CN103664897B

CN103664897B - Dihydropyrimidines and its application in medicine

Info

Publication number: CN103664897B
Application number: CN201310391314.4A
Authority: CN
Inventors: 张英俊; 任青云; 刘辛昌; 王超磊; S·戈尔德曼
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2012-09-01
Filing date: 2013-08-31
Publication date: 2018-04-03
Anticipated expiration: 2033-08-31
Also published as: CN103664897A

Abstract

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

Description

Dihydropyrimidines and its application in medicine

Invention field

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

Background of invention

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

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

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

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

Abstract of invention

The present invention relates to novel dihydropyridine compound and treatment and the method for prevention HBV infection.

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

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

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

A is key ,-O- ,-S- or-a NR⁵-；

R is-X-Z；

X is-(CR⁷R^7a)_m- or-C (=O)-；

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

Wherein, B is a key ,-(CR⁷R^7a)_m- or-C (=O)-；

W is CR⁷Or N；

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

R¹For aryl or heteroaryl；

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

R³For substituted aryl or substituted heteroaryl, wherein the substituent on the aryl or heteroaryl can be any Selected from-(CR⁷R^7a)_m- S (=O)_q-R⁸、-(CR⁷R^7a)_m- S (=O)_q-N(R⁸R^8a) or-(CR⁷R^7a)_m- C (=O) O-R⁸；

R⁴For hydrogen, deuterium or C₇-C₄Alkyl；

R⁵For hydrogen, deuterium, alkyl ,-(CR⁷R^7a)_m- C (=O) O-R⁸, alkenyl or alkynyl；

R⁶For hydrogen, deuterium, alkyl ,-(CR⁷R^7a)_m- C (=O) O-R⁸、-(CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m- C (= O)-(CR⁷R^7a)_m-OR⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m-O-R⁸、-(CR⁷R^7a)_m- C (=O)- (CR⁷R^7a)_m-N(R⁸R^8a), alkenyl or alkynyl；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, haloalkyl, alkyl or aryl；Or R⁷、R^7aBe attached thereto C atoms form cycloalkyl together；

Each R⁸And R^8aIndependently be hydrogen, deuterium, alkyl, haloalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, Cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or cycloheteroalkylalkyl；

Each R⁹It independently is hydrogen, deuterium, alkyl, amino, cyano group ,-(CR⁷R^7a)_m- S (=O)_q-R⁸、-(CR⁷R^7a)_m- OS (= O)_q-R⁸Or-(CR⁷R^7a)_m- S (=O)_qO-R⁸；

Each n independently is 0,1,2 or 3；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2；With

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

Some embodiments wherein：

Z is C₆-C₁₀Aryl or 5-6 unit's heteroaryls, the aryl or heteroaryl can by one or more selected from hydrogen, deuterium, Fluorine, chlorine, bromine, iodine, C₁-C₄Alkyl, cyano group, hydroxyl, nitro, amino, the substituent of trifluoromethyl or trifluoromethoxy are substituted, Or Z is the subformula as shown in formula (III)：

Wherein, B is a key ,-(CR⁷R^7a)_m- or-C (=O)-；

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

R⁶For hydrogen, deuterium, C₁-C₄Alkyl, C₂-C₄Alkenyl ,-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m-O- R⁸、-(CR⁷R^7a)_m- C (=O) O-R⁸、-(CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-N(R⁸R^8a)、- (CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-OR⁸Or C₂-C₄Alkynyl；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, C₁-C₆Alkyl, C₁-C₄Haloalkyl or C₆-C₁₀Aryl；Or R⁷、 R^7aC is formed together with the C atoms being attached thereto₃-C₈Cycloalkyl；

Each R⁸And R^8aIt independently is hydrogen, deuterium, C₁-C₆Alkyl, C₁-C₄Haloalkyl, C₆-C₁₀Aryl, C₆-C₁₀Aryl C₁-C₄ Alkyl, C₁-C₉Heteroaryl, C₁-C₉Heteroaryl C₁-C₄Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Cycloalkyl C₁-C₄Alkyl, C₂-C₁₀Heterocycle Base or C₂-C₁₀Heterocyclic radical C₁-C₄Alkyl；

Each R⁹It independently is hydrogen, deuterium, C₁-C₄Alkyl, amino, cyano group ,-(CR⁷R^7a)_m- S (=O)_q-R⁸、-(CR⁷R^7a)_m-OS (=O)_q-R⁸Or-(CR⁷R^7a)_m- S (=O)_qO-R⁸；

Each n independently is 0,1,2 or 3；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2.

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

Each R⁶It independently is hydrogen, deuterium, methyl, ethyl, propyl group ,-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m- O-R⁸、-(CR⁷R^7a)_m- C (=O) O-R⁸、-(CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-N(R⁸R^8a)、 Or-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-OR⁸；

Each R⁷And R^7aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls, 1- methyl-props Base, phenyl, or R⁷、R^7aCyclopropyl is formed together with the C atoms being attached thereto；

Each R⁸And R^8aIt independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls or 1- methyl Propyl group；

Each R⁹It independently is hydrogen, deuterium, amino, cyano group, methyl, ethyl or propyl group；

Each n independently is 0,1 or 2；

In some embodiments, R³For substituted C₆-C₁₀Aryl or substituted 5-6 unit's heteroaryls, wherein the aryl Or the substituent on heteroaryl can arbitrarily be selected from-(CR⁷R^7a)_m- S (=O)_q-R⁸、-(CR⁷R^7a)_m- S (=O)_q-N(R⁸R^8a)、 Or-(CR⁷R^7a)_m- C (=O) O-R⁸。

In other embodiment, R³For following subformula：

Wherein each X¹It independently is S, NR¹¹Or CR¹²R^12a；

Each X², X³, X⁴, X⁵, and X⁶N or CR can independently be with identical or different¹²；Wherein, X², X³, X⁴, X⁵, and X⁶ At most simultaneously four are N；

Each R¹⁰It independently is-(CR⁷R^7a)_m- C (=O) O-R⁸；

Each R¹¹It independently is hydrogen, deuterium or-(CR⁷R^7a)_m- C (=O) O-R⁸；

Each R¹²And R^12aIt independently is hydrogen, deuterium or-(CR⁷R^7a)_m- C (=O) O-R⁸；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, F, Cl, Br, C₁-C₄Alkyl, C₁-C₄Haloalkyl or C₆-C₁₀Aryl；Or R⁷、 R^7aC is formed together with the C atoms being attached thereto₃-C₈Cycloalkyl；

Each R⁸It independently is hydrogen, deuterium, C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₆-C₁₀Aryl, C₆-C₁₀Aryl C₁-C₄Alkyl, C₁-C₉Heteroaryl, C₁-C₉Heteroaryl C₁-C₄Alkyl, C₃-C₁₀Cycloalkyl, C₃-C₁₀Cycloalkyl C₁-C₄Alkyl, C₂-C₁₀Heterocyclic radical or C₂-C₁₀Heterocyclic radical C₁-C₄Alkyl；

Each m independently is 0,1,2,3 or 4；

Each p independently is 1 or 2；

In other embodiments, R³For following subformula：

Each R¹⁰It independently is-(CR⁷R^7a)_m- C (=O) OR⁸；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 1- methyl-propyls, 2- methyl-props Base, isopropyl, phenyl, or R⁷、R^7aCyclopropyl is formed together with the C atoms being attached thereto；

Each R⁸It independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl, the tert-butyl group, 2- methyl-propyls or 1- methyl-propyls；

Each m independently is 0,1,2,3 or 4；

Each p independently is 1 or 2.

In some embodiments,

R⁷For C₆-C₁₀Aryl, wherein the aryl can be monosubstituted or identical or different by fluorine, deuterium, chlorine, nitro or bromine It is polysubstituted；

R²For hydrogen, deuterium or C₁-C₄Alkyl；

R⁵For hydrogen, deuterium or C₁-C₄Alkyl.

In other embodiment,

R¹For phenyl, wherein the phenyl can be monosubstituted or identical or different take by fluorine, deuterium, chlorine, nitro or bromine more Generation；

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

Or it is subjected on its enantiomter, diastereoisomer, dynamic isomer, hydrate, solvate or medicine word Salt, wherein：

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

R²For hydrogen, deuterium or C₁-C₄Alkyl；

R³For substituted aryl or substitution 5-6 unit's heteroaryls；Substituent on wherein described aryl or heteroaryl can appoint Meaning is selected from-(CR⁷R^7a)_m- C (=O) O-R⁸；

R⁶For hydrogen, deuterium, C₁-C₄Alkyl ,-(CR⁷R^7a)_m- C (=O) O-R⁸、-(CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m-C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m-O-R⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-N(R⁸R^8a) or-(CR⁷R^7a)_m-C (=O)-(CR⁷R^7a)_m-OR⁸；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₆-C₁₀Aryl；Or R⁷、R^7aTherewith Connected C atoms form C together₃-C₈Cycloalkyl；

Each R⁸And R^8aIt independently is H, deuterium or C₁-C₆Alkyl；

Each R¹³It independently is fluorine, chlorine, nitro or bromine；

Each p independently is 1 or 2；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2.

In some embodiments, R⁶For hydrogen, deuterium, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group ,- (CR⁷R^7a)_m-C(=O)O-R⁸、-(CR⁷R^7a)_m-C(=O)R⁸、-(CR⁷R^7a)_m-C(=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m-O-R⁸、- (CR⁷R^7a)_m-C(=O)-(CR⁷R^7a)_m-N(R⁸R^8a) or-(CR⁷R7^a)_m-C(=O)-(CR⁷R^7a)_m-OR⁸；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls, 2- Methyl-propyl, phenyl；Or R⁷、R^7aCyclopropyl is formed together with the C atoms being attached thereto；

Each R⁸And R^8aIndependently be H, deuterium, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, 1- methyl-propyls or Person's 2- methyl-propyls；

In other embodiments, R³Independently selected from following subformula：

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

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

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

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

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

In certain embodiments, the salt of the present invention obtained by alkali is alkali metal, alkaline-earth metal, ammonium or N⁺ (R¹⁴)₄Salt.

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

Wherein, in other embodiment, R of the present invention¹⁴It is H, deuterium, C₁-C₄Alkyl, C₆-C₁₀Aryl, C₆- C₁₀Aryl C₁-C₄Alkyl etc..

On the one hand, the present invention relates to pharmaceutical composition, comprising compound of the present invention, and its it is pharmaceutically acceptable Carrier, excipient, diluent, assistant agent, medium or combinations thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Detailed description of the invention book

Definition and general terms

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

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

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

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

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

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

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

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

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

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

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

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

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

Term " halogen " refers to F, C1, Br or I.

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

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

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

Term " aryl " can be used alone or the big portion as " aralkyl " " aralkoxy " or " aryloxy alkyl " Point, represent altogether containing the monocyclic of 6-14 yuan of rings, it is bicyclic, and the carbocyclic ring system of three rings, wherein, at least one member ring systems are aromatic series , each of which member ring systems include 3-7 yuan of rings, and only an attachment point is connected with the remainder of molecule.Term " virtue Base " can be exchanged with term " aromatic rings " and used, as aromatic rings can include phenyl, naphthyl and anthracene.And the aryl can be with It is substituted or non-substituted, wherein substituent can be, but be not limited to, hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkane Amino, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl.

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Represent altogether containing the monocyclic of 5-14 yuan of rings, it is bicyclic, and three-ring system, wherein at least one member ring systems are aromatic, and at least One member ring systems includes one or more hetero atoms, and each of which member ring systems include 3-7 yuan of rings, and an only attachment point with Molecule remainder is connected.Term " heteroaryl " can exchange use with term " heteroaromatic " or " heteroaromatics ".And The heteroaryl can be substituted or non-substituted, and wherein substituent can be, but be not limited to, hydrogen, deuterium, fluorine, chlorine, bromine, iodine, Alkyl, alkoxy, alkylamino, haloalkyl, cyano group, hydroxyl, nitro, amino, trifluoromethoxy or trifyl.

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

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

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

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

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

Term " alkylthio group " includes 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 " halogenated alkylthio " includes C_1-10Haloalkyl be connected on bivalent sulfur atom, wherein haloalkyl has Implication as described in the present invention.Some of embodiments are that halogenated alkylthio is the C of lower level_1-3Halogenated alkylthio, it is such Example includes, but is not limited to trifluoromethylthio.

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_1-6Alkyl group on.Other embodiment is aromatic alkyl group or aryl alkyl Group refers to contain C_1-3Alkyl " benzene alkylene ".Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..And virtue Aryl on alkyl can be further by hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, alkoxy, alkylamino, haloalkyl, cyano group, hydroxyl Base, nitro, amino, trifluoromethoxy or trifyl.

Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.Some of them are implemented Example is that alkyl amino is one or two C_1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Other Embodiment is that alkyl amino is C_1-3Lower level alkylamino group.Suitable alkylamino group can be monoalkyl ammonia Base or dialkyl amido, such example include, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- Lignocaine etc..

Term " aminoalkyl " includes the C substituted by one or more amino_1-10Straight or branched alkyl group, wherein Alkyl group has implication as described in the present invention.Some of embodiments are that aminoalkyl is by one or more amino bases The substituted C of group_1-6" aminoalkyl of lower level ", such example includes, but is not limited to, aminomethyl, aminoethyl, ammonia third Base, ammonia butyl and ammonia hexyl.

Term " alkoxy carbonyl group " expression alkyl-O-C (=O)-, wherein alkyl has implication as described in the present invention.Wherein one A little embodiments are that the alkyl group in alkoxy carbonyl group is C_1-6The alkyl of lower level, such example include, but is not limited to, first Epoxide carbonyl, ethoxy carbonyl, and propoxycarbonyl.

Term " carboxyalkyl " includes the C that can be substituted by one or more carboxyls_1-10Straight or branched alkyl, wherein Carboxyl and alkyl group have implication as described in the present invention.Such example includes, but is not limited to, carboxymethyl, carboxylic propyl group Etc..

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

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

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

Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below：T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vo1.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008,7,255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

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

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

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, the compound of 1994. present invention can include asymmetric center or chiral centre, therefore Different stereoisomers be present.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture, constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, 1 or (+), (-) use To name the symbol that compound linearly polarized light rotates, (-) or 1 refer to that compound is left-handed, and prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50：50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause do not have stereoselectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.

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

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et a1., describe Pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malic acid, 2- hydroxyls Base propionic acid, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, Fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydroiodic acid Salt, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, Mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- Phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, Valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.This hair It is bright to be also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble or dispersion product It can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is pharmaceutically acceptable Salt further comprise appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydrogen-oxygen Compound, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, 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, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

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

A is key ,-O- ,-S- or-a NR⁵-；

R is-X-Z；

X is-(CR⁷R^7a)_m- or-C (=O)-；

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

Wherein, B is a key ,-(CR⁷R^7a)_m- or-C (=O)-；

W is CR⁷Or N；

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

R¹For aryl or heteroaryl；

R⁴For hydrogen, deuterium or C₁-C₄Alkyl；

Each n independently is 0,1,2 or 3；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2；With

Wherein, some embodiments are：

Wherein, B is a key ,-(CR⁷R^7a)_m- or-C (=O)-；

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

Each n independently is 0,1,2 or 3；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2.

