CN106496190A

CN106496190A - New type NS 5B inhibitor and application thereof

Info

Publication number: CN106496190A
Application number: CN201610907990.6A
Authority: CN
Inventors: 沈乐欣
Original assignee: Beijing Ruiji Good Health Science And Technology Co Ltd
Current assignee: Beijing Ruiji Good Health Science And Technology Co Ltd
Priority date: 2016-10-18
Filing date: 2016-10-18
Publication date: 2017-03-15

Abstract

The invention discloses there is the new type NS 5B inhibitor and its derivative of formula (I) structure, and its medicinal usage.For the NS5B target spots of hepatitis C, compared with control compound Sofosbuvir, activity is higher and toxicity is lower for formula (I) compound of the present invention.

Description

New type NS 5B inhibitor and application thereof

Technical field

The invention belongs to technical field of pharmaceuticals, is related to a kind of new type NS 5B inhibitor and application thereof.

Technical background

Hepatitis C is that the one kind caused by HCV (Hepatitis Cvirus, HCV) is serious threatens the mankind The liver diseases of health.1989, HCV was confirmed to be non-A type, the main pathogens of non-hepatitis B first.According to world health Tissue (WHO) report, the people for accounting for world population 3% in 2000 has infected this viroid, and there are about 3,000,000～400 every year Ten thousand new cases.It is 0.7%～3.1% in China's Healthy crowd's HCV-Ab IgG positive rate, about 40,000,000 people.Due to viral organism The many factors such as feature and host immune function, immunity of organism are often difficult to effectively remove virus, cause about 50-80% HCV infection person develops into chronic hepatitis, and wherein 20-30% will develop into cirrhosis, and have 1-4% to send out in liver cirrhosis patient every year Transform into liver cancer.

At present, the standard treatments in Chinese hepatitis are that glycol interferon (PEG-IFN) is closed with Ribavirin With.PEG-IFN on the market includes the PEG-Intron of Schering Plough company, Roche Holding Ag Pegasys；Ribavirin bag Include Rebetol, the Copegus of Roche Holding Ag of Schering Plough company, and its various imitation medicines.But should from continued viral From the point of view of answering rate (SVR), current this standard treatments effect is less desirable, and clinical cure rate is about 50%.And at present The administration time of this therapy is long, the hepatitis patient of such as HCV-I types, needs continuous use 48 weeks, while also often sending out The serious bad reaction of life, such as with spirit in terms of problem, there is flu-like symptoms and generation haematics toxicity, from And cause the successful cure rate of existing therapy to be less than 10%.Therefore, a kind of new mechanism, more high-efficiency low-toxicity are developed HCV inhibitor is particularly important.

In recent years, the scheme of international treatment hepatitis is gradually changed to DAA medications (directly antiviral) therapeutic modality.At present The principal item of list marketing has, the Sofosbuvir of lucky Leadd B.V and its compound Harvoni, AbbVie Corp. Viekria Pak, the Zepatier of MSD Corp. etc..Hepatitis DAA therapeutic scheme, with cure rate is higher, taking convenience, controls Cycle is short and the more low advantage of side effect is treated, but its expensive medical expense also makes most hepatitis patients hope and halt.It can be seen that More hepatitis DAA medicines are developed, the selectivity for suffering from hepatitis person's medication are improved, is broken up monopoly, reduce drug cost, Seem particularly significant.

HCV virus body is the positive chain RNA virus of coating, and HCV-RNA about 9500-10000bp are constituted, 5 ' and 3 ' non-volumes Code area (NCR) has 319-341bp, and 27-55bp respectively, containing several forward and inverted repeats, may be with gene duplication Relevant, genome array order is 5'-C-E1-E2-p7-NS2-NS3-NS4-NS5-3', and it is about 3014 that can encode a length The polyprotein precursor of individual amino acid, after the latter can be through host cell and viral oneself protein enzyme effect, is cracked into 10 kinds of viruses Albumen, the nucleocapsid protein (or claiming core protein, Core) and two kinds of glycoprotein including three kinds of structural proteins, i.e. molecular weight 19KD (E1 albumen of the molecular weight for 33KD, the E2 albumen of molecular weight 72Kd).P7 is encoded to albumen in a kind of film, and its function is probably one Plant ion channel.Nonstructural protein portion then includes NS2, NS3, NS4A, NS5A and NS5B, the life of non-structural protein contrast virus Cycle living is extremely important.There is proteinase activity to participate in the cutting of viral polyprotein precursors for NS2 and NS3.Additionally, NS3 albumen There are helicase activities also, participate in the HCV-RNA molecules that untwist, to assist rna replicon, the function of NS4 is unclear.NS5A is one Phospoprotein is planted, can be interacted with multiple host cell proteins, for the duplication of virus plays an important role.And NS5B then has The rna polymerase activity for having RNA to rely on, participates in HCV genome duplications, and therefore, NS5B polymerases are considered as that HCV duplications are compound Necessary component in body.

The suppression of HCV-NS5B polymerases prevents the formation of double-strand HCV RNA, therefore constitutes exploitation HCV specificity anti- The attractive approach of virus therapy.Viral gene replicase NS5B is the rna dependent rna polymerase of virus, with RNA For the rna replicon activity of template, it is responsible for the duplication of HCV genomes.NS5B genes are that HCV is peculiar, in the HCV diseases of various genotype All highly conserved in poison, and which lacks corresponding gene in mammalian cell gene group.The cell being uninfected by is generally not Expression RNA rely on RNA (RaffaeleDe Francesco, Antiviral Research, 58：1-16 (2003)), therefore, NS5B becomes the promising target for the treatment of hepatitis C.

The research and development of inventor's long campaigns antiviral drugs, design, screen and synthesized such as the compound of formula (I) structure, Experiment in vitro proves that the compound is replicated to HCV virus with obvious inhibitory activity, to finding broad-spectrum high efficacy antiviral drugs tool Significant.

Content of the invention

An object of the present invention is to propose a kind of new type NS 5B inhibitor, and the inhibitor is replicated with bright to HCV virus Aobvious inhibitory activity.The second object of the present invention is to propose medicine of the NS5B inhibitor for preparing prevention or treatment hepatitis C to use On the way.

Inventor's discovery, the compound of formula (I) or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate and its salt, and its quaternized nitrogen analog is used as new NS5B inhibitor plays a role.The non-nucleoside HCVNS5B AG14361 phases known in the art related in structure Than the difference of the compounds of this invention is, by the specific skeleton structure of certain height, acts on the suppression of NS5B polymerases Preparation finger and thumb interaction area, the compounds of this invention are very rapidly converted into the compound of Functional inactivation (Bressanelli S,Proc.Natl Acad.Sci.,1999,96:13034).

For achieving the above object, on the one hand, the invention provides the compound or its dynamic isomer of a kind of formula (I), right Isomers, diastereoisomer, racemic modification, metabolin, N- oxides, prodrug, hydrate, solvate and its salt is reflected, and Its quaternized nitrogen analog,

Wherein,

R is aryl or heteroaryl, can contain 1 to 4 substituent, and its substituent can be halogen, amino, hydroxyl, nitre Base, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 The alkylamino of individual carbon atom, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, 1 to 20 carbon The alkoxyacyl of atom, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, 1 to 20 carbon atom Haloalkyl, the halogenated alkoxy of 1 to 20 carbon atom, aryl or heteroaryl；

Z is covalent bond, the alkylene of 1 to 20 carbon atom or contains-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- Linear structure, circulus or its combine；

A and B be each independently halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, 1 to 20 The alkoxyl of carbon atom, the thiazolinyl of 2 to 20 carbon atoms, the alkenyloxy group of 2 to 20 carbon atoms, the cycloalkanes of 5 to 14 carbon atoms Base, the Heterocyclylalkyl of 5 to 14 carbon atoms, the cyclenes epoxide of 5 to 14 carbon atoms, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, The cycloalkyl-alkyl of 5 to 14 carbon atoms, the hetercycloalkylalkyl of 5 to 14 carbon atoms, the cyclenes epoxide of 5 to 14 carbon atoms Alkyl, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms, the aminoalkyl of 1 to 20 carbon atom, the alkane ammonia of 1 to 20 carbon atom Base, the acyl group of 2 to 20 carbon atoms, the acylamino- of 2 to 20 carbon atoms, the alkoxyacyl of 1 to 20 carbon atom, 1 to 20 The alkylthio of individual carbon atom, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom.

