CN107793409A

CN107793409A - Dihydropyrimidines and its application in medicine

Info

Publication number: CN107793409A
Application number: CN201710783447.4A
Authority: CN
Inventors: 任青云; 刘辛昌; 张英俊; S·戈尔德曼
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2016-09-05
Filing date: 2017-09-04
Publication date: 2018-03-13
Anticipated expiration: 2037-09-04
Also published as: CN107793409B

Abstract

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

Description

Dihydropyrimidines and its application in medicine

Technical field

A kind of purposes the present invention relates to Dihydropyrimidines and its as medicine, especially as treat and Prevent the purposes of the medicine of hepatitis B.Formed the invention further relates to these Dihydropyrimidines with other antivirotics Composition, and its for treating and preventing the application of hepatitis B (HBV) infection.

Background technology

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

The conventional medicine for being licensed for treating chronic hepatitis is interferon and Lamivudine (lamivudine).However, Interferon only has medium activity, and has higher toxicity；Although Lamivudine (lamivudine) has good Activity, but amplification is rapid over the course for the treatment of for its drug resistance, and the effect that usually had a rebound after treatment is stopped, rummy husband The IC of fixed (3-TC)₅₀It is worth for 300nM (Science, 299 (2003), 893-896).

Deres etc. is reported using Bay41-4109, Bay39-5493 as the cyclosubstituted dihydropyridine of the heteroaryl of representative (HAP) compound, such compound can play a part of suppressing hbv replication by preventing the formation of normal nucleocapsid. Bay41-4109 shows preferable pharmacokinetic properties (Science, 299 (2003), 893-896) in clinical studies, leads to The research for crossing its mechanism of action finds that the cyclosubstituted Dihydropyrimidines of heteroaryl pass through the 113-143 ammonia with core protein Base acid residue effect, the angle between the dimer to form nucleocapsid is changed, result in unstable expansion nucleocapsid, add The degraded (Biochem.Pharmacol.66 (2003), 2273-2279) of fast core protein.

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

Novel dihydropyridine compound of the present invention has preferable inhibitory activity, pharmacokinetic property, molten The advantages that Xie Xing, stability and less toxicity, it has good application prospect in terms of resisting HBV virus.

Abstract of invention

The present invention relates to novel dihydropyridine compound and its use in medicine of the treatment with prevention HBV infection is prepared On the way.Especially, compound involved in the present invention, and its pharmaceutically acceptable composition, HBV senses can effectively be suppressed Dye.

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

Or its enantiomter, diastereoisomer, dynamic isomer, solvate or pharmaceutically acceptable salt, its In each R, R¹、R²、R³There is implication of the present invention with f.

In some embodiments, R is-X-Z；

X is-(CR⁷R^7a)_t- or-C (=O)-；

Z is the subformula shown in formula (II)：

W is CR⁷Or N；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

Each R¹Independently be hydrogen, F, Cl, Br, I, cyano group, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, Methylamino, ethylamino, nitro, 4- trifluoromethyls, (trifluoromethyl) phenyl of 3,5- bis- or trifluoromethyl；

R²For hydrogen, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, cycloalkyl, cycloalkyl-alkyl or heterocyclic radical alkane Base；

R³For C_6-10The heteroaryl of aryl or 5-6 annular atom composition, wherein, the C_6-10Aryl and 5-6 annular atom group Into heteroaryl can with individually optional by 1,2,3,4 or 5 selected from fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alcoxyl Base, cyano group, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the aryl of haloalkyl substitution, halogen substitution Aryl or the substituent of trifyl substituted；

Each R⁴It independently is hydrogen, deuterium, F, Cl, Br or C_1-4Alkyl；

R⁵For-(CR⁹R^9a)_m-R⁸；

R⁶For alkyl, alkenyl or alkynyl；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, alkyl, haloalkyl ,-(CH₂)_m- OH or-(CH₂)_m- C (=O) O-R⁸；

R⁸For heteroaryl or heterocyclic radical, wherein, described aryl and heteroaryl can be with individually optional by 1,2,3,4 or 5 It is individual to be selected from fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyano group, hydroxyl, nitro, alkylamino, amino, fluoroform Aryl, the aryl of halogen substitution or the substituent of trifyl that base, trifluoromethoxy, haloalkyl substitute are substituted；

Each R^9aAnd R⁹It independently is hydrogen, deuterium, F, Cl, Br, C_1-4Alkyl or C_1-4Haloalkyl；

N is 0,1,2,3,4 or 5；

Each t independently is 0,1 or 2；

Each m independently is 0,1,2,3 or 4；

F is 0,1,2,3 or 4；

Q is 0,1 or 2.

In some embodiments, Z is the subformula shown in formula (III)：

Each R⁴It independently is hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl or isopropyl；

R⁵For-(CR⁹R^9a)_m-R⁸；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

R⁶For C_1-4Alkyl；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, C_1-4Alkyl, C_1-4Haloalkyl or-(CH₂)_m- C (=O) O-R⁸；

R⁸The heteroaryl or the heterocyclic radical of 5-6 annular atom composition formed for 5-6 annular atom, wherein, described 5-6 The heterocyclic radical of the heteroaryl of annular atom composition and 5-6 annular atom composition with individually optional can be selected from by 1,2,3,4 or 5 (=O), (=S), C_1-4Alkyl or C_1-4The substituent of alkoxy is substituted；

Each R^9aAnd R⁹It independently is hydrogen, deuterium, F, Cl, methyl, ethyl or trifluoromethyl.

In other embodiments, the subformula that the Z is as follows：

Each R⁵It independently is-(CR⁹R^9a)_m-R⁸；

R⁶For C_1-4Alkyl；

Each R^9aAnd R⁹It independently is hydrogen, deuterium, F, Cl, methyl or ethyl；

Each R⁸The heterocyclic radical that the heteroaryl of 5-6 annular atom composition or 5-6 annular atom form independently is, wherein described 5-6 annular atom composition heteroaryl and the heterocyclic radical that forms of 5-6 annular atom can be with individually optional by 1,2,3,4 or 5 It is individual to be selected from (=O), (=S) or C_1-4The substituent of alkyl is substituted.

In other embodiments, the R⁸For following subformula：

Wherein, each R¹⁰It independently is hydrogen, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, the R²For methyl, ethyl, n-propyl or isopropyl；

R³For phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl or imidazole radicals, wherein, it is described Phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl and imidazole radicals can with individually optional by 1,2, 3rd, 4 or 5 substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl are substituted.

In other embodiments, the compounds of this invention has the structure as shown in formula (IV) or (IVa),

Or its enantiomter, diastereoisomer, dynamic isomer, solvate or pharmaceutically acceptable salt, its In,

The Z is the subformula shown in formula (III)：

Y is-(CR⁷R^7a)_t- or-O-；

Each R¹It independently is hydrogen, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyano group, trifluoromethyl or methoxy Base；

R²For methyl, ethyl, n-propyl or isopropyl；

R³For phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl or imidazole radicals, wherein, it is described Phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl and imidazole radicals can with individually optional by 1,2, 3rd, 4 or 5 substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl are substituted；

R⁵For-(CR⁹R^9a)_m-R⁸；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl or isopropyl；

R⁸For

Each R¹⁰It independently is hydrogen, methyl, ethyl, n-propyl or isopropyl；

Each n independently is 0,1,2,3,4 or 5；

T is 0,1 or 2；

M is 0,1,2,3 or 4；

F is 0,1,2 or 3.

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

On the other hand, present invention also offers a kind of pharmaceutical composition for including compound of the present invention, it enters one Step includes pharmaceutically acceptable carrier or combinations thereof.

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

In certain embodiments, pharmaceutical composition of the present invention, wherein other Anti-HBV drugs polymerize for HBV Enzyme inhibitor, immunomodulator or interferon.

In certain embodiments, pharmaceutical composition of the present invention, wherein other Anti-HBV drugs are rummy husband It is fixed, Sebivo, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, gram Pressgang is determined, emtricitabine, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', and interferon-' alpha '- 2a, interferon beta-1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, disease Malicious azoles, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, peace Puli is near, Phosphazid, Heplisav, Interferon Alpha-2b, left-handed miaow Azoles or Propagermanium.

On the other hand, present invention also offers the compound or described pharmaceutical composition to prepare for preventing, treating Or the purposes in the medicine of mitigation patient's viral disease.

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

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

On the other hand, it is used to prevent, treat or mitigate to prepare the present invention relates to described compound or pharmaceutical composition Purposes in the medicine of patient's hepatitis B disease, including give patient's compound as described in the present invention or of the present invention The dose therapeutically effective of pharmaceutical composition.

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

Another aspect of the present invention is related to prevention, treatment or the method for mitigating patient's HBV illnesss, and methods described contains comprising use The pharmaceutically acceptable effective dose for having the pharmaceutical composition of the compound of the present invention is administered to patient.

The compound that another aspect of the present invention is directed to use with the present invention is used to preventing, handle or treating patient HBV to produce Illness, and mitigate the purposes of the medicine of its order of severity.

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

Another aspect of the present invention is related to a kind of method for suppressing HBV infection, and this method includes cell with effectively suppressing HBV's Compound or the composition contact of the present invention.Other embodiment is, methods described further comprising cell with it is other The contact of HBV therapeutic agents.

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

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

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

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

Detailed description of the invention book

Definition and general terms

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

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

As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. In general, term " substituted ", represents that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless Other aspects show that an optional substituted radical can have a substituent to be taken in each commutable position of group Generation.When more than one position can be substituted by one or more substituents selected from specific group in given structural formula, that Substituent with identical or different can substitute in each position.Wherein described substituent can be, but be not limited to fluorine, Chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyano group, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoro methoxy Base, the aryl of haloalkyl substitution, the aryl or trifyl of halogen substitution.

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

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

Term " alkenyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one C-C is sp² The group of double bond, wherein alkenyl with individually optional can be substituted by one or more substituents described in the invention, including Group has negation " suitable " or " E " " Z " positioning, wherein specific example includes, but is not limited to, vinyl (- CH=CH₂)、 Pi-allyl (- CH₂CH=CH₂), etc..

Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one C-C is sp Three keys, wherein alkynyl group with individually optional can be substituted by one or more substituents described in the invention, specifically Example includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), etc..

Term " annular aliphatic ", " carbocyclic ring ", " carbocylic radical " refer to monovalence or multivalence, and non-aromatic, saturation or part are not Saturated rings, include monocyclic or 7-12 carbon atom two rings of 3-12 carbon atom.Bicyclic carbocyclic ring with 7-12 atom can be with It is two rings [4,5], [5,5], [5,6] or [6,6] system, while it can be two rings [5,6] to have the bicyclic carbocyclic rings of 9 or 10 atoms Or [6,6] system.Suitable cyclic aliphatic group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.Ring-type fat The example of fat race group further comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- rings Amyl group -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl - 3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " cycloalkyl " represents that containing 3-12 carbon atom monovalent or multivalence saturation is monocyclic, bicyclic or three ring bodies System.In one embodiment, cycloalkyl includes 3-12 carbon atom；In another embodiment, it is former to include 3-8 carbon for cycloalkyl Son；In yet another embodiment, cycloalkyl includes 3-6 carbon atom.The group of naphthene base can it is independently unsubstituted or Substituted by one or more substituents described in the invention.