In some embodiments,

The subformula that Z is as follows：

Each R⁶It independently is hydrogen, deuterium, methyl, ethyl, propyl group ,-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m- O-R⁸、-(CR⁷R^7a)_m- C (=O) O-R⁸、-(CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)m-N(R⁸R^8a)、 Or-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-OR⁸；

Each n independently is 0,1 or 2；

In some embodiments,

Wherein each X¹It independently is S, NR¹¹Or CR¹²R^12a；

Each R¹⁰It independently is-(CR⁷R^7a)_m- C (=O) O-R⁸；

Each R¹²And R¹²A independently is hydrogen, deuterium or-(CR⁷R^7a)_m- C (=O) O-R⁸；

Each m independently is 0,1,2,3 or 4；

Each p independently is 1 or 2；

In some embodiments,

R³For following subformula：

Each R¹⁰It independently is-(CR⁷R^7a)_m- C (=O) OR⁸；

Each m independently is 0,1,2,3 or 4；

Each p independently is 1 or 2.

In other embodiment,

R¹For C₆-C₁₀Aryl, wherein the aryl can be monosubstituted or identical or different by fluorine, deuterium, chlorine, nitro or bromine It is polysubstituted；

R²For hydrogen, deuterium or C₁-C₄Alkyl；

R⁵For hydrogen, deuterium or C₁-C₄Alkyl.

In other embodiment,

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

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

R²For hydrogen, deuterium or C₁-C₄Alkyl；

Each R⁸And R^8aIt independently is H, deuterium or C₁-C₆Alkyl；

Each R¹³It independently is fluorine, chlorine, nitro or bromine；

Each p independently is 1 or 2；

Each m independently is 0,1,2,3 or 4；

Each q independently is 0,1 or 2.

In some embodiments,

R⁶For hydrogen, deuterium, methyl, ethyl, propyl group, butyl, isopropyl, the tert-butyl group ,-(CR⁷R^7a)_m- C (=O) O-R⁸、- (CR⁷R^7a)_m- C (=O) R⁸、-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-O-(CR⁷R^7a)_m-O-R⁸、-(CR⁷R^7a)_m- C (=O)- (CR⁷R^7a)_m-N(R⁸R^8a) or-(CR⁷R^7a)_m- C (=O)-(CR⁷R^7a)_m-OR⁸；

In some embodiments,

R³Independently selected from following subformula：

Or

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

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

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

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

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

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

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

If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N⁺(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, deuterium, C₁-C₄Alkyl, C₆-C₁₀Aryl, C₆-C₁₀Aryl C₁-C₄Alkyl etc., and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium To inorganic salts.Also appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydrogen-oxygen are included Compound, carboxylate, 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 1-38 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.The present invention's Compound can effectively suppress hepatitis type B virus in composition, be held suitable for disease caused by virus is especially acute and chronic The treatment of continuous HBV virus infection, the chronic viral diseases that HBV triggers may cause morbid state to become serious, chronic HBV Infection can cause hepatic sclerosis and/or canceration of hepatic cell in many cases.

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

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

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

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

As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load Body, assistant agent, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below：In Remington：The Science and Practice Of Pharmacy, 2lst edition, 2005, ed.D.B.Troy, Lippincott Williams＆Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show different Carrier can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition.Except any conventional carrier The incompatible scope of compound of medium and the present invention, such as caused any bad biological effect or with can pharmaceutically connect The caused interaction in harmful manner of any other component for the composition received, their purposes are also that the present invention is considered Scope.

It can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger；Aluminium；Aluminum oxide；It is stearic Sour aluminium；Lecithin；Haemocyanin such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Potassium sorbate；Saturation The partial glyceride mixtures of vegetable fatty acid；Water；Electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate；Salt is such as Sodium chloride, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxypropylene-blocking Condensate；Lanolin；Sugar such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Thing such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa Beans 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 and perfume (or spice) Material, preservative and antioxidant.For convenience, local anesthetic, preservative, buffer etc. can be directly dissolved in carrier.

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

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

Oral tablet and capsule can contain excipient such as adhesive, such as syrup, Arabic gum, sorbierite, tragacanth, or Polyvinylpyrrolidone；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 a Lamivudine, Sebivo, tenofovir disoproxil, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, emtricitabine, Fa Puluowei, interferon, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α -1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin 2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol, or Propagermanium etc..

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

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

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

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

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

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

General synthetic method

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

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

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

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

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

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

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

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

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

Table 1

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

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

MeCN, CH₃CN acetonitriles

NH₃·H₂O ammoniacal liquor

NH₄Cl sal-ammoniacs

DCM, CH₂Cl₂Dichloromethane

CHCl₃Chloroform, chloroform

CDCl₃Deuterochloroform

CCl₄Carbon tetrachloride

DMSO dimethyl sulfoxide (DMSO)s

D₂O heavy water

Ac₂O acetic anhydrides

Pd-C palladiums-carbon

Boc tertbutyloxycarbonyls

NaH sodium hydrides

Na₂SO₄Sodium sulphate

Et₃N, TEA triethylamine

NBS N-bromo-succinimides

H₂O water

ML milliliters

Mmol mMs

G grams

RT, rt room temperature

Rt retention times

The present invention can prepare intermediate by following methods：

Intermediate 1

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

Intermediate 8A

Compound 8A, it can be prepared by above-mentioned method, wherein R^8’For alkyl-O-, alkyl-NH-, (alkyl)₂- N-, alkyl-O- alkyl-O-, alkyl-O-C (=O)-or Trifluoromethylcarbonyl-O-.Compound 3A and compound 4A are in alkaline bar Under part, compound 5A being obtained, then being reacted with 6A, generation compound 7A is acidified, obtains product 8A.

Intermediate 12A

Compound 12A, it can be prepared by above-mentioned method.Compound 9A and compound 10A react to obtain chemical combination Thing 11A, then reacted with sodium methoxide, ammonium chloride, it is then acidified, obtain compound 12A.

The logical formula (I) of the present invention or (Ia) compound can be prepared by following methods：

Embodiment 1

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

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

Embodiment 2

In addition, pyrimidines 6, can be prepared, wherein R by the method for reaction scheme 2¹, R², R³, A, and Z With implication as described in the present invention.Amidine or its hydrochloric acid salt compounds 7, aldehyde compound 2 and compound 3 are in appropriate inertia In solvent (such as alcohol reagent), cyclization obtains compound 8.

Compound 8 and chlorinating agent are reacted, obtain compound 9.Then compound 9 and R³H is molten in appropriate inertia In agent, compound 4 is generated；Compound 4 and bromating agent are reacted in atent solvent, bromination product 5 is obtained, then in alkali Under the conditions of property, product 6 is obtained with ZH substitution reactions in appropriate atent solvent.

Embodiment 3

In addition, pyrimidines 6, can be prepared, wherein R by the method for reaction scheme 3^3aFor substituted aryl Or the heteroaryl of substitution, wherein the substituent on the aryl or heteroaryl can arbitrarily be selected from-(CR⁷R^7a)_m- S (=O)_q- R¹⁴Or-(CR⁷R^7a)_m- C (=O) O-R¹⁴、-(CR⁷R^7a)_m- S (=O)_q-N(R¹⁴R^14a)；Each R¹⁴And R^14aIt is independently alkyl, halogen Substituted alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or cycloheteroalkylalkyl； R¹, R², R³, R⁷, R^7a, A, m, q and Z have implication as described in the present invention.

(such as alcohols tries in appropriate atent solvent for amidine or its hydrochloric acid salt compounds 7, aldehyde compound 2 and compound 3 Agent) in, cyclization obtains compound 8.

Compound 8 and chlorinating agent are reacted, obtain compound 9.Then compound 9 and R^3aH is molten in appropriate inertia In agent, compound 4a is generated；Compound 4a and bromating agent are reacted in atent solvent, obtain bromination product 5a, then In the basic conditions, product 6a is obtained with ZH substitution reactions in appropriate atent solvent, compound 6a is in alkali or acid condition Under, hydrolysis obtains product 6.

Embodiment 4

In addition, pyrimidines 6, can be prepared, wherein R by the method for reaction scheme 4^3aFor substituted aryl Or the heteroaryl of substitution, wherein the substituent on the aryl or heteroaryl can arbitrarily be selected from-(CR⁷R^7a)_m- S (=O)_q- R¹⁴Or-(CR⁷R^7a)_m- C (=O) O-R¹⁴、-(CR⁷R^7a)_m- S (=O)_q-N(R¹⁴R^14a)；Each R¹⁴And R^14aIt independently is alkyl, halogen Substituted alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or cycloheteroalkylalkyl； R¹, R², R³, R⁷, R^7a, A, m, q and Z have implication as described in the present invention.

(such as alcohols tries in appropriate atent solvent for amidine or its hydrochloric acid salt compounds 1a, aldehyde compound 2 and compound 3 Agent) in, cyclization obtains compound 4a.

Compound 4a and bromating agent are reacted in atent solvent, bromination product 5a is obtained, then in alkalescence condition Under, obtain product 6a with ZH substitution reactions in appropriate atent solvent.Under alkali or acid condition, hydrolysis obtains compound 6a Product 6.

Specific embodiment

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

Embodiment 1：

4- (the bromo- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- methoxyl group -2- oxos Ethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- cyano thiazole -4- bases) ethyl acetate

Cuprous cyanide (7.28g, 80mmol), anhydrous acetonitrile (30mL), nitrous acid uncle are sequentially added in 250mL three-necked bottles Butyl ester (10mL, 80mmol), 50 DEG C are warming up to, the nothing of 2- (thiazolamine -4- bases) ethyl acetate (7.5g, 40mmol) is added dropwise Water-acetonitrile (20mL) solution, add in 1h, continue to react 2.5h.Remove solvent, product crude product column chromatographic isolation and purification (stone under reduced pressure Oily ether/ethyl acetate (V/V)=25/1), obtain slightly yellow liquid (2g, 25%).

¹H NMR (400MHz, DMSO-d₆)：δ 4.01 (q, 2H), 3.72 (s, 2H), 1.16 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) acetate hydrochloride

2- (2- cyano thiazole -4- bases) ethyl acetate (2.17g, 11mmol), methanol are sequentially added in 50mL eggplant-shape bottles Sodium (0.84g, 15.5mmol), ammonium chloride (0.88g, 16.5mmol), absolute methanol (50mL), the lower 25 DEG C of stirrings of nitrogen protection are anti- Answer 24h.Filtering, solvent is evaporated off in filtrate decompression, and acetone (12mL) is added into residue, stirs 3h, filtering, and product is with a small amount of third Ketone rinse, obtain light yellow solid (1.63g, 63%).

MS-ESI：(ESI, pos.ion) m/z：200.1[M+1]⁺；

¹H NMR (400MHz, D₂O)：δ 6.76 (s, 1H), 3.77 (s, 3H), 3.68 (s, 2H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Sequentially added in dry reaction bottle 2- (2- carbonamidines thiazole-4-yl) acetate hydrochloride (2.35g, 10mmol), the bromo- 4- fluorobenzaldehydes (2.03g, 10mmol) of 2-, ethyl acetoacetate (1.56g, 12mmol), sodium acetate In (1.07g, 13mmol), absolute methanol (40mL), in N₂Flow back 12h under the conditions of protecting lower 80 DEG C, and filtering, filtrate decompression is evaporated off Solvent, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtain yellow solid (2.48g, 50%).

MS-ESI：(ESI, pos.ion) m/z：496.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.84 (br.s, 1H), 7.77 (s, 1H), 7.55-7.20 (m, 3H), 5.89 (s, 1H), 3.92 (q, 2H), 3.90 (s, 2H), 3.62 (s, 3H), 2.47 (s, 3H), 1.03 (t, 3H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiophenes are sequentially added in dry reaction bottle Azoles -2- bases) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (1g, 2mmol), CCl₄(40mL), heats up under nitrogen protection To 60 DEG C.NBS (0.39g, 2.2mmol) is added portionwise in nitrogen stream protection, finishes and continues to react 10min, is cooled to 25 DEG C, mistake Filter, filtrate decompression are evaporated off solvent, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtain yellow Solid (0.81g, 70%).

MS-ESI：(ESI, pos.ion) m/z：574.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.88 (br.s, 1H), 7.78 (s, 1H), 7.56-7.23 (m, 3H), 6.01 (s, 1H), 4.68 (dd, 2H), 3.98 (q, 2H), 3.91 (s, 2H), 3.62 (s, 3H), 1.06 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- methoxyl groups - 2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- methoxyl groups -2- are sequentially added in dry reaction bottle Oxoethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (1.15g, 2mmol), absolute methanol (20mL), three second Amine (0.45g, 4.4mmol), thiomorpholine dioxide. HCl (0.42g, 2.4mmol), the lower 25 DEG C of stirrings of nitrogen protection 12h.Remove solvent under reduced pressure, the addition dichloromethane (150mL) into residue, organic layer saturated common salt water washing (100mL × 2), anhydrous sodium sulfate drying.Solvent, product crude product column chromatographic isolation and purification (petroleum ether/acetic acid second is evaporated off in filtering, filtrate decompression Ester (V/V)=3/1), obtain yellow solid (0.2g, 17%).

MS-ESI：(ESI, pos.ion) m/z：629.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.61 (br.s, 1H), 7.72 (s, 1H), 7.58-7.18 (m, 3H), 6.02 (s, 1H), 4.17 (d, 1H), 3.98 (d, 1H), 3.94 (s, 2H), 3.92 (q, 2H), 3.65 (s, 3H), 3.17-3.10 (m, 4H), 3.05-2.85 (m, 4H), 1.05 (t, 3H)

Embodiment 2：

2- (2- (4- (the bromo- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -5- (carbethoxyl group) -1, 4- dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

Sequentially added in dry reaction bottle 4- (the bromo- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) - 2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (50mg, 0.08mmol), Ethanol (5mL), after stirring and dissolving is complete at 25 DEG C, add the water (2mL) of lithium hydroxide monohydrate (38.8mg, 0.92mmol) Solution, 25min is stirred at 25 DEG C.Dichloromethane (100mL), saturated aqueous common salt (30mL) are sequentially added into reaction solution, uses vinegar Acid tune pH to 4-5, extracting and demixing, organic layer anhydrous sodium sulfate drying,.Solvent, product crude product post layer is evaporated off in filtering, filtrate decompression Analysis isolates and purifies (methylene chloride/methanol (V/V)=25/1), obtains yellow solid (30mg, 60%).

MS-ESI：(ESI, pos.ion) m/z：615.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.58 (br.s, 1H), 7.41 (s, 1H), 7.31-6.93 (m, 3H), 6.19 (s, 1H), 4.37 (d, 1H), 4.06 (q, 2H), 3.98 (d, 1H), 3.92 (s, 2H), 3.25 (br.s, 4H), 2.95 (br.s, 4H), 1.13 (t, 3H)

Embodiment 3：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- (morpholino first Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- methoxyl groups -2- are sequentially added in dry reaction bottle Oxoethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (1.15g, 2mmol), absolute ethyl alcohol (20mL), morpholine (0.7g, 8mmol), the lower 25 DEG C of stirrings 12h of nitrogen protection.Remove solvent under reduced pressure, ethyl acetate is added into residue (150mL), organic layer saturated common salt water washing (100mL × 2), anhydrous sodium sulfate drying.Solvent is evaporated off in filtering, filtrate decompression, Product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=3/1), obtain yellow solid by yellow solid (0.47g, 40%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.75 (br.s, 1H), 7.72 (s, 1H), 7.57-7.17 (m, 3H), 6.02 (s, 1H), 3.96-3.94 (d, 1H), 3.92 (q, 2H), 3.90 (s, 2H), 3.86 (d, 1H), 3.67 (s, 3H), 3.63 (br.s, 4H), 2.56 (br.s, 4H), 1.05 (t, 3H)

Embodiment 4：

2- (2- (4- (the bromo- 4- fluorophenyls of 2-) -6- (morpholinomethyl) -5- (carbethoxyl group)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- Base) thiazole-4-yl) acetic acid

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- (morpholino first Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (47mg, 0.08mmol), lithium hydroxide monohydrate (38.8mg, 0.92mmol) Yellow solid (25mg, 55%) is obtained by the synthetic method of embodiment 2.