When the compound of the description present invention, unless otherwise indicated by context, otherwise, term is explained according to following definitions： Term " aryl " represents that there are monocyclic (i.e. phenyl) or (the such as naphthalene or anthracene) that condense or multiple aromatic rings for covalently connecting Polyunsaturated, aromatic hydrocarbon radical, usually contains 5 to 14 annular atoms, and more preferably 5-12, more preferred 5-10 are individual；With And most preferably 5-8；Wherein at least one ring is aromatics.The aromatic ring can optionally include to three condensed with which Other ring (cycloalkyl, heterocyclic radical, or heteroaryls).Additionally, aryl includes that the part hydrogenation for enumerating carbon-loop system herein is derivative Thing.The non-limiting examples of aryl include phenyl, xenyl, biphenylene, 5- or 6- tetralyls, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8- base, 1- or 2- naphthyls, 1-, 2-, or 3- indenyls, 1-, 2-, or 9- anthryls, 1-2-, 3-, 4-, or 5- acenaphthylenes Base, 3-, 4-, or 5- acenaphthenyls, 1-, 2-, 3-, 4-, or 10- phenanthryl, 1- or 2- pentalene bases, 1,2-, 3-, or 4- fluorenyls, 4- or 5- indanyls, 5-, 6-, 7-, or 8- tetralyls, 1,2,3,4- tetralyl, Isosorbide-5-Nitrae-ihydro naphthyl, dibenzo [a, d] Cycloheptenyl, and 1-, 2-, 3-, 4-, or 5- pyrenyl.Aryl rings optionally can be substituted by one or more substituents, that is, Say, which can optionally have the aryl of one or more substituents in arbitrarily utilizable tie point.This substituent Non-limiting examples be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, amino carbonyl, azido, cyano group, alkyl, cycloalkyl, Thiazolinyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxyl ,-SO₂-NH₂, aryl, heteroaryl, aralkyl, haloalkyl, halo Alkoxyl, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonyl amino, heterocyclic radical, alkylcarbonylaminoalkyl, Aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfoxide ,-SO₂R^a, alkylthio group, carboxyl, etc. wherein R^aIt is Alkyl or cycloalkyl.

Term " heteroaryl " is obtained when representing and replacing the ring carbon atom in above-mentioned aromatic yl group with one or more hetero atoms The substituent for arriving.Term " heteroaryl " itself or the part as another group represent but are not limited to 5 to 14 carbon-atom aromatics Ring or ring system, the ring or ring system contain 1 to 3 ring that is condensing or covalently connecting, usually contain 5 to 14 ring originals Son, more preferably 5-12, more preferred 5-10；And most preferably 5-8；At least one of the ring or ring system is aromatics, its In these rings one or more in one or more carbon atoms can use oxygen, nitrogen or sulphur atom are replaced, wherein nitrogen and sulphur Hetero atom can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.This ring can be fused to aryl, ring Alkyl, heteroaryl or heterocyclic ring.The non-limiting examples of this heteroaryl, including：Pyrrole radicals, furyl, thienyl, pyrazoles Base, imidazole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, di azoly, thiadiazolyl group, tetrazole radical, Triazolyl, thiatriazole base, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, piperazine base, Dioxin base, thiazinyl, three Piperazine base, imidazo [2,1-b] [1,3] thiazolyl, thieno [3,2-b] furyl, thieno [3,2-b] thienyl, thieno [2,3-d] [1,3] thiazolyl, thieno [2,3-d] imidazole radicals, tetrazolo [1,5-a] pyridine radicals, indyl, indolizine base, different Yin Diindyl base, benzofuranyl, benzopyranyl, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4- dihydros -1 (2H) - Benzopyranyl, -1 (2H)-benzopyranyl of 3,4- dihydro, isobenzofuran-base, benzothienyl, isobenzo-thienyl, Yin Oxazolyl, benzimidazolyl, 1,3- benzoxazolyl group, 1,2- benzo isoxazolyl, 2,1- benzo isoxazolyls, 1,3- benzothiazole Base, 1,2- benzisothia oxazolyl, 2,1- benzisothia oxazolyls, BTA base, 1,2,3- benzodiazole base, 2,1,3- benzos Di azoly, 1,2,3- diazosulfide base, 2,1,3- diazosulfide bases, thienopyridine base, purine radicals, imidazo [1, 2-a] pyridine radicals, -1 (6H)-base of 6- oxos-pyridazine, -1 (2H)-base of 2- oxo pyridines, -1 (6H)-base of 6- oxos-pyridazine, 2- oxygen For -1 (2H)-base of pyridine, 1,3- benzodioxole group, quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoline Quinoline base, 7- azaindolyls, 6- azaindolyls, 5- azaindolyls, 4- azaindolyls.

Term " alkyl " itself or the part as other substituents refer to formula C_xH_2x+1Fully saturated hydrocarbon, wherein x It is greater than or equal to 1 numeral.Usually, alkyl of the invention includes 1 to 20 carbon atom.Alkyl can be straight or branched , and can be substituted as noted herein.When being marked on after carbon atom under used herein, the subscript refers to life The carbon atom number that the group of name can contain.For example, " C₁-C₁₀" it is equal to C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉Or C₁₀. “C₁-C₂₀" it is equal to C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂、C₁₃、C₁₄、C₁₅、C₁₆、C₁₇、C₁₈、C₁₉、C₂₀.“C₂- C₁₀”、“C₃-C₁₀" etc. definition similar, repeat no more.It is preferred that, alkyl is C₁-C₂₀Alkyl, C₁-C₁₀Alkyl, C₁-C₈Alkyl, C₁-C₆ Alkyl, or C₁-C₄Alkyl.Further, for example, C₁-C₆Alkyl includes all straight chains with 1 to 6 carbon atom, side chain Alkyl, so that include methyl, ethyl, n-propyl, isopropyl, butyl and its isomers (such as normal-butyl, isobutyl group and tertiary fourth Base), amyl group and its isomers, hexyl and its isomers.

Term " alkoxyl " represents that there is formula-OR^bResidue, wherein R^bIt is alkyl.It is preferred that, alkoxyl is C₁-C₂₀Alcoxyl Base, C₁-C₁₀Alkoxyl, C₁-C₈Alkoxyl, C₁-C₆Alkoxyl, or C₁-C₄Alkoxyl.The non-limiting examples of alkoxyl include first Epoxide, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec- butoxy, t-butoxy, amoxy and own oxygen Base.

Term " aminoalkyl " represents the one or more CH in alkyl₂In H atom by amino or substituted-amino (i.e. amine Base) alkyl.It is preferred that, aminoalkyl is C₁-C₂₀Aminoalkyl, C₁-C₁₀Aminoalkyl, C₁-C₈Aminoalkyl, C₁-C₆Aminoalkyl, or C₁-C₄ Aminoalkyl.The non-limiting examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, ammonia isopropyl, ammonia butyl, ammonia isobutyl group, Ammonia sec-butyl, ammonia tert-butyl, ammonia amyl group and ammonia hexyl.

Term " alkylamino " represents that one or two H atom in amino is further substituted with by alkyl or substituted alkyl Amino.It is preferred that, alkylamino is C₁-C₂₀Alkylamino, C₁-C₁₀Alkylamino, C₁-C₈Alkylamino, C₁-C₆Alkylamino, or C₁-C₄Alkane ammonia Base.The non-limiting examples of alkylamino include methylamino, and dimethylamino, ethylamino, lignocaine, the third amino, dipropyl amino are different Third amino, diisopropylaminoethyl, fourth amino, dibutylamino, i-butylamino, two i-butylaminos, sec- fourth amino, two sec- fourth amino, Tert- fourth amino, two tert- fourth amino, penta amino, two tert- fourth amino, own amino and two own amino.

Term " alkyl acyl " itself or the part as other substituents refer to-C (=O) R^c, wherein R^cIt is as above Defined for alkyl.It is preferred that, alkyl acyl is C₁-C₂₀Alkyl acyl, C₁-C₁₀Alkyl acyl, C₁-C₈Alkyl acyl, C₁-C₆ Alkyl acyl, or C₁-C₄Alkyl acyl.The non-limiting examples of alkyl acyl include methyl acyl group, ethyl group acyl group, propane Base acyl group, isopropyl alkyl acyl, butane group acyl group, isobutyl alkyl acyl, sec- butane group acyl group, tert- butane group acyl group, pentane Base acyl group and hexyl acyl group.

Term " alkylamidoalkyl " itself or the part as other substituents refer to-NHC (=O) R^d, wherein R^dBe as Defined described previously for alkyl.It is preferred that, alkylamidoalkyl is C₁-C₂₀Alkylamidoalkyl, C₁-C₁₀Alkylamidoalkyl, C₁-C₈Alkyl Amide groups, C₁-C₆Alkylamidoalkyl, or C₁-C₄Alkylamidoalkyl.The non-limiting examples of alkylamidoalkyl include methyl acyl Amido, ethyl group amide groups, propyl amide groups, isopropyl alkylamidoalkyl, butane group amide groups, isobutyl alkylamidoalkyl, sec- Butane group amide groups, tert- butane group amide groups, pentyl amide groups and hexyl amide groups.