Term " h annular atom forms ", wherein h is integer, typically describes the number of ring member nitrogen atoms in molecule, in institute The number for stating ring member nitrogen atoms in molecule is h.For example, piperidyl is 6 molecular heterocyclic radicals of original.

Term " heterocyclic radical " refers to comprising 3-12 annular atom, the saturation of non-aromatic or part it is undersaturated it is monocyclic, Bicyclic or three-ring system, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Wherein, the heterocyclyl groups can appoint Selection of land is substituted by the substituent that one or more present invention describe.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrogen base, And-CH₂- group can be optionally by-C (=O)-or-C (=S)-replacement.The sulphur atom of ring can optionally be oxidized to S- Oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxides.In some embodiments, heterocyclic radical is 3-7 former Molecular heterocyclic radical, refers to monovalent or multivalence comprising 3-7 annular atom, and saturation or part are undersaturated nonaromatic Monocyclic or bicyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.In other embodiments, heterocyclic radical is 5 Former molecular heterocyclic radical, refer to the unit price comprising 5 annular atoms or multivalence, saturation or part are undersaturated, nonaro-maticity It is monocyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.In other embodiments, heterocyclic radical is 6 atoms The heterocyclic radical of composition, refer to the unit price comprising 6 annular atoms or multivalence, saturation or part are undersaturated, nonaromatic list Ring, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.It is molecular full that 6 molecular heterocyclic radicals of original include 6 originals The undersaturated heterocyclic radical of the heterocyclic radical of sum and part.

The example of heterocyclic radical includes, but are not limited to：Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also wraps Include heterocyclic group and saturation or part unsaturation ring or heterocyclic fused formed group.The example of heterocycle includes, but and unlimited In pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydric thiapyran Base, piperidyl, morpholinyl, thio-morpholinyl, thioxanes base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, sulphur Heterocycle butyl, homopiperidinyl, glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diaza Zhuo Ji, sulphur azatropylidene base, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane Hexyl, 1,3- dioxies amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, miaow Oxazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos [4.1.0] heptyl, azepine Bicyclic [2.2.2] hexyl, 3H- indyl quinolizine bases and N- pyridine radicals urea.The example of heterocyclic group also includes, 1,1- sulphur dioxide For morpholinyl.Wherein, carbon atom includes, but are not limited to hybar X base, 1,2,4- thiophenes two by the example of oxo (=O) on ring (4H) -one of azoles -5 base, (4H) -one of 1,2,4- oxadiazoles -5 base, (3H) -one of 1,3,4- oxadiazoles -2 base, 1H-1,2,4- triazoles -5 (4H) -one base etc., wherein, the example that carbon atom is substituted by=S on ring include, but are not limited to 1,2,4- oxadiazoles -5 (4H) - Thioketones base, 1,3,4- oxadiazoles -2 (3H)-thioketones base, 1,3,4- oxadiazoles -2 (3H)-thioketones base etc..And the heterocyclic radical can To be substituted or non-substituted, wherein substituent can be, but be not limited to fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkane Epoxide, cyano group, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, aryl, the halogen of haloalkyl substitution take The aryl or trifyl in generation.

Term " cycloheteroalkylalkyl " includes the alkyl of heterocyclic radical substitution, and such example includes, but is not limited to pyrroles -2- Methyl and morpholine -4- methyl etc..

Term " heterocyclylalkoxy " includes the remainder phase of the alkoxy, wherein oxygen atom and molecule of heterocyclic radical substitution Even, such example includes, but is not limited to pyrroles -2- methoxyl groups and piperidines -2- ethyoxyls etc..

Term " heterocyclic radical alkylamino " includes the remainder phase of the alkylamino, wherein nitrogen-atoms and molecule of heterocyclic radical substitution Even；Wherein heterocyclic radical and alkylamino radicals have implication as described in the present invention, and such example includes, but is not limited to piperazine Piperazine -2- ethylaminos, morpholine -4- propoxyl group, morpholine -4- ethylaminos etc..

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

Term " halogen " or " halogen atom " refer to F, Cl, Br or I.

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

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

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy can be by one The situation that individual or multiple identical or different halogen atoms are substituted.Wherein alkyl, alkenyl and alkoxy base have such as this hair Bright described implication, it is fluoride-based etc. that such example includes, but is not limited to trifluoromethyl, trifluoromethoxy, 2-.

Term " aryl " can be used alone or the big portion as " aralkyl " " aralkoxy " or " aryloxy alkyl " Point, it is monocyclic to represent that 6-14 annular atom is combined into, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are virtues Fragrant race, each of which member ring systems include 3-7 annular atom, and only an attachment point is connected with the remainder of molecule. Term " aryl " can be exchanged with term " aromatic rings " and used, as aromatic rings can include phenyl, naphthyl and anthryl.It is and described Aryl can be substituted or non-substituted, and wherein substituent can be, but be not limited to, fluorine, chlorine, bromine, iodine, (=O), (=S), Alkyl, alkoxy, cyano group, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the virtue of haloalkyl substitution Base, the aryl or trifyl of halogen substitution.

Term " heteroaryl " represents to contain 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic and three-ring system, wherein at least one ring is aromatic rings, and at least one aromatic rings includes one or more hetero atoms, Each of which member ring systems include the ring of 5-7 annular atom composition, and have one or more tie points and molecule remainder phase Even.Term " heteroaryl " can exchange use with term " heteroaromatic ", " hetero-aromatic ring " or " heteroaromatics ".In some implementations In scheme, heteroaryl is miscellaneous to be formed comprising 1,2,3 or 4 heteroatomic 5-12 annular atom for being independently selected from nitrogen, sulphur and oxygen Aryl.In other implementation cases, heteroaryl is comprising 1,2,3 or 4 heteroatomic 5-10 for being independently selected from nitrogen, sulphur and oxygen The heteroaryl of annular atom composition.In other embodiments, heteroaryl is to be independently selected from nitrogen, sulphur and oxygen comprising 1,2,3 or 4 Heteroatomic 5-6 annular atom composition heteroaryl.And the heteroaryl can be substituted or non-substituted, wherein substituting Base can be, but be not limited to, fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyano group, hydroxyl, nitro, alkane ammonia Base, amino, trifluoromethyl, trifluoromethoxy, the aryl of haloalkyl substitution, the aryl or trifyl of halogen substitution.

The example of hetero-aromatic ring includes following monocyclic, but it is monocyclic to be not limited to these：1,2,4- oxadiazoles -5 (4H)-thioketones Base, (4H) -one of 1,2,4- thiadiazoles -5 base, (4H) -one of 1,2,4- oxadiazoles -5 base, 1,3,4- oxadiazoles -2 (3H)-thioketones base, (4H) -one of 1H-1,2,4- triazoles -5 base, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazoles Base, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrroles Cough up base, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- Triazolyl), 2- thienyls, 3- thienyls, pyranose, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, pyrazinyl, cyanuro 1,3,5, di azoly, thiadiazolyl group, triazine radical etc.；Also following pair is included Ring but to be not limited to these bicyclic：Benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- Indyl), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- Isoquinolyl or 4- isoquinolyls) etc..

Term " heteroaryl alkyl " represents that alkyl group is substituted by one or more identical or different heteroaryl groups, Wherein alkyl group and heteroaryl groups has an implication as described in the present invention, such example include, but is not limited to pyridine- 2- ethyls, thiazole -2- methyl, imidazoles -2- ethyls, pyrimidine -2- propyl group etc..

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

Term " alkylthio group " includes C_1-10The alkyl of straight or branched is connected on the sulphur atom of divalence, wherein alkyl group With implication as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level_1-3Alkylthio group, such example Include, but is not limited to methyl mercapto (CH₃S-), ethylmercapto group etc..

Term " aralkyl ", " aryl alkyl " include the alkyl group of aryl substitution, and wherein aryl and alkyl group has Implication as described in the present invention.Some of embodiments are that aromatic alkyl group or aromatic yl alkyl group refer to the " aralkyl of lower level Base " group, i.e. aromatic yl group are connected to C_1-6On alkyl group.Other embodiment is aromatic alkyl group or aryl alkyl base Group refers to contain C_1-3" the benzene alkylene " of alkyl.Wherein instantiation includes phenyl methyl (that is, benzyl), diphenyl methyl, phenethyl Deng.And the aryl on aralkyl can be optionally further by fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyanogen Base, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the aryl of haloalkyl substitution, the virtue of halogen substitution The substituent of base or trifyl is substituted.

Term " alkyl amino ", " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Hydrogen atom in group is separately substituted by one or two identical or different alkyl group, and wherein alkyl group has Implication as described in the present invention.Some of embodiments are that alkyl amino is one or two C_1-6Alkyl is connected on nitrogen-atoms Lower level alkylamino group.Other embodiment is that alkyl amino is C_1-3Lower level alkylamino group. Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first Amino, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..

Term " aryl of haloalkyl substitution " includes to be taken by one or more identical or different haloalkyls The aryl in generation, wherein haloalkyl and aromatic yl group have implication as described in the present invention.Such example includes, but and unlimited In 2- trifluoromethyls, 3,5- bis- (trifluoromethyl) phenyl, 3- trifluoromethyls, 4- trifluoromethyls, 2,6- bis- (trifluoromethyl) phenyl etc..

Term " aryl of halogen substitution " includes the virtue that can be substituted by one or more identical or different halogen atoms Base, wherein halogen atom (halogen) and aromatic yl group have implication as described in the present invention.Such example includes, but and unlimited In fluorophenyl, difluorophenyl, trifluorophenyl, chlorphenyl, dichlorophenyl, trichlorophenyl, bromophenyl, tribromo phenyl, dibromobenzene Base, fluorochlorobenzene base, bromofluorobenzene base, chloro-bromobenzene base etc..

Term " cycloalkyl-alkyl " represents that alkyl group can be by one or more identical or different group of naphthene base institutes Substitution, wherein cycloalkyl and alkyl group have implication as described in the present invention.Such example includes, but is not limited to hexamethylene Ylmethyl, cyclopropylethyl etc..

As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula a institutes Show) represent substituent any commutable position on ring and can substitute, and can be the substitution for including enantiomter, As shown in formula b, c, d, e, f, g and h.

