CN103880823B - Application as the spiro-compound of hepatitis c inhibitor and its in medicine - Google Patents

Application as the spiro-compound of hepatitis c inhibitor and its in medicine Download PDF

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CN103880823B
CN103880823B CN201310711751.XA CN201310711751A CN103880823B CN 103880823 B CN103880823 B CN 103880823B CN 201310711751 A CN201310711751 A CN 201310711751A CN 103880823 B CN103880823 B CN 103880823B
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aryl
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CN103880823A (en
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张英俊
张健存
谢洪明
任青云
胡柏林
巫锡伟
付长萍
李石凤
王朝禾
李静
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YICHANG HEC CHANGJIANG PHARMACEUTICAL Co.,Ltd.
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention provides the spiro-compound as hepatitis c inhibitor and its purposes in medicine.A kind of compound be formula (I) shown in compound or formula (I) shown in compound stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.In addition, present invention also offers the pharmaceutical composition for including the compound, the compound and described pharmaceutical composition are used to suppress the purposes that HCV is replicated and suppressed at least one of HCV virus protein function, and the compound and described pharmaceutical composition are used to preventing, handle, treat or mitigating the HCV infection of patient or the purposes of hepatitis C disease.

Description

Application as the spiro-compound of hepatitis c inhibitor and its in medicine
Invention field
The invention belongs to drug field and it is related to the compound, described for treating HCV (HCV) infection Composition of compound and application thereof and application method.Especially, compound of the present invention is NS5A can be used as to suppress The spiro-compound of agent.More particularly it relates to it can suppress by the NS5A protein functions of HCV coding Compound, the pharmaceutical composition of the compound and the method for suppressing NS5A protein functions.
Background of invention
HCV is main human pathogen, estimates about 1.7 hundred million people of whole world infection, infects people for human immunodeficiency virus type 1 Several 5 times.And the major part among these HCV infection individuals can develop into serious progressive hepatopathy, including hepatic sclerosis and liver Cell cancer.Therefore, chronic HCV infection will be global patient because of hepatopathy and the main reason for premature death.
At present, maximally effective HCV therapy is the drug combination using alpha-interferon and Ribavirin, is produced in 40% patient It is raw to continue effect.Newest clinical effectiveness shows, during as monotherapy, pegylated alfa-interferons are better than unmodified α-dry Disturb element.However, even with the experimental treatment scheme including pegylated alfa-interferons and Ribavirin combination, big portion Point patient can not also continue to reduce viral load, and many patients are often with some side reactions, and can not treat for a long time.Cause This, the method for new effective treatment HCV infection is urgent at present required.
HCV is positive chain RNA virus.According to the ratio to the amino acid sequence derived and the extensive similitude of 5 ' non-translational regions Compared with HCV is classified into the single category of flaviviridae (Flaviviridae family).All members of flaviviridae All it is the envelope virus particle of the genome containing positive chain RNA, the genome is turned over by single uninterrupted ORFs (ORF's) Translate, encode all known virus specified proteins.
Considerable heterogeneity be present in the nucleotides and coded amino acid sequence of whole HCV genomes. The main genotype of at least seven is identified, and discloses individual hypotype more than 50.In by HCV infection cell, viral RNA is turned over Polyprotein is translated into, and is split into 10 kinds body proteins.It is structural proteins in amino terminal, followed by E1 and E2.In addition, also There are 6 kinds of non-structural proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, it plays very heavy in HCV life cycles The role (see, e.g., Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005) wanted.
Distribution of the HCV main genotypes in the whole world is different, although having 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 heterogeneities.
Single-stranded HCV rna genes group length is about 9500 nucleotides, has a single ORFs, and coding is single about The large-scale polyprotein of 3000 amino acid.In infection cell, the polyprotein on multiple sites by leukoprotease and Virus protein cleavage, produce structure and non-structural (NS) albumen.For HCV, ripe non-structural protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) be formed by what two kinds of virus proteases were realized.It is generally acknowledged that the first is metal egg White enzyme, cut in NS2-NS3 contacts；It is included in NS3 (also referred to herein as NS3 protease) N-terminal region second Serine protease, it mediates all follow-up cuttings in NS3 downstreams, is cis in NS3-NS4A cleavage sites, in remaining NS4A- NS4B, NS4B-NS5A, NS5A-NA5B site are then to be trans.NS4A albumen seems there are multiple functions, plays NS3 protease cofactors Effect, and NS3 and other rdrp virus components may be assisted to carry out film positioning.The formation of NS3 albumen and NS4A compounds Seemingly process event, on all sites improve proteolytic efficiency necessary to.NS3 albumen also shows ribonucleoside triphosphote Enzyme and DBPA activity.NS5B (also known as HCV polymerases herein) is to participate in the RNA dependent on RNA that HCV is replicated to polymerize Enzyme.
The compounds of this invention is to be used to treat patient's HCV infection, and the compound optionally suppresses the duplication of HCV virus. Specifically, the compounds of this invention is effective compound for suppressing NS5A protein functions.HCV NS5A albumen see, for example, Tan, S.-L.,Katzel,M.G.,Virology2001,284,1-12;And Park, K.-J.;Choi,S.-H,J.Biological Chemistry,2003。
Abstract of invention
The present invention relates to the method that new spiro-compound and HCV-Ab IgG infect.The compounds of this invention or pharmaceutical composition To HCV infection, particularly there is good inhibiting effect to HCV NS5A albumen.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound or formula (I) shown in formula (I) Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, it can pharmaceutically connect The salt or prodrug received,
Wherein, each A and A ' independently be a key, alkylidene, alkenylene, cycloalkylidene, sub- Heterocyclylalkyl ,- (CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)- (CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A and A ' It independently is following group：
Wherein, each X1Or X2It independently is O, S, NR6Or CR7R7a；
X4For (CR7R7a)n、-Y1=N-, O, S or NR6;
W is carbocylic radical or heterocyclic radical；
Each Y1And Y2It independently is N or CR7；
Z is-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b- or-(CH2)a-O-(CH2)b-；
Wherein each a and b independently is 0,1,2 or 3；
Each c independently is 1 or 2；
Each d independently is 1 or 2；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
F is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
Each e independently is 0,1,2,3 or 4；
Each X and X ' independently are N or CR7；
Each Y and Y ' independently are H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, α-ammonia The optical isomer of base acid groups or a-amino acid group, or each Y and Y ' independently are following construction unit：-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12；
Each U independently be-C (=O)-,-C (=S)-,-S (=O)-or-S (=O)2-；
Each t independently is 0,1,2,3 or 4；
Each k independently is 0,1 or 2；
Each R1、R2、R3And R4It independently is H, deuterium, alkyl, miscellaneous alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl or virtue Base, or R1、R23-8 circle heterocycles or 3-8 members carbocyclic ring, C are formed with X-CH5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic Or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4And X '-CH form 3-8 circle heterocycles or carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense it is miscellaneous it is bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；
Each R5It independently is H, deuterium, hydroxyl, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkane Epoxide, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (= O)r- or amino-sulfonyl；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(= O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkoxy, aryl, heteroaryl Base, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, alkyl Sulfonyl, alkyloxysulfonyl, alkyl sulphinyl, alkyl sulphonyl epoxide, alkyl sulphinyl epoxide, heterocyclic radical alkylamino Or aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-, aliphatic, halogenated aliphatic, hydroxy aliphatic Race, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, Heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyl oxy aliphatic, fragrant ammonia Base aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocyclic radical or carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkoxy, aryl, heteroaryl Base, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, alkyl Sulfonyl, alkyloxysulfonyl, alkyl sulphinyl, alkyl sulphonyl epoxide, alkyl sulphinyl epoxide, heterocyclic radical alkylamino Or aryloxy group；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, aliphatic, miscellaneous alkyl, halogenated aliphatic, hydroxyl group aliphatic, ammonia Base aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle Base aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyl oxy aliphatic, fragrant amino fat Fat race, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocyclic radical or carbocylic radical；
Each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, miscellaneous alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O )r-, alkyl-S (=O)rO-, alkyl-S (=O)r- or amino-sulfonyl；
Each R9、R9a、R10And R11It independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Alkyl, haloalkyl, hydroxy alkyl, heteroaryl alkyl, cycloheteroalkylalkyl or cycloalkyl-alkyl；
Each R12It independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC (=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、 R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl, miscellaneous alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl or aralkyl；
Or R11、R124-7 yuan of rings can be randomly formed with the atom being attached thereto；With
With each R13And R13aIt independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl Base；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aSubstituted or non-substituted 3-8 can be randomly formed with nitrogen-atoms Yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
The following group of each of which:Alkylidene, alkenylene, cycloalkylidene, sub- Heterocyclylalkyl ,-(CR8R8a)n-O- (CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C (=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O- (CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)- (CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-O-(CR9R9a)t-R12、NR6、CR7R7a、CR7、-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)- (CH2)b-、-(CH2)a-O-(CH2)b-、R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl-OC (=O)-, alkyl- C (=O)-, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-、R13R13aNS(=O)-、R13OS(=O)-、R13S(= O)-, alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkylamino, alkyl, miscellaneous alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, α-ammonia Base acid, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12The miscellaneous bicyclic, alkoxy of spiral shell, aliphatic, halo fat Fat race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, Heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyloxy group Base aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, haloalkyl, alkenyl, alkynyl, virtue Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Base alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, heterocyclic radical alkylamino or aryloxy group can optionally by One or more is selected from deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkene Base, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, alkoxy, the hydroxyl of hydroxyl substitution Substituted alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, Alkyl-the S (=O) of hydroxyl substitution2- or the substituent of Carboxyalkoxy substituted.
In some of these embodiments, wherein W is C3-8Carbocylic radical or C2-10Heterocyclic radical.
In some of these embodiments, whereinConstruction unit is selected from following subformula：
Wherein, each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each X6It independently is CR7R7a、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each f independently is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
E is 0,1,2,3 or 4；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkane Acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl Sulfonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitre Base, C1-6Alkylamino, C3-10Cycloalkyl or C6-10Aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
With each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Virtue Base C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical.
In some of these embodiments, wherein,Construction unit is selected from following subformula：
Wherein, X6For O, S ,-Y1=N-、NR6Or CR7R7a;
Each Y1It independently is N or CH；
Each f independently is 0,1,2,3 or 4；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkane Acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl Sulfonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro Or C1-6Alkylamino；
Each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alcoxyl Base C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Virtue Base C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkyl, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclylamino group C1-6Alkyl, C3-10Cycloalkanes Base amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-8Carbocylic radical.
In some of these embodiments, wherein each A and A ' independently are key, a C1-6Alkylidene, C2-6Alkenylene, C3-8Cycloalkylidene, C2-10Sub- Heterocyclylalkyl ,-(CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)- C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(= O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A And A ' independently is following group：
Wherein, each X1And X2It independently is O, S, NR6Or CR7R7a；
Each Y1And Y2It independently is N or CR7；
Z is-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b- or-(CH2)a-O-(CH2)b-；
Each a and b independently are 0,1,2 or 3；
Each c independently is 1 or 2；
Each d independently is 1 or 2；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-C1-6Alkyl, R13S(=O)-C1-6Alkane Base, R13R13aN-C(=O)-C1-6Alkyl, R13aR13N-C1-6Alkoxy, R13S(=O)-C1-6Alkoxy, R13R13aN-C(=O)-C1-6 Alkoxy, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6 Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino or C6-10Aryloxy group；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkyl, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclylamino group C1-6Alkyl, C3-10Cycloalkanes Base amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-8Carbocylic radical；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
With each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-、C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (= O)r- or amino-sulfonyl.
In some of these embodiments, wherein each A and A ' independently are key ,-a CH2-、-(CH2)2-、-CH= CH-、-CH=CH-CH2-、-N(R5)-、-C(=O)-、-C(=S)-、-C(=O)-O-、-C(=O)N(R5)-、-OC(=O)N(R5)-、- OC(=O)O-、-N(R5)C(=O)N(R5)-、-(R5)N-S(=O)2-、-S(=O)2-、-OS(=O)2-、-(R5)N-S(=O)-、-S(= O)-,-OS (=O)-, or each A and A ' independently be following group：
Wherein, X1For O or S；
Each Y1It independently is N or CH；
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alcoxyl Base C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、C1-6Alcoxyl Base, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, sulfydryl or nitro；
With each R13And R13aIt independently is as H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10 Aryl, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan with nitrogen-atoms To be randomly formed, substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
In some of these embodiments, wherein, each R1、R2、R3And R4It independently is selected from H, deuterium, C1-8Alkyl, C1-8It is miscellaneous Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-9Heteroaryl or C6-10Aryl, or R1、R2Appoint with X-CH Meaning ground forms 3-8 circle heterocycles or 3-8 members carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous It is bicyclic；R3、R4And X '-CH are randomly formed 3-8 circle heterocycles or 3-8 members carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense it is miscellaneous it is bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2And X-CH, or R3、R4And to be randomly formed 3-8 members miscellaneous by X '-CH Ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2It is selected from the Y-X-CH heterocycles formed or condensed ring or spiro ring system Following subformula：
Wherein, each R15It independently is H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl, C1-3Alcoxyl Base, C1-3Alkylamino, C1-3Alkylthio group, C6-10Fragrant amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryloxy, C1-9Heteroaryl C1-3Alkyl or C2-10Heterocyclic radical；
Each R6It independently is hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
With each n1And n2It independently is 1,2,3 or 4.
In other embodiments, wherein R3、R4And the heterocycles that are formed of Y '-X '-CH or condensed ring or spiro ring system choosing From following subformula：
Wherein, each R15It independently is H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl, C1-3Alcoxyl Base, C1-3Alkylamino, C1-3Alkylthio group, C6-10Fragrant amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryloxy, C1-9Heteroaryl C1-3Alkyl or C2-10Heterocyclic radical；
Each R6It independently is hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
With each n1And n2It independently is 1,2,3 or 4.
In some of these embodiments, it has such as formula（II）Shown structure：
Wherein,Construction unit is following subformula：
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CH2)e；
E is 0,1,2,3 or 4；
Each f independently is 0,1,2,3 or 4
Each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each X6It independently is CH2、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each A and A ' independently are key, a C1-6Alkylidene, C2-6Alkenylene, C3-8Cycloalkylidene, C2-10Sub- heterocycle alkane Base ,-(CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)- (CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A and A ' It independently is following group：
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, amino first Acyl group, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R5aAnd R6aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6 Alkyl sulphonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, Nitro, C1-6Alkylamino, C3-10Cycloalkyl or C6-10Aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Aliphatic, C1-6Alkoxy C1-6Fat Race, C1-6Alkylamino C1-6Aliphatic, C6-10Aryl C1-6Aliphatic, C1-9Heteroaryl C1-6Aliphatic, C2-10Heterocyclic radical C1-6Fat Race, C3-10Cycloalkyl C1-6Aliphatic, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；Wherein described group In aliphatic be alkyl, alkyl is, but is not limited to, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Aliphatic, C2-6Miscellaneous alkyl, C1-6Alkoxy C1-6Fat Race, C1-6Alkylamino C1-6Aliphatic, C6-10Aryl C1-6Aliphatic, C2-10Heterocyclic radical C1-6Aliphatic, C3-10Cycloalkyl C1-6Fat Race, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；Aliphatic in wherein described group is alkyl, alkyl For, but be not limited to, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10 Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (= O)-、C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O )r- or amino-sulfonyl；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
With each Y4And Y4' it independently is a key, O, S ,-(CH2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、- CF2-、-CHR5a-、-CR5aR6a、-CH2S(=O)rOr-CH2N(R6)-。
In other embodiments, it has such as formula（III）Shown structure：
In other embodiments, it has such as formula（IV）Shown structure：
Wherein, each Q2And Q3It independently is O, S, C (=O), NR6Or CR7R7a。
In other embodiments, it has such as formula（V）Shown structure：
Wherein e is 1,2,3 or 4.
In some of these embodiments, wherein, each Y and Y ' independently are a-amino acid group.
In other embodiments, wherein a-amino acid group is selected from isoleucine, leucine, lysine, egg ammonia Acid, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, dried meat ammonia Acid, serine, to tyrosine, arginine, histidine, cysteine, glycine, methyl amimoacetic acid, N, N- dimethylglycines, Kosé Propylhomoserin, norvaline, nor-leucine, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, a junket The group that propylhomoserin or hydroxy-proline are formed.
In other embodiments, wherein the a-amino acid in the a-amino acid group is D configurations.
In other embodiments, wherein the a-amino acid in the a-amino acid group is L-configuration.
In some of these embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)-(CR9R9a)t-U- (CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R11)-(CR9R9a)t- R12。
In other embodiments, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-C(=O)-R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C(=O)- R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-C(=O)-O-R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C(=O)- O-R13。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)-(CR9R9a)t-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-C(=O)-(CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-O-(CR9R9a)t- R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-R12, wherein R11、R124-7 yuan of rings can be formed with the atom being attached thereto.
In other embodiments, wherein, each R9、R9a、R10And R11It independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkane Base, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
Each R12It independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC (=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、 R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Ring Alkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
Each t independently is 0,1,2,3 or 4；
0,1 or 2 independently are with each k.