Term " alkoxyacyl " itself or the part as other substituents refer to-C (=O) OR^e, wherein R^eBe as Defined described previously for alkyl.It is preferred that, alkoxyacyl is C₁-C₂₀Alkoxyacyl, C₁-C₁₀Alkoxyacyl, C₁-C₈Alcoxyl Base acyl group, C₁-C₆Alkoxyacyl, or C₁-C₄Alkoxyacyl.The non-limiting examples of alkoxyacyl include methane epoxide Acyl group, second alkoxyacyl, the third alkoxyacyl, isopropyl alkoxyacyl, fourth alkoxyacyl, isobutyl alkoxyacyl, sec- Fourth alkoxyacyl, tert- fourth alkoxyacyl, penta alkoxyacyl and own alkoxyacyl.

Term " alkylthio " represents the one or more CH in alkyl₂In H atom by sulfydryl (- SH) or substituted sulfhydryl The alkyl of (i.e. alkylthio group).It is preferred that, alkylthio is C₁-C₂₀Alkylthio, C₁-C₁₀Alkylthio, C₁-C₈Alkylthio, C₁- C₆Alkylthio, or C₁-C₄Alkylthio.The non-limiting examples of alkylthio include first alkylthio, second alkylthio, third Alkylthio, isopropyl alkylthio, fourth alkylthio, isobutyl alkylthio, sec- fourth alkylthio, tert- fourth alkylthio, penta Alkylthio and own alkylthio.

Term " alkylthio group " represents the mercapto is further substituted with by alkyl or substituted alkyl by the H atom in sulfydryl (- SH) Base.It is preferred that, alkylthio group is C₁-C₂₀Alkylthio group, C₁-C₁₀Alkylthio group, C₁-C₈Alkylthio group, C₁-C₆Alkylthio group, or C₁-C₄Alkylthio group. The non-limiting examples of alkylthio group include methane sulfenyl, ethane sulfenyl, propane sulfenyl, isopropyl alkylthio group, butane sulfenyl, iso-butane Sulfenyl, sec- butane sulfenyl, tert- butane sulfenyl, pentane sulfenyl, and hexane sulfenyl.

Term " alkyl halide (oxygen) base " represents the one or more CH in alkyl₂In the alkane that is optionally substituted by halogen of H atom (oxygen) base.Halogen is selected from fluorine, chlorine, bromine and iodine.It is preferred that, alkyl halide (oxygen) base is C₁-C₂₀Alkyl halide (oxygen) base, C₁-C₁₀Alkyl halide (oxygen) base, C₁-C₈Alkyl halide (oxygen) base, C₁-C₆Alkyl halide (oxygen) base, or C₁-C₄Alkyl halide (oxygen) base.Alkyl halide (oxygen) base non- Limitative examples include halide (oxygen) base, halothane (oxygen) base, halogenopropane (oxygen) base, halo isopropyl alkane (oxygen) base, Butyl halide (oxygen) base, halo iso-butane (oxygen) base, halo sec- butane (oxygen) base, halo tert- butane (oxygen) base, halo pentane (oxygen) base, and halo hexane (oxygen) base.Further, the non-limiting examples of such as haloalkyl include chloro first (oxygen) base, 1- bromo second (oxygen) bases, fluoro first (oxygen) base, difluoro first (oxygen) base, fluoroform (oxygen) base, 1,1,1- trifluoro second (oxygen) base, etc. Deng.

Term " cycloalkyl " refers to the alkyl of saturation and ring-type, and itself is represented but not as the part of another group It is limited to 5 to 14 carbon-atom cycloaliphatic ring or ring system.Cycloalkyl usually contain 5 to 14 annular atoms, more preferably 5-12, more It is preferred that 5-10；And most preferably 5-8.The non-limiting examples of cycloalkyl include cyclopenta, cyclohexyl, 2-, or 3- methyl Cyclopenta, suberyl, and 2-, 3-, or 4- methylcyclohexyl.

Term " Heterocyclylalkyl " refers to the alkyl of saturation and ring-type, itself or as another group part represent but It is not limited to 5 to 14 carbon-atom cycloaliphatic ring or ring system.Usually containing 5 to 14 annular atoms, more preferably 5-12, more preferably 5-10；And most preferably 5-8；Wherein these rings one or more in one or more carbon atoms by O, N or S atom Replace, wherein nitrogen and sulfur heteroatom can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.Heterocyclylalkyl Non-limiting examples include 2-, or 3- oxocyclopentyls, 1,2-, or 3- azepine cyclopenta, 2-, or 3- thia cyclopenta, 2-, 3-, or 4- oxacyclohexyls, 1-, 2-, 3-, or 4- piperidyls, 2-, 3-, or 4- thia cyclohexyl, etc..

Term " cycloalkenyl group ", " heterocycloalkenyl ", " cycloalkyl-alkyl ", " hetercycloalkylalkyl ", " cyclenes epoxide alkyl ", " heterocycle alkenyloxy group alkyl " is similar with above-mentioned " alkyl " and " (miscellaneous) cycloalkanes (alkene) base ", can have one or more double bonds, but Do not possess armaticity simultaneously, repeat no more.

Further, the compound of formula (I) of the present invention or its dynamic isomer, enantiomter, diastereoisomer, outer Raceme, metabolin, N- oxides, prodrug, hydrate, solvate and its salt, and its following institute of quaternized nitrogen analog Show：

Wherein,

R is aryl or heteroaryl, can contain 1 to 4 substituent, and its substituent can be halogen, amino, hydroxyl, nitre Base, cyano group, the alkyl of 1 to 10 carbon atom, the alkoxyl of 1 to 10 carbon atom, the aminoalkyl of 1 to 10 carbon atom, 1 to 10 The alkylamino of individual carbon atom, the alkyl acyl of 2 to 10 carbon atoms, the alkyl amido of 2 to 10 carbon atoms, 1 to 10 carbon The alkoxyacyl of atom, the alkylthio of 1 to 10 carbon atom, the alkylthio group of 1 to 10 carbon atom, 1 to 10 carbon atom Haloalkyl, the halogenated alkoxy of 1 to 10 carbon atom, aryl or heteroaryl；

Z is covalent bond, the alkylene of 1 to 10 carbon atom or contains-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- Linear structure, circulus or its combine；

A and B be each independently halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 10 carbon atom, 1 to 10 The alkoxyl of carbon atom, the thiazolinyl of 2 to 10 carbon atoms, the alkenyloxy group of 2 to 10 carbon atoms, the cycloalkanes of 5 to 10 carbon atoms Base, the Heterocyclylalkyl of 5 to 10 carbon atoms, the cyclenes epoxide of 5 to 10 carbon atoms, the heterocycle alkenyloxy group of 5 to 10 carbon atoms, The cycloalkyl-alkyl of 5 to 10 carbon atoms, the hetercycloalkylalkyl of 5 to 10 carbon atoms, the cyclenes epoxide of 5 to 10 carbon atoms Alkyl, the heterocycle alkenyloxy group alkyl of 5 to 10 carbon atoms, the aminoalkyl of 1 to 10 carbon atom, the alkane ammonia of 1 to 10 carbon atom Base, the acyl group of 2 to 10 carbon atoms, the acylamino- of 2 to 10 carbon atoms, the alkoxyacyl of 1 to 10 carbon atom, 1 to 10 The alkylthio of individual carbon atom, the haloalkyl of 1 to 10 carbon atom, the halogenated alkoxy of 1 to 10 carbon atom.

Wherein,

R is aryl or heteroaryl, can contain 1 to 4 substituent, and its substituent can be halogen, amino, hydroxyl, nitre Base, cyano group, the alkyl of 1 to 6 carbon atom, the alkoxyl of 1 to 6 carbon atom, the aminoalkyl of 1 to 6 carbon atom, 1 to 6 carbon The alkylamino of atom, the alkyl acyl of 2 to 6 carbon atoms, the alkyl amido of 2 to 6 carbon atoms, the alkane of 1 to 6 carbon atom Epoxide acyl group, the alkylthio of 1 to 6 carbon atom, the alkylthio group of 1 to 6 carbon atom, the haloalkyl of 1 to 6 carbon atom, 1 Halogenated alkoxy, aryl or heteroaryl to 6 carbon atoms；

Z is covalent bond, the alkylene of 1 to 6 carbon atom or contains-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- Linear structure, circulus or its combination；

A and B are each independently halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 6 carbon atom, 1 to 6 carbon The alkoxyl of atom, the thiazolinyl of 2 to 6 carbon atoms, the alkenyloxy group of 2 to 6 carbon atoms, the cycloalkyl of 5 to 8 carbon atoms, 5 to The Heterocyclylalkyl of 8 carbon atoms, the cyclenes epoxide of 5 to 8 carbon atoms, the heterocycle alkenyloxy group of 5 to 8 carbon atoms, 5 to 8 carbon The cycloalkyl-alkyl of atom, the hetercycloalkylalkyl of 5 to 8 carbon atoms, the cyclenes epoxide alkyl of 5 to 8 carbon atoms, 5 to 8 The heterocycle alkenyloxy group alkyl of carbon atom, the aminoalkyl of 1 to 6 carbon atom, the alkylamino of 1 to 6 carbon atom, 2 to 6 carbon atoms Acyl group, the acylamino- of 2 to 6 carbon atoms, the alkoxyacyl of 1 to 6 carbon atom, the alkylthio of 1 to 6 carbon atom, 1 The halogenated alkoxy of haloalkyl, 1 to 6 carbon atom to 6 carbon atoms.

