodiment 1

Pyrimidines 6, can prepare by the method for reaction scheme 1, wherein R ¹, R ², R ³, A, and Z has implication as described in the present invention.Amidine or its hydrochloride compounds 1, aldehyde compound 2 and compound 3 are in suitable inert solvent (as alcohol reagent), and Cheng Huan obtains compound 4.

Compound 4 and bromizating agent are reacted in inert solvent, obtain bromination product 5, under alkaline condition, in suitable inert solvent, obtain product 6 with ZH substitution reaction subsequently.

Embodiment 2

In addition, pyrimidines 6, can prepare by the method for reaction scheme 2, wherein R ¹, R ², R ³, A, and Z has implication as described in the present invention.Amidine or its hydrochloride compounds 7, aldehyde compound 2 and compound 3 are in suitable inert solvent (as alcohol reagent), and Cheng Huan obtains compound 8.

Compound 8 and chlorizating agent are reacted, obtain compound 9.Then compound 9 and R ³h, in suitable inert solvent, generates compound 4; Compound 4 and bromizating agent are reacted in inert solvent, obtain bromination product 5, under alkaline condition, in suitable inert solvent, obtain product 6 with ZH substitution reaction subsequently.

Embodiment 3

In addition, pyrimidines 6, can prepare by the method for reaction scheme 3, wherein R ¹, R ², R ³, A, and Z has implication as described in the present invention.Compound 8 and bromizating agent are reacted in inert solvent, obtain bromination product 10; Under alkaline condition, in suitable inert solvent, obtain compound 11 with ZH substitution reaction; Further carry out reacting generating compound 12 with chlorizating agent; Subsequently, compound 12 and R ³h reaction, obtains product 6.

Specific embodiment

The following examples can the present invention will be further described, yet these embodiment should be as the restriction to scope of the present invention.

Embodiment 1

4-(the bromo-4-fluorophenyl of 2-)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:1-methyl-3-cyano group-1H-1,2,4-triazole

In the dry three-necked bottle of 250mL, add successively 3-cyano group-1H-1,2,4-triazole (2.35g, 25mmol), Anhydrous potassium carbonate (3.45g, 25mmol) and anhydrous acetonitrile (90mL), after stirring, drip methyl iodide (3.53g, 25mmol), 70 ℃ of reaction 6h, filter.Filtrate decompression is steamed and is desolventized, and in resistates, adds water (200mL), with methylene dichloride (200mL * 2) extraction, after being dried, is spin-dried for to obtain white solid (2.3g, 85%).

MS-ESI:(ESI,pos.ion)m/z：109.0[M+1] ⁺;

¹H?NMR(400MHz，CDCl ₃)：δ8.29(s，1H)，3.19(s，3H)。

Step 2:1-methyl isophthalic acid H-1,2,4-triazole-3-amitraz hydrochloride

In the dry three-necked bottle of 100mL, add 1-methyl-3-cyano group-1H-1,2,4-triazole (20g, 185mmol) and anhydrous methanol (500mL), add subsequently sodium methylate (14g, 259mmol) and ammonia chloride (14.8g, 277.5mmol), 5 ℃ are stirred 12h.Filter, filtrate decompression is steamed and is desolventized, and resistates is pulled an oar with acetone, filters, and obtains white solid (23.44g, 78.8%).

MS-ESI:(ESI,pos.ion)m/z：126.1[M+1] ⁺;

¹H?NMR(400MHz,D ₂O):δ8.40(s,1H),3.89(s,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

In 100mL dry reaction bottle, add successively the bromo-4-fluorobenzaldehyde of 2-(4.1g, 20mmol), methyl aceto acetate (2.6g, 20mmol), 1-methyl isophthalic acid H-1,2,4-triazole-3-amitraz hydrochloride (3.3g, 20mmol), sodium acetate, anhydrous (1.66g, 20mmol) and dehydrated alcohol (45mL), 80 ℃ of reaction 6h.Be cooled to 25 ℃.Filter, filtrate decompression is steamed and is desolventized, and crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtains yellow solid powder (5.3g, 63%).

MS-ESI:(ESI,pos.ion)m/z：422.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.03(s,1H),7.39-6.93(m,3H),6.15(s,1H),4.07-4.02(m,2H),3.96(s,3H),2.53(s,3H),1.14(t,3H)。

Step 4:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

In 100mL dry reaction bottle, add successively 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate (5.07g, 12mmol) and CCl ₄(150mL), be warming up to 70 ℃, add NBS (2.1g, 12mmol), insulation reaction 30min, filters, and filtrate decompression is steamed and desolventized, crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtains yellow solid (2.4g, 40%).

MS-ESI:(ESI,pos.ion)m/z：500.0[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.81(br.s,1H),8.06(s,1H),7.35-6.90(m,3H),6.11(s,1H),4.23(q,2H),4.01(q,2H),3.92(s,3H),1.15(t,3H)。

Step 5:4-(the bromo-4-fluorophenyl of 2-)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

In dry reaction bottle, add successively 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate (1g, 2mmol), dehydrated alcohol (50mL) and morpholine (0.7g, 8mmol), 25 ℃ of reaction 12h, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtain yellow solid (0.3g, 30%).

MS-ESI:(ESI,pos.ion)m/z：507.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.49(s,1H),8.05(s,1H),7.35-6.90(m,3H),6.23(s,1H),4.05-3.79(m,8H),3.97(s,3H),2.63(br.s,4H),1.15(t,3H)。

Embodiment 2

4-(the bromo-4-fluorophenyl of 2-)-6-((1,1-dioxy base thiomorpholine) methyl)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

In 100mL dry reaction bottle, add successively 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (1g, 2mmol), dehydrated alcohol (40mL), thiomorpholine dioxide hydrochloride (0.41g, 2.4mmol) and triethylamine (0.24g, 2.4mmol), 25 ℃ of reaction 12h.Filter, filtrate decompression is steamed and is desolventized, and product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=4/1), obtains yellow solid (0.42g, 37.6%).