In other embodiments, wherein, each R9、R9a、R10And R11It independently is H, deuterium, methyl, ethyl, isopropyl Base, cyclohexyl, isobutyl group or phenyl；
Each R12It independently is-C (=O) R13、-C(=O)-O-R13、-C(=O)NR13R13a, methyl, ethyl, propyl group, phenyl, ring Hexyl, morpholinyl or piperidyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
With each R13And R13aIt independently is H, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl.
In other embodiments, it has such as formula（VI）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（VII）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-3Hydroxy alkyl, methyl, ethyl, isopropyl, isobutyl group, tertiary fourth Base, pi-allyl, propargyl, trifluoroethyl, phenyl, pyranose, morpholinyl, benzyl, piperazinyl, cyclopenta, cyclopropyl, cyclohexyl Or C1-9Heteroaryl；
Wherein described C1-3Hydroxy alkyl, methyl, ethyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, propargyl, three Fluoro ethyl, phenyl, pyranose, morpholinyl, benzyl, piperazinyl, cyclopenta, cyclopropyl, cyclohexyl or C1-9Heteroaryl can be optional Ground is substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（VIII）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n2It independently is 1,2,3 or 4；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（IX）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n1It independently is 1,2,3 or 4；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（X）Shown structure
Wherein, each R5aIt independently is H, deuterium, C1-4Alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4；
Each Y1It independently is N or CR7；
Each R6And R7It independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl or benzyl；
Each R14And R14aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
WhereinConstruction unit is following subformula：
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
In some of these embodiments, it has such as formula（XI）Shown structure
Wherein, each R5aIt independently is H, deuterium, C1-4Alkyl, F, Cl, Br or I；
F is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
X6For (CR7R7a)n、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each i, n and e independently are 1,2,3 or 4；
Each R6、R7And R7aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl or benzyl；
Each R14And R14aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Wherein described C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryloxy can be optionally Substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group；
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
In other embodiments, wherein, each R5aIt independently is H, deuterium, methyl, ethyl, F, Cl, Br or I;
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl, cyclohexyl or benzyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl or the tert-butyl group；
With each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy；
Wherein described methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group, methoxyl group, ethoxy Base, phenoxy group, tert-butoxy or the tert-butyl group optionally can be taken by one or more selected from deuterium, F, Cl, Br, hydroxyl, cyano group Substituted for base.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition to include any of the above described one kindization Compound.
In some of these embodiments, the pharmaceutical composition can also further include pharmaceutically acceptable carrier, Excipient, diluent, assistant agent, medium or its combination.
In some of these embodiments, it further includes the medicine of other HCV-Ab IgGs.
In other embodiments, wherein the medicine of the HCV-Ab IgG be interferon, it is Ribavirin, interleukin-22, white Interleukin 6, interleukin 12, promote to produce the compound of 1 type helper T lymphocyte response, RNA interfering, antisense RNA, miaow quinoline not moral, flesh Glycosides 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody (Bavituximab), CivacirTM, ripple Puri Wei (boceprevir), TVR (telaprevir), Erlotinib (erlotinib), daclatasvir, simeprevir、asunaprevir、vaniprevir、faldaprevir、ABT-450、danoprevir、sovaprevir、 MK-5172、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ABT-267、EDP239、PPI- 668、GS-5816、samatasvir(IDX-719)、MK-8742、MK-8325、GSK-2336805、PPI-461、TMC-435、 MK-7009、BI-2013335、ciluprevir、BMS-650032、ACH-1625、ACH-1095、VX-985、IDX-375、VX- 500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、EP-013420、VBY-376、TMC-649128、R- 7128、PSI-7977、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI- 879、HCV-796、HCV-371、VCH-916、VCH-222、ANA-598、MK-3281、ABT-333、ABT-072、PF- 00868554、BI-207127、GS-9190、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、 TMC647055 or its combination.
In other embodiments, wherein the interferon be Interferon Alpha-2b, Pegylation interferon-' alpha ', Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or its combination.
In some of these embodiments, it further includes at least one HCV inhibitor, the HCV inhibitor For suppressing HCV reproduction processes and suppressing at least one of HCV virus protein function；The HCV reproduction processes are entered selected from HCV The complete viral cycle for the HCV for entering, shell, translate, replicate, assembling or discharging.Described HCV virus albumen is selected from metalloprotein Enzyme, NS2, NS3, NS4A, NS4B, NS5A, NS5B；And HCV virus replicates required internal ribosome inlet point (IRES) With inosine monophosphate dehydrogenase (IMPDH).
On the other hand, compound or pharmaceutical composition of the present invention its be used to suppressing HCV reproduction processes and suppress HCV At least one of virus protein function；The HCV reproduction processes be selected from HCV enter, shelling, translation, replicate, assembling or release HCV complete viral cycle.Described HCV virus albumen be selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B；And HCV virus replicates required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
On the other hand, it can be used to prepare the present invention relates to the compounds of this invention or pharmaceutical composition and be used to prevent, handle, control Treat or mitigate patient's hepatitis C disease medicine purposes, including give patient effective amounts compound as described herein or Pharmaceutical composition of the present invention.
Another aspect of the present invention be related to formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), Or (XI) method of preparation, separation and the purifying of compound for being included (X).
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will in detail list the document corresponding to the content of the materialization of determination, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, and these may be such as right Like that comprising within the scope of the present invention defined in it is required that.Those skilled in the art will identify it is many similar or equivalent to Method and material described by this, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.There is many documents and similar material to distinguish or contradict with the present patent application, including but be not limited to term Definition, the usage of term, the technology of description, or the scope controlled such as the present patent application.
The present invention will apply defined below unless other aspects show.According to the purpose of the present invention, chemical element is according to member Plain periodic table, CAS versions and Chemical Physics handbook, 75thEd., 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito, 1999 Hes " March's Advanced Organic Chemistry ", Michael B.Smith and Jerry March, John Wiley＆ Sons, New York, 2007, during all above-mentioned bibliography are both incorporated herein by reference.
As described in the present invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or such as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or unsubstituted ".In general, art Language " optionally " is whether located at before term " substituted ", and expression gives one or more of structure hydrogen atom specific Substituent is substituted.Unless otherwise indicated, an optional substituted radical can have a substituent group is each can Substituted position is substituted.When more than one position can be by the one or more selected from specific group in given structural formula Substituent is substituted, then substituent with identical or different can substitute in each position.Wherein described substituent can be, But be not limited to, deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkenyl, Alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, the alkoxy of hydroxyl substitution, hydroxyl substitution Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl Substituted alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
Terminology used in the present invention " aliphatic " or " fatty group ", represent straight chain (i.e. non-branched) or side chain, substitution or Alkyl unsubstituted fully saturated or containing one or more degrees of unsaturation.Unless otherwise detailed instructions, fatty group contains 1-20 carbon atom, some of embodiments are that fatty group contains 1-10 carbon atom, and other embodiment is, Fatty group contains 1-8 carbon atom, and other embodiment is that fatty group contains 1-6 carbon atom, and other is real The scheme of applying is that fatty group contains 1-4 carbon atom, and other embodiment is that fatty group contains 1-3 carbon atom. Suitable fatty group includes, but is not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl, such as first Base, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, hexyl, isobutyl group, sec-butyl, vinyl etc..
Term " halogenated aliphatic " or " halogenated aliphatic base " represent fatty group by one or more identical or different Halogen atom is substituted, and wherein fatty group has an implication as described in the present invention, and halogen atom is fluorine, chlorine, bromine or iodine, such reality Example includes, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, 2- chlorovinyls etc..
Term " hydroxyl group aliphatic " or " hydroxyl group aliphatic base " represent that fatty group is taken by one or more oh groups In generation, wherein fatty group, have implication as described in the present invention, and such example includes, but is not limited to ethoxy, 2- hydroxyls Propyl group, methylol etc..
Term " amino aliphatic " or " amino fatty group " represent that fatty group is taken by one or more amino groups In generation, wherein fatty group, have implication as described in the present invention, and such example includes, but is not limited to amino methyl, 2- ammonia Base ethyl, 2- amino isopropyls etc..
Term " alkyl " represents 1-20 carbon atom, or 1-10 carbon atom, or 1-8 carbon atom, or 1-6 carbon original Son, or 1-4 carbon atom, or the univalence hydrocarbyl of the saturated straight chain of 1-3 carbon atom or side chain, wherein alkyl independently and can appoint Selection of land is substituted by one or more substituents described in the invention.The example of alkyl includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary fourth Base (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl- 1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3))、2- Methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3) C(CH3)3), n-heptyl, n-octyl etc..Term " alkyl " and its prefix " alkane " use here, all comprising straight chain and side chain Saturated carbon chains.Term " alkylene " uses here, represents that eliminating two hydrogen atoms from straight or branched saturation hydrocarbons obtains Saturation bivalent hydrocarbon radical, such example includes, but is not limited to, methylene, ethylidene, isopropylidene etc..
Term " alkenyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom Straight or branched monovalent hydrocarbon, wherein at least one position is undersaturated condition, i.e., a C-C is sp2Double bond, wherein alkene Base group independently and optionally can be substituted by one or more substituents described in the invention, including group has negation, " suitable " or " E ", the specific example of the positioning of " Z ", wherein alkenyl include, but is not limited to, vinyl (- CH=CH2), pi-allyl (-CH2CH=CH2) etc..
Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom Straight or branched monovalent hydrocarbon, wherein at least one position is undersaturated condition, i.e., a C-C is the keys of sp tri-, wherein alkynes Base group independently and optionally can be substituted by one or more substituents described in the invention, and wherein alkynyl is specifically real Example includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH) etc..
Term " alkyl of hydroxyl substitution " represents that alkyl group is substituted by one or more oh groups, wherein alkyl base Group has implication of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyls Deng.
Term " haloalkyl " represents that alkyl group is substituted by one or more identical or different halogen atoms, wherein alkane Base group has implication as described in the present invention, and halogen atom is fluorine, chlorine, bromine or iodine, and such example includes, but is not limited to three Methyl fluoride, trifluoroethyl, chloromethyl, methyl fluoride etc..
Term " hydroxy alkyl " represents that alkyl group is substituted by one or more oh groups, and wherein alkyl group has Implication as described in the present invention, such example include, but is not limited to ethoxy, 2- hydroxypropyls, methylol etc..
Term " aminoalkyl " represents that alkyl group is substituted by one or more amino groups, and wherein alkyl group has Implication as described in the present invention, such example include, but is not limited to amino methyl, 2- amino-ethyls, 2- amino isopropyls Deng.
Term " alkylidene " represents to remove from the saturated hydrocarbyl of straight or branched the saturation obtained by two hydrogen atoms Bivalent hydrocarbon radical group.And the alkylidene can be substituted or non-substituted, and wherein substituent can be, but be not limited to, Deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro or virtue Epoxide.Such example includes, but is not limited to, methylene（-CH2-）, ethylidene（-CH2-CH2-）, isopropylidene（-CH2- CH(CH3)-）, ethane -1,1- diyls, 2- methoxy propane -1,1- diyls, 2- hydroxy propane -1,1- diyls, 2- methyl -2- hydroxyls Base propane -1,1- diyls etc..
Term " alkenylene " represents to remove the alkylene group obtained by two hydrogen atoms from the alkene of straight or branched. And the alkenylene can be substituted or non-substituted, and wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, Halogen, cyano group, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro or aryloxy group.Such reality Example includes, but is not limited to, ethenylidene（-CH=CH-）, sub- isopropenyl（-C(CH3)=CH-）, 3- methoxyl group propylene -1,1- Diyl, 2- methyl butene -1,1- diyls etc..
Term " sub- carbocylic radical " (" cycloalkylidene ") represents monocyclic containing 3-12 carbon atom or 7-12 carbon atom The bicyclic hydrocarbon ring of saturation divalence removed obtained by two hydrogen atoms, wherein carbocylic radical or cycloalkyl have as described in the present invention Implication, such example include, but is not limited to, the amyl- 1- alkenylenes of cyclopropylidene, sub- cyclobutyl, cyclopentylene, 1- rings, 1- Amyl- 2- alkenylenes of ring etc..
Term " sub- heterocyclic radical " represents monocyclic, bicyclic or three-ring system, and one or more atoms independently select in its middle ring It from hetero atom, and can be fully saturated or comprising one or more degrees of unsaturation, but be not belonging to the fragrant same clan have two Individual tie point is connected with molecule remainder, and wherein heterocyclyl groups have implication as described in the present invention.Such example bag Include, but be not limited to, piperidines-Isosorbide-5-Nitrae-diyl, piperazine-Isosorbide-5-Nitrae-diyl, tetrahydrofuran -2,4- diyl, tetrahydrofuran -3,4- bis- Base, azetidine -1,3- diyls, pyrrolidines -1,3- diyls etc..
Term " sub- cycloheteroalkylalkyl " represents that cycloheteroalkylalkyl removes the group obtained by two hydrogen atoms, wherein heterocyclic radical Alkyl has implication as described in the present invention.Such example includes, but is not limited to morpholine -4- methylmethylenes, piperidines-N- Methylmethylene etc..
Term " halogeno alkylen " represents that there are haloalkyl moiety two tie points to be connected with molecule remainder.Wherein Alkylene group has implication as described in the present invention, and such example includes, but is not limited to diflouromethylene（-CF2-）Deng.
Term " arlydene " represents that there are aryl systems two tie points to be connected with molecule remainder.Wherein aromatic yl group With implication as described in the present invention, such example includes, but is not limited to, phenylene, sub- p-fluorophenyl etc..
Term " sub- aralkyl " represents that aralkyl system has two tie points to be connected with molecule remainder, wherein aralkyl With implication as described in the present invention.Such example includes, but is not limited to benzene methylene, benzene ethylene etc..
Term " inferior heteroaryl " represents that there are heteroaromatic system two tie points to be connected with molecule remainder.Wherein heteroaryl Base group has implication as described in the present invention, and such example includes, but is not limited to, sub- pyridine radicals, sub- pyrrole radicals, sub- thiophene Oxazolyl, sub- imidazole radicals etc..
Term " heteroarylalkylene " represents that there are heteroaryl alkyl system two tie points to be connected with molecule remainder, Wherein heteroaryl alkyl has implication as described in the present invention, and such example includes, but is not limited to pyridine -2- ethylenes, thiophene Azoles -2- methylenes, imidazoles -2- ethylenes, pyrimidine -2- methylenes etc..
Term " sub- condensed-bicyclic base " represents that there are fused bicyclic carbocycle two tie points to be connected with molecule remainder, its Middle condensed-bicyclic base has implication as described in the present invention.Such example include, but is not limited to bicyclic [3.1.0] hexane- 3,6- diyls etc..
Term " Asia condenses miscellaneous bicyclic group " represents that condensing miscellaneous bicyclic system has two tie points and molecule remainder phase Even.Such example includes, but is not limited to 3- azabicyclos [3.1.0] hexane -3,6- diyl etc..
Term " sub- condensed-bicyclic base alkyl " represents that condensed-bicyclic base alkyl has two tie points and molecule remainder It is connected, wherein condensed-bicyclic base alkyl has implication as described in the present invention.
Term " Asia condense miscellaneous bicyclic group alkyl " represent to condense miscellaneous bicyclic group alkyl have two tie points and molecule remaining Part is connected, wherein condensing miscellaneous bicyclic group alkyl has implication as described in the present invention.
Term " sub- spiral shell bicyclic group " represents that there are spiral shell bicyclic system two tie points to be connected with molecule remainder, wherein spiral shell Bicyclic group has implication as described in the present invention.Such example includes, but be not limited to 5- spiral shells [2.4] heptane -5,7- diyl, Spiral shell [4.4] nonane -2,7- diyls etc..
Term " the sub- miscellaneous bicyclic group of spiral shell " represents that there are the miscellaneous bicyclic system of spiral shell two tie points to be connected with molecule remainder, its The middle miscellaneous bicyclic group of spiral shell has implication as described in the present invention.Such example includes, but is not limited to 5- azaspiros [2.4] heptan Alkane -5,7- diyls, 2- azaspiros [4.4] nonane -2,7- diyls etc..
Term " sub- spiral shell bicyclic group alkyl " represents that spiral shell bicyclic group alkyl system has two tie points and molecule remainder It is connected, wherein spiral shell bicyclic group alkyl has implication as described in the present invention.
Term " the sub- miscellaneous bicyclic group alkyl of spiral shell " represent spiral shell miscellaneous bicyclic group alkyl system have two tie points and molecule remaining Part is connected, and the wherein miscellaneous bicyclic group alkyl of spiral shell has implication as described in the present invention.
Term " miscellaneous alkyl " represents to may be inserted into one or more hetero atoms, wherein alkyl group and hetero atom in alkyl chain With implication as described in the present invention.Unless otherwise detailed instructions, miscellaneous alkyl group contains 1-10 carbon atom, and other is real The scheme of applying is that miscellaneous alkyl group contains 1-8 carbon atom, and other embodiment is that it is former that miscellaneous alkyl group contains 1-6 carbon Son, other embodiment are that miscellaneous alkyl group contains 1-4 carbon atom, and other embodiment is miscellaneous alkyl group Contain 1-3 carbon atom.Such example includes, but is not limited to, CH3OCH2-、CH3CH2OCH2-、CH3SCH2-、(CH3)2NCH2-、(CH3)2CH2OCH2-、CH3OCH2CH2-、CH3CH2OCH2CH2- etc..