In addition, it is necessary to explanation, unless otherwise explicitly pointing out, the describing mode used in the whole text herein " each ... and ... independently be ", " ... and ... be each independently " and " ... and ... separately for " can exchange, and should do extensively Reason and good sense solution, it can both refer in different groups, not influenceed mutually between expressed specific option between same-sign, It can represent in identical group, not influenceed mutually between expressed specific option between same-sign.For example, such as formula p, Multiple R⁴Specific option it is unaffected from each other.

There are two tie points to be connected with molecule remainder as described in the invention, in system, for example, shown in formula q, table Show can be E ends or be E ' end be connected with molecule remainder, i.e., in the case of molecular structure is rational, the company at both ends The mode of connecing can exchange.

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

Term " prodrug " used in the present invention, represent a compound and be converted into vivo shown in formula (I) or formula (Ia) Compound.Such conversion is hydrolyzed or is precursor structure through enzymatic conversion in blood or tissue in blood by pro-drug Influence.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester as pro-drug in existing invention Class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as the present invention In a compound include hydroxyl, you can be acylated to obtain the compound of prodrug form.Other pro-drugs Form includes phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug Complete discuss may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

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

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

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

Term " dynamic isomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Mutual inversion of phases is built by low energy.Such as proton tautomer (i.e. prototropic dynamic isomer) includes migrating by proton Change, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) dynamic isomer includes Recombinate the change of bonding electrons.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: It is 1-19,1977. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed have hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate or by described on books document Other method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- Hydracrylate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, first Hydrochlorate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen Iodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, the third two Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acids salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt. The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble is scattered Product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically may be used The salt of receiving further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, as halide, Hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

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

When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- are (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document：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 its pharmaceutically acceptable composition, can effectively suppress HBV infection.

In some embodiments, R is-X-Z；

X is-(CR⁷R^7a)_t- or-C (=O)-；

Z is the subformula shown in formula (II)：

W is CR⁷Or N；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

Each R⁴It independently is hydrogen, deuterium, F, Cl, Br or C_1-4Alkyl；

R⁵For-(CR⁹R^9a)_m-R⁸；

R⁶For alkyl, alkenyl or alkynyl；

N is 0,1,2,3,4 or 5；

Each t independently is 0,1 or 2；

Each m independently is 0,1,2,3 or 4；

F is 0,1,2,3 or 4；

Q is 0,1 or 2.

In some embodiments, Z is the subformula shown in formula (III)：

R⁵For-(CR⁹R^9a)_m-R⁸；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

R⁶For C_1-4Alkyl；

In other embodiments, the subformula that the Z is as follows：

Each R⁵It independently is-(CR⁹R^9a)_m-R⁸；

R⁶For C_1-4Alkyl；Each R^9aAnd R⁹It independently is hydrogen, deuterium, F, Cl, methyl or ethyl；

In other embodiments, the R⁸For following subformula：

In some embodiments, the R²For methyl, ethyl, n-propyl or isopropyl；

The Z is the subformula shown in formula (III)：

Y is-(CR⁷R^7a)_t- or-O-；

R²For methyl, ethyl, n-propyl or isopropyl；

R⁵For-(CR⁹R^9a)_m-R⁸；

R⁸For

Each n independently is 0,1,2,3,4 or 5；

T is 0,1 or 2；

M is 0,1,2,3 or 4；

F is 0,1,2 or 3.

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

In other embodiments, the compounds of this invention includes the compound of one of, or its mapping is different Structure body, diastereoisomer, dynamic isomer, solvate or pharmaceutically acceptable salt, but it is not limited to these compounds：

On the other hand, present invention also offers a kind of pharmaceutical composition containing compound of the present invention, and its in medicine Acceptable carrier or combinations thereof on.

In certain embodiments, pharmaceutical composition of the present invention, wherein other Anti-HBV drugs are rummy husband Fixed, Sebivo, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, gram Pressgang is fixed, emtricitabine, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', and interferon-' alpha '- 2a, interferon beta-1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, disease Malicious azoles, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, peace Puli are near, Phosphazid, Heplisav, Interferon Alpha-2b, left-handed miaow Azoles or Propagermanium.

On the other hand, compound or described pharmaceutical composition of the present invention are used in preparation and are used to prevent, treat or subtract The medicine of light patient's viral disease.

In certain embodiments, the use of compound or described pharmaceutical composition of the present invention, wherein described viral Disease refers to disease caused by hepatitis B infection or hepatitis B infection.

In other embodiment, the use of compound or described pharmaceutical composition of the present invention, wherein the second Type virus infection causes disease to refer to hepatic sclerosis or canceration of hepatic cell.

On the other hand, the present invention relates to prevention, treatment or the method for mitigating patient's viral disease, wherein, methods described Comprising using the present invention compound or pharmaceutical composition pharmaceutically acceptable effective dose patient is administered.

In certain embodiments, the method for the invention, wherein the viral disease refers to hepatitis B infection or second Disease caused by type virus infection.

In other embodiment, the method for the invention, wherein the hepatitis B infection causes disease to refer to liver Hardening or canceration of hepatic cell.

On the other hand, the present invention relates to described compound or pharmaceutical composition to prepare for preventing, treating or mitigating The purposes of the medicine of patient's hepatitis B disease.

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

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

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

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

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

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

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

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

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

If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Or using organic Acid, as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2 hydroxy propanoic acid, citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.

If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N⁺(R¹⁴)₄Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N⁺(R¹⁴)₄Salt, such as R¹⁴It is H, C_1-4Alkyl, C_6-10Aryl, C_6-10Aryl C_1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine, and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. Also appropriate, nontoxic ammonium, quaternary ammonium salt and the amine cation of gegenions formation are included, such as halide, hydroxide, carboxylation Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

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

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

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

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

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

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

As described in the invention, pharmaceutical composition of the present invention is included shown in formula (I) or (Ia) of any present invention Compound, further applied comprising pharmaceutically acceptable auxiliary material, such as these auxiliary materials, the present invention, including it is any molten Agent, solid excipient, diluent, adhesive, disintegrant, or other liquid excipients, dispersant, flavouring or suspending agent, table Face activating agent, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., it is suitable for distinctive target Formulation.As described by documents below：In Remington:The Science and Practice of Pharmacy, 21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different auxiliary materials can be applied to medicine The preparation of acceptable composition and their known preparation methods on.Except any conventional auxiliary material and the chemical combination of the present invention The incompatible scope of thing, for example, caused any bad biological effect or with pharmaceutically acceptable composition it is any its His component caused interaction in harmful manner, their purposes are also the scope that the present invention is considered.

It can be included, but is not limited to as the material of pharmaceutically acceptable auxiliary material, ion-exchanger；Aluminium；Aluminum stearate；Ovum Phosphatide；Haemocyanin, such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Potassium sorbate；Saturation vegetable butter The partial glyceride mixtures of fat acid；Water；Salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxypropylene-blocking polymerization Body；Lanolin；Sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Thing, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol；Phosphate buffer solution；It is nontoxic with other Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate；Colouring agent；Releasing agent；Coating agents；Sweetener；Flavor enhancement；Spices； Preservative and antioxidant.

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

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

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

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

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

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

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

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

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

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

Another aspect of the present invention be related to a kind of compound of the invention or pharmaceutical composition prepare be used for prevent, treat or Mitigate the purposes of the medicine of patient's hepatitis B disease, including give patient's pharmaceutically acceptable effective dose and patient is carried out Administration.Hepatitis B disease refers to cause caused liver diseases by hepatitis B virus infection or hepatitis B infection, including acute Hepatitis, chronic hepatitis, hepatic sclerosis and stem cell cancer.Acute hepatitis b virus infection can be asymptomatic or show as Acute Hepatic Inflammation shape.Chronic viral infection patient suffers from active disease, can develop into hepatic sclerosis and liver cancer.

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

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

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

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

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

General synthetic method

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

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

The embodiments described below, unless otherwise indicated, all temperature are set to degree Celsius (DEG C).Reagent is bought In goods providers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from Shantou Western Gansu Province chemical plant, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao is risen Imperial chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.

Chromatographic column uses silicagel column, and silica gel (200-300 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃,d₆-DMSO,CD₃OD or d₆- acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets), br.s (broadened singlet, wide list Peak).Coupling constant J, unit are represented with hertz (Hz).

By being equipped with G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, ESI sources are applied to LC-MS spectrometers.

Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent 6120 serial LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detectors should For analyzing, ESI sources are applied to LC-MS spectrometers.

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

Table 1：Condition of gradient elution

Time (min)	A(CH₃CN, 0.1%HCOOH)	B(H₂O, 0.1%HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purifying is evaluated by the series of high efficiency liquid chromatograies (HPLC) of Agilent 1100, wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.

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

MeCN,CH₃CN acetonitriles

DCM,CH₂Cl₂Dichloromethane

CHCl₃Chloroform, chloroform

CDC1₃Deuterochloroform

CCl₄Carbon tetrachloride

Boc tertbutyloxycarbonyls

PE petroleum ethers

EtOAc, EA ethyl acetate

EtOH ethanol

TCDI thio-carbonyldiimidazoles

CDI carbonylic imidazoles

- 5- the alkene of DBU 1,5- diazabicylos [5.4.0] 11

HCl hydrogen chloride

K₂CO₃Potassium carbonate

NaHCO₃Sodium acid carbonate

NaOH sodium hydroxides

NaCl sodium chloride

Na₂SO₄Sodium sulphate

Et₃N, TEA triethylamine

NBS N-bromo-succinimides

D₂O heavy water

H₂O water

ML milliliters

RT, rt room temperature

Rt retention times

H₂Hydrogen

The ethyl acetate solution of HCl/EA hydrogen chloride

HOAt 1- hydroxyl -7- azo BTAs

DIPEA N, N- diisopropylethylamine

DCC N, N '-dicyclohexylcarbodiimide

DMF dimethylformamides

THF tetrahydrofurans

DMSO dimethyl sulfoxide (DMSO)s

CuCN cuprous cyanides

CH₃OH methanol

N₂Nitrogen

NH₄Cl ammonium chlorides

Ac₂O acetic anhydrides

t_1/2Half-life period

AUC area under the drug-time curve

Vss apparent steady state distribution volumes

CL, clearance clearance rate

F, absolute bioavailability bioavilabilities

Dose dosage

T_maxPeak time

C_maxCmax

hr^*The ng/mL blood concentration * times

Synthetic method

Following synthetic schemes lists the experimental procedure for preparing compound disclosed in the present invention.Wherein, each R¹、R²、R⁴、R⁵、 N, m and f has implication as described in the present invention.

Synthetic schemes 1

Compound 6a can be prepared by synthetic schemes 1, and 1a first obtains compound 2a with Boc anhydride reactions, be changed Compound 2a reacts to obtain compound with ethyl chloroformate reaction generation 3a, compound 3a under alkali (such as TEA) effect with ammoniacal liquor 4a, compound 4a react generation 5a in the presence of oxalyl chloride, and finally, compound 5a is in the presence of sodium azide and ammonium chloride Reaction generation midbody compound 6a.