MS-ESI:(ESI,pos.ion)m/z：555.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.22(s,1H),8.06(s,1H),7.32-6.95(m,3H),6.24(s,1H),4.35(q,2H),4.06(q,2H),3.92(s,3H),3.26(br.s,4H),3.17(br.s,4H),1.15(t,3H)。

Embodiment 3

4-(the bromo-4-fluorophenyl of 2-)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-6-((1-oxygen base thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (1g, 2mmol) with thiomorpholine monoxide hydrochloride (0.62g, 4mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.3g, 55%).

MS-ESI:(ESI,pos.ion)m/z：539.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.27(s,1H),8.02(s,1H),7.35-6.98(m,3H),6.19(s,1H),4.35-4.21(m,2H),4.06(q,2H),3.91(s,3H),3.12(br.s,4H),2.98(br.s,4H),1.12(t,3H)。

Embodiment 4

4-(the bromo-4-fluorophenyl of 2-)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By the bromo-4-fluorobenzaldehyde of 2-(4g, 20mmol), methyl acetoacetate (2.32g, 20mmol) and 1-methyl isophthalic acid H-1,2,4-triazole-3-amitraz hydrochloride (3.3g, 20mmol) obtains yellow solid (4.08g, 50%) by the synthetic method of embodiment 1 step 3.

MS-ESI:(ESI,pos.ion)m/z：408.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.03(s,1H),7.39-6.93(m,3H),6.15(s,1H),3.96(s,3H),3.65(s,3H),2.53(s,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-brooethyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (4g, 9.8mmol) and NBS (1.92g, 10.8mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (3g, 63%).

MS-ESI:(ESI,pos.ion)m/z：486.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.05(s,1H),7.41-6.97(m,3H),6.11(s,1H),4.23-4.11(m,2H),3.93(s,3H),3.69(s,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By 4-(the bromo-4-fluorophenyl of 2-)-6-brooethyl-2-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (3g, 6.2mmol) and morpholine (2.2g, 24.8mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (2.3g, 75%).

MS-ESI:(ESI,pos.ion)m/z：493.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.49(s,1H),8.05(s,1H),7.35-6.90(m,3H),6.16(s,1H),4.25-4.10(m,2H),3.95(s,3H),3.82(br.s,4H),3.69(s,3H),2.63(br.s,4H)。

Embodiment 5

4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-(morpholino methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

Step 1:3-carbonamidine-1H-1,2,4-triazole hydrochloride

In 30mL tube sealing, add successively 3-cyano group-1H-1,2,4-triazole (1.88g, 20mmol) and anhydrous methanol (20mL), add subsequently sodium methylate (1.3g, 24mmol), at 100 ℃, heat 12h, add again ammonia chloride (1.28g, 24mmol), at 100 ℃, continue heating 12h.Be chilled to 25 ℃, filter, filtrate decompression is steamed and is desolventized, to adding in resistates a large amount of acetone to separate out to no longer including solid in solution.Filter, obtain white solid (2.36g, 80%).

MS-ESI:(ESI,pos.ion)m/z：112.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.25(br.s,1H),8.45(s,1H),6.97(br.s,2H)。

Step 2:4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-methyl-formiate

In 30mL tube sealing, add successively 1H-1,2,4-triazole-3-amitraz hydrochloride (0.59g, 4mmol), the chloro-4-fluorobenzaldehyde of 2-(0.63g, 4mmol), methyl acetoacetate (0.51g, 4.4mmol) and anhydrous methanol (10mL).Lower 1 hour of 120 ℃ of microwave reactions.Be chilled to 25 ℃, reaction solution is spin-dried for, and crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=2/1), obtains yellow solid (0.63g, 45%).

MS-ESI:(ESI,pos.ion)m/z：350.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.23(s,1H),7.39-6.99(m,3H),6.12(s,1H),3.65(s,3H),2.53(s,3H)。

Step 3:4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-brooethyl-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-methyl-formiate (0.7g, 2mmol) and NBS (0.4g, 2.2mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (0.55g, 65%).

MS-ESI:(ESI,pos.ion)m/z：428.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.26(s,1H),7.41-7.03(m,3H),6.11(s,1H),4.25-4.13(m,2H),3.66(s,3H)。

Step 4: methyl-4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylicesters

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-brooethyl-1,4-dihydro-pyrimidin-5-methyl-formiate (0.51g, 1.2mmol) and morpholine (0.42g, 4.8mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid powder (0.32g, 60%).

MS-ESI:(ESI,pos.ion)m/z：435.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.60(s,1H),8.50(s,1H),7.42-7.14(m,3H),6.06(s,1H),3.88(q,2H),3.67(br.s,4H),3.51(s,3H),2.54(br.s,4H)。

Embodiment 6

4-(the bromo-4-fluorophenyl of 2-)-6-(((R)-3-fluorine Pyrrolidine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 1H-1,2,4-triazole-3-amitraz hydrochloride (1.48g, 10mmol), the bromo-4-fluorobenzaldehyde of 2-(2.03g, 10mmol) and methyl aceto acetate (1.3g, 10mmol) by the synthetic method of embodiment 5 steps 2, obtain micro-yellow solid (1.67g, 41%).

MS-ESI:(ESI,pos.ion)m/z：408.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.27(s,1H),7.45-7.08(m,3H),6.08(s,1H),4.09(q,2H),2.51(s,3H),1.06(t,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (4.08g, 10mmol) and NBS (1.96g, 11mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (3g, 62%).

MS-ESI:(ESI,pos.ion)m/z：486.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.31(s,1H),7.48-7.09(m,3H),6.11(s,1H),4.39-4.22(m,2H),4.04(q,2H),1.04(t,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-6-(((R)-3-fluorine Pyrrolidine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with (R)-3-fluorine Pyrrolidine hydrochloride (0.25g, 2mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.14g, 30%).