Term " alicyclic ", " alicyclic group ", " annular aliphatic base ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refer to Monovalence or multivalence, non-aromatic, the undersaturated ring of saturation or part, and do not include hetero atom, including 3-12 carbon atom Monocyclic or 7-12 carbon atom two rings.Bicyclic carbocyclic with 7-12 atom can be two rings [4,5], [5,5], [5, 6] or [6,6] system, while to have the bicyclic carbocyclics of 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitably Annular aliphatic base includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of annular aliphatic base includes, but absolutely Be not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, Cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, ring are pungent Base, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl etc..And " the annular aliphatic base " or " carbocyclic ring ", " carbon Ring group ", " cycloalkyl " can be substituted or unsubstituted, and wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, Halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl Base substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl Base substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
Term " cycloalkyl oxy " or " carbocylic radical epoxide " include cycloalkyl or the carbocylic radical optionally substituted, such as institute of the present invention Definition, it is connected on oxygen atom, and be connected by oxygen atom with remaining molecule, such example includes, but is not limited to ring Propyl group epoxide, cyclopentyloxy, cyclohexyl epoxide, cyclopropyl epoxide of hydroxyl substitution etc..
Term " cycloalkyl amino " represents that the group of naphthene base that amino group is optionally substituted by one or two substitutes, its Middle cycloalkyl has implication as described in the present invention, and such example includes, but is not limited to cyclopropylamino, cyclopenta ammonia Base, Cyclohexylamino, the cyclopropylamino of hydroxyl substitution, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " carbocylic radical epoxide alkoxy " represents that alkoxy is substituted by one or more carbocylic radical epoxide groups, wherein Alkoxy and carbocylic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to cyclopropyl Oxymethoxy, cyclopropyl epoxide ethyoxyl, cyclopentyloxy ethyoxyl, cyclohexyl epoxide ethyoxyl, cyclohexenyl group -3- epoxides Ethyoxyl etc..
Term " cycloalkyl oxy aliphatic " or " cycloalkyl oxy fatty group " represent that fatty group is one or more The cycloalkyl oxy group optionally substituted is substituted, and wherein fatty group and cycloalkyl oxy group have as described in the present invention Implication, such example include, but is not limited to cyclopropyl epoxide methyl, cyclopropyl epoxide ethyl, cyclopentyloxymethyl, ring Amyl group epoxide ethyl, cyclohexyl epoxide ethyl, halogenated cyclopropyl epoxide ethyl etc..
Term " cycloalkyl amino aliphatic " or " cycloalkyl amino fatty group " represent that fatty group is one or more The cycloalkylamino group optionally substituted is substituted, and wherein fatty group and cycloalkylamino group have as described in the present invention Implication, such example include, but is not limited to Cyclopropylaminomethyl, cyclopropylaminoethyl, clopentylamino methyl, ring Pentyl amino ethyl, Cyclohexylamino ethyl, halogenated cyclopropyl amino-ethyl etc..
Term " cycloalkyl aliphatic " or " cycloalkyl fatty group " represent that fatty group can be by one or more cycloalkyl Group is substituted, and wherein cycloalkyl and fatty group have implication as described in the present invention, and such example includes, but and unlimited In Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc..
Term " cycloalkyl alkoxy " (" carbocyclylalkoxy ") represents alkoxy base by one or more cycloalkyl (" carbocylic radical ") group is substituted, and wherein cycloalkyl (" carbocylic radical ") group and alkoxy base have and contained as described in the present invention Justice, such example include, but is not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopenta ethyoxyl, cyclohexyl ethoxy Base, cyclohexyl methoxy, cyclopropyl propoxyl group etc..
Term " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably here, all referring to it is monocyclic, Bicyclic or three-ring system, one or more carbon atoms are independent in its middle ring and optionally substituted by hetero atom, the hetero atom With implication as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, but be definitely not virtue The fragrant same clan, only a tie point are connected to other molecules up.One or more ring hydrogen atoms it is independent and optionally by One or more substituents described in the invention are substituted.Some of embodiments are " heterocycle ", " heterocyclic radical ", " heterolipid Ring race " or " heterocycle " group be 3-7 yuan of rings it is monocyclic (1-6 carbon atom and the 1-3 hetero atom selected from N, O, P, S, herein S or P optionally substitutes to obtain such as SO, SO by one or more oxygen atoms2、PO、PO2Group, when described ring is ternary During ring, only one of which hetero atom), or bicyclic (4-9 carbon atom and the 1-3 miscellaneous originals selected from N, O, P, S of 7-10 members Son, optionally substitute to obtain such as SO, SO by one or more oxygen atoms in this S or P2、PO、PO2Group).
Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and close formed group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thioxane base, thiazolidinyl, oxazole alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Homopiperidinyl, glycidyl, azacycloheptyl, oxepane base, thia suberyl, 4- Methoxy-piperidin -1- bases, 1,2,3, 6- tetrahydropyridine -1- bases, oxygen azepineBase, diazaBase, sulphur azepineBase, pyrrolin -1- bases, 2- pyrrolinyls, 3- pyrroles Cough up quinoline base, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxies amyl group, pyrazolinyl, two thiophenes Alkyl, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 1, 2,6- thiadiazine alkane 1,1- dioxo -2- bases, 4- hydroxyl -1,4- azepine phosphine 4- oxide -1- bases, 2- hydroxyls -1- (piperazine - 1- yls) ethyl ketone -4- bases, 2- hydroxyls -1- ((the 4H)-yl of 5,6- dihydro -1,2,4- triazines -1) ethyl ketone -4- bases, 5,6- dihydros -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyls -1- (5,6- dihydropyridines -1 (2H)-yl) ethyl ketone -4- bases, 3- azabicyclos [3.1.0] Hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- methyl -5,6,7,8- tetrahydrochysenes-[1,2,4] three Azoles [1,5-c] pyrimidine -6- bases, 4,5,6,7- tetrahydrochysene isoxazoles [4,3-c] pyridine -5- bases, 3H- indyl 2- oxygen -5- azepines are double Ring [2.2.1] heptane -5- bases, 2- oxygen -5- azabicyclos [2.2.2] octane -5- bases, quinolizine base and N- pyridine radicals urea.Heterocycle The example of group also includes, the pyrimidine two that two carbon atoms are substituted by oxygen atom on 1,1- dioxidothiomorpholinyl and its middle ring Ketone group.And the heterocyclic radical can be substituted or unsubstituted, and wherein substituent can be, but be not limited to, deuterium, oxo (= O), hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, Aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
Term " cycloheteroalkylalkyl " includes the alkyl of heterocyclic radical substitution；Term " heterocyclylalkoxy " substitutes including heterocyclic radical Alkoxy, wherein oxygen atom is connected with the remainder of molecule；Term " heterocyclic radical alkylamino " includes the alkane of heterocyclic radical substitution Amino, wherein nitrogen-atoms are connected with the remainder of molecule.Wherein heterocyclic radical, alkyl, alkoxy and alkylamino have such as this hair Bright described implication, such example include, but is not limited to pyrroles -2- ylmethyls, morpholine -4- bases ethyl, morpholine -4- base second Epoxide, piperazine -4- base oxethyls, piperidin-4-yl ethylamino etc..
Term " heterocyclic radical aliphatic " or " heterocyclic radical fatty group " represent the fatty group of heterocyclic radical substitution, wherein heterocycle Base and fatty group have an implication as described in the present invention, such example include, but is not limited to pyrroles -2- methyl, piperidines - 2- ethyls, piperazine -2- ethyls, piperidines -2- methyl etc..
Term " heterocyclic radical epoxide " includes the heterocyclic radical optionally substituted, as defined herein, is connected on oxygen atom, Wherein oxygen atom is connected with the remainder of molecule, and such example includes, but is not limited to pyrroles -2- epoxides, pyrroles's -3- oxygen Base, piperidines -2- epoxides, piperidines -3- epoxides, piperazine -2- epoxides, piperidines -4- epoxides etc..
Term " heterocyclylamino group " represent amino group substituted by one or two heterocyclyl groups, wherein nitrogen-atoms with The remainder of molecule is connected, and heterocyclic radical has implication as described in the present invention, and such example includes, but and unlimited In pyrroles -2- amino, pyrroles -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine -2- amino, two Pyrroles's -2- amino etc..
Term " heterocyclic radical epoxide alkoxy " represents that alkoxy is substituted by one or more heterocyclic radical epoxide groups, wherein Alkoxy and heterocyclic radical epoxide group have implication as described in the present invention, and such example includes, but is not limited to, and pyrroles- 2- Oxymethoxies, pyrroles's -3- epoxides ethyoxyl, piperidines -2- epoxides ethyoxyl, piperidines -3- epoxides ethyoxyl, piperazine -2- oxygen Ylmethoxy, piperidines -4- epoxide ethyoxyls etc..
Term " heterocyclic radical epoxide aliphatic " or " heterocyclic radical epoxide fatty group " represent that fatty group is one or more Heterocyclic radical epoxide group is substituted, and wherein fatty group and heterocyclic radical epoxide group has implication as described in the present invention, so Example include, but is not limited to, pyrroles's-2- epoxides methyl, piperazine-3- epoxides ethyl, piperazine-2- epoxides ethyl, morpholine -2- Epoxide methyl, piperidines -2- epoxide ethyls etc..
Term " heterocyclylamino group aliphatic " or " heterocyclylamino group fatty group " represent that fatty group is one or more Heterocyclylamino group group is substituted, and wherein fatty group and heterocyclylamino group group has implication as described in the present invention, so Example include, but is not limited to pyrroles -2- amino methyls, piperazine -3- amino-ethyls, piperazine -2- amino-ethyls, piperidines -2- Amino-ethyl, morpholine -2-amino methyl etc..
Term " hetero atom " represents one or more O, S, N, P and Si atoms, includes the form of any oxidation state of N, S and P； The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N (such as 3,4- bis- N in hydrogen -2H- pyrrole radicals), NH (such as NH in pyrrolidinyl) or NR (such as NR in the pyrrolidinyl of N- substitutions).
Term " halogen " refers to F, Cl, Br or I.
Used term is " undersaturated " in the present invention represents that structure division contains one or more degrees of unsaturation.
Term " alkoxy " used in the present invention, is related to alkyl, as defined herein, is connected by oxygen atom Onto main carbochain, such example includes, but is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy etc..And institute It can be substituted or unsubstituted to state alkoxy, and wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyanogen Base, alkoxy, alkyl, alkenyl, alkynyl, sulfydryl, nitro etc..
Term " alkoxy of hydroxyl substitution " represents that alkoxy base is substituted by one or more oh groups, wherein alkane Epoxide has implication as described in the present invention, and such example includes, but is not limited to hydroxyl methoxyl group, 2- hydroxyl-oxethyls, 2- Hydroxy propyloxy group, 2- hydroxyl isopropyl oxygen etc..
Term " aminoalkoxy " represents that alkoxy base is substituted by one or more amino groups, and wherein alkoxy has There is implication as described in the present invention, such example includes, but is not limited to ammonia methoxyl group, 2- amino ethoxies, 2- aminopropans Epoxide, 2- amino isopropoxies etc..
Term " azido alkoxy " represents that alkoxy is substituted by one or more azido groups, and wherein alkoxy has Have an implication as described in the present invention, such example include, but is not limited to 2- nitrine base oxethyl, 3- azidos propoxyl group, 2- azido propoxyl group etc..
Term " alkyloxy-alkoxy " represents that alkoxy base is substituted by one or more alkoxy bases, wherein alcoxyl Base group has implication as described in the present invention, and such example includes, but is not limited to methoxymethoxy, methoxyl group ethoxy Base, (ethoxymethyl) epoxide, ethoxy ethoxy, ethoxy-c epoxide etc..
Term " alkoxy aliphatic " or " alkoxy fatty group " represent fatty group by one or more alkoxy bases Group is substituted, and wherein fatty group and alkoxy base have implication as described in the present invention, and such example includes, but not It is limited to methoxy, ethoxyl methyl, ethoxyethyl group, ethoxy-c alkenyl etc..
Term " alkylamino aliphatic " or " alkylamino fatty group " represent fatty group by one or more alkylamino bases Group is substituted, and wherein fatty group and alkylamino radicals have implication as described in the present invention, and such example includes, but not It is limited to dimethylaminoethyl, methylaminoethyl, Diethylaminomethyl, diethyllaminoethyl etc..
Term " alkylthio group aliphatic " or " alkylthio group fatty group " represent fatty group by one or more alkylthio group bases Group is substituted, and wherein fatty group and alkylthio radicals have implication as described in the present invention, and such example includes, but not It is limited to methylmercaptoethyl, methylthio, ethylthio-ethyl, methyl mercapto acrylic etc..
Term " haloalkyl ", " haloalkenyl group " and " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy can be by one The situation that individual or multiple halogen atoms are substituted, such example include, but is not limited to the chloro- vinyl of trifluoromethyl, 2-, three Fluorine methoxyl group etc..
Term " aryl " can be used alone or the big portion as " aralkyl ", " aralkoxy " or " aryloxy alkyl " Point, monocyclic, bicyclic and three rings the carbocyclic ring system containing 6-14 yuan of rings altogether is represented, wherein, at least one member ring systems are aromatic series , each of which member ring systems include 3-7 yuan of rings, and only an attachment point is connected with the remainder of molecule.Term " virtue Base " can be exchanged with term " aromatic rings " and used, as aromatic rings can include phenyl, naphthyl and anthryl.And the aryl can To be substituted or unsubstituted, wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyano group, aryl, miscellaneous Aryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, alkoxy, the hydroxyl of hydroxyl substitution Base substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (= O)-, hydroxyl substitution alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
Term " aromatic yl aliphat " or " aromatic yl aliphat base " represent the virtue that fatty group is optionally substituted by one or more Base group is substituted, and wherein fatty group and aromatic yl group have implication as described in the present invention, and such example includes, but simultaneously It is not limited to phenethyl, benzyl, to methylphenylethyl, styryl etc..
Term " aryloxy group " includes the aryl optionally substituted, as defined herein, is connected on oxygen atom, and by Oxygen atom is connected with molecule remainder, and wherein aromatic yl group has implication as described in the present invention, and such example includes, but It is not limited to phenoxy group, toloxyl, ethylbenzene epoxide etc..
Term " fragrant amino " represents that the aromatic yl group that amino group is optionally substituted by one or two substitutes, wherein aryl With implication as described in the present invention, such example includes, but is not limited to phenyl amino, p-fluorophenyl amino, diphenyl Amino, xylyl amino, di-p-tolyl amino etc..
Term " aryloxy group alkyl epoxide " represents that alkoxy is substituted by the aryloxy group that one or more optionally substitutes, its Middle alkoxy and aryloxy group have implication as described in the present invention, and such example includes, but is not limited to phenoxy group first Epoxide, phenoxy group, Phenoxypropoxy etc..
Term " aryloxy group aliphatic " or " aryloxy group fatty group " represent fatty group by one or more optionally substitutions Aryloxy group substituted, wherein aryloxy group and fatty group have implication as described in the present invention, and such example includes, But it is not limited to phenoxymethyl, Phenoxyethyl, tolyloxyethyl, phenoxy propyl etc..
Term " fragrant amino aliphatic " or " fragrant amino fatty group " represent fatty group by one or more optional Substituted fragrant amino group is substituted, and wherein fragrant amino and fatty group have implication as described in the present invention, such example Include, but is not limited to phenylaminomethyl, phenylaminoethyl, toluidino ethyl, phenylamino propyl group, phenylamino pi-allyl etc..
Term " alkoxy aryl " represents that alkoxy base is substituted by the aryl that one or more optionally substitutes, wherein virtue Base and alkoxy have implication of the present invention, and such example includes, but is not limited to Phenylmethoxy, phenyl ethoxy Base, p-methylphenyl methoxyl group, phenyl-propoxy etc..
Term " aryl alkane amino " represents that alkylamino radicals are substituted by the aromatic yl group that one or more optionally substitutes, its Middle aryl and alkylamino have implication of the present invention, and such example includes, but is not limited to phenyl methylamino, phenyl second Amino, phenylpropylamino, p-methylphenyl methylamino etc..
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Represent that monocyclic, the bicyclic and three-ring system containing 5-14 yuan of rings, wherein at least one member ring systems are aromatic altogether, and at least one Individual member ring systems include one or more hetero atoms, and wherein hetero atom has implication of the present invention, each of which member ring systems Comprising 3-7 yuan of rings, and only an attachment point is connected with molecule remainder.Term " heteroaryl " can be with term " heteroaromatic " Or " heteroaromatics " is exchanged and used.And the heteroaryl can be substituted or unsubstituted, and wherein substituent can be, But it is not limited to, it is deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, miscellaneous Ring group, sulfydryl, nitro, aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkane Base-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)2-, carboxyl substitution Alkoxy etc..
Other embodiment is, heteroaromatic includes following monocyclic, but it is monocyclic to be not limited to these：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazoles Base, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- Pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazinyl (such as 3- pyridazinyls), 2- thiophenes Oxazolyl, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazolyls), 2- thiophene Base, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- Oxadiazolyl, 1,2,3- triazolyls, 1,2,3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, 1,3, 4- thiadiazoles -2- bases, pyrazinyl, pyrazine -2- bases, cyanuro 1,3,5, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyrrole Pyridine -6- bases；Also include following bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, Indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls) and isoquinolyl (such as 1- Isoquinolyl, 3- isoquinolyls or 4- isoquinolyls).
