CN105968101A - Compounds adopted as hepatitis C inhibitors and applications thereof in medicines - Google Patents

Abstract

The invention relates to compounds adopted as hepatitis C inhibitors and applications thereof in medicines, and particularly provides compounds shown as a formula (I) or stereoisomers, tautomers, enantiomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof used for treating hepatitis C viraus (HCV) infection or hepatitis C. The invention also discloses pharmaceutical compositions containing the compounds and a method of treating the hepatitis C viraus (HCV) infection or hepatitis C through using the compounds or the pharmaceutical compositions.

Description

As the compound of hepatitis c inhibitor and the application in medicine thereof

Invention field

The invention belongs to drug world, be particularly used for treating the compound, described that hepatitis C virus (HCV) infects Compositions of compound and application thereof and using method.

Background of invention

HCV is main human pathogen, estimates that about 1.7 hundred million people are infected in the whole world, infects people for human immunodeficiency virus type 1 5 times of number.And the major part in the middle of these HCV infection individualities can develop into serious Progressive symmetric erythrokeratodermia hepatopathy, including liver cirrhosis regulating liver-QI Cell carcinoma.Therefore, chronic HCV infection will be the main cause of global patient's premature death because of hepatopathy.

HCV is positive chain RNA virus.According to the ratio to the extensive similarity of the aminoacid sequence derived and 5 ' untranslated regions Relatively, in HCV is classified into the single genus of flaviviridae (Flaviviridae family).All members of flaviviridae Being all the envelope virus particle containing positive chain RNA genome, this genome is turned over by single uninterrupted open reading frame (ORF's) Translate, encode all known virus specified proteins.

Considerable heterogeneity is there is in the nucleotide and coded aminoacid sequence of whole HCV genome.? Identify at least 7 main genotype, and disclose more than 50 hypotype.By in HCV infection cell, viral RNA is turned over It is translated into polyprotein, and is split into 10 kinds body proteins.Being structural protein at amino terminal, E1 and E2 is following closely.It addition, also Having 6 kinds of non-structural proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, it plays the heaviest in HCV life cycle The role that wants (see, e.g., Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).

The distribution in the whole world of the main genotypes of HCV is different, although carried out lots of genes type to pathogenesis and treatment The research of effect, but still do not know the clinical importance of HCV genetic heterogeneity.

Strand HCV rna gene group length is about 9500 nucleotide, has single open reading frame, encode single about 3000 amino acid whose large-scale polyproteins.In infection cell, this polyprotein on multiple sites by leukoprotease and Virus protein cleavage, produces structure and non-structural (NS) albumen.For HCV, ripe non-structural protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) be formed by two-strain protease realize.It is generally acknowledged that the first is metal egg White enzyme, cuts at NS2-NS3 contact；The second is included in NS3 (also referred to herein as NS3 protease) N end regions Serine protease, it mediates all of follow-up cutting in NS3 downstream, is cis at NS3-NS4A cleavage site, at remaining NS4A- NS4B, NS4B-NS5A, NS5A-NS5B site is then trans.NS4A albumen seems there is several functions, plays NS3 protease cofactor Effect, and NS3 and other rdrp virus components may be assisted to carry out film location.NS3 albumen and the formation of NS4A complex Seemingly process event, all sites improves necessary to proteolytic efficiency.NS3 albumen also demonstrates ribonucleoside triphosphote Enzyme and DBPA activity.NS5B (being also known as HCV polymerase herein) is to participate in the RNA polymerization depending on RNA that HCV replicates Enzyme.

Summary of the invention

The compounds of this invention is for treating patient's HCV infection, and this compound optionally suppresses the duplication of HCV virus.

The present invention relates to the method that HCV-Ab IgG infects.The present invention provide compound or pharmaceutical composition to HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a are respectively provided with good inhibition, the compound of present invention offer simultaneously or medicine Compositions also has good inhibition to HCVGT1b L31V, GT1b Y93H persister.Therefore, the invention provides The full genome HCV with overriding resistance suppresses medicine, and has preferable bioavailability.

On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I) Stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolism are produced Thing, pharmaceutically acceptable salt or prodrug,

Wherein, A is-(CR⁷R^7a)_m-、-CR⁷=CR^7a-、-(CH₂)_nO-,-N=CR⁷-、-NR⁷-CR⁷R^7a-、-CR⁷R^7a- NR⁷-、-O(CH₂)_n-、-CR⁷=N-,-S (CH₂)_n-、-(CH₂)_nS-or-NR^9a-；

X and X¹It is each independently N or CR^7b；

Y and Y¹Be each independently H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (= O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰Or a-amino acid group；

Wherein a-amino acid group is selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, color Propylhomoserin, valine, alanine, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, the brightest ammonia Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline institute shape The group become；

R¹、R²、R³And R⁴It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl； Or R¹、R²It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell Ring；Or R³、R⁴With X¹-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous dicyclo, spiral shell dicyclo or spiral shell Miscellaneous dicyclo；

Each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl, Thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Base alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, miscellaneous Ring group alkylamino or aryloxy group；

Each R⁷、R^7a、R^7b、R⁸、R^8aAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, Deuteroalkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl Alkylamino, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy Base, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (= O)_rO-, alkyl-OS (=O)_rO-, alkyl-S (=O)_r-, heterocyclic radical alkylamino or aryloxy group；

Each R⁹And R¹⁰Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or ammonia Base sulfonyl；

Each f, n and t independently be 0,1,2,3 or 4；

M is 1,2,3 or 4；With

Each r independently be 0,1 or 2；

The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (=O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo, The miscellaneous dicyclo of spiral shell dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclic radical alkane Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl, Heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia Base formoxyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or amino-sulfonyl individually optionally by 1, 2,3 or 4 are selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, halo Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl Amino, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)₂-, hydroxyl substituted alkyl-S (=O)-, hydroxyl takes Alkyl-the S (=O) in generation₂-or the substituent group of the substituted alkoxyl of carboxyl replaced.

At some embodiments, each R¹、R²、R³And R⁴Independently be H, C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_3-10Cycloalkanes Base, C_2-10Heterocyclic radical, C_1-9Heteroaryl or C_6-10Aryl；Or R¹、R²With X-CH be randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell；Or R³、R⁴With X¹-CH is randomly formed 3- 8 yuan of heterocycles, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell；Wherein institute The 3-8 unit heterocycle stated, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell is only Stand and be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C by 1,2,3 or 4_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkylamino, C_1-6Alkylthio group, C_6-10Virtue Base amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle The substituent group of base is replaced.

In some embodiments, wherein R¹、R²The heterocycle, condensed ring or the spiro ring system that are formed with Y-X-CH are selected from following sub-knot Structure formula:

Wherein R³、R⁴With Y¹-X¹Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following subformula:

Wherein, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkylamino, C_1-6Alkylthio group, C_6-10Virtue Base amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle Base；

Each R^9bIndependently be hydrogen, deuterium, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Hydroxy alkyl, C_1-6Aminoalkyl, C_1-6Alcoxyl Base C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylthio group C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_1-9Heteroaryl, C_6-10Virtue Base, C_2-10Heterocyclic radical or C_3-8Cycloalkyl；

With each n₁And n₂Independently be 1,2,3 or 4.

At other embodiments, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-3Alkane Base, C_1-3Haloalkyl, C_1-3Alkoxyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Halogenated alkoxy C_1-3Alkyl, C_1-3Alkylamino, C_1-3 Alkylthio group, C_6-10Arylamino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Ring Alkyl or C_2-10Heterocyclic radical；With

Each R^9bIndependently be hydrogen, deuterium, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Hydroxy alkyl, C_1-3Aminoalkyl, C_1-3Alcoxyl Base C_1-3Alkyl, C_1-3Alkylamino C_1-3Alkyl, C_1-3Alkylthio group C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, C_1-9Heteroaryl, C_6-10Virtue Base, C_2-10Heterocyclic radical or C_3-8Cycloalkyl.

At other embodiments, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, methyl, second Base, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy ylmethyl, trifluoro Methoxy, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenyl amino, benzene oxygen Base, pyrrole radicals, morpholinyl or piperazinyl；With

Each R^9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, first Epoxide methyl, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.

At some embodiments, each R⁷、R^7a、R^7bAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10 Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6 Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamyl Base, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10 Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group；With

Each r independently be 0,1 or 2.

At some embodiments, Y and Y¹It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Virtue Base, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl or-C (=O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰；

Each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Deuteroalkyl, C_1-6 Haloalkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Aryl C_1-6 Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10 Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10 Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclic radical Amino, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group；

R⁹And R¹⁰It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Aryl, C_1-9Heteroaryl Base, C_6-10Aryl C_1-6Alkyl, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (= O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-S (=O)_r-or amino-sulfonyl；

T is 0,1,2,3 or 4；With

Each r independently be 0,1 or 2.

At other embodiments, R⁹And R¹⁰Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-OC (=O)-, isopropyl-OC (=O)-, tertiary fourth Base-OC (=O)-, methyl-C (=O)-, ethyl-C (=O)-, isopropyl-C (=O)-, normal-butyl-C (=O)-, isobutyl group-C (=O)-, carbamoyl, methyl-carbamoyl, ethylamino formoxyl, methyl-OS (=O)₂-, cyclopropyl-OS (=O)₂-, first Base-S (=O)₂O-, cyclopropyl-S (=O)₂O-or amino-sulfonyl.

In some embodiments, the compounds of this invention has the structure shown in formula (II), (IIa), (IIb) or (III), or formula (II), the structural upright isomer shown in (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomer, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:

Wherein, A is-O-,-S-,-NH-,-CH₂-S-、-CH₂-O-、-CH₂-NH-、-O-CH₂-、-NH-CH₂-、-S-CH₂- Or-CH₂-CH₂-；

Wherein, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-3Alkyl, C_1-3Alkyl halide Base, C_1-3Alkoxyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Halogenated alkoxy C_1-3Alkyl, C_1-3Alkylamino, C_1-3Alkylthio group, C_6-10Virtue Base amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle Base；

With each n₁And n₂Independently be 1,2,3 or 4.

At other embodiments, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Deuteroalkyl, C_1-6Haloalkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, Nitro, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Miscellaneous Ring group C_1-6Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl- OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10Heterocyclic radical C_1-6Alkane Amino or C_6-10Aryloxy group.

At other embodiments, the most each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, first Base, ethyl, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoro-methoxy first Base, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenylamino Base, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl.

At some embodiments, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxyl, C_6-10Arylamino, C_1-9Heteroaryl ammonia Base, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_6-10Virtue Base C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclic radical ammonia Base, C_1-6Alkyl acyl, C_1-6Alkyl acyloxy, C_1-6Alkoxyacyl, C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group.

At other embodiments, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene Base, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, phenyl amino, sulfydryl or nitre Base.

At some embodiments, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, ethyl, Isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated ethyl, deuterated propyl group, deuterated isopropyl, methoxy Base, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy ethyl, 1-methoxy-propyl, 2-methoxyl group Propyl group, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, vinyl, alkene Propyl group, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.

On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises an any of the above described change Compound.

In some embodiments, this pharmaceutical composition can also comprise pharmaceutically acceptable carrier, figuration further Agent, diluent, adjuvant, vehicle or a combination thereof.

In other embodiments, it further comprises other the medicine of HCV-Ab IgG, wherein said HCV-Ab IgG Medicine is the change that interferon, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce 1 type helper T lymphocyte response Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bar Dimension former times monoclonal antibody, hepatitis C immunoglobulin, Civacir^TM, EBP520, TVR, erlotinib, his Wei of Dacca, U.S. of department Wei, Ah that Wei, vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、 Ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Lurui Wei, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX- 136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184、IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、 VCH-916、lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir、furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、 MK-8325、JNJ-47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、 BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, I Pool Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF- 961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、 MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、 GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB- 9200, ITX-5061, ID-12 or a combination thereof；Described interferon is Interferon Alpha-2b, the interferon-ALPHA of Pegylation, interferon α-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.

In other embodiments, other the medicine of HCV-Ab IgG wherein said be used for suppressing HCV reproduction process and/ Or the function of suppression HCV virus protein；Described HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV replicate, HCV assembles or HCV release；Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine monophosphate dehydrogenase (IMPDH).

On the other hand, the present invention provides the compounds of this invention or the pharmaceutical composition purposes in preparing medicine, described medicine Thing is for suppressing HCV reproduction process and/or the function of suppression HCV virus protein；Described HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV duplication, HCV assemble or HCV release；Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine Monophosphate dehydrogenase (IMPDH).

On the other hand, the present invention provides the compounds of this invention or the pharmaceutical composition purposes in preparing medicine, described medicine Thing is used for preventing, process, treat or alleviate HCV infection or hepatitis C disease.

Another aspect of the present invention relate to the compound that formula (I), (II), (IIa), (IIb) and (III) is comprised preparation, Separate and the method for purification.

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

Detailed description of the invention book

Definition and general terms

Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed or chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.

It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.

Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.

Term used in the present invention " study subject " refers to animal.Typical described animal is mammal.Tested right As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Try liking people.

Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.

It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.

The present invention uses " in some embodiments " or " in other embodiments " before technical characteristic definition, represents fixed herein The technical characteristic of justice can be any with other the technical characteristic drawn by " in some embodiments " or " in other embodiments " Be combined into complete technical scheme.

" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..

" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.

" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.

" diastereomer " refers to two or more chiral centre and the stereoisomerism of its molecule mirror image the most each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.

Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Many organic compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time, May occur in which this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.

According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.

By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes being come by the restructuring of some bonding electronss The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization be pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One concrete reality of phenol-keto tautomerism Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms is within the scope of the present invention.

Intranuclear tautomerism (Annular tautomerism) is the tautomeric one of proton translocation, and wherein proton can To account for the two or more positions in heterocycle, the two isomer coexists in an equilibrium system, mutual with at a relatively high speed Phase inversion.Such as: 1H-and 3H-imidazoles；1H, 2H-and 4H-1,2,4-triazole；1H-and 2H-iso-indoles.Involved in the present invention Structure fragment, following structure fragment Aa and Ab, or Ba and Bb, for intranuclear tautomerism body；Owing to two isomers coexist, for Narration simplicity, the present invention only mentions that the structure of one of which isomer, where the most in office mention that intranuclear tautomerism body is wherein appointed What a kind of structure, then it represents that the most simultaneously mention another kind of structure, although as the present invention is only given the chemical combination containing Aa structure fragment Thing, but the compound essence that the tautomer of this compound contains structure fragment Ab is given the most simultaneously；Although such as this Compound containing Ba structure fragment only occurs in bright, but the compound that the tautomer of this compound contains structure fragment Bb is real Matter is given the most simultaneously.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.It is said that in general, art Language " substituted " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless other aspect tables Bright, an optional substituted radical can replace in each commutable position of group.When in given structural formula not One or more substituent groups that only position can be selected from concrete group are replaced, then substituent group can identical or differently Replace in each position.When substituent group is described as " being independently selected from " group, and the most each substituent group selects, therefore independently of one another Each substituent group can be same to each other or different to each other.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.

At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C_1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Containing 1-4 carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-pro-pyl (n- Pr、-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), the tert-butyl group (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2-amyl group (-CH (CH₃)CH₂CH₂CH₃), 3-amyl group (-CH (CH₂CH₃)₂), 2-methyl-2-butyl (-C (CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH (CH₃)CH(CH₃)₂), 3-methyl isophthalic acid-butyl (-CH₂CH₂CH(CH₃)₂), 2-first Base-1-butyl (-CH₂CH(CH₃)CH₂CH₃), n-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH (CH₃) CH₂CH₂CH₂CH₃), 3-hexyl (-CH (CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-amyl group (-C (CH₃)₂CH₂CH₂CH₃), 3-first Base-2-amyl group (-CH (CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-amyl group (-CH (CH₃)CH₂CH(CH₃)₂), 3-methyl-3-penta Base (-C (CH₃)(CH₂CH₃)₂), 2-methyl-3-amyl group (-CH (CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C (CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl, etc..

Term " haloalkyl ", or " halogenated alkoxy " expression alkyl or alkoxy base are by one or more halogen atoms Being replaced, such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " hydroxy alkyl " or " the substituted alkyl of hydroxyl " represent that alkyl group is taken by one or more oh groups In generation, wherein alkyl group has implication of the present invention.Such example comprises, but be not limited to methylol, ethoxy, 1, 2-dihydroxy ethyl etc..

Term " aminoalkyl " or " the substituted alkyl of amino " represent that alkyl group is taken by one or more amino groups In generation, wherein alkyl group has implication of the present invention.

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent group that the present invention describes is replaced.

Term " alkoxyalkyl " represents that alkoxy base is connected with molecule remainder by alkyl, wherein alkoxyl with Alkyl group has implication as described in the present invention.The example of alkoxy-alkyl group includes, but is not limited to, methoxy methyl Base, methoxy ethyl, 2-methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, 1-propoxy methyl, 2-third Epoxide ethyl, 1-butoxymethyl, 2-methyl-l-Among, 2-butoxymethyl, etc..

Term " alkyl acyl " or " alkoxyacyl " represent that alkyl or alkoxyl are by acyl group and molecule remainder phase Even, wherein alkyl, alkoxyl have implication as described in the present invention with acyl group.In certain embodiments, this kind of embodiment is permissible For alkyl-OC (=O)-, alkyl-OS (=O)_r-, alkyl-C (=O)-, alkyl-S (=O)_r-。

Term " alkyl acyloxy " or " alkoxy acyloxy " represent alkyl or alkoxyl by acyloxy and molecule remaining Part is connected, and wherein alkoxyl, alkyl have implication as described in the present invention with acyloxy.In certain embodiments, this kind of reality Executing example can be alkyl-C (=O) O-, alkyl-OC (=O) O-, alkyl-S (=O)_rO-, alkyl-OS (=O)_rO-。

Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, and formula is R-M (=O)-.Generally the M atom in acyl group is all carbon, sulfur.Term " acyloxy " refers to that acyl group passes through oxygen atom and its remaining part of molecule Split-phase group formula even is R-M (=O) O-.

Term " halogenated alkoxy alkyl " represents the group that halogenated alkoxy is connected with molecule remainder by alkyl, its Middle halogenated alkoxy and alkyl have implication as described in the present invention.

Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two C_1-6Alkyl is connected to the alkylamino group on nitrogen-atoms.Other embodiment is, alkyl amino is one or two C_1-3 Alkyl is connected to the alkylamino group on nitrogen-atoms.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amino Base, such example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..

Term " alkyl amino alkyl " represents the group that alkylamino is connected with molecule remainder, wherein alkylamino by alkyl With alkyl, there is implication as described in the present invention.

Term " alkylthio group " represents the group that alkyl group is connected with molecule remainder, wherein alkyl tool by sulphur atom There is implication as described in the present invention.

Term " alkylthio alkyl " represents the group that alkylthio group is connected with molecule remainder, wherein alkylthio group by alkyl With alkyl, there is implication as described in the present invention.

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is a carbon-to-carbon sp²Double bond, wherein, described alkenyl group can optionally be retouched by one or more present invention The substituent group stated is replaced, and it includes " cis " and the location of " trans ", or " E " and the location of " Z ".In an embodiment In, alkenyl group comprises 2-8 carbon atom；In another embodiment, alkenyl group comprises 2-6 carbon atom；In another reality Executing in scheme, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (-CH= CH₂), pi-allyl (-CH₂CH=CH₂) etc..

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is carbon-to-carbon sp tri-key, wherein, described alkynyl group can optionally be retouched by one or more present invention The substituent group stated is replaced.In one embodiment, alkynyl group comprises 2-8 carbon atom；In another embodiment, alkynyl Group comprises 2-6 carbon atom；In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example bag of alkynyl group Include, but be not limited to, acetenyl (-C ≡ CH), propargyl (-CH₂C ≡ CH), 1-propinyl (-C ≡ C-CH₃) etc..

Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies System.In one embodiment, cycloalkyl comprises 3-12 carbon atom；In another embodiment, to comprise 3-8 carbon former for cycloalkyl Son；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.

Term " cycloalkyl-alkyl " represents the group that cycloalkyl is connected with molecule remainder, wherein cycloalkyl by alkyl With alkyl, there is implication as described in the present invention.

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Dividing undersaturated monocycle, dicyclo or three rings, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom, but at least one of which Ring is not belonging to the fragrance same clan.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrilo, and-CH₂-group can optionally by- C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring Butyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrochysene Furyl, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, Dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene Alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-benzodioxole base, 2-oxa--5-azabicyclo [2.2.1] Hept-5-base.-CH in heterocyclic radical₂-group by-C (O)-substituted example include, but not limited to 2-oxo-pyrrolidine base, oxo- 1,3-thiazolidinyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base.The reality that in heterocyclic radical, sulphur atom is oxidized Example include, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can be optionally by one Individual or multiple substituent groups described in the invention are replaced.

In one embodiment, heterocyclic radical is 3-8 former molecular heterocyclic radical, refers to comprise the full of 3-8 annular atoms With or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 3-8 is individual former Molecular heterocyclic radical can be carbon back or nitrilo, and-CH₂-group can be optionally by-C (=O)-replacement.The sulphur atom of ring Can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.4-7 atom group The example of the heterocyclic radical become includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrole Cough up quinoline base, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, Tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, tetrahydrochysene thiophene Mutter base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, high piperazine Piperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase.-CH in heterocyclic radical₂- Group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidines by-C (=O)-substituted example Ketone group, 3,5-dioxy piperazine piperidinyl and hybar X base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to ring Fourth sulfuryl, 1,1-dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can optionally by one or Multiple substituent groups described in the invention are replaced.

In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to comprise the saturated of 4 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is replaced selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 4 Former molecular heterocyclic radical can be carbon back or nitrilo, and-CH₂-group can be optionally by-C (=O)-replacement.The sulfur of ring is former Son can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.4 atom groups The example of the heterocyclic radical become includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.4 described atoms The heterocyclyl groups of composition can optionally be replaced by one or more substituent groups described in the invention.

In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, refers to comprise the saturated of 5 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 5 atom groups The heterocyclic radical become can be carbon back or nitrilo, and-CH₂-group can be optionally by-C (=O)-replacement.The sulphur atom of ring is permissible Optionally it is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.5 former molecular miscellaneous The example of ring group includes, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazoles Quinoline base, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur Cyclopenta.-CH in heterocyclic radical₂-group is included, but not limited to 2-oxo-pyrrolidine base, oxygen by-C (=O)-substituted example Generation-1,3-thiazolidinyl.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base.Described 5 former Molecular heterocyclyl groups can optionally be replaced by one or more substituent groups described in the invention.