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.75 (br.s, 1H), 7.68 (s, 1H), 7.57-7.20 (m, 3H), 6.02 (s, 1H), 3.96 (d, 1H), 3.94 (q, 2H), 3.86 (d, 1H), 3.79 (s, 2H), 3.66 (br.s, 4H), 2.46 (br.s, 4H), 1.05 (t, 3H)

Embodiment 5：

4- (2,4- dichlorophenyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- (morpholinomethyl) - 1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2,4- dichlorophenyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) acetate hydrochloride (1.92g, 8.1mmol), 2,4- dichlorobenzaldehydes (1.42g, 8.1mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.13g, 30%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.85 (br.s, 1H), 7.78 (s, 1H), 7.57-7.21 (m, 3H), 6.05 (s, 1H), 4.01 (q, 2H), 3.90 (s, 2H), 3.65 (s, 3H), 2.56 (s, 3H), 1.05 (t, 3H)

Step 2) 2- (2- (4- (2,4- dichlorophenyl) -6- (bromomethyl) -5- (carbethoxyl group)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- Base) thiazole-4-yl) methyl acetate

By 4- (2,4- dichlorophenyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates (0.94g, 2mmol), NBS (0.36g, 2mmol) obtain yellow by the synthetic method of the step 4 of embodiment 1 Solid (0.55g, 50%).

MS-ESI：(ESI, pos.ion) m/z：546.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.83 (br.s, 1H), 7.75 (s, 1H), 7.57-7.21 (m, 3H), 6.03 (s, 1H), 4.13 (q, 4H), 4.01 (q, 2H), 3.90 (s, 2H), 3.68 (s, 3H), 1.05 (t, 3H)

Step 3) 4- (2,4- dichlorophenyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- (morpholinoes Methyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- (4- (2,4- dichlorophenyl) -6- (bromomethyl) -5- (carbethoxyl group)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiophenes Azoles -4- bases) methyl acetate (1.1g, 2mmol), morpholine (0.7g, 8mmol) obtain yellow solid by the synthetic method of embodiment 3 (0.66g, 60%).

MS-ESI：(ESI, pos.ion) m/z：553.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.78 (br.s, 1H), 7.76 (s, 1H), 7.60-7.20 (m, 3H), 6.01 (s, 1H), 3.98-3.96 (d, 1H), 3.93 (q, 2H), 3.91 (s, 2H), 3.88 (d, 1H), 3.66 (s, 3H), 3.64 (br.s, 4H), 2.56 (br.s, 4H), 1.05 (t, 3H)

Embodiment 6：

2- (2- (4- (2,4 dichloro benzene base) -6- (morpholinomethyl) -5- (carbethoxyl group) -1,4- dihydro-pyrimidin -2- bases) Thiazole-4-yl) acetic acid

By 4- (2,4- dichlorophenyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) -6- (morpholino first Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.44g, 0.8mmol), lithium hydroxide monohydrate (0.39g, 9.2mmol) press The synthetic method of embodiment 2 obtains yellow solid (0.32g, 75%).

MS-ESI：(ESI, pos.ion) m/z：539.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.79 (br.s, 1H), 7.68 (s, 1H), 7.58-7.22 (m, 3H), 6.02 (s, 1H), 3.98 (dd, 1H), 3.94 (q, 2H), 3.88 (dd, 1H), 3.78 (s, 2H), 3.65 (br.s, 4H), 2.48 (br.s, 4H), 1.05 (t, 3H)

Embodiment 7：

4- (the chloro- 4- fluorophenyls of 2-) -6-4 (the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (4- (2- methoxyl group -2- oxos Ethyl) thiazol-2-yl) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -6- (methyl) -5- (carbethoxyl group)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- Base) thiazole-4-yl) methyl acetate

By 2- (2- carbonamidines thiazole-4-yl) acetate hydrochloride (1.92g, 8.1mmol), the chloro- 4- fluorobenzaldehydes of 2- (1.59g, 10mmol), ethyl acetoacetate (1.56g, 12mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.46g, 40%).

MS-ESI：(ESI, pos.ion) m/z：451.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.84 (br.s, 1H), 7.75 (s, 1H), 7.58-7.23 (m, 3H), 6.04 (s, 1H), 3.99 (q, 2H), 3.91 (s, 2H), 3.66 (s, 3H), 2.57 (s, 3H), 1.03 (t, 3H)

Step 2) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazole -2- Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -6- (methyl) -5- (carbethoxyl group)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiophenes Azoles -4- bases) methyl acetate (0.9g, 2mmol), NBS (0.36g, 2mmol) obtain yellow by the synthetic method of the step 4 of embodiment 1 and consolidate Body (0.42g, 40%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.79 (br.s, 1H), 7.73 (s, 1H), 7.57-7.23 (m, 3H), 6.00 (s, 1H), 4.13 (d, 2H), 4.01 (q, 2H), 3.90 (s, 2H), 3.68 (s, 3H), 1.05 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (4- (2- methoxyl groups - 2- oxoethyls) thiazol-2-yl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (1.06g, 2mmol), thiomorpholine dioxide. HCl (0.42g, 2.4mmol) are pressed The synthetic method of the step 5 of embodiment 1 obtains yellow solid (0.44g, 38%).

MS-ESI：(ESI, pos.ion) m/z：585.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.65 (br.s, 1H), 7.72 (s, 1H), 7.58-7.19 (m, 3H), 6.01 (s, 1H), 4.18 (dd, 1H), 3.99 (dd, 1H), 3.98 (s, 2H), 3.94 (q, 2H), 3.65 (s, 3H), 3.17-3.10 (m, 4H), 3.05-2.85 (m, 4H), 1.05 (t, 3H)

Embodiment 8：

2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -64 (the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (carbethoxyl group) -1,4- Dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

By 4- (the chloro- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- methoxyl group -2- oxygen For ethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.47g, 0.8mmol), lithium hydroxide monohydrate (0.39g, 9.2mmol) obtains yellow solid (0.24g, 52%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：571.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.66 (br.s, 1H), 7.42 (s, 1H), 7.33-6.96 (m, 3H), 6.12 (s, 1H), 4.39 (dd, 1H), 4.11 (q, 2H), 3.99 (dd, 1H), 3.93 (s, 2H), 3.26 (br.s, 4H), 2.95 (br.s, 4H), 1.13 (t, 3H)

Embodiment 9：

4- (2,4- dichlorophenyl) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- ethyoxyl -2- oxo second Base) thiazol-2-yl) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- carbonamidines thiazole-4-yl) ethyl acetate acetate

2- (2- cyano thiazole -4- bases) ethyl acetate (1.96g, 10mmol), hydrochloric acid are sequentially added in dry reaction bottle Azanol (1.39g, 20mmol), triethylamine (3.04g, 30mmol), dichloromethane (60mL), 25 DEG C of stirring 2h, are removed under reduced pressure molten Agent, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=5/1), obtains white solid.Into above-mentioned solid according to Secondary addition acetic acid (10mL), Ac₂O (1mL), Pd-C (10%, 0.2g), the lower 25 DEG C of stirrings 12h of atmosphere of hydrogen, diatomite filtering, Solvent is evaporated off in filtrate decompression, product crude acetone recrystallization, obtains gray solid (0.82g, 30%).

MS-ESI：(ESI, pos.ion) m/z：214.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 6.76 (s, 1H), 4.02 (q, 2H), 3.68 (s, 2H), 3.45 (br.s, 2H), 1.92 (s, 3H), 1.02 (t, 3H)

Step 2) 4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl acetate acetate (2.73g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (2.65g, 55%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.81 (br.s, 1H), 7.71 (s, 1H), 7.53-7.19 (m, 3H), 6.09 (s, 1H), 4.18 (q, 2H), 4.01 (q, 2H), 3.72 (s, 2H), 2.46 (s, 3H), 1.15 (t, 3H), 1.05 (t, 3H)

Step 3) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates (4.82g, 10mmol), NBS (1.96g, 11mmol) are obtained yellow by the synthetic method of the step 4 of embodiment 1 Color solid (3.42g, 61%).

MS-ESI：(ESI, pos.ion) m/z：560.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.72 (br.s, 1H), 7.71 (s, 1H), 7.51-7.21 (m, 3H), 6.05 (s, 1H), 4.53 (dd, 2H), 4.16 (q, 2H), 4.05 (q, 2H), 3.73 (s, 2H), 1.11 (t, 3H), 1.04 (t, 3H)

Step 4) 4- (2,4- dichlorophenyl) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- ethyoxyls -2- Oxoethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -1, 4- dihydro-pyrimidin -5- Ethyl formates (5.61g, 10mmol), thiomorpholine dioxide. HCl (1.71g, 10mmol) are by real The synthetic method for applying the step 5 of example 1 obtains yellow solid (4.25g, 69%).

MS-ESI：(ESI, pos.ion) m/z：615.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.79 (br.s, 1H), 7.69 (s, 1H), 7.55-7.24 (m, 3H), 6.03 (s, 1H), 4.48 (dd, 2H), 4.13 (q, 2H), 4.07 (q, 2H), 3.78 (s, 2H), 3.22 (br.s, 4H), 2.93 (br.s, 4H), 1.13 (t, 3H), 1.01 (t, 3H)

Embodiment 10：

4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- (morpholine methyl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

Step 1) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl acetate acetate (2.73g, 10mmol), methyl acetoacetate (1.16g, 10mmol), the chloro- 4- fluorobenzaldehydes (1.59g, 10mmol) of 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.21g, 49%).

MS-ESI：(ESI, pos.ion) m/z：452.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.81 (br.s, 1H), 7.72 (s, 1H), 7.53-7.25 (m, 3H), 6.06 (s, 1H), 3.99 (q, 2H), 3.85 (s, 2H), 3.71 (s, 3H), 2.47 (s, 3H), 1.03 (t, 3H)

Step 2) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- Dihydro-pyrimidin -5- methyl formates (0.45g, 1mmol), NBS (0.2g, 1.1mmol) are obtained by the synthetic method of the step 4 of embodiment 1 Yellow solid (0.33g, 63%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.83 (br.s, 1H), 7.69 (s, 1H), 7.51-7.23 (m, 3H), 6.02 (s, 1H), 4.49 (dd, 2H), 4.01 (q, 2H), 3.81 (s, 2H), 3.68 (s, 3H), 1.02 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- (morpholines Methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.53g, 1mmol), morpholine (0.35g, 4mmol) are obtained yellow by the synthetic method of embodiment 3 Color solid (0.39g, 73%).

MS-ESI：(ESI, pos.ion) m/z：537.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.83 (br.s, 1H), 7.69 (s, 1H), 7.51-7.23 (m, 3H), 6.02 (s, 1H), 4.49 (dd, 2H), 4.01 (q, 2H), 3.81 (s, 2H), 3.68 (s, 3H), 3.63 (br.s, 4H), 2.47 (br.s, 4H), 1.02 (t, 3H)

Embodiment 11：

6- ((1H- tetrazole -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) Thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl acetate acetate (2.73g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), the bromo- 4- fluorobenzaldehydes (2.03g, 10mmol) of 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.14g, 42%).

MS-ESI：(ESI, pos.ion) m/z：510.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.79 (br.s, 1H), 7.75 (s, 1H), 7.57-7.25 (m, 3H), 5.93 (s, 1H), 4.06 (q, 2H), 3.99 (q, 2H), 3.83 (s, 2H), 2.49 (s, 3H), 1.13 (t, 3H), 1.03 (t, 3H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- Dihydro-pyrimidin -5- Ethyl formates (0.51g, 1mmol), NBS (0.2g, 1.1mmol) are obtained by the synthetic method of the step 4 of embodiment 1 Yellow solid (0.32g, 55%).

MS-ESI：(ESI, pos.ion) m/z：587.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.84 (br.s, 1H), 7.73 (s, 1H), 7.57-7.28 (m, 3H), 5.99 (s, 1H), 4.52 (dd, 2H), 4.03 (q, 2H), 3.94 (q, 2H), 3.85 (s, 2H), 1.15 (t, 3H), 1.08 (t, 3H)

Step 3) 6- ((1H- tetrazole -1- bases) methyl) -4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxygen For ethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.59g, 1mmol), 1H- tetrazoles (0.14g, 2mmol) press the conjunction of the step 5 of embodiment 1 Yellow solid (0.25g, 43%) is obtained into method.

MS-ESI：(ESI, pos.ion) m/z：578.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.85 (br.s, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.53-7.21 (m, 3H), 6.01 (s, 1H), 5.97-5.91 (m, 2H), 4.10 (q, 2H), 3.92 (q, 2H), 3.88 (s, 2H), 1.11 (t, 3H), 1.03 (t, 3H)

Embodiment 12：

((1- oxos are thio by -6- by 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) Morpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- methoxyl group -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.58g, 1mmol), thiomorpholine monoxide hydrochloride (0.31g, 2mmol) are by real The synthetic method for applying the step 5 of example 1 obtains yellow solid (0.4g, 66%).

MS-ESI：(ESI, pos.ion) m/z：613.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.66 (br.s, 1H), 7.74 (s, 1H), 7.58-7.24 (m, 3H), 6.05 (s, 1H), 4.19 (d, 1H), 3.97 (d, 1H), 3.94 (s, 2H), 3.91 (q, 2H), 3.66 (s, 3H), 3.13 (br.s, 4H), 2.95 (br.s, 4H), 1.02 (t, 3H)

Embodiment 13：

2- (2- (6- ((5- amino -1H- tetrazole -1- bases) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -5- (methoxycarbonyl group) - Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

Step 1) 6- ((5- amino -1H- tetrazole -1- bases) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethoxies Base -2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.53g, 1mmol), 1H- tetrazole -5- amino (0.17g, 2mmol) press the step of embodiment 1 Rapid 5 synthetic method obtains yellow solid (0.22g, 41%).

MS-ESI：(ESI, pos.ion) m/z：535.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.69 (br.s, 1H), 7.76 (s, 1H), 7.59-7.23 (m, 3H), 6.03 (s, 1H), 5.97 (dd, 2H), 4.34 (br, s, 2H), 4.01 (q, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 1.05 (t, 3H)

Step 2) 2- (2- (6- ((5- amino -1H- tetrazole -1- bases) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -5- (methoxies Carbonyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

By 6- ((5- amino -1H- tetrazole -1- bases) methyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyls -2- Oxoethyl) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.54g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) obtains yellow solid (0.45g, 88%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：507.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.72 (br.s, 1H), 7.73 (s, 1H), 7.59-7.22 (m, 3H), 6.01 (s, 1H), 5.91 (dd, 2H), 4.27 (br.s, 2H), 3.91 (s, 2H), 3.69 (s, 3H)

Embodiment 14：

6- ((3- cyano group -1H-1,2,4- triazole -1- bases) methyl) -4- (2,4- dichlorophenyl) -2- (4- (2- ethoxies Base -2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -1, 4- dihydro-pyrimidin -5- Ethyl formates (0.56g, 1mmol), 1H-1,2,4- triazole -3- cyano group (0.19g, 2mmol) are by implementation The synthetic method of the step 5 of example 1 obtains yellow solid (0.23g, 40%).

MS-ESI：(ESI, pos.ion) m/z：574.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.73 (br.s, 1H), 8.43 (s, 1H), 7.71 (s, 1H), 7.52-7.21 (m, 3H), 6.01 (s, 1H), 5.77 (dd, 2H), 4.11 (q, 2H), 4.03 (q, 2H), 3.81 (s, 2H), 1.13 (t, 3H), 1.03 (t, 3H)

Embodiment 15：

6- ((4- (2- (tert-butylamine base) acetyl group) piperazine -1- bases) methyl) -4- (2,4- dichlorophenyl -2- (4- (2- second Epoxide -2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

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

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

MS-ESI：(ESI, pos.ion) m/z：207.1[M+1-56]⁺；

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

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

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

MS-ESI：(ESI, pos.ion) m/z：300.2[M+1]⁺；

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

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

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

MS-ESI：(ESI, pos.ion) m/z：200.2[M+1]⁺.