Wherein,

R is aryl, can contain 1 to 4 substituent, its substituent can be halogen, amino, hydroxyl, nitro, cyano group, 1 The alkoxyl of alkyl, 1 to 20 carbon atom to 20 carbon atoms, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 carbon atom Alkylamino, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, the alkane of 1 to 20 carbon atom Epoxide acyl group, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, the alkyl halide of 1 to 20 carbon atom Base, the halogenated alkoxy of 1 to 20 carbon atom, aryl or heteroaryl；Preferably, its substituent can be halogen, amino, hydroxyl Base, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the aminoalkyl of 1 to 20 carbon atom, The alkylamino of 1 to 20 carbon atom, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, 1 to 20 The alkoxyacyl of individual carbon atom, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, 1 to 20 carbon The haloalkyl of atom, the halogenated alkoxy of 1 to 20 carbon atom；It is highly preferred that its substituent can be halogen, amino, hydroxyl Base, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the aminoalkyl of 1 to 20 carbon atom, The alkylamino of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, 1 to 20 carbon The haloalkyl of atom, the halogenated alkoxy of 1 to 20 carbon atom；It is further preferred that its substituent can be halogen, amino, Hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the halo of 1 to 20 carbon atom Alkyl, the halogenated alkoxy of 1 to 20 carbon atom；Most preferably, its substituent can be halogen, nitro, cyano group, 1 to 20 The haloalkyl of carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；

Wherein,

R is heteroaryl, can contain 1 to 4 substituent, and its substituent can be halogen, amino, hydroxyl, nitro, cyanogen Base, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 carbon The alkylamino of atom, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, 1 to 20 carbon atom Alkoxyacyl, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, the halogen of 1 to 20 carbon atom Substituted alkyl, the halogenated alkoxy of 1 to 20 carbon atom, aryl or heteroaryl；Preferably, its substituent can be halogen, amino, Hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the ammonia alkane of 1 to 20 carbon atom Base, the alkylamino of 1 to 20 carbon atom, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, 1 The alkylthio of alkoxyacyl, 1 to 20 carbon atom to 20 carbon atoms, the alkylthio group of 1 to 20 carbon atom, 1 to 20 The haloalkyl of individual carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；It is highly preferred that its substituent can be halogen, ammonia Base, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the ammonia of 1 to 20 carbon atom Alkyl, the alkylamino of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, 1 to The haloalkyl of 20 carbon atoms, the halogenated alkoxy of 1 to 20 carbon atom；It is further preferred that its substituent can be halogen, Amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, 1 to 20 carbon atom Haloalkyl, the halogenated alkoxy of 1 to 20 carbon atom；Most preferably, its substituent can be halogen, nitro, cyano group, 1 to The haloalkyl of 20 carbon atoms, the halogenated alkoxy of 1 to 20 carbon atom；

Wherein,

Z is the alkylene of 1 to 20 carbon atom；Preferably, Z is the alkylene of 1 to 15 carbon atom；It is highly preferred that Z be 1 to The alkylene of 10 carbon atoms；It is further preferred that Z is the alkylene of 1 to 10 carbon atom；It is further preferred that Z is 1 to 8 carbon atom Alkylene；Most preferably, Z is the alkylene of 1 to 6 carbon atom；

Wherein,

Z is containing-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- linear structure, circulus；Preferably, Z It is containing-O- ,-S- ,-NH- ,-CO-, the linear structure of-CS-, circulus；It is highly preferred that Z be containing-O- ,-S- ,- NH- ,-CO-, the linear structure of-CS-；Most preferably, Z be containing-O- ,-S- ,-CO- ,-CS- linear structure；

Wherein,

Z is the alkylene of 1 to 20 carbon atom and contains-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- linear junction Structure, the combination of circulus；Preferably, Z be 1 to 20 carbon atom alkylene with containing-O- ,-S- ,-NH- ,-CO- ,-CS- ,- SO-、-SO₂- linear structure combination；It is highly preferred that Z be 1 to 20 carbon atom alkylene with containing-O- ,-S- ,-CO- ,- The combination of the linear structure of CS-；Most preferably, Z be 1 to 20 carbon atom alkylene with containing-O- ,-S- linear structure with And the combination containing-CO-, the linear structure of-CS-；

Wherein,

A is halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alcoxyl of 1 to 20 carbon atom Base, the thiazolinyl of 2 to 20 carbon atoms, the alkenyloxy group of 2 to 20 carbon atoms, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 carbon The alkylamino of atom, the acyl group of 2 to 20 carbon atoms, the acylamino- of 2 to 20 carbon atoms, the alkoxyl of 1 to 20 carbon atom Acyl group, the alkylthio of 1 to 20 carbon atom, the haloalkyl of 1 to 20 carbon atom, the haloalkoxy of 1 to 20 carbon atom Base；Preferably, A is halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alcoxyl of 1 to 20 carbon atom Base, the aminoalkyl of 1 to 20 carbon atom, the alkylamino of 1 to 20 carbon atom, the alkyl acyl of 2 to 20 carbon atoms, 2 to 20 The alkyl amido of individual carbon atom, the alkoxyacyl of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, 1 to 20 The alkylthio group of individual carbon atom, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；It is highly preferred that A For halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, 1 to 20 The aminoalkyl of carbon atom, the alkylamino of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, 1 to 20 carbon atom Alkylthio group, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；It is further preferred that A be halogen, Amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, 1 to 20 carbon atom Haloalkyl, the halogenated alkoxy of 1 to 20 carbon atom；Most preferably, A is halogen, nitro, cyano group, 1 to 20 carbon atom Alkyl, the alkoxyl of 1 to 20 carbon atom；

B is the cycloalkyl of 5 to 14 carbon atoms, the Heterocyclylalkyl of 5 to 14 carbon atoms, the cyclenes of 5 to 14 carbon atoms Epoxide, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, the cycloalkyl-alkyl of 5 to 14 carbon atoms, the heterocycle of 5 to 14 carbon atoms Alkyl-alkyl, the cyclenes epoxide alkyl of 5 to 14 carbon atoms, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms.

Wherein,

A is the cycloalkyl of 5 to 14 carbon atoms, the Heterocyclylalkyl of 5 to 14 carbon atoms, the cyclenes of 5 to 14 carbon atoms Epoxide, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, the cycloalkyl-alkyl of 5 to 14 carbon atoms, the heterocycle of 5 to 14 carbon atoms Alkyl-alkyl, the cyclenes epoxide alkyl of 5 to 14 carbon atoms, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms.

B is halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alcoxyl of 1 to 20 carbon atom Base, the thiazolinyl of 2 to 20 carbon atoms, the alkenyloxy group of 2 to 20 carbon atoms, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 carbon The alkylamino of atom, the acyl group of 2 to 20 carbon atoms, the acylamino- of 2 to 20 carbon atoms, the alkoxyl of 1 to 20 carbon atom Acyl group, the alkylthio of 1 to 20 carbon atom, the haloalkyl of 1 to 20 carbon atom, the haloalkoxy of 1 to 20 carbon atom Base；Preferably, B is halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alcoxyl of 1 to 20 carbon atom Base, the aminoalkyl of 1 to 20 carbon atom, the alkylamino of 1 to 20 carbon atom, the alkyl acyl of 2 to 20 carbon atoms, 2 to 20 The alkyl amido of individual carbon atom, the alkoxyacyl of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, 1 to 20 The alkylthio group of individual carbon atom, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；It is highly preferred that B For halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, 1 to 20 The aminoalkyl of carbon atom, the alkylamino of 1 to 20 carbon atom, the alkylthio of 1 to 20 carbon atom, 1 to 20 carbon atom Alkylthio group, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom；It is further preferred that B be halogen, Amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, 1 to 20 carbon atom Haloalkyl, the halogenated alkoxy of 1 to 20 carbon atom；Most preferably, B is halogen, nitro, cyano group, 1 to 20 carbon atom Alkyl, the alkoxyl of 1 to 20 carbon atom.