In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, refers to comprise the saturated of 6 annular atomses Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 6 atom groups The heterocyclic radical become can be carbon back or nitrilo, and-CH₂-group can be optionally by-C (=O)-replacement.The sulphur atom of ring is permissible Optionally it is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.6 former molecular miscellaneous The example of ring group includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur generation Quinoline base, piperazinyl, dialkyl group, dithiane base, thiophene alkyl.-CH in heterocyclic radical₂-group is by-C (=O)-substituted example Include, but not limited to 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base.In heterocyclic radical, sulphur atom is oxidized Example includes, but not limited to 1,1-dioxothiomorpholinyl.6 described former molecular heterocyclyl groups can be optional Ground is replaced by one or more substituent groups described in the invention.

The most in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to comprise 7-12 annular atoms Saturated or part undersaturated spiral shell dicyclo or condensed-bicyclic, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless Additionally illustrating, 7-12 former molecular heterocyclic radical can be carbon back or nitrilo, and-CH₂-group can optionally by-C (= O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen Compound.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: indoline base, 1,2,3,4-tetrahydroisoquinoline Base, 1,3-benzodioxole base, 2-oxa--5-azabicyclo [2.2.1] hept-5-base.Described 7-12 former molecular miscellaneous Cyclic groups can optionally be replaced by one or more substituent groups described in the invention.

Term " heterocyclic radical epoxide " or " heterocyclylamino group " represent heterocyclic radical by oxygen atom or nitrogen-atoms and molecule remaining The group that part is connected, wherein heterocyclic radical has implication of the present invention.

Term " cycloheteroalkylalkyl " includes the substituted alkyl of heterocyclic radical；Term " heterocyclylalkoxy " includes that heterocyclic radical replaces Alkoxyl, wherein oxygen atom is connected with the remainder of molecule；Term " heterocyclic radical alkylamino " includes the substituted alkane of heterocyclic radical Amino, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein heterocyclic radical, alkyl, alkoxyl and alkylamino have such as this Bright described implication, such example includes, but is not limited to pyrroles's-2-ylmethyl, morpholine-4-base ethyl, morpholine-4-base second Epoxide, piperazine-4-base oxethyl, piperidin-4-yl ethylamino etc..

Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprises 3-7 Molecular ring, and have one or more attachment point to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " exchange use.The example of aromatic yl group can include phenyl, naphthyl and anthracene.Described aromatic yl group can individually optional ground quilt One or more substituent groups described in the invention are replaced.

Term " aryloxy group " represents the group that aryl is connected with molecule remainder by oxygen atom, and wherein aryl has this Implication described in invention.

Term " virtue amino " " arylamino " represents that amino group is replaced by one or two aromatic yl group, such reality Example includes, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on virtue amino can be replaced further.

Term " aryl alkyl " includes the substituted alkyl of aryl, and wherein alkyl is connected with the remainder of molecule；Term " virtue Base alkoxyl " include the substituted alkoxyl of aryl, wherein oxygen atom is connected with the remainder of molecule；Term " aryl alkane amino " Including the substituted alkylamino of aryl, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein aryl, alkyl, alkoxyl and alkane Amino has implication as described in the present invention.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, Dicyclo and three-ring system, at least one of which member ring systems is aromatic, and at least one member ring systems comprises one or more miscellaneous Atom, each of which member ring systems comprises 5-7 former molecular ring, and has one or more attachment point and molecule remainder It is connected.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups is appointed Selection of land is replaced by one or more substituent groups described in the invention.In one embodiment, 5-10 is individual former molecular miscellaneous Aryl comprises 1,2,3 or 4 hetero atom being independently selected from O, S and N.The example of heteroaryl groups includes, but is not limited to, 2-furan Mutter base, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-is different Oxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine Base, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazole radical (such as 5-tetrazole radical), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrrole Oxazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3- Triazolyl, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, 1,3,5-triazine Base；Also include following dicyclo, but be not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indole Base (such as 2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl are (such as 1-isoquinoline Quinoline base, 3-isoquinolyl or 4-isoquinolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine radicals, etc..

Term " heteroaryloxy " represents the group that heteroaryl is connected with molecule remainder, wherein heteroaryl by oxygen atom There is implication of the present invention.

Term " heteroaryl amino " " heteroaryl amino " represents that amino group is replaced by one or two heteroaryl groups.

Term " heteroaryl alkyl " includes the substituted alkyl of heteroaryl, and wherein alkyl is connected with the remainder of molecule；Art Language " heteroarylalkoxy " includes the substituted alkoxyl of heteroaryl, and wherein oxygen atom is connected with the remainder of molecule；Term is " miscellaneous Aryl alkane amino " include the substituted alkylamino of heteroaryl, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein heteroaryl, Alkyl, alkoxyl and alkylamino have implication as described in the present invention.

Term " carbocylic radical " and " carbocyclic ring " are used interchangeably herein, all referring to comprising the saturated of 3-12 carbon atom or portion Divide undersaturated monocycle, dicyclo or three rings, but at least one of which ring is not belonging to the fragrance same clan.Unless otherwise indicated, on carbocyclic ring -CH₂-group can be optionally by-C (=O)-replacement.Carbocylic radical comprises 3-8 carbon atom in certain embodiments.One In a little embodiments, carbocylic radical comprises 5 carbon atoms.In certain embodiments, carbocylic radical comprises 6 carbon atoms.

Term " condensed-bicyclic ", " condensed-bicyclic base " is used interchangeably herein, all referring to the saturated of unit price or multivalence or Part is undersaturated and member ring systems, and described and member ring systems refers to the bicyclic system of non-aromatic.Such system can comprise solely Vertical or the unsaturated system of conjugation, but its core texture do not comprise aromatic rings or heteroaromatic (but aromatic group can be made For substituent group thereon).In certain embodiments, condensed-bicyclic contains 5-12 carbon atom.

Term " volution base ", " spiral shell bicyclic group " is used interchangeably herein, refers to the saturated or part of unit price or multivalence not Saturated rings system, one of them ring originates from specific ring carbon atom on another ring.In certain embodiments, screw togather dicyclo to contain There is 5-12 carbon atom.

Such as, as disclosed below, a saturated also member ring systems (ring B and B ') is referred to as " condensed-bicyclic ", and ring A In two saturated member ring systems, share a carbon atom with ring B, be referred to as " volution " or " spiral shell dicyclo ".

When the annular atoms in " condensed-bicyclic " or " spiral shell dicyclo " contains at least one hetero atom, " condensed-bicyclic base " or " spiral shell bicyclic group " is referred to as " condensing miscellaneous dicyclo " or " the miscellaneous dicyclo of spiral shell ", and the most each ring can be carbocylic radical or heterocyclic radical.? In some embodiments, condense miscellaneous dicyclo or screw togather miscellaneous dicyclo and contain 5-12 carbon atom.

Term " oxo " represents that quilt=O replaces.

Term " hydroxyl " expression-OH.

Term " amino " expression-NH₂。

Term " cyano group " expression-CN.

Term " sulfydryl " expression-SH.

Term " nitro " expression-NO₂。

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N is (as 3, in 4-dihydro-2 h-pyrrole base N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).

Term " n former molecular ", wherein n is integer, and the number of ring member nitrogen atoms in typical description molecule, described In molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is 10 former molecular carbocylic radical groups.

The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.

As described in the present invention, substituent group draw formed on a ring being bonded the center of receiving member ring systems (as formula (b1), (b2), shown in (b3)) represent substituent group (R⁵)_n、R⁶、(R¹⁵)_n1Can replace any commutable position on ring.

The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-are (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description that group is 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.

Term used in the present invention " prodrug ", represent a compound be converted in vivo formula (I), (II), (IIa), And the compound shown in (III) (IIb).Such conversion is hydrolyzed by prodrug or in blood through enzyme in blood or tissue It is converted into the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can conduct Prodrug have phenyl ester class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino Esters of gallic acid.A such as compound in the present invention comprises hydroxyl, i.e. can be acylated the chemical combination obtaining prodrug form Thing.Other prodrug form includes phosphate ester, if these phosphate compounds are that the di on parent obtains Arrive.It is referred to documents below: T.Higuchi and V.Stella, Pro-drugs about the discussion that prodrug is complete as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche, ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry, 2008,51,2328-2345。

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

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit When, amine cation that nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid Compound, 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 molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.

Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly-half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.

Can by its derivative organic acid obtaining salt include such as acetic acid, propanoic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salt.

Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, and 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

It addition, compound disclosed by the invention, including their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that include solvation And unsolvated form.

Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as²H,³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, such as, and its In there is radiosiotope, as³H、¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (uses¹⁴C), kinetics research (uses such as²H or³H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread SPECT (single photon emission computed tomography) (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art Embodiment and the preparation process suitable isotope labeling reagent of described use in the routine techniques known or the present invention substitute former Carry out used unmarked reagent to prepare.

Additionally, higher isotope particularly deuterium is (i.e.,²H or D) replacement can provide some treat advantage, these advantages are Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band Come.Should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I), (II), (IIa), (IIb) and (III) compound. The concentration of such higher isotope particularly deuterium can be defined by the isotope enrichment factor.Term used in the present invention " with Position element enrichment factor " refer to specified ratio between isotopic isotope abundance and natural abundance.If chemical combination of the present invention The substituent group of thing is designated as deuterium, and this compound has at least 3500 (at each appointment D-atom for each D-atom specified The deuterium of 52.5% mixes), at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (75% Deuterium mix), at least 5500 deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuteriums of 95% Mix), at least 6466.7 deuterium of 97% (mix), at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuteriums of 99.5% Mix) the isotope enrichment factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be that isotope replaces Such as D₂O, acetone-d₆、DMSO-d₆Those solvates.

On the other hand, the present invention relates to prepare formula (I), compound that (II), (IIa), (IIb) and (III) are comprised Intermediate.

On the other hand, the present invention relates to the compound that formula (I), (II), (IIa), (IIb) and (III) is comprised preparation, Separate and the method for purification.

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention, pharmacy Upper acceptable carrier, excipient, diluent, adjuvant, solvent, or combinations thereof.At some embodiments, pharmaceutical composition Can be liquid, solid, semi-solid, gel or spray-type.

" combine " fixed Combination represented in single dosage unit form or the medicine box of the part for combined administration, its The middle present invention comes into the open compound and combined partner can be in same time individual application or can be at a certain time interval Use respectively, particularly make associating companion show cooperation, such as synergism.As the term is employed herein " co-administered " or " administering drug combinations " etc. are intended to include the single individuality (such as patient) that selected COMBINATION OF THE INVENTION is applied to need it, and are intended to Including wherein material without going through identical route of administration or the therapeutic scheme used simultaneously." medicine group as the term is employed herein Close product " represent the product mixed by more than one active component or obtained by combination, and both included the fixing of active component Combination also includes non-fixed combinations.Term " fixing joint " represent the active component such as present invention come into the open compound and COMBINATION OF THE INVENTION with The form of single entities or dosage is applied to patient simultaneously.Term " on-fixed associating " represents that the active component such as present invention comes into the open Compound and COMBINATION OF THE INVENTION all as corpus separatum simultaneously, common or limit ground without special time and be successively applied to patient, wherein should It is applied in the treatment effect level providing two kinds of compounds in the patient.The latter applies also for HAART, such as, use 3 Plant or more kinds of active component.

It should be noted that the term " suppression HCV virus protein " in the present invention should be interpreted broadly, it had both included suppression The expression of HCV virus protein, also includes the activity level suppressing HCV virus protein, the assembling of virus and emission levels.Its In, HCV protein expression level includes but not limited to: the translation skill of viral protein gene, the post translational modification level of albumen, son Levels of replication for hereditary material etc..

The description of the compounds of this invention

The present invention relates to the method that HCV-Ab IgG infects.HCV infection is had and well presses down by the compounds of this invention or pharmaceutical composition Make and use.

On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I) Stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolism are produced Thing, pharmaceutically acceptable salt or prodrug,

Wherein, A is-(CR⁷R^7a)_m-、-CR⁷=CR^7a-、-(CH₂)_nO-,-N=CR⁷-、-NR⁷-CR⁷R^7a-、-CR⁷R^7a- NR⁷-、-O(CH₂)_n-、-CR⁷=N-,-S (CH₂)_n-、-(CH₂)_nS-or-NR^9a-；

X and X¹It is each independently N or CR^7b；

Y and Y¹Be each independently H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (= O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰Or a-amino acid group；

Wherein a-amino acid group is selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, color Propylhomoserin, valine, alanine, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, the brightest ammonia Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline institute shape The group become；

R¹、R²、R³And R⁴It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl； Or R¹、R²It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell Ring；Or R³、R⁴With X¹-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous dicyclo, spiral shell dicyclo or spiral shell Miscellaneous dicyclo；

Each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl, Thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Base alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, miscellaneous Ring group alkylamino or aryloxy group；

Each R⁷、R^7a、R^7b、R⁸、R^8aAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, Deuteroalkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl Alkylamino, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy Base, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (= O)_rO-, alkyl-OS (=O)_rO-, alkyl-S (=O)_r-, heterocyclic radical alkylamino or aryloxy group；

Each R⁹And R¹⁰Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or ammonia Base sulfonyl；

Each f, n and t independently be 0,1,2,3 or 4；

M is 1,2,3 or 4；With

Each r independently be 0,1 or 2；

The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (=O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo, The miscellaneous dicyclo of spiral shell dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclic radical alkane Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl, Heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia Base formoxyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or amino-sulfonyl individually optionally by 1, 2,3 or 4 are selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, halo Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl Amino, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)₂-, hydroxyl substituted alkyl-S (=O)-, hydroxyl takes Alkyl-the S (=O) in generation₂-or the substituent group of the substituted alkoxyl of carboxyl replaced.

In certain embodiments, A is-O-,-S-,-NH-,-CH₂-S-、-CH₂-O-、-CH₂-NH-、-O-CH₂-、-NH- CH₂-、-S-CH₂-or-CH₂-CH₂-。

In certain embodiments, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Virtue Base, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxyl, C_6-10Arylamino, C_1-9Heteroaryl Amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_6-10 Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclic radical Amino, C_1-6Alkyl acyl, C_1-6Alkyl acyloxy, C_1-6Alkoxyacyl, C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group.

In certain embodiments, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C_1-3Alkyl, C_1-3Haloalkyl, C_2-4Thiazolinyl, C_2-4Alkynyl, C_2-8Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Virtue Base, C_1-9Heteroaryl, C_6-10Aryl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkoxyl, C_6-10Arylamino, C_1-9Heteroaryl Amino, C_6-10Aryl C_1-3Alkylamino, C_1-9Heteroaryl C_1-3Alkylamino, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkyl, C_6-10 Aryl C_1-3Alkoxyl, C_1-9Heteroaryl C_1-3Alkoxyl, C_2-8Heterocyclic radical epoxide, C_2-8Heterocyclic radical C_1-3Alkoxyl, C_2-8Heterocyclic radical ammonia Base, C_1-3Alkyl acyl, C_1-3Alkyl acyloxy, C_1-3Alkoxyacyl, C_2-8Heterocyclic radical C_1-3Alkylamino or C_6-10Aryloxy group.

In certain embodiments, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene Base, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, phenyl amino, sulfydryl or nitre Base.

In certain embodiments, each R¹、R²、R³And R⁴Independently be H, C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_3-10Cycloalkanes Base, C_2-10Heterocyclic radical, C_1-9Heteroaryl or C_6-10Aryl；Or R¹、R²With X-CH be randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell；Or R³、R⁴With X¹-CH is randomly formed 3- 8 yuan of heterocycles, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell；Wherein institute The 3-8 unit heterocycle stated, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell is only Stand and be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C by 1,2,3 or 4_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkylamino, C_1-6Alkylthio group, C_6-10Virtue Base amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle The substituent group of base is replaced.

In certain embodiments, R¹、R²The heterocycle, condensed ring or the spiro ring system that are formed with Y-X-CH are selected from following minor structure Formula:

In certain embodiments, wherein R³、R⁴With Y¹-X¹Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following Subformula:

In certain embodiments, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-6Alkane Base, C_1-6Haloalkyl, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkylamino, C_1-6 Alkylthio group, C_6-10Arylamino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Ring Alkyl or C_2-10Heterocyclic radical.

In certain embodiments, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-3Alkane Base, C_1-3Haloalkyl, C_1-3Alkoxyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Halogenated alkoxy C_1-3Alkyl, C_1-3Alkylamino, C_1-3 Alkylthio group, C_6-10Arylamino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Ring Alkyl or C_2-10Heterocyclic radical.

In certain embodiments, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, methyl, second Base, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy ylmethyl, trifluoro Methoxy, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenyl amino, benzene oxygen Base, pyrrole radicals, morpholinyl or piperazinyl.

In certain embodiments, each R^9bIndependently be hydrogen, deuterium, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Hydroxy alkyl, C_1-6 Aminoalkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylthio group C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_1-9Heteroaryl, C_6-10Aryl, C_2-10Heterocyclic radical or C_3-8Cycloalkyl.

In certain embodiments, each R^9bIndependently be hydrogen, deuterium, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Hydroxy alkyl, C_1-3 Aminoalkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Alkylamino C_1-3Alkyl, C_1-3Alkylthio group C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, C_1-9Heteroaryl, C_6-10Aryl, C_2-10Heterocyclic radical or C_3-8Cycloalkyl.

In certain embodiments, each R^9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxyl Methyl, amino methyl, methoxy, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or hexamethylene Base.

In certain embodiments, each R⁷、R^7a、R^7bAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl Base C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamyl Base, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10 Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group；Independently be 0,1 or 2 with each r.

In certain embodiments, each R⁷、R^7a、R^7bAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-3Alkyl, C_1-3Haloalkyl, C_2-4Thiazolinyl, C_2-4Alkynyl, C_2-8Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_2-8Heterocyclic radical C_1-3Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-3Alkylamino, C_1-9Heteroaryl Base C_1-3Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-3Alkoxyl, C_1-9Heteroaryl C_1-3Alkoxyl, C_2-8Heterocyclic radical epoxide, C_2-8Heterocyclic radical C_1-3Alkoxyl, C_2-8Heterocyclylamino group, C_1-3Alkyl-OC (=O)-, C_1-3Alkyl-C (=O)-, carbamoyl, C_1-3Alkyl-OS (=O)_r-、C_1-3Alkyl-S (=O)_rO-、C_1-3Alkyl-OS (=O)_rO-、C_1-3Alkyl-S (=O)_r-、C_2-8Miscellaneous Ring group C_1-3Alkylamino or C_6-10Aryloxy group；Independently be 0,1 or 2 with each r.

In certain embodiments, each R⁷、R^7a、R^7bAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, ethyl, vinyl, acetenyl, cyclopropyl or phenyl；1 or 2 is independently be with each r.

In certain embodiments, wherein Y and Y¹It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl or-C (=O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰。

In certain embodiments, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Deuteroalkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Virtue Base C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Heterocyclic radical C_1-6Alkane Base, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl oxygen Base, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl acyl, C_1-6Alkyl acyloxy, C_1-6Alkoxyacyl, C_1-6Alkyl sulphonyl, C_1-6Alcoxyl Base sulfonyl, C_1-6Alkyl sulphinyl, C_1-6Alkyl sulphonyl epoxide, C_1-6Alkyl sulphinyl epoxide, C_1-6Alkyl-OC (= O)-、C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group.

In certain embodiments, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-4Alkyl, C_1-4Deuteroalkyl, C_1-4Haloalkyl, C_2-4Thiazolinyl, C_2-4Alkynyl, C_2-8Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Virtue Base C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Cycloalkyl C_1-3Alkyl, C_2-8Heterocyclic radical C_1-3Alkane Base, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-3Alkylamino, C_1-9Heteroaryl C_1-3Alkylamino, C_1-9Heteroaryl oxygen Base, C_6-10Aryl C_1-3Alkoxyl, C_1-9Heteroaryl C_1-3Alkoxyl, C_2-8Heterocyclic radical epoxide, C_2-8Heterocyclic radical C_1-3Alkoxyl, C_2-8 Heterocyclylamino group, C_1-3Alkyl acyl, C_1-3Alkyl acyloxy, C_1-3Alkoxyacyl, C_1-3Alkyl sulphonyl, C_1-3Alkoxyl sulphur Acyl group, C_1-3Alkyl sulphinyl, C_1-3Alkyl sulphonyl epoxide, C_1-3Alkyl sulphinyl epoxide, C_1-4Alkyl-OC (=O)-, C_1-4Alkyl-C (=O)-, carbamoyl, C_1-4Alkyl-OS (=O)_r-、C_1-4Alkyl-S (=O)_rO-、C_1-4Alkyl-OS (= O)_rO-、C_1-4Alkyl-S (=O)_r-、C_2-8Heterocyclic radical C_1-3Alkylamino or C_6-10Aryloxy group.

In certain embodiments, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, second Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated ethyl, deuterated propyl group, deuterated isopropyl, Methoxyl group, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy ethyl, 1-methoxy-propyl, 2-first Epoxide propyl group, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, ethylene Base, pi-allyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.

In certain embodiments, R⁹And R¹⁰It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamyl Base, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-S (=O)_r-or amino-sulfonyl.

In certain embodiments, R⁹And R¹⁰Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-OC (=O)-, isopropyl-OC (=O)-, tertiary fourth Base-OC (=O)-, methyl-C (=O)-, ethyl-C (=O)-, isopropyl-C (=O)-, normal-butyl-C (=O)-, isobutyl group-C (=O)-, carbamoyl, methyl-carbamoyl, ethylamino formoxyl, methyl-OS (=O)₂-, cyclopropyl-OS (=O)₂-, first Base-S (=O)₂O-, cyclopropyl-S (=O)₂O-or amino-sulfonyl.

In certain embodiments, t is 0,1,2,3 or 4.

In certain embodiments, each r independently be 0,1 or 2.

In certain embodiments, each n₁And n₂Independently be 1,2,3 or 4.