Step 4) 6- ((4- (2- (tert-butylamine base) acetyl group) piperazine -1- bases) methyl) -4- (2,4- dichlorophenyl -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -1, 4- dihydro-pyrimidin -5- Ethyl formates (0.56g, 1mmol), 2- (tert-butylamine base) -1- (piperazine -1- bases) acetyl group trifluoroacetate (0.63g, 2mmol) obtains yellow solid (0.34g, 50%) by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：679.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.82 (br.s, 1H), 7.74 (s, 1H), 7.52-7.21 (m, 3H), 6.06 (s, 1H), 4.48 (dd, 2H), 4.13 (q, 2H), 4.07 (q, 2H), 3.78 (s, 2H), 3.62 (s, 2H), 3.48 (br.s, 4H), 3.39 (br.s, 4H), 1.13 (t, 3H), 1.11 (s, 9H), 1.01 (t, 3H)

Embodiment 16：

2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -5- (methoxycarbonyl group) -6- ((4- (2- (2- methoxy ethoxies) acetyl group) Piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

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

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

MS-ESI：(ESI, pos.ion) m/z：303.2[M+1]⁺；

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

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

By 4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- t-butyl formates (0.57g, 1.88mmol), trifluoro Acetic acid (5.6mL) obtains brownish oil shape thing (0.55g, 93%) by the synthetic method of the step 3 of embodiment 11.

MS-ESI：(ESI, pos.ion) m/z：203.2[M+1]⁺.

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- ((4- (2- (2- methoxy ethoxies) acetyl group) piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.53g, 1mmol), 2- (2- methoxy ethoxies) -1- (piperazine -1- bases) acetyl group three Fluoroacetate (0.63g, 2mmol) obtains yellow solid (0.3g, 46%) by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：652.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.81 (br.s, 1H), 7.72 (s, 1H), 7.53-7.27 (m, 3H), 6.17 (s, 1H), 4.20 (s, 2H), 4.09 (dd, 2H), 4.04 (q, 2H), 3.82 (s, 2H), 3.72 (s, 3H), 3.69-3.67 (m, 2H), 3.57-3.53 (m, 4H), 3.51-3.49 (m, 2H), 3.47-3.42 (m, 4H), 3.39 (s, 3H), 1.02 (t, 3H)

Step 4) 2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -5- (methoxycarbonyl group) -6- ((4- (2- (2- methoxy ethoxies) Acetyl group) piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) thiazole-4-yl) acetic acid

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- ((4- (2- (2- Methoxy ethoxy) acetyl group) piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.65g, 1mmol), hydrogen-oxygen Change lithium monohydrate (0.42g, 10mmol) and be prepared into yellow solid (0.49g, 78%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z.624.2 [M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.80 (br.s, 1H), 7.71 (s, 1H), 7.52-7.26 (m, 3H), 6.15 (s, 1H), 4.22 (s, 2H), 4.11 (dd, 2H), 3.81 (s, 2H), 3.74 (s, 3H), 3.68-3.64 (m, 2H), 3.55-3.51 (m, 4H), 3.50-3.47 (m, 2H), 3.46-3.41 (m, 4H), 3.39 (s, 3H)

Embodiment 17：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- ((4- (2- hydroxyl second Acyl group) piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

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

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

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

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

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

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

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

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) -6- ((4- (2- glycolyls) piperazine -1- bases) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (2- ethyoxyl -2- oxoethyls) thiazol-2-yl) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.59g, 1mmol), 2- oxos -2- (piperazine -1- bases) ethyl trifluoro-acetate trifluoro second Hydrochlorate (0.71g, 2mmol) obtains yellow solid (0.22g, 34%) by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：652.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.71 (br.s, 1H), 7.71 (s, 1H), 7.59-7.17 (m, 3H), 6.17 (s, 1H), 4.19 (s, 2H), 4.11 (d, 2H), 4.04 (q, 2H), 3.94 (s, 2H), 3.92 (q, 2H), 3.85 (br.s, 2H), 3.42 (br.s, 2H), 2.65 (br.s, 4H), 1.11 (t, 3H), 1.05 (t, 3H)

Embodiment 18：

2- (3- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -2- bases) - 1H-1,2,4- triazole -1- bases) acetic acid

Step 1) 2- (3- cyano group -1H-1,2,4- triazole -1- bases)-ethyl acetate

Dried in 250mL in three-necked bottle and sequentially add 3- cyano group -1H-1, it is 2,4- triazoles (5g, 53.15mmol), anhydrous Potassium carbonate (3.67g, 26.58mmol), anhydrous acetonitrile (90mL), bromoacetate (8.88g, 53.15mmol), 25 DEG C of stirrings 12h, filtering.Solvent is evaporated off in filtrate decompression, into crude product add dichloromethane (200mL), organic layer be washed with water (100mL × 2), organic layer anhydrous sodium sulfate drying, remove solvent under reduced pressure and obtain white solid (8g, 84%).

MS-ESI：(ESI, pos.ion) m/z：181.2[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.34 (s, 1H), 5.06 (s, 2H), 4.31 (q, 2H), 1.32 (t, 3H)

Step 2) 2- (3- carbonamidines -1H-1,2,4- triazole -1- bases) acetate hydrochloride

By 2- (3- cyano group -1H-1,2,4- triazole -1- bases)-ethyl acetate (2g, 11.2mmol), sodium methoxide (0.85g, 15.68mmol), ammonium chloride (0.89g, 16.8mmol) by the synthetic method of the step 2 of embodiment 1 obtain pale solid (1.44g, 55%).

MS-ESI：(ESI, pos.ion) m/z：184.2[M+1]⁺；

¹H NMR (400MHz, D₂O)：δ 8.60 (s, 1H), 8.34 (s, 1H), 5.26 (s, 2H), 3.73 (s, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By the bromo- 4- fluorobenzaldehydes (0.55g, 2.73mmol) of 2-, ethyl acetoacetate (0.35g, 2.73mmol), 2- (3- Carbonamidine -1H-1,2,4- triazole -1- bases) acetate hydrochloride (0.6g, 2.73mmol) press the step 3 of embodiment 1 synthesis side Method obtains yellow solid (0.6g, 45%).

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

¹H NMR (400MH, CDCl₃)：δ 8.21 (s, 1H), 7.39-7.35 (m, 1H), 7.28-7.26 (m, 1H), 6.97- 6.94 (m, 1H), 6.16 (s, 1H), 5.05 (s, 2H), 4.25 (q, 2H), 4.05 (q, 2H), 2.52 (br.s, 3H), 1.28 (t, 3H), 1.12 (t, 3H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2, 4- triazole -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (0.45g, 0.91mmol), NBS (0.16g, 0.91mmol) press the step of embodiment 1 Rapid 4 synthetic method obtains yellow solid (0.36g, 69%).

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

¹H NMR (400MHz, CDCl₃)：δ 8.23 (s, 1H), 7.45-7.41 (m, 1H), 7.31-7.27 (m, 1H), 7.03- 6.99 (m, 1H), 6.10 (s, 1H), 5.03 (s, 2H), 4.99 (d, 1H), 4.67 (d, 1H), 4.26 (q, 2H), 4.13 (q, 2H), 1.29 (t, 3H), 1.17 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- Base) -6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- tri- Nitrogen azoles -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.57g, 1mmol), morpholine (0.35g, 4mmol) is by embodiment 3 Synthetic method obtains yellow solid (0.35g, 60%).

MS-ESI：(ESI, pos.ion) m/z：579.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.51 (br.s, 1H), 8.22 (s, 1H), 7.34-6.90 (m, 3H), 6.23 (s, 1H), 5.00 (s, 2H), 4.26 (q, 2H), 4.02 (q, 2H), 3.84-3.80 (m, 6H), 2.62 (br.s, 4H), 1.29 (t, 3H), 1.13 (t, 3H)

Step 6) 2- (3- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin - 2- yls) -1H-1,2,4- triazole -1- bases) acetic acid

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) - 6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.58g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) yellow solid (0.47g, 85%) is prepared into by the synthetic method of embodiment 2.

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

¹H NMR (4 () () MHz, CDCl₃)：δ 8.27 (s, 1H), 7.36-6.92 (m, 3H), 6.22 (s, 1H), 4.86 (s, 2H), 4.41 (dd, 2H), 4.07 (q, 2H), 3.87 (br.s, 4H), 2.98 (br.s, 4H), 1.13 (t, 3H)

Embodiment 19：

2- (3- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- ((1- oxos thiomorpholine) methyl)-Isosorbide-5-Nitraes-two Hydrogen pyrimidine -2-base) -1H-1,2,4- triazole -1- bases) acetic acid

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazoles -3- Base) -6- ((1- oxos thiomorpholine) methyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- three Nitrogen azoles -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.57g, 1mmol), thiomorpholine monoxide hydrochloride (0.31g, 2mmol) yellow solid (0.35g, 57%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：611.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.53 (br.s, 1H), 8.24 (s, 1H), 7.39-6.96 (m, 3H), 6.21 (s, 1H), 5.02 (s, 2H), 4.25 (q, 2H), 4.01 (q, 2H), 3.87-3.82 (m, 2H), 3.15 (br.s, 4H), 2.97 (br.s, 4H), 1.27 (t, 3H), 1.16 (t, 3H)

Step 2) 2- (3- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- ((1- oxos thiomorpholine) methyl) - 1,4- dihydro-pyrimidin -2- bases) -1H-1,2,4- triazole -1- bases) acetic acid

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) - 6- ((1- oxos thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.61g, 1mmol), lithium hydroxide one are hydrated Thing (0.42g, 10mmol) is prepared into yellow solid (0.45g, 78%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：583.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.26 (s, 1H), 7.38-6.96 (m, 3H), 6.20 (s, 1H), 4.89 (s, 2H), 4.43 (dd, 2H), 4.09 (q, 2H), 3.19 (br.s, 4H), 2.99 (br.s, 4H), 1.13 (t, 3H)

Embodiment 20：

2- (3- (4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (carbethoxyl group) -1, 4- dihydro-pyrimidin -2- bases) -1H-1,2,4- triazole -1- bases) acetic acid

Step 1) 4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazoles -3- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (3- carbonamidines -1H-1,2,4- triazole -1- bases) acetate hydrochloride (2.2g, 10mmol), acetoacetate The chloro- 4- fluorobenzaldehydes (1.59g, 10mmol) of ethyl ester (1.3g, 10mmol), 2- obtain yellow by the synthetic method of the step 3 of embodiment 1 Solid (2.02g, 45%).

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

¹H NMR (400MHz, CDCl₃)：δ 8.23 (s, 1H), 7.37-7.33 (m, 1H), 7.26-7.23 (m, 1H), 6.95- 6.92 (m, 1H), 6.14 (s, 1H), 5.02 (s, 2H), 4.23 (q, 2H), 4.06 (q, 2H), 2.51 (s, 3H), 1.26 (t, 3H), 1.11 (t, 3H)

Step 2) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2, 4- triazole -3- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (0.45g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.3g, 57%).

MS-ESI：(ESI, pos.ion) m/z：528.0[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.24 (s, 1H), 7.42-7.39 (m, 1H), 7.33-7.29 (m, 1H), 7.04- 6.99 (m, 1H), 6.12 (s, 1H), 5.04 (s, 2H), 4.97 (d, 1H), 4.69 (d, 1H), 4.25 (q, 2H), 4.14 (q, 2H), 1.28 (t, 3H), 1.14 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (1- (2- ethyoxyls - 2- oxoethyls) -1H-1,2,4- triazole -3- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- three Nitrogen azoles -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.53g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) yellow solid (0.35g, 60%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：583.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.50 (br.s, 1H), 8.20 (s, 1H), 7.34-6.94 (m, 3H), 6.25 (s, 1H), 5.05 (s, 2H), 4.22 (q, 2H), 4.02 (q, 2H), 3.86-3.83 (m, 2H), 3.26 (br.s, 4H), 2.95 (br.s, 4H), 1.26 (t, 3H), 1.12 (t, 3H)

Step 4) 2- (3- (4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (ethoxy carbonyls Base) -1,4- dihydro-pyrimidin -2- bases) -1H-1,2,4- triazole -1- bases) acetic acid

By 4- (the chloro- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (1- (2- ethyoxyl -2- oxygen For ethyl) -1H-1,2,4- triazole -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.58g, 1mmol), lithium hydroxide one Hydrate (0.42g, 10mmol) obtains yellow solid (0.47g, 85%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：555.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.26 (s, 1H), 7.35-6.94 (m, 3H), 6.22 (s, 1H), 4.92 (s, 2H), 4.44 (dd, 2H), 4.11 (q, 2H), 3.38 (br.s, 4H), 2.94 (br.s, 4H), 1.10 (t, 3H)

Embodiment 21：

4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- three Nitrogen azoles -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.53g, 1mmol), morpholine (0.35g, 4mmol) is by embodiment 3 Synthetic method obtains yellow solid (0.37g, 70%).

MS-ESI：(ESI, pos.ion) m/z：535.2[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.56 (br.s, 1H), 8.24 (s, 1H), 7.34-6.97 (m, 3H), 6.19 (s, 1H), 5.02 (s, 2H), 4.23 (q, 2H), 4.01 (q, 2H), 3.84-3.78 (m, 6H), 2.50 (br.s, 4H), 1.26 (t, 3H), 1.12 (t, 3H)

Embodiment 22：

4- (2,4- dichlorophenyl) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (1- (2- ethyoxyl -2- oxo second Base) -1H-1,2,4- triazole -3- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 4- (2,4- dichlorophenyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (3- carbonamidines -1H-1,2,4- triazole -1- bases) acetate hydrochloride (2.2g, 10mmol), acetoacetate Ethyl ester (1.3g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol) obtain yellow by the synthetic method of the step 3 of embodiment 1 Solid (1.77g, 38%).

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

¹H NMR (400MH, CDCl₃)：δ 8.18 (s, 1H), 7.42-6.97 (m, 3H), 6.17 (s, 1H), 5.09 (s, 2H), 4.19 (q, 2H), 4.03 (q, 2H), 2.52 (s, 3H), 1.24 (t, 3H), 1.10 (t, 3H)

Step 2) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2, 4- triazole -3- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (2,4- dichlorophenyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (0.47g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.33g, 60%).

MS-ESI：(ESI, pos.ion) m/z：544.0[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.17 (s, 1H), 7.59-7.31 (m, 3H), 6.15 (s, 1H), 5.08 (s, 2H), 4.91 (d, 1H), 4.67 (d, 1H), 4.21 (q, 2H), 4.11 (q, 2H), 1.23 (t, 3H), 1.10 (t, 3H)

Step 3) 4- (2,4- dichlorophenyl) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (1- (2- ethyoxyls -2- Oxoethyl) -1H-1,2,4- triazole -3- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- tri- Nitrogen azoles -3- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.55g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) yellow solid (0.37g, 62%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：599.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.21 (s, 1H), 7.41-7.02 (m, 3H), 6.15 (s, 1H), 5.08 (s, 2H), 4.27 (q, 2H), 4.08 (q, 2H), 3.91-3.81 (m, 2H), 3.28 (br.s, 4H), 2.95 (br.s, 4H), 1.23 (t, 3H), 1.10 (t, 3H)

Embodiment 23：

6- ((4- Acetylpiperazine -1- bases) methyl) -2- (nitrogen of 1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- three Azoles -3- bases) -4- (2- nitrobenzene) -1,4- dihydro-pyrimidin -5- methyl formates

Step 1) 2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -6- methyl -4- (2- nitre Base benzene) -1,4- dihydro-pyrimidin -5- methyl formates

By 2- (3- carbonamidines -1H-1,2,4- triazole -1- bases) acetate hydrochloride (2.2g, 10mmol), acetoacetate Methyl esters (1.17g, 10mmol), 2- nitrobenzaldehydes (1.51g, 10mmol) obtain yellow by the synthetic method of the step 3 of embodiment 1 and consolidated Body (1.71g, 40%).