Term " heteroaryl epoxide " includes the heteroaryl optionally substituted, as defined herein, is connected on oxygen atom, And it is connected by oxygen atom with molecule remainder, wherein heteroaryl groups have implication as described in the present invention, such reality Example includes, but is not limited to pyridine -2- epoxides, thiazole -2- epoxides, imidazoles -2- epoxides, pyrimidine -2- epoxides etc..
Term " heteroaryl epoxide aliphatic " or " heteroaryl epoxide fatty group " represent that fatty group is one or more The heteroaryl epoxide group optionally substituted is substituted, and wherein fatty group and heteroaryl epoxide group have as described in the present invention Implication, such example include, but is not limited to pyridine -2- epoxides ethyl, thiazole -2- epoxides methyl, imidazoles -2- epoxide second Base, pyrimidine -2- epoxide propyl group etc..
Term " sulfonyl ", no matter it is single use or is used in conjunction with other terms such as " alkyl sulphonyl ", respectively table Show the group-SO of divalence2-。
Term " alkyl sulphonyl " refers to alkyl-substituted sulphonyl groups, forms alkyl sulphonyl (- SO2Alkyl, such as- SO2CH3)。
Term " sulfonamides ", " amino-sulfonyl " and " sulfamoyl " represents the sulphonyl groups of amino substitution, forms ammonia Sulfonyl (- SO2NH2)。
Term " carboxyl ", no matter it is single use or (such as " carboxyalkyl "), expression-CO is used in conjunction with other terms2H；
Term " carbonyl ", no matter it is single use or (such as " amino carbonyl " or " acyloxy ") is used in conjunction with other terms, Represent-(C=O)-.
Term " alkoxy of carboxyl substitution " represents that alkoxy base is substituted by one or more carboxylic groups, wherein alkane Epoxide and carboxylic group have implication as described in the present invention, and such example includes, but is not limited to Carboxvmethoxv, carboxyl Ethyoxyl etc..
Term " aralkyl " includes the alkyl group of aryl substitution.Some of embodiments are that aromatic alkyl group refers to " aralkyl of lower level " group, i.e. aromatic yl group are connected to C1-6Alkyl group on.Other embodiment is aralkyl Base group refers to contain C1-3Alkyl " benzene alkylene ".Wherein instantiation includes benzyl, diphenyl methyl, phenethyl.Aralkyl On aryl further can be substituted by halogen, alkyl, alkoxy, haloalkyl and halogenated alkoxy.
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of divalence.Some of them are implemented Scheme is that alkylthio group is the C of lower level1-3Alkylthio group, such example include, but is not limited to methyl mercapto (CH3S-)。
Term " halogenated alkylthio " includes C1-10Haloalkyl be connected on bivalent sulfur atom.Some of embodiments It is that halogenated alkylthio is the C of lower level1-3Halogenated alkylthio, such example include, but is not limited to trifluoromethylthio.
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amine groups separately Substituted by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl connects The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C1-3Lower level alkane Base amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but simultaneously It is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " alkylamino halogenated alkoxy " represents that halogenated alkoxy is substituted by one or more alkylamino radicals, wherein Halogenated alkoxy and alkylamino radicals have implication as described in the present invention, and such example includes, but is not limited to methylamino Difluoromethoxy, ethylamino trifluoromethoxy etc..
Term " heteroaryl amino " represents that amine groups are substituted by one or two heteroaryl, and wherein heteroaryl has this hair Bright described implication, such example include, but is not limited to N- thienyl amino etc..Some of embodiments are heteroaryls Hetero-aromatic ring on base amino can be further substituted.
Term " heteroaryl aliphatic " or " heteroarylaliphatic " represent fatty group by one or more heteroaryl institutes Substitution, wherein heteroaryl and fatty group have an implication of the present invention, such example include, but is not limited to thiophene- 2- acrylic, pyridine -4- ethyls, imidazoles -2- methyl, furans -2- ethyls, indoles -3- methyl etc..
Term " heteroaryl alkyl " represents that alkyl group is substituted by one or more heteroaryls, wherein heteroaryl and alkyl Group has implication of the present invention, and such example includes, but is not limited to imidazoles -2- methyl, furans -2- ethyls, Yin Diindyl -3- methyl etc..
Term " heteroarylalkylamino " is connected to other including the heteroarylalkyl group containing nitrogen-atoms by nitrogen-atoms On group, wherein heteroaryl alkyl has implication as described in the present invention, and such example includes, but is not limited to pyridine -2- Base methylamino, thiazol-2-yl ethylamino, imidazoles -2- bases ethylamino, the amino of pyrimidine -2-base third, pyrimidine -2-base methylamino etc..
Term " aminoalkyl " includes the C substituted by one or more amino1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the C substituted by one or more amino groups1-6" aminoalkyl of lower level ", this The example of sample includes, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " alkylaminoalkyl group " includes the alkyl group substituted by alkylamino.Some of embodiments are alkyl Aminoalkyl is C1-6The alkyl amino alkyl of lower level.Other embodiment is that alkylaminoalkyl group is C1-3Lower level Alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group substitute, and such example includes, but simultaneously It is not limited to, N- Methylaminomethyls, N, N- dimethyl aminoethyls, N, N- diethylamino methyl etc..
Term " carboxyalkyl " includes the C that can be substituted by one or more carboxyls1-10Straight or branched alkyl, so Example include, but is not limited to, carboxymethyl, carboxylic propyl group etc..
Term " aryloxy group " includes the aryl that optionally substitutes, as defined herein as be connected on oxygen atom, and And be connected by oxygen atom with molecule remainder, such example includes, but is not limited to phenoxy group etc..
Term " heteroarylalkoxy " is connected to other including the heteroarylalkyl group containing oxygen atom by oxygen atom On group, wherein heteroaryl alkyl has implication as described in the present invention, and such example includes, but is not limited to pyridine -2- Ylmethoxy, thiazol-2-yl ethyoxyl, imidazoles -2- base oxethyls, pyrimidine -2-base propoxyl group, pyrimidine -2-base methoxyl group etc..
Term " cycloalkyl-alkyl " represents the alkyl group of the cycloalkyl substitution optionally substituted, and such example includes, but It is not limited to cyclohexyl methyl.Described cycloalkyl further can be substituted by deuterium, halogen, alkyl, alkoxy and hydroxyl.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " represent saturation or undersaturated and member ring systems Or bridged-ring system, be related to non-aromatic and ring or bridged-ring system, as shown in formula (a1), i.e. ring A1 and ring A2 shares a key, One alkane chain or a miscellaneous alkane chain, wherein j are 0,1,2,3 or 4.Such system can include independent or conjugation unsaturation State, but its core texture does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).Fusion is double Each ring in ring is either carbocyclic ring or is miscellaneous alicyclic, and such example includes, but is not limited to, and hexahydro-furans is simultaneously [3,2-b] furans, 2,3,3a, 4,7,7a- hexahydro -1H- indenes, 7- azabicyclos [2.3.0] heptane, condensed-bicyclic [3.3.0] are pungent Alkane, condensed-bicyclic [3.1.0] hexane, bicyclic [2.2.1] heptane, 2- azabicyclos [2.2.1] heptane, 1,2,3,4,4a, 5,8, 8a- octahydro naphthalenes, these are included within the system of condensed-bicyclic or bridged ring.And the condensed-bicyclic base can be substitution or Unsubstituted, wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, miscellaneous Aryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, alkoxy, the hydroxyl of hydroxyl substitution Base substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (= O)-, hydroxyl substitution alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
Term " condensing miscellaneous bicyclic group " represents saturation or undersaturated and member ring systems or bridged-ring system, is related to non-aromatic And member ring systems or bridged-ring system.Such system can include independent or conjugation undersaturated condition, but its core texture is not Include aromatic rings or heteroaromatic (but aromatic series can be as substituent thereon).And at least one member ring systems include one or Multiple hetero atoms, each of which member ring systems include 3-7 yuan of rings, i.e. the 1-3 comprising 1-6 carbon atom and selected from N, O, P, S is individual Hetero atom, optionally substitute to obtain such as SO, SO by one or more oxygen atoms in this S or P2、PO、PO2Group, so Example include, but is not limited to hexahydro-furans simultaneously [3.2-b] furans, 6- azabicyclos [3.2.0] heptane, 2- azabicyclos [3.1.0] heptane, 3- azabicyclos [3.1.0] heptane, 7- azabicyclos [2.3.0] heptane, 2- azabicyclos [2.2.1] heptane Deng.And the miscellaneous bicyclic group of fusion can be substituted or unsubstituted, and wherein substituent can be, but be not limited to, deuterium, oxygen Generation (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, mercapto Base, nitro, aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (= O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)2-, carboxyl substitution alkoxy Etc..
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " represent a ring originating from special on another ring Ring-type carbon.For example, ring A and ring B share a carbon atom in the member ring systems of two saturations, then it is referred to as " loop coil ".Loop coil Each ring of the inside is either carbocyclic ring or is miscellaneous alicyclic.Such example includes, but is not limited to 2,7- diaza spiros [4.4] nonane -2- bases, 7- oxygen -2- azaspiros [4.5] decane -2- bases, 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4] heptane -5- bases, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyl -5- nitrogen Miscellaneous spiral shell [2.4] heptane -5- bases etc..And the spiral shell bicyclic group can be substituted or unsubstituted, and wherein substituent can be, but Be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, Alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (= O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)2-, carboxyl Substituted alkoxy etc..
Term " sub- spiral shell bicyclic group " represents that there are spiral shell bicyclic group system two tie points to be connected with molecule remainder, wherein Spiral shell bicyclic group has implication as described in the present invention.
Term " the miscellaneous bicyclic group of spiral shell " represents a ring originating from particularly ring-shaped carbon on another ring.For example, such as institute above Description, ring A and ring B share a carbon atom in the member ring systems of two saturations, then are referred to as " loop coil ".And at least one ring System includes one or more hetero atoms, and each of which member ring systems include 3-7 yuan of rings, i.e., comprising 1-6 carbon atom and are selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain such as SO, SO by one or more oxygen atoms in this S or P2、PO、 PO2Group, such example include, but is not limited to 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane - 5- bases, 5- azaspiros [2.4] heptane -5- bases, 7- hydroxyl -5- azaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4] heptane - 6- bases, Isosorbide-5-Nitrae-dioxy -7- azaspiros [4.4] nonane -8- bases etc..And the miscellaneous bicyclic group of spiral shell can be substitution or unsubstituted , wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkane Epoxide, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, hydroxyl substitution Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, hydroxyl Substituted alkyl-S (=O)2-, the alkoxy etc. of carboxyl substitution.
A-amino acid group of the present invention is removed the group that hydroxyl formed by the carboxyl of a-amino acid, its with X or X ' connections, and the a-amino acid group optionally can be selected from deuterium, F, Cl, Br, I, hydroxyl or cyano group by one or more Substituent substituted.Such as
As described in the present invention, substituent draws a key connection to the member ring systems formed on the ring at center (such as formula (a) institute Show) represent substituent (R5a)fIt can be substituted any commutable position on ring.For example, formula (a) represents W1 rings, W2 rings Or any position that may be substituted can be substituted on W rings.
As described in the present invention, there are two tie points to be connected with other groups in member ring systems, as shown in formula (b), represent Ring W3 E ends and E' ends can be connected with other groups, and in the present invention, the group that E and E' both ends are connected is can With exchange.
As described in the present invention, dotted line key represents a double bond or singly-bound inside member ring systems.For example, the structure of formula (c) Represent any one structure elected inside formula (d).
Unless otherwise indicated, structural formula described in the invention includes all isomeric forms, (such as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism))：Such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and (Z), the rotamer of (E).Therefore, the single three-dimensional chemical isomer of compound of the invention or its is right Reflect isomers, diastereoisomer, or the mixture of geometric isomer (or rotamer) and belong to the scope of the present invention.
In addition, it is necessary to explanation, unless otherwise explicitly pointing out, the describing mode used in the whole text herein " each ... independently be ", " ... independently be " and " ... be each independently " can exchange, and all should be interpreted broadly, and it both can be with Refer in different groups, do not influence mutually, can also represent identical between expressed specific option between same-sign Group in, do not influenceed mutually between expressed specific option between same-sign, with R9Exemplified by, structural formula "-U- (CR9R9a)t-R12" and structural formula "-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t- R12" R between the two9Specific option it is unaffected from each other, meanwhile, in same chemical formula "-[U- (CR9R9a)t-N(R10)- (CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12" in, multiple R9Specific option it is unaffected from each other.
Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can have phenyl ester class, aliphatic as pro-drug in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs：Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by passing through oxidation, reduction, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker,Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.The compound of the present invention can include asymmetric center or chiral centre, therefore Different stereoisomers be present.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture, constitute a part of the invention.Very More organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description optics During reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for The symbol of compound linearly polarized light rotation is named, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to compound It is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific three-dimensional Isomers can be that enantiomer, the mixture of isomers are commonly referred to as enantiomeric mixture.50:50 mixture of enantiomers It is referred to as racemic mixture or racemic modification, this may cause do not have stereoselectivity or stereotaxis in chemical reaction process Property.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack optics Activity.
Term " dynamic isomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Mutual inversion of phases is built by low energy.Such as proton tautomer (i.e. prototropic dynamic isomer) includes migrating by proton Change, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) dynamic isomer includes Recombinate the change of bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al., Described in J.Pharmaceutical Sciences, 66,1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed Include, but is not limited to, reacted with amino group the inorganic acid salt to be formed have hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by other method such as ion-exchange described on books document.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3- phenylpropionic acids salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4's Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble divides Scattered product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium etc..Pharmaceutically Acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation Thing, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- are (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl etc..For protection group Group's in general description 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。
It should be noted that the term " suppressing HCV virus albumen " in the present invention should be interpreted broadly, it both includes suppressing The expression of HCV virus albumen, also include the activity level for suppressing HCV virus albumen, viral assembling and emission levels.Its In, HCV protein expression levels include but is not limited to：The translation skill of viral protein gene, the posttranslational modification of albumen are horizontal, sub Levels of replication for inhereditary material, etc..
The description of the compounds of this invention
Spiro-compound and its pharmaceutical preparation of the present invention, can effectively suppress HCV infection, can especially suppress HCV The activity of NS5A albumen.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound or formula (I) shown in formula (I) Stereoisomer, geometrical isomerism
Body, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or preceding Medicine,
Wherein, each A and A ' independently be a key, alkylidene, alkenylene, cycloalkylidene, sub- Heterocyclylalkyl ,- (CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)- (CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A and A ' It independently is following group：
Wherein, each X1Or X2It independently is O, S, NR6Or CR7R7a；
X4For (CR7R7a)n、-Y1=N-, O, S or NR6;
W is carbocylic radical or heterocyclic radical；
Each Y1And Y2It independently is N or CR7；
Z is-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b- or-(CH2)a-O-(CH2)b-；
Wherein each a and b independently is 0,1,2 or 3；
Each c independently is 1 or 2；
Each d independently is 1 or 2；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
F is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
Each e independently is 0,1,2,3 or 4；
Each X and X ' independently are N or CR7；
Each Y and Y ' independently are H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, α-ammonia The optical isomer of base acid groups or a-amino acid group, or each Y and Y ' independently are following construction unit：-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12；
Each U independently be-C (=O)-,-C (=S)-,-S (=O)-or-S (=O)2-；
Each t independently is 0,1,2,3 or 4；
Each k independently is 0,1 or 2；
Each R1、R2、R3And R4It independently is H, deuterium, alkyl, miscellaneous alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl or virtue Base, or R1、R23-8 circle heterocycles or 3-8 members carbocyclic ring, C are formed with X-CH5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic Or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4And X '-CH form 3-8 circle heterocycles or carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense it is miscellaneous it is bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；
Each R5It independently is H, deuterium, hydroxyl, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkane Epoxide, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (= O)r- or amino-sulfonyl；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13、-N(R13)C(= O)-R13、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkoxy, aryl, heteroaryl Base, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, alkyl Sulfonyl, alkyloxysulfonyl, alkyl sulphinyl, alkyl sulphonyl epoxide, alkyl sulphinyl epoxide, heterocyclic radical alkylamino Or aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-, aliphatic, halogenated aliphatic, hydroxy aliphatic Race, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, Heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyl oxy aliphatic, fragrant ammonia Base aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocyclic radical or carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkoxy, aryl, heteroaryl Base, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, alkyl Sulfonyl, alkyloxysulfonyl, alkyl sulphinyl, alkyl sulphonyl epoxide, alkyl sulphinyl epoxide, heterocyclic radical alkylamino Or aryloxy group；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, aliphatic, miscellaneous alkyl, halogenated aliphatic, hydroxyl group aliphatic, ammonia Base aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle Base aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyl oxy aliphatic, fragrant amino fat Fat race, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocyclic radical or carbocylic radical；
Each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, miscellaneous alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O )r-, alkyl-S (=O)rO-, alkyl-S (=O)r- or amino-sulfonyl；
Each R9、R9a、R10And R11It independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Alkyl, haloalkyl, hydroxy alkyl, heteroaryl alkyl, cycloheteroalkylalkyl or cycloalkyl-alkyl；
Each R12It independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC (=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、 R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl, miscellaneous alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl or aralkyl；
Or R11、R124-7 yuan of rings can be randomly formed with the atom being attached thereto；With
With each R13And R13aIt independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl Base；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aSubstituted or non-substituted 3-8 can be randomly formed with nitrogen-atoms Yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
The following group of each of which:Alkylidene, alkenylene, cycloalkylidene, sub- Heterocyclylalkyl ,-(CR8R8a)n-O- (CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C (=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O- (CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)- (CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12、-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-O-(CR9R9a)t-R12、NR6、CR7R7a、CR7、-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)- (CH2)b-、-(CH2)a-O-(CH2)b-、R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-, alkyl-OC (=O)-, alkyl- C (=O)-, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-、R13R13aNS(=O)-、R13OS(=O)-、R13S(= O)-, alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxies, R13S (=O)-alkoxy, R13R13aN-C (=O)-alkylamino, alkyl, miscellaneous alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, α-ammonia Base acid, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12The miscellaneous bicyclic, alkoxy of spiral shell, aliphatic, halo fat Fat race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, Heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide aliphatic, cycloalkyloxy group Base aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, haloalkyl, alkenyl, alkynyl, virtue Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Base alkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, heterocyclic radical alkylamino or aryloxy group can optionally by One or more is selected from deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, alkene Base, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, alkoxy, the hydroxyl of hydroxyl substitution Substituted alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substitution alkyl-S (=O)-, Alkyl-the S (=O) of hydroxyl substitution2- or the substituent of Carboxyalkoxy substituted.