In certain embodiments, the compounds of this invention has the structure shown in formula (II), (IIa), (IIb) or (III), or Structural upright isomer shown in formula (II), (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomerism Body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:

In certain embodiments, the compounds of this invention its there is structure shown below:

Or it is its stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, molten Agent compound, metabolite, pharmaceutically acceptable salt or prodrug.

(in this article, form of presentation is " shown in formula (I), (II), (IIa), (IIb) or (III) for the compound of the present invention The stereoisomer of compound, geometric isomer shown in compound or formula (I), (II), (IIa), (IIb) or (III), make a variation mutually Structure body, enantiomer, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or front Medicine "), may be used for producing medical product treatment acute and chronic HCV infection, described in the invention including those.Further, originally The compound of invention may be used for producing the goods of HCV-Ab IgG.Thus, the compound of the present invention may be used for producing a kind of pharmaceuticals It is used for alleviating, stop, control or treat the disease that HCV is mediated.Thus, the compound of the present invention can serve as pharmaceutical composition Active component, this pharmaceutical composition can include the compound representated by formula (I), (II), (IIa), (IIb) or (III), also At least one pharmaceutically acceptable carrier, adjuvant or diluent can be comprised further.

Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " is meant that, the thing used Matter or compositions must be to be suitable on chemistry or toxicity mating with other components of composition preparation and the mammal for treating 's.Those skilled in the art can be carried out specifically chosen " medicine according to using the object such as people of other components and used treatment Acceptable on " material or compositions.

The salt of the compound of the present invention also includes for preparation or purification formula (I), (II), (IIa), (IIb) or (III) institute Show the enantiomer that compound shown in the intermediate of compound or formula (I), (II), (IIa), (IIb) or (III) separates Salt, but it is not necessarily pharmaceutically acceptable salt.

If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably Method prepares, and such as, uses mineral acid or organic acid.Wherein, the example of mineral acid includes but not limited to hydrochloric acid, hydrogen bromine Acid, sulphuric acid, nitric acid and phosphoric acid etc..The example of organic acid includes but not limited to acetic acid, maleic acid, succinic acid, mandelic acid, rich horse Acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；α-hydroxyl Acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulphur Acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid etc..

If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g., Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, and such as glycine and arginine, ammonia, such as primaquine, secondary Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium Inorganic salt.

The compositions of the compounds of this invention, preparation and administration

Described pharmaceutical composition comprises the compound of any present invention.This pharmaceutical composition can also comprise further Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.Described pharmaceutical composition may be used for controlling Treat hepatitis C virus (HCV) to infect or hepatitis C disease.

Described pharmaceutical composition comprises the medicine of HCV-Ab IgG further.The medicine of described HCV-Ab IgG can be any of not It is same as other of the compounds of this invention for the medicine of HCV-Ab IgG.For example, it is possible to be interferon, ribavirin, interleukin-22, Bai Jie Element 6, interleukin 12, promotion produce the compound of 1 type helper T lymphocyte response, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Ba Wei former times monoclonal antibody, hepatitis C immunoglobulin, Civacir^TM, EBP520, TVR, erlotinib, his Wei of Dacca, the beautiful Wei of department, Ah that Wei, vaniprevir, Faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、ravidasvir、velpatasvir、 Samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Luruiwei, sovaprevir, ACH-1095, VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin、 VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184, IDX102, R-1479, UNX- 08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、VCH-916、lomibuvir、MK-3281、 dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A-837093、JKT-109、Gl-59728、 GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir, furaprevir, setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、MK-8325、JNJ-47910382、 ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、BC-2125、alloferon、 Nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, Debiopharm, MK-3682, MK- 8408、GS-9857、CD-AdNS3、pibrentasvir、RG-101、glecaprevir、BZF-961、INO-8000、MBL- HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、MK-1075、ACH- 0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、 MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、 ID-12 or a combination thereof；In certain embodiments, described interferon is Interferon Alpha-2b, the interferon-ALPHA of Pegylation, interference Element α-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.Described pharmaceutical composition, enters One step comprises at least one HCV inhibitor, and described HCV inhibitor is used for suppressing HCV reproduction process and/or suppression HCV virus egg White function；Described HCV reproduction process includes that HCV enters, HCV shells, HCV translation, HCV duplication, HCV assembling or HCV release； Described HCV virus protein is selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and HCV virus replication Required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).

When can be used for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I), (II), (IIa), (IIb) Or (III) compound and pharmaceutically acceptable salt thereof can give as unprocessed chemical drugs, it is alternatively arranged as drug regimen The active component of thing provides.Therefore, present invention also provides for pharmaceutical composition, and this pharmaceutical composition includes therapeutically effective amount The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound or its pharmaceutically acceptable salt and One or more pharmaceutically acceptable carriers, diluent or excipient.Term as used herein " therapeutically effective amount " refers to Be enough to demonstrate the total amount of each active component of significant patient benefit (such as viral load minimizing).Individually live when using When property composition is individually dosed, this term only refers to this composition.When combination application, and though this term then refer to combination, successively or with Time be administered time, all cause the combined amount of the active component of therapeutic effect.The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and pharmaceutically acceptable salt thereof are described above.From compatible with other compositions of preparation and To its receiver harmless in the sense that from the point of view of, carrier, diluent or excipient must be acceptable.According to present invention On the other hand, also providing for the method for preparing pharmaceutical preparation, the method includes the compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable loads Body, diluent or excipient mixing.Term used in the present invention " pharmaceutically acceptable " refers to such compound, former Material, compositions and/or dosage form, they are in the range of rational medicine judges, it is adaptable to patient tissue contacts and without excessively poison Property, zest, allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and be both effective to Determine purposes.

Pharmaceutical preparation can be in unit dosage forms, and each unit dose contains the active component of scheduled volume.The change of present invention The dosage level of compound is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, excellent Selected introductions, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually are used for preventing or treating with monotherapy The disease of HCV mediation.Generally can be by every day about 1 to about 5 time or the drug regimen giving present invention as continuous infusion Thing.This kind of dose regimen can be used as long-term or short-term therapy.The amount of active component to prepare single dosage form is mixed with carrier material By according to disease to be treated, the order of severity of disease, administration time, route of administration, the discharge rate of compound used therefor, treatment Time and patient age, sex, body weight and situation and change.Preferably unit dosage forms is the day containing hereinbefore active component Dosage or divided dose or the unit dosage forms of its appropriate fraction.The available low dose being already clearly below compound optimal dose starts to control Treat.Hereafter, escalated dose is carried out with less increment until reaching optimum efficiency in this case.It is said that in general, most desirably Give the concentration level of compound be generally can anti-virus aspect provide effective result without regard to cause any harmful or Poisonous side effect.

When the compositions of present invention comprise the compound of present invention and one or more other treatment medicines or During the combination of prophylactic agent, the dosage level of compound and other medicine, generally in monotherapy scheme, accounts for normal administration The about 10-150% of dosage, more preferably accounts for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable to by any suitable way Footpath is administered, such as by oral (including oral cavity or Sublingual), rectum, nose, locally (include oral cavity, Sublingual or percutaneous), vagina or Parenteral (in including subcutaneous, Intradermal, intramuscular, intraarticular, intrasynovial, breastbone, in sheath, intralesional, intravenous or corium bet Penetrate or infusion) approach.This kind of preparation can be prepared, such as by by active component and load by any known method of art of pharmacy Body or excipient mixing.Preferred oral is administered or drug administration by injection.

The pharmaceutical preparation being suitable to oral administration is provided by independent unit, such as capsule or tablet；Powder or granule； Solution in aqueous or non-aqueous liquid or suspensoid；Edible foam formulations or foaming preparations (whip)；Or oil-in-water breast Liquor or water in oil emulsion liquor.

For example, for oral administration in the form of a tablet or capsule, active medicine component can with pharmaceutically can connect The oral, non-toxic inert carrier (such as ethanol, glycerol, water etc.) being subject to mixes mutually.By compound powder being broken into suitable fine chi Very little, and with by as pulverize pharmaceutical carrier (edible saccharide such as such as starch or mannitol etc.) mixing prepare powder.Also Correctives, preservative, dispersant and coloring agent can be there is.

By preparing pulverulent mixture as above, and it is loaded in the gelatin shell of shaping, prepares capsule.At dress Before filling out operation, can be by fluidizer and lubricant (such as colloidal silica, Pulvis Talci, magnesium stearate, calcium stearate or solid-state Polyethylene Glycol) it is added in pulverulent mixture.Also can add when the lower capsule of clothes by improve medicine utilizability disintegrating agent or Solubilizing agent (such as agar, calcium carbonate or sodium carbonate).

When needing in addition or be required, it is possible to suitable binding agent, lubricant, disintegrating agent and coloring agent are mixed mixture In.Suitably binding agent includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis Natural gum (such as Radix Acaciae senegalis, tragakanta or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol etc..For these dosage forms Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes, but are not limited to starch, methylcellulose, agar, Bentonite, xanthan Glue etc..Such as, by making pulverulent mixture, pelletize or pre-tabletting, add lubricant and disintegrating agent, tabletted, thus make Piece agent.By the compound suitably pulverized and diluent as described above or base material, optional and binding agent (such as carboxymethyl fibre Dimension element, alginate, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorption accelerator (quaternary salt) and/or Absorbent (such as Bentonite, Kaolin or dicalcium phosphate) mixes, and prepares pulverulent mixture.Useful binders (such as syrup, shallow lake Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) pressurize after moistening and sieve, by powder Shape granulating mixture.The alternative method pelletized is, can be by pulverulent mixture by tablet machine, and result is the best by formation Agglomerate smashes and makes granule.Can be by adding stearic acid, stearate, Pulvis Talci or mineral oil make particle lubrication to prevent from gluing On the punch die of tablet machine.Then by the mixture tabletted through lubrication.The compound of present invention also can be with free stream Dynamic inert carrier mixing, it is not necessary to just can tabletted by granulation or pre-tableting step.Can provide transparent or opaque by The protectiveness bag that Lac seal coat, sugar-coat or polymeric material clothing and waxiness polishing clothing (polish coating of wax) form Clothing material.Can be added to dyestuff in these coating materials distinguish different unit dose.

Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, thus specified rate contains There is the compound of scheduled volume.Syrup can be prepared by being dissolved in suitably seasoned aqueous solution by compound, and elixir can lead to Cross use non-toxic vehicle to prepare.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain Pears alcohol ether), preservative, taste masking additive (such as Oleum menthae or natural sweetener or saccharin or other artificial sweeteners) etc..

If appropriate, the dosage unit preparations micro encapsulation of oral administration can be used for.Also preparation can be made and prolong Time or sustained release, such as by coating or be embedded in the microparticle material such as polymer, wax.

The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and pharmaceutically can connect The salt being subject to can give with liposome delivery systems, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Lipid Body can be made up of multiple phospholipid (such as cholesterol, octadecylamine or phosphatidylcholine).

The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and pharmaceutically can connect The salt being subject to also can pass medicine by using monoclonal antibody as single carrier (compound molecule is coupled).Compound also may be used With as can the soluble polymer coupling of target medicine carrier.This base polymer can include that polyvinylpyrrolidone, pyrans are common Polymers, poly-hydroxypropyhnethacrylamide phenol, polyhydroxyethylaspart or the polyoxygenated replaced by palmitoyl residues Ethylene polylysine.Additionally, compound can be with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this Base polymer such as polylactic acid, poly-epsilon-caprolactone, poly butyric, poe, polyacetals, poly-dihydropyran, paracyanogen base third Olefin(e) acid ester and the cross-linked copolymer of hydrogel or amphipathic nature block polymer.

The pharmaceutical preparation being suitable to percutaneous dosing can be as discrete patch (discrete patch) to protect in a long time Hold and receiver's epidermis close contact.Such as, active component can be passed medicine by by iontophoresis patch, generally can be found in Pharmaceutical Research 1986,3(6),318。

The pharmaceutical preparation being suitable to topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste Agent, gel, spray, aerosol, oil formulation or transdermal patch.

The pharmaceutical preparation being suitable to rectally can be as suppository or as enema offer.

The pharmaceutical preparation (wherein carrier is solid) being suitable to nose administration includes that particle diameter is such as 20-500 micrometer range Pulvis grossus, by being administered in snuffing mode, is i.e. quickly sucked from close to the pulvis grossus container of nose by nasal passage.Wherein carry Body is liquid, be adapted as nasal mist or appropriate formulation that nasal drop is administered includes aqueous solution agent or the oil of active component Property solution.

Be suitable to the pharmaceutical preparation by inhalation and include minuteness particle powder (dust) or mist agent (mist), can use not Dosage compresed gas aerosol, nebulizer, insufflator or other matters with type metering deliver the device of aerosol spray Middle preparation.

The pharmaceutical preparation being suitable to vagina administration can be with vaginal suppository, vagina plug, ointment, cream, gel, paste, foam Agent or spray provide.

Be suitable to the pharmaceutical preparation of parenteral and include aqueous and non-aqueous sterile injection solution and aqueous and non-aqueous Sterile suspensions, aqueous and non-aqueous sterile injection solution can contain antioxidant, buffer agent, antibacterial and make described preparation The solute isotonic with receptor's blood waiting, aqueous and non-aqueous sterile suspensions can include suspending agent and thickening agent.Preparation is permissible Unit dose or multi-dose container provide, and the peace such as sealed is triumphant and bottle, and under the conditions of lyophilization (lyophilizing) can be saved in, Only need to add sterile liquid carrier, such as water for injection before use.The injection solution and the suspensoid that face used time configuration can be by Prepared by sterile powder injection, granule and tablet.

It will be appreciated that in addition to the composition being particularly mentioned above, preparation also includes relevant with described preparation type Other composition commonly used in the art, this kind of preparation being for example suitable for oral administration can include correctives.

The compounds of this invention and the purposes of pharmaceutical composition

The invention provides compound or the pharmaceutical composition purposes in preparing medicine of the present invention, described medicine can For suppression HCV reproduction process and/or the function of suppression HCV virus protein；Described HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV duplication, HCV assemble or HCV release；Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine Monophosphate dehydrogenase (IMPDH).Arbitrary compound of the present invention or pharmaceutical composition may be used for treating hepatitis C virus (HCV) infection or hepatitis C disease.

Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, farther include patient is administered other HCV medicine, thus, it is possible to carry out therapeutic alliance, wherein said HCV-Ab IgG by the compound of the present invention and other anti-HCV medicaments Medicine be that interferon, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce 1 type helper T lymphocyte response Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Ba Wei former times monoclonal antibody, hepatitis C immunoglobulin, Civacir^TM, EBP520, TVR, erlotinib, his Wei, department of Dacca A beautiful Wei, Ah that Wei, vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、 Ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Lurui Wei, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX- 136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184、IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、 VCH-916、lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir、furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、 MK-8325、JNJ-47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、 BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, I Pool Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF- 961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、 MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、 GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB- 9200, ITX-5061, ID-12 or a combination thereof.Wherein said interferon be Interferon Alpha-2b, the interferon-ALPHA of Pegylation, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.

And comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, comprise other HCV-Ab IgG medicines further The administration of thing, wherein, other anti-HCV medicaments can be with the compounds of this invention or its pharmaceutical composition administering drug combinations, of the present inventionization Compound or pharmaceutical composition are as single dosage form, or separate compound or pharmaceutical composition are as a part for multi-pharmaceutics.Its He can be administered simultaneously with the compounds of this invention or not be administered simultaneously by anti-HCV medicament.The situation of the latter, administration can be staggered and be carried out As 6h, 12h, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months are carried out.

The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as The present invention is discussed.

General building-up process

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I), (II), (IIa), (IIb) or (III).Following reaction scheme and reality Execute example for being further illustrated by present disclosure.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, two bimodal), dt (doublet of triplets, double triplets).Coupling is normal Number, represents with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrogrph of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Being applied to analyze, ESI source is applied to LC-MS spectrogrph.

Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrogrph of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should For analyzing, ESI source is applied to LC-MS spectrogrph.

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

Table 1

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

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

AlCl₃Aluminum chloride

AcOK potassium acetate

AcOH acetic acid

Ac₂O acetic anhydride

BBr₃Boron tribromide

Boc tert-butoxycarbonyl

n-BuNH₂N-butylamine

CuBr₂Copper bromide

CH₃CN acetonitrile

CDCl₃Deuterochloroform

CH₃COONH₄,NH₄OAc ammonium acetate

CH₃COCl chloroacetic chloride

DCM dichloromethane

DIPEA diisopropyl ethyl amine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

DMAP DMAP

DDQ 2,3-bis-chloro-5,6-dicyano-1,4-benzoquinone

EtOH ethanol

Et₃N triethylamine

EtOAc, EA ethyl acetate

EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride

EtOH/H₂O ethanol and aqueous mixtures

Et₃SiH triethyl silicane

FBS hyclone

G gram

H, hr hour

H₂O water

HCl hydrogen chloride

The ethyl acetate solution of HCl/EtOAc hydrogen chloride

H₂SO₄Sulphuric acid

K₂CO₃Potassium carbonate

KNO₃Potassium nitrate

Na₂S₂O₄Sodium thiosulfate

Na₂CO₃Sodium carbonate

NH₄F ammonium fluoride

MnO₂Manganese dioxide

MeOH methanol

Ml, mL milliliter

Mmol mM

PE petroleum ether

Py pyridine

Pd palladium

Pd(dppf)₂Cl₂Double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride

Pd(dppf)Cl₂·CH₂Cl₂Double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex

Pd(PPh₃)₄Four triphenyl phosphorus palladiums

PBS phosphate buffered saline (PBS)

Rt, r.t. room temperature

Selectfluor selectivity fluorine reagent

Tf trifluoroacetyl group

Tf₂O trifluoromethanesulfanhydride anhydride

TFA,CF₃COOH trifluoroacetic acid

TLC thin layer chromatography

THF oxolane

TMSCl trim,ethylchlorosilane

TMS TMS

Synthetic method

Synthetic method 1

Compound s-10 can be prepared by synthetic method 1, wherein R¹⁵、R^8aAs defined herein.Compound s- 1 obtains compound s-2 with trifluoromethanesulfonic acid anhydride reactant under the effect of alkali, and compound s-2 bromination obtains compound s-3, chemical combination Thing s-3 reacts with compound s-4 under the effect of alkali and obtains compound s-5, and compound s-5 and ammonium acetate cyclization obtain compound S-6, compound s-6 oxidation obtains compound s-7, and compound s-7 deprotection obtains compound s-8, compound s-8 and compound S-9 obtains compound s-10 by condensation reaction.

Synthetic method 2

Compound s-23 can be prepared by synthetic method 2, wherein R¹⁵、R⁸As defined herein.Compound s- 11 obtain compound s-12 under the effect of reducing agent, and it is de-that compound s-12 acetylation obtains compound s-13, compound s-13 Methyl obtains compound s-14, compound s-14, and under the effect of alkali and trifluoromethanesulfonic acid anhydride reactant obtains compound s-15, changes Compound s-15 bromination obtains compound s-16, compound s-16 and compound s-17 and becomes ester to obtain compound s-under the effect of alkali 18, compound s-18 and ammonium acetate reaction obtain compound s-19, compound s-19 and react under the catalysis of palladium and obtain compound S-20, reacts with compound s-22 after compound s-20 deprotection again and obtains compound s-23.

Synthetic method 3:

Compound s-27 can be prepared by synthetic method 3, wherein R¹⁵、R⁸Determine such as the present invention independently of one another Justice.Compound s-8 and compound s-20 coupling under the catalysis of palladium obtains compound s-24, and compound s-24 is through deprotection After, it is condensed to yield compound s-27 with compound s-26.

Synthetic method 4:

Compound s-28 can be prepared by synthetic method 4, wherein R¹⁵、R⁸、R^8aIndependently of one another such as institute of the present invention Definition.Compound s-20 and compound s-23 coupling reaction under the catalysis of palladium obtains compound s-28.

Embodiment

Embodiment 1

Synthetic route:

Synthesis step

Step 1) synthesis of compound 1-2A

At 0 DEG C, trifluoromethanesulfanhydride anhydride (10.44g, 37.0mmol) is added drop-wise to compound 1-1A (5.0g, 30.83mmol) with in dichloromethane (60mL) solution of pyridine (3.0g, 37.0mmol), add rear room temperature reaction 8h, reaction knot Bundle adds 30mL washing, and separatory, organic facies anhydrous sodium sulfate is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=10:1), obtain product 8.5g, productivity 94.4%.

¹H NMR(400MHz,DMSO-d₆): δ 8.02 (d, J=8.7Hz, 1H), 7.54 (d, J=2.2Hz, 1H), 7.44 (dd, J=8.7,2.4Hz, 1H), 3.02 (t, J=6.0Hz, 2H), 2.66 2.61 (m, 2H), 2.10 2.03 (m, 2H) ppm.

Step 2) synthesis of compound 1-3A

By compound 1-2A (3.0g, 10.2mmol), copper bromide (4.5g, 20.4mmol) joins EtOH (30mL) solvent In 60 DEG C reaction 2h, reaction terminate after with kieselguhr filter, filtrate is spin-dried for, then with DCM (40mL × 2) dissolve, organic facies washing, Anhydrous sodium sulfate is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains brownish red grease 3.6g, productivity 95%.

¹H NMR(400MHz,CDCl₃): δ 8.22 (d, J=8.7Hz, 1H), 7.31 7.22 (m, 2H), 4.75 (t, J= 4.1Hz, 1H), 3.47 3.33 (m, 1H), 2.99 (dt, J=17.4,4.2Hz, 1H), 2.65 2.45 (m, 2H) ppm.

Step 3) synthesis of compound 1-4A

By compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL) is placed in bottle and adds Heat, to 50 DEG C, is then slowly added dropwise acetonitrile (10mL) solution of compound 1-7 (1.6g, 7.4mmol), continues reaction after adding, Being spin-dried for reactant liquor after reaction completely, add water, EtOAc extracts, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE: EtOAc (V:V)=4:1), obtain product 3.0g, productivity 88%.

¹H NMR(400MHz,CDCl₃): δ 8.22 (d, J=8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t,1H),3.47(t,2H),3.17(t,2H),2.99(t,4H),2.65(m,2H),1.25(t,9H)ppm；MS-ESI,m/z: 508.10[M+H]⁺.