MS-ESI:(ESI,pos.ion)m/z：495.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.06(s,1H),8.19(s,1H),7.35-7.24(m,2H),7.19-6.99(m,1H),6.42(s,1H),5.19-4.96(m,1H),4.08(q,2H),3.97-3.86(m,2H),3.14-3.03(m,1H),2.81-2.75(m,1H),2.43-2.37(m,1H),2.13-1.46(m,3H),1.16(t,3H)。

Embodiment 7

4-(the bromo-4-fluorophenyl of 2-)-6-(((R)-2-fluorine Pyrrolidine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with (R)-2-fluorine Pyrrolidine hydrochloride (0.25g, 2mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.18g, 36%).

MS-ESI:(ESI,pos.ion)m/z：495.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.23(s,1H),8.27(s,1H),7.32-7.26(m,2H),7.12-7.03(m,1H),5.88(s,1H),5.04-4.88(m,1H),4.22(d,2H),4.07(q,2H),3.01-2.87(m,1H),2.54-2.41(m,1H),2.05-1.53(m,4H),1.12(t,3H)。

Embodiment 8

4-(the bromo-4-fluorophenyl of 2-)-6-(((R)-2-sec.-propyl morpholine) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with (R)-2-sec.-propyl morpholine (0.26g, 2mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.23g, 43%).

MS-ESI:(ESI,pos.ion)m/z：535.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.05(s,1H),8.24(s,1H),7.35-7.28(m,2H),7.14-7.06(m,1H),6.15(s,1H),4.12(q,2H),3.70-3.48(m,4H),2.70-2.55(m,4H),2.21-2.03(m,2H),1.10(t,3H),0.98(d,6H)。

Embodiment 9

4-(the bromo-4-fluorophenyl of 2-)-6-((4-methylpiperazine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with 1-methylpiperazine (0.4g, 4mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.32g, 65%).

MS-ESI:(ESI,pos.ion)m/z：506.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.52(s,1H),8.26(s,1H),7.37-7.28(m,2H),7.14-7.06(m,1H),6.28(s,1H),4.11(q,2H),3.94-3.81(m,2H),2.42(br.s,8H),2.19(s,3H),1.10(t,3H)。

Embodiment 10

6-((4-ethanoyl piperazine-1-yl) methyl)-4-(the bromo-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1; 2; 4-triazole-3-yl)-1; 4-dihydro-pyrimidin-5-ethyl formate (0.49g; 1mmol) and 1-(piperazine-1-yl) ethanoyl (0.26g; 2mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.3g, 57%).

MS-ESI:(ESI,pos.ion)m/z：534.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.86(s,1H),8.23(s,1H),7.37-7.27(m,2H),7.14-7.06(m,1H),6.07(s,1H),4.05(q,2H),3.92-3.83(m,2H),3.46(t,4H),2.44(t,4H),2.08(s,3H),1.12(t,3H)。

Embodiment 11

4-(the bromo-4-fluorophenyl of 2-)-2-(1H-1,2,4-triazole-3-yl)-6-((4-(2,2,2-trifluoroacetyl group) piperazine-1-yl) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1; 2; 4-triazole-3-yl)-1; 4-dihydro-pyrimidin-5-ethyl formate (0.49g; 1mmol) and 1-(trifluoroacetyl group) piperazine (0.36g; 2mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.31g, 52%).

MS-ESI:(ESI,pos.ion)m/z：588.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.12(s,1H),8.24(s,1H),7.38-7.29(m,2H),7.14-7.07(m,1H),6.20(s,1H),4.06(q,2H),3.94-3.81(m,2H),3.43(t,4H),2.48(t,4H),1.13(t,3H)。

Embodiment 12

4-(the bromo-4-fluorophenyl of 2-)-6-(((R)-2-((dimethylamino) methyl) morpholine) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with (S)-N, N-dimethyl-1-(morpholine-2-yl) methylamine hydrochloride (0.36g, 2mmol) obtains yellow solid (0.36g, 65%) by the synthetic method of embodiment 2.

MS-ESI:(ESI,pos.ion)m/z：550.2[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.25(s,1H),8.27(s,1H),7.39-7.27(m,2H),7.14-7.06(m,1H),6.24(s,1H),4.11(q,2H),3.96-3.83(m,2H),3.70-3.48(m,3H),2.89(dd,1H),2.78-2.58(m,3H),2.48(dd,1H),2.25(s,6H),2.13(dd,1H),1.16(t,3H)。

Embodiment 13

4-(the bromo-4-fluorophenyl of 2-)-6-((4-(ethoxycarbonyl) piperazine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1: piperazine-1-ethyl formate

In dry reaction bottle, add successively piperazine (2g, 23.2mmol) and water (10mL), 25 ℃ of stirring and dissolving are complete, are cooled to 0 ℃, slowly drip methyl alcohol (20mL) solution of Vinyl chloroformate (1.26g, 11.6mmol).Drip to finish, stir 4h at 25 ℃, stop stirring.In reaction solution, add saturated sodium-chloride water solution (30mL), methylene dichloride (200mL), extracting and demixing, organic layer anhydrous sodium sulfate drying successively.Remove solvent under reduced pressure, crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=40/1), obtains white solid (0.62g, 33.7%).

MS-ESI:(ESI,pos.ion)m/z：159.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ4.14(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-fluorophenyl of 2-)-6-((4-(ethoxycarbonyl) piperazine-1-yl) methyl)-2-(1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-3-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol), piperazine-1-ethyl formate (0.32g, 2mmol) by the synthetic method of embodiment 2, obtain yellow solid (0.33g, 59%).