In some of these embodiments, wherein W is C3-8Carbocylic radical or C2-10Heterocyclic radical.
In some of these embodiments, whereinConstruction unit is selected from following subformula：
Wherein, each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each X6It independently is CR7R7a、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each f independently is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
E is 0,1,2,3 or 4；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkane Acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl Sulfonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitre Base, C1-6Alkylamino, C3-10Cycloalkyl or C6-10Aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
With each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Virtue Base C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical.
In some of these embodiments, wherein,Construction unit is selected from following subformula：
Wherein, X6For O, S ,-Y1=N-、NR6Or CR7R7a;
Each Y1It independently is N or CH；
Each f independently is 0,1,2,3 or 4；
Each R5aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkane Acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl Sulfonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro Or C1-6Alkylamino；
Each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alcoxyl Base C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Virtue Base C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkyl, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclylamino group C1-6Alkyl, C3-10Cycloalkanes Base amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-8Carbocylic radical.
In some of these embodiments, wherein each A and A ' independently are key, a C1-6Alkylidene, C2-6Alkenylene, C3-8Cycloalkylidene, C2-10Sub- Heterocyclylalkyl ,-(CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)- C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(= O)-(CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A And A ' independently is following group：
Wherein, each X1And X2It independently is O, S, NR6Or CR7R7a；
Each Y1And Y2It independently is N or CR7；
Z is-(CH2)a-、-CH=CH-、-N=CH-、-(CH2)a-N(R5)-(CH2)b- or-(CH2)a-O-(CH2)b-；
Each a and b independently are 0,1,2 or 3；
Each c independently is 1 or 2；
Each d independently is 1 or 2；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkane Base, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclic radical ammonia Base C1-6Alkyl, C3-10Cycloalkyl amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、-C(=O) NR13R13a、-OC(=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(= O)-R13a、R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13aR13N-C1-6Alkyl, R13S(=O)-C1-6Alkane Base, R13R13aN-C(=O)-C1-6Alkyl, R13aR13N-C1-6Alkoxy, R13S(=O)-C1-6Alkoxy, R13R13aN-C(=O)-C1-6 Alkoxy, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxy, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6 Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Aryl C1-6Alkyl, C6-10Fragrant amino, C1-9Heteroaryl amino or C6-10Aryloxy group；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C1-6Haloalkyl, C1-6Hydroxyl Alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C3-10Cycloalkyl C1-6Alkyl, C6-10Aryloxy group C1-6Alkyl, C2-10Heterocyclic radical epoxide C1-6Alkyl, C3-10Cycloalkyl oxy C1-6Alkyl, C6-10Fragrant amino C1-6Alkyl, C2-10Heterocyclylamino group C1-6Alkyl, C3-10Cycloalkanes Base amino C1-6Alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-8Carbocylic radical；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
With each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-、C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (= O)r- or amino-sulfonyl.
In some of these embodiments, wherein each A and A ' independently are key ,-a CH2-、-(CH2)2-、-CH= CH-、-CH=CH-CH2-、-N(R5)-、-C(=O)-、-C(=S)-、-C(=O)-O-、-C(=O)N(R5)-、-OC(=O)N(R5)-、- OC(=O)O-、-N(R5)C(=O)N(R5)-、-(R5)N-S(=O)2-、-S(=O)2-、-OS(=O)2-、-(R5)N-S(=O)-、-S(= O)-,-OS (=O)-, or each A and A ' independently be following group：
Wherein, X1For O or S；
Each Y1It independently is N or CH；
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alcoxyl Base C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
Each R6aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R13aR13N-、C1-6Alcoxyl Base, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, sulfydryl or nitro；
With each R13And R13aIt independently is as H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10 Aryl, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan with nitrogen-atoms To be randomly formed, substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
In some of these embodiments, wherein, each R1、R2、R3And R4It independently is selected from H, deuterium, C1-8Alkyl, C1-8It is miscellaneous Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-9Heteroaryl or C6-10Aryl, or R1、R2Appoint with X-CH Meaning ground forms 3-8 circle heterocycles or 3-8 members carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous It is bicyclic；R3、R4And X '-CH are randomly formed 3-8 circle heterocycles or 3-8 members carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense it is miscellaneous it is bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2And X-CH, or R3、R4And to be randomly formed 3-8 members miscellaneous by X '-CH Ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2It is selected from the Y-X-CH heterocycles formed or condensed ring or spiro ring system Following subformula：
Wherein, each R15It independently is H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl, C1-3Alcoxyl Base, C1-3Alkylamino, C1-3Alkylthio group, C6-10Fragrant amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryloxy, C1-9Heteroaryl C1-3Alkyl or C2-10Heterocyclic radical；
Each R6It independently is hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
With each n1And n2It independently is 1,2,3 or 4.
In other embodiments, wherein R3、R4And the heterocycles that are formed of Y '-X '-CH or condensed ring or spiro ring system choosing From following subformula：
Wherein, each R15It independently is H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl, C1-3Alcoxyl Base, C1-3Alkylamino, C1-3Alkylthio group, C6-10Fragrant amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryloxy, C1-9Heteroaryl C1-3Alkyl or C2-10Heterocyclic radical；
Each R6It independently is hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocyclic radical or C3-8Carbocylic radical；
With each n1And n2It independently is 1,2,3 or 4.
In some of these embodiments, it has such as formula（II）Shown structure：
Wherein,Construction unit is following subformula：
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CH2)e；
E is 0,1,2,3 or 4；
Each f independently is 0,1,2,3 or 4
Each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each X6It independently is CH2、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each A and A ' independently are key, a C1-6Alkylidene, C2-6Alkenylene, C3-8Cycloalkylidene, C2-10Sub- heterocycle alkane Base ,-(CR8R8a)n-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-N(R5)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-N(R5)- (CR8R8a)p-、-(CR8R8a)n-C(=O)-O-(CR8R8a)p-、-(CR8R8a)n-N(R5)-S(=O)r-N(R5)-(CR8R8a)p-、- (CR8R8a)n-S(=O)r-(CR8R8a)p-、-(CR8R8a)n-S(=O)r-O-(CR8R8a)p-、-(CR8R8a)n-C(=O)- (CR8R8a)p-、-(CR8R8a)n-C(=S)-(CR8R8a)p-、-(CR8R8a)n-N(R5)-C(=O)-O-(CR8R8a)p-, or each A and A ' It independently is following group：
Each R5It independently is H, deuterium, hydroxyl, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, amino first Acyl group, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)r- or amino-sulfonyl；
Each R5aAnd R6aIt independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6 Alkyl sulphonyl epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, Nitro, C1-6Alkylamino, C3-10Cycloalkyl or C6-10Aryloxy group；
Each R6It independently is hydrogen, deuterium, R13R13aNC(=O)-、R13OC(=O)-、R13C(=O)-、R13R13aNS(=O)-、R13OS (=O)-、R13S(=O)-、R13R13aNS(=O)2-、R13OS(=O)2-、R13S(=O)2-、C1-6Aliphatic, C1-6Alkoxy C1-6Fat Race, C1-6Alkylamino C1-6Aliphatic, C6-10Aryl C1-6Aliphatic, C1-9Heteroaryl C1-6Aliphatic, C2-10Heterocyclic radical C1-6Fat Race, C3-10Cycloalkyl C1-6Aliphatic, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
Each R7And R7aIt independently is H, deuterium, F, Cl, Br, I, C1-6Aliphatic, C2-6Miscellaneous alkyl, C1-6Alkoxy C1-6Fat Race, C1-6Alkylamino C1-6Aliphatic, C6-10Aryl C1-6Aliphatic, C2-10Heterocyclic radical C1-6Aliphatic, C3-10Cycloalkyl C1-6Fat Race, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical or C3-10Carbocylic radical；
Each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10 Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl-OC (= O)-、C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O )r- or amino-sulfonyl；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
Each n independently is 0,1,2 or 3；
Each p independently is 0,1,2 or 3；
Each r independently is 0,1 or 2；
With each Y4And Y4' it independently is a key, O, S ,-(CH2)n-、-CH=CH-、-S(=O)r-、-CH2O-、-CH2S-、- CF2-、-CHR5a-、-CR5aR6a、-CH2S(=O)rOr-CH2N(R6)-。
In other embodiments, it has such as formula（III）Shown structure：
In other embodiments, it has such as formula（IV）Shown structure：
Wherein, each Q2And Q3It independently is O, S, C (=O), NR6Or CR7R7a。
In other embodiments, it has such as formula（V）Shown structure：
Wherein e is 1,2,3 or 4.
In some of these embodiments, wherein, each Y and Y ' independently are a-amino acid group.
In other embodiments, wherein a-amino acid group is selected from isoleucine, leucine, lysine, egg ammonia Acid, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, dried meat ammonia Acid, serine, to tyrosine, arginine, histidine, cysteine, glycine, methyl amimoacetic acid, N, N- dimethylglycines, Kosé Propylhomoserin, norvaline, nor-leucine, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, a junket The group that propylhomoserin or hydroxy-proline are formed.
In other embodiments, wherein the a-amino acid in the a-amino acid group is D configurations.
In other embodiments, wherein the a-amino acid in the a-amino acid group is L-configuration.
In some of these embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)-(CR9R9a)t-U- (CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R11)-(CR9R9a)t- R12。
In other embodiments, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-C(=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-C(=O)-R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C(=O)- R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-C(=O)-O-R13。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C(=O)- O-R13。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k- U-(CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)-(CR9R9a)t-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-C(=O)-(CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-U- (CR9R9a)t-O-(CR9R9a)t-R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-O-(CR9R9a)t- R12。
In other embodiments, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-R12, wherein R11、R124-7 yuan of rings can be formed with the atom being attached thereto.
In other embodiments, wherein, each R9、R9a、R10And R11It independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkane Base, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl Base alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
Each R12It independently is R13aR13N-、-C(=O)R13、-C(=S)R13、-C(=O)-O-R13、-C(=O)NR13R13a、-OC (=O)NR13R13a、-OC(=O)OR13、-N(R13)C(=O)NR13R13a、-N(R13)C(=O)OR13a、-N(R13)C(=O)-R13a、 R13R13aN-S(=O)2-、R13S(=O)2-、R13S(=O)2N(R13a)-、R13OS(=O)2-、C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Ring Alkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
Each R13And R13aIt independently is H, deuterium, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue Base, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan be with nitrogen-atoms It is randomly formed that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic；
Each t independently is 0,1,2,3 or 4；
0,1 or 2 independently are with each k.
In other embodiments, wherein, each R9、R9a、R10And R11It independently is H, deuterium, methyl, ethyl, isopropyl Base, cyclohexyl, isobutyl group or phenyl；
Each R12It independently is-C (=O) R13、-C(=O)-O-R13、-C(=O)NR13R13a, methyl, ethyl, propyl group, phenyl, ring Hexyl, morpholinyl or piperidyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
With each R13And R13aIt independently is H, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl.
In other embodiments, it has such as formula（VI）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（VII）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-3Hydroxy alkyl, methyl, ethyl, isopropyl, isobutyl group, tertiary fourth Base, pi-allyl, propargyl, trifluoroethyl, phenyl, pyranose, morpholinyl, benzyl, piperazinyl, cyclopenta, cyclopropyl, cyclohexyl Or C1-9Heteroaryl；
Wherein described C1-3Hydroxy alkyl, methyl, ethyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, propargyl, three Fluoro ethyl, phenyl, pyranose, morpholinyl, benzyl, piperazinyl, cyclopenta, cyclopropyl, cyclohexyl or C1-9Heteroaryl can be optional Ground is substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（VIII）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n2It independently is 1,2,3 or 4；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（IX）Shown structure：
Wherein, each R14And R14aIt independently is H, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10 Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n1It independently is 1,2,3 or 4；
Wherein described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Aryl, C1-9Heteroaryl Base, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl optionally can be substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some of these embodiments, it has such as formula（X）Shown structure
Wherein, each R5aIt independently is H, deuterium, C1-4Alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4；
Each Y1It independently is N or CR7；
Each R6And R7It independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl or benzyl；
Each R14And R14aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
WhereinConstruction unit is following subformula：
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
In some of these embodiments, it has such as formula（XI）Shown structure
Wherein, each R5aIt independently is H, deuterium, C1-4Alkyl, F, Cl, Br or I；
F is 0,1,2,3 or 4；
Each Q1And Q2It independently is NR6, O, S, C (=O) or (CR7R7a)e；
X6For (CR7R7a)n、-Y1=N-, O, S or NR6;
Each Y1It independently is N or CR7；
Each i, n and e independently are 1,2,3 or 4；
Each R6、R7And R7aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl or benzyl；
Each R14And R14aIt independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Wherein described C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryloxy can be optionally Substituted by one or more substituents selected from deuterium, F, Cl, Br, hydroxyl, cyano group；
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
In other embodiments, wherein, each R5aIt independently is H, deuterium, methyl, ethyl, F, Cl, Br or I;
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl, cyclohexyl or benzyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl or the tert-butyl group；
With each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy；
Wherein described methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group, methoxyl group, ethoxy Base, phenoxy group, tert-butoxy or the tert-butyl group optionally can be taken by one or more selected from deuterium, F, Cl, Br, hydroxyl, cyano group Substituted for base.
In some of these embodiments, it includes the structure of one of：
Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate or pharmacy Upper acceptable salt.
The compound of the present invention（Herein, form of presentation " formula (I) compound and its stereoisomer, geometrical isomerism Body, dynamic isomer, nitrogen oxides, hydrate, solvate and pharmaceutically acceptable salt and prodrug " may be collectively referred to as " this The compound of invention "）, can be used for producing medical product treatment acute and chronic HCV infection, including those are described in the invention. Further, compound of the invention can be used for the product for producing HCV-Ab IgG.Thus, compound of the invention can be used for giving birth to Produce a kind of pharmaceuticals to be used for mitigating, prevent, control or treating the illness that HCV is mediated, particularly HCV NS5A are protein mediated Disease.Thus, compound of the invention may be used as the active component of pharmaceutical composition, and the pharmaceutical composition can include formula （I）Representative compound, it can also further include at least one pharmaceutically acceptable carrier, assistant agent or diluent.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " is meant that, used thing Matter or composition must be adapted to match with the other components of composition preparation on chemistry or toxicity and for the mammal for the treatment of 's.Those skilled in the art can carry out specifically chosen " medicine according to used other components and the object of used treatment such as people The material or composition of acceptable on ".
The salt of the compound of the present invention also includes being used to preparing or purifying the intermediate of compound shown in formula (I) or formula (I) The salt of the enantiomter of shown compound separation, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document Method is prepared, for example, using inorganic acid or organic acid.Wherein, the example of inorganic acid includes but is not limited to hydrochloric acid, hydrogen bromine Acid, sulfuric acid, nitric acid and phosphoric acid etc..The example of organic acid includes but is not limited to acetic acid, maleic acid, butanedioic acid, mandelic acid, rich horse Acid, malonic acid, pyruvic 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；Amino acid, such as asparatate 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, 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.Suitable salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.
The composition of the compounds of this invention, preparation and administration
Described pharmaceutical composition includes the compound of any present invention.The pharmaceutical composition can also be included further Pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination.Described pharmaceutical composition can be used for controlling HCV (HCV) infection or hepatitis C disease are treated, especially, it has to HCV NS5A albumen suppresses to make well With.