Step 4) synthesis of compound 1-5A

By compound 1-4A (2.7g, 5.3mmol), ammonium acetate (2.5g, 31.8mmol) joins toluene (30mL) solvent In 115 DEG C reaction 12h, reaction terminate after add water (10mL), then with EtOAc (30mL × 2) extract, organic facies washing, anhydrous Sodium sulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains gray solid 1.8g, productivity 69%.

¹H NMR(400MHz,CDCl₃):δ8.12(s,1H),7.32(m,2H),5.18(t,1H),3.85(t,2H),3.27 (t,2H),2.99(t,2H),2.45(m,4H),1.28(t,9H)ppm；MS-ESI,m/z:488.8[M+H]⁺.

Step 5) synthesis of compound 1-6A

Manganese dioxide (3.2g, 37mmol) is dividedly in some parts compound 1-5A (1.8g, 3.7mmol), dichloromethane (40mL) reaction being stirred at room temperature in solution, react 4 days, filter with kieselguhr after reaction completely, filtrate is washed, and is dried, silicagel column Chromatography purification (PE:EtOAc (V:V)=3:1), obtains product 1.6g, productivity 88.9%.

¹H NMR(400MHz,CDCl₃):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),3.37 (t,2H),2.59(t,2H),2.35(m,2H),1.26(t,9H)ppm；MS-ESI,m/z:485.9[M+H]⁺.

Step 6) synthesis of compound 1-2

Compound 1-1 (15.0g, 92.49mmol), triethyl silicane (70.0g, 601mmol), TFA (300mL) are added Back flow reaction in two mouthfuls of bottles, TLC monitoring reaction course, 6h reaction completely, is poured in frozen water after reaction completely, then is used EtOAc (100mL × 2) extract, and organic facies sodium bicarbonate solution neutralizes, and washing is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE), product 12.2g, productivity 88% are obtained.¹H NMR(400MHz,CDCl₃): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J =7.4Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 2.97 (d, J=15.4,7.5Hz, 4H), 2.20 2.11 (m,2H)ppm.

Step 7) synthesis of compound 1-3

At 0 DEG C, chloroacetic chloride (6.4g, 82mmol) is slowly added drop-wise to compound 1-2 (10g, 67.5mmol) tri-chlorination In the solution of the DCM (80mL) of aluminum (11.7g, 87.8mmol), add rear room temperature and continue reaction 4h, after reaction completely, pour frozen water into In, extracting with DCM (60mL × 2), organic facies is dried, and decompression is spin-dried for, and purifies (PE:DCM (V:V)=5:1) with silica gel column chromatography, Obtain product 8.9g, yield 70%.¹H NMR(400MHz,CDCl₃): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J=7.4Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 2.97 (t, J=15.4,7.5Hz, 4H), 2.20 2.11 (m, 2H) ppm.

Step 8) synthesis of compound 1-4

At 0 DEG C, Boron tribromide (8.7g, 35mmol) is slowly added drop-wise to the DCM of compound 1-3 (5.5g, 29mmol) (50mL), in solution, continue reaction after adding, pour in frozen water after reaction completely, extract with EtOAc (40mL × 3), organic Being dried mutually, decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains product 2.1g, yield 41%.

¹H NMR(400MHz,DMSO-d₆): δ 7.66 (d, J=8.4Hz, 1H), 6.69 (d, J=8.4Hz, 1H), 3.13 (t, J=7.5Hz, 2H), 2.72 (t, J=7.5Hz, 2H), 2.44 (s, 3H), 2.01 1.94 (m, 2H) ppm.

Step 9) synthesis of compound 1-5

At 0 DEG C, trifluoromethanesulfanhydride anhydride (1.3g, 4.7mmol) is added drop-wise to compound 1-4 (0.75g, 4.3mmol) and In dichloromethane (20mL) mixed liquor of pyridine (0.5g, 6.0mmol), adding rear room temperature reaction 4h, TLC monitors reaction, reaction Adding washing after Wan Quan, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE), obtains product 1.2g, productivity 91%.

¹H NMR(400MHz,CDCl₃): δ 7.76 (d, J=8.6Hz, 1H), 7.19 (d, J=8.6Hz, 1H), 3.35 (t, J =7.5Hz, 2H), 3.05 (t, J=7.6Hz, 2H), 2.61 (s, 3H), 2.23 2.11 (m, 2H) ppm.

Step 10) synthesis of compound 1-6

Compound 1-5 (1.2g, 3.9mmol) and copper bromide (1.7g, 7.6mmol) are joined in EtOH (20mL) solvent 60 DEG C of reaction 2h, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, then dilutes with DCM (20mL × 2), and organic facies is washed, nothing Aqueous sodium persulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains compound 1.25g, productivity 80.5%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=7.6Hz, 2H), 3.07 (t, J=7.6Hz, 2H), 2.29 2.14 (m, 2H) ppm.

Step 11) synthesis of compound 1-8

At 0 DEG C, triethylamine (0.6g, 6mmol) is added drop-wise to compound 1-6 (1.4g, 3.6mmol) and compound 1-7 In dichloromethane (20mL) mixed liquor of (1.0g, 4.6mmol), adding rear room temperature reaction, TLC monitors reaction, after reaction completely Adding washing, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains product 1.5g, productivity 79%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (s, 1H),4.43(s,2H),3.36(t,2H),3.16(t,2H),3.07(t,4H),2.29(m,4H),1.36(t,9H)ppm；MS- ESI,m/z:522.8[M+H]⁺.

Step 12) synthesis of compound 1-9

By compound 1-8 (1.1g, 2.1mmol), ammonium acetate (0.81g, 10.5mmol) joins toluene (20mL) solvent In 115 DEG C reaction 12h, reaction terminate after add water (10mL), then with EtOAc (30mL × 2) extract, organic facies washing, anhydrous Sodium sulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains gray solid 0.8g, productivity 80%.

¹H NMR(400MHz,CDCl₃): δ 7.88 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,2H),2.86(t,4H),2.29(m,2H),1.35(t,9H)ppm；MS- ESI,m/z:502.8[M+H]⁺.

Step 13) synthesis of compound 1-11

By compound 1-9 (0.4g, 0.8mmol), pinacol borate 1-10 (0.24g, 0.95mmol), Pd (dppf) Cl₂·CH₂Cl₂(0.07g, 0.086mmol) and AcOK (0.23g, 2.0mmol) are suspended in the DMF of 20mL, under nitrogen protection It is heated to 100 DEG C of reaction 4h.Reactant liquor is cooled to room temperature, adds the water of 10mL, and EtOAc (30mL × 2) extracts, and organic facies is used again Wash 2 times, be dried, be spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain product 0.3g, productivity 78%.

¹H NMR(400MHz,CDCl₃): δ 7.98 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,2H),2.86(t,4H),2.29(m,2H),1.35(t,9H),1.25(t, 12H)ppm；MS-ESI,m/z:480.4[M+H]⁺.

Step 14) synthesis of compound 1-12

By compound 1-11 (0.8g, 1.7mmol), compound 1-6A (0.73g, 1.5mmol), Pd (PPh₃)₄(0.20g, 0.17mmol) and K₂CO₃(0.69mg, 5.0mmol) is suspended in EtOH/H₂In O (30mL, V:V=3:1), the lower heating of nitrogen protection To 90 DEG C of reaction 3h.After reaction completely, screw out most solutions, then extract (20mL × 2) with DCM, merge organic facies, be dried, It is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.5g, productivity 40%.

¹H NMR(400MHz,CDCl₃):δ7.98(s,1H),7.52(d,2H),7.32(m,2H),7.22(m,2H),5.33 (s,1H),4.93(s,2H),3.26(m,4H),3.10(m,4H),2.76(m,4H),2.19(m,6H),1.25(m,9H),1.29 (m,9H)ppm；MS-ESI,m/z:689.2[M+H]⁺.

Step 15) synthesis of compound 1-13

The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 1-12 (0.5g, 0.7mmol) is molten In agent (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains brown Solid 0.4g, productivity 87%.

MS-ESI,m/z:489.3[M+H]⁺.

Step 16) synthesis of compound 1

Compound 1-13 (0.40g, 0.82mmol), compound 1-14 (0.316g, 1.8mmol), EDCI (0.377g, 1.97mmol) it is suspended in 10mL dichloromethane with 2-oxime cyan-acetic ester (0.07g, 0.49mmol), will under the conditions of 0 DEG C DIPEA (0.530g, 4.1mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride washes, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silica gel Column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g, productivity 53%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,2H),2.36 (m,4H),2.09(m,6H),1.05(m,12H)ppm；MS-ESI,m/z:802.7[M+H]⁺.

Embodiment 2

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 2-4A

Compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL) are placed in bottle and add Heat, to 50 DEG C, is then slowly added dropwise acetonitrile (10mL) solution of 5-methyl-Boc-proline 2-7 (1.38g, 6.04mmol), adds Continuing reaction after complete, be spin-dried for reactant liquor after reaction completely, add water, EtOAc extracts, and organic layer is dried, and decompression is spin-dried for, silicagel column Chromatography purification (PE:EtOAc (V:V)=4:1), obtains product 1.5g, productivity 44%.

¹H NMR(400MHz,CDCl₃): δ 8.22 (d, J=8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t,1H),3.47(t,2H),3.17(t,1H),2.99(t,4H),2.65(m,2H),1.35(t,3H),1.25(t,9H)ppm； MS-ESI,m/z:522.1M+H]⁺.

Step 2) synthesis of compound 2-5A

By compound 2-4A (1.5g, 2.9mmol), ammonium acetate (1.6g, 21mmol) joins in toluene (30mL) solvent 115 DEG C of reaction 12h, reaction adds water, then extracts with EtOAc (30mL × 2) after terminating, organic facies is washed, and anhydrous sodium sulfate is done Dry, vacuum rotary steam, recycle silicon gel column chromatography eluting (PE:EtOAc (V:V)=6:1), obtain gray solid 1.0g, productivity 69%.

¹H NMR(400MHz,CDCl₃):δ8.12(s,1H),7.32(m,2H),5.18(t,1H),3.85(t,2H),3.27 (t,1H),2.99(t,2H),2.45(m,4H),1.35(t,3H),1.28(t,9H)ppm；MS-ESI,m/z:502.8[M+H]⁺.

Step 3) synthesis of compound 2-6A

Manganese dioxide (1.7g, 20mmol) is dividedly in some parts the dichloromethane of compound 2-5A (1.0g, 2.0mmol) (40mL) in solution, reaction 4 day being stirred at room temperature, filter with kieselguhr after reaction completely, filtrate is washed, and is dried, and decompression is spin-dried for, silicon Gel column chromatography eluting (PE:EtOAc (V:V)=3:1), obtains product 0.8g, productivity 80%.

¹H NMR(400MHz,CDCl₃):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),3.37 (t,1H),2.59(t,2H),2.35(m,2H),1.35(t,3H),1.26(t,9H)ppm；MS-ESI,m/z:500.8[M+H]⁺.

Step 4) synthesis of compound 2-8

At 0 DEG C, triethylamine (0.9g, 8.9mmol) is added drop-wise to compound 1-6 (2.3g, 5.95mmol), compound 2- In dichloromethane (20mL) mixed liquor of 7 (1.23g, 5.36mmol), adding rear room temperature reaction, TLC monitors reaction, and reaction is completely Rear addition 10mL washes, and saturated sodium-chloride is washed, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V) =6:1), obtain product 1.6g, productivity 50.3%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (s, 1H),4.43(s,2H),3.36(t,2H),3.16(t,2H),3.07(t,3H),2.29(m,4H),1.45(t,3H),1.36(t, 9H)ppm,MS-ESI,m/z:535.8[M+H]⁺.

Step 5) synthesis of compound 2-9

By compound 2-8 (1.6g, 3.0mmol), ammonium acetate (1.4g, 18mmol) joins in toluene (20mL) solvent 115 DEG C of reaction 12h, reaction adds water, then extracts with EtOAc (30mL × 2) after terminating, organic facies is washed, and anhydrous sodium sulfate is done Dry, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain gray solid 1.0g, productivity 65%.

¹H NMR(400MHz,CDCl₃): δ 7.88 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,1H),2.86(t,4H),2.29(m,2H),1.39(t,3H),1.35(t, 9H)ppm；MS-ESI,m/z:516.2[M+H]⁺.

Step 6) synthesis of compound 2-11

By compound 2-9 (1.0g, 1.94mmol), pinacol connection borate 1-10 (0.6g, 2.1mmol), Pd (dppf) Cl₂·CH₂Cl₂(0.17g, 0.19mmol) and AcOK (0.57g, 5.82mmol) are suspended in the DMF of 20mL, under nitrogen protection It is heated to 100 DEG C of reaction 4h.Reactant liquor is cooled to room temperature, adds the water of 10mL, then extracts 2 times with EtOAc, merges organic facies again Wash with water 2 times, be dried, be spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain product 0.9g, productivity 90%.

¹H NMR(400MHz,CDCl₃): δ 7.98 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,1H),2.86(t,4H),2.29(m,2H),1.35(t,12H),1.25 (t,12H)ppm；MS-ESI,m/z:494.4[M+H]⁺.

Step 7) synthesis of compound 2-12

By compound 2-11 (1.0g, 2.0mmol), compound 2-6A (0.9g, 1.8mmol), Pd (PPh₃)₄(0.23g, 0.2mmol) and K₂CO₃(0.84mg, 6.1mmol) is suspended in the EtOH/H of 30mL₂In O (V:V=3:1), the lower heating of nitrogen protection To 90 DEG C of reaction 3h.After reaction completely, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic facies, dry Dry, it is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 1.0g, productivity 69%.

¹H NMR(400MHz,CDCl₃):δ7.98(s,1H),7.52(d,2H),7.32(m,2H),7.22(m,2H),5.33 (s,1H),4.93(s,2H),3.26(m,4H),3.10(m,2H),2.76(m,4H),2.19(m,6H),1.35(t,6H),1.29 (m,9H),1.25(m,9H)ppm；MS-ESI,m/z:717.8[M+H]⁺.

Step 8) synthesis of compound 2-13

The dichloromethane that HCl/EtOAc (4N, 5mL) is added drop-wise at 0 DEG C compound 2-12 (1.1g, 1.5mmol) is molten In agent (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains palm fibre Color solid 0.7g, productivity 68.6%.

MS-ESI,m/z:517.9[M+H]⁺.

Step 15) synthesis of compound 2

By compound 2-13 (0.60g, 0.905mmol), compound 1-14 (0.349g, 1.99mmol), EDCI (0.417g, 2.17mmol) and 2-oxime cyan-acetic ester (0.077g, 0.543mmol) are suspended in 10mL dichloromethane, 0 Under the conditions of DEG C, DIPEA (0.585g, 4.525mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.React Quan Hou, adds ammonia (2mL) stirring 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, Decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.6g, productivity 79.7%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,2H),2.36(m,4H),2.09 (m,6H),1.35(m,6H),1.05(m,12H)ppm；MS-ESI,m/z:832.4[M+H]⁺。

Embodiment 3

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 3-7

The dichloromethane that HCl/EtOAc (4N, 6mL) is added drop-wise at 0 DEG C compound 1-6A (1.8g, 3.7mmol) is molten In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown Solid 0.8g, productivity 47%.

MS-ESI,m/z:385.8[M+H]⁺.

Step 2) synthesis of compound 3-9

By compound 3-7 (1.5g, 3.27mmol), compound 1-14 (0.687g, 3.92mmol), EDCI (0.752g, 3.92mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.186g, 1.31mmol) DIPEA (1.27g, 9.82mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia Water (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, is spin-dried for reactant liquor, Silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 1.4g, productivity 79%.

¹H NMR(400MHz,CDCl₃):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),4.18 (t,1H),3.37(t,3H),3.07(t,1H),2.85(m,2H),2.59(m,2H),2.45(m,2H),1.01(m,6H)ppm； MS-ESI,m/z:543.2[M+H]⁺.

Step 3) synthesis of compound 3-12

By compound 1-11 (0.7g, 1.5mmol), compound 3-9 (0.873g, 1.6mmol), Pd (PPh₃)₄(0.17g, 0.15mmol) and K₂CO₃(0.61mg, 4.4mmol) is suspended in the EtOH/H of 30mL₂In O (V:V=3:1), add under nitrogen protection Heat reacts 3h to 90 DEG C.After reaction completely, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic facies, It is dried, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.8g, productivity 70%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,3H),2.36 (m,4H),2.09(m,6H),1.05(m,9H)ppm；MS-ESI,m/z:747.5[M+H]⁺.

Step 4) synthesis of compound 3-13

The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 3-12 (0.7g, 0.9mmol) is molten In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown Solid 0.6g, productivity 89%.

MS-ESI,m/z:647.4[M+H]⁺.

Step 5) synthesis of compound 3

By compound 3-13 (0.60g, 0.835mmol), compound 3-14 (0.21g, 1.0mmol), EDCI (0.192g, 1.0mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.048g, 0.334mmol) DIPEA (0.324g, 2.505mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add Ammonia (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for Reactant liquor, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtain gray solid 0.45g, productivity 64%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,4H),7.36(m,4H),7.21(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.36(m,4H),2.09 (m,6H),1.05(m,6H)ppm；MS-ESI,m/z:837.7[M+H]⁺.

Embodiment 4

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 4-7

At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solvent of compound 2-6A (0.8g, 2mmol) (15mL), in, reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, it is solid that re-crystallizing in ethyl acetate purification obtains brown Body 0.56g, productivity 90%.

MS-ESI,m/z:400.2[M+H]⁺.

Step 2) synthesis of compound 4-9

By compound 4-7 (0.9g, 2.3mmol), compound 1-14 (0.47g, 2.7mmol), EDCI (0.52g, 2.7mmol) it is suspended in dichloromethane (10mL), under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.13g, 0.91mmol) DIPEA (0.87g, 6.7mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia Water (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silicon Gel column chromatography eluting (PE:EtOAc (V:V)=1:1), obtains gray solid 0.8g, productivity 60%.

¹H NMR(400MHz,CDCl₃):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),4.18 (t,1H),3.37(t,3H),2.85(m,2H),2.59(m,2H),2.45(m,2H),1.25(m,3H),1.01(m,6H)ppm； MS-ESI,m/z:557.3[M+H]⁺.

Step 3) synthesis of compound 4-12

By compound 1-11 (0.731g, 1.5mmol), compound 4-9 (0.853g, 1.5mmol), Pd (PPh₃)₄ (0.17g, 0.15mmol) and K₂CO₃(0.61mg, 4.4mmol) is suspended in EtOH/H₂In O (30mL, V:V=3:1), nitrogen is protected Protect down and be heated to 90 DEG C of reaction 3h.After reaction completely, decompression screws out most solutions, then extracts with DCM (20mL × 2), merges Organic facies, is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.7g, productivity 60%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,2H),2.36 (m,4H),2.09(m,6H),1.35(m,3H),1.05(m,9H)ppm；MS-ESI,m/z:792.3[M+H]⁺.

Step 4) synthesis of compound 4-13

The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 4-12 (0.8g, 1.0mmol) is molten In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown Solid 0.6g, productivity 90%.

MS-ESI,m/z:661.5[M+H]⁺.

Step 5) synthesis of compound 4

By compound 4-13 (0.60g, 0.92mmol), compound 3-14 (0.23g, 1.1mmol), EDCI (0.21g, 1.1mmol) it is suspended in 10mL dichloromethane with 2-oxime cyan-acetic ester (0.06g, 0.37mmol), will under the conditions of 0 DEG C DIPEA (0.360g, 2.8mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride washes, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silica gel Column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.40g, productivity 50%,

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,4H),7.36(m,4H),7.21(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.36(m,3H),2.09 (m,6H),1.59(m,3H),1.05(m,6H)ppm；MS-ESI,m/z:852.5[M+H]⁺。

Embodiment 5

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 5-3

At 0 DEG C, triethylamine (0.98g, 9.68mmol) is added drop-wise to compound 1-6 (2.5g, 5.81mmol) and chemical combination In dichloromethane (20mL) mixed liquor of thing 5-2 (1.5g, 5.81mmol), adding rear room temperature reaction, TLC monitors reaction, reaction Adding water (10mL) after Wan Quan to wash, saturated sodium-chloride is washed, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtain product 2.0g, productivity 55%.

¹H NMR(400MHz,CDCl₃): δ 7.67 (d, J=8.6Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 5.28 (ddd, J=60.3,53.6,16.3Hz, 2H), 4.43 (dt, J=15.2,8.0Hz, 1H), 3.82 3.66 (m, 1H), 3.46 3.34 (m, 5H), 3.32 (t, J=7.5Hz, 2H), 3.23 (dd, J=10.7,7.7Hz, 1H), 3.05 (t, J=7.4Hz, 2H), 2.61 2.46 (m, 2H), 2.25 2.12 (m, 2H), 1.77 (s, 1H), 1.45 (d, J=10.3Hz, 9H) ppm；MS-ESI,m/ z:566.2[M+H]⁺.

Step 2) synthesis of compound 5-4

Compound 5-3 (2.1g, 3.71mmol), ammonium acetate (1.72g, 22.3mmol) are joined toluene (20mL) solvent In 115 DEG C reaction 12h, reaction terminate after add water, then with EtOAc extract (30mL × 2), organic facies wash, anhydrous sodium sulfate It is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains gray solid 1.5g, productivity 74%.

¹H NMR(400MHz,CDCl₃): δ 7.16 (s, 1H), 7.10 (d, J=8.6Hz, 1H), 5.00 (t, J=7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J=4.9Hz, 1H), 3.41 3.32 (m, 4H), 3.11 (dt, J=15.1,6.8Hz, 5H), 2.78 (d, J=47.9Hz, 1H), 2.63 2.39 (m, 2H), 2.25 2.15 (m, 2H), 1.51 (s, 9H) ppm；MS-ESI,m/ z:546.3[M+H]⁺.

Step 3) synthesis of compound 5-6

By compound 5-4 (1.55g, 2.84mmol), pinacol borate 1-10 (0.866g, 3.41mmol), Pd (dppf)Cl₂·CH₂Cl₂(0.232g, 0.284mmol) and AcOK (0.835g, 8.52mmol) are suspended in the DMF of 20mL, nitrogen 100 DEG C of reaction 4h it are heated under gas shielded.Reactant liquor is cooled to room temperature, adds the water of 10mL, then extracts 2 times with EtOAc, organic Being washed with water mutually 2 times, be dried, decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=3:1), obtains product 1.3g, produces Rate 87%.