MS-ESI:(ESI,pos.ion)m/z：564.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ10.50(s,1H),8.29(s,1H),7.34-7.26(m,2H),7.13-7.05(m,1H),6.21(s,1H),4.13-4.04(m,4H),3.96-3.85(m,2H),3.19(t,4H),2.48(t,4H),1.19-1.08(m,6H)。

Embodiment 14

4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

Step 1:4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-methyl-formiate

By the chloro-4-fluorobenzaldehyde of 2-(3.16g, 20mmol), methyl acetoacetate (2.32g, 20mmol), 1-ethyl-1H-1,2,4-triazole-3-amitraz hydrochloride (3.6g, 20mmol) by the synthetic method of embodiment 1 step 3, obtain yellow solid powder (3.02g, 40%).

MS-ESI:(ESI,pos.ion)m/z：378.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.10(s,1H),7.39-6.99(m,3H),6.12(s,1H),4.09-4.03(m,2H),3.66(s,3H),2.56(s,3H),1.51(t,3H)。

Step 2:4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-brooethyl-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-methyl-formiate (2.91g, 7.7mmol), NBS (1.51g, 8.47mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (2.15g, 62%).

MS-ESI:(ESI,pos.ion)m/z：456.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.16(s,1H),7.41-6.98(m,3H),6.10(s,1H),4.31-4.25(m,2H),4.05-3.92(m,2H),3.65(s,3H),1.49(t,3H)。

Step 3:4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-brooethyl-1,4-dihydro-pyrimidin-5-methyl-formiate (1.92g, 4.2mmol), morpholine (1.46g, 16.8mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (1.02g, 51%).

MS-ESI:(ESI,pos.ion)m/z：463.2[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.61(s,1H),8.12(s,1H),7.37-6.90(m,3H),6.18(s,1H),4.26-4.19(m,2H),4.11-3.92(m,2H),3.83(br.s,4H),3.68(s,3H),2.63(br.s,4H),1.54(t,3H)。

Embodiment 15

4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-ethyl formate

By the chloro-4-fluorobenzaldehyde of 2-(3.16g, 20mmol), methyl aceto acetate (2.6g, 20mmol), 1-ethyl-1H-1,2,4-triazole-3-amitraz hydrochloride (3.6g, 20mmol) obtains yellow solid powder (6.8g, 87%) by the synthetic method of embodiment 1 step 3.

MS-ESI:(ESI,pos.ion)m/z：392.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ8.06(s,1H),7.41-6.94(m,3H),6.16(s,1H),4.28-4.22(m,2H),4.07-4.02(m,2H),2.53(s,3H),1.53(t,3H),1.13(t,3H)。

Step 2: ethyl-4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-brooethyl-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylicesters

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-ethyl formate (3g, 7.7mmol), NBS (1.51g, 8.47mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (2.32g, 64%).

MS-ESI:(ESI,pos.ion)m/z：470.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ³):δ8.12(s,1H),7.43-6.99(m,3H),6.12(s,1H),4.29-4.23(m,2H),4.19-4.10(m,2H),4.06-3.93(m,2H),1.53(t,3H),1.13(t,3H)。

Step 3:4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-brooethyl-1,4-dihydro-pyrimidin-5-ethyl formate (2g, 4.2mmol), morpholine (1.46g, 16.8mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (1.02g, 51%).

MS-ESI:(ESI,pos.ion)m/z：477.2[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.50(s,1H),8.07(s,1H),7.37-6.85(m,3H),6.25(s,1H),4.26(q,2H),4.13-3.90(m,4H),3.83(br.s,4H),2.63(br.s,4H),1.54(t,3H),1.13(t,3H)。

Embodiment 16

4-(the chloro-4-fluorophenyl of 2-)-6-((1,1-dioxy base thiomorpholine) methyl)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the chloro-4-fluorophenyl of 2-)-2-(1-ethyl-1H-1,2,4-triazole-3-yl)-6-brooethyl-1,4-dihydro-pyrimidin-5-ethyl formate (2g, 4.2mmol), thiomorpholine 1,1-dioxide hydrochloride (1.44g, 8.4mmol) obtains yellow solid (1.39g, 63%) by the synthetic method of embodiment 2.MS-ESI:(ESI,pos.ion)m/z：525.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.34(s,1H),8.09(s,1H),7.34-6.95(m,3H),6.21(s,1H),4.21(q,2H),4.17-3.95(m,4H),3.31(br.s,4H),2.97(br.s,4H),1.57(t,3H),1.13(t,3H)。

Embodiment 17

2-(1-benzyl-1H-1,2,4-triazole-3-yl)-4-(the chloro-4-fluorophenyl of 2-)-6-((1,1-dioxy base thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:1-benzyl-1H-1,2,4-triazole-3-cyano group

By 3-cyano group-1H-1,2,4-triazole (9.4g, 100mmol), benzyl bromine (20.5g, 120mmol) are pressed embodiment 1 step 1 operation, obtain yellow glutinous shape thing (12.9g, 70%).

MS-ESI:(ESI,pos.ion)m/z：185.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ8.21(s,1H),7.43-7.31(m,4H),7.29-7.21(m,1H),5.43(s,2H)。

Step 2:1-benzyl-1H-1,2,4-triazole-3-amitraz hydrochloride

By 1-benzyl-1H-1,2,4-triazole-3-cyano group (18.4g, 100mmol), sodium methylate (5.4g, 100mmol), ammonium chloride (6.42g, 120mmol) obtain gray solid (16.4g, 69%) by the synthetic method of embodiment 1 step 2.

MS-ESI:(ESI,pos.ion)m/z：202.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ8.51(s,1H),7.48-7.18(m,5H),7.11(s,1H),6.90(s,2H),5.42(s,2H)。

Step 3:2-(1-benzyl-1H-1,2,4-triazole-3-yl)-4-(the chloro-4-fluorophenyl of 2-)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-ethyl formate

By 1-benzyl-1H-1,2,4-triazole-3-amitraz hydrochloride (2.38g, 10mmol), the chloro-4-fluorobenzaldehyde of 2-(1.59g, 10mmol), methyl aceto acetate (1.3g, 10mmol) obtains yellow solid (2.27g, 50%) by the synthetic method of embodiment 1 step 3.