Synthetic schemes 2

Compound 11a can be prepared by synthetic schemes 2, and 8a first obtains compound 9a with hydration hydrazine reaction, so Afterwards, (such as DIPEA) generates midbody compound 10a to compound 9a with triphosgene reaction in the basic conditions.

Synthetic schemes 3

Compound 13a can be prepared by synthetic schemes 3, first compound 5a and hydroxylamine hydrochloride, in sodium acid carbonate In the presence of reaction obtain compound 12a, then, the work of compound 12a and thio-carbonyldiimidazole in catalyst (such as DBU) Midbody compound 13a is generated with lower reaction.

Synthetic schemes 4

Compound 14a can be prepared by synthetic schemes 4, and compound 14a first acts on thio-carbonyldiimidazole, Midbody compound b is generated, then, compound b reacts in the presence of boron trifluoride ether solution obtains midbody compound 14a。

Synthetic schemes 5

Compound 15a can be prepared by synthetic schemes 5, and compound 12a and carbonyl dimidazoles effect generation are middle Body compound 15a.

Synthetic schemes 6

Compound 19a can be prepared by synthetic schemes 6, and (ethyl acetate of such as hydrogen chloride is molten in acid by intermediate 16a Liquid) in the presence of slough Boc blocking groups, obtaining compound 17a, compound 17a and compound 18a, (compound 18a is referred to CN104650068 synthetic method 2 and embodiment obtains or with reference to the synthetic schemes 7 in WO2015144093 and implementation Example method be prepared) in the basic conditions (such as TEA, potassium carbonate) reaction obtain Anti-HBV effect compound 19a.

Embodiment

Embodiment 1：(R) -6- (((R) -3- (1H-TETRAZOLE -5- bases) morpholine) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1) (3S) -3- carbamoyl morpholine -4- t-butyl formates

Sequentially added into 250mL there-necked flasks (S) -4- (di-tert-butyl dicarbonate) morpholine -3- formic acid (2.0g, 8.6mmol) with THF (20mL), after mixture is stirred at room temperature uniformly, triethylamine (1.3g, 13mmol), reactant are added System is cooled to 0 DEG C, then adds ethyl chloroformate (1.2g, 11mmol).Reactant mixture insulated and stirred 20 minutes, then be warming up to It is stirred at room temperature 2 hours.After having reacted, reaction solution is cooled to 0 DEG C, adds ammoniacal liquor (8mL), insulated and stirred 10 minutes, then It is warming up to room temperature and continues stirring 3 hours.Remove solvent under reduced pressure, water (50mL) is added into gained residue, then use ethyl acetate (50mL × 2) are extracted, and the organic phase of merging is washed with saturated aqueous common salt (50mL × 2), is then concentrated under reduced pressure, obtains title compound For colorless oil (1.75g, 89%).

MS-ESI:(ESI,pos.ion)m/z：131.3[M+H-100]⁺。

Step 2) (R)-N-Boc-3- cyano group morpholines

DMF (0.2g, 2.74mmol) and acetonitrile (8mL) are sequentially added into 50mL reaction bulb, mixture is cooled to 0 DEG C, oxalyl chloride (0.34g, 2.7mmol) dichloromethane (2mL) solution is then added dropwise again, after adding, the insulation of gained mixture after Continuous stirring 20 minutes.Then add (3S) -3- carbamoyl morpholine -4- t-butyl formates (0.3g, 1.3mmol) and pyridine The solution of the acetonitrile (3mL) of (0.12g, 1.52mmol), after adding, reaction 1 hour is stirred at room temperature in gained mixture.React Afterwards, add water quenching to go out reaction, then extracted with ethyl acetate (25mL × 2), the organic phase of merging is washed with saturated aqueous common salt (30mL × 2) Wash, anhydrous sodium sulfate drying, it is white solid (0.21g, 75.9%) to remove solvent under reduced pressure and obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：213.2[M+H]⁺, 235.2 [M+Na]⁺。

Step 3) (R) -3- (1H- tetrazole -5- bases) morpholine -4- t-butyl formates

(R)-N-Boc-3- cyano group morpholine (0.2g, 0.94mmol) and DMF are sequentially added into 50mL single port bottle (2mL), after dissolving completely is stirred at room temperature in mixture, add sodium azide (0.1g, 1.54mmol) and NH₄Cl(74mg, 1.4mmol), under nitrogen protection, gained reactant mixture is heated to 100 DEG C of simultaneously stirring reaction 6 hours, is then cooled at room temperature It is stirred overnight.After having reacted, add water (20mL) reaction is quenched, with watery hydrochloric acid tune pH value to 3, then with ethyl acetate (25mL × 3) extract, organic phase saturated common salt water washing (30mL × 3), anhydrous sodium sulfate drying, filtering, the filtrate decompression inspissation of merging Contracting, it is colourless grease (0.15g, 62.4%) to obtain title compound.

MS-ESI:(ESI,neg.ion)m/z：254.2[M-H]^-。

Step 4) (R) -3- (1H- tetrazole -5- bases) morpholine hydrochloride

(R) -3- (1H- tetrazole -5- bases) morpholine -4- t-butyl formates are sequentially added into 100mL single port bottle (0.15g, 0.59mmol) and HCl ethyl acetate solution (4mol/L, 15mL), reactant mixture are stirred at room temperature 2 hours. After having reacted, filtering, filter cake is washed with a small amount of ethyl acetate, is then dried in vacuo at 50 DEG C, and obtaining title compound is White solid (0.11g, 82.1%).

Step 5) (R) -6- (((R) -3- (1H- tetrazole -5- bases) morpholine) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (0.21g, 0.48mmol), K₂CO₃(0.17g, 1.2mmol), (R) -3- (1H- tetra- Nitrogen azoles -5- bases) morpholine hydrochloride (0.11g, 0.48mmol) and absolute ethyl alcohol (8mL), reactant mixture protects and room in nitrogen It is stirred overnight under temperature.Filtering, filtrate decompression concentration add water (25mL) dilution, and resulting solution adjusts the left sides of its pH to 3 with watery hydrochloric acid The right side, then extracted with ethyl acetate (30mL × 2).The organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate decompression inspissation Contracting, gained residue through silica gel column chromatography (PE/EA (V/V)=3/1) purify, obtain title compound for yellow solid (0.18g, 71.91%).

MS-ESI:(ESI,pos.ion)m/z：519.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.70(s,1H),8.06(d,,1H),7.96(d,1H),7.43– 7.38(m,2H),7.17(td,1H),5.97(s,1H),4.38(s,1H),4.04-3.95(m,3H),3.83–3.77(m,2H), 3.47(s,3H),3.37–3.27(m,1H),3.03–2.93(m,1H),2.63–2.57(m,1H)。

Embodiment 2：(R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((S) -3- (5- oxo -4,5- dihydro -1,3,4- Evil bis- Azoles -2- bases) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1) (S) -3- (formylhydrazine) morpholine -4- t-butyl formates

(S)-N-Boc-3- morpholines methyl formate (2.0g, 8.2mmol), methanol are sequentially added into 100mL single port bottle (20mL) and hydrazine hydrate (1.2g, 24mmol), mixture are heated to 80 DEG C and are stirred overnight.After having reacted, it is concentrated under reduced pressure, to residual Stay and water and each 50mL of ethyl acetate are added in thing, stand, layering, water layer is extracted with EA (50mL × 3) again, and the organic layer of merging is used Saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, gained residue is through silica gel column chromatography (PE/EA (V/V)=15/1) purify title compound is white solid (1.4g, 70%).

MS-ESI:(ESI,pos.ion)m/z：146.2[M+H-100]⁺。

Step 2) (S) -3- (5- oxo -4,5- dihydro -1,3,4- oxadiazole -2- bases) morpholine -4- t-butyl formates

Sequentially added into 100mL single port bottle (S)-N-Boc-3- formylhydrazines-morpholine (0.9g, 3.6693mmol) and THF (40mL), after mixture is stirred at room temperature uniformly, add diisopropylethylamine (1.2g, 9.3mmol), solid dissolving After completely, triphosgene (0.55g, 1.853mmol) THF (6mL) solution is slowly added to.Finish, reactant mixture is warming up to 80 DEG C and stirring reaction 4 hours.After having reacted, room temperature is cooled to, and be quenched instead with the sodium bicarbonate aqueous solution (200mL) of saturation Should, gained mixture is extracted with ethyl acetate (100mL × 3).The organic phase of merging is washed with the saline solution (100mL × 2) of saturation Wash, anhydrous sodium sulfate drying, filter, filtrate decompression concentration, gained residue is purified through silica gel column chromatography (pure EA), obtained titled Compound is colourless grease (0.78g, 78.36%).

MS-ESI:(ESI,pos.ion)m/z：172.2[M+H-100]⁺, 294.2 [M+Na]⁺。

Step 3) (S) -5- (morpholine -3- bases) -1,3,4- oxadiazoles -2 (3H) -one hydrochloride

(S) -3- (5- oxo -4,5- dihydro -1,3,4- oxadiazole -2- bases) is sequentially added into 50mL single port bottle Quinoline -4- t-butyl formates (0.25g, 0.92mmol) and ethyl acetate (5mL), after dissolving completely is stirred at room temperature in mixture, add HCl ethyl acetate solution (4mol/L, 10mL), finishes, gradually separates out white solid, continues stirring 1 hour, then filters. Filter cake washs through ethyl acetate, then is dried in vacuo, and it is white solid (0.11g, 57.5%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：172.1[M+H]⁺。

Step 4) (R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((S) -3- (5- oxo -4,5- dihydro -1,3,4- oxadiazoles - 2- yls) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (0.64g, 1.439mmol), K₂CO₃(0.5g, 3.62mmol), (S) -5- (morpholine - 3- yls) -1,3,4- oxadiazole -2 (3H) -one hydrochloride (0.3g, 1.44mmol) and absolute ethyl alcohol (20mL), reactant mixture nitrogen Gas shielded and it is stirred overnight at room temperature.After having reacted, reactant mixture is filtered, then filtrate decompression is concentrated.Gained residue With water and each 80mL dilutions of ethyl acetate, resulting solution is adjusted to pH=7 with watery hydrochloric acid, stood, layering, aqueous phase ethyl acetate (50mL × 2) extract.The organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate decompression concentration.Gained residue is through preparing Thin layer chromatography (DCM/CH₃OH (V/V)=15/1) purifying, it is yellow solid (0.18g, 23.28%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：535.1[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm):12.35(s,1H),9.62(s,1H),8.05(d,1H),7.95(d, 1H),7.43–7.38(m,2H),7.17(td,1H),6.02(s,1H),4.26(d,1H),4.03(d,1H),3.95-3.82(m, 3H),3.77–3.73(m,2H),3.50(s,3H),3.03–3.00(m,1H),2.56–2.53(m,1H)。