Described pharmaceutical composition further includes the medicine of HCV-Ab IgG.The medicine of the HCV-Ab IgG can be it is any of not Be same as the compounds of this invention other be used for HCV-Ab IgG medicine.For example, can be interferon, Ribavirin, interleukin-22, Bai Jie Element 6, interleukin 12, promote to 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 antibodies（Bavituximab）, CivacirTM, ripple Puri Wei (boceprevir), TVR (telaprevir), Erlotinib（erlotinib）、daclatasvir、 simeprevir、asunaprevir、vaniprevir、faldaprevir、ABT-450、danoprevir、sovaprevir、 MK-5172、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ABT-267、EDP239、PPI- 668、GS-5816、samatasvir（IDX-719）、MK-8742、MK-8325、GSK-2336805、PPI-461、TMC-435、 MK-7009、BI-2013335、ciluprevir、BMS-650032、ACH-1625、ACH-1095、VX-985、IDX-375、VX- 500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、EP-013420、VBY-376、TMC-649128、R- 7128、PSI-7977、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI- 879、HCV-796、HCV-371、VCH-916、VCH-222、ANA-598、MK-3281、ABT-333、ABT-072、PF- 00868554、BI-207127、GS-9190、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、 TMC647055 or its combination.Wherein, the 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 its combination.Described pharmaceutical composition, further wrap Containing at least one HCV inhibitor, the HCV inhibitor is used to suppress HCV reproduction processes and suppresses HCV virus protein function extremely It is one of few, wherein the HCV reproduction processes enter selected from HCV, shelled, translating, replicating, assembling or the HCV of release complete disease The malicious cycle；Described HCV virus albumen is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B；And HCV diseases Poison replicates required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
When available for treating, the compounds of this invention of therapeutically effective amount, especially formula（I）Compound and its pharmaceutically may be used The salt of receiving can be given as unprocessed chemicals, and the active component for being alternatively arranged as pharmaceutical composition provides.Therefore, this hair Bright content also provides pharmaceutical composition, and the pharmaceutical composition includes this compounds of this invention of therapeutically effective amount, especially formula（I） Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient.Herein Used term " therapeutically effective amount " refers to be enough to show significant patient benefit（Such as viral load is reduced）It is each The total amount of active component.When being administered alone using single active component, the term only refers to the composition.When combination application, No matter the term then refers to combination, when being sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.The present invention Compound, especially formula（I）Compound and its pharmaceutically acceptable salt are as described above.From compatible with preparation other compositions and For in the sense that harmless to its recipient, carrier, diluent or excipient must be acceptable.According to present invention On the other hand, the method for preparing pharmaceutical preparation is also provided, this method is included the compounds of this invention, especially formula（I）Change Compound or its pharmaceutically acceptable salt mix with one or more pharmaceutically acceptable carriers, diluent or excipient.This Term used in invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they Rational medicine judge in the range of, suitable for patient tissue contacts and without excessive toxicity, excitant, allergy or with it is reasonable The symmetrical other problemses of interests/Hazard ratio and complication, and effective for given application.
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）It is excellent between body weight/day and about 250 mg/kg body weight/days Selected introductions usually are used to prevent or treat between about 0.05mg/kg body weight/days and about 100mg/kg body weight/days with monotherapy The disease of HCV mediations.The drug regimen of present invention can be generally given by daily about 1 to about 5 time or as continuous infusion Thing.This kind of dose regimen can be used as therapy in long or short term.Mixed with carrier material to prepare the amount of the active component of single formulation By according to disease to be treated, the order of severity of disease, administration time, method of administration, the discharge rate of compound used therefor, treatment Time and patient age, sex, body weight and situation and change.Preferable unit dosage forms are the days containing hereinbefore active component The unit dosage forms of dosage or divided dose or its appropriate fraction.It can start to control with the low dose of already clearly below compound optimal dose Treat.Hereafter, escalated dose is come until reaching optimum efficiency in this case with less increment.In general, most desirably The concentration level for giving compound be generally can anti-virus aspect provide effective result without regard to cause it is any harmful or Poisonous side effect.
When present invention composition include present invention compound and one or more other treatment medicines or During the combination of prophylactic agent, the dosage level of compound and other medicine accounts for normal administration generally in monotherapy scheme The about 10-150% of dosage, more preferably account for the about 10-80% of normal dosage.Pharmaceutical preparation is suitable to pass through any suitable approach Administration, such as by oral（Including oral cavity or sublingual）, rectum, nose, part（Including oral cavity, sublingual or percutaneous）, vagina or stomach It is parenteral（Including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, in breastbone, in intrathecal, focus, intravenous or intradermal injection Or infusion）Approach.It can prepare this kind of preparation by any known method of art of pharmacy, such as by by active component and carrier Or excipient mixing.It is preferred that oral administration or drug administration by injection.
Pharmaceutical preparation suitable for oral administration is provided by independent unit, such as capsule or tablet；Powder or granule； Solution or supensoid agent in water-based or non-aqueous liquid；Edible foam formulations or foaming preparations（whip）；Or oil-in-water breast Liquor or water in oil emulsion liquor.
For example, can be with can pharmaceutically connect for oral administration in the form of a tablet or capsule, active medicine component The oral, non-toxic inert carrier received（Such as ethanol, glycerine, water etc.）Mix.By the way that compound powder is broken into suitable fine chi It is very little, and the pharmaceutical carrier with equally being crushed（Such as the edible carbohydrate such as starch or mannitol）Mix to prepare powder.Also Flavouring, preservative, dispersant and colouring agent may be present.
By preparing pulverulent mixture as described above, and it is loaded into the gelatin shell of shaping, to prepare capsule.Filling Fill out before operation, can be by glidant and lubricant（Such as colloidal silica, talcum powder, magnesium stearate, calcium stearate or solid-state Polyethylene glycol）It is added in pulverulent mixture.Can also add when taking capsule by improve medicine utilizability disintegrant or Solubilizer（Such as agar, calcium carbonate or sodium carbonate）.
When needing in addition or be required, also suitable adhesive, lubricant, disintegrant and colouring agent can be mixed mixture In.Suitable adhesive includes starch, gelatin, natural sugar（Such as glucose or beta lactose）, corn sweetener, natural and synthesis Natural gum（Such as gum arabic, tragacanth or mosanom）, carboxymethyl cellulose, polyethylene glycol etc..For these formulations Lubricant includes enuatrol, sodium chloride etc..Disintegrant includes but is not limited to starch, methylcellulose, agar, bentonite, xanthan Glue etc..For example, by the way that pulverulent mixture, granulation or pre- tabletting is made, lubricant and disintegrant are added, it is tabletted, so as to make Piece agent.By the compound suitably crushed and diluent as described above or base-material, optionally and adhesive（Such as carboxymethyl is fine Tie up element, alginates, gelatin or polyvinylpyrrolidone）, dissolving inhibitor（Such as paraffin）, absorbsion accelerator（Quaternary salt）And/or Absorbent（Such as bentonite, kaolin or Dicalcium Phosphate）Mixing, to prepare pulverulent mixture.Useful binders（Such as syrup, shallow lake Slurry, mucialga of arabic gummy（acadiamucilage）Or cellulosic material or polymeric material solution）Pressurize and sieve after wetting, by powder Shape granulating mixture.Granulation an alternative be, can by pulverulent mixture by tablet press machine, result be will be formed it is bad Agglomerate smashes particle is made again.Can be by adding stearic acid, stearate, talcum powder or mineral oil make particle lubrication to prevent from gluing Onto the punch die of tablet press machine.Then it is the mixture through lubrication is tabletted.The compound of present invention can also be with free flow Dynamic inert carrier mixing, without can be tabletted by granulation or pre- tableting step.Can provide it is transparent or opaque by Shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing（polish coating of wax）The protectiveness bag of composition Clothing material.Dyestuff can be added in these coating materials to distinguish different unit doses.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, so as to which specified rate contains There is the compound of scheduled volume.Syrup can be by the way that compound be dissolved in the suitably seasoned aqueous solution to prepare, and elixir can lead to Cross using non-toxic vehicle to prepare.Solubilizer and emulsifying agent can also be added（Such as ethoxylated isostearyl alcohols and polyoxyethylene mountain Pears alcohol ether）, preservative, flavoring additive（Such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners）Deng.
If appropriate, can be by the dosage unit preparations microencapsulation for oral administration.Also preparation can be made and prolonged When or sustained release, such as by being coated or being embedded in the microparticle materials such as polymer, wax.
The compounds of this invention, especially formula（I）Compound and its pharmaceutically acceptable salt can pass medicine system with liposome System is given, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be by a variety of phosphatide（Such as courage is consolidated Alcohol, octadecylamine or phosphatidyl choline）Form.
The compounds of this invention, especially formula（I）Compound and its pharmaceutically acceptable salt also can be by using monoclonals Antibody is as single carrier（Compound molecule is coupled）Pass medicine.Compound also can with as can target medicine carrier can Soluble polymer is coupled.This kind of polymer may include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide Phenol, polyhydroxyethylaspart or the polyethylene-oxide polylysine substituted by palmitoyl residues.In addition, compound can Be coupled with a kind of Biodegradable polymeric, for reaching the controlled release of medicine, this kind of polymer such as PLA, poly- ε-oneself in Ester, poly butyric, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel cross-linked copolymer or Amphipathic nature block polymer.
Pharmaceutical preparation suitable for percutaneous dosing can be protected in a long time as discrete patch (discrete patch) Hold and recipient's epidermis close contact.For example, active component can generally be can be found in by passing medicine by electro-ionic osmosis patch Pharmaceutical Research1986,3(6),318。
Pharmaceutical preparation suitable for being locally administered can be made into ointment, cream, supensoid agent, lotion, powder, solution, paste Agent, gel, spray, aerosol, oil formulation or transdermal patch.
Pharmaceutical preparation suitable for rectally can be used as suppository or be provided as enema.
Pharmaceutical preparation (wherein carrier is solid) suitable for nose administration is such as 20-500 micrometer ranges including particle diameter Dust base, by being administered in a manner of snuffing, i.e., quickly sucked from the coarse powder agent container close to nose by nasal passage.Wherein carry Body is liquid, be adapted as nasal mist or the appropriate formulation of nasal drop administration includes the aqueous solution agent or oil of active component Property solution.
Suitable for including minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation, can use not Dosage compresed gas aerosol, nebulizer, insufflator or other matters of same type metering deliver the device of aerosol spray Middle preparation.
Pharmaceutical preparation suitable for vagina administration can be with vaginal plug, vagina plug, cream, creme, gel, paste, foam Agent or spray provide.
Pharmaceutical preparation suitable for parenteral includes water-based and non-aqueous sterile injection solution agent and water-based and non-aqueous Sterile suspensions, water-based and non-aqueous sterile injection solution agent can contain antioxidant, buffer, bacteriostatic agent and make the preparation The isotonic solute with receptor's blood waiting, water-based and non-aqueous sterile suspensions may include suspending agent and thickener.Preparation can be with Unit dose or multi-dose container provide, for example, sealing peace is triumphant and bottle, and can be stored under the conditions of freeze-drying (lyophilized), Only sterile liquid carrier, such as water for injection need to be being added before use.The injection solution and supensoid agent for facing used time configuration can be by It is 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 the preparation type Other compositions commonly used in the art, be for example suitable for be administered orally this kind of preparation may include flavouring.
The purposes of the compounds of this invention and pharmaceutical composition
In the purposes the invention provides the compound or pharmaceutical composition of the present invention in medicine is prepared, the medicine can For suppressing HCV reproduction processes and suppressing at least one of HCV virus protein function.The HCV reproduction processes are entered selected from HCV The complete viral cycle for the HCV for entering, shell, translate, replicate, assembling or discharging.Described HCV virus albumen is selected from metalloprotein Enzyme, NS2, NS3, NS4A, NS4B, NS5A, NS5B；And HCV virus replicates required internal ribosome inlet point (IRES) With inosine monophosphate dehydrogenase (IMPDH).
Any compound or pharmaceutical composition of the present invention can be used for treating HCV (HCV) infection or third Type hepatitis disease, especially, it has good inhibiting effect to HCV NS5A albumen.
The treatment method being administered comprising the compounds of this invention or pharmaceutical composition, further comprises other are administered to patient HCV medicines, thus, it is possible to the compound of the present invention and other anti-HCV medicaments are subjected to therapeutic alliance, wherein the HCV-Ab IgG Medicine is interferon, Ribavirin, interleukin-22, interleukin 6, interleukin 12, the change for promoting 1 type helper T lymphocyte response of generation Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, bar Tie up former times monoclonal antibody（Bavituximab）、CivacirTM, EBP520 (boceprevir), TVR (telaprevir), angstrom sieve For Buddhist nun (erlotinib), daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450、danoprevir、sovaprevir、MK-5172、vedroprevir、BZF-961、GS-9256、 narlaprevir、ANA975、ABT-267、EDP239、PPI-668、GS-5816、samatasvir(IDX-719)、MK- 8742、MK-8325、GSK-2336805、PPI-461、TMC-435、MK-7009、BI-2013335、ciluprevir、BMS- 650032、ACH-1625、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX- 136、IDX-316、EP-013420、VBY-376、TMC-649128、R-7128、PSI-7977、INX-189、IDX-184、 IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、HCV-371、VCH-916、VCH- 222、ANA-598、MK-3281、ABT-333、ABT-072、PF-00868554、BI-207127、GS-9190、A-837093、 JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.Wherein described interferon be interferon-' alpha '- 2b, the interferon-' alpha ' of Pegylation, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon γ or its combination.
And the treatment method being administered comprising the compounds of this invention or pharmaceutical composition, further comprising other HCV-Ab IgG medicines The administration of thing, wherein, other anti-HCV medicaments can be with the compounds of this invention or its pharmaceutical composition administering drug combinations, the present inventionization Compound or pharmaceutical composition are as single formulation, or the part of separated compound or pharmaceutical composition as multi-form.Its He can be administered simultaneously with the compounds of this invention or not be administered simultaneously anti-HCV medicament.The situation of the latter, administration can stagger progress Such as progress in 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
The present invention compound or pharmaceutically acceptable composition " effective dose " or " effective dose " refer to processing or Mitigate the effective dose that one or more present invention are previously mentioned the severity of illness.The method according to the invention, compound and combination The order of severity that thing can be any dosage and any method of administration to be efficiently used for handling or mitigate disease.Required standard True amount will change according to the situation of patient, and this is depending on ethnic, the age, the general condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or composition can with one or more other therapeutic agents administering drug combinations, such as What the present invention was discussed.
General building-up process
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13、d6-DMSO、CD3OD or d6- acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, it is wide Peak), dd (doublet of doublets, two bimodal), dt (doublet of triplets, double triplets).Coupling is normal Number, represented with hertz (Hz).
By being equipped with G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, ESI sources are applied to LC-MS spectrometers.
Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent6120 series LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detector applications In analysis, ESI sources are applied to LC-MS spectrometers.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；HPLC peak value is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultra-pure water solution (phase B).Condition of gradient elution is as shown in table 1：
Table 1
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatogram (HPLC), wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.