¹H NMR(400MHz,CDCl₃): δ 7.16 (s, 1H), 7.10 (d, J=8.6Hz, 1H), 5.00 (t, J=7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J=4.9Hz, 1H), 3.41 3.32 (m, 4H), 3.11 (m, 5H), 2.78 (d, 1H), 2.63–2.39(m,2H),2.25–2.15(m,2H),1.51(s,9H),1.25(m,12H)ppm；MS-ESI,m/z:524.3[M+ H]⁺.

Step 4) synthesis of compound 5-7

By compound 5-6 (0.500g, 0.955mmol), compound 4-9 (0.53g, 0.955mmol), Pd (PPh₃)₄ (0.110g, 0.095mmol) and K₂CO₃(0.391mg, 2.87mmol) is suspended in the EtOH/H of 30mL₂In O (V:V=3:1), nitrogen 90 DEG C of reaction 3h it are heated under gas shielded.After reaction completely, decompression screws out most solutions, then extracts with DCM (20mL × 2), Merging organic facies, be dried, decompression is spin-dried for, silica gel column chromatography purification (DCM:EtOAc (V:V)=1:2), obtains gray solid 0.5g, productivity 70%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.11(m,5H),3.00(m,4H),2.66(m,4H),2.56 (m,2H),2.36(m,3H),2.09(m,6H),1.35(m,3H),1.05(m,9H)ppm；MS-ESI,m/z:804.8[M+H]⁺.

Step 5) synthesis of compound 5-8

At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solution of compound 5-7 (0.6g, 0.7mmol) (15mL), in, reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate washing purification obtains brown solid 0.45g, productivity 84%.

MS-ESI,m/z:705.4[M+H]⁺.

Step 6) synthesis of compound 5

By compound 5-8 (0.55g, 0.72mmol), compound 3-14 (0.178g, 0.852mmol), EDCI (0.163g, 0.852mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.04g, 0.284mmol) DIPEA (0.275g, 2.13mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add Ammonia (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, Silica gel column chromatography purification (PE:EtOAc (V:V)=1:3), obtains gray solid 0.35g, productivity 55%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.52(d,4H),7.36(m,4H),7.31(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.21(m,5H),3.09(m,4H),3.01(m,4H),2.66(m,4H),2.26 (m,2H),2.09(m,6H),1.59(m,3H),1.05(m,6H)ppm；MS-ESI,m/z:896.0[M+H]⁺.

Embodiment 6

Synthetic route:

Synthesis step

Step 1) synthesis of compound 7-2A

6-bromine 2-naphthylamine hydrochloride 7-1A (2.00g, 7.73mmol, 1.00eq) is added in DMF (15mL), adds DMAP(0.02g,0.16mmol,0.02eq),Et₃N (3.70mL, 2.70mmol, 3.50eq), is down to 0 DEG C, drips acetic anhydride (1.09mL, 11.60mmol, 1.50eq), drips complete room temperature reaction 3h.After reaction completely, reactant liquor is poured in 30mL water, have white Color solid separates out, and after stirring 0.5h, directly filters, and filter cake washes with water three times, is dried to obtain product 1.78g white solid, produces Rate 87.46%.

¹H NMR(400MHz,DMSO-d₆): δ 10.20 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.84 (d, J= 8.9Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.64 7.58 (m, 1H), 7.56 (dd, J=8.7,1.5Hz, 1H), 2.11 (s,3H)ppm.

Step 2) synthesis of compound 7-3A

By compound 7-2A (5.0g, 18.93mmol, 1.00eq), KNO₃(2.30g, 22.71mmol, 1.20eq) adds Dissolve to AcOH (35mL) solvent, under the conditions of 20 DEG C, drip H₂SO₄(5.14mL, 94.65mmol, 5.00eq), drips complete After, 30 DEG C of reaction 7h.Reaction is directly poured in water (50mL) after terminating, and has yellow-brown solid to separate out, directly filters, filter cake water (20mL × 3) wash, and are dried to obtain 5.34g yellow-brown solid, productivity 91.31%.

¹H NMR(400MHz,CDCl₃): δ 8.98 (s, 1H), 8.49 (d, J=9.2Hz, 1H), 8.03 (s, 1H), 7.92 (t, J=8.0Hz, 2H), 7.72 (dd, J=9.2,1.4Hz, 1H), 2.31 (s, 3H) ppm.

Step 3) synthesis of compound 7-4A

Compound 7-3A (3.78g, 12.23mmol, 1.00eq) is added THF (20mL) and is placed in bottle dissolving, add 6N HCl (10.5mL, 61.10mmol, 5.00eq), is heated to 80 DEG C, reacts 7h.After reaction completely, it is cooled to room temperature, will reaction Liquid is poured in 50mL frozen water, has yellow solid to separate out, and filters, and filter cake use water (15mL × 3) washs, and is dried, obtains product 3.00g Yellow-brown solid, productivity 91.90%.¹H NMR(400MHz,CDCl₃): δ 8.60 (d, J=9.3Hz, 1H), 7.84 (s, 1H), 7.68 (t, J=8.6Hz, 2H), 6.94 (d, J=9.0Hz, 1H), 6.46 (s, 2H) ppm；MS-ESI,m/z:267.1[M+H]⁺.

Step 4) synthesis of compound 7-5A

Compound 7-4A (4.00g, 14.97mmol, 1.00eq) is added in Isosorbide-5-Nitrae-dioxane (30mL) and dissolves, ice bath Under the conditions of drip Na₂S₂O₄(8.68g,44.93mmol,3.00eq)、Na₂CO₃(1.58g, 14.97mmol, 1.00eq's) is water-soluble Liquid (30mL), drips complete rear chamber temperature reaction 5h.Directly pour in water (30mL) after reaction completely, have cinerous solid to separate out, Filtering, filter cake use water (15mL × 3) washs, and is dried, obtains product 3.2g cinerous solid, productivity 91.01%.

¹H NMR(400MHz,CDCl₃): δ 7.89 (d, J=1.4Hz, 1H), 7.60 (d, J=9.0Hz, 1H), 7.49 (dd, J=9.0,1.7Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 3.70 (d, J=18.9Hz, 4H) ppm；MS-ESI,m/z:237.2[M+H]⁺. step 5) synthesis of compound 7-6A

By (S)-N-tertbutyloxycarbonyl pyrrolidine-2-formic acid (9.06g, 42.17mmol, 1.00eq), ethyl chloroformate (4.58g, 42.17g, 1.00eq) is dissolved in DCM (100mL), at-10 DEG C, is slowly added dropwise Et₃N(8.8mL,63.26mmol, 1.50eq), after dropping, being incubated 10min, filter, filter cake DCM (10mL × 2) washs, and filtrate is standby.By compound 7- 5A (10g, 42.17mmol, 1.00eq) is dissolved in DCM (80mL), is cooled to-5 DEG C, drips above-mentioned filtrate, straight after dropping Meet placement room temperature reaction 2h.After reaction completely, being directly added into water (100mL), extract separatory, aqueous phase continues DCM (50mL × 2) extraction Take, merge organic facies, be dried, be spin-dried for obtaining crude product 18.00g brownish black solid, productivity 95.18%.

¹H NMR(400MHz,CDCl₃): δ 7.90 (s, 1H), 7.65 (d, J=9.0Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.16 (d, J=8.6Hz, 1H), 4.61 4.34 (m, 3H), 4.00 (d, J=5.1Hz, 1H), 2.43 (s, 2H), 2.13 (dd, J=12.8,7.1Hz, 2H), 1.90 1.63 (m, 2H), 1.54 (s, 9H) ppm；MS- ESI,m/z:434.2[M+H]⁺.

Step 6) synthesis of compound 7-7A

Compound 7-6A (18.00g, 43.27mmol, 1.00eq) is added in acetic acid (80mL), directly heats to 50 DEG C, Reaction 5h.Remove part acetic acid after reaction completely, add EtOAc (100mL), water (50mL) stirring, remove residue with sodium carbonate Acetic acid, to pH=8, then extracts separatory, and aqueous phase continues, with EtOAc (20mL × 2) extraction, to merge organic facies；Organic facies continues Washing with water (50mL), separatory, organic facies is dried, and screws out and obtains product 16.03g brown solid, productivity 93.06%.

¹H NMR(400MHz,CDCl₃):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H), 3.37-3.21(t,2H),2.59-2.30(t,2H),2.35-2.11(m,2H),1.26(t,9H)ppm；MS-ESI,m/z: 416.2[M+H]⁺.

Step 7) synthesis of compound 7-1

By compound 5-6 (600mg, 1.15mmol, 1.0eq), compound 7-7A (477mg, 1.15mmol, 1.0eq), carbon Acid potassium (316mg, 2.29mmol, 2.0eq), four triphenyl phosphorus palladiums (29mg, 0.034mmol, 0.03eq) join 10mL ethanol With in 3mL water, 90 DEG C are reacted 18h.Reactant liquor is poured in 50mL water, extract (30mL × 3) with dichloromethane, organic facies nothing Aqueous sodium persulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white solid product 0.68g, yield 80.9%.

¹H NMR(400MHz,CDCl₃): δ 11.61-10.64 (m, 2H), 8.67 (s, 1H), 7.79 (dd, J=98.4, 31.8Hz, 5H), 7.39 (d, J=7.2Hz, 1H), 7.21 (s, 1H), 5.26 (d, J=4.3Hz, 1H), 5.06 (t, J= 7.3Hz,1H),3.93–3.78(m,1H),3.62–3.47(m,2H),3.43–3.29(m,4H),3.27–3.04(m,5H), 2.90 2.70 (m, 1H), 2.51 (ddd, J=19.3,13.9,6.6Hz, 2H), 2.29 (d, J=4.2Hz, 2H), 2.17 2.03 (m, 4H), 1.54 (d, J=11.0Hz, 18H) ppm；MS-ESI,m/z:733.20[M+H]⁺.

Step 8) synthesis of compound 7-2

Compound 7-1 (0.68g, 0.93mmol, 1.0eq) is joined in DCM (15mL), drip HCl/EtOAc at 0 DEG C (4N, 3mL) solution, drips off room temperature reaction 12h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 320mg, yield 63.1%.

¹H NMR(600MHz,DMSO-d₆): δ 8.48 (d, J=8.3Hz, 1H), 8.04 (s, 1H), 7.78 (d, J= 50.0Hz, 1H), 7.73 7.51 (m, 3H), 7.34 (d, J=7.6Hz, 1H), 7.24 (s, 1H), 4.46 (t, J=7.0Hz, 1H), 4.20 (t, J=7.7Hz, 1H), 3.32 (d, J=7.2Hz, 4H), 3.25 (s, 3H), 3.08 (dt, J=24.6,6.9Hz, 4H), 3.01 2.91 (m, 2H), 2.74 (dd, J=10.1,5.5Hz, 1H), 2.40 (dd, J=13.6,7.1Hz, 1H), 2.29 2.15 (m, 2H), 2.05 (dd, J=13.7,6.8Hz, 2H), 1.82 (td, J=13.5,6.3Hz, 2H), 1.69 1.52 (m, 1H)ppm；MS-ESI,m/z:533.3[M+H]⁺.

Step 9) synthesis of compound 7

By compound 7-2 (250mg, 0.469mmol, 1.0eq), compound 7-3 (209mg, 1.03mmol, 2.2eq), 2- Oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) join DCM (15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 5h are added.Reactant liquor is poured in water (30mL), Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 300mg, yield 72.7%.

¹H NMR(400MHz,CDCl₃): δ 11.35 10.31 (m, 2H), 8.65 (s, 1H), 7.91 (d, J=45.9Hz, 2H), 7.69 (d, J=23.4Hz, 2H), 7.48 (s, 1H), 7.36 (d, J=6.2Hz, 1H), 7.15 (d, J=19.1Hz, 1H), 5.93 5.71 (m, 2H), 5.70 5.54 (m, 1H), 5.38 (t, J=7.7Hz, 1H), 4.83 4.31 (m, 2H), 4.14 3.98 (m, 1H), 3.88 (d, J=20.9Hz, 2H), 3.73 (d, J=5.9Hz, 6H), 3.66 3.54 (m, 2H), 3.45 (d, J= 8.8Hz, 1H), 3.39 (t, J=22.3Hz, 6H), 3.24 2.88 (m, 7H), 2.79 (dd, J=10.1,9.2Hz, 1H), 2.72 2.58 (m, 1H), 2.51 (dd, J=12.3,7.7Hz, 1H), 2.36 (dd, J=23.8,11.5Hz, 1H), 2.22 2.11 (m, 2H), 1.99 (s, 2H), 1.17 (dd, J=18.8,5.7Hz, 4H), 0.89 (dd, J=6.9,4.0Hz, 2H) ppm； MS-ESI,m/z:879.3[M+H]⁺.

Embodiment 7

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 10-1

Compound 2-12 (1.25g, 1.74mmol, 1.0eq) is joined in DCM (15mL), drip HCl/ at 0 DEG C EtOAc (3mL) solution, drips off room temperature reaction 6h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 800mg, yield 89%.

¹H NMR(400MHz,CDCl₃): δ 8.43 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=12.3Hz, 4H), 7.40 (d, J=7.9Hz, 1H), 7.21 (s, 1H), 4.71 (dd, J=8.5,5.9Hz, 1H), 4.58 4.43 (m, 1H), 3.43 (ddd, J=30.0,14.4,6.3Hz, 2H), 3.25 3.00 (m, 4H), 2.42 (dd, J=12.8,8.4Hz, 1H), 2.30 (dt, J= 20.9,8.3Hz, 1H), 2.24 2.08 (m, 4H), 1.99 (dd, J=12.6,5.9Hz, 2H), 1.52 1.37 (m, 2H), 1.34–1.25(m,6H)ppm；MS-ESI,m/z:517.3[M+H]⁺.

Step 2) synthesis of compound 10

By compound 10-1 (280mg, 0.54mmol, 1.0eq), compound 10-2 (294mg, 1.36mmol, 2.5eq), 2-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM (15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 6h are added.Reactant liquor is poured in water (30mL), Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:EtOAc (V:V) =1:2), obtain faint yellow solid product 368mg, yield 74.2%.

¹H NMR(400MHz,CDCl₃):δ12.21–10.33(m,2H),8.80–8.46(m,1H),8.07–7.85(m, 2H), 7.82 7.62 (m, 2H), 7.51 (dd, J=42.1,33.3Hz, 1H), 7.33 (s, 1H), 7.26 7.04 (m, 1H), 5.49 (dt, J=14.2,7.7Hz, 2H), 5.28 5.16 (m, 1H), 4.75 4.62 (m, 1H), 4.41 4.29 (m, 2H), 4.03 (dd, J=16.4,9.9Hz, 2H), 3.90 3.68 (m, 6H), 3.54 2.94 (m, 10H), 2.42 (ddd, J=33.7, 17.1,9.5Hz, 2H), 2.20 2.08 (m, 3H), 1.90 (ddd, J=52.2,26.1,7.8Hz, 10H), 1.68 1.49 (m, 3H), 1.40 1.27 (m, 6H), 1.17 (d, J=5.8Hz, 2H) ppm；MS-ESI,m/z:915.5[M+H]⁺.

Embodiment 8

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 11-2:

By compound 4-7 (1.27g, 2.7mmol), compound 7-3 (0.62g, 3mmol), EDCI (0.62g, 3.3mmol) It is suspended in dichloromethane (20mL) with 2-oxime cyan-acetic ester (0.15g, 1.1mmol), under the conditions of 0 DEG C, by DIPEA (1.1g, 8.2mmol) is added dropwise in reactant liquor, after dripping off, and room temperature reaction 2h.Screw out solvent, residue ethyl acetate (100mL) extraction, saturated nacl aqueous solution (50mL) washs, and anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel column chromatography Purification (PE:EtOAc (V:V)=3:1), obtains brown solid 0.93g, productivity 60%.

¹H NMR(400MHz,CDCl₃): δ 13.71 10.69 (m, 1H), 8.57 8.34 (m, 1H), 7.94 (dd, J= 70.9,22.8Hz, 2H), 7.59 (dd, J=24.5,15.0Hz, 1H), 7.43 (s, 1H), 5.96 (dd, J=87.7,33.4Hz, 1H), 5.46 (dd, J=38.5,30.6Hz, 1H), 4.73 4.23 (m, 2H), 3.70 (s, 3H), 3.36 (s, 3H), 2.55 2.12 (m, 2H), 2.04 (s, 3H), 1.44 1.35 (m, 3H), 1.13 (d, J=5.9Hz, 3H) ppm；MS(ESI,pos.ion) m/z:572.2[M+H]⁺.

Step 2) synthesis of compound 11-3:

By compound 5-6 (0.65g, 1.2mmol), compound 11-2 (0.69g, 1.2mmol), Pd (PPh₃)₄(0.2g, 0.12mmol) and K₂CO₃(0.6g, 3.6mmol) is suspended in the mixed solvent of EtOH (20mL) and water (4mL), under nitrogen protection It is heated to 90 DEG C of reactions.Crossing kieselguhr, screw out solvent, residue ethyl acetate (200mL) extracts, saturated nacl aqueous solution (50mL) washing, anhydrous sodium sulfate is dried, back-out solvent, residue silica gel column chromatography (PE:EtOAc (V:V)=1:3) purification, Obtain brown solid 0.45g, productivity 44%.

¹H NMR(400MHz,CDCl₃):δ13.55–10.67(m,1H),8.05–7.82(m,2H),7.75–7.59(m, 3H), 7.41 7.29 (m, 1H), 7.18 (d, J=8.5Hz, 1H), 6.21 5.87 (m, 1H), 5.67 5.36 (m, 1H), 5.05 (t, J=7.3Hz, 1H), 4.46 (ddd, J=76.6,33.7,27.1Hz, 2H), 3.92 3.80 (m, 3H), 3.75 3.66 (m, 2H),3.54(s,1H),3.37(s,6H),3.30(s,2H),3.20–3.04(m,6H),2.64–2.42(m,3H),2.30– 1.95(m,6H),1.51(s,9H),1.26(m,6H)ppm；MS(ESI,pos.ion)m/z:820.4[M+H]⁺.

Step 3) synthesis of compound 11-4:

Compound 11-3 (0.45g, 0.54mmol) is dissolved in DCM (10mL), under the conditions of 0 DEG C, is slowly added dropwise hydrochloric acid second Acetate solution (4M/L, 3mL), after dripping, room temperature reaction 3h.Screwing out solvent, residue ethyl acetate is pulled an oar, and filters. Filter cake use water (10mL) dissolves, and adds potassium carbonate and adjusts pH value to 8-9, sucking filtration, obtains product 0.35g, productivity 90%.

¹H NMR(400MHz,CDCl₃):δ13.55–10.67(m,1H),8.05–7.82(m,2H),7.75–7.59(m, 3H), 7.41 7.29 (m, 1H), 7.18 (d, J=8.5Hz, 1H), 6.21 5.87 (m, 1H), 5.67 5.36 (m, 1H), 5.05 (t, J=7.3Hz, 1H), 4.46 (ddd, J=76.6,33.7,27.1Hz, 2H), 3.92 3.80 (m, 3H), 3.75 3.66 (m, 2H),3.54(s,1H),3.37(s,6H),3.30(s,1H),3.20–3.04(m,6H),2.64–2.42(m,3H),2.30– 1.95(m,7H),1.26(m,6H)ppm；MS(ESI,pos.ion)m/z:720.2[M+H]⁺.

Step 4) synthesis of compound 11:

By compound 11-4 (0.35g, 0.49mmol), compound 11-5 (0.1g, 0.53mmol), EDCI (0.11g, 0.58mmol) it is suspended in dichloromethane (20mL), 0 DEG C of condition with 2-oxime cyan-acetic ester (0.028g, 0.19mmol) Under, DIPEA (0.19g, 1.5mmol) is added dropwise in reactant liquor, after dripping off, room temperature reaction 2h.Screw out solvent, residue second Acetoacetic ester (100mL) dissolves, and saturated nacl aqueous solution (50mL) washs, and anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel Column chromatography (DCM:EtOAc (V:V)=2:1), obtains white solid 0.3g, productivity 70%.

¹H NMR(400MHz,CDCl₃): δ 8.59 (s, 1H), 7.98 (d, J=13.6Hz, 1H), 7.68 (dd, J=20.5, 8.0Hz, 3H), 7.35 (d, J=8.1Hz, 1H), 7.20 (d, J=6.7Hz, 1H), 5.98 5.68 (m, 1H), 5.56 (dd, J= 20.1,6.7Hz,2H),5.36–5.24(m,2H),4.70–4.28(m,3H),4.19–3.82(m,3H),3.79–3.56(m, 6H), 3.40 (s, 6H), 3.29 (d, J=11.8Hz, 2H), 3.14 3.04 (m, 6H), 2.34 1.97 (m, 5H), 1.83 1.40 (m, 4H), 1.39 1.22 (m, 7H), 1.13 (d, J=6.0Hz, 2H), 0.91 0.71 (m, 6H) ppm；MS(ESI,pos.ion) m/z:891.5[M+H]⁺.

Embodiment 9

Synthetic route:

Synthesis step:

By compound 10-0 (280mg, 0.54mmol, 1.0eq), compound 11-5 (256mg, 1.36mmol, 2.5eq), 2-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM (15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 18h are added.Reactant liquor is poured in water (30mL), Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:EtOAc (V:V) =1:2), obtain faint yellow solid product 150mg, yield 32.2%.