Embodiment 3：(R) -6- (((R) -2- (2- (1H- tetrazole -5- bases) ethyl) morpholine) methyl) -4- (the chloro- 4- fluorine of 2- Phenyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-2- (3- amino -3- oxopropyls) morpholine

(R)-N-Boc-3- morpholines propionic acid (12.0g, 46.32mmol) and tetrahydrofuran are added into 500mL there-necked flasks (300mL), dissolution of raw material and after stirring are cooled to 0 DEG C, under nitrogen protection, sequentially add triethylamine (7.0g, 69.18mmol) and ethyl chloroformate (5.7g, 60.32mmol).Reactant mixture insulated and stirred 20 minutes, then heats to 25 DEG C, and continue stirring 2 hours, be then cooled to 0 DEG C, add ammoniacal liquor (40mL), and insulated and stirred 10 minutes, then it is warming up to 25 DEG C, continue stirring 3 hours.After having reacted, concentration of reaction solution, water (250mL) dilution, water layer acetic acid second are added into residue Ester (250mL × 3) is extracted, and the organic phase of merging washed with saturated aqueous common salt (250mL × 2), then with anhydrous sodium sulfate drying, mistake Filter and be concentrated under reduced pressure, it is white solid (10g, 83.6%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：159.10[M+H-100]⁺。

Step 2：(R)-N-Boc- (2- cyano ethyls) morpholine

DMF (170mg, 2.33mmol) and acetonitrile (8mL) are sequentially added into 50mL reaction bulb, after stirring, drop Temperature is added dropwise dichloromethane (2mL) solution of oxalyl chloride (0.30g, 2.42mmol), finished, insulated and stirred 20min, then to 0 DEG C The acetonitrile (3mL) for adding (R)-N-Boc-3- morpholines propionamide (300mg, 1.16mmol) and pyridine (110mg, 1.39mmol) is molten Liquid, finish, be warming up to 25 DEG C, continue to stir 1h.After having reacted, it is quenched with water (20mL), aqueous layer with ethyl acetate (25mL × 2) Extraction, the organic layer of merging are washed with aqueous hydrochloric acid solution (1%) and saturated aqueous common salt (30mL × 2) successively, and anhydrous sodium sulfate is done Dry, national standard is simultaneously concentrated under reduced pressure, and it is light yellow oil (250mg, 89.6%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：263.10[M+Na]⁺。

Step 3：(R)-N-Boc-2- (2- (1H- tetrazole -5- bases) ethyl) morpholine

Sequentially added in 50mL single port bottle (R)-N-Boc- (2- cyano ethyls) morpholine (400mg, 1.66mmol) and DMF (6mL), after stirring and dissolving is complete, sequentially add sodium azide (860mg, 13.23mmol) and NH₄Cl(705mg, 13.30mmol), reactant mixture is warming up to 100 DEG C under nitrogen protection, and insulated and stirred 20 hours.After having reacted, reactant System is cooled to 25 DEG C, then adjusts pH to 3 with watery hydrochloric acid (2M), adds water and ethyl acetate each (50mL) dilutes, extracting and demixing, Aqueous phase is extracted with ethyl acetate (25mL × 2) again, merges the brine It (50mL × 3) of organic phase saturation, anhydrous slufuric acid Sodium is dried, and concentration, gained residue purifies through silica gel column chromatography (PE/EA (V/V)=1/1), and it is colourless to obtain title compound Grease (137mg, 29%).

MS-ESI:(ESI,pos.ion)m/z：284.30[M+H]⁺。

Step 4：(R) -2- (2- (1H- tetrazole -5- bases) ethyl) morpholine hydrochloride

In 50mL single port bottle add (R)-N-Boc-2- (2- (1H- tetrazole -5- bases) ethyl) morpholine (130mg, 0.46mmol) with ethyl acetate (5mL), stirring and dissolving, HCl ethyl acetate solution (4mol/L, 10mL) is added, is added Finish, reactant mixture was in 25 DEG C small stirring 3 hours.After having reacted, reactant mixture is concentrated under reduced pressure, obtaining title compound is Brown oil (100mg, 99.2%).

Step 5：(R) -6- (((R) -2- (2- (1H- tetrazole -5- bases) ethyl) morpholine) methyl) -4- (the chloro- 4- fluorobenzene of 2- Base) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (250mg, 0.56mmol) and potassium carbonate (183mg, 1.32mmo), (R) -2- (2- (1H- tetrazole -5- bases) ethyl) morpholine hydrochloride (100mg, 0.45mmol) and ethanol (8mL).Reactant mixture is protected in nitrogen Shield and 25 DEG C at be stirred overnight, then filter, filtrate decompression concentration, residue add water (50mL) and ethyl acetate (50mL) it is dilute Release, then pH value is adjusted to 4 with watery hydrochloric acid (2M), liquid separation, aqueous phase is extracted with ethyl acetate (50mL × 2), and the organic phase of merging is used Anhydrous sodium sulfate drying, filtering, the contracting of filtrate decompression inspissation, gained residue are pure through silica gel column chromatography (PE/EA (V/V)=2/1) Change, it is yellow solid (150mg, 60.24%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：547.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ 15.93 (s, 1H), 9.68 (s, 1H), 7.95 (d, J=3.4Hz, 2H), 7.49–7.32(m,2H),7.19–7.17(m,,1H),6.04(s,1H),3.95–3.84(m,3H),3.63–3.48(m,5H), 3.00–2.91(m,2H),2.83–2.72(m,2H),2.38(s,1H),2.07(s,1H),1.88–1.78(m,2H)。

Embodiment 4：(R) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -6- (((R) -2- (2- (thio -4,5- of 5- Dihydro -1,2,4- oxadiazole -3- bases) ethyl) morpholine) methyl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R, Z)-N-Boc-2- (3- amino -3- (oximido) propyl group) morpholine

(R)-N-Boc- (2- cyano ethyls) morpholine (2.3g, 9.6mmol), salt are sequentially added into 100mL single port bottle Sour azanol (1.0g, 14.39mmol), NaHCO₃(1.3g, 15.47mmol) and methanol (50mL), reactant mixture is at 60 DEG C Reaction 12 hours, is then cooled to 25 DEG C, refilters, and product crude product purifies through silica gel column chromatography (EA), and obtaining title compound is White solid (2.1g, 80%).

MS-ESI:(ESI,pos.ion)m/z：274.10[M+H]⁺。

Step 2：(R)-N-Boc-2- (2- (thio -4,5- dihydros -1,2,4- oxadiazoles -3- bases of 5-) ethyl) morpholine

(R, Z)-N-Boc-2- (3- amino -3- (oximido) propyl group) morpholine is sequentially added into 50mL single port bottle (200mg, 0.73mmol), thio-carbonyldiimidazole (260mg, 1.46mmol), DBU (445mg, 2.93mmol, 100mass%) With acetonitrile (10mL).Reactant mixture is protected with nitrogen, and is stirred 12 hours at 25 DEG C.After having reacted, reaction system is depressurized Concentration, residue are diluted with water (50mL), then adjust pH to 3 with watery hydrochloric acid (2M), then be extracted with ethyl acetate (50mL × 3).The organic phase of merging is washed with watery hydrochloric acid (2M, 50mL × 2), anhydrous sodium sulfate drying, concentration, and it is shallow to obtain title compound Brown solid (200mg, 86.66%).

MS-ESI:(ESI,pos.ion)m/z：216.0[M+H-100]⁺；338.1[M+Na]⁺。

Step 3:(R)-3- (2- (morpholine -2-yl) ethyl)-1,2,4- oxadiazoles-5 (4H)-thioketones hydrochloride

Sequentially added into 50mL single port bottle (R)-N-Boc-2- (2- (thio -4,5- dihydros -1,2,4- oxadiazoles of 5- - 3- yls) ethyl) morpholine (200mg, 0.63mmol), ethyl acetate (5mL), stirring and dissolving, add HCl ethyl acetate solution (4mol/L, 15mL), is finished, and reactant mixture continues stirring 2 hours.After having reacted, reaction system is concentrated under reduced pressure, obtains title Compound is light butter thing (150mg, 93.97%).MS-ESI:(ESI,pos.ion)m/z：216.2[M+H]⁺。

Step 4：(R) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -6- (((R) -2- (2- (thio -4,5- two of 5- Hydrogen -1,2,4- oxadiazole -3- bases) ethyl) morpholine) methyl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (270mg, 0.61mmol), potassium carbonate (200mg, 1.45mmol), (R) -3- (2- (morpholine -2-yl) ethyl)-1,2,4- oxadiazoles-5 (4H)-thioketones hydrochloride (150mg, 0.59mmol) and ethanol (10mL).Instead Answer mixture to be stirred 12 hours at nitrogen protection and 25 DEG C, then filter, filtrate decompression concentration, residue adds water (30mL) Diluted with ethyl acetate (50mL), then the pH value of system is adjusted to 4 with watery hydrochloric acid (2M), liquid separation, aqueous phase ethyl acetate (50mL × 3) extract, the organic phase anhydrous sodium sulfate drying of merging, filtering, the contracting of filtrate decompression inspissation, gained residue is through silicagel column (PE/EA (V/V)=1/1) purifying is chromatographed, it is yellow solid (180mg, 52.16%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：579.1[M+H]⁺。

Embodiment 5：(R) ((((5- oxo -4,5- dihydros -1,3,4- is disliked 2- (R) -2- -4- (the chloro- 4- fluorophenyls of 2-) -6- Diazole -2- bases) ethyl) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-2- (3- diazanyl -3- oxopropyls) morpholine

Into 100mL single port bottle add (R)-N-Boc-2- (3- methoxyl group -3- oxopropyls) morpholine (3.0g, 11.02mmol) with methanol (20mL), after stirring, hydrazine hydrate (4mL) is added.Reactant mixture stirs 12 at 60 DEG C Hour, 25 DEG C are then cooled to, then concentrate, residue adds water (100mL) dilution, and water layer is extracted (100mL × 3) with EA, is closed And organic phase is purified with concentration, gained residue is dried through silica gel column chromatography (PE/EA (V/V)=1/1), obtains title compound For colourless grease (2.3g, 77%).

MS-ESI:(ESI,pos.ion)m/z：174.2[M+H-100]⁺；296.3[M+Na]⁺。

Step 2：(R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,3,4- oxadiazoles -2- bases) ethyl) morpholine

Sequentially added into 100mL single port bottle (R)-N-Boc-2- (3- diazanyl -3- oxopropyls) morpholine (600mg, 2.20mmol) with THF (20mL), after stirring, DIPEA (700mg, 5.42mmol) is added, and be slowly added to triphosgene Tetrahydrofuran (6mL) solution of (325mg, 1.09mmol).Finish, reactant mixture reacts 1 hour at 80 DEG C, then cools Reaction is quenched to 25 DEG C, then with the sodium bicarbonate solution (30mL) of saturation, is next extracted with ethyl acetate (30mL × 3).Close And organic phase saturation brine It (30mL × 2), the organic phase anhydrous sodium sulfate drying of merging, filtering, filtrate It is concentrated under reduced pressure.For gained residue through preparing thin layer chromatography (PE/EA (V/V)=1/2) purifying, it is colourless to obtain title compound Grease (430mg, 65.45%).