MS-ESI：(ESI, pos.ion) m/z：429.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.25 (s, 1H), 7.52-7.48 (m, 2H), 7.45-7.40 (m, 1H), 7.37- 7.32 (m, 1H), 6.07 (s, 1H), 5.02 (s, 2H), 4.21 (q, 2H), 3.71 (s, 3H), 2.48 (s, 3H), 1.13 (t, 3H)

Step 2) 6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -4- (2- nitrobenzene) -1,4- dihydro-pyrimidin -5- methyl formates

By 2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -6- methyl -4- (2- nitros Benzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.43g, 1mmol), NBS (0.2g, 1.1mmol) press the step 4 of embodiment 1 conjunction Yellow solid (0.23g, 45%) is obtained into method.

MS-ESI：(ESI, pos.ion) m/z：507.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.23 (s, 1H), 7.51-7.45 (m, 2H), 7.43-7.39 (m, 1H), 7.37- 7.30 (m, 1H), 6.09 (s, 1H), 5.03 (s, 2H), 4.52 (dd, 2H), 4.24 (q, 2H), 3.68 (s, 3H), 1.11 (t, 3H).

Step 3) 6- ((4- Acetylpiperazine -1- bases) methyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2, 4- triazole -3- bases) -4- (2- nitrobenzene) -1,4- dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -4- (2- nitre Base benzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.51g, 1mmol), N- Acetylpiperazines (0.27g, 2mmol) press embodiment 1 The synthetic method of step 5 obtains yellow solid (0.27g, 48%).

MS-ESI：(ESI, pos.ion) m/z：555.2[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.27 (s, 1H), 7.50-7.43 (m, 2H), 7.41-7.37 (m, 1H), 7.35- 7.30 (m, 1H), 6.10 (s, 1H), 5.07 (s, 2H), 4.21 (q, 2H), 4.09 (dd, 2H), 3.68 (s, 3H), 3.65-3.56 (m, 4H), 2.62 (br.s, 4H), 2.21 (s, 3H), 1.11 (t, 3H)

Embodiment 24：

6- ((4- (2- (tert-butoxy) -2- oxoethyls) piperazine -1- bases) methyl) -2- (1- (2- ethyoxyl -2- oxos Ethyl) -1H-1,2,4- triazole -3- bases) -4- (2- nitrobenzene) -1,4- dihydro-pyrimidin -5- methyl formates

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

Piperazine anhydrous (2g, 23.2mmol), acetonitrile (40mL), 25 DEG C of stirrings are sequentially added in 100mL dry reaction bottles After dissolving completely, bromo-acetic acid tert-butyl (2.26g, 11.6mmol) acetonitrile (20mL) solution is slowly added dropwise.Drop finishes, 25 DEG C of continuation Stir 4h.Filtering, filtrate decompression are evaporated off solvent, dichloromethane (100mL), saturated aqueous common salt are sequentially added into residue (50mL), extracting and demixing, organic layer anhydrous sodium sulfate drying.Remove solvent, crude product column chromatographic isolation and purification (dichloromethane under reduced pressure Alkane/methanol (V/V)=60/1), obtain colorless oil (0.4g, 17%).

MS-ESI：(ESI, pos.ion) m/z：201.2[M+1]⁺；

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

Step 2) 6- ((4- (2- (tert-butoxy) -2- oxoethyls) piperazine -1- bases) methyl) -2- (1- (2- ethyoxyls - 2- oxoethyls) -1H-1,2,4- triazole -3- bases) -4- (2- nitrobenzene) -1,4- dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -2- (1- (2- ethyoxyl -2- oxoethyls) -1H-1,2,4- triazole -3- bases) -4- (2- nitre Base benzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.51g, 1mmol), 2- (piperazine -1- bases) tert-butyl acetate (0.4g, 2mmol) yellow solid (0.27g, 43%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：627.3[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 8.23 (s, 1H), 7.53-7.45 (m, 2H), 7.43-7.38 (m, 1H), 7.36- 7.32 (m, 1H), 6.13 (s, 1H), 5.05 (s, 2H), 4.22 (q, 2H), 4.12 (dd, 2H), 3.69 (s, 3H), 3.17 (s, 2H), 2.99 (br.s, 4H), 2.59 (br.s, 4H), 1.43 (s, 9H), 1.11 (t, 3H)

Embodiment 25：

1- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -2- bases) - 1H-1,2,4- triazole -3- formic acid

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- oxo -1,2,3,4- tetrahydropyrimidine -5- Ethyl formates

Urea (2.90g, 48mmol), ethyl acetoacetate (5.22g, 40mmol), 2- are sequentially added in 100mL eggplant type bottles Bromo- 4- fluorobenzaldehydes (8.12g, 40mmol), trim,ethylchlorosilane (3.81g, 35mmol), sodium iodide (5.25g, 35mmol), Anhydrous acetonitrile (50mL), 12h is stirred at 25 DEG C.Filtering, with a small amount of acetonitrile rinse, obtains white solid (5.72g, 40%).

MS-ESI：(ESI, pos.ion) m/z：357.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.80 (br.s, 1H), 9.22 (br.s, 1H), 6.97-6.85 (m, 3H), 6.10 (s, 1H), 4.06 (q, 2H), 2.52 (s, 3H), 1.12 (t, 3H)

Step 2) (the bromo- 4- fluorophenyls of 2-) chloro- 6- methyl isophthalic acids of -2-, 4- dihydro-pyrimidin -5- Ethyl formates

4- (the bromo- 4- fluorophenyls of 2-) -6- methyl -2- oxos -1,2 are sequentially added in 100mL eggplant type bottles, 3,4- tetrahydrochysenes are phonetic Pyridine -5- Ethyl formates (3.56g, 10mmol), POCl3 (15mL), 4h is reacted in 110 DEG C under nitrogen protection, is cooled to 25 DEG C, remove POCl3 under reduced pressure.Chloroform (100mL) is added into residue, pH value is adjusted to 6-8 with concentrated ammonia liquor.Organic layer is eaten Salt water washing (80mL × 3), anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (petroleum ether/ Ethyl acetate (V/V)=5/1), obtain white solid (1.73g, 46%).

MS-ESI：(ESI, pos.ion) m/z：375.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.82 (br.s, 1H), 6.92-6.83 (m, 3H), 6.12 (s, 1H), 4.08 (q, 2H), 2.52 (s, 3H), 1.08 (t, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (3- cyano group -1,2,4- triazole -1- bases) -6- methyl isophthalic acids, 4- dihydros Pyrimidine -5- Ethyl formates

By (the bromo- 4- fluorophenyls of 2-) chloro- 6- methyl isophthalic acids of -2-, 4- dihydro-pyrimidin -5- Ethyl formates (3.77g, 10mmol), 3- cyano group -1,2,4- triazoles (2.82g, 30mmol), potassium carbonate (2.76g, 20mmol), absolute ethyl alcohol (80mL), nitrogen are protected Lower 60 DEG C of reactions 8h is protected, room temperature is cooled to, filters, solvent, product crude product column chromatographic isolation and purification (oil is evaporated off in filtrate decompression Ether/ethyl acetate (V/V)=3/1), obtain faint yellow solid (2.16g, 50%).

MS-ESI：(ESI, pos.ion) m/z：433.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.68 (br.s, 1H), 8.14 (s, 1H), 7.53-7.19 (m, 3H), 6.12 (s, 1H), 4.06 (q, 2H), 2.46 (s, 3H), 1.12 (t, 3H)

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

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (3- cyano group -1,2,4- triazole -1- bases) -6- methyl isophthalic acids, 4- dihydro-pyrimidins - 5- Ethyl formates (0.35g, 0.8mmol), chloroform (15mL), NBS (0.14g, 0.81mmol) press the synthesis of the step 4 of embodiment 1 Method obtains pale yellow oil (0.33g, 80%).

MS-ESI：(ESI, pos.ion) m/z：511.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.67 (br.s, 1H), 8.15 (s, 1H), 7.52-7.18 (m, 3H), 6.10 (s, 1H), 4.59-4.40 (m, 2H), 4.09 (q, 2H), 1.10 (t, 3H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -6- (morpholine methyl) - 1,4- dihydro-pyrimidin -5- Ethyl formates

Sequentially added in 25mL reaction bulbs 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (3- cyano group -1H-1,2, 4- triazole -1- bases)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.51g, 1mmol), morpholine (0.17g, 2mmol), anhydrous second Alcohol, 1h being stirred at 25 DEG C, removes solvent under reduced pressure, ethyl acetate (200mL), the washing of organic layer saturated common salt are added to remaining species To wash (100mL × 2), organic layer removes solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)= 2/1) yellow solid (0.16g, 30%), is obtained.

MS-ESI：(ESI, pos.ion) m/z：518.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.62 (br.s, 1H), 8.11 (s, 1H), 7.50-7.21 (m, 3H), 6.12 (s, 1H), 4.52 (dd, 2H), 4.11 (q, 2H), 3.62 (br.s, 4H), 2.46 (br.s, 4H), 1.10 (t, 3H)

Step 6) 1- (4- (the bromo- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholinomethyl) -1,4- dihydro-pyrimidins - 2- yls) -1H-1,2,4- triazole -3- formic acid

Sequentially added in 25mL eggplant-shape bottles and add 4- (the bromo- 4- fluorophenyls of 2-) -2- (nitrogen of 3- cyano group -1H-1,2,4- three Azoles -1- bases) -6- (morpholine methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.52g, 1mmol), aqueous hydrochloric acid solution (2mol/L, 10mL), 1h is stirred at 40 DEG C, be cooled to 25 DEG C, ammoniacal liquor adjusts pH to 6-7, and water layer is extracted (80mL × 3) with dichloromethane, organic Layer anhydrous sodium sulfate drying, depressurized solvent, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=1/1), is obtained Yellow solid (0.18g, 33%).

MS-ESI：(ESI, pos.ion) m/z：537.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.17 (s, 1H), 8.03 (s, 1H), 7.58-7.22 (m, 3H), 6.07 (s, 1H), 3.97 (q, 2H), 3.86 (d, 2H), 3.67 (d, 4H), 2.55 (s, 4H), 1.05 (t, 3H)

Embodiment 26：

1- (4- (the chloro- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -2- bases) - 1H-1,2,4- triazole -3- formic acid

Step 1) 4- (the chloro- 4- fluorophenyls of 2-) -6- methyl -2- oxo -1,2,3,4- tetrahydropyrimidine -5- Ethyl formates

By urea (2.90g, 48mmol), ethyl acetoacetate (5.22g, 40mmol), the chloro- 4- fluorobenzaldehydes of 2- (6.34g, 40mmol) white solid (4.75g, 38%) is obtained by the synthetic method of the step 1 of embodiment 25.

MS-ESI：(ESI, pos.ion) m/z：313.7[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.77 (br.s, 1H), 9.20 (br.s, 1H), 6.96-6.83 (m, 3H), 6.11 (s, 1H), 4.03 (q, 2H), 2.51 (s, 3H), 1.10 (t, 3H)

The chloro- 4- of step 2) 2- (the chloro- 4- fluorophenyls of 2-) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -6- methyl -2- oxos -1,2,3,4- tetrahydropyrimidine -5- Ethyl formates (3.13g, 10mmol), POCl3 (15mL) obtains white solid (1.32g, 40%) by the synthetic method of the step 2 of embodiment 25.

MS-ESI：(ESI, pos.ion) m/z：331.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.80 (br.s, 1H), 6.90-6.80 (m, 3H), 6.09 (s, 1H), 4.09 (q, 2H), 2.54 (s, 3H), 1.06 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates

By (the chloro- 4- fluorophenyls of 2-) chloro- 6- methyl isophthalic acids of -2-, 4- dihydro-pyrimidin -5- Ethyl formates (3.31g, 10mmol), 3- cyano group -1,2,4- triazoles (2.82g, 30mmol) by the synthetic method of the step 3 of embodiment 25 obtain faint yellow solid (1.87g, 48%).

MS-ESI：(ESI, pos.ion) m/z：389.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.62 (br.s, 1H), 8.12 (s, 1H), 7.51-7.17 (m, 3H), 6.10 (s, 1H), 4.04 (q, 2H), 2.49 (s, 3H), 1.09 (t, 3H)

Step 4) 4- (the chloro- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -1, 4- dihydro-pyrimidin -5- Ethyl formates

4- (the chloro- 4- fluorophenyls of 2-) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -6- methyl isophthalic acids, 4- dihydros is phonetic Pyridine -5- Ethyl formates (0.39g, 1mmol), chloroform (15mL), NBS (0.2g, 1.1mmol) press the synthesis side of the step 4 of embodiment 1 Method obtains pale yellow oil (0.23g, 50%).

MS-ESI：(ESI, pos.ion) m/z：467.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.62 (br.s, 1H), 8.11 (s, 1H), 7.50-7.15 (m, 3H), 6.11 (s, 1H), 4.61-4.41 (m, 2H), 4.05 (q, 2H), 1.07 (t, 3H)

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -6- (morpholine methyl) - 1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (3- cyano group -1H-1,2,4- triazole -1- bases)-Isosorbide-5-Nitrae-two Hydrogen pyrimidine -5- Ethyl formates (0.47g, 1mmol), morpholine (0.17g, 2mmol) are obtained micro- by the synthetic method of the step 5 of embodiment 25 Yellow solid (0.12g, 26%).

MS-ESI：(ESI, pos.ion) m/z：474.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.56 (br.s, 1H), 8.08 (s, 1H), 7.49-7.23 (m, 3H), 6.08 (s, 1H), 4.50 (dd, 2H), 4.13 (q, 2H), 3.63 (br.s, 4H), 2.48 (br.s, 4H), 1.07 (t, 3H)

Step 6) 1- (4- (the chloro- 4- fluorophenyls of 2-) -5- (carbethoxyl group) -6- (morpholinomethyl) -1,4- dihydro-pyrimidins - 2- yls) -1H-1,2,4- triazole -3- formic acid

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (3- cyano group -1H-1,2,4- triazole -1- bases) -6- (morpholine methyl)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates (0.47g, 1mmol), aqueous hydrochloric acid solution (2mol/L, 10mL) press the synthesis of the step 6 of embodiment 25 Method obtains yellow solid (0.14g, 29%).