MS-ESI:(ESI,pos.ion)m/z：454.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.81(s,1H),8.71(s,1H),7.78(dd,1H),7.53-7.19(m,6H),7.04-6.98(m,1H),6.02(s,1H),5.44(s,2H),4.03(q,2H),2.46(s,3H),1.12(t,3H)。

Step 4:2-(1-benzyl-1H-1,2,4-triazole-3-yl)-6-(brooethyl)-4-(the chloro-4-fluorophenyl of 2-)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 2-(1-benzyl-1H-1,2,4-triazole-3-yl)-4-(the chloro-4-fluorophenyl of 2-)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-ethyl formate (0.45g, 1mmol), NBS (0.2g, 1.1mmol) by the synthetic method of embodiment 1 step 4, obtain yellow glutinous shape thing (0.31g, 58%).

MS-ESI:(ESI,pos.ion)m/z：532.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.77(s,1H),8.65(s,1H),7.73(dd,1H),7.51-7.16(m,6H),7.06-6.99(m,1H),6.07(s,1H),5.41(s,2H),4.63(dd,2H),4.08(q,2H),1.15(t,3H)。

Step 5:2-(1-benzyl-1H-1,2,4-triazole-3-yl)-4-(the chloro-4-fluorophenyl of 2-)-6-((1,1-dioxy base thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 2-(1-benzyl-1H-1,2,4-triazole-3-yl)-6-(brooethyl)-4-(the chloro-4-fluorophenyl of 2-)-1,4-dihydro-pyrimidin-5-ethyl formate (0.53g, 1mmol), thiomorpholine 1,1-dioxide (0.34g, 2mmol) obtains yellow solid (0.36g, 61%) by the synthetic method of embodiment 2.

MS-ESI:(ESI,pos.ion)m/z：587.2[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.73(s,1H),8.61(s,1H),7.69(dd,1H),7.51-7.19(m,6H),7.03-6.95(m,1H),6.08(s,1H),5.43(s,2H),4.12(q,2H),3.96-3.81(m,2H),3.23(br.s,4H),2.97(br.s,4H),1.13(t,3H)。

Embodiment 18

4-(the bromo-4-fluorophenyl of 2-)-6-(morpholino methyl)-2-(1H-1,2,4-triazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-ethyl formate

In 100mL eggplant type bottle, add successively urea (2.90g, 48mmol), methyl aceto acetate (5.22g, 40mmol), the bromo-4-fluorobenzaldehyde of 2-(8.12g, 40mmol), trimethylchlorosilane (3.81g, 35mmol), sodium iodide (5.25g, 35mmol) and anhydrous acetonitrile (50mL), at 25 ℃, stir 12h.Filter, with a small amount of acetonitrile rinse, obtain white solid (5.72g, 40%).

MS-ESI:(ESI,pos.ion)m/z：357.0[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.80(br.s,1H),9.22(br.s,1H),6.97-6.85(m,3H),6.10(s,1H),4.06(q,2H),2.52(s,3H),1.12(t,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-) the chloro-6-methyl isophthalic acid of-2-, 4-dihydro-pyrimidin-5-ethyl formate

In 100mL eggplant type bottle, add successively 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-oxo-1; 2; 3; 4-tetrahydropyrimidine-5-ethyl formate (3.56g; 10mmol) and phosphorus oxychloride (15mL); under nitrogen protection, in 110 ℃ of reaction 4h, be cooled to 25 ℃, remove phosphorus oxychloride under reduced pressure.In resistates, add chloroform (100mL), use strong aqua adjust pH to 6-8.Salt solution washing (80mL * 3) for organic layer, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=5/1), obtains white solid (1.73g, 46%).

MS-ESI:(ESI,pos.ion)m/z：375.0[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.82(br.s,1H),6.92-6.83(m,3H),6.12(s,1H),4.08(q,2H),2.52(s,3H),1.08(t,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-1,2,4-triazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

In dry reaction bottle, add successively 4-(the bromo-4-fluorophenyl of 2-) the chloro-6-methyl isophthalic acid of-2-, 4-dihydro-pyrimidin-5-ethyl formate (3.76g, 10mmol), 1H-1,2,4-triazole (1.38g, 20mmol), salt of wormwood (2.76g, 20mmol) and dehydrated alcohol (80mL), 60 ℃ of reaction 8h, are cooled to room temperature, filter, filtrate decompression is steamed and is desolventized, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtains faint yellow solid (2.2g, 55%).

MS-ESI:(ESI,pos.ion)m/z：408.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.80(s,1H),8.93(s,1H),8.03(s,1H),7.29-6.97(m,3H),6.12(s,1H),4.06(q,2H),2.52(s,3H),1.08(t,3H)。

Step 4:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-1,2,4-triazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (4.08g, 10mmol) and NBS (1.96g, 11mmol) by the synthetic method of embodiment 1 step 4, obtain yellow solid (2.73g, 56%).

MS-ESI:(ESI,pos.ion)m/z：486.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.82(s,1H),8.90(s,1H),8.01(s,1H),7.27-6.95(m,3H),6.10(s,1H),4.56-4.41(m,2H),4.05(q,2H),1.07(t,3H)。

Step 5:4-(the bromo-4-fluorophenyl of 2-)-6-(morpholino methyl)-2-(1H-1,2,4-triazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) and morpholine (0.35g, 4mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.31g, 62%).