In one preferred embodiment, the compound of formula (I) of the present invention or its dynamic isomer, enantiomter, Diastereoisomer, racemic modification, metabolin, N- oxides, prodrug, hydrate, solvate and its salt, and its quaternized Nitrogen analog is selected from following compounds：

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (suberyl) -5-)-N- (4- nitropyridine -2- bases) fourth Acid amides formula (I-1)；

2- (4- (cyclohexene -3- bases) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2,3- dicyano furans Mutter -5- bases) acetamide formula (I-2)；

2- (4- (cyclohexyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (dinitrophenyl group) Acetamide formula (I-3)；

3- (4- (tetrahydrofuran -2- bases) -5- cyano group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (the chloro- 2- thiophenes of 3- Fen base) propionamide formula (I-4)；

2- (4- (cyclohexyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3,5- difluorophenyls) acetyl Amine formula (I-5)；

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (CycloheptylmethyI) -5-)-N- (3- nitro-pyrrole -2- Base) butyramide formula (I-6)；

3- (4- (2- (cyclohexene -3- bases) ethyl) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2- cyanogen Base phenyl) propionamide formula (I-7)；

2- (4- (cyclohexyl methyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3,5- difluorophenyls) Acetamide formula (I-8)；

3- (4- (3- (tetrahydrofuran -2- bases) propyl group) -5- methyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3- Bromo-2-pyridyl base) propionamide formula (I-9)；

5- (4- (2- (4,5- dihydro-thiophene -2- bases) ethyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulphur Base)-N- (3- Trifluoromethoxyphen-ls) pentanamide formula (I-10)；

2- (4- (cyclohexene -1- bases) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2,3- dicyano furans Mutter -5- bases) acetamide formula (I-11)；

3- (4- (tetrahydrofuran -3- bases) -5- cyano group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (the chloro- 2- thiophenes of 3- Fen base) propionamide formula (I-12)；

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (CycloheptylmethyI) -5-)-N- (3- nitro-pyrrole -2- Base) butyramide formula (I-13)；

5- (4- (2- (4,5- dihydro-thiophene -2- bases) ethyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulphur Base)-N- (3- Trifluoromethoxyphen-ls) pentanamide formula (I-14)；

2- (4- (cyclohexyl methyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (4- sulfoamido benzene Base) acetamide formula (I-15).

Unless otherwise indicated by context, term " the compounds of this invention " broadly can represent including formula (I) compound and Any derivative.Term " derivative " represent the dynamic isomer of the compounds of this invention, enantiomter, diastereoisomer, Racemic modification, metabolin, N- oxides, prodrug, hydrate, solvate and its salt, and their quaternized nitrogen is similar Thing, etc..

For example, the compounds of this invention can be in the form of different dynamic isomers, and the dynamic isomer includes But it is not limited to geometric isomer, rotamer, E/Z- isomers, three-dimensional chemical isomer, and corresponding to the change in the present invention The isomers of identical substituent present on the different position of ring present in compound.All this possible dynamic isomer and Its mixture is included within the scope of the present invention.

The compounds of this invention can contain one or more asymmetric carbon atoms, and the asymmetric carbon atom serves as in chirality The heart, its can cause different optical forms (such as enantiomter, diastereoisomer and racemic modification).The present invention includes All may configuration whole this optical forms, and its mixture.

The N- oxides of the compounds of this invention represent that one of them or several N atoms are oxidized to the present invention of N- oxides Compound.

The quaternized nitrogen analog of the compounds of this invention represents the quaternized present invention of one of them or several N atoms Compound.

The hydrate and solvate of the compounds of this invention represents hydrone or solvent molecule to crystallize or non-crystalline forms Participate in the material for forming the compounds of this invention solid form.

The salt of the compounds of this invention includes the pharmaceutically acceptable salt of the compound shown in formula (I).Pharmaceutically acceptable Salt include, acid addition salts such as hydrogen chlorate, hydrobromic acid wherein applicable, derived from pharmaceutically acceptable inorganic and organic acid Salt, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4- methoxy benzoic acids Salt, 2- or 4-HBA salt, 4- chloro benzoates, benzene sulfonate, nicotinate, mesylate, ascorbate, acetic acid Salt, succinate, lactate, glutarate, gluconate, hydroxyl naphthalene carboxylate, oleate and amino-acid salt, conventional amino Hydrochlorate refer to glycinate, alanine salt, phenylalanine salt, aspartate, aspartate, methionine salt, lysine salt, Tryptophan salt, glutamate and threonine salt etc.；And the salt prepared from pharmaceutically acceptable inorganic and organic base, derived from inorganic base Salt include aluminium, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, sub- manganese, potassium, sodium, zinc and bismuth salt, be particularly preferred to be ammonium, calcium, Magnesium, potassium, sodium salt.Salt derived from pharmaceutically acceptable organic base includes primary, secondary and tertiary amine, cyclic amine such as arginine glycine betaine, choline Deng salt.

The derivative of the compounds of this invention can be with further to its metabolin, N- oxides and prodrug.These forms It is well-known to those skilled in the art.

Formula (I) compound of the present invention can be prepared in a manner known in the art, for example, it is possible to first prepare formula (II) Midbody compound, then reacted with R-H, obtained formula (I) compound；

Wherein, L is leaving group, and for example aforementioned (I) compound of R, Z, A and B is defined.

Again or, the midbody compound of formula (III) first can be prepared, then reacted with R-Z-L, obtained formula (I) change Compound；

Furthermore, can first prepare L₁-Z-L₂Midbody compound, the then midbody compound and R-H with formula (III) Reacted, obtained formula (I) compound；

Wherein, L₁And L₂For leaving group, for example aforementioned (I) compound of R, Z, A and B is defined.

Formula (I) compound of the present invention can be preparing according to other ways known.

In synthetic reaction, the solvent that adopted can be selected from benzene, toluene, chloroform, n-hexane, hexamethylene, dichloromethane, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methyl alcohol, ethanol, acetone, One or more mixed solvent in tetrahydrofuran, ether, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.It is preferred that N, Dinethylformamide, tetrahydrofuran, acetone, acetonitrile or dichloromethane.The alkali for being adopted can be triethylamine, diisopropyl second Amine, DBU, potassium carbonate, sodium carbonate, saleratus or sodium acid carbonate, preferably potassium carbonate；Reaction temperature be subzero 20 DEG C to 100 DEG C, It is preferred that 10 DEG C to 60 DEG C；

On the other hand, the invention provides formula (I) compound of the present invention is in the medicine for preparing prevention or treatment hepatitis C Purposes.

For medicinal usage, the compounds of this invention can be formulated as the form of pharmaceutical preparation or pharmaceutical composition, the medicine Thing preparation or pharmaceutical composition are comprising at least one the compounds of this invention and at least one pharmaceutically acceptable carrier, diluent Or excipient and/or auxiliary agent, and the optionally compound comprising one or more other pharmaceutical active.

For example, pharmaceutical preparation of the invention can be adapted for peroral administration form, be suitable for use in local administration (including eye ) form, be suitable for use in by suction, by skin patch, by implant, by suppository, wait the form of administration.This Suitable form of medication (such as solid, semi-solid or liquid, depending on administering mode) and the method prepared for which and load Body, diluent and excipient.

The pharmaceutical preparation of the present invention includes tablet, pill, powder, lozenge, pouch, cachet, suspension, emulsion, solution, Syrup, aerosol, ointment, creme, lotion, soft hard gelatin capsule, suppository, drops, the solution of sterile injectable and nothing Bacterium bag fills powder.Administration for pill form and/or for continuous administration, which can adopt carrier, excipient, and dilution Agent is prepared, the carrier, excipient, and diluent applies to this preparaton, such as lactose, glucose, sucrose, mountain in itself Pears alcohol, mannitol, starch, gum arabic, calcium phosphate, alginates, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, poly- second Vinyl pyrrolidone, polyethylene glycol, cellulose, sterilized water, methylcellulose, methyl-and propylhydroxy benzoate, talcum, Magnesium stearate, edible oil, vegetable oil and mineral oil or its suitable mixture.The preparaton can optionally contain other The material of pharmaceutical active and the other materials generally used in pharmaceutical formulation, such as lubricant, wetting agent, emulsification and suspending Agent, dispersant, disintegrant, filler, filler, preservative, sweetener, flavouring, flowing regulator, releasing agent, etc..Described group Compound can also be formulated to, there is provided quick, the lasting or release that delays of the compound of the activity for wherein containing, for example Liposome or hydrophilic high mol matrix using the polymer based on Native Gel or synthesis.In order to strengthen according to medicine of the present invention The solubility and/or stability of the compound of composition, advantageously can adopt α-, β-or gamma-cyclodextrin or they spread out Biological.