MS-ESI：(ESI, pos.ion) m/z：493.1[M+1]⁺；

¹H NMR (400MHz, CDCl₃)：δ 9.12 (s, 1H), 8.01 (s, 1H), 7.55-7.21 (m, 3H), 6.04 (s, 1H), 3.95 (q, 2H), 3.82 (d, 2H), 3.63 (br.s, 4H), 2.52 (br.s, 4H), 1.02 (t, 3H)

Embodiment 27：

4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- cyano thiazole -4- bases) -2 Methylpropionic acid ethyl ester

By 2- (thiazolamine -4- bases) -2 Methylpropionic acid ethyl ester (2.14g, 10mmol), cuprous cyanide (1.79g, 20mmol) micro- brown liquid (0.56g, 25%) is obtained by the synthetic method of the step 1 of embodiment 1

MS-ESI：(ESI, pos.ion) m/z：225.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.52 (s, 1H), 4.11 (q, 2H), 1.75 (s, 6H), 1.23 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) -2 Methylpropionic acid ethyl ester acetate

By 2- (2- cyano thiazole -4- bases) -2 Methylpropionic acid ethyl ester (2.24g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) gray solid (2.35g, 78%) is obtained by the synthetic method of the step 1 of embodiment 9

MS-ESI：(ESI, pos.ion) m/z：242.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.65 (br.s, 1H), 7.80 (s, 1H), 6.88 (br.s, 2H), 4.15 (q, 2H), 2.01 (s, 3H), 1.72 (s, 6H), 1.22 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) -2 Methylpropionic acid ethyl ester acetate (3.01g, 10mmol), ethyl acetoacetate The chloro- 4- fluorobenzaldehydes (1.59g, 10mmol) of (1.3g, 10mmol), 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.12g, 43%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.96 (s, 1H), 7.82 (s, 1H), 7.64-7.31 (m, 3H), 5.97 (s, 1H), 4.12 (q, 2H), 4.05 (q, 2H), 2.46 (s, 3H), 1.74 (s, 6H), 1.13 (t, 3H), 1.04 (t, 3H)

Step 4) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acid-oxopropans - 2- yls) thiazol-2-yl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (0.49g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.28g, 50%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 9.82 (s, 1H), 7.85 (s, 1H), 7.71-7.32 (m, 3H), 6.23 (s, 1H), 4.81 (dd, 2H), 4.12 (q, 2H), 4.03 (q, 2H), 1.68 (s, 6H), 1.24 (t, 3H), 1.04 (t, 3H)

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- (morpholinomethyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) Thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.57g, 1mmol), morpholine (0.35g, 4mmol) is by embodiment 3 Synthetic method obtains yellow solid (0.39g, 67%).

MS-ESI：(ESI, pos.ion) m/z：579.2[M+1]⁺；

¹H NMR (400MHz, DMSO- (d₆)：δ 9.65 (s, 1H), 7.82 (s, 1H), 7.63-7.29 (m, 3H), 5.94 (s, 1H), 4.12-4.03 (m, 4H), 3.95 (dd, 2H), 3.68 (br.s, 4H), 2.57 (br.s, 4H), 1.77 (s, 6H), 1.19 (t, 3H), 1.02 (t, 3H)

Embodiment 28：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) -6- (morpholinomethyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

Step 1) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- methyl formates

By 2- (2- carbonamidines thiazole-4-yl) -2 Methylpropionic acid ethyl ester acetate (3.01g, 10mmol), methyl acetoacetate The bromo- 4- fluorobenzaldehydes (2.03g, 10mmol) of (1.16g, 10mmol), 2- obtain yellow by the synthetic method of the step 3 of embodiment 1 and consolidated Body (2.05g, 39%).

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

¹H NMR (400MHz, DMSO- (d₆)：δ 9.86 (s, 1H), 7.78 (s, 1H), 7.67-7.35 (m, 3H), 6.02 (s, 1H), 4.10 (q, 2H), 3.71 (s, 3H), 2.46 (s, 3H), 1.71 (s, 6H), 1.16 (t, 3H)

Step 2) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acid-oxopropans - 2- yls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- methyl formates (0.52g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.34g, 57%).

MS-ESI：(ESI, pos.ion) m/z：602.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.83 (s, 1H), 7.73 (s, 1H), 7.63-7.32 (m, 3H), 6.08 (s, 1H), 4.34 (dd, 2H), 4.13 (q, 2H), 3.68 (s, 3H), 1.78 (s, 6H), 1.13 (t, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- (morpholinomethyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) Thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.6g, 1mmol), morpholine (0.35g, 4mmol) press embodiment 3 conjunction Yellow solid (0.44g, 72%) is obtained into method.

MS-ESI：(ESI, pos.ion) m/z：609.1[M+1]⁺；

¹H NMR (400MHz, DMSO- (d₆)：δ 9.76 (s, 1H), 7.74 (s, 1H), 7.61-7.25 (m, 3H), 6.01 (s, 1H), 4.17 (q, 2H), 3.99 (dd, 2H), 3.72 (s, 3H), 3.63 (br.s, 4H), 2.52 (br.s, 4H), 1.71 (s, 6H), 1.12 (t, 3H)

Embodiment 29：

2- (2- (4- (2,4- dichlorophenyl) -5- (carbethoxyl group) -6- ((1- epoxides thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydros Pyrimidine -2-base) thiazole-4-yl) -2 Methylpropionic acid

Step 1) 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) -2 Methylpropionic acid ethyl ester acetate (3.01g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.68g, 33%).

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

¹H NMR (400MHz, DMSO- (d₆)：δ 9.49 (s, 1H), 7.82 (s, 1H), 7.72-7.29 (m, 3H), 6.04 (s, 1H), 4.18 (q, 2H), 4.02 (q, 2H), 2.56 (s, 3H), 1.65 (s, 6H), 1.19 (t, 3H), 1.06 (t, 3H)

Step 2) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- Base) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates (0.51g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.3g, 51%).

MS-ESI：(ESI, pos.ion) m/z：588.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.52 (s, 1H), 7.78 (s, 1H), 7.65-7.29 (m, 3H), 6.06 (s, 1H), 4.51 (dd, 2H), 4.15 (q, 2H), 4.01 (q, 2H), 1.68 (s, 6H), 1.16 (t, 3H), 1.03 (t, 3H)

Step 3) 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazole -2- Base) -6- ((1- epoxides thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) Thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.59g, 1mmol), thiomorpholine monoxide hydrochloride (0.31g, 2mmol) yellow solid (0.4g, 64%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：627.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.70 (s, 1H), 7.62 (s, 1H), 7.62-7.26 (m, 3H), 6.21 (s, 1H), 4.15 (q, 2H), 4.06 (q, 2H), 3.95-3.81 (m, 2H), 3.14-2.52 (m, 8H), 1.74 (s, 6H), 1.19- 1.04 (m, 6H)

Step 4) 2- (2- (4- (2,4- dichlorophenyl) -5- (carbethoxyl group) -6- ((1- epoxides thiomorpholine) methyl) -1, 4- dihydro-pyrimidin -2- bases) thiazole-4-yl) -2 Methylpropionic acid

By 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyls -2- methyl isophthalic acids-oxopropan -2- bases) thiazol-2-yl) - 6- ((1- epoxides thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.63g, 1mmol), lithium hydroxide one are hydrated Thing (0.42g, 10mmol) obtains yellow solid (0.49g, 81%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：599.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 12.69 (br.s, 1H), 9.67 (s, 1H), 7.82 (s, 1H), 7.62-7.25 (m, 3H), 6.18 (s, 1H), 4.08 (q, 2H), 3.97-3.89 (m, 2H), 3.21-2.57 (m, 8H), 1.77 (s, 6H), 1.16 (s, 3H)

Embodiment 30：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- (morpholinomethyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

Step 1) 3- (2- cyano thiazole -4- bases) -3 Methylbutanoic acid methyl esters

By 3- (thiazolamine -4- bases) -3 Methylbutanoic acid methyl esters (2.14g, 10mmoD, cuprous cyanide (1.79g, 20mmol) micro- brown liquid (0.45g, 20%) is obtained by the synthetic method of the step 1 of embodiment 1

MS-ESI：(ESI, pos.ion) m/z：225.1[M+1]⁺；

¹H NMR (400MHz, DMSO) δ 7.37 (s, 1H), 3.61 (s, 3H), 2.81 (s, 2H), 1.44 (s, 6H)

Step 2) 3- (2- carbonamidines thiazole-4-yl) -3 Methylbutanoic acid methyl ester hydrochloride

By 3- (2- cyano thiazole -4- bases) -3 Methylbutanoic acid methyl esters (2.24g, 10mmol), sodium methoxide (0.65g, 12mmol), ammonium chloride (0.8g, 15mmol) obtains gray solid (1.94g, 70%) by the synthetic method of the step 2 of embodiment 1

MS-ESI：(ESI, pos.ion) m/z：242.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.28 (br.s, 1H), 7.55 (s, 1H), 6.90 (br.s, 2H), 3.65 (s, 3H), 2.71 (s, 2H), 1.36 (s, 6H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes -2- bases) thiazole -2- Base) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- methyl formates

By 3- (2- carbonamidines thiazole-4-yl) -3 Methylbutanoic acid methyl ester hydrochloride (2.78g, 10mmol), methyl acetoacetate The bromo- 4- fluorobenzaldehydes (2.03g, 10mmol) of (1.16g, 10mmol), 2- obtain yellow by the synthetic method of the step 3 of embodiment 1 and consolidated Body (2.1g, 40%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 10.28 (s, 1H), 7.55 (s, 1H), 7.35-7.03 (m, 3H), 6.02 (s, 1H), 3.66 (br.s, 6H), 2.72 (s, 2H), 2.54 (s, 3H), 1.41 (s, 6H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes - 2- yls) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes -2- bases) thiazol-2-yl) - 6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- methyl formates (0.52g, 1mmol), NBS (0.2g, 1.1mmol) are by the step 4 of embodiment 1 Synthetic method obtains yellow solid (0.29g, 48%).

MS-ESI：(ESI, pos.ion) m/z：602.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.18 (s, 1H), 7.45 (s, 1H), 7.39-7.05 (m, 3H), 6.02 (s, 1H), 4.53 (dd, 2H), 3.69 (br.s, 6H), 2.75 (s, 2H), 1.35 (s, 6H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes -2- bases) thiazole -2- Base) -6- (morpholinomethyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (4- methoxyl group -2- methyl -4- oxo-butanes -2- bases) Thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- methyl formates (0.6g, 1mmol), morpholine (0.35g, 4mmol) press embodiment 3 conjunction Yellow solid (0.4g, 65%) is obtained into method.

MS-ESI：(ESI, pos.ion) m/z：609.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.17 (s, 1H), 7.55 (s, 1H), 7.45-7.13 (m, 3H), 6.21 (s, 1H), 3.98 (dd, 2H), 3.71 (br.s, 6H), 3.61 (br.s, 4H), 2.81 (s, 2H), 2.57 (br.s, 4H), 1.38 (s, 6H).

Embodiment 31：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiazol-2-yl) -6- (morpholinoes Methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- cyano thiazole -4- bases) ethyl propionate

By 2- (thiazolamine -4- bases) ethyl propionate (2g, 10mmol), cuprous cyanide (1.79g, 20mmol) by implementation The synthetic method of the step 1 of example 1 obtains micro- brown liquid (0.59g, 28%)

MS-ESI：(ESI, pos.ion) m/z：211.1[M+1]⁺；

¹H NMR (400MHz, DMSO- (d₆)：δ 7.54 (s, 1H), 4.69 (q, 1H), 4.21 (q, 2H), 1.51 (d, 3H), 1.22 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) ethyl propionate acetate

By 2- (2- cyano thiazole -4- bases) ethyl propionate (2.1g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) by real The synthetic method for applying the step 1 of example 9 obtains gray solid (2g, 70%)

MS-ESI：(ESI, pos.ion) m/z：228.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.48 (s, 1H), 7.82 (s, 1H), 6.90 (s, 2H), 4.63 (q, 1H), 4.21 (q, 2H), 1.99 (s, 3H), 1.51 (d, 3H), 1.16 (t, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiazol-2-yl) -6- Methyl isophthalic acid, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl propionate acetate (2.87g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), the bromo- 4- fluorobenzaldehydes (2.03g, 10mmol) of 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.36g, 45%).

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

¹H NMR (400MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.72 (s, 1H), 7.35-7.02 (m, 3H), 6.14 (s, 1H), 4.21 (q, 2H), 4.08 (q, 2H), 3.82 (q, 1H), 2.56 (s, 3H), 1.51 (d, 3H), 1.19-1.05 (m, 6H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiophenes Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.52g, 1mmol), NBS (0.2g, 1.1mmol) press the synthesis side of the step 4 of embodiment 1 Method obtains yellow solid (0.31g, 51%).

MS-ESI：(ESI, pos.ion) m/z：602.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.78 (s, 1H), 7.39-7.02 (m, 3H), 6.11 (s, 1H), 4.53 (dd, 2H), 4.18 (q, 2H), 4.06 (q, 2H), 3.61 (q, 1H), 1.54 (d, 3H), 1.23-1.07 (m, 6H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiazol-2-yl) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- ethyoxyl -1- oxopropan -2- bases) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.6g, 1mmol), morpholine (0.35g, 4mmol) press embodiment 3 synthetic method Obtain yellow solid (0.41g, 68%).

MS-ESI：(ESI, pos.ion) m/z：609.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.29 (s, 1H), 7.81 (s, 1H), 7.33-6.97 (m, 3H), 6.17 (s, 1H), 4.25 (q, 1H), 4.14-4.03 (m, 4H), 3.91-3.84 (m, 2H), 3.67 (br.s, 4H), 2.57 (br.s, 4H), 1.48 (d, 3H), 1.21-1.07 (m, 6H)

Embodiment 32：

2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (carbethoxyl group) -1, 4- dihydro-pyrimidin -2- bases) thiazole-4-yl) butyric acid

Step 1) 2- (2- cyano thiazole -4- bases) ethyl butyrate

2- (thiazolamine -4- bases) ethyl butyrate (2.14g, 10mmol), cuprous cyanide (1.79g, 20mmol) are pressed The synthetic method of the step 1 of embodiment 1 obtains micro- brown liquid (0.47g, 21%)

MS-ESI：(ESI, pos.ion) m/z：225.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.64 (s, 1H), 4.37 (t, 1H), 4.21 (q, 2H), 2.18-2.05 (m, 2H), 1.18 (t, 3H), 0.96 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) ethyl butyrate acetate

2- (2- cyano thiazole -4- bases) ethyl butyrate (2.24g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) are pressed The synthetic method of the step 1 of embodiment 9 obtains gray solid (1.96g, 65%).

MS-ESI：(ESI, pos.ion) m/z：242.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.38 (s, 1H), 7.72 (s, 1H), 6.85 (s, 2H), 4.56 (t, 1H), 4.18 (q, 2H), 2.15-2.09 (m, 2H), 1.20 (t, 3H), 0.89 (t, 3H)

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -6- Methyl isophthalic acid, 4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl butyrate acetate (3.01g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), the chloro- 4- fluorobenzaldehydes (1.59g, 10mmol) of 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.93g, 39%).