¹H NMR(400MHz,CDCl₃): δ 11.96 10.36 (m, 2H), 8.83 8.50 (m, 1H), 7.94 (dd, J= 39.4,12.5Hz, 2H), 7.83 7.62 (m, 2H), 7.46 (dd, J=92.2,12.5Hz, 2H), 7.21 (d, J=17.5Hz, 1H), 5.60 5.40 (m, 2H), 5.26 (dd, J=20.5,11.7Hz, 1H), 4.82 4.63 (m, 1H), 4.39 4.23 (m, 2H), 3.72 (d, J=6.9Hz, 6H), 3.25 3.01 (m, 4H), 2.57 2.25 (m, 2H), 2.14 (dd, J=20.5, 14.8Hz, 3H), 2.05 1.95 (m, 1H), 1.94 1.77 (m, 3H), 1.66 (dd, J=7.2,4.4Hz, 3H), 1.30 (d, J =5.2Hz, 6H), 1.20 (t, J=13.7Hz, 4H), 1.05 (dd, J=15.6,6.7Hz, 2H), 0.99 0.94 (m, 2H), 0.89 (dd, J=13.8,6.3Hz, 6H), 0.77 (dd, J=12.2,6.6Hz, 2H) ppm；MS-ESI,m/z:859.5[M+H ]⁺.

Embodiment 10

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 15-2

Compound 15-1 (0.664g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.It is spin-dried for molten Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces Product 1.42g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06 3.52 (m, 3H), 3.40-3.22 (m, 1H), 3.06 (t, J=7.5Hz, 2H), 2.83 2.64 (m, 1H), 2.58 2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 13H), 0.9 (t, J=5.6Hz, 3H) ppm.

Step 2) synthesis of compound 15-3

Compound 15-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.31g, receive Rate 95%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61 3.22 (m, 1H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85 2.59 (m, 1H), 2.29 2.14 (m, 2H), 1.52 (m, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:530.2[M+H]⁺.

Step 3) synthesis of compound 15-4

By compound 15-3 (1.26g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, silica gel Column chromatography purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.85g, yield 71%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48-3.40(m,1H),3.38–2.88(m,4H),2.80–2.59(m,1H),2.19–2.07(m,2H),1.52-1.34(m, 12H), 1.36 (s, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:508.3[M+H]⁺.

Step 4) synthesis of compound 15-6

By compound 15-4 (558mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.70g, yield 87%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 4H), 2.44 2.21 (m, 2H), 2.20 2.08 (m, 2H), 2.00 1.86 (m, 2H), 1.55-1.34 (m, 21H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z: 731.3[M+H]⁺.

Step 5) synthesis of compound 15-7

Compound 15-6 (0.70g, 0.95mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product Product 428mg, yield 85%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.15 (m, 1H), 3.15 2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H), 1.94 1.65 (m, 5H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:531.4[M+ H]⁺.

Step 6) synthesis of compound 15

By compound 15-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL) In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM (15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:MeOH (V:V)=10: 1), white solid product 232mg, yield 55% are obtained.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 2H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 1H), 3.06 (s, 3H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59 2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 3H), 1.32-1.18 (m, 4H) 0.89 (m, 15H) ppm；MS-ESI, m/z:845.4[M+H]⁺.

Embodiment 11

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 16-2

Compound 16-1 (0.81g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces Product 1.56g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 6.50 (t, 1H), 5.54 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06 3.52 (m, 3H), 3.40-3.22 (m, 4H), 3.06 (t, J=7.5Hz, 2H), 2.83 2.64 (m, 1H), 2.58 2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 10H) ppm.

Step 2) synthesis of compound 16-3

Compound 16-2 (1.56g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.38g, receive Rate 91%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 6.50 (t, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0,13.0Hz, 1H), 3.61 3.22 (m, 4H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85–2.59(m,1H),2.29–2.14(m,2H),1.52(s,9H)ppm；MS-ESI,m/z:582.2[M+H]⁺.

Step 3) synthesis of compound 16-4

By compound 16-3 (1.38g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, then silicon Gel column chromatography eluting (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.95g, yield 72%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 6.5 (t, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7, 13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38 2.88 (m, 7H), 2.80 2.59 (m, 1H), 2.19 2.07(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI,m/z:560.3[M+H]⁺.

Step 4) synthesis of compound 16-5

By compound 16-4 (615mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.82g, yield 95%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 6.50 (t, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1, 13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 7H), 2.44 2.21 (m, 2H), 2.20 2.08 (m, 2H), 2.00 1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H), 1.32-1.18 (m, 3H) ppm；MS-ESI,m/ z:783.3[M+H]⁺.

Step 5) synthesis of compound 16-6

Compound 16-5 (0.82g, 1.05mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C EtOAc (3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 543mg, yield 89%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 6.50 (t, 1H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.15 (m, 4H), 3.15 2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J =5.5Hz, 2H), 1.94 1.65 (m, 2H), 1.32-1.18 (m, 3H) ppm；MS-ESI,m/z:583.4[M+H]⁺.

Step 6) synthesis of compound 16

By compound 16-6 (291mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) joins in DCM (15mL), add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), extract with DCM (15mL × 3), organic facies anhydrous slufuric acid Sodium is dried, and is spin-dried for, and crosses post, silica gel column chromatography purification (DCM:MeOH (V:V)=10:1), obtains white solid product 256mg, yield 57%.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 3H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 3H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59 2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 1H), 1.32-1.18 (m, 3H) 0.89 (dd, J=16.3,5.8Hz, 12H)ppm；MS-ESI,m/z:897.4[M+H]⁺.

Embodiment 12

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 22-2

Compound 22-1 (0.63g, 2.7mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added In acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces Product 1.43g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06 3.52 (m, 3H), 3.31 (t, J=7.4Hz, 2H), 3.06 (t, J=7.5Hz, 2H), 2.83 2.64 (m, 1H), 2.58 2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (d, J=10.1Hz, 10H) ppm.

Step 2) synthesis of compound 22-3

Compound 22-2 (1.40g, 2.59mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.23g, receive Rate 91.2%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61 3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85 2.59 (m, 1H), 2.29–2.14(m,2H),1.52(s,9H)ppm；MS-ESI,m/z:520.2[M+H]⁺.

Step 3) synthesis of compound 22-4

By compound 22-3 (1.23g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, silica gel column chromatography Purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.74g, yield 63%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38 2.88 (m, 5H), 2.80 2.59 (m, 1H), 2.19 2.07 (m, 2H), 1.52(s,9H),1.36(s,12H)ppm；MS-ESI,m/z:498.4[M+H]⁺.

Step 4) synthesis of compound 22-5

By compound 22-4 (550mg, 1.10mmol, 1.0eq), compound 7-7A (460g, 1.10mmol, 1.0eq), carbon Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.765g, yield 97.8%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81 2.62 (m, 1H), 2.44 2.21 (m, 2H), 2.20 2.08 (m, 2H), 2.00 1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:707.4 [M+H]⁺.

Step 5) synthesis of compound 22-6

Compound 22-5 (0.76g, 1.1mmol, 1.0eq) is joined in DCM (10mL), drip HCl/EtOAc at 0 DEG C (4N, 3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 500mg, yield 92%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.21 (m, 2H), 3.15 2.85 (m, 7H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H),1.94–1.65(m,2H)ppm；MS-ESI,m/z:507.4[M+H]⁺.

Step 6) synthesis of compound 22

By compound 22-6 (280mg, 0.552mmol, 1.0eq), compound 1-14 (213mg, 1.22mmol, 2.2eq), 2-oxime cyan-acetic ester (62mg, 0.44mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM (15mL), in, EDCI (232mg, 1.22mmol, 2.2eq), room temperature reaction 3h are added.Reactant liquor is poured in water (30mL), Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 270mg, yield 59.50%.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 2H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59 2.07 (m, 5H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:821.2[M+H]⁺.

Embodiment 13

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 31-1

By compound 1-11 (0.8g, 1.7mmol, 1eq), compound 1-5A (0.73g, 1.5mmol, 0.9eq), Pd (PPh₃)₄(0.20g, 0.17mmol, 0.1eq) and K₂CO₃The EtOH/H that (0.69mg, 5.0mmol, 3eq) is suspended in₂O(30mL, V:V=3:1), in, 90 DEG C of reaction 3h under nitrogen protection, it are heated to.After reaction completely, screw out most solutions, then with DCM (20mL × 2) extraction, merges organic facies, is dried, is spin-dried for, silica gel column chromatography purification (PE:EA (V:V)=2:1), obtains gray solid 0.5g, productivity 40%.

¹H NMR(400MHz,CDCl₃):δ7.98(s,1H),7.52(d,2H),7.22(m,2H),5.33(s,1H),4.93 (s,2H),3.26(m,4H),3.20(m,2H),3.10(m,4H),2.76-2.62(m,4H),2.19-1.95(m,6H),1.25 (m,9H),1.29(m,9H)ppm；MS-ESI,m/z:691.5[M+H]⁺.

Step 2) synthesis of compound 31-2

At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 31-1 (0.5g, 0.7mmol, 1eq) In alkane solvents (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains Brown solid 0.4g, productivity 87%.MS-ESI,m/z:491.6[M+H]⁺.

Step 3) synthesis of compound 31

By compound 31-2 (0.40g, 0.82mmol, 1eq), compound 1-14 (0.316g, 1.8mmol, 2.2eq), EDCI (0.377g, 1.97mmol, 2.4eq) and 2-oxime cyan-acetic ester (0.07g, 0.49mmol, 0.6eq) is suspended in dichloro In methane (10mL), under the conditions of 0 DEG C, DIPEA (0.530g, 4.1mmol, 5eq) is added dropwise in reactant liquor, after dripping off, moves into 2h is stirred at room temperature.After reaction completely, adding ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride is washed, nothing Aqueous sodium persulfate is dried, and filters, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g, Productivity 53%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.62(d,2H),7.21(m,2H),5.43(s,1H),5.10 (s,2H),3.56-3.42(m,4H)3.31(m,2H),3.16-2.83(m,4H),2.72-2.63(m,4H),2.56-2.41(m, 4H),2.38(m,2H),2.36-2.21(m,4H),2.09-1.82(m,6H),1.05(m,12H)ppm；MS-ESI,m/z: 806.3[M+H]⁺.

Embodiment 14

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 32-2

By compound 1-6 (1.45g, 2.65mmol, 1.0eq) and (3S)-2-(tertbutyloxycarbonyl)-2-azabicyclo [2.2.1] heptane-3-carboxylic acid 32-1 (0.82g, 0.34mmol, 1.1eq) joins in acetonitrile (10mL), drips three at 0 DEG C Ethamine (0.39g, 3.9mmol, 1.5eq), drips off room temperature reaction 2h.Screw out solvent, add water (20mL), then extract with DCM (10mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil product 1.45g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.74 7.61 (m, 1H), 7.20 (d, J=8.5Hz, 1H), 5.28 (ddd, J= 62.1,49.1,16.3Hz, 2H), 4.32 (d, J=51.5Hz, 1H), 3.95 (d, J=29.9Hz, 1H), 3.32 (t, J= 6.0Hz, 2H), 3.06 (t, J=7.2Hz, 2H), 2.97 2.82 (m, 1H), 2.27 2.11 (m, 2H), 2.06 1.94 (m, 1H), 1.85 1.76 (m, 1H), 1.69 1.62 (m, 2H), 1.56 (dd, J=11.3,6.9Hz, 1H), 1.46 (d, J= 18.4Hz,9H),1.36–1.30(m,1H)ppm.

Step 2) synthesis of compound 32-3

Compound 32-2 (1.45g, 2.65mmol, 1.0eq) and ammonium acetate (1.22g, 15.9mmol, 6.0eq) are added In toluene (10mL), 115 DEG C of reaction 15h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.1g, Yield 79%.

¹H NMR(400MHz,CDCl₃): δ 10.73 (d, J=211.3Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.12 (t, J=13.6Hz, 2H), 4.43 (d, J=8.5Hz, 1H), 4.16 (s, 1H), 3.41 (d, J=18.3Hz, 1H), 3.11 (dt, J=23.2,7.3Hz, 4H), 2.19 (dt, J=15.0,7.6Hz, 2H), 2.00 (d, J=10.0Hz, 1H), 1.87 (td, J= 11.1,5.1Hz,1H),1.77–1.67(m,4H),1.53(s,9H)ppm；MS-ESI,m/z:528.10[M+H]⁺.

Step 3) synthesis of compound 32-4

By compound 32-3 (1.03g, 1.95mmol, 1.0eq), connection pinacol borate (0.52g, 2.05mmol, 1.05eq), potassium acetate (0.57g, 5.86mmol, 3.0eq), Pd (dppf)₂Cl₂(57mg, 0.078mmol, 0.04eq), adds In DMF (10mL), the lower 100 DEG C of reaction 11h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silicagel column Chromatography purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.96g, yield 97%.

¹H NMR(400MHz,CDCl₃): δ 10.67 (d, J=221.7Hz, 1H), 7.79 (s, 0.5H), 7.66 (d, J= 7.7Hz, 1H), 7.25 (s, 0.5H), 7.19 (s, 1H), 4.45 (s, 1H), 4.17 (s, 1H), 3.42 (d, J=20.6Hz, 1H), 3.19 (t, J=7.5Hz, 2H), 3.10 3.02 (m, 2H), 2.11 (dd, J=14.6,7.3Hz, 2H), 2.02 (d, J= 9.9Hz, 1H), 1.93 1.84 (m, 1H), 1.74 (dd, J=15.4,10.4Hz, 4H), 1.53 (s, 9H), 1.36 (s, 12H) ppm；MS-ESI,m/z:506.25[M+H]⁺.

Step 4) synthesis of compound 32-5

By compound 32-4 (0.6g, 1.2mmol, 1eq), compound 7-7A (0.49g, 1.2mmol, 1eq), Pd (PPh₃)₄ (0.14g, 0.12mmol, 0.1eq) and K₂CO₃(0.49mg, 3.6mmol, 3eq) is suspended in EtOH/H₂In O (30mL, 3:1), nitrogen 90 DEG C of reaction 3h it are heated under gas shielded.After reaction completely, screw out most solutions, then extract with DCM (20mL × 2), merge Organic facies, is dried, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.6g, productivity 70%.

¹H NMR(400MHz,CDCl₃):δ7.98(s,1H),7.72(d,2H),7.32(m,2H),7.22(m,2H),5.53 (s,1H),4.63(s,2H),3.26(m,4H),3.10-2.85(m,4H),2.76-2.51(m,4H),2.23-2.09(m,6H), 1.82-1.69(m,2H),1.25(m,9H),1.29(m,9H)ppm.

Step 5) synthesis of compound 32-6

At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 32-5 (0.5g, 0.7mmol, 1eq) In alkane solvents (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains Brown solid 0.36g, productivity 79%.

Step 6) synthesis compound 32

By compound 32-6 (0.67g, 1.02mmol, 1eq), compound 1-14 (0.429g, 2.45mmol, 2.4eq), EDCI (0.472g, 2.45mmol, 2.4eq) and 2-oxime cyan-acetic ester (0.116g, 0.817mmol, 0.8eq) is suspended in two In chloromethanes (10mL), under the conditions of 0 DEG C, DIPEA (0.792g, 6.13mmol, 6eq) is added dropwise in reactant liquor, after dripping off, Immigration is stirred at room temperature 2h.After reaction completely, add ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride Washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for reactant liquor, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains Lycoperdon polymorphum Vitt Solid 0.4g, productivity 51%.

¹H NMR(400MHz,CDCl₃):δ8.10(s,1H),7.72(d,2H),7.46(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56-3.45(m,4H)3.16-3.01(m,4H),3.10-2.87(m,4H),2.66-2.51(m, 4H),2.56-2.39(m,2H),2.36(m,4H),2.09-1.93(m,6H),1.81-1.72(m,2H)1.23-1.05(m, 12H)ppm.

Embodiment 15

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 33-2

Lithium (0.56g, 80mmol, 4eq) is joined in oxolane (20mL), at 0 DEG C add TMSCl (7.67mL, 60mmol, 3eq), then drip compound 33-1 (2.08g, 20mmol, 1eq), after dripping, room temperature reaction 6 days.Add at 0 DEG C Methanol (10mL) cancellation is reacted, and adds water (25mL), and with petroleum ether extraction (40mL × 3), merges the anhydrous sulfur of organic facies Acid sodium is dried, and concentrates at 25 DEG C.Obtain 4.9g yellow fluid, yield 98%.

GC/MS:[M⁺]=250.2.

Step 2) synthesis of compound 33-3

Compound 33-2 (4.9g, 19.6mmol, 1eq) is dissolved in oxolane (50mL), at 40 DEG C, drips DDQ The tetrahydrofuran solution (15mL) of (2.22g, 9.8mmol, 0.5eq).React 1h at 40 DEG C, add water (100mL) cancellation reaction, It is extracted with ethyl acetate (40mL × 4) again.Merge organic facies, use water (50mL), saturated aqueous sodium carbonate (80mL) respectively, satisfy Wash with saline solution (50mL), then be dried with anhydrous sodium sulfate, concentrate at 25 DEG C, obtain the thick product of 5.0g, yield 103%.

GC/MS:[M⁺]=248.1.

Step 3) synthesis of compound 33-4

Compound 33-3 (4.96g, 20mmol, 1eq) is dissolved in methanol (50mL), at 0 DEG C drip bromine (3.1mL, 60mmol, 3eq) methanol solution (10mL), drip rear room temperature reaction overnight.Add water (100mL) cancellation reaction, then use stone Oil ether extraction (100mL × 3), merges organic facies saturated aqueous common salt (50mL) and washs, and anhydrous sodium sulfate is dried, and concentrates.Obtain Residue silica gel column chromatography purification (PE), obtain 2.5g product, productivity 48%.

¹H NMR(400MHz,CDCl₃):δ7.17(s,2H),3.09(s,4H)ppm.

Step 4) synthesis of compound 33-5

By compound 33-4 (2.5g, 9.54mmol, 1eq), tributyl (1-ethoxy ethylene) stannum (2.93mL, 8.60mmol, 0.9eq) and dichloro two triphenylphosphine palladium (0.35g, 0.48mmol, 0.05eq) be dissolved in dioxane (25mL), Nitrogen is protected, microwave reaction 1h at 100 DEG C.Kieselguhr filter, filtrate add dichloromethane (20mL) and hydrochloric acid (1.5N, 20mL), stirring 2h, then extract with dichloromethane (50mL) under room temperature, organic facies anhydrous sodium sulfate is dried, and concentrates at 25 DEG C. Residue silica gel column chromatography purification (PE:EtOAc (V:V)=30:1-20:1), obtains 1.2g white solid, productivity 56%.

¹H NMR(400MHz,CDCl₃): δ 7.62 (d, J=8.4,1H), 7.40 (d, J=8.4,1H), 3.41 (t, J= 7.6Hz, 2H), 3.21 (t, J=7.6Hz, 2H), 2.49 (s, 3H) ppm.

Step 5) synthesis of compound 33-6

By compound 33-5 (1.2g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) joins EtOH (20mL) 60 DEG C of reaction 2h in solvent, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, and adds DCM (40mL), and uses water (20mL) washing, anhydrous sodium sulfate is dried, vacuum rotary steam, then silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains Brownish red grease 1.38g, productivity 85%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=7.6Hz, 2H), 3.07 (t, J=7.6Hz, 2H) ppm.

Step 6) synthesis of compound 33-8

At 0 DEG C, triethylamine (0.6g, 6mmol, 1.5eq) is added drop-wise to compound 33-6 (1.1g, 3.6mmol, 1eq), In dichloromethane (20mL) mixed liquor of compound 1-7 (1.0g, 4.6mmol, 1.3eq), adding rear room temperature reaction, TLC monitors Reaction, adds washing (10mL) after reaction completely, and saturated sodium-chloride is washed, and organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE: EtOAc (V:V)=6:1), obtain product 1.29g, productivity 82%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (m, 1H),4.43(s,2H),3.36(m,2H),3.16(m,2H),3.07(m,4H),2.29(m,2H),1.36(t,9H)ppm；MS- ESI,m/z:438.1[M+H]⁺.

Step 7) synthesis of compound 33-9

Compound 33-8 (1.13g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, cross post, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.01g, yield 93%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (s, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0, 13.0Hz, 1H), 3.61 3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85 2.59 (m, 2H), 1.52 (s, 9H)ppm；MS-ESI,m/z:418.2[M+H]⁺.

Step 8) synthesis of compound 33-11

By compound 33-9 (1.0g, 2.4mmol, 1.0eq), connection pinacol borate (0.63g, 2.5mmol, 1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silica gel column layer Analysis purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.78g, yield 70%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4, 12.0Hz,1H),3.38–2.88(m,5H),2.80–2.59(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI, m/z:466.4[M+H]⁺.

Step 9) synthesis of compound 33-13

By compound 33-11 (512mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon Acid potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) With in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract (30mL with dichloromethane × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white solid Body product 0.727g, yield 98%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81 2.62 (m, 2H), 2.44 2.21 (m, 2H), 2.00 1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:675.4[M+H]⁺.

Step 10) synthesis of compound 33-14

Compound 33-13 (0.72g, 1.07mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C EtOAc (3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 471mg, yield 93%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.21 (m, 2H), 3.15 2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J=5.5Hz, 2H), 1.94 1.65 (m, 2H) ppm； MS-ESI,m/z:475.4[M+H]⁺.

Step 11) synthesis of compound 33

By compound 33-14 (238mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL) In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM (15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:MeOH (V:V)=10: 1), white solid product 241mg, yield 61% are obtained.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 2H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 2H), 2.59 2.07 (m, 3H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:789.3[M+H]⁺.

Embodiment 16

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 34-1

By compound 1-1 (8.1g, 50mmol, 1eq), n-butylamine (4.38g, 60mmol, 1.2eq) and TFA (1.14g, 10mmol, 0.2eq) join in toluene (100mL), at 120 DEG C, back flow reaction is overnight.Screw out solvent, add ethyl acetate (100mL), and washing with saturated sodium bicarbonate aqueous solution (30mL), anhydrous sodium sulfate is dried, and concentrates.The residue second obtained Nitrile (100mL) dissolves, and adds Selectfluor (35.4g, 100mmol, 2eq), back flow reaction 3h at 85 DEG C.Cool to again Room temperature, is slowly added dropwise concentrated hydrochloric acid (30mL), stirs 10 minutes, adds ethyl acetate (200mL), and wash with water (50mL × 2).Organic facies anhydrous sodium sulfate is dried, and concentrates.Silica gel column chromatography purification (PE:EtOAc (V:V)=10:1), obtains 4.0g yellow Color fluid, yield 40%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (t, J=7.6Hz, 1H), 7.61 (d, J=8.2Hz, 1H), 7.22 (d, J =8.6Hz, 1H), 3.90 (s, 3H), 3.06 (t, J=12.3Hz, 2H) ppm.