MS-ESI:(ESI,pos.ion)m/z：322.2[M+Na]⁺。

Step 3：(R)-5- (2- (morpholine -2-yl) ethyl)-1,3,4- oxadiazoles-2 (3H) -one hydrochloride

(R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,3,4- oxadiazoles -2- are added into 50mL single port bottle Base) ethyl) morpholine (450mg, 1.50mmol), is dissolved, then be slowly added into HCl ethyl acetate solution with 5mL ethyl acetate (4mol/L,10mL).Finish, reactant mixture stirs 1 hour at 25 DEG C, is then concentrated under reduced pressure, and it is micro- to obtain title compound Brown oil (250mg, 83.47%).

MS-ESI:(ESI,pos.ion)m/z：200.2[M+H]⁺。

Step 4：(R) ((((5- oxo -4,5- dihydros -1,3,4- dislikes two to 2- to (R) -2- to -4- (the chloro- 4- fluorophenyls of 2-) -6- Azoles -2- bases) ethyl) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (470mg, 1.06mmol), potassium carbonate (366mg, 2.65mmol), (R) -5- (2- (morpholine -2-yl) ethyl) (3H) the -one hydrochloride of-1,3,4- oxadiazoles-2 (250mg, 1.06mmol) and ethanol (10mL).Reaction Mixture nitrogen protect and 25 DEG C at stir 12 hours, then filter, filtrate decompression concentration concentrates, residue with water (50mL) and EA (50mL) dilutes, and the stirring of gained mixture is lower to use ethyl acetate (50mL × 3) again with watery hydrochloric acid (2M) tune pH to neutrality, water layer Extraction, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, gained residue is through silica gel column chromatography (PE/EA (V/V)=1/2) purify, it is colourless grease (240mg, 40.19%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：563.12[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ12.02(br,1H),9.69(s,1H),8.01–7.92(m,2H),7.44– 7.37 (m, 2H), 7.19-7.15 (m, 1H), 6.04 (s, 1H), 3.89 (d, J=8.3Hz, 3H), 3.63-3.47 (m, 5H), 2.78 (t, J=10.5Hz, 2H), 2.61-2.58 (m, 2H), 2.40-2.35 (m, 1H), 2.06 (t, J=10.5Hz, 1H), 1.75–1.65(m,2H)。

Embodiment 6：(R)-methyl -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -2- (2- (5- oxo -4,5- dihydro -1,2, 4- thiadiazoles -3- bases) ethyl) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles -3- bases) ethyl) morpholine

(R, Z)-N-Boc-2- (3- amino -3- (oximido) propyl group) morpholine is sequentially added into 50mL single port bottle (510mg, 1.86mmol), thio-carbonyldiimidazole (665mg, 3.73mmol) and THF (20mL).Reactant mixture nitrogen is protected It is lower and 25 DEG C at stir 1 hour, be then concentrated under reduced pressure, gained residue adds water (50mL) and diluted, water layer with EA (100mL × 4) extract, organic phase merges, and then dries concentration.

THF (20mL) is added into above-mentioned concentration residue, after stirring, at 25 DEG C, adds boron trifluoride thereto Ether (794mg, 5.59mmol), is finished, and gained mixture stirs 3 hours, is then added sodium bicarbonate solution (50mL) and is quenched Reaction, aqueous layer with ethyl acetate (40mL × 3) extraction merge organic phase, and the organic phase of merging is with saturated aqueous common salt (50mL × 2) Washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title compound for light brown oily substance (350mg, 59.5%).

MS-ESI:(ESI,pos.ion)m/z：338.1[M+Na]⁺。

Step 2：(R)-3- (2- (morpholine -2-yl) ethyl)-1,2,4- thiadiazoles-5 (4H) -one hydrochloride

Sequentially added into 50mL single port bottle (R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles - 3- yls) ethyl) morpholine (350mg, 1.11mmol) and ethyl acetate (5mL), after stirring and dissolving is complete, add HCl acetic acid Ethyl ester solution (4mol/L, 15mL).Reactant mixture stirs 2 hours at 25 DEG C, is then concentrated under reduced pressure, and obtains title compound and is Light brown oily substance (280mg, 100%).

MS-ESI:(ESI,pos.ion)m/z：216.0[M+H]⁺。

Step 3：(R)-methyl -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -2- (2- (5- oxo -4,5- dihydros -1,2,4- Thiadiazoles -3- bases) ethyl) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (530mg, 1.19mmol), potassium carbonate (410mg, 2.97mmol), (R) -3- (2- (morpholine -2-yl) ethyl) (4H) the -one hydrochloride of-1,2,4- thiadiazoles-5 (300mg, 1.19mmol) and ethanol (10mL).Reaction Mixture stirs 12 hours under nitrogen protection and at 25 DEG C, then filters, filtrate decompression concentration, residue add water (50mL) and EA (50mL) dilutes, and then adjusts pH value to neutrality, water layer to be extracted again with ethyl acetate (50mL × 3) with watery hydrochloric acid (2M), merges Organic phase, the organic phase of merging are purified through silica gel column chromatography (PE/EA (V/V)=1/1), obtained with concentration, gained residue is dried Title compound is yellow solid (180mg, 26.1%).

MS-ESI:(ESI,pos.ion)m/z：578.05[M+H]⁺。

Embodiment 7：(R)-methyl -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -2- (2- (5- oxo -4,5- dihydro -1,2, 4- oxadiazoles -3- bases) ethyl) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- bases) ethyl) morpholine

(R, Z)-N-Boc-2- (3- amino -3- (oximido) propyl group) morpholine is sequentially added into 50mL single port bottle (200mg, 0.73mmol), carbonylic imidazole (240mg, 1.48mmol) and dioxane (10mL).Reactant mixture is protected in nitrogen Stirring 12 hours under shield and at 110 DEG C, be then concentrated under reduced pressure, gained residue adds water (100mL) and EA (100mL) dilutions, Gained mixture adjusts pH to 4 with watery hydrochloric acid (2M), and water layer is extracted with ethyl acetate (50mL × 3) again, merges organic phase, merging Organic phase is washed with watery hydrochloric acid (50mL × 2) and saturated aqueous common salt (50mL × 2) respectively, organic layer anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration, it is brownish oil (150mg, 68.5%) to obtain title compound.MS-ESI:(ESI, pos.ion)m/z：200.20[M+H-100]⁺；322.20[M+Na]⁺。

Step 2：(R)-3- (2- (morpholine -2-yl) ethyl)-1,2,4- oxadiazoles-5 (4H) -one hydrochloride

Sequentially added in 50mL single port bottle (R)-N-Boc-2- (2- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles - 3- yls) ethyl) morpholine (130mg, 0.43mmol) and ethyl acetate (5mL), after stirring and dissolving is complete, add HCl acetic acid Ethyl ester solution (4mol/L, 10mL), reactant mixture are stirred 3 hours for 25 DEG C, are then concentrated under reduced pressure again, and it is brown to obtain title compound Color grease (100mg, 97.7%).

MS-ESI:(ESI,pos.ion)m/z：200.1[M+H]⁺；

Step 3：(R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -2- (2- (5- oxo -4,5- dihydro -1,2,4- Evil bis- Azoles -3- bases) ethyl) morpholino) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (188mg, 0.42mmol), potassium carbonate (150mg, 1.08mmol), (R) -3- (2- (morpholine -2-yl) ethyl) (4H) the -one hydrochloride of-1,2,4- oxadiazoles-5 (100mg, 0.42mmol) and ethanol (10mL).Reaction Mixture stirs 12 hours with 25 DEG C under nitrogen protection, then filters, filtrate decompression concentration, residue add water (50mL) and EA (50mL) is diluted, and then adjusting pH value with watery hydrochloric acid (2M), water layer is extracted with ethyl acetate (50mL × 3) again, is merged organic to 4 Phase, the organic phase anhydrous sodium sulfate drying of merging, filters and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EA (V/V)=1/2) purify, it is yellow solid (150mg, 62.8%) to obtain title compound.

¹HNMR(400MHz,CDCl₃) δ 9.57 (s, 1H), 7.86 (d, J=3.1Hz, 1H), 7.48 (d, J=3.1Hz, 1H),7.27(s,1H),7.18–7.10(m,1H),6.95–6.88(m,1H),6.21(s,1H),4.12–4.01(m,2H), 3.96–3.85(m,2H),3.82–3.75(m,1H),3.62(s,3H),2.91–2.79(m,2H),2.78–2.64(m,2H), 2.63–2.55(m,1H),2.24–2.15(m,1H),1.95–1.84(m,1H),1.82–1.73(m,1H)。

Embodiment 8 (R) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -6- (((R) -3- (thio -4,5- two of 5- Hydrogen -1,2,4- oxadiazole -3- bases) morpholino) methyl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R, Z)-N-Boc-3- (N'- hydroxy formamidines) morpholine

(R)-N-Boc-3- cyano group morpholine (500mg, 2.36mmol), hydrochloric acid hydroxyl are sequentially added into 100mL single port bottle Amine (196mg, 2.82mmol), NaHCO₃(277mg, 3.30mmol) and methanol (10mL).Reactant mixture reacts 3 at 60 DEG C Hour, then it is concentrated under reduced pressure, concentrated residues thing is beaten with ethyl acetate (15mL), filtering, and filtrate concentration, obtaining title compound is White solid (520mg, 90.00%).MS-ESI:(ESI,pos.ion)m/z：246.2[M+H]⁺。

Step 2：(R)-N-Boc-3- (thio -4,5- dihydros -1,2,4- oxadiazoles -3- bases of 5-) morpholine

Sequentially added into 50mL single port bottle (R, Z)-N-Boc-3- (N'- hydroxy formamidines) morpholine (200mg, 0.82mmol), thio-carbonyldiimidazole (300mg, 1.68mmol), DBU (500mg, 3.29mmol) and acetonitrile (10mL).Reaction Mixture stirs 12 hours at 25 DEG C, is then concentrated under reduced pressure, and residue adds water (50mL) and ethyl acetate (50mL) dilution, The pH value of system is adjusted to 3 with watery hydrochloric acid (2M) again, liquid separation, aqueous phase is extracted with ethyl acetate (50mL × 2), merges organic phase point Do not washed and the brine It of saturation with watery hydrochloric acid (2M) (50mL × 2), then subtracted with anhydrous sodium sulfate drying, filtering, filtrate Inspissation contracting is pressed, it is brown solid (200mg, 85.4%) to obtain title compound.MS-ESI:(ESI,pos.ion)m/z：188.1 [M+H]⁺。

Step 3：(R) -3- (morpholine -3- bases) -1,2,4- oxadiazoles -5 (4H)-thioketones hydrochloride

(R)-N-Boc-3- (thio -4,5- dihydros -1,2,4- oxadiazoles -3- of 5- are sequentially added into 50mL single port bottle Base) morpholine (200mg, 0.70mmol) and ethyl acetate (5mL), after stirring and dissolving is complete, add HCl ethyl acetate solution (4mol/L,10mL).Reactant mixture stirs 2 hours at 25 DEG C, is then concentrated under reduced pressure, and it is white solid to obtain title compound (150mg, 96.33%).