The use of brief word below is through the present invention：
HOAc acetic acid
MeCN,CH3CN acetonitriles
NH3Ammonia
NH4C1 sal-ammoniacs
BBr3Boron tribromide
BSA bovine serum albumin(BSA)s
Br2Bromine
BOC, Boc tert-butoxycarbonyl
Cs2CO3Cesium carbonate
CHCl3Chloroform
CDC13Deuterochloroform
Cu copper
CuI cuprous iodides
Et2O ether
DMF N,N-dimethylformamides
DMAP DMAPs
DMSO dimethyl sulfoxide (DMSO)s
EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
Dppa diphenyl phosphate azides
EtOAc ethyl acetate
EA ethyl acetate
HBr hydrobromic acids
HCl hydrochloric acid
HOAt, HOAT 1- hydroxyl -7- azepine BTAs
HOBT 1- hydroxy benzo triazoles
H2Hydrogen
H2O2Hydrogen peroxide
Fe iron
LDA lithium diisopropyl amidos
MCPBA metachloroperbenzoic acids
MgSO4Magnesium sulfate
MeOH,CH3OH methanol
MeI iodomethane
CH2Cl2, DCM dichloromethane
NMP 1-METHYLPYRROLIDONEs
ML, m milliliter
N2Nitrogen
Pd/C palladiums/carbon
PE petroleum ethers (60-90 DEG C)
PBS phosphate buffered saline (PBS)s
POC13POCl3
Pd(PPh3)4Four triphenyl phosphorus palladiums
Pd(dppf)Cl2Double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
K2CO3Potassium carbonate
KOH potassium hydroxide
RT, rt room temperature
Rt retention times
NaHCO3Sodium acid carbonate
NaBH4Sodium borohydride
NaBH3CN sodium cyanoborohydrides
NaOtBu sodium tert-butoxides
NaOH sodium hydroxides
NaClO2Sodium chlorite
NaCl sodium chloride
NaH2PO4Sodium dihydrogen phosphate
NaH sodium hydrides
NaI sodium iodides
Na2SO4Sodium sulphate
TBTU O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters
THF tetrahydrofurans
Et3N, TEA triethylamine
TFA trifluoroacetic acids
P(t-bu)3Three (tert-butyl group) phosphines
NBS N-bromo-succinimides
TBAI tetrabutylammonium iodides
H2O water
TEAF triethylamine formic acid
PPA polyphosphoric acids
Tf2O trifluoromethanesulfanhydride anhydrides
HCl.EA hydrogen chloride ethyl acetate
DIPEA diisopropyl ethyl amines
DME glycol dimethyl ethers
HATU 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
NIS N- N-iodosuccinimides
TFAA TFAAs
SEMCl 2- (trimethylsilyl) ethoxymethyl chlorine
Dess-Martin (Dai Si-Martin's oxidant) (1,1,1- triacetoxyl groups) -1,1- dihydro -1,2- benzenesulfonyls - 3 (1H) -one
TsOH p-methyl benzenesulfonic acid
TMSA trimethyl silicane ethyl-acetylenes
Maxwell acid 2,2- dimethyl -1,3- dioxane -4,6- diketone
Double (2- methoxy ethyls) the amino sulfur trifluorides of BAST
SbCl3Antimony trichloride
SmCl3Samarium trichloride
LiHMDS LHMDSs
TMSCl trim,ethylchlorosilanes
PhNTf2Double (fluoroform sulphonyl) imines of N- phenyl
TBDMSOTf fert-butyidimethylsilyl p-methyl benzenesulfonic acid base silanes
Et2NSF3Diethylamide sulfur trifluoride
MTBE methyl tertiary butyl ether(MTBE)s
LiN(SiMe3)2Two (trimethyl silicane) lithium amides
PPh3MeBr bromomethyl triphenylphosphines
Double sulphur -2,4- phosphines the alkane of (4- methoxyphenyls) -1,3- two of Lawesson ' s Reagent (Louth reagent) 2,4- - 2,4- disulphide
MTBE methyl tertiary butyl ether(MTBE)s
TEBAC benzyltriethylammoinium chlorides
I2Iodine
DAST diethylin sulfur trifluorides
IPA isopropanols
TCCA TCCAs
TEMPO 2,2,6,6- tetramethyl piperidines-nitrogen-oxide
IMPDH inosine monophosphate dehydrogenases
IRES internal ribosome inlet points
Synthetic method
Synthetic method 1
Compound 16 can be prepared by synthetic method 1.Wherein, each A1, A2And A3Independently selected from N or CR7, each X7 Or X8It independently is the leaving groups such as F, Cl, Br, I, OTf, also, each X6, w, R5a, f, Y4, R14aAnd R16aWith institute such as of the present invention The implication stated, Pg are amino protecting group, such as Boc, Fmoc, Cbz etc..Compound 1 occurs bromine substitution reaction and obtains compound 2, changes Compound 2 obtains compound 3 in the reaction system of diethyl malonate and alkali, and compound 3 reacts in NaCl systems To compound 4, compound 4 hydrolyzes in the presence of alkali and obtains compound 5, and compound 5 is in the presence of alchlor and acyl chlorides Compound 6 is obtained, the cyclization in the presence of alkali of compound 6 obtains compound 7, and compound 7 is changed in the presence of reducing agent Compound 8.Compound 9 and compound 9-1 occurs condensation reaction and obtains the mixture of compound 10 and 11, then in acetate system Heating cyclization obtains compound 12, and the deprotection of compound 12 obtains compound 13, and is further condensed to yield with compound 13-2 Compound 14, compound 14 react to obtain compound 15, compound 15 and chemical combination under the catalysis of palladium with connection boric acid pinacol ester Thing 8 carries out coupling reaction under the catalysis of palladium and obtains target compound 16.
Synthetic method 2
Target compound 26 can be prepared by synthetic method 2, wherein, X7For leaving groups such as F, Cl, Br, I, OTf Group, also, each R5a, f, W, X6, Y4', R14And R16With implication as described in the present invention, Pg is amino protecting group, such as Boc, Fmoc, Cbz etc..Reduction reaction occurs in the presence of borine and obtains compound 17 by compound 9-1-1, then in Dai Si-Martin Oxidation under obtain compound 18, the cyclization in the presence of ammoniacal liquor and glyoxal of compound 18 obtains compound 19, compound 19 Reacted to obtain compound 20 with NIS, compound 20 sloughs an iodine in the reaction system of sodium sulfite and obtains compound 21, the deprotection of compound 21 obtains compound 22, and condensation reaction further occurs with compound 13-2-2 and obtains compound 23, Compound 23 reacts to obtain compound 24 under palladium chtalyst with TMSA, and compound 24 takes off TMS under the catalysis of alkali and obtains chemical combination Thing 25, compound 25 carry out coupling reaction with compound 8 under palladium chtalyst and obtain target compound 26.
Synthetic method 3
Target compound 35 can be prepared by synthetic method 3, wherein, each X7Or X8F, Cl, Br, I independently are, The leaving groups such as OTf, also, each R5a, f, W, X6, Y2, R6a, Y4, Y2, R14, R14a, R16And R16aWith containing as described in the present invention Justice, Pg are amino protecting group, such as Boc, Fmoc, Cbz etc..Compound 9-1 is condensed to yield compound 28 with compound 27, then exists Cyclization is heated in ammonium acetate system and obtains compound 29, obtains compound 30 after the deprotection of compound 29, and further with change Compound 13-2 is condensed to yield compound 31, and compound 31 reacts to obtain compound under the catalysis of palladium with connection boric acid pinacol ester 32, coupling reaction occurs under palladium chtalyst and obtains compound 33 for compound 32 and compound 8, compound 33 under the catalysis of palladium and Connection boric acid pinacol ester reacts to obtain compound 34, and further carries out coupling reaction under palladium chtalyst with compound 23 and obtain mesh Mark compound 35.
Synthetic method 4
Target compound 40 can be prepared by synthetic method 4, wherein, X7For leaving groups such as F, Cl, Br, I, OTf Group, also, each Y4, R5a, w, f, X6, R14And R16With implication as described in the present invention.Pg is amino protecting group, such as Boc, Fmoc, Cbz etc..The deprotection of compound 36 obtains compound 37, and condensation reaction further occurs with compound 13-2-2 and obtains Compound 38.Compound 38 reacts to obtain compound 39 under the catalysis of palladium with connection boric acid pinacol ester, and further with chemical combination Coupling reaction occurs under the catalysis of palladium and obtains target compound 40 for thing 8.
Synthetic method 5
Target compound 49 can be prepared by synthetic method 3, wherein, each X7Or X8F, Cl, Br, I independently are, The leaving groups such as OTf, also, each Y4, R6a, w, R5a, f, X6, Y4', R14And R14a, R16And R16aWith containing as described in the present invention Justice, Pg are amino protecting group, such as Boc, Fmoc, Cbz etc..Compound 9-1-1 is condensed with compound 41 in the presence of alkali Reaction obtains compound 42, and compound 42 heats cyclization in ammonium acetate system and obtains compound 43, and compound 43 is urged palladium Change it is lower react to obtain compound 44 with connection boric acid pinacol ester, compound 44, which is deprotected, obtains compound 45, and further with change Compound 13-2 is condensed to yield compound 46, and compound 46 occurs coupling reaction with compound 8 under palladium chtalyst and obtains compound 47, Compound 47 reacts to obtain compound 48 under the catalysis of palladium with connection boric acid pinacol ester, and is further urged with compound 23 in palladium Change lower progress coupling reaction and obtain target compound 49.
Embodiment
Embodiment 1
Synthetic route：
Step 1）Compound 1-2 synthesis
By NBS（2.16g,12mmol）With compound 1-1（2.54g,10mmol）It is dissolved in CCl4（20mL）In, at 0 DEG C, delay It is slow to instill dibenzoyl peroxide（0.24g,1.0mmol）, drop finishes, and after being stirred at room temperature 15 minutes, flows back 7.0 hours.React Quan Hou, remove CCl4, residue addition EtOAc（100mL）Afterwards, water is used respectively（50mL×3）It is anhydrous with saturated common salt water washing Sodium sulphate is dried, and crude product 4.0g is obtained after concentration, is directly used in and is reacted in next step.
MS(ESI,pos.ion)m/z:335.8[M+H]+；
1H NMR(400MHz,CDCl3):δ6.70(t,1H),4.73(d,2H)ppm。
Step 2）Compound 1-3 synthesis
By NaH（60%,3.13g,78mmol）It is suspended in DMF（100mL）In, it is slowly dropped into diethyl malonate （12.54g,78mmol）, drop finish, 100 DEG C reaction 40 minutes after be down to room temperature reaction.Add compound 1-2（11.81g, 35.60mmol）, finish, after reacting at room temperature 30 minutes, 75 DEG C are reacted 1.0 hours.After reaction completely, saturated ammonium chloride solution is used （50mL）Reaction is quenched, adds EtOAc（150mL）, organic phase is separated, respectively with water and saturated common salt water washing, anhydrous slufuric acid Sodium is dried, and product 14g is obtained after concentration, is directly used in and is reacted in next step.
1H NMR(400MHz,CDCl3):δ6.93(m,1H),4.18-4.13(q,4H),3.84-3.81(m,1H),3.35, 3.33(dd,dd,2H),1.23-1.19(m,6H)ppm。
Step 3）Compound 1-4 synthesis
By compound 1-3（14g）It is dissolved in DMSO（100mL）In, at room temperature, it is slowly added to NaCl（4.10g,70mmol）With Water（0.64g,35.6mmol）, after adding, 100 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc （200mL）Dilute reaction solution, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=20/1）Obtain product 9.0g.
1H NMR(400MHz,CDCl3):δ6.88(t,1H),4.11-4.06(q,2H),3.05,3.03,3.01(m,m,m, 2H),2.69-2.65(m,2H),1.24-1.20(m,3H)ppm。
Step 4）Compound 1-5 synthesis
By compound 1-4（3.42g,10mmol）It is dissolved in methanol（20mL）In, the NaOH aqueous solution is instilled at 0 DEG C（0.8g, 20mL）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, watery hydrochloric acid is used（1M）PH to 5 is adjusted, removes methanol, water layer is with dilute salt Acid（1M）PH to 2 is adjusted, uses EtOAc（50mL×3）Extraction, organic phase anhydrous Na2SO4Dry, white solid is obtained after concentration 2.82g yield：90%.
MS(ESI,pos.ion)m/z:315.1[M+H]+；
1H NMR(400MHz,CDCl3):δ9.94(brs,1H),6.93(t,1H),3.05,3.03,3.01(m,m,m, 2H),2.79,2.77,2.75(d,d,d,2H)ppm。
Step 5）Compound 1-6 synthesis
At -10 DEG C, by oxalyl chloride（0.93mL,11mmol）It is slowly dropped into compound 1-5（3.14g,10mmol）And DMF （0.05mL）DCM（40mL）In solution, drop finishes, stand-by without handling after reacting at room temperature 1.0 hours.
At -15 DEG C, by freshly prepd above-claimed cpd（3.32g,10mmol）It is slowly dropped into AlCl3（1.73g,13mmol） DCM（30mL）In suspension, drop finishes, isothermal reaction 2.0 hours.After reaction completely, reaction solution is poured slowly into frozen water, point Go out organic layer, water layer DCM（30mL×3）Extraction, merge organic phase, washed respectively with clear water and saturated sodium carbonate solution, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain pale yellow powder 2.37g yield：80%.
MS(ESI,pos.ion)m/z:296.5[M+H]+；
1H NMR(400MHz,CDCl3):δ2.96-2.93(m,2H),2.81-2.78(m,2H)ppm。
Step 6）Compound 1-7 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 1-6（2.96g, 10mmol）, Isosorbide-5-Nitrae-dibromobutane（1.31mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（30mL）Suspension In, drop finishes, and is warming up to 60 DEG C and reacts 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（100mL）In, separate out solid Body.Filtering, solid EtOAc（50mL）After dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography after concentration Isolate and purify（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain product 2.63g, yield：75%.
MS(ESI,pos.ion)m/z:351.5[M+H]+；
1H NMR(400MHz,CDCl3):δ2.65-2.63(m,2H),1.94-1.64(m,6H),1.25-1.15(m,2H) ppm。
Step 7）Compound 1-8 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 1-7（3.5g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.86g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:337.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.81-2.79(m,4H),1.77-1.46(m,6H),1.34-1.24(m,2H) ppm。
Step 8）Compound 1-10 synthesis
At 0 DEG C, by DIPEA（19.5mL,118mmol）It is added to compound 1-9（23g,107mmol）With compound HATU （48.82g,128.4mmol）THF（250mL）In solution, after isothermal reaction 0.5 hour, compound 1-9-2 is added portionwise （22.1g,119mmol）, after adding, react at room temperature 4.0 hours.After reaction completely, add water（100mL）Reaction is quenched, removes THF, use EtOAc（200mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtained after concentration thick Product.Crude product obtained above is dissolved in glacial acetic acid（100mL）In, 40 DEG C of reactions are overnight.After reaction completely, concentration reaction Liquid, residue EtOAc（400mL）Dissolving, sodium carbonate liquor（150mL×3）Washing, anhydrous sodium sulfate drying, is passed through after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain product 31.6g, yield：81%.
MS(ESI,pos.ion)m/z:367.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.68(s,1H),7.42-7.40(m,1H),7.30-7.28(m,1H),5.11- 5.09(m,1H),3.45-3.43(m,2H),2.94-2.93(m,1H),2.21-2.18(m,2H),2.01-1.91(m,1H), 1.49(s,9H)ppm。
Step 9）Compound 1-11 synthesis
By compound 1-10（10g,27.39mmol）It is dissolved in EtOAc（50mL）, at 0 DEG C, instill the ethyl acetate of hydrogen chloride Solution（60mL,4M）Afterwards, react at room temperature 8.0 hours, after reaction completely, filtering, obtained after being eluted repeatedly with ethyl acetate yellowish Color solid 8.16g, yield：86.5%.
MS(ESI,pos.ion)m/z:267.1[M+H]+。
Step 10）Compound 1-12 synthesis
By compound 1-11（6.35g,18.8mmol）, compound 1-11-2（4.94g,28.2mmol）And EDCI（5.4g, 28.2mmol）It is dissolved in DCM（100mL）, at 0 DEG C, DIPEA is slowly added dropwise（18.64mL,112.8mmol）Afterwards, 3.0 are reacted at room temperature Hour.After reaction completely, water is added（100mL）Reaction is quenched, uses DCM（150mL×3）Extraction, organic phase saturated aqueous common salt Washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain solid 6.74g yield：85%.
MS(ESI,pos.ion)m/z:424.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.59-7.51(m,1H),7.34-7.21(m,2H),5.42-5.38(m,2H), 4.34-4.30(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),3.04-2.98(m,1H), 2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),0.88-0.84(m,6H)ppm。
Step 11）Compound 1-13 synthesis
By compound 1-12（3.0g,7.1mmol）, compound 1-12-2（2.72g,10.7mmol）, Pd (dppf) Cl2· CH2Cl2（0.65g,0.8mmol）And KOAc（2.09g,21.3mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （30mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, diatomite Filtering, filtrate use water respectively（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 2.1g, yield：62.9%.
MS(ESI,pos.ion)m/z:471.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.87-7.80(m,1H),7.71-7.66(m,2H),5.47-5.42(m,2H), 4.34-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H), 2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),1.35(s,12H),0.88-0.84(m,6H) ppm。
Step 12）Compound 1-14 synthesis
By compound 1-8（0.33g,1.0mmol）, compound 1-13（0.99g,2.1mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And K2CO3（0.35g,2.5mmol）It is suspended in DME（5.0mL）And water（1.0mL）In, under nitrogen protection, 90 DEG C Reaction 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, respectively with clear water and saturation Brine It, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=50/1） To faint yellow solid 0.39g, yield：45%.MS(ESI,pos.ion)m/z:864.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67(q,2H),7.59,7.57(d,d,2H),7.40,7.38(d,d,2H), 5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78 (m,2H),3.66(s,3H),3.65-3.64(m,2H),3.63(s,3H),2.84-2.82(m,4H),2.39-2.10(m,8H), 2.01-1.86(m,4H),1.73-1.52(m,4H),1.50-1.40(m,2H),1.28-1.18(m,2H),1.02-0.89(m, 12H)ppm。
Embodiment 2
Synthetic route：
Step 1）Compound 2-1 synthesis
By compound 1-9（10.0g,46.6mmol）It is dissolved in THF（100mL）In, under 0 DEG C of nitrogen protection, by borine （100mL,1M in THF）It is slowly dropped into reaction bulb, drop finishes, isothermal reaction 3 hours.After reaction completely, methanol is used（80mL） Reaction is quenched, through column chromatographic isolation and purification after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain colorless oil 7.04g yield：75.2%.
1H NMR(400MHz,CDCl3):δ3.99-3.87(br,1H),3.68-3.51(m,2H),3.48-3.39(m, 1H),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H)ppm。
Step 2）Compound 2-2 synthesis
By compound 2-1（7.0g,34.8mmol）It is dissolved in DCM（250mL）In, at 0 DEG C, by Dai Si-Martin（20.7g, 48.8mmol）Oxidant is added portionwise in reaction bulb, after adding, is reacted at room temperature 2.0 hours.After reaction completely, water is added （250mL）Dilute reaction solution, filter, after filtrate layered, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, concentration By column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain colorless oil 3.5g, yield：50.7%.