Step 2) synthesis of compound 34-2

By compound 34-1 (4.0g, 20mmol, 1eq), triethyl silicane (11.6g, 100mmol, 5eq), TFA (40mL) Joining back flow reaction in two mouthfuls of bottles, TLC monitoring reaction course, 6h reaction completely, is poured in frozen water after reaction completely, then is used EtOAc (40mL × 2) extracts, and organic facies sodium bicarbonate solution neutralizes, and washing is dried, is spin-dried for, silica gel column chromatography purification (PE), product 3.35g, productivity 91% are obtained.

¹H NMR(400MHz,CDCl₃): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J=7.4Hz, 1H), 6.73 (d, J =8.1Hz, 1H), 3.90 (s, 3H), 3.23 (t, J=12.3,4H) ppm.

Step 3) synthesis of compound 34-3

At 0 DEG C, chloroacetic chloride (1.7g, 21.6mmol, 1.2eq) is slowly added drop-wise to compound 34-2 (3.32g, 18mmol, 1eq), in DCM (20mL) solution of aluminum chloride (3.11g, 23.4mmol, 1.3eq), add rear room temperature and continue anti- Should, to pour in frozen water after reaction completely, extract with DCM (2 × 20mL), organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE: DCM (V:V)=5:1), obtain product 3.38g, yield 83%.

¹H NMR(400MHz,CDCl₃): δ 7.72 (d, J=8.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 3.90 (s, 3H), 3.23 (t, J=12.3,4H), 2.55 (s, 3H) ppm.

Step 4) synthesis of compound 34-4

At 0 DEG C, Boron tribromide (4.51g, 18mmol, 1.2eq) is slowly added drop-wise to compound 34-3 (3.38g, 15mmol, 1eq) DCM (50mL) solution in, continue reaction after adding, pour in frozen water, with EtOAc (40mL after reaction completely × 3) extraction, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains product 2.23g, yield 70%.

¹H NMR(400MHz,CDCl₃): δ 7.72 (d, J=8.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 3.23 (t, J =12.3,4H), 2.55 (s, 3H) ppm.

Step 5) synthesis of compound 34-5

At 0 DEG C, trifluoromethanesulfanhydride anhydride (3.4g, 12mmol, 1.2eq) is added drop-wise to compound 34-4 (2.12g, 10mmol, 1eq), in dichloromethane (40mL) mixed liquor of pyridine (1.96g, 20mmol, 2eq), add rear room temperature reaction, TLC Monitoring reaction, adds water (10mL) after reaction completely and washes, and saturated sodium-chloride is washed, and is dried, and organic facies is dried, and is spin-dried for, silica gel column layer Analysis purification (PE), obtains product 3.27g, productivity 95%.

¹H NMR(400MHz,CDCl₃): δ 7.82 (d, J=8.2Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 3.23 (t, J =12.3,2H), 3.03 (t, J=12.3,2H), 2.55 (s, 3H) ppm.

Step 6) synthesis of compound 34-6

By compound 34-5 (1.84g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) joins EtOH (20mL) 60 DEG C of reaction 2h in solvent, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, and adds DCM (40mL), and uses water (20mL) washing, anhydrous sodium sulfate is dried, vacuum rotary steam, then silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains Brownish red grease 1.38g, productivity 85%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=12.3Hz, 2H), 3.07 (t, J=12.3Hz, 2H) ppm.

Step 7) synthesis of compound 34-7

At 0 DEG C, triethylamine (0.6g, 6mmol, 1.5eq) is added drop-wise to compound 34-6 (1.52g, 3.6mmol, 1eq), in dichloromethane (20mL) mixed liquor of L-Boc-proline (1.0g, 4.6mmol, 1.3eq), add rear room temperature reaction, TLC monitors reaction, adds water (10mL) and wash after reaction completely, and saturated sodium-chloride is washed, and organic facies is dried, and is spin-dried for, silica gel column chromatography Purification (PE:EtOAc (V:V)=6:1), obtains product 1.63g, productivity 81%.

¹H NMR(400MHz,CDCl₃): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (m, 1H),4.43(s,2H),3.36(m,2H),3.16(m,2H),3.07(m,4H),2.29(m,2H),1.36(t,9H)ppm；MS- ESI,m/z:558.1[M+H]⁺.

Step 8) synthesis of compound 34-8

Compound 34-7 (1.45g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.33g, receive Rate 95%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (s, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0, 13.0Hz, 1H), 3.61 3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85 2.59 (m, 2H), 1.52 (s, 9H)ppm；MS-ESI,m/z:538.2[M+H]⁺.

Step 9) synthesis of compound 34-9

By compound 34-8 (1.29g, 2.4mmol, 1.0eq), connection pinacol borate (0.63g, 2.5mmol, 1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silica gel column layer Analysis purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.89g, yield 72%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4, 12.0Hz,1H),3.38–2.88(m,5H),2.80–2.59(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI, m/z:516.4[M+H]⁺.

Step 10) synthesis of compound 34-10

By compound 34-9 (567mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon Acid potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) With in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract (30mL with dichloromethane × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white solid Body product 0.757g, yield 95%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81 2.62 (m, 2H), 2.44 2.21 (m, 2H), 2.00 1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:725.4[M+H]⁺.

Step 11) synthesis of compound 34-11

Compound 34-10 (0.725g, 1.0mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product Product 483mg, yield 92%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.21 (m, 2H), 3.15 2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J=5.5Hz, 2H), 1.94 1.65 (m, 2H) pm； MS-ESI,m/z:525.4[M+H]⁺.

Step 12) synthesis of compound 34

By compound 34-11 (263mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL) In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM (15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:MeOH (V:V)=10: 1), white solid product 239mg, yield 57% are obtained.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 2H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 2H), 2.59 2.07 (m, 3H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:839.3[M+H]⁺.

Embodiment 17

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 35-2

Compound 1-6 (1.2g, 3.1mmol, 1.0eq) and compound 35-1 (0.82g, 0.34mmol, 1.1eq) is added In acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.47g, 4.6mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces Product 1.72g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.68 (d, J=8.5Hz, 1H), 7.20 (d, J=8.2Hz, 1H), 5.45 (dd, J=63.1,16.2Hz, 1H), 5.12 (dd, J=55.0,16.2Hz, 1H), 4.58 (ddd, J=26.2,8.5,3.4Hz, 1H), 3.51 3.34 (m, 2H), 3.32 (d, J=7.0Hz, 2H), 3.05 (t, J=7.1Hz, 2H), 2.39 (dd, J=12.6, 8.8Hz, 1H), 2.26 2.12 (m, 2H), 2.09 (d, J=12.7Hz, 1H), 1.46 (d, J=3.4Hz, 9H), 0.63 (dd, J =13.4,8.3Hz, 4H) ppm.

Step 2) synthesis of compound 35-3

Compound 35-2 (1.70g, 3.1mmol, 1.0eq) and ammonium acetate (1.4g, 19mmol, 6.0eq) are joined first In benzene (10mL), 115 DEG C of reaction 15h.Being spin-dried for by toluene, add water (50mL), then extract (15mL × 3) with DCM, organic facies is used Anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.33g, yield 81%.

¹H NMR(400MHz,CDCl₃): δ 10.88 (d, J=214.7Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.18 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.13 (s, 1H), 3.53 (d, J=10.0Hz, 1H), 3.20 3.07 (m, 5H), 2.80 (d, J=10.6Hz, 1H), 2.37 (s, 1H), 2.21 (d, J=6.8Hz, 2H), 1.52 (s, 9H), 0.89 (dd, J= 9.6,5.4Hz, 1H), 0.63 (ddd, J=18.6,11.0,4.9Hz, 3H) ppm；MS-ESI,m/z:528.20[M+H]⁺.

Step 3) synthesis of compound 35-4

By compound 35-3 (1.25g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.69g, 7.11mmol, 3.0eq), Pd (dppf)₂Cl₂(52mg, 0.071mmol, 0.03eq), adds In DMF (10mL), the lower 100 DEG C of reaction 16h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, silica gel column layer Analysis purification (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.0g, yield 83%.

¹H NMR(400MHz,CDCl₃): δ 10.83 (d, J=222.3Hz, 1H), 7.81 (s, 1H), 7.66 (d, J= 7.5Hz, 1H), 7.22 (s, 1H), 5.14 (d, J=6.2Hz, 1H), 3.52 (d, J=10.3Hz, 1H), 3.38 2.97 (m, 5H),2.79(s,1H),2.56–2.28(m,1H),2.21–2.08(m,2H),1.52(s,9H),1.36(s,12H),0.90(s, 1H),0.73–0.52(m,3H)ppm；MS-ESI,m/z:506.4[M+H]⁺.

Step 4) synthesis of compound 35-5

By compound 35-4 (600mg, 1.19mmol, 1.0eq), compound 7-7A (494g, 1.19mmol, 1.0eq), carbon Acid potassium (0.33g, 2.37mmol, 2.0eq), four triphenyl phosphorus palladiums (41mg, 0.035mmol, 0.03eq) join ethanol (10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 10h.Reactant liquor is poured in water (50mL), extract with dichloromethane Taking (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), White solid product 0.80g, yield 94%.

¹H NMR(400MHz,CDCl₃): δ 11.56-10.55 (m, 2H), 8.68 (d, J=13.5Hz, 1H), 8.00 (s, 1H), 7.87 (d, J=7.1Hz, 1H), 7.72 (d, J=25.8Hz, 2H), 7.58 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 5.32 5.09 (m, 2H), 3.56 (dd, J=37.5,26.4Hz, 3H), 3.15 (dd, J=26.7,3.2Hz, 4H), 2.84 (dd, J=13.4,10.1Hz, 1H), 2.46 2.25 (m, 2H), 2.20 2.08 (m, 2H), 1.79-170 (m, 4H), 1.61 1.44 (m, 18H), 0.86 (d, J=2.9Hz, 1H), 0.79 0.43 (m, 3H) ppm；MS-ESI,m/z:715.4 [M+H]⁺.

Step 5) synthesis of compound 35-6

Compound 35-5 (0.80g, 1.1mmol, 1.0eq) is joined in DCM (15mL), drip HCl/EtOAc at 0 DEG C (4N, 3mL) solution, drips off room temperature reaction 15h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain yellow solid product 590mg, yield 100%.

¹H NMR(400MHz,DMSO-d₆): δ 8.48 (d, J=8.4Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.69 (d, J=11.0Hz, 3H), 7.34 (d, J=7.9Hz, 1H), 7.24 (s, 1H), 4.43 (dt, J=14.8,7.2Hz, 2H), 3.45 (d, J=7.0Hz, 2H), 3.09 (dd, J=16.1,7.5Hz, 4H), 3.01 2.90 (m, 2H), 2.82 (d, J= 9.9Hz, 1H), 2.21 (dt, J=14.2,7.8Hz, 1H), 2.12 1.98 (m, 4H), 1.81 (dd, J=14.0,7.0Hz, 2H), 1.06 (t, J=7.0Hz, 1H), 0.56 (t, J=13.3Hz, 3H) ppm；MS-ESI,m/z:515.2[M+H]⁺.

Step 6) synthesis of compound 35

By compound 35-6 (280mg, 0.54mmol, 1.0eq), compound 1-14 (209mg, 1.20mmol, 2.2eq), 2-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM (15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 18h are added.Reactant liquor is poured in water (30mL), Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 243mg, yield 53.88%.

¹H NMR(400MHz,CDCl₃): δ 12.97 10.31 (m, 2H), 8.63 (d, J=7.6Hz, 1H), 7.90 (dd, J =45.6,19.8Hz, 2H), 7.68 (dd, J=21.5,8.3Hz, 2H), 7.39 (d, J=32.9Hz, 2H), 7.19 (s, 1H), 5.64 (dd, J=83.6,38.2Hz, 4H), 4.48 4.26 (m, 1H), 4.15 (dd, J=6.0,4.1Hz, 1H), 4.00 3.87 (m, 1H), 3.83 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 3.13 (dd, J=18.7,11.1Hz, 4H), 2.51 (dd, J =27.9,23.1Hz, 2H), 2.40 2.26 (m, 1H), 2.26 1.96 (m, 5H), 1.79 1.69 (m, 1H), 1.69 1.58 (m,1H),1.05–0.83(m,12H),0.84–0.56(m,4H)ppm；MS-ESI,m/z:829.4[M+H]⁺.

Embodiment 18

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 36-2

By 5-methoxyl group-3,4-naphthane-1 (2H)-one 36-1 (12g, 68mmol), triethyl silicane (26.3g, 272mmol), ammonium fluoride (8.3g, 272mmol) be dissolved in trifluoroacetic acid (100mL), 72 DEG C reaction 6h.Screw out solvent, residue Dissolving by ethyl acetate (300mL × 2), organic facies sodium bicarbonate solution neutralizes, and washing is dried, is spin-dried for, residue silicagel column Chromatography purification (PE), obtains colorless oil 10g, productivity 90%.

¹H NMR(400MHz,CDCl₃): δ 7.15 (t, J=7.9Hz, 1H), 6.75 (dd, J=21.5,7.9Hz, 2H), 3.88 (s, 3H), 2.84 (t, J=5.6Hz, 2H), 2.74 (t, J=5.9Hz, 2H), 1.91 1.80 (m, 4H) ppm；MS(ESI, pos.ion)m/z:163.2[M+H]⁺.

Step 2) synthesis of compound 36-3

Compound 36-2 (11g, 67.8mmol), aluminum chloride (13.7g, 100mmol) are dissolved in DCM (100mL), 0 Chloroacetic chloride (7g, 88mmol), after dropping, room temperature reaction 24h is dripped under the conditions of DEG C.Reactant liquor is poured in frozen water, use second Acetoacetic ester (200mL × 2) extracts, washing, is dried, is spin-dried for, residue silica gel column chromatography purification (PE), obtains pale yellow oil 4g, productivity 28%.

¹H NMR(400MHz,CDCl₃): δ 7.63 (d, J=8.6Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 3.87 (s, 3H), 3.04 (t, J=5.8Hz, 2H), 2.75 2.57 (m, 2H), 2.55 (s, 3H), 1.75 (td, J=7.3,3.6Hz, 4H) ppm；MS(ESI,pos.ion)m/z:205.1[M+H]⁺.

Step 3) synthesis of compound 36-4

Compound 36-3 (9g, 44mmol) is dissolved in N-Methyl pyrrolidone (90mL), adds pyridine hydrobromide salt (28g, 176mmol), reacts 4h under the conditions of 180 DEG C.Reactant liquor is joined in water (400mL), with ethyl acetate (300mL × 2) extraction, merges organic layer, and saturated aqueous common salt (150mL) washs, and is dried, residue silica gel column chromatography purification (PE:EtOAc (V: V)=10:1), obtain white solid 4g, productivity 47.7%.

¹H NMR(400MHz,CDCl₃): δ 7.58 (d, J=8.4Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 3.10 (t, J =6.1Hz, 2H), 2.82 2.60 (m, 2H), 2.57 (s, 3H), 1.98 1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/z: 191.2[M+H]⁺.

Step 4) synthesis of compound 36-5

At 0 DEG C, trifluoromethanesulfanhydride anhydride (6.5g, 23mmol) is added drop-wise to compound 36-4 (4g, 21mmol), pyridine In dichloromethane (120mL) mixed liquor of (2.2g, 27mmol), add rear room temperature reaction 3h.Reactant liquor water (30mL) is washed Washing, organic facies is dried, and is spin-dried for, residue silica gel column chromatography purification (PE:EtOAc (V:V)=10:1), obtains colorless oil 2.8g, productivity 40%.

¹H NMR(400MHz,CDCl₃): δ 7.58 (d, J=8.4Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 3.10 (t, J =6.1Hz, 2H), 2.82 2.60 (m, 2H), 2.57 (s, 3H), 1.98 1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/z: 323.2[M+H]⁺.

Step 5) synthesis of compound 36-6

Joining in ethanol (50mL) by compound 36-5 (2.6g, 8mmol), copper bromide (3.6g, 16mmol), 60 DEG C anti- Answer 2h.Reactant liquor kieselguhr filters, and filtrate is spin-dried for, and dissolves with DCM (50mL × 2), and saturated nacl aqueous solution (30mL) washs, Anhydrous sodium sulfate is dried, and is spin-dried for, yellow solid 2.8g, productivity 87%.

¹H NMR(400MHz,CDCl₃): δ 7.60 (d, J=8.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 4.66 (s, 2H), 3.10 (t, J=6.1Hz, 2H), 2.82 2.60 (m, 2H), 1.98 1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/ z:401.3[M+H]⁺.

Step 6) synthesis of compound 36-7

At 0 DEG C, triethylamine (1.1g, 10mmol) is added drop-wise to compound 36-6 (2.8g, 7mmol), N-tertiary butyloxycarbonyl In the dichloromethane (60mL) of base-L-PROLINE (2.0g, 9mmol), add rear room temperature reaction 8h.Reactant liquor water (20mL) is washed Washing, anhydrous sodium sulfate is dried, and is spin-dried for, residue silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains colorless oil Thing 3g, productivity 80%.

¹H NMR(400MHz,CDCl₃): δ 7.40 (d, J=8.5Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 5.05 (ddd, J=63.0,51.9,16.7Hz, 2H), 4.48 4.26 (m, 1H), 3.64 3.22 (m, 2H), 2.98 2.65 (m, 4H), 2.13 1.67 (m, 8H), 1.43 (d, J=13.2Hz, 9H) ppm；MS(ESI,pos.ion)m/z:536.0[M+H]⁺.

Step 7) synthesis of compound 36-8

Compound 36-7 (3g, 5.6mmol), ammonium acetate (2.6g, 33mmol) are joined in toluene (60mL), 110 DEG C Reaction 12h.Reaction adds water (20mL) after terminating, and extracts by ethyl acetate (50mL × 2), and organic facies is washed, anhydrous sodium sulfate It is dried, vacuum rotary steam, residue silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.8g, produce Rate 30%.

¹H NMR(400MHz,CDCl₃): δ 7.43 (s, 1H), 7.21 7.07 (m, 1H), 7.04 (s, 1H), 4.99 (d, J= 5.2Hz, 1H), 3.43 (s, 2H), 3.00 2.75 (m, 4H), 2.24 1.95 (m, 5H), 1.78 (dt, J=48.8,24.0Hz, 4H),1.58–1.41(m,9H)ppm；MS(ESI,pos.ion)m/z:516.1[M+H]⁺.

Step 8) synthesis of compound 36-9

By compound 36-8 (0.8g, 1.6mmol), pinacol connection boron ester (0.5g, 1.9mmol), Pd (dppf) Cl₂· CH₂Cl₂(0.25g, 0.3mmol), AcOK (0.5g, 4.7mmol) are suspended in DMF (20mL), are heated to 100 under nitrogen protection DEG C reaction 4h.Reactant liquor is cooled to room temperature, adds water (60mL), sucking filtration, after solid with methylene chloride dissolves, is spin-dried for, silicagel column Chromatography purification (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.65g, productivity 80%.

¹H NMR(400MHz,CDCl₃): δ 10.76 (s, 1H), 7.65 (d, J=7.6Hz, 1H), 7.03 (s, 2H), 5.00 (d, J=5.4Hz, 1H), 3.43 (d, J=5.3Hz, 2H), 2.84 (s, 3H), 2.10 (dd, J=60.9,20.7Hz, 3H), 1.86–1.69(m,6H),1.51(s,9H),1.36(s,12H)ppm；MS(ESI,pos.ion)m/z:494.3[M+H]⁺.

Step 9) synthesis of compound 36-10

By compound 36-9 (0.65g, 1.3mmol), compound 4-9 (0.64g, 1.03mmol), Pd (PPh₃)₄(0.23g, 0.2mmol)、K₂CO₃(0.54g, 4mmol) is dissolved in ethanol (16mL) and water (4mL), under nitrogen protection, and 90 DEG C of reaction 3h.Rotation Going out solvent, residue DCM (80mL) is extracted twice, and organic layer saturated nacl aqueous solution (20mL) washs, anhydrous sodium sulfate It is dried, screws out solvent, residue silica gel column chromatography purification (DCM:EtOAc (V:V)=2:1), obtain yellow solid 0.7g, productivity 70%.

¹H NMR(400MHz,CDCl₃): δ 13.87 9.99 (m, 2H), 8.62 (d, J=8.5Hz, 1H), 8.05 7.77 (m, 2H), 7.68 (t, J=8.6Hz, 1H), 7.63 7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J= 45.6,22.5Hz, 1H), 5.03 (d, J=5.4Hz, 1H), 4.29 (s, 1H), 3.98 3.68 (m, 3H), 3.57 3.38 (m, 3H), 2.94 (t, J=30.7Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90 1.66 (m, 9H), 1.52(s,9H),1.34–1.22(m,4H),1.19–1.09(m,5H)ppm；MS(ESI,pos.ion)m/z:774.6[M+H]⁺.

Step 10) synthesis of compound 36-11

At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 36-10 (0.7g, 0.9mmol) (16mL), in, rear room temperature reaction 3h is dripped off.Screwing out reactant liquor, residue ethyl acetate is pulled an oar, and filters.Filter cake use water (10mL) Dissolve, add potassium carbonate and adjust pH value to 8-9, sucking filtration, obtain yellow solid 0.58g, productivity 92%.

¹H NMR(400MHz,CDCl₃): δ 13.87 9.99 (m, 2H), 8.62 (d, J=8.5Hz, 1H), 8.05 7.77 (m, 2H), 7.68 (t, J=8.6Hz, 1H), 7.63 7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J= 45.6,22.5Hz, 1H), 5.03 (d, J=5.4Hz, 1H), 4.29 (s, 1H), 3.98 3.68 (m, 3H), 3.57 3.38 (m, 4H), 2.94 (t, J=30.7Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90 1.66 (m, 9H), 1.34–1.22(m,4H),1.19–1.09(m,5H)ppm；MS(ESI,pos.ion)m/z:674.3[M+H]⁺.