MS-ESI:(ESI,pos.ion)m/z：493.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.75(s,1H),8.83(s,1H),8.12(s,1H),7.46-6.97(m,3H),6.12(s,1H),4.09(q,2H),3.97-3.84(m,2H),3.61(br.s,4H),2.46(br.s,4H),1.06(t,3H)。

Embodiment 19

4-(the bromo-4-fluorophenyl of 2-)-6-((1,1-dioxy base thiomorpholine) methyl)-2-(1H-1,2,4-triazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-1,2,4-triazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) with thiomorpholine 1,1-dioxy base hydrochloride (0.34g, 2mmol) obtains yellow solid (0.28g, 51%) by the synthetic method of embodiment 2.

MS-ESI:(ESI,pos.ion)m/z：541.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.29(s,1H),8.94(s,1H),8.05(s,1H),7.37-6.97(m,3H),6.18(s,1H),4.33(d,1H),4.04(q,2H),3.96(d,1H),3.23(br.s,4H),2.99(br.s,4H),1.12(t,3H)。

Embodiment 20

4-(the bromo-4-fluorophenyl of 2-)-2-(5-methyl-2H-tetrazole-2-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-Oxy-1,2,3,4-tetrahydropyrimidine-5-ethyl formate (0.71g, 2mmol), chloroform (20mL), NBS (0.39g, 2.2mmol) by embodiment 1 step 4 synthetic method, obtain micro-brown oil (0.46g, 53%).

MS-ESI:(ESI,pos.ion)m/z：434.9[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.13(br.s,1H),7.41(br.s,1H),7.43-7.39(m,1H),7.17-7.11(m,2H),5.78(s,1H),4.98(dd,2H),4.08(q,2H),1.10(t,3H).

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-(morpholine methyl)-2-Oxy-1,2,3,4-tetrahydropyrimidine-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-ethyl formate (0.44g, 1mmol), morpholine (0.35g, 4mmol) obtains micro-brown solid (0.19g, 43%) by embodiment 1 step 5 synthetic method.

MS-ESI:(ESI,pos.ion)m/z：442.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.21(s,1H),7.52(s,1H),7.43-7.38(m,1H),7.20-7.12(m,2H),5.84(s,1H),4.08(q,2H),3.87-3.79(m,2H),3.68(br.s,4H),2.46(br.s,4H),1.09(t,3H).

Step 3:4-(the bromo-4-fluorophenyl of 2-) the chloro-6-of-2-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(morpholine methyl)-2-Oxy-1,2,3,4-tetrahydropyrimidine-5-ethyl formate (0.88g, 2mmol), phosphorus oxychloride (2mL) obtains gray solid (0.22g, 47%) by embodiment 18 step 2 synthetic methods.

MS-ESI:(ESI,pos.ion)m/z：460.0[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.68(s,1H),7.38-7.22(m,2H),7.14-7.16(m,1H),5.83(s,1H),4.05(q,2H),3.92-3.83(m,2H),3.65(br.s,4H),2.47(br.s,4H),1.06(t,3H).

Step 4:4-(the bromo-4-fluorophenyl of 2-)-2-(5-methyl-2H-tetrazole-2-yl)-6-(morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-) the chloro-6-of-2-(morpholine methyl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.46g, 1mmol), 5-methyl-2H-tetrazole (0.17g, 2mmol) obtains faint yellow solid (0.18g, 36%) by embodiment 18 step 3 synthetic methods.

MS-ESI:(ESI,pos.ion)m/z：508.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.80(s,1H),7.39-6.98(m,3H),6.23(s,1H),4.09-3.88(m,4H),3.83(br.s,4H),2.76(s,3H),2.65(br.s,4H),1.12(t,3H).

Embodiment 21

4-(the bromo-4-fluorophenyl of 2-)-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-6-(morpholino methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By (the bromo-4-fluorophenyl of 2-) chloro-6-methyl isophthalic acid of-2-, 4-dihydro-pyrimidin-5-ethyl formate (3.77g, 10mmol), 5-methyl isophthalic acid H-tetrazole (1.68g, 20mmol) obtains faint yellow solid (1.99g, 47%) by the synthetic method of embodiment 18 steps 3.

MS-ESI:(ESI,pos.ion)m/z：423.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.83(s,1H),7.41-7.07(m,3H),6.36(s,1H),4.13(q,2H),2.49(s,3H),2.42(s,3H),1.06(t,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.42g, 1mmol), chloroform (10mL) and NBS (0.2g, 1.1mmol) by the synthetic method of embodiment 1 step 4, obtain faint yellow oily matter (0.25g, 49%).

MS-ESI:(ESI,pos.ion)m/z：501.0[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.89(s,1H),7.48-7.12(m,3H),6.31(s,1H),4.51(dd,2H),4.08(q,2H),2.45(s,3H),1.08(t,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-6-(morpholino methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(5-methyl isophthalic acid H-tetrazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.5g, 1mmol) and morpholine (0.35g, 4mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.26g, 52%).

MS-ESI:(ESI,pos.ion)m/z：508.1[M+1] ⁺;

¹H?NMR(400MHz,DMSO-d ₆):δ9.71(s,1H),7.47-7.25(m,2H),7.17-7.07(m,1H),6.28(s,1H),4.03(q,2H),3.95-3.83(m,2H),3.65(br.s,4H),2.52(s,3H),2.48(br.s,4H),1.04(t,3H)。

Embodiment 22

4-(the bromo-4-fluorophenyl of 2-)-6-(morpholino methyl)-2-(1H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By (the bromo-4-fluorophenyl of 2-) chloro-6-methyl isophthalic acid of-2-, 4-dihydro-pyrimidin-5-ethyl formate (3.77g, 10mmol) by the synthetic method of embodiment 18 steps 3, obtain faint yellow solid (1.76g, 43%) with 1H-tetrazole (1.4g, 20mmol).