Additionally, cosolvent such as alcohols solvent can improve the solubility and/or stability of compound.In Aquo-composition Preparation in, add the present invention compound salt can be preferably, its reason be salt be conducive to increase water dissolves Degree.

Pharmaceutical preparation can be prepared in a manner known in the art, be usually directed to mixing at least one according to the present invention's Compound and one or more pharmaceutically acceptable carriers, are preferably carried out under sterile conditions.

Present invention also offers a kind of pharmaceutical formulation, the preparation is by the inhibitor described in claim 1 and medicinal load Body auxiliary material or diluent are constituted；Wherein, the method for administration of the pharmaceutical formulation is selected from emulsion, solution, supensoid agent, aerosol And the form of dry powder formulations carries out local administration, or it is administered with tablet, capsule, syrup, powder or particulate oral preparation, or with The form of solution or suspension carries out parenteral, or carries out subcutaneous administration；Or per rectum administration in the form of suppository, or thoroughly Skin is administered.

Formula (I) provided by the present invention compound has obvious HCV-Ab IgG virus activity, is as preparing anti-hepatitis C The active component of virus drugs, that is, as the medicine that active component is used for preparing the prevention of different dosage form or treatment hepatitis C Thing.

The dosage of formula (I) compound or derivatives thereof can become with the age of administering mode and patient, body weight and the state of an illness Change.For example, when being administered with injection form, dosage generally in the scope of about 0.001-100mg/kg/ days, preferably about The scope of 0.1-10mg/kg/ days.When being administered with oral dosage form, dosage is generally in the model of about 0.1-200mg/kg/ days Enclose, preferably in the scope of about 0.1-80mg/kg/ days.

Compared with prior art, NS5B target spot of the formula (I) compound of the present invention for HCV virus, the higher and toxicity of activity Lower.Therefore, it is expected to become a kind of new mechanism, more high-efficiency low-toxicity HCV inhibitor.

Specific embodiment

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate this Bright rather than restriction the scope of the present invention.In addition, it is to be understood that after present disclosure has been read, those skilled in the art The present invention can be made various changes or modifications, these equivalent form of values equally fall within what the application appended claims were limited Scope.

Will be helpful to understand the present invention by following embodiments, but the scope of the present invention can not be limited.

Embodiment 1：Formula (I-1) compound

In 100mL there-necked flasks, chloro- 2- ammonia generation -2,3- dihydro-pyrimidin -4 (1 hydrogen) -one 9.81g of 6- (suberyl) -5- is added (0.049mo1), DMF 50mL, potassium carbonate 7.46g (0.54mo1), add bromo- N- (the 4- nitros of 4- after stirring 30min under room temperature Pyridine -2- bases) butyramide 14.1g (0.049mol), 8h is reacted under room temperature, TLC following responses are to raw material point pyrimidinone compound Disappear, stop reaction.Reactant liquor is poured into frozen water mixed liquor 480mL, stirring separates out precipitation, and suction filtration, frozen water are washed, after drying Crude product, obtains sterling formula (I-1) compound, yield through Gossypol recrystallized from chloroform：28.6%.MS(ESI)：m/z 465.5[M-H]^-、 467.5[M+H]⁺、490.5[M+Na]⁺.

Embodiment 2：Formula (I-2) compound

Respectively using -4 (1 hydrogen) -one of 6- (cyclohexene -3- bases) -5- nitro -2- oxo -2,3- dihydro-pyrimidins and the bromo- N- of 4- Thio -2,3- the dihydros of the chloro- 2- of 6- (suberyl) -5- in (2,3- dicyano furans -5- bases) acetamide alternative embodiment 1 are phonetic - 4 (1 hydrogen) -one of pyridine and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, Obtain formula (I-2) compound.MS(ESI)：m/z 444.0[M-H]^-、446.0[M+H]⁺、469.0[M+Na]⁺.

Embodiment 3：Formula (I-3) compound

Respectively using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (cyclohexyl) -5- methoxyl group -2- and the bromo- N- of 4- (2, 4- dinitrophenyls) thio-2,3- dihydro-pyrimidins-4 (1 hydrogen) of the chloro- 2- of 6- (suberyl)-5- in acetamide alternative embodiment 1- Ketone and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtained formula (I- 3) compound.MS(ESI)：m/z 493.2[M-H]^-、495.2[M+H]⁺、518.2[M+Na]⁺.

Embodiment 4：Formula (I-4) compound

Bromo- using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (tetrahydrofuran -2- bases) -5- cyano group -2- and 4- respectively Thio -2,3- the dihydro-pyrimidins -4 (1 of the chloro- 2- of 6- (suberyl) -5- in N- (the chloro- 2- thienyls of 3-) propionamide alternative embodiment 1 Hydrogen) -one and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtain formula (I-4) compound.MS(ESI)：m/z 406.6[M-H]^-、408.6[M+H]⁺、431.6[M+Na]⁺.

Embodiment 5：Formula (I-5) compound

Respectively using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (cyclohexyl) -5- ethyl -2- and the bromo- N- (3,5- of 2- Difluorophenyl) thio -2,3- dihydro-pyrimidins -4 (1 hydrogen) -one of the chloro- 2- of 6- (suberyl) -5- in acetamide alternative embodiment 1 and The bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, is reacted according to the method for embodiment 1 and is purified, and obtains formula (I-5) change Compound.MS(ESI)：m/z 406.1[M-H]^-、408.1[M+H]⁺、430.1[M+Na]⁺.

Embodiment 6：Formula (I-6) compound

Respectively using chloro- -4 (1 hydrogen) -one of 2- ammonia generation -2,3- dihydro-pyrimidins of 6- (CycloheptylmethyI) -5- and the bromo- N- (3- of 4- Nitro-pyrrole -2- bases) thio -2,3- dihydro-pyrimidins -4 (1 of the chloro- 2- of 6- (suberyl) -5- in butyramide alternative embodiment 1 Hydrogen) -one and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtain formula (I-6) compound.MS(ESI)：m/z 500.7[M-H]^-、502.7[M+H]⁺、525.7[M+Na]⁺.

Embodiment 7：Formula (I-7) compound

Respectively using 6- (2- (cyclohexene -3- bases) ethyl) -5- nitro -2- oxo -2,3- dihydro-pyrimidin -4 (1 hydrogen) -one Thio -2,3- the dihydros of the chloro- 2- of 6- (suberyl) -5- in bromo- with 4- N- (2- cyano-phenyls) propionamide alternative embodiment 1 are phonetic - 4 (1 hydrogen) -one of pyridine and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, Obtain formula (I-7) compound.MS(ESI)：m/z 569.3[M-H]^-、571.3[M+H]⁺、594.3[M+Na]⁺.

Embodiment 8：Formula (I-8) compound

Respectively using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (cyclohexyl methyl) -5- ethyl -2- and the bromo- N- of 2- Thio -2,3- the dihydro-pyrimidins -4 (1 of the chloro- 2- of 6- (suberyl) -5- in (3,5- difluorophenyls) acetamide alternative embodiment 1 Hydrogen) -one and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtain formula (I-8) compound.MS(ESI)：m/z 420.1[M-H]^-、422.1[M+H]⁺、444.1[M+Na]⁺.

Embodiment 9：Formula (I-9) compound

Respectively using 6- (3- (tetrahydrofuran -2- bases) propyl group) thio -2,3- dihydro-pyrimidins -4 (1 hydrogen) of -5- methyl -2- - Thio-the 2,3- of the chloro- 2- of 6- (suberyl) -5- in ketone and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide alternative embodiment 1 - 4 (1 hydrogen) -one of dihydro-pyrimidin and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 And purifying, obtain formula (I-9) compound.MS(ESI)：m/z 476.2[M-H]^-、478.2[M+H]⁺、501.2[M+Na]⁺.

Embodiment 10：Formula (I-10) compound

Respectively using 6- (2- (4,5- dihydro-thiophene -2- bases) ethyl) thio -2,3- dihydro-pyrimidins -4 of -5- methoxyl group -2- The chloro- 2- sulphur of 6- (suberyl) -5- in (1 hydrogen) -one and the bromo- N- of 4- (3- Trifluoromethoxyphen-ls) pentanamide alternative embodiment 1 - 4 (1 hydrogen) -one of generation -2,3- dihydro-pyrimidins and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, enter according to the method for embodiment 1 Row reaction and purifying, obtain formula (I-10) compound.MS(ESI)：m/z 529.1[M-H]^-、531.1[M+H]⁺、554.1[M+ Na]⁺.