Step 11) synthesis of compound 36:

Compound 36-11 (0.28g, 0.41mmol), (S)-2-((methoxycarbonyl base) amino)-3 Methylbutanoic acid 1-14 (0.09g, 0.5mmol), 2-oxime cyan-acetic ester (0.024g, 0.165mmol) are dissolved in DCM (10mL), under room temperature condition Add EDCI (0.1g, 0.5mmol), room temperature reaction 2h.The cancellation that adds water is reacted, and adds DCM (50mL) extraction, screws out solvent, residue Dissolve with methanol (20mL), add ammonia (1mL), after stirring 5min, be spin-dried for, extract with DCM (50mL), saturated nacl aqueous solution (10mL) washing, anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel column chromatography purification (DCM:EtOAc:MeOH (V:V:V) =20:10:1), obtain white solid 0.2g, productivity 60%.

¹H NMR(400MHz,CDCl₃):δ10.80(m,2H),8.78–8.40(m,1H),8.02–7.80(m,2H), 7.73–7.48(m,3H),7.19(m,2H),7.05(s,1H),5.63–5.38(m,3H),5.32(s,1H),4.48–4.24(m, 3H),3.94(s,1H),3.85(s,1H),3.77–3.63(m,4H),3.50–3.22(m,2H),3.09–2.78(m,4H), 2.69 (s, 1H), 2.52 2.25 (m, 1H), 2.20 (s, 1H), 2.04 (s, 3H), 1.45 (s, 1H), 1.28 (t, J=7.1Hz, 4H), 1.18 (d, J=6.0Hz, 2H), 1.12 (m, 4H), 1.02 0.76 (m, 11H) ppm；MS(ESI,pos.ion)m/z: 831.6[M+H]⁺.

Embodiment 19

Synthetic route:

Synthesis step:

By compound 36-11 (0.28g, 0.41mmol), (S)-2-cyclohexyl-2-((methoxycarbonyl base) amino) acetic acid 37-1 (0.102g, 0.46mmol), 2-oxime cyan-acetic ester (0.024g, 0.16mmol) are dissolved in DCM (10mL), room temperature bar EDCI (0.098g, 0.5mmol), room temperature reaction 2h is added under part.The cancellation that adds water is reacted, and adds DCM (50mL) extraction, screws out solvent, Residue methanol (20mL) dissolves, and adds ammonia (1mL), after stirring 5min, is spin-dried for, extracts with DCM (50mL), saturated sodium-chloride Solution (10mL) washs, and anhydrous sodium sulfate is dried, back-out solvent, residue silica gel column chromatography purification (DCM:EtOAc:MeOH (V: V:V)=20:10:1), obtain white solid 0.2g.

¹H NMR(400MHz,CDCl₃): δ 12.82 10.07 (m, 2H), 8.86 8.40 (m, 1H), 7.86 (dd, J= 22.5,12.4Hz, 2H), 7.53 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 5.65 5.41 (m, 3H), 5.31 (d, J= 6.7Hz,1H),4.32(m,3H),3.97–3.80(m,3H),3.78–3.61(m,6H),2.87(m,6H),2.48–2.15(m, 4H), 2.06 (s, 1H), 1.45 (s, 3H), 1.28 (m, 6H), 1.21 1.07 (m, 6H), 0.99 (t, J=6.7Hz, 3H), 0.95–0.78(m,6H)ppm；MS(ESI,pos.ion)m/z:871.8[M+H]⁺.

Embodiment 20

Synthetic route:

Synthesis step:

Step 1) synthesis of compound 38-2

Compound 38-1 (0.664g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces Product 1.42g, yield 100%.

¹H NMR(400MHz,CDCl₃): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06 3.52 (m, 3H), 3.40-3.22 (m, 2H), 3.06 (t, J=7.5Hz, 2H), 2.83 2.64 (m, 1H), 2.58 2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 12H), 0.9 (t, J=5.6Hz, 3H) ppm.

Step 2) synthesis of compound 38-3

Compound 38-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.28g, receive Rate 93%.

¹H NMR(400MHz,CDCl₃): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61 3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85 2.59 (m, 1H), 2.29 2.14 (m, 2H), 1.52 (m, 11H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:530.2[M+H]⁺.

Step 3) synthesis of compound 38-4

By compound 38-3 (1.26g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)₂Cl₂(69mg, 0.094mmol, 0.04eq), joins In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, then silicon Gel column chromatography eluting (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.82g, yield 68%.

¹H NMR(400MHz,CDCl₃): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38 2.88 (m, 5H), 2.80 2.59 (m, 1H), 2.19 2.07 (m, 2H), 1.52 (m, 11H), 1.36 (s, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:508.3[M+H]⁺.

Step 4) synthesis of compound 38-5

By compound 38-4 (558mg, 1.10mmol, 1.0eq), compound 15-5 (473g, 1.10mmol, 1.0eq), carbon Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.75g, yield 93%.

¹H NMR(400MHz,CDCl₃): δ 11.88 10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22 7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51 5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 5H), 2.44 2.21 (m, 2H), 2.20 2.08 (m, 2H), 2.00 1.86 (m, 2H), 1.55 (m, 20H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:731.3 [M+H]⁺.

Step 5) synthesis of compound 38-6

Compound 38-5 (0.75g, 1.03mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product Product 502mg, yield 92%.

¹H NMR(400MHz,DMSO-d₆): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96 7.49 (m, 4H), 7.45 7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70 4.18 (m, 2H), 3.30 3.15 (m, 2H), 3.15 2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H), 1.94 1.65 (m, 4H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:531.4[M+ H]⁺.

Step 6) synthesis of compound 38

By compound 38-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL) In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM (15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (DCM:MeOH (V:V)=10: 1), white solid product 296mg, yield 70% are obtained.

¹H NMR(400MHz,CDCl₃):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47 5.62 (m, 2H), 5.62 5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46 3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59 2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80 1.58 (m, 3H), 1.32-1.18 (m, 3H) 0.89 (m, 15H) ppm；MS-ESI, m/z:845.4[M+H]⁺.

Biotic experiment

Biological Examples 1:HCV Subgenomic replicon is analyzed

Experiment purpose:

Evaluation compound is to HCV wild type replicon GT1a, GT1b and GT2a, and HCV replicon chimera GT3a, GT 4a, GT5a and GT6a, and GT1b L31V, the inhibitory action of GT1b Y93H persister.

Experimental technique:

GT1a, GT1b and GT2a replicon active testing: will be with G418 resistant gene NEO and luciferase reporter gene The RNA point hit method respectively transient transfection of HCV GT1a H77 replicon, GT1b Con1b replicon and GT2a JFH1 replicon To Huh-7 cell, add G418 and screen 3～4 weeks, build stable transfected cells strain.Huh7-H77 and Huh7-JFH1 is surely turned thin Born of the same parents' strain is diluted to 5 × 10⁴/ mL, inoculates 200 μ L to 96 orifice plates, Huh7-Con1b stable cell strain is diluted to 1 × 10⁵/ mL, connects Plant 50 μ L to 384 orifice plates.After 16-24h, using 3 times of gradient dilutions, diluted chemical compound is extremely closed by the dilution process of 11 dilution point Suitable concentration, uses POD^TMCompound after dilution is added in 96 orifice plates by 810 microwell plate pretreatment systems, and the DMSO in each hole is eventually Concentration is 0.5%.At 37 DEG C, 5%CO₂CO₂After constant temperature culture hatches 72h, in every hole, add the luciferase inspection of 40 μ L Test agent (Promega Bright-Glo), after 5min, detects with chemiluminescence detection system (Envision).Use Experimental result is processed by GraphPad Prism software, the EC50 of computerized compound replicon each to HCV suppression.

GT3a, GT4a, GT5a, GT6a mosaic type replicon and GT1b L31V, GT1b Y93H persister active testing: logical Cross electric-shocking method by HCV GT1b/GT3a-NS5A, HCV GT1b/GT4a-NS5A, HCV GT1b/GT5a-NS5A, HCV GT1b/GT6a-NS5A is fitted together to replicon rna and HCV GT1b L31V, HCV GT1b Y93H drug resistance replicon rna proceed to respectively Huh7 cell, is inoculated into cell in the 96 hole brassboards containing respective concentration compound with the density in 10000, every hole subsequently. Compound DMSO mother solution is diluted, adds in 96 hole brassboards, DMSO final concentration of 0.5%.By cell at 5%CO₂, 37 Cultivate 72 hours under the conditions of DEG C.In cell hole, add luciferase luminous substrate Bright-Glo, send out with chemistry after waiting 5 minutes Optical detection system Envision detects Luminescence signal value, and initial data (RLU) is used for computerized compound inhibitory activity. By suppression percent import GraphPad Prism software carry out nonlinear fitting calculate curve corresponding to compound and Inhibitory activity (EC50) numerical value to hepatitis C virus replicon.

The EC50 result of compound genocopy each to HCV is as shown in table 2.

Table 2

Conclusion: in table, result display the compounds of this invention is to HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a Replicon is respectively provided with good inhibitory activity, HCVGT1b L31V, GT1b Y93H persister is also had well suppression simultaneously Activity, i.e. the compounds of this invention are the full genome type HCV inhibitor of anti-drug resistance.

Biological Examples 2:SD P of Rats K screening test

Experimental technique:

Taking male SD rat and be divided into two groups, often group 3, one group of intravenous injection the compounds of this invention, dosage is 1.0mg/kg, Another group is orally administered to described compound 5.0mg/kg.After administration in 24h take a blood sample 8～9 time points.Build according to sample concentration The standard curve of vertical OK range, uses AB SCIEX API4000 type LC-MS/MS, measures in plasma sample under MRM pattern The concentration of described compound.According to pharmaceutical concentration-time curve, the WinNonLin 6.3 non-compartment model method of software is used to calculate Pharmacokinetic parameters.Result is as shown in table 3.

Table 3

Conclusion: table 3 result display the compounds of this invention has preferable bioavailability.

It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and And can be embodied in other concrete form without departing from its essential characteristics.It is therefore contemplated that each embodiment is the most all It is considered illustrative and nonrestrictive, should refer to appended claims rather than these embodiments aforementioned, therefore, All changes in the implication of appended claims equivalents and scope are included in herein.

In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature It is contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is differed Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any One or more embodiments or example combine in an appropriate manner.

Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art is without departing from the principle of the present invention and objective In the case of above-described embodiment can be changed within the scope of the invention, revise, replace and modification, the scope of the present invention Limited by claim and equivalent thereof.

Claims (21)

1. a compound, it is the stereoisomer of compound, geometrical isomerism shown in the compound shown in formula (I) or formula (I) Body, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,

Wherein, A is-(CR⁷R^7a)_m-、-CR⁷=CR^7a-、-(CH₂)_nO-,-N=CR⁷-、-NR⁷-CR⁷R^7a-、-CR⁷R^7a-NR⁷-、-O (CH₂)_n-、-CR⁷=N-,-S (CH₂)_n-、-(CH₂)_nS-or-NR^9a-；

X and X¹It is each independently N or CR^7b；

Y and Y¹Be each independently H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (=O)- (CR⁸R^8a)_t-N(R⁹)-R¹⁰Or a-amino acid group；

Wherein a-amino acid group selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, Valine, alanine, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, arginine, Histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, nor-leucine, bird The base that propylhomoserin, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline are formed Group；

R¹、R²、R³And R⁴It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl；Or R¹、 R²It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous dicyclo, spiral shell dicyclo or the miscellaneous dicyclo of spiral shell；Or R³、R⁴With X¹-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell Ring；

Each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl, alkene Base, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, heterocycle Base alkylamino or aryloxy group；

Each R⁷、R^7a、R^7b、R⁸、R^8aAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, deuterated Alkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl Alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl alkane ammonia Base, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, miscellaneous Ring group amino, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-、 Alkyl-OS (=O)_rO-, alkyl-S (=O)_r-, heterocyclic radical alkylamino or aryloxy group；

Each R⁹And R¹⁰Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC (= O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or amino Sulfonyl；

Each f, n and t independently be 0,1,2,3 or 4；

M is 1,2,3 or 4；With

Each r independently be 0,1 or 2；

The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (= O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo, spiral shell The miscellaneous dicyclo of dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, Arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl, heteroaryl Base alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, amino first Acyl group, alkyl-OS (=O)_r-, alkyl-S (=O)_rO-, alkyl-S (=O)_r-or amino-sulfonyl individually optionally by 1,2,3 Or 4 selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, alkyl halide Base, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl ammonia Base, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C (= O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)₂-, hydroxyl substituted alkyl-S (=O)-, hydroxyl substituted Alkyl-S (=O)₂-or the substituent group of the substituted alkoxyl of carboxyl replaced.

Compound the most according to claim 1, wherein, each R¹、R²、R³And R⁴Independently be H, C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_3-10Cycloalkyl, C_2-10Heterocyclic radical, C_1-9Heteroaryl or C_6-10Aryl；Or R¹、R²It is randomly formed 3-8 unit with X-CH Heterocycle, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12The miscellaneous dicyclo of spiral shell；Or R³、R⁴With X¹-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo or C_5-12 The miscellaneous dicyclo of spiral shell；Wherein said 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C_5-12Condensed-bicyclic, C_5-12Condense miscellaneous dicyclo, C_5-12Spiral shell dicyclo Or C_5-12The miscellaneous dicyclo of spiral shell individually optionally by 1,2,3 or 4 selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkane ammonia Base, C_1-6Alkylthio group, C_6-10Arylamino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl or C_2-10The substituent group of heterocyclic radical is replaced.

Compound the most according to claim 1, wherein R¹、R²Heterocycle, condensed ring or the spiro ring system choosing formed with Y-X-CH From following subformula:

Wherein R³、R⁴With Y¹-X¹Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following subformula:

Wherein, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Halogenated alkoxy C_1-6Alkyl, C_1-6Alkylamino, C_1-6Alkylthio group, C_6-10Aryl Amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle Base；

Each R^9bIndependently be hydrogen, deuterium, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Hydroxy alkyl, C_1-6Aminoalkyl, C_1-6Alkoxyl C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylthio group C_1-6Alkyl, C_6-10Aryl C_1-6Alkyl, C_1-9Heteroaryl, C_6-10Aryl, C_2-10Heterocyclic radical or C_3-8Cycloalkyl；

With each n₁And n₂Independently be 1,2,3 or 4.

Compound the most according to claim 3, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl Base, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Alkoxyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Halogenated alkoxy C_1-3Alkyl, C_1-3Alkane Amino, C_1-3Alkylthio group, C_6-10Arylamino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkane Base, C_3-8Cycloalkyl or C_2-10Heterocyclic radical；With

Each R^9bIndependently be hydrogen, deuterium, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Hydroxy alkyl, C_1-3Aminoalkyl, C_1-3Alkoxyl C_1-3Alkyl, C_1-3Alkylamino C_1-3Alkyl, C_1-3Alkylthio group C_1-3Alkyl, C_6-10Aryl C_1-3Alkyl, C_1-9Heteroaryl, C_6-10Aryl, C_2-10Heterocyclic radical or C_3-8Cycloalkyl.

Compound the most according to claim 3, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl Base, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy Ylmethyl, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, benzene Base amino, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl；With

Each R^9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group Methyl, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.

Compound the most according to claim 1, wherein, each R⁷、R^7a、R^7bAnd R^9aIndependently be H, deuterium, oxo (=O), hydroxyl Base, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkanes Base, sulfydryl, nitro, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6 Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6 Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkane Base-S (=O)_r-、C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group；Independently be 0,1 or 2 with each r.

Compound the most according to claim 1, wherein Y and Y¹It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl ,-C (=O)-(CR⁸R^8a)_t-N(R⁹)-R¹⁰；

Each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Deuteroalkyl, C_1-6Halo Alkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, sulfydryl, nitro, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10Aryl Amino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclic radical ammonia Base, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (= O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group；

R⁹And R¹⁰It is each independently H, deuterium, C_1-6Alkyl, C_3-8Cycloalkyl, C_2-10Heterocyclic radical, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamoyl, C_1-6Alkyl-OS (=O)_r-、 C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-S (=O)_r-or amino-sulfonyl；

T is 0,1,2,3 or 4；With

Each r independently be 0,1 or 2.

Compound the most according to claim 7, R⁹And R¹⁰It is each independently H, deuterium, methyl, ethyl, isopropyl, positive fourth Base, isobutyl group, sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-OC (=O)-, isopropyl-OC (=O)-, the tert-butyl group-OC (=O)-, methyl-C (=O)-, ethyl-C (=O)-, isopropyl-C (=O)-, normal-butyl-C (= O)-, isobutyl group-C (=O)-, carbamoyl, methyl-carbamoyl, ethylamino formoxyl, methyl-OS (=O)₂-, ring third Base-OS (=O)₂-, methyl-S (=O)₂O-, cyclopropyl-S (=O)₂O-or amino-sulfonyl.

Compound the most according to claim 1, it has the structure shown in formula (II), (IIa), (IIb) or (III), or Structural upright isomer shown in formula (II), (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomerism Body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:

Wherein, A is-O-,-S-,-NH-,-CH₂-S-、-CH₂-O-、-CH₂-NH-、-O-CH₂-、-NH-CH₂-、-S-CH₂-or- CH₂-CH₂-；

Wherein, each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Alkoxyl, C_1-3Alkoxy C_1-3Alkyl, C_1-3Halogenated alkoxy C_1-3Alkyl, C_1-3Alkylamino, C_1-3Alkylthio group, C_6-10Aryl Amino, C_6-10Aryloxy group, C_1-9Heteroaryl, C_1-9Heteroaryl epoxide, C_1-9Heteroaryl C_1-3Alkyl, C_3-8Cycloalkyl or C_2-10Heterocycle Base；

With each n₁And n₂Independently be 1,2,3 or 4.

Compound the most according to claim 9, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C_1-6Alkyl, C_1-6Deuteroalkyl, C_1-6Haloalkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Ring Alkyl, sulfydryl, nitro, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkyl, C_3-8Cycloalkyl C_1-6 Alkyl, C_2-10Heterocyclic radical C_1-6Alkyl, C_6-10Arylamino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl-OC (=O)-, C_1-6Alkyl-C (=O)-, carbamyl Base, C_1-6Alkyl-OS (=O)_r-、C_1-6Alkyl-S (=O)_rO-、C_1-6Alkyl-OS (=O)_rO-、C_1-6Alkyl-S (=O)_r-、C_2-10 Heterocyclic radical C_1-6Alkylamino or C_6-10Aryloxy group.

11. compounds according to claim 9, the most each R¹⁵Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyanogen Base, hydroxyl, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoro Methoxy, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, second ammonia Base, phenyl amino, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl.

12. according to described compound arbitrary in claim 1-11, each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, Amino, F, Cl, Br, I, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_2-10Heterocyclic radical, C_3-8Cycloalkyl, Sulfydryl, nitro, C_6-10Aryl, C_1-9Heteroaryl, C_6-10Aryl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxyl, C_6-10Virtue Base amino, C_1-9Heteroaryl amino, C_6-10Aryl C_1-6Alkylamino, C_1-9Heteroaryl C_1-6Alkylamino, C_1-9Heteroaryl epoxide, C_1-9Miscellaneous Aryl C_1-6Alkyl, C_6-10Aryl C_1-6Alkoxyl, C_1-9Heteroaryl C_1-6Alkoxyl, C_2-10Heterocyclic radical epoxide, C_2-10Heterocyclic radical C_1-6 Alkoxyl, C_2-10Heterocyclylamino group, C_1-6Alkyl acyl, C_1-6Alkyl acyloxy, C_1-6Alkoxyacyl, C_2-10Heterocyclic radical C_1-6Alkane Amino or C_6-10Aryloxy group.

13. compounds according to claim 12, the most each R⁵And R⁶Independently be H, deuterium, oxo (=O), hydroxyl, ammonia Base, F, Cl, Br, I, cyano group, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, first Epoxide, ethyoxyl, vinyl, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, benzene Base amino, sulfydryl or nitro.

14. according to the arbitrary described compound of claim 1-11, wherein, each R⁸And R^8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated second Base, deuterated propyl group, deuterated isopropyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy Base ethyl, 1-methoxy-propyl, 2-methoxy-propyl, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, trifluoromethyl, vinyl, pi-allyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl, anilino-.

15. compounds according to claim 1, its solid with structure shown below or structure shown below is different Structure body, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy Upper acceptable salt or prodrug:

16. a pharmaceutical composition, wherein said pharmaceutical composition comprises the chemical combination according to any one of claim 1-15 Thing, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

17. pharmaceutical compositions according to claim 16, it further comprises other the medicine of HCV-Ab IgG.

18. pharmaceutical compositions according to claim 17, other the medicine of HCV-Ab IgG wherein said is interferon, Li Ba Wei Lin, interleukin-22, interleukin 6, interleukin 12, promotion produce the compound of 1 type helper T lymphocyte response, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Ba Wei former times monoclonal antibody, hepatitis C Immunoglobulin, Civacir^TM, EBP520, TVR, erlotinib, his Wei of Dacca, the beautiful Wei of department, Ah that Wei, Vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir, vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、ravidasvir、 Velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Luruiwei, sovaprevir、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、 IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX- 184、IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、VCH- 916、lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir、furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、 MK-8325、JNJ-47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、 BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, I Pool Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF- 961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、 MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、 GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB- 9200, ITX-5061, ID-12 or a combination thereof；Described interferon is Interferon Alpha-2b, the interferon-ALPHA of Pegylation, interferon α-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.

19. according to the pharmaceutical composition described in claim 17, and other the medicine of HCV-Ab IgG wherein said is used for suppressing HCV Reproduction process and/or the function of suppression HCV virus protein；Described HCV reproduction process includes that HCV enters, HCV shells, HCV turns over Translate, HCV replicates, HCV assembles or HCV release；Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine monophosphate dehydrogenation Enzyme (IMPDH).

Compound according to any one of 20. claim 1-15 or the drug regimen according to any one of claim 16-19 Thing purposes in preparing medicine, described medicine is for suppressing HCV reproduction process and/or the function of suppression HCV virus protein；Institute State HCV reproduction process and include that HCV enters, HCV shells, HCV translation, HCV duplication, HCV assembling or HCV release；Described HCV is sick Toxalbumin is selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the inside required for HCV virus replication Ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).

Compound according to any one of 21. claim 1-15 or the drug regimen according to any one of claim 16-19 Thing purposes in preparing medicine, described medicine is used for preventing, process, treat or alleviate HCV infection or hepatitis C disease.