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

¹H NMR (400MHz, DMSO-d₆) δ 10.02 (s, 1H), 7.82 (s, 1H), 7.58-7.22 (m, 3H), 6.27 (s, 1H), 4.45 (t, 1H), 4.18 (q, 2H), 4.11 (q, 2H), 2.48 (s, 3H), 2.14-2.09 (m, 2H), 1.17-1.05 (m, 6H), 0.83 (t, 3H)

Step 4) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiophenes Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.49g, 1mmol), NBS (0.2g, 1.1mmol) press the synthesis side of the step 4 of embodiment 1 Method obtains yellow solid (0.3g, 52%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 10.02 (s, 1H), 7.65 (s, 1H), 7.55-7.18 (m, 3H), 6.17 (s, 1H), 4.52 (dd, 2H), 4.39 (t, 1H), 4.15 (q, 2H), 4.08 (q, 2H), 2.12-2.08 (m, 2H), 1.15-1.08 (m, 6H), 0.81 (t, 3H)

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (4- (1- ethyoxyls - 1- oxo-butanes -2- bases) thiazol-2-yl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.57g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) Yellow solid (0.34g, 55%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：627.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆) δ 9.81 (s, 1H), 7.75 (s, 1H), 7.62-7.23 (m, 3H), 6.14 (s, 1H), 4.50-4.41 (m, 2H), 4.32 (t, 1H), 4.23 (q, 2H), 4.11 (q, 2H), 3.28 (br.s, 4H), 2.95 (br.s, 4H), 2.14-2.09 (m, 2H), 1.17-1.06 (m, 6H), 0.86 (t, 3H)

Step 6) 2- (2- (4- (the chloro- 4- fluorophenyls of 2-) -6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (ethoxy carbonyls Base) -1,4- dihydro-pyrimidin -2- bases) thiazole-4-yl) butyric acid

By 4- (the chloro- 4- fluorophenyls of 2-) -6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (1- ethyoxyl -1- oxygen For butane -2- bases) thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.63g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) obtains yellow solid (0.45g, 75%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：599.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆) δ 10.38 (br.s, 1H), 9.86 (s, 1H), 7.65 (s, 1H), 7.61-7.26 (m, 3H), 6.13 (s, 1H), 4.47-4.40 (m, 2H), 4.29 (t, 1H), 4.09 (q, 2H), 3.26 (br.s, 4H), 2.92 (br.s, 4H), 2.12-2.08 (m, 2H), 1.07 (t, 3H), 0.82 (t, 3H)

Embodiment 33：

2- (2- (6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (carbethoxyl group) -4- (2- nitrobenzophenones) -1,4- two Hydrogen pyrimidine -2-base) thiazole-4-yl) butyric acid

Step 1) 2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -6- methyl -4- (2- nitrobenzene Base) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl butyrate acetate (3.01g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2- nitrobenzaldehydes (1.51g, 10mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.99g, 41%).

MS-ESI：(ESI, pos.ion) m/z：487.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.98 (s, 1H), 8.21-7.94 (m, 1H), 7.78-7.45 (m, 3H), 6.07 (s, 1H), 4.57-3.91 (m, 5H), 2.49 (s, 3H), 2.15-2.11 (m, 2H), 1.21-1.09 (m, 6H), 0.81 (t, 3H).

Step 2) 6- (bromomethyl) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -4- (2- nitros Phenyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -6- methyl -4- (2- nitrobenzophenones) -1, 4- dihydro-pyrimidin -5- Ethyl formates (0.49g, 1mmol), NBS (0.2g, 1.1mmol) press the synthetic method of the step 4 of embodiment 1 Obtain yellow solid (0.33g, 59%).

MS-ESI：(ESI, pos.ion) m/z：565.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.82 (s, 1H), 8.17-7.98 (m, 1H), 7.78-7.49 (m, 3H), 6.15 (s, 1H), 4.62 (dd, 2H), 4.51-3.90 (m, 5H), 2.13-2.08 (m, 2H), 1.21-1.05 (m, 6H), 0.84 (t, 3H)

Step 3) 6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiophenes Azoles -2- bases) -4- (2- nitrobenzophenones) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazol-2-yl) -4- (2- nitrobenzene Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.57g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) Yellow solid (0.42g, 68%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：620.2[M+1]⁺；

¹H NMR (4 () () MHz, DMSO-d₆)：δ 9.81 (s, 1H), 8.14-7.87 (m, 1H), 7.79-7.45 (m, 3H), 6.13 (s, 1H), 4.59-4.54 (m, 2H), 4.48-3.93 (m, 5H), 3.28 (br.s, 4H), 2.93 (br.s, 4H), 2.16- 2.09 (m, 2H), 1.23-1.08 (m, 6H), 0.88 (t, 3H)

Step 4) 2- (2- (6- ((the epoxide thiomorpholines of 1,1- bis-) methyl) -5- (carbethoxyl group) -4- (2- nitrobenzophenones) - 1,4- dihydro-pyrimidin -2- bases) thiazole-4-yl) butyric acid

By 6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (1- ethyoxyl -1- oxo-butanes -2- bases) thiazole -2- Base) -4- (2- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.62g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) obtains yellow solid (0.44g, 74%) by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：592.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.62 (br.s, 1H), 9.86 (s, 1H), 8.11-7.84 (m, 1H), 7.75-7.43 (m, 3H), 6.11 (s, 1H), 4.59-4.55 (m, 2H), 4.39-4.05 (m, 3H), 3.26 (br.s, 4H), 2.95 (br.s, 4H), 2.13-2.09 (m, 2H), 1.13 (t, 3H), 0.81 (t, 3H)

Embodiment 34：

4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiazol-2-yl) -6- ((1- oxos Thiomorpholine) methyl) -1,4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 2- (2- cyano thiazole -4- bases) ethyl hexanoate

2- (thiazolamine -4- bases) ethyl hexanoate (2.42g, 10mmol), cuprous cyanide (1.79g, 20mmol) are pressed The synthetic method of the step 1 of embodiment 1 obtains micro- brown liquid (0.56g, 22%).

MS-ESI：(ESI, pos.ion) m/z：253.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.54 (s, 1H), 4.54 (t, 1H), 4.21 (q, 2H), 2.34-1.68 (m, 2H), 1.49-1.14 (m, 7H), 1.04 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) ethyl hexanoate acetate

2- (2- cyano thiazole -4- bases) ethyl hexanoate (2.52g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) are pressed The synthetic method of the step 1 of embodiment 9 obtains gray solid (2.27g, 69%).

MS-ESI：(ESI, pos.ion) m/z：270.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.38 (s, 1H), 7.82 (s, 1H), 6.88 (s, 2H), 4.21 (q, 2H), 3.82 (s, 1H), 2.02 (d, 2H), 1.98 (s, 3H), 1.51-1.17 (m, 7H), 0.82 (s, 3H)

Step 3) 4- (2,4 dichloro benzene base) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiazol-2-yl) -6- first Base -1,4- dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) ethyl hexanoate acetate (3.3g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (2.15g, 40%).

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

¹H NMR (400MHz, DMSO-d₆)：δ 10.03 (s, 1H), 7.82 (s, 1H), 7.62-7.22 (m, 3H), 6.13 (s, 1H), 4.21 (q, 2H), 4.08 (q, 2H), 3.94 (t, 1H), 2.53 (s, 3H), 2.15-1.85 (m, 2H), 1.52-1.14 (m, 10H), 0.97-0.80 (m, 3H)

Step 4) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiophenes Azoles -2- bases) -1,4- dihydro-pyrimidin -5- Ethyl formates

By 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiazol-2-yl) -6- methyl - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.54g, 1mmol), NBS (0.2g, 1.1mmol) press the synthesis side of the step 4 of embodiment 1 Method obtains yellow solid (0.3g, 49%).

MS-ESI：(ESI, pos.ion) m/z：616.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 11.18 (s, 1H), 7.79 (s, 1H), 7.64-7.21 (m, 1H), 6.47 (s, 1H), 4.89 (s, 2H), 4.36 (t, 1H), 4.20 (q, 2H), 4.07 (q, 2H), 2.39-1.77 (m, 2H), 1.49-1.26 (m, 3H), 1.25-1.07 (m, 7H), 0.95-0.79 (m, 3H)

Step 5) 4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiazol-2-yl) -6- ((1- oxos thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (1- ethyoxyl -1- oxohexane -2- bases) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.62g, 1mmol), thiomorpholine monoxide hydrochloride (0.31g, 2mmol) Yellow solid (0.43g, 65%) is obtained by the synthetic method of the step 5 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：655.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.83 (s, 1H), 7.72 (s, 1H), 7.61-7.22 (m, 1H), 6.31 (s, 1H), 4.67 (s, 2H), 4.31 (t, 1H), 4.21 (q, 2H), 4.09 (q, 2H), 3.17 (br.s, 4H), 2.97 (br.s, 4H), 2.32-1.79 (m, 2H), 1.45-1.23 (m, 3H), 1.22-1.03 (m, 7H), 0.93-0.74 (m, 3H)

Embodiment 35：

4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazol-2-yl) -6- (morpholine methyl) -1, 4- dihydro-pyrimidin -5- Ethyl formates

Step 1) 1- (2- cyano thiazole -4- bases) ethylene-acetic acid ethyl ester

By 1- (thiazolamine -4- bases) ethylene-acetic acid ethyl ester (2.12g, 10mmol), cuprous cyanide (1.79g, 20mmol) micro- brown liquid (0.47g, 21%) is obtained by the synthetic method of the step 1 of embodiment 1.

MS-ESI：(ESI, pos.ion) m/z：223.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.54 (s, 1H), 4.16 (q, 2H), 1.64-1.43 (m, 4H), 1.17 (t, 3H).

Step 2) 1- (2- carbonamidines thiazole-4-yl) ethylene-acetic acid ethyl ester acetate

By 1- (2- cyano thiazole -4- bases) ethylene-acetic acid ethyl ester (2.22g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) gray solid (2.25g, 75%) is obtained by the synthetic method of the step 1 of embodiment 9.

MS-ESI：(ESI, pos.ion) m/z：240.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.68 (s, 1H), 7.82 (s, 1H), 6.90 (s, 2H), 4.16 (q, 2H), 2.01 (s, 3H), 1.71-1.29 (m, 4H), 1.22 (t, 3H)

Step 3) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazol-2-yl) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 1- (2- carbonamidines thiazole-4-yl) ethylene-acetic acid ethyl ester acetate (2.99g, 10mmol), ethyl acetoacetate The bromo- 4- fluorobenzaldehydes (2-03g, 10mmol) of (1.3g, 10mmol), 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.2g, 41%).

MS-ESI：(ESI, pos.ion) m/z：536.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.94 (s, 1H), 7.82 (s, 1H), 7.35-6.98 (m, 3H), 6.18 (s, 1H), 4.16-4.05 (m, 4H), 2.51 (s, 3H), 1.74-1.33 (m, 4H), 1.19-1.04 (m, 6H)

Step 4) 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazol-2-yl) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates (0.54g, 1mmol), NBS (0.2g, 1.1mmol) are obtained yellow by the synthetic method of the step 4 of embodiment 1 Color solid (0.33g, 53%).

MS-ESI：(ESI, pos.ion) m/z：614.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.69 (s, 1H), 7.72 (s, 1H), 7.47-7.02 (m, 3H), 6.13 (s, 1H), 4.55 (dd, 2H), 4.14-4.01 (m, 4H), 1.68-1.32 (m, 4H), 1.17-1.02 (m, 6H)

Step 5) 4- (the bromo- 4- fluorophenyls of 2-) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazol-2-yl) -6- (morpholine first Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (the bromo- 4- fluorophenyls of 2-) -6- (bromomethyl) -2- (4- (1- (carbethoxyl group) cyclopropyl) thiazol-2-yl) -1, 4- dihydro-pyrimidin -5- Ethyl formates (0.62g, 1mmol), morpholine (0.35g, 4mmol) obtain yellow by the synthetic method of embodiment 3 Solid (0.37g, 59%).

MS-ESI：(ESI, pos.ion) m/z：621.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.73 (s, 1H), 7.69 (s, 1H), 7.53-7.12 (m, 3H), 6.11 (s, 1H), 4.22-4.16 (m, 2H), 4.12-3.98 (m, 4H), 3.65 (br.s, 4H), 2.48 (br.s, 4H), 1.62-1.32 (m, 4H), 1.15-1.02 (m, 6H)

Embodiment 36：

2- (2- (6- ((1,1- bis- epoxide thiomorpholine) methyl) -5- (carbethoxyl group) -4- (2- nitrobenzene)-Isosorbide-5-Nitrae-dihydro Pyrimidine -2-base) thiazole-4-yl) -2- phenylacetic acids

Step 1) 2- (2- cyano thiazole -4- bases) -2- ethyl phenylacetates

By 2- (thiazolamine -4- bases) -2- ethyl phenylacetates (2.62g, 10mmol), cuprous cyanide (1.79g, 20mmol) micro- brown liquid (0.79g, 29%) is obtained by the synthetic method of the step 1 of embodiment 1

MS-ESI：(ESI, pos.ion) m/z：273.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.51 (s, 1H), 7.41-7.33 (m, 3H), 7.25-7.13 (m, 2H), 5.43 (s, 1H), 4.21 (q, 2H), 1.19 (t, 3H)

Step 2) 2- (2- carbonamidines thiazole-4-yl) -2- ethyl phenylacetate acetate

By 2- (2- cyano thiazole -4- bases) -2- ethyl phenylacetates (2.72g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) gray solid (2.38g, 68%) is obtained by the synthetic method of the step 1 of embodiment 9

MS-ESI：(ESI, pos.ion) m/z：290.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.48 (s, 1H), 7.62 (s, 1H), 7.49-7.30 (m, 3H), 7.24- 7.10 (m, 2H), 6.60 (br.s, 2H), 5.33 (s, 1H), 4.21 (q, 2H), 1.12 (t, 3H)

Step 3) 2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiazol-2-yl) -6- methyl -4- (2- nitrobenzene) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 2- (2- carbonamidines thiazole-4-yl) -2- ethyl phenylacetates acetate (3.49g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2- nitrobenzaldehydes (1.51g, 10mmol) obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (2.2g, 41%).

MS-ESI：(ESI, pos.ion) m/z：535.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：610.21 (s, 1H), 8.13-7.98 (m, 1H), 7.69 (s, 1H), 7.66- 7.52 (m, 3H), 7.49-7.31 (m, 3H), 7.29-7.11 (m, 2H), 6.07 (s, 1H), 5.38 (s, 1H), 4.21 (q, 2H), 4.08 (q, 2H), 2.51 (s, 3H), 1.18-1.05 (m, 6H)

Step 4) 6- (bromomethyl) -2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiazol-2-yl) -4- (2- nitros Benzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiazol-2-yl) -6- methyl -4- (2- nitrobenzene)-Isosorbide-5-Nitrae - Dihydro-pyrimidin -5- Ethyl formates (0.53g, 1mmol), NBS (0.2g, 1.1mmol) are obtained by the synthetic method of the step 4 of embodiment 1 Yellow solid (0.25g, 40%).

MS-ESI：(ESI, pos.ion) m/z：613.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.27 (s, 1H), 8.11-8.03 (m, 1H), 7.64 (s, 1H), 7.61- 7.51 (m, 3H), 7.45-7.30 (m, 3H), 7.27-7.10 (m, 2H), 6.04 (s, 1H), 5.32 (s, 1H), 4.42-4.33 (m, 2H), 4.21 (q, 2H), 4.04 (q, 2H), 1.13-1.02 (m, 6H)

Step 5) 6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiophenes Azoles -2- bases) -4- (2- nitrobenzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiazol-2-yl) -4- (2- nitrobenzene) - Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.61g, 1mmol), thiomorpholine dioxide. HCl (0.34g, 2mmol) are by real The synthetic method for applying the step 5 of example 1 obtains yellow solid (0.41g, 62%).