MS-ESI:(ESI,pos.ion)m/z：409.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ10.18(s,1H),9.61(s,1H),7.42-7.05(m,3H),6.22(s,1H),4.05(q,2H),2.56(s,3H),1.10(t,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(1H-tetrazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.41g, 1mmol), chloroform (10mL) and NBS (0.2g, 1.1mmol) by the synthetic method of embodiment 1 step 4, obtain faint yellow oily matter (0.27g, 56%).

MS-ESI:(ESI,pos.ion)m/z：487.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ10.11(s,1H),9.58(s,1H),7.47-7.09(m,3H),6.24(s,1H),4.49(dd,2H),4.08(q,2H),1.12(t,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-6-(morpholino methyl)-2-(1H-tetrazole-1-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(1H-tetrazole-1-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol) and morpholine (0.35g, 4mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.29g, 58%).

MS-ESI:(ESI,pos.ion)m/z：494.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ10.13(s,1H),9.76(s,1H),7.43-7.03(m,3H),6.21(s,1H),4.07(q,2H),3.93-3.85(m,2H),3.79(br.s,4H),2.61(br.s,4H),1.12(t,3H)。

Embodiment 23

4-(the bromo-4-fluorophenyl of 2-)-6-(morpholine methyl)-2-(2H-tetrazole-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

Step 1:4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(2H-tetrazole-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By (the bromo-4-fluorophenyl of 2-) chloro-6-methyl isophthalic acid of-2-, 4-dihydro-pyrimidin-5-ethyl formate (3.76g, 10mmol) by the synthetic method of embodiment 18 steps 3, obtain faint yellow solid (1.96g, 48%) with 2H-tetrazole (1.4g, 20mmol).

MS-ESI:(ESI,pos.ion)m/z：409.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.62(s,1H),9.34(s,1H),7.41-6.96(m,3H),6.19(s,1H),4.03(q,2H),2.48(s,3H),1.05(t,3H)。

Step 2:4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(2H-tetrazole-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-methyl-2-(2H-tetrazole-2-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.41g, 1mmol), chloroform (10mL), NBS (0.2g, 1.1mmol) by the synthetic method of embodiment 1 step 4, obtain faint yellow oily matter (0.22g, 46%).

MS-ESI:(ESI,pos.ion)m/z：487.0[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.69(s,1H),9.27(s,1H),7.44-6.99(m,3H),6.22(s,1H),4.47(dd,2H),4.06(q,2H),1.08(t,3H)。

Step 3:4-(the bromo-4-fluorophenyl of 2-)-6-(morpholine methyl)-2-(2H-tetrazole-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-ethyl formate

By 4-(the bromo-4-fluorophenyl of 2-)-6-(brooethyl)-2-(2H-tetrazole-2-yl)-1,4-dihydro-pyrimidin-5-ethyl formate (0.49g, 1mmol), morpholine (0.35g, 4mmol) by the synthetic method of embodiment 1 step 5, obtain yellow solid (0.31g, 63%).

MS-ESI:(ESI,pos.ion)m/z：494.1[M+1] ⁺;

¹H?NMR(400MHz,CDCl ₃):δ9.76(s,1H),9.25(s,1H),7.37-6.99(m,3H),6.23(s,1H),4.07-4.02(m,3H),3.91-3.87(m,1H),3.83(br.s,4H),2.66(br.s,4H),1.12(t,3H)。

Embodiment 24

With HBV HepG2.2.15 cell strain, carry out In Vitro Anti HBV drug activity determination experiment

I. experimental technique:

QPCR detection cell culture fluid viral DNA content computerized compound are to viral inhibition percentage (%Inh), and specific experiment method is as follows:

Inoculation HepG2.2.15 cell is to 96 hole microwell plates (40,000 cells/well), and second day adds containing the cell culture fluid of compound to be tested processes cell, surveys the compound of inhibition per-cent and does two-pack hole, and compound final concentration is 500nmol.Within the 5th day, change the nutrient solution containing medicine, within the 8th day, collect culture supernatant and extract the DNA in supernatant.

Viral DNA extracts: with reference to QIAamp96DNA Blood Kit(QIAGEN51161).

Quantitative PCR: according to PCR system configurations reaction mixture; Mixed solution is added to 384 hole PCR Sptting plates (quantitatively special-purpose); Add the standard substance template of having diluted in proportion; Add sample template; With shrouding film, 384 orifice plates are sealed up; According to program operation quantitative PCR instrument.

Compound calculates hbv replication inhibition percentage: %Inh.=[1-adds compound treatment HBV DNA amount/DMSO control treatment HBVDNA amount] * 100.

II. experimental result:

The inhibition percentage (%Inh) of measuring the vitro inhibition hbv replication of compound of the present invention according to aforesaid method, the results are shown in following table 2:

Table 2

III. conclusion:

Result demonstration, embodiment 1,4,5,14,15 inhibition HBV replication percentage are greater than 80 ﹪, demonstrate the effect that compound of the present invention has stronger anti-hbv replication.This compounds has antiviral activity beyond expectation to HBV, is therefore applicable to the various diseases that treatment causes because of HBV virus infection.

Although, above used general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.

Claims

1. suc as formula (I) or the compound (Ia),

A be a key ,-O-,-S-or-N (R ⁵)-;

R is-X-Z;

X is-(CR ⁷r ^7a) _m-or-C (=O)-;

Z is minor structure formula as shown in the formula (II):

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

W is CR ⁷, or N;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ¹for aryl or heteroaryl;

R ⁴for hydrogen, deuterium or C ₁-C ₄alkyl;

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

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

Each q is 0,1 or 2 independently; With

2. compound according to claim 1, wherein:

Z is minor structure formula as shown in the formula (III):

Wherein, B is a key ,-(CR ⁷r ^7a) _m-or-C (=O)-;

Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

R ⁶for hydrogen, deuterium, C ₁-C ₄alkyl, C ₂-C ₄thiazolinyl ,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-O-(CR ⁷r ^7a) _m-O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) O-R ⁸,-(CR ⁷r ^7a) _m-C (=O) R ⁸,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-N (R ⁸r ^8a) ,-(CR ⁷r ^7a) _m-C (=O)-(CR ⁷r ^7a) _m-OR ⁸, or C ₂-C ₄alkynyl;

Each R ^7aand R ⁷be hydrogen, deuterium, F, Cl, Br, C independently ₁-C ₆alkyl, C ₁-C ₆haloalkyl or C ₆-C ₁₀aryl; Or R ⁷, R ^7aform C together with the C atom being attached thereto ³-C ⁸cycloalkyl;

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

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

Each q is 0,1 or 2 independently.