Embodiment 11：Formula (I-11) compound

Respectively using -4 (1 hydrogen) -one of 6- (cyclohexene -1- bases) -5- nitro -2- oxo -2,3- dihydro-pyrimidins and the bromo- N- of 4- Thio -2,3- the dihydros of the chloro- 2- of 6- (suberyl) -5- in (2,3- dicyano furans -5- bases) acetamide alternative embodiment 1 are phonetic - 4 (1 hydrogen) -one of pyridine and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, Obtain formula (I-11) compound.MS(ESI)：m/z 444.0[M-H]^-、446.0[M+H]⁺、469.0[M+Na]⁺.

Embodiment 12：Formula (I-12) compound

Bromo- using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (tetrahydrofuran -3- bases) -5- cyano group -2- and 4- respectively Thio -2,3- the dihydro-pyrimidins -4 (1 of the chloro- 2- of 6- (suberyl) -5- in N- (the chloro- 2- thienyls of 3-) propionamide alternative embodiment 1 Hydrogen) -one and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtain formula (I-12) compound.MS(ESI)：m/z 406.6[M-H]^-、408.6[M+H]⁺、431.6[M+Na]⁺.

Embodiment 13：Formula (I-13) compound

Respectively using chloro- -4 (1 hydrogen) -one of 2- ammonia generation -2,3- dihydro-pyrimidins of 6- (suberyl) -5- and 4- bromo- N- (3- nitros Pyrroles's -2- bases) thio -2,3- dihydro-pyrimidins -4 (1 hydrogen) -one of the chloro- 2- of 6- (suberyl) -5- in butyramide alternative embodiment 1 Bromo- with 4- N- (4- nitropyridine -2- bases) butyramide, is reacted according to the method for embodiment 1 and is purified, obtained formula (I-13) Compound.MS(ESI)：m/z 486.7[M-H]^-、488.7[M+H]⁺、511.7[M+Na]⁺.

Embodiment 14：Formula (I-14) compound

Respectively using 6- (2- (4,5- dihydro-thiophene -2- bases) methyl) thio -2,3- dihydro-pyrimidins -4 of -5- methoxyl group -2- The chloro- 2- sulphur of 6- (suberyl) -5- in (1 hydrogen) -one and the bromo- N- of 4- (3- Trifluoromethoxyphen-ls) pentanamide alternative embodiment 1 - 4 (1 hydrogen) -one of generation -2,3- dihydro-pyrimidins and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, enter according to the method for embodiment 1 Row reaction and purifying, obtain formula (I-14) compound.MS(ESI)：m/z 515.1[M-H]^-、517.1[M+H]⁺、540.1[M+ Na]⁺.

Embodiment 15：Formula (I-15) compound

Respectively using thio -4 (1 hydrogen) -one of -2,3- dihydro-pyrimidins of 6- (cyclohexyl methyl) -5- ethyl -2- and the bromo- N- of 2- Thio -2,3- the dihydro-pyrimidins -4 (1 of the chloro- 2- of 6- (suberyl) -5- in (4- sulfoamido phenyl) acetamide alternative embodiment 1 Hydrogen) -one and the bromo- N- of 4- (4- nitropyridine -2- bases) butyramide, are reacted according to the method for embodiment 1 and are purified, obtain formula (I-15) compound.MS(ESI)：m/z 461.1[M-H]^-、463.1[M+H]⁺、485.1[M+Na]⁺.

Embodiment 16：Formula (I) compound of embodiment of the present invention 1-15 suppresses HCV virus ability to prove by following experiment

A.NS5B polymerase Inhibition tests

This test for determine formula (I) compound of the present invention and control compound Sofosbuvir (isopropyl ((S)- (((2R, 3R, 4R, 5R) -5- (fluoro- 3- hydroxyls -4-4 methyl tetrahydrochysene furans of -1 (2H)-base -4- of 2,4- dicarbapentaborane -3,4- dihydro-pyrimidins Mutter -2- bases) methoxyl group) (phenoxy group)-ALANINE ester) suppress the RNA for depending on RNA of HCV (HCV) to be polymerized The ability of enzymatic activity of the enzyme (NS5B) on heteromeric RNA template.

Experimental procedure：

Experiment buffer condition：(50 μ L- total amounts/reactant)

20mM Tris、pH7.5、50μM EDTA、5mM DTT、2mM MgCl₂, 80mM KCl, 0.4U/ μ L RNAsin (Promega, content (stock) are 40 units/L)

(a 500-nt RNA made with T7 run-off transcriptions, with from hepatitis C genotype group for 0.75 μ g t500 The sequence in NS2/3 regions)

1.6 μ g purifying hepatitis NS5B (amino acid for having 21 C- ends to truncate is formed)

1 μM of A, C, U, GTP (ribonucleoside triphosphote mixture)

[α-³²P]-GTP or [α-³³P]-GTP

The compound is tested under the various concentration of up to 100 μM of ultimate densities.

Prepare the reaction buffer of the appropriate amount for including enzyme and template t500.The formula (I) of embodiment of the present invention 1-15 is changed Compound is moved in the hole of 96 orifice plates.Preparing includes the mixture of radioactive label GTP, and is moved to the hole of 96 orifice plates In.Enzyme-template reaction solution initiation reaction is added, and makes reaction carry out 1-2 hours at room temperature.

Add 20 μ L0.5M EDTA, pH8.0 quenching reactions.Including blank test, quenching solution is being added in blank test It is added in NTPs before entering reaction buffer.

Reactant after 50 μ L are quenched is dripped on DE81 filter discs (Whatman), and which is dried 30 minutes.Use 0.3M first Sour ammonium, pH8 (150mL is used in washing every time, and the cpm in 1mL washing lotions generally washes 6 times less than 100) washing filter disc.In flicker In counter, filter disc is counted in 5mL scintillation solutions.

Suppression percentage is calculated by following formula：[1- is (in the blank reactions of cpm- in test reaction to suppress %= Cpm)/(cpm in control reaction in the blank reactions of cpm-)] × 100.

The result of the test of formula (I) compound and control compound Sofosbuvir of embodiment of the present invention 1-15 (suppresses The IC of NS5B polymerases₅₀Value) table 1 is listed in, wherein A represents its IC₅₀Value is less than 1 μM, and B represents its IC₅₀Value 1 μM to 10 μM it Between, C represents its IC₅₀It is worth between 10 μM to 50 μM, D represents its IC₅₀Value is more than 50 μM.

Formula (I) compound of 1 embodiment of the present invention 1-15 of table suppresses the result of NS5B polymerases

B. hepatitis C virus HCV inhibitory activity is determined

The suppression that formula (I) compound and control compound Sofosbuvir of embodiment of the present invention 1-15 is replicated to HCV is lived Property be with HCV luciferase reporter gene analysis methods (HCVReplicon Reporter Luciferase Assay) determine 's.The cell model of experiment is the Huh-7 clones that HCV luciferase reporter genes surely turn；Formula (I) compound to be measured and right 10mM is formulated as according to compound Sofosbuvir stock solution dimethyl sulfoxide (DMSO)s, during experiment, a series of ladders is diluted to culture medium Degree concentration, is typically diluted to 8 to 10 concentration.The internal reference compound of test is Cyclosporine.

The program of test is：The formula to be measured (I) of variable concentrations was changed after 96 well culture plate upper 24 hours by cell growth Compound and control compound Sofosbuvir are added in the cell of culture with internal reference compound.After 48 hours, detected with ELIASA Uciferase activity.The half-inhibition concentration IC of compound₅₀Value can pass through under a series of variable concentrations, and test-compound is to fluorescence The suppression numerical value of plain enzymatic activity is calculated.

C. the toxotest of formula (I) compound and control compound Sofosbuvir to cell

Formula (I) compound and control compound Sofosbuvir of embodiment of the present invention 1-15 is to use to the toxicity of cell MTT cytotoxicity assay are determined.The cell model of experiment is the Huh-7 that HCV luciferase reporter genes surely turn Clone；Formula (I) compound to be measured and control compound Sofosbuvir stock solution dimethyl sulfoxide (DMSO)s are formulated as 10mM, real A series of gradient concentrations are diluted to culture medium when testing, 8 to 10 concentration are typically diluted to.The internal reference compound of test is Cyclosporine.

The program of test is：By cell growth on 96 well culture plates, the formula to be measured (I) of variable concentrations is changed after 24 hours Compound and control compound Sofosbuvir are added in the cell of culture with internal reference compound.After 48 hours, MTT is added to training Cultivate in foster cell 4 hours, then absorbance is detected with ELIASA.The half-inhibition concentration CC of compound₅₀Value can pass through one Under serial variable concentrations, tested formula (I) compound and control compound Sofosbuvir are carried out to the suppression numerical value of cytoactive Calculate.