MS-ESI：(ESI, pos.ion) m/z：668.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.22 (s, 1H), 8.15-8.07 (m, 1H), 7.74 (s, 1H), 7.66- 7.51 (m, 3H), 7.47-7.33 (m, 3H), 7.27-7.16 (m, 2H), 6.07 (s, 1H), 5.38 (s, 1H), 4.39-4.28 (m, 2H), 4.19 (q, 2H), 4.06 (q, 2H), 3.26 (br.s, 4H), 2.96 (br.s, 4H), 1.15-1.04 (m, 6H)

Step 6) 2- (2- (6- ((1,1- bis- epoxide thiomorpholine) methyl) -5- (carbethoxyl group) -4- (2- nitrobenzene) -1, 4- dihydro-pyrimidin -2- bases) thiazole-4-yl) -2- phenylacetic acids

By 6- ((1,1- bis- epoxide thiomorpholine) methyl) -2- (4- (2- ethyoxyl -2- oxo -1- phenethyls) thiazole -2- Base) -4- (2- nitrobenzene)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates (0.67g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) yellow solid (0.51g, 80%) is obtained by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：640.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 9.98 (s, 1H), 8.12-8.04 (m, 1H), 7.71 (s, 1H), 7.59- 7.51 (m, 3H), 7.48-7.31 (m, 3H), 7.25-7.12 (m, 2H), 6.02 (s, 1H), 5.48 (s, 1H), 4.33-4.24 (m, 2H), 4.03 (q, 2H), 3.22 (br.s, 4H), 2.91 (br.s, 4H), 1.11 (t, 3H)

Embodiment 37：

3- (2- (4- (2,4- dichlorophenyl -5- (carbethoxyl group) -6- ((1- epoxides thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydros Pyrimidine -2-base) thiazole-4-yl) propionic acid

Step 1) 3- (2- cyano thiazole -4- bases) ethyl propionate

By 3- (thiazolamine -4- bases) ethyl propionate (2g, 10mmol), cuprous cyanide (1.79g, 20mmol) by implementation The synthetic method of the step 1 of example 1 obtains micro- brown liquid (0.46g, 22%)

MS-ESI：(ESI, pos.ion) m/z：211.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 7.25 (s, 1H), 4.03 (q, 2H), 3.15 (t, 2H), 2.52 (t, 2H), 1.07 (t, 3H)

Step 2) 3- (2- carbonamidines thiazole-4-yl) ethyl propionate acetate

By 3- (2- cyano thiazole -4- bases) ethyl propionate (2.1g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) by real The synthetic method for applying the step 1 of example 9 obtains gray solid (1.87g, 65%)

MS-ESI：(ESI, pos.ion) m/z：228.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.72 (s, 1H), 7.53 (s, 1H), 6.88 (s, 2H), 4.06 (q, 2H), 3.15-3.08 (m, 2H), 2.68-2.37 (m, 2H), 1.99 (s, 3H), 1.07 (t, 3H)

Step 3) 4- (2,4- dichlorophenyl) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- dihydro-pyrimidin -5- Ethyl formates

By 3- (2- carbonamidines thiazole-4-yl) ethyl propionate acetate (2.87g, 10mmol), ethyl acetoacetate (1.3g, 10mmol), 2,4- dichlorobenzaldehydes (1.75g, 10mmol) by the synthetic method of the step 3 of embodiment 1 obtain yellow solid (1.89g, 38%).

MS-ESI：(ESI, pos.ion) m/z：496.1[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.21 (s, 1H), 7.72 (d, 1H), 7.55-7.22 (m, 3H), 6.09 (s, 1H), 4.05-3.89 (m, 4H), 3.15-3.08 (m, 2H), 2.62-2.49 (m, 2H), 2.46 (s, 3H), 1.18-1.05 (m, 6H).

Step 4) 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazole -2- Base)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 4- (2,4- dichlorophenyl) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazol-2-yl) -6- methyl isophthalic acids, 4- bis- Hydrogen pyrimidine -5- Ethyl formates (0.5g, 1mmol), NBS (0.2g, 1.1mmol) obtain yellow by the synthetic method of the step 4 of embodiment 1 Solid (0.33g, 58%).

MS-ESI：(ESI, pos.ion) m/z：574.0[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 11.12 (s, 1H), 7.68 (d, 1H), 7.51 (s, 1H), 7.32-7.21 (m, 2H), 5.99 (s, 1H), 4.57 (dd, 2H), 4.14-3.93 (m, 4H), 3.19 (t, 2H), 2.41 (t, 2H), 1.11-1.04 (m, 6H).

Step 5) 4- (2,4- dichlorophenyl) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazol-2-yl) -6- ((1- oxygen Base thiomorpholine) methyl)-Isosorbide-5-Nitrae-dihydro-pyrimidin -5- Ethyl formates

By 6- (bromomethyl) -4- (2,4- dichlorophenyl) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazol-2-yl) -1, 4- dihydro-pyrimidin -5- Ethyl formates (0.58g, 1mmol), thiomorpholine monoxide hydrochloride (0.31g, 2mmol) are by implementation The synthetic method of the step 5 of example 1 obtains yellow solid (0.39g, 63%).

MS-ESI：(ESI, pos.ion) m/z：613.2[M+1]⁺；

¹H NMR (400MHz, DMSO-d₆)：δ 10.22 (br.s, 1H), 7.73 (d, 1H), 7.64 (s, 1H), 7.43-7.19 (m, 2H), 6.04 (s, 1H), 4.35-4.22 (m, 2H), 4.19-3.99 (m, 4H), 3.25 (t, 2H), 3.12 (br.s, 4H), 2.94 (br.s, 4H), 2.38 (t, 2H), 1.17-1.08 (m, 6H)

Step 6) 3- (2- (4- (2,4- dichlorophenyl -5- (carbethoxyl group) -6- ((1- epoxides thiomorpholine) methyl) -1, 4- dihydro-pyrimidin -2- bases) thiazole-4-yl) propionic acid

By 4- (2,4 dichloro benzene base) -2- (4- (3- ethyoxyl -3- oxopropyls) thiazol-2-yl) -6- ((1- epoxide sulphur For morpholine) methyl) -1,4- dihydro-pyrimidin -5- Ethyl formates (0.61g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) yellow solid (0.44g, 75%) is obtained by the synthetic method of embodiment 2.

MS-ESI：(ESI, pos.ion) m/z：585.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ11.06(br.s,1H),9.86(br.s,1H),7.69(d,1H),7.58 (s,1H),7.48-7.22(m,2H),6.07(s,1H),4.25-4.14(m,2H),4.03(q,2H),3.21(t,2H),3.16 (br.s,4H),2.94(br.s,4H),2.33(t,2H),1.04(t,3H).

Embodiment 38：

4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- (morpholinoes Methyl) -1,4- dihydro-pyrimidin -5- methyl formates

Step 1) 3- (2- cyano thiazole -4- bases) ethyl butyrate

3- (thiazolamine -4- bases) ethyl butyrate (2.14g, 10mmol), cuprous cyanide (1.79g, 20mmol) are pressed The synthetic method of the step 1 of embodiment 1 obtains micro- brown liquid (0.65g, 29%)

MS-ESI：(ESI, pos.ion) m/z：225.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ7.37(s,1H),4.01(q,2H),3.86-3.55(m,1H),2.85- 2.71(m,2H),1.27(d,3H),1.03(t,3H).

Step 2) 3- (2- carbonamidines thiazole-4-yl) ethyl butyrate acetate

3- (2- cyano thiazole -4- bases) ethyl butyrate (2.24g, 10mmol), hydroxylamine hydrochloride (0.83g, 12mmol) are pressed The synthetic method of the step 1 of embodiment 9 obtains gray solid (1.87g, 62%)

MS-ESI：(ESI, pos.ion) m/z：242.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ10.32(s,1H),7.55(s,1H),6.69(br.s,2H),4.08(q, 2H),3.61-3.54(m,1H),2.85-2.64(m,2H),2.01(s,3H),1.29(d,3H),1.07(t,3H).

Step 3) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- Methyl isophthalic acid, 4- dihydro-pyrimidin -5- methyl formates

By 3- (2- carbonamidines thiazole-4-yl) ethyl butyrate acetate (3.01g, 10mmol), methyl acetoacetate (1.16g, 10mmol), the chloro- 4- fluorobenzaldehydes (1.59g, 10mmol) of 2- obtain yellow solid by the synthetic method of the step 3 of embodiment 1 (1.92g, 40%).

MS-ESI：(ESI, pos.ion) m/z：480.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ10.32(s,1H),7.68(dd,1H),7.61(s,1H),7.36-7.14 (m,2H),6.08(s,1H),4.07(q,2H),3.69(dd,1H),3.65(s,3H),2.90-2.68(m,2H),2.49(s, 3H),1.28(d,3H),1.07(t,3H).

Step 4) 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiophenes Azoles -2- bases) -1,4- dihydro-pyrimidin -5- methyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- methyl - 1,4- dihydro-pyrimidin -5- methyl formates (0.48g, 1mmol), NBS (0.2g, 1.1mmol) press the synthesis side of the step 4 of embodiment 1 Method obtains yellow solid (0.3g, 53%).

MS-ESI：(ESI, pos.ion) m/z：558.0[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ10.19(s,1H),7.63(dd,1H),7.55(s,1H),7.39-7.17 (m,2H),6.04(s,1H),4.51(dd,2H),4.04(q,2H),3.66(dd,1H),3.62(s,3H),2.93-2.65(m, 2H),1.24(d,3H),1.07(t,3H).

Step 5) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -5- methyl formates

By 6- (bromomethyl) -4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazole -2- Base) -1,4- dihydro-pyrimidin -5- methyl formates (0.56g, 1mmol), morpholine (0.35g, 4mmol) press embodiment 3 synthetic method Obtain yellow solid (0.4g, 72%).

MS-ESI：(ESI, pos.ion) m/z：565.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ10.26(s,1H),7.59(dd,1H),7.52(s,1H),7.41-7.19 (m,2H),6.06(s,1H),4.41-4.27(m,2H),4.09(q,2H),3.68-3.63(m,5H),3.59(s,3H),2.91- 2.69(m,2H),2.45(br.s,4H),1.26(d,3H),1.02(t,3H).

Step 6) 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- (morpholinomethyl) -1,4- dihydro-pyrimidin -5- methyl formates

By 4- (the chloro- 4- fluorophenyls of 2-) -2- (4- (4- ethyoxyl -4- oxo-butanes -2- bases) thiazol-2-yl) -6- (morpholines For methyl) -1,4- dihydro-pyrimidin -5- methyl formates (0.57g, 1mmol), lithium hydroxide monohydrate (0.42g, 10mmol) press The synthetic method of embodiment 2 obtains yellow solid (0.41g, 77%).

MS-ESI：(ESI, pos.ion) m/z：537.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆)：δ10.92(br.s,1H),9.93(s,1H),7.61(dd,1H),7.55(s, 1H),7.44-7.19(m,2H),6.03(s,1H),4.38-4.22(m,2H),3.71-3.61(m,5H),3.56(s,3H), 2.87-2.69(m,2H),2.48(br.s,4H),1.22(d,3H).

Embodiment 39：

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

I. experimental method：

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

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

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

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

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

II. experimental result：

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

Table 2

III. conclusion：

As a result show, embodiment 1,3,5,7,9,10,11,12 suppresses hbv replication percentage and is more than 80%, shows this hair Bright described compound has the function that stronger Anti-HBV activity replicates.This kind of compound has antiviral work beyond expectation to HBV Property, therefore suitable for treatment various diseases caused by HBV virus infection.

Claims

1. one kind has the compound as shown in formula (IV) or (IVa),

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

Y is-O- or-S (=O)_q-；

R²For C₁-C₄Alkyl；

R³For substituted 5-6 unit's heteroaryls；Substituent on wherein described heteroaryl is selected from-(CR⁷R^7a)_m- C (=O) O-R⁸, its In, m 1,2,3 or 4；

Each R^7aAnd R⁷It independently is hydrogen, deuterium, C₁-C₆Alkyl, C₁-C₄Haloalkyl, C₆-C₁₀Aryl；Or R⁷、R^7aBe attached thereto C atoms form C together₃-C₈Cycloalkyl；

Each R⁸It independently is H, deuterium or C₁-C₆Alkyl；

Each R¹³It independently is fluorine, chlorine or bromine；

Each p independently is 1 or 2；

Each q independently is 0,1 or 2.

2. compound according to claim 1, wherein：

Each R^7aAnd R⁷It independently is hydrogen, deuterium, methyl, ethyl, propyl group, butyl or phenyl；Or R⁷、R^7aWith the C atoms being attached thereto Cyclopropyl is formed together；

Each R⁸It independently is H, deuterium, methyl, ethyl, propyl group or butyl.

3. compound according to claim 2, wherein：

Each R^7aAnd R⁷It independently is hydrogen, deuterium, methyl, ethyl, isopropyl, the tert-butyl group, 1- methyl-propyls, 2- methyl-propyls or benzene Base；Or R⁷、R^7aCyclopropyl is formed together with the C atoms being attached thereto；

Each R⁸It independently is H, deuterium, methyl, ethyl, isopropyl, the tert-butyl group, 1- methyl-propyls or 2- methyl-propyls.

4. compound according to claim 1, wherein：

R³Independently selected from following subformula：

5. compound according to claim 1, the structure comprising one of：

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

6. according to the compound described in claim 1-5 any one, or its enantiomter, mutually diastereoisomer, variation Structure body, pharmaceutically acceptable salt, wherein the salt is acylate, inorganic acid salt or the salt obtained by alkali.

7. compound according to claim 6, or its enantiomter, diastereoisomer, dynamic isomer, pharmaceutically Acceptable salt, wherein, inorganic acid salt is hydrochloride, hydrobromate, perchlorate, phosphate or sulfate.

8. compound according to claim 6, or its enantiomter, diastereoisomer, dynamic isomer, pharmaceutically Acceptable salt, wherein, acylate is carboxylate or sulphur hydrochlorate.

9. compound according to claim 8, or its enantiomter, diastereoisomer, dynamic isomer, pharmaceutically Acceptable salt, wherein, carboxylate be acetate, oxalates, maleate, tartrate, citrate, succinate or Malonate.

10. compound according to claim 8, or its enantiomter, diastereoisomer, dynamic isomer, pharmacy Upper acceptable salt, wherein, sulphur hydrochlorate is mesylate, esilate, benzene sulfonate, toluene fulfonate or naphthalene sulfonic acids Salt.

11. compound according to claim 6, or its enantiomter, diastereoisomer, dynamic isomer, pharmacy Upper acceptable salt, wherein, the salt obtained by alkali is alkali metal, alkaline-earth metal or N⁺(R¹⁴)₄Salt, wherein, R¹⁴Be H, deuterium, C₁-C₄Alkyl, C₆-C₁₀Aryl or C₆-C₁₀Aryl C₁-C₄Alkyl.

12. compound according to claim 11, or its enantiomter, diastereoisomer, dynamic isomer, pharmacy Upper acceptable salt, wherein, alkali metal or alkali salt are sodium salt, lithium salts, sylvite, calcium salt or magnesium salts.

13. a kind of pharmaceutical composition, include any described compounds of claim 1-5, and its pharmaceutically acceptable assistant agent.

14. pharmaceutical composition according to claim 13, wherein the assistant agent includes pharmaceutically acceptable carrier, figuration Agent, diluent, medium.

15. pharmaceutical composition according to claim 13, it further includes Anti-HBV drugs.

16. pharmaceutical composition according to claim 15, wherein Anti-HBV drugs are HBV AG14361s, immunological regulation Agent or interferon.

17. pharmaceutical composition according to claim 15, wherein Anti-HBV drugs have Lamivudine, Sebivo, for promise good fortune Wei ester, Entecavir, Aldoforwe ester, Alfaferone, Alloferon, Celmoleukin, Clevudine, emtricitabine, method Pu Luowei, precious sweet clever CP, Recomvinated Interferon α-2a, interferon α-1b, interferon-' alpha ', Intederon Alpha-2a, interferon beta-1a, interferon α-2, in vain Cytokine -2, mivotilate, Nitazoxanide, Peg-IFN alpha-2b α -2a, virazole, Recomvinated Interferon α-2a-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, levamisol, or Propagermanium.

18. any described compounds of claim 1-5 or any described pharmaceutical compositions of claim 13-17 are preparing use Purposes in the medicine of disease caused by prevention, processing, treatment or mitigation patient's hepatitis B infection or hepatitis B infection.

19. purposes according to claim 18, wherein hepatitis B infection cause disease to refer to hepatic sclerosis or hepatocellular carcinoma Become.

20. purposes according to claim 18, wherein viral disease refer to hepatitis B disease.