MS-ESI:(ESI,pos.ion)m/z：188.1[M+H]⁺；

Step 4：(R) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazol-2-yl) -6- (((R) -3- (thio -4,5- dihydros of 5- - 1,2,4- oxadiazole -3- bases) morpholino) methyl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (300mg, 0.67mmol), potassium carbonate (231mg, 1.67mmol), (R) -3- ( Quinoline -3- bases) -1,2,4- oxadiazoles -5 (4H)-thioketones hydrochloride (150mg, 0.67mmol) and ethanol (10mL).Reactant mixture Stir 12 hours at 25 DEG C, then filter, filtrate decompression concentration, residue adds water (50mL) and EA (50mL) to dilute, then Adjusting pH value with watery hydrochloric acid (2M), water layer is extracted with ethyl acetate (50mL × 3) again, merges organic phase, and the organic phase of merging is used to 3 Anhydrous sodium sulfate drying, filter and concentrate, gained residue purifies through silica gel column chromatography (PE/EA (V/V)=1/5), obtains title Compound is yellow solid (153mg, 41.4%).

MS-ESI:(ESI,pos.ion)m/z：552.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ10.15–9.75(m,1H),8.08–7.86(m,2H),7.50–7.28(m, 2H),7.26–7.08(m,1H),6.04–5.91(m,1H),4.90–4.70(m,2H),4.07–3.78(m,2H),3.72–3.63 (m,1H),3.62–3.43(m,5H),2.93–2.69(m,2H)。

Embodiment 9 (R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -3- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles - 3- yls) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-3- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles -3- bases) morpholine

Sequentially added into 50mL single port bottle (R, Z)-N-Boc-3- (N'- hydroxy formamidines) morpholine (300mg, 1.22mmol), thio-carbonyldiimidazole (430mg, 2.41mmol) and THF (10mL).Reactant mixture under nitrogen protection and 25 DEG C are stirred 1 hour, then add water (30mL) and ethyl acetate (20mL) dilution, liquid separation extraction, and aqueous phase uses ethyl acetate again (20mL × 2) extract, and merge organic phase.Organic phase is washed with saturated aqueous common salt (50mL × 2) again, organic relevant anhydrous slufuric acid Sodium is dried, and is filtered and is concentrated under reduced pressure, obtains light brown oily substance.

Above-mentioned grease is dissolved in THF (10mL), at 25 DEG C, is slowly added to BFEE thereto (520mg,3.66mmol).Finishing, reactant mixture stirs 2 hours at 25 DEG C, then adds water (30mL) and reaction is quenched, then Being extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase washed with saturated aqueous common salt (30mL × 2), then with anhydrous sulphur Sour sodium is dried, and is filtered and is concentrated under reduced pressure, it is light brown oil product (200mg, 56.92%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：188.2[M+H-100]⁺；310.2[M+Na]⁺。

Step 2：(R) -3- (morpholine -3- bases) -1,2,4- thiadiazoles -5 (4H) -one hydrochloride

(R)-N-Boc-3- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles -3- are sequentially added into 50mL single port bottle Base) morpholine (200mg, 0.70mmol) and ethyl acetate (5mL), after original paper dissolving completely, it is slow added into HCl ethyl acetate Solution (4mol/L, 10mL), is finished, and reactant mixture was in 25 DEG C small stirring 2 hours.After having reacted, reactant mixture is depressurized Concentration, it is that title compound is white solid (150mg, 96.33%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：188.1[M+H]⁺。

Step 3：(R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -3- (5- oxo -4,5- dihydro -1,2,4- thiadiazoles - 3- yls) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (300mg, 0.67mmol), potassium carbonate (231mg, 1.67mmol), (R) -3- ( Quinoline -3- bases) (4H) the -one hydrochloride of -1,2,4- thiadiazoles -5 (150mg, 0.67mmol) and ethanol (10mL).Reactant mixture exists Nitrogen protect and 25 DEG C at stir 12 hours, then filter, filtrate decompression concentration, residue addition water (50mL) and ethyl acetate (50mL) is diluted, then adjusts pH value to 3 with watery hydrochloric acid (2M), and liquid separation, aqueous phase is extracted with ethyl acetate (50mL × 2), merging Organic phase anhydrous sodium sulfate drying, filtering, the contracting of filtrate decompression inspissation, gained residue is through silica gel column chromatography (PE/EA (V/V) =1/1) purify, it is yellow solid (180mg, 48.71%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：552.2[M+H]⁺；

Embodiment 10：(R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -3- (5- oxo -4,5- dihydro -1,2,4- Evil bis- Azoles -3- bases) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

Synthetic route：

Step 1：(R)-N-Boc-3- (5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) morpholine

Sequentially added into 50mL single port bottle (R, Z)-N-Boc-3- (N'- hydroxy formamidines) morpholine (500mg, 2.04mmol), carbonyl dimidazoles (1.0g, 6.20mmol) and dioxane (15mL).Reactant mixture stirs 12 at 110 DEG C Hour, then filter, filtrate decompression concentration, residue adds water (50mL) and EA (50mL) to dilute, and is then adjusted with watery hydrochloric acid (2M) PH value is to 3, and liquid separation, water layer is extracted with ethyl acetate (50mL × 3) again, merges organic phase, and organic phase point uses watery hydrochloric acid successively The saline solution of (50mL × 2) and saturation (50mL × 2) washs, then with anhydrous sodium sulfate drying, filters and be concentrated under reduced pressure, obtain title Compound is brownish oil (320mg, 57.87%).

MS-ESI:(ESI,pos.ion)m/z：172.2[M+H-100]⁺；294.2[M+23]⁺。

Step 2：(R) -3- (morpholine -3- bases) -1,2,4- oxadiazoles -5 (4H) -one hydrochloride

(R)-N-Boc-3- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- are sequentially added into 50mL single port bottle Base) morpholine (450mg, 1.66mmol) and ethyl acetate (7mL), after stirring and dissolving is complete, add HCl ethyl acetate solution (4mol/L,20mL).Finish, reactant mixture stirs 2 hours at 25 DEG C, is then concentrated under reduced pressure, and obtains title compound as white Solid (320mg, 92.9%).

MS-ESI:(ESI,pos.ion)m/z：172.1[M+H]⁺。

Step 3：(R) -4- (the chloro- 4- fluorophenyls of 2-) -6- (((R) -3- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles - 3- yls) morpholine) methyl) -2- (thiazol-2-yl) -1,4- dihydro-pyrimidin -5- methyl formates

(R) -6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (thiazole -2- are sequentially added into 50mL single port bottle Base) -1,4- dihydro-pyrimidin -5- methyl formates (685mg, 1.54mmol), potassium carbonate (530mg, 3.83mmol), (R) -3- ( Quinoline -3- bases) (4H) the -one hydrochloride of -1,2,4- oxadiazoles -5 (320mg, 1.54mmol) and ethanol (10mL).Reactant mixture exists Stir 12 hours under nitrogen protection and at 25 DEG C, then filter, filtrate decompression concentration, residue adds water (50mL) and EA (50mL) Dilution, then adjusting pH value with watery hydrochloric acid (2M), layering, water layer is extracted with ethyl acetate (50mL × 3) again, is merged organic to 6~7 Phase, the organic phase anhydrous sodium sulfate drying of merging, filters and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EA (V/V/)=1/1) purify, it is yellow solid (240mg, 29.11%) to obtain title compound.

MS-ESI:(ESI,pos.ion)m/z：536.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ12.40(br,1H),9.58(s,1H),8.13–7.83(m,2H),7.52– 7.23 (m, 2H), 7.27-7.04 (m, 1H), 6.03 (s, 1H), 4.21-4.01 (m, 2H), 3.91 (d, J=2.9Hz, 3H), 3.79–3.69(m,2H),3.50(s,3H),3.08–2.96(m,1H)。

Biological activity test

Test 1：Anti-HBV activity EC₅₀Method of testing

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

Experimental method：

QPCR detects cell culture fluid viral DNA content and calculates concentration (EC when compounds on viral suppresses half₅₀), Specific experiment method is as follows：

HepG2.2.15 cells are inoculated with to 96 porocyte culture plates (40,000 cells/well), are added within second day containing different dense Spend cell culture fluid processing cell (final concentration of 16.4 μM of compound highest, 3 times of gradient dilutions, 9 dilutions of testing compound Point, duplicate hole).The nutrient solution containing medicine to be measured is changed within 5th day, culture supernatant is collected within the 8th day and extracts the DNA in supernatant.

Viral DNA extracts：With reference to QIAamp 96DNA Blood Kit (QIAGEN 51161).

Quantitative PCR：Reaction mixture is configured according to PCR system, it is (quantitative special that mixed liquor is added into 96 hole PCR reaction plates With)；(standard items template maximum concentration is 1 × 10 to the standard items template that addition has diluted in proportion⁷Copies/ul, 9 times of dilutions 7 It is individual, least concentration 10copies/ul)；Add sample form；96 orifice plates are sealed up with shrouding film；Transported according to setting program Row quantitative PCR apparatus.

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

Calculate EC of the compound to hbv replication₅₀Value：Using the analysis softwares of GraphPad Prism 5, from " four parameters this Meaning equation " calculates EC₅₀Value.

Table:2：EC of the compound to hbv replication₅₀Value

Embodiment	EC₅₀
		Embodiment 1	365.65nmol
Embodiment 3	250.45nmol

Conclusion：Experimental data shows that the compounds of this invention has preferable inhibitory activity to HBV, in terms of resisting HBV virus There is good application prospect.

Test 2：Cell toxicant and selectivity index

Test compound cell toxicant and selection exponential experiment

Experimental method：

HepDE cells are laid in 96 orifice plates (5 × 103 cell per well), are handled using compound for determining EC50.Processing After 5 days, 20uL CCK-8 reagents detection cell survival rate is added, after 37 DEG C are incubated 2 hours, ELIASA detection 450nm and 630nm The absorbance value of wavelength, determining every kind of compound causes the concentration (CC50) of host cell lethal 50%.

The relative effectiveness of inducing cell death and compound suppressing virus replication be defined as selecting index (CC50 values/ EC50 values).Based on CC50 and EC50 data, it is determined that selection index.