Table 2 formula (I) chemical combination microbic activity testing result

Compound	IC₅₀	CC₅₀
			Formula (I-1) compound	0.105	＞ 10
Formula (I-2) compound	0.099	＞ 10
			Formula (I-3) compound	0.104	＞ 10
Formula (I-4) compound	0.106	＞ 10
			Formula (I-5) compound	0.102	＞ 10
Formula (I-6) compound	0.107	＞ 10
			Formula (I-7) compound	0.108	＞ 10
Formula (I-8) compound	0.089	＞ 10
			Formula (I-9) compound	0.098	＞ 10
Formula (I-10) compound	0.104	＞ 10
			Formula (I-11) compound	0.105	＞ 10
Formula (I-12) compound	0.097	＞ 10
			Formula (I-13) compound	0.110	＞ 10
Formula (I-14) compound	0.103	＞ 10
			Formula (I-15) compound	0.102	＞ 10
Sofosbuvir	0.110	＞ 10

By contrast above as can be seen that being directed to the NS5B target spots of hepatitis C, formula (I) compound of the present invention and control Compound Sofosbuvir is compared, and activity is higher and toxicity is lower.This shows that formula (I) compound of the present invention is expected to become a kind of complete New mechanism, more high-efficiency low-toxicity HCV inhibitor.

The preferred embodiments of the present invention are the foregoing is only, the present invention is not limited to, for the skill of this area For art personnel, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, made any repair Change, equivalent, improvement etc., be all contained within protection scope of the present invention.

Claims

1. a kind of compound of formula (I) or its dynamic isomer, enantiomter, diastereoisomer, racemic modification, metabolism Thing, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog,

Wherein,

R is aryl or heteroaryl, can contain 1 to 4 substituent, and its substituent can be halogen, amino, hydroxyl, nitro, cyanogen Base, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom, the aminoalkyl of 1 to 20 carbon atom, 1 to 20 carbon The alkylamino of atom, the alkyl acyl of 2 to 20 carbon atoms, the alkyl amido of 2 to 20 carbon atoms, 1 to 20 carbon atom Alkoxyacyl, the alkylthio of 1 to 20 carbon atom, the alkylthio group of 1 to 20 carbon atom, the halogen of 1 to 20 carbon atom Substituted alkyl, the halogenated alkoxy of 1 to 20 carbon atom, aryl or heteroaryl；

Z is covalent bond, the alkylene of 1 to 20 carbon atom or contains-O- ,-S- ,-NH- ,-CO- ,-CS- ,-SO- ,-SO₂- linear Structure, circulus or its combination；

A and B are each independently halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 20 carbon atom, 1 to 20 carbon original Son alkoxyl, the thiazolinyl of 2 to 20 carbon atoms, the alkenyloxy group of 2 to 20 carbon atoms, the cycloalkyl of 5 to 14 carbon atoms, 5 The cyclenes epoxide of Heterocyclylalkyl, 5 to 14 carbon atoms to 14 carbon atoms, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, 5 to The cycloalkyl-alkyl of 14 carbon atoms, the hetercycloalkylalkyl of 5 to 14 carbon atoms, the cyclenes epoxide alkane of 5 to 14 carbon atoms Base, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms, the aminoalkyl of 1 to 20 carbon atom, the alkylamino of 1 to 20 carbon atom, The acyl group of 2 to 20 carbon atoms, the acylamino- of 2 to 20 carbon atoms, the alkoxyacyl of 1 to 20 carbon atom, 1 to 20 carbon The alkylthio of atom, the haloalkyl of 1 to 20 carbon atom, the halogenated alkoxy of 1 to 20 carbon atom.

2. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, R is virtue Base, can contain 1 to 4 substituent, its substituent can be halogen, nitro, cyano group, the haloalkyl of 1 to 20 carbon atom, The halogenated alkoxy of 1 to 20 carbon atom.

3. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, R is miscellaneous Aryl, can contain 1 to 4 substituent, and its substituent can be the alkyl halide of halogen, nitro, cyano group, 1 to 20 carbon atom Base, the halogenated alkoxy of 1 to 20 carbon atom.

4. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, Z is 1 Alkylene to 6 carbon atoms.

5. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, Z be containing There is the linear structure of-O- ,-S- ,-CO- ,-CS-.

6. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, Z is 1 Alkylene to 20 carbon atoms is combined with containing-O-, the linear structure of-S- and containing-CO-, the linear structure of-CS-.

7. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, A is halogen Element, nitro, cyano group, the alkyl of 1 to 20 carbon atom, the alkoxyl of 1 to 20 carbon atom；B is the cycloalkanes of 5 to 14 carbon atoms Base, the Heterocyclylalkyl of 5 to 14 carbon atoms, the cyclenes epoxide of 5 to 14 carbon atoms, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, The cycloalkyl-alkyl of 5 to 14 carbon atoms, the hetercycloalkylalkyl of 5 to 14 carbon atoms, the cyclenes epoxide of 5 to 14 carbon atoms Alkyl, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms.

8. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, A is 5 The Heterocyclylalkyl of cycloalkyl, 5 to 14 carbon atoms to 14 carbon atoms, the cyclenes epoxide of 5 to 14 carbon atoms, 5 to 14 The heterocycle alkenyloxy group of carbon atom, the cycloalkyl-alkyl of 5 to 14 carbon atoms, the hetercycloalkylalkyl of 5 to 14 carbon atoms, 5 to The cyclenes epoxide alkyl of 14 carbon atoms, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms；B be halogen, nitro, cyano group, 1 to The alkyl of 20 carbon atoms, the alkoxyl of 1 to 20 carbon atom.

9. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog, wherein, described Compound is selected from following compounds：

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (suberyl) -5-)-N- (4- nitropyridine -2- bases) butyramide Formula (I-1)；

2- (4- (cyclohexene -3- bases) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2,3- dicyano furans - 5- yls) acetamide formula (I-2)；

2- (4- (cyclohexyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (dinitrophenyl group) acetyl Amine formula (I-3)；

3- (4- (tetrahydrofuran -2- bases) -5- cyano group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (the chloro- 2- thienyls of 3-) Propionamide formula (I-4)；

2- (4- (cyclohexyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3,5- difluorophenyls) acetamide formula

(I-5)；

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (CycloheptylmethyI) -5-)-N- (3- nitro-pyrrole -2- bases) fourth Acid amides formula (I-6)；

3- (4- (2- (cyclohexene -3- bases) ethyl) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2- cyano group benzene Base) propionamide formula (I-7)；

2- (4- (cyclohexyl methyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3,5- difluorophenyls) acetyl Amine formula (I-8)；

(3- is bromo- for-N- for 3- (4- (3- (tetrahydrofuran -2- bases) propyl group) -5- methyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls) 2- pyridine radicals) propionamide formula (I-9)；

5- (4- (2- (4,5- dihydro-thiophene -2- bases) ethyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3- Trifluoromethoxyphen-ls) pentanamide formula (I-10)；

2- (4- (cyclohexene -1- bases) -5- nitro -6- carbonyl -1,6- dihydro-pyrimidin -2- epoxides)-N- (2,3- dicyano furans - 5- yls) acetamide formula (I-11)；

3- (4- (tetrahydrofuran -3- bases) -5- cyano group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (the chloro- 2- thienyls of 3-) Propionamide formula (I-12)；

4- (the chloro- 6- carbonyls -1,6- dihydro-pyrimidins -2- amino of 4- (CycloheptylmethyI) -5-)-N- (3- nitro-pyrrole -2- bases) fourth Acid amides formula (I-13)；

5- (4- (2- (4,5- dihydro-thiophene -2- bases) ethyl) -5- methoxyl group -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (3- Trifluoromethoxyphen-ls) pentanamide formula (I-14)；

2- (4- (cyclohexyl methyl) -5- ethyl -6- carbonyl -1,6- dihydro-pyrimidin -2- sulfenyls)-N- (4- sulfoamido phenyl) second Acid amides formula (I-15).

10. compound according to claim 1 or its dynamic isomer, enantiomter, diastereoisomer, racemic Body, metabolin, N- oxides, prodrug, hydrate, solvate or its salt, and its quaternized nitrogen analog is in preparation prevention Or the purposes in treatment hepatitis C medicine, which can be formulated as the form of pharmaceutical preparation or pharmaceutical composition, the medicine system Agent or pharmaceutical composition are also comprising at least one pharmaceutically acceptable carrier, diluent or excipient and/or auxiliary agent, Yi Jiren Compound of the selection of land comprising one or more other pharmaceutical active.