3. compound according to claim 2, wherein:

Z is minor structure formula as follows:

Each n is 0,1 or 2 independently;

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

4. compound according to claim 1, wherein:

R ³for 5 yuan of heteroaryls containing 3 or 4 nitrogen-atoms, wherein said 5 yuan of heteroaryls that contain 3 or 4 nitrogen-atoms can be by one or more by hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C ¹-C ⁴alkyl, C ¹-C ⁴alkoxyl group, C ¹-C ⁴alkylamino, C ⁶-C ¹⁰aryl C ¹-C ⁴alkyl, C ¹-C ⁴haloalkyl, cyano group, hydroxyl, nitro or amino substituting group replace; Wherein, R ³be not

5. compound according to claim 4, wherein, R ³for following minor structure formula:

Wherein, R ³be not

Each p is 0 or 1 independently.

6. compound according to claim 1, wherein:

R ²for hydrogen, deuterium or C ₁-C ₄alkyl;

R ⁵for hydrogen, deuterium or C ₁-C ₄alkyl.

7. compound according to claim 6, wherein:

8. compound according to claim 1, it has suc as formula (IV) or the structure (IVa),

Z is the minor structure formula as shown in formula V:

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) ^q-or-N (R ⁶)-;

R ²for hydrogen, deuterium or C ₁-C ₄alkyl;

Each R ⁸and R ^8abe hydrogen, deuterium, C independently ₃-C ₈cycloalkyl, C ₁-C ₄haloalkyl or C ₁-C ₆alkyl;

Each R ¹¹be fluorine, deuterium, chlorine, nitro or bromine independently;

Each k is 1 or 2 independently;

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

Each n is 0,1 or 2 independently;

Each q is 0,1 or 2 independently.

9. compound according to claim 8, wherein:

Z is the minor structure formula as shown in formula V:

Wherein, Y is-(CR ⁷r ^7a) _m-,-O-,-S-,-S (=O) _q-or-N (R ⁶)-;

Each q is 0,1 or 2 independently;

Each n is 0,1 or 2 independently;

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

10. compound according to claim 9, wherein:

Z is independently selected from following minor structure formula:

11. compounds according to claim 8, wherein

R ³for triazolyl or tetrazyl, wherein said triazolyl or tetrazyl can be replaced by one or more hydrogen, deuterium, methyl, ethyl, propyl group, phenyl methyl, 1-phenylethyl, 2-phenylethyl, cyano group, hydroxyl, nitro or amino substituting groups of being selected from; Wherein, R ³be not

12. compounds according to claim 11, wherein:

R ³independently selected from following minor structure formula:

13. compounds according to claim 1, comprise following one of them structure:

Or its enantiomer, diastereomer, tautomer, hydrate, solvate or pharmacy acceptable salt.

14. according to the compound described in claim 1-13, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, and wherein said salt is organic acid salt, inorganic acid salt or the salt that obtains by alkali.

15. compounds according to claim 14, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, inorganic acid salt is hydrochloride, hydrobromate, perchlorate, phosphoric acid salt or vitriol.

16. compounds according to claim 14, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, organic acid salt is carboxylate salt or sulphur hydrochlorate.

17. compounds according to claim 16, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, carboxylate salt is acetate, oxalate, maleate, tartrate, Citrate trianion, succinate or malonate.

18. compounds according to claim 16, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, sulphur hydrochlorate is mesylate, esilate, benzene sulfonate, tosylate or naphthalenesulfonate.

19. compounds according to claim 14, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, the salt obtaining by alkali is basic metal, alkaline-earth metal, ammonium or N ⁺(R ¹²) ₄salt.

20. compounds according to claim 19, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, basic metal or alkaline earth salt are sodium salt, lithium salts, sylvite, calcium salt or magnesium salts.

21. compounds according to claim 19, or its enantiomer, diastereomer, tautomer, pharmacy acceptable salt, wherein, R ¹²h, deuterium, C ₁-C ₄alkyl, C ₆-C ₁₀aryl or C ₆-C ₁₀aryl C ₁-C ₄alkyl.

22. pharmaceutical compositions, comprise the arbitrary described compound of claim 1-13, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

23. pharmaceutical compositions according to claim 22, it further comprises anti-HBV medicine.

24. pharmaceutical compositions according to claim 23, wherein anti-HBV medicine is HBV AG14361, immunomodulator or Interferon, rabbit.

25. pharmaceutical compositions according to claim 23, wherein anti-HBV medicine has lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, Alfacon-1 b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, polyoxyethylene glycol Intederon Alpha-2a, virazole, Wellferon-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, LEVAMISOLE HCL, or propagermanium.

26. rights to use require the arbitrary described compounds of 1-13 or the arbitrary described pharmaceutical composition of claim 22-25 for the preparation of preventing, process, treat or alleviating the purposes in the medicine of disease viral disease.

27. purposes according to claim 26, wherein virus disease refers to the disease that hepatitis B infection or hepatitis B infection cause.

28. purposes according to claim 27, wherein hepatitis B infection causes that disease refers to liver cirrhosis or canceration of hepatic cell.

29. purposes according to claim 26, wherein virus disease refers to hepatitis B disease.