Table:3：The CC of Compound cellular poison₅₀Value

Embodiment	CC₅₀
		Embodiment 1	>150μmol
Embodiment 3	>150μmol

Conclusion：Cell toxicant and selectivity index experimental data show, the compounds of this invention small toxicity.

Test 3：Pharmacokinetic studies of the compounds of this invention in beasle dog, mouse, rat

(1) beasle dog PK test experiments

PK determination experiment method of the compound in beasle dog body：

The oral gavage of beasle dog gives 2.5mg/kg or 5mg/kg or intravenous administration 1mg/kg or 2mg/kg test Compound.

Temporally point (0.083,0.25,0.5,1,2,4,6,8 and 24 hour) venous blood collection after administration, be collected in plus EDTA-K₂Anticoagulant tube in.Plasma sample is after liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, with multiple reaction from Son monitoring (MRM) mode carries out quantitative analysis.Pharmacokinetics is calculated using the softwares of WinNonlin 6.3 with non-compartment model method to join Number.

Conclusion：Medicine shows that the compounds of this invention has preferable pharmacokinetic property for experimental data, in Anti-HBV activity disease Malicious aspect has good application prospect.

(2) mouse PK test experiments：

PK determination experiment method of the compound in Mice Body：

ICR its mouse oral gavages give 10mg/kg or the test compound through tail vein injection 2mg/kg or 10mg/kg. Temporally point (0.083,0.25,0.5,1,2,4,6,8 and 24 hour) orbital vein is taken a blood sample after administration, is collected in and is added EDTA-K₂ Anticoagulant tube in.Plasma sample is after liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, with multiple reaction ion monitoring (MRM) mode carries out quantitative analysis.Pharmacokinetic parameters are calculated with non-compartment model method using the softwares of WinNonlin 6.1.

(3) SD P of Rats K test experiments：

PK determination experiment method of the compound in SD rat bodies：

Rat oral gavage gives 2.5mg/kg or 5mg/kg or intravenous administration 1mg/kg test compound.

Temporally point (0.083,0.25,0.5,1,2,5,7 and 24 hour) venous blood collection after administration, is collected in plus EDTA- K₂Anticoagulant tube in.Plasma sample is after liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, with multiple reaction ion monitoring (MRM) mode carries out quantitative analysis.Pharmacokinetic parameters are calculated with non-compartment model method using the softwares of WinNonlin 6.3.

Test 4：Different genera hepatomicrosome stability test

Hepatomicrosome stability experiment method of the compound in different genera：

The μ L of mixed solution 30 of blank solution and hepatomicrosome are added into 96 orifice plates, 15 μ L are added in each hole containing to be measured The buffer solution of compound, it is parallel to make two parts of samples.Temporally point adds 15 μ L NADPH solution after 37 DEG C of preincubate 10min (8mM), final concentration of 1 μM of testing compound, the concentration of hepatomicrosome is 0.1mg/mL, the final concentration of 2mM of NADPH.Respectively Incubation 0,15,30,60min, incubation add 150 μ L acetonitriles (containing the internal standard) in mixed system after terminating.Sample after dilution in acetonitrile Product centrifuge 5min under 4000rpm, take 150 μ L of supernatant liquid to be analyzed to LC-MS/MS.

Conclusion：Hepatomicrosome stability experiment as shown by data, the compounds of this invention stability are preferable.

Test 5：Solubility test method

The experimental test procedures of compound solubility：

Unless otherwise specified, weigh the test sample for being ground into fine powder or measure liquid test sample, as 25 DEG C of ± 2 DEG C of constant volumes In the solvent of amount, every 5min strength shaking 30s, the dissolving situation in 30min is observed, such as without visually visible particles of solute Or during drop, that is, it is considered as and is completely dissolved.Easily dissolving means that solute 1g (mL) can dissolve in solvent is less than 1mL；

It is readily soluble to mean that solute 1g (mL) dissolve in solvent 1~less than 10mL；

Dissolving means that solute 1g (mL) can dissolve in solvent 10~less than 30mL；

It is slightly molten to mean that solute 1g (mL) dissolve in solvent 30~less than 100mL；

Slightly soluble means that solute lg (mL) can dissolve in solvent 100~less than 1000mL；

Soluble,very slightly means that solute 1g (mL) can dissolve in solvent 1000~less than 10000mL；

It is almost insoluble or insoluble mean that solute 1g (mL) can not be completely dissolved in solvent 10000mL.

Conclusion：Solubility experiment as shown by data, the compounds of this invention dissolubility are preferable.

Test 6：HERG method of testings

The experimental test procedures of compounds on cardiac

Sequentially added in 384 orifice plates compound/positive reference substance/negative controls, the membrane-bound fragment containing hERG passages, There is the tracer of high affinity with hERG passages, 25 DEG C, 250rpm is incubated 4 hours.Each hole is measured with multi-function microplate reader Fluorescence polarization value, calculate compound to the relative inhibition and 50% inhibition concentration (IC of hERG passages₅₀)。

Conclusion：HERG test experiments as shown by data, small toxicity of the compounds of this invention to heart.

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

Claims

1. a kind of compound as shown in formula (I) or (Ia),

Or its enantiomter, diastereoisomer, dynamic isomer, solvate or pharmaceutically acceptable salt,

Wherein, R is-X-Z；

X is-(CR⁷R^7a)_t- or-C (=O)-；

Z is the subformula shown in formula (II)：

W is CR⁷Or N；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

Each R¹It independently is hydrogen, F, Cl, Br, I, cyano group, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, first ammonia Base, ethylamino, nitro, 4- trifluoromethyls, (trifluoromethyl) phenyl of 3,5- bis- or trifluoromethyl；

R²For hydrogen, alkyl, alkenyl, alkynyl, aryl alkyl, heteroaryl alkyl, cycloalkyl, cycloalkyl-alkyl or cycloheteroalkylalkyl；

R³For C_6-10The heteroaryl of aryl or 5-6 annular atom composition, wherein, the C_6-10What aryl and 5-6 annular atom formed Heteroaryl can be with individually optional by 1,2,3,4 or 5 selected from fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyanogen Base, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the aryl of haloalkyl substitution, the virtue of halogen substitution The substituent of base or trifyl is substituted；

Each R⁴It independently is hydrogen, deuterium, F, Cl, Br or C_1-4Alkyl；

R⁵For-(CR⁹R^9a)_m-R⁸；

R⁶For alkyl, alkenyl or alkynyl；

R⁸For heteroaryl or heterocyclic radical, wherein, described aryl and heteroaryl with individually optional can be selected from by 1,2,3,4 or 5 Fluorine, chlorine, bromine, iodine, (=O), (=S), alkyl, alkoxy, cyano group, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoro Aryl, the aryl of halogen substitution or the substituent of trifyl that methoxyl group, haloalkyl substitute are substituted；

N is 0,1,2,3,4 or 5；

Each t independently is 0,1 or 2；

Each m independently is 0,1,2,3 or 4；

F is 0,1,2,3 or 4；

Q is 0,1 or 2.

2. compound according to claim 1, wherein：

Z is the subformula shown in formula (III)：

R⁵For-(CR⁹R^9a)_m-R⁸；

Y is-(CR⁷R^7a)_t- ,-O- ,-S (=O)_q- or-NR⁶-；

R⁶For C_1-4Alkyl；

R⁸The heteroaryl or the heterocyclic radical of 5-6 annular atom composition formed for 5-6 annular atom, wherein, 5-6 described ring is former The heterocyclic radical of molecular heteroaryl and 5-6 annular atom composition can with individually optional by 1,2,3,4 or 5 selected from (=O), (=S), C_1-4Alkyl or C_1-4The substituent of alkoxy is substituted；

3. compound according to claim 1, wherein：

The subformula that the Z is as follows：

Each R⁵It independently is-(CR⁹R^9a)_m-R⁸；

R⁶For C_1-4Alkyl；

Each R⁸The heterocyclic radical that the heteroaryl of 5-6 annular atom composition or 5-6 annular atom form independently is, wherein described 5-6 The heteroaryl of individual annular atom composition and the heterocyclic radical of 5-6 annular atom composition with individually optional can be selected from by 1,2,3,4 or 5 (=O), (=S) or C_1-4The substituent of alkyl is substituted.

4. compound according to claim 1, wherein, the R⁸For following subformula：

5. compound according to claim 1, wherein, the R²For methyl, ethyl, n-propyl or isopropyl；

R³For phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl or imidazole radicals, wherein, described benzene Base, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl and imidazole radicals can with individually optional by 1,2,3,4 or 5 substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl are substituted.

6. compound according to claim 1, it has the structure as shown in formula (IV) or (IVa),

Or its enantiomter, diastereoisomer, dynamic isomer, solvate or pharmaceutically acceptable salt, wherein,

The Z is the subformula shown in formula (III)：

Y is-(CR⁷R^7a)_t- or-O-；

Each R¹It independently is hydrogen, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyano group, trifluoromethyl or methoxyl group；

R²For methyl, ethyl, n-propyl or isopropyl；

R³For phenyl, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl or imidazole radicals, wherein, described benzene Base, thiazolyl, thienyl, pyridine radicals, pyrazolyl, oxazolyl, furyl and imidazole radicals can with individually optional by 1,2,3,4 or 5 substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl are substituted；

R⁵For-(CR⁹R^9a)_m-R⁸；

R⁸For

Each n independently is 0,1,2,3,4 or 5；

T is 0,1 or 2；

M is 0,1,2,3 or 4；

F is 0,1,2 or 3.

7. the compound according to claim 1 or 6, wherein,

The Z is selected from following subformula：

8. compound according to claim 1, it includes the structure of one of：

Or its enantiomter, diastereoisomer, dynamic isomer, solvate or it can pharmaceutically connect The salt received.

9. a kind of pharmaceutical composition, include the compound described in claim any one of 1-8, and its pharmaceutically acceptable carrier Or combinations thereof.

10. pharmaceutical composition according to claim 9, it further includes other Anti-HBV drugs.

11. pharmaceutical composition according to claim 10, wherein other Anti-HBV drugs be HBV AG14361s, Immunomodulator or interferon.

12. pharmaceutical composition according to claim 11, wherein other Anti-HBV drugs are Lamivudine, for than husband Fixed, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, grace His bent shore, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta- 1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a - A, sizofiran, Euforavac, peace Puli be near, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol or Propagermanium.

13. the pharmaceutical composition described in compound or claim any one of 9-12 described in claim any one of 1-8 is being made Purposes in the medicine of standby prevention, treatment or mitigation patient's viral disease.

14. purposes according to claim 13, wherein the viral disease refers to hepatitis B infection or hepatitis B Disease caused by infection.

15. purposes according to claim 14, wherein the hepatitis B infection causes disease to refer to that hepatic sclerosis or liver are thin Born of the same parents' canceration.