1H NMR(400MHz,CDCl3):δ9.46(d,1H,J=2.8Hz),4.08-4.03(m,1H),3.51-3.42(m, 2H),2.01-1.93(m,2H),1.91-1.84(m,2H),1.43(s,9H)ppm。
Step 3）Compound 2-3 synthesis
By compound 2-2（3.5g,17.6mmol）And ammoniacal liquor（13mL）It is dissolved in methanol（30mL）In, at 0 DEG C, by glyoxal （40%,8mL）The aqueous solution slowly instill in reaction bulb, drop finish, room temperature reaction overnight.After reaction completely, passed through after concentration of reaction solution Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 1.99g, yield：47.6%.
MS(ESI,pos.ion)m/z:238.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t, 2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Step 4）Compound 2-4 synthesis
By compound 2-3（2.0g,8.4mmol）It is dissolved in DCM（60mL）, at 0 DEG C, by N- N-iodosuccinimides（3.8g, 16.8mmol）It is added portionwise in reaction bulb, isothermal reaction 1.5 hours.After reaction completely, reaction solution saturated common salt water washing, Anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 2.59g yield：63.1%.
MS(ESI,pos.ion)m/z:490.1[M+H]+；
1H NMR(400MHz,CDCl3):δ4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02 (m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Step 5）Compound 2-5 synthesis
By compound 2-4（1.6g,3.27mmol）It is suspended in second alcohol and water（v/v=3/7）Mixed solvent（50mL）In, By sodium sulfite（3.7g,29mmol）Add in mixed liquor and flow back 17 hours.After reaction completely, ethanol is removed, residue adds Water（50mL）, use ethyl acetate（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, after concentration Through column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 1.0g, yield：84%.
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz), 3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Step 6）Compound 2-6 synthesis
At room temperature, by the ethyl acetate solution of hydrogen chloride（5mL,4M）It is added drop-wise to compound 2-5（1.50g,4.13mmol） EtOAc（10mL）In solution, drop finishes, and reaction is overnight.After reaction completely, filtering, solid 1.2g, yield are obtained：86.5%.Directly Connect for reacting in next step.MS(ESI,pos.ion)m/z:264.1[M+H]+。
Step 7）Compound 2-7 synthesis
By compound 2-6（1.2g,3.6mmol）, compound 1-12-2（0.68g,3.9mmol）And EDCI（0.75g, 3.9mmol）It is suspended in DCM（20mL）In, after being stirred 5 minutes at 0 DEG C, it is slowly dropped into DIPEA（2.38mL,14.4mmol）, drop Finish, react at room temperature 2.0 hours.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase saturated ammonium chloride solution Washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain yellowish Color foam solid 1.31g, yield：86.8%.
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m, 1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m, 3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 8）Compound 2-8 synthesis
By compound 2-7（0.58g,1.38mmol）, PdCl2(PPh3)2（98mg,0.14mmol）, tetrabutylammonium iodide （1.53g,4.14mmol）And CuI（78mg,0.41mmol）It is dissolved in DMF（5mL）In, under nitrogen protection, it is slowly added to three second Amine（2.0mL）, after being stirred at room temperature 10 minutes, it is slowly dropped into TMSA（0.98mL,6.89mmol）, drop is complete, and 70 DEG C of reactions are overnight.Instead After answering completely, diatomite filtering, filtrate adds water（20mL）Dilution, water layer EtOAc（20mL×3）Extraction, merge organic phase, Anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/1）Product 0.3g is obtained, Yield：55.8%.
MS(ESI,pos.ion)m/z:391.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H), 4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H), 0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Step 9）Compound 2-9 synthesis
By compound 2-8（0.34g,0.87mmol）And K2CO3（0.60g,4.35mmol）It is dissolved in MeOH（2mL）And THF （2mL）In the mixed solvent, react at room temperature 6.0 hours.After reaction completely, solvent is removed, residue adds water（10mL）, use EtOAc（10mL×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography after concentration Isolate and purify（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 0.23g, yield：82.6%.
MS(ESI,pos.ion)m/z:319.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J= 4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H), 2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 10）Compound 2-10 synthesis
By compound 1-8（0.13g,0.39mmol）, compound 2-9（0.31g,0.975mmol）, PdCl2(PPh3)2 （14.1mg,0.02mmol）, CuI（33mg,0.172mmol）, PPh3（0.23g,0.86mmol）It is added in reaction bulb, nitrogen Under protection, DMF is added（10mL）, it is slowly dropped into triethylamine（5.0mL）, drop finishes, and after being stirred at room temperature 10 minutes, 90 DEG C of reactions 10 are small When.After reaction completely, diatomite is filtered, and water is added in filtrate（20mL）, use EtOAc（20mL×3）Extraction, merge organic phase, With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 60/1）Obtain product 95mg, yield：30%.
MS(ESI,pos.ion)m/z:811.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.48(s,2H),5.51-5.47(m,2H),5.32,5.30(d,d,2H), 4.41-4.36(m,1H),3.89-3.83(m,2H),3.73-3.66(m,2H),3.63(s,6H),3.12-3.10(m,4H), 2.32-1.92(m,10H),1.79-1.58(m,4H),1.53-1.43(m,2H),1.32-1.22(m,2H),0.97,0.95(m, m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 3
Synthetic route：
Step 1）Compound 3-1 synthesis
By compound 3-1-0（30g,107.9mmol）And compound 1-9（25.5g,118.7mmol）It is dissolved in DCM （250mL）In, at 0 DEG C, it is slowly dropped into DIPEA（21.4mL,129.5mmol）, drop is complete, reacts at room temperature 3.0 hours.Reaction is complete Afterwards, frozen water is used（100mL）Reaction, water layer EtOAc is quenched（100mL×3）Extraction, organic phase saturated common salt water washing, nothing Water Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain white solid 40.4g yield：91%.
MS(ESI,pos.ion)m/z:412.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.78-7.75(m,2H),7.65-7.63(m,2H),5.53-5.15(m,2H), 4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m, 1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 2）Compound 3-2 synthesis
By compound 3-1（15g,36.4mmol）And ammonium acetate（42g,54.6mmol）It is suspended in toluene（150mL）In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（100mL）Reaction, water layer EtOAc is quenched（100mL ×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous Na SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=5/1）Obtain product 12.1g, yield：85%.
MS(ESI,pos.ion)m/z:392.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.78-7.75(m,2H),7.65-7.63(m,2H),7.21-7.20(m,1H), 5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m, 2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 3）Compound 3-3 synthesis
By compound 3-2（10g,25.5mmol）It is dissolved in EtOAc（50mL）In, add the ethyl acetate solution of hydrogen chloride （60mL,4M）Afterwards, react at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc（30mL）Mashing Afterwards, faint yellow solid 8.0g, yield are filtrated to get：86.2%.
MS(ESI,pos.ion)m/z:292.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.76-7.73(m,2H),7.66-7.63(m,2H),7.21-7.20(m,1H), 5.50-5.22(m,2H),4.49-4.39(m,1H),3.61-3.56(m,1H),3.49-3.39(m,1H),2.31-2.21(m, 2H),2.12-2.01(m,1H),1.98-1.85(m,1H)ppm。
Step 4）Compound 3-4 synthesis
By compound 3-3（7.01g,19.26mmol）, compound 1-11-2（5.06g,28.9mmol）And EDCI （5.56g,28.9mmol）It is dissolved in DCM（100mL）, at 0 DEG C, it is slowly dropped into DIPEA（21mL,127mmol）Afterwards, react at room temperature 3.0 hour.After reaction completely, water is added（100mL）, water layer DCM（100mL×3）Extraction, merge organic phase, eaten with saturation Salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Consolidate Body 7.6g, yield：88%.
MS(ESI,pos.ion)m/z:450.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H), 5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.85-3.81(m,1H),3.72(s,3H), 3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.04-1.02(m,1H), 0.88-0.86(d,6H)ppm。
Step 5）Compound 3-5 synthesis
By compound 3-4（4.99g,11.1mmol）, compound 1-12-2（4.24g,16.7mmol）, Pd (dppf) Cl2·CH2Cl2（0.91g,1.11mmol）And KOAc（3.30g,33.4mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （50mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）After dilute reaction solution, diatom Soil filtering, filtrate use water respectively（100mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 3.95g, yield：71.4%.
1H NMR(400MHz,CDCl3):δ7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H), 5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.5-3.81(m,1H),3.72(s,3H), 3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.32-1.45(m,12H), 1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Step 6）Compound 3-6 synthesis
By compound 1-8（0.33g,1.0mmol）, compound 3-5（0.5g,1.0mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, is injected separately into DME（10mL）And pure water（2mL）, N2Protect Under shield, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Dilute reaction solution, water layer EtOAc （60mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=100/1）Obtain weak yellow foam shape thing 0.25g, yield：40%.
MS(ESI,pos.ion)m/z:626.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51- 7.50,7.49-7.48(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.36(m,1H), 3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.84-2.81(m,2H),2.75-2.72(m,2H), 2.30-1.92(m,5H),1.74-1.54(m,4H),1.53-1.43(m,2H),1.31-1.21(m,2H),0.97,0.95(m, m,3H),0.90,0.89(m,m,3H)ppm。
Step 7）Compound 3-7 synthesis
By compound 3-6（0.62g,1.0mmol）, compound 1-12-2（0.28g,1.1mmol）, Pd (dppf) Cl2· CH2Cl2（81.7mg,0.1mmol）And KOAc（0.25g,2.5mmol）It is placed in reaction bulb, injects DMF（3.0mL）, N2Protection Under, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（30mL）After dilute reaction solution, diatomite mistake Filter, filtrate use water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.34g, yield：50%.
MS(ESI,pos.ion)m/z:673.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23- 7.22,7.21-7.20(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H), 3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.80-2.77(m,2H),2.66-2.63(m,2H), 2.30-1.92(m,5H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33,1.30(q,q,12H),0.97,0.95 (m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 8）Compound 3-8 synthesis
By compound 3-7（0.67g,1.0mmol）, compound 2-7（0.43g,1.02mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, is injected separately into EtOH（10mL）And pure water（2mL）, N2 Under protection, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, adds water（20mL）Dilute reaction solution, water layer EtOAc （20mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 293mg, yield：35%.
MS(ESI,pos.ion)m/z:840.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.68-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57 (m,m,3H),7.40(s,1H),6.08,6.06(d,d,1H),5.44-5.40(m,1H),5.32,5.29(d,d,1H),5.23- 5.19(m,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.69-3.66(m,2H), 3.65(s,3H),3.63(s,3H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.31-1.92(m,10H),1.73- 1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 4
Synthetic route：
Step 1）Compound 4-1 synthesis
By compound 1-10（4.11g,11.27mmol）, compound 1-12-2（4.29g,16.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.65g,0.8mmol）And KOAc（2.76g,28.17mmol）It is placed in reaction bulb, N2Under protection, DMF is added （30mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, diatomite Filtering, filtrate use water respectively（60mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 3.02g, yield：65%.
MS(ESI,pos.ion)m/z:414.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.69(s,1H),7.45-7.43(m,1H),7.32-7.30(m,1H),5.12- 5.10(m,1H),3.45-3.43(m,2H),2.95-2.94(m,1H),2.25-2.22(m,2H),2.01-1.91(m,1H), 1.49(s,9H),1.35(s,12H)ppm。
Step 2）Compound 4-2 synthesis
By compound 4-1（0.58g,1.4mmol）It is dissolved in EtOAc（5.0mL）In, add the ethyl acetate solution of hydrogen chloride （5mL,4M）Afterwards, react at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc（10mL）After mashing, It is filtrated to get faint yellow solid 0.49g, yield：91%.
MS(ESI,pos.ion)m/z:314.2[M+H]+。
Step 3）Compound 4-3 synthesis
By compound 4-2（1.0g,2.6mmol）, compound 4-2-2（0.59g,3.1mmol）, EDCI（0.55g, 2.86mmol）With HOAT（0.35g,2.6mmol）It is suspended in DCM（15mL）In, at 0 DEG C, it is slowly dropped into DIPEA（1.72mL, 10.4mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（40mL）Dilute reaction solution, chlorination is used respectively Aqueous ammonium and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=1/2）Obtain white solid 1.17g, yield：93%.
MS(ESI,pos.ion)m/z:485.4[M+H]+；
1H NMR(400MHz,CDCl3):δ10.62(brs,1H),8.22(m,1H),7.73-7.65(m,2H),5.72(d, 1H,J=8.0Hz),5.43(d,1H,J=8.0Hz),4.35-4.31(m,1H),3.95-3.88(m,1H),3.78-3.75(m, 1H),3.69-3.67(m,4H),3.08-3.04(m,1H),2.43-2.37(m,1H),2.25-2.15(m,2H),1.91(s, 1H),1.74-1.72(m,1H),1.52-1.50(m,1H),1.35(s,12H),1.24(t,2H,J=8.0Hz),1.12-1.10 (m,1H),0.93-0.88(m,1H)ppm。
Step 4）Compound 4-4 synthesis
By compound 3-6（0.62g,1.0mmol）, compound 4-3（0.53g,1.1mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, is injected separately into EtOH（10mL）And pure water（2mL）, N2 Under protection, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, adds water（20mL）Dilute reaction solution, water layer EtOAc （20mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 0.36g, yield：40%.
MS(ESI,pos.ion)m/z:452.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.80,7.77(d,d,1H),7.70(q,1H),7.66-7.65,7.64-7.62 (m,m,2H),7.59(s,1H),7.48-7.47,7.46-7.45(m,2H),7.18,7.16(d,d,1H),5.32,5.29(d, d,1H),5.28,5.26(d,d,1H),5.23-5.19(m,1H),5.13-5.09(m,1H),4.45-4.36(m,2H),3.85- 3.77(m,2H),3.69-3.64(m,2H),3.63(s,6H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.42- 2.34(m,1H),2.30-1.80(m,9H),1.73-1.39(m,7H),1.27-1.11(m,3H),0.97,0.96(m,m,3H), 0.91,0.89(m,m,3H),0.88,0.86(m,m,3H),0.85,0.83,0.81(m,m,m,3H)ppm。
Embodiment 5
Synthetic route：
Step 1）Compound 5-2 synthesis
By compound 5-1（25g,125.6mmol）, NBS（24.5g,138.2mmol）With p-TSA（3.4g,20.9mmol） It is placed in reaction bulb, under nitrogen protection, 100 DEG C are reacted 2.0 hours.After reaction completely, it is cooled to room temperature, adds DCM（200mL）It is dilute After releasing reaction solution, water is used respectively（50mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain product 24.7g, yield：71%.
MS(ESI,pos.ion)m/z:279.9[M+H]+；
1H NMR(400MHz,CDCl3):δ8.95(d,1H,J=1.12Hz),8.11-8.14(m,1H),7.66-7.68(m, 1H),4.41(s,2H)ppm。
Step 2）Compound 5-3 synthesis
By compound 5-2（5.0g,17.9mmol）And compound 5-2-2（5.36g,19.7mmol）It is dissolved in MeCN （100mL）In, at 0 DEG C, it is slowly dropped into DIPEA（3.3mL,19.7mmol）, drop is complete, reacts at room temperature 3.0 hours.Reaction is complete Afterwards, concentration of reaction solution, residue add water（100mL）, then use EtOAc（100mL×3）Extraction, merge organic phase, it is anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（PE/EtOAc(v/v)=3/1）Obtain product 8.06g, yield：96%.
MS(ESI,pos.ion)m/z:470.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.88(s,1H),8.04(d,1H,J=3.88Hz),7.65(d,1H,J= 4.16Hz),5.61-5.59(m,1H),5.48(d,1H,J=8.32Hz),5.23(d,1H,J=8.3Hz),4.67(t,1H,J= 5.72Hz),4.31(t,1H,J=7.52Hz),3.86-3.84(m,1H),3.73-3.71(m,1H),3.66(s,3H),2.34- 2.15(m,4H),1.01(t,3H),0.94-0.93(m,3H),0.88-0.85(m,1H)ppm。
Step 3）Compound 5-4 synthesis
By compound 5-3（2.0g,4.25mmol）And ammonium acetate（4.9g,83mmol）It is suspended in dimethylbenzene（50mL） In, 130 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction, water layer EtOAc is quenched（50mL ×3）Extraction, merge organic phase, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（PE/EtOAc(v/v)=2/1） To product 1.39g, yield：73%.
MS(ESI,pos.ion)m/z:450.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.70(s,1H),7.93(d,1H,J=6.92Hz),7.45(d,1H,J= 8.28Hz),5.41(d,1H,J=4.6Hz),5.24-5.22(m,1H),4.32(m,1H),3.85-3.83(m,1H),3.67(s, 3H),3.63-3.62(m,3H),3.05-3.03(m,1H),2.31-1.93(m,4H),1.04-1.03(m,1H),0.88(s, 3H),0.86(s,3H)ppm。
Step 4）Compound 5-5 synthesis
By compound 5-4（2.33g,5.2mmol）, compound 1-12-2（1.59g,6.25mmol）, Pd (dppf) Cl2· CH2Cl2（0.43g,0.52mmol）And KOAc（1.54g,15.63mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （20mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After diluting reaction, diatomite Filtering, filtrate use water respectively（60mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 1.68g, yield：65%.
MS(ESI,pos.ion)m/z:498.4[M+H]+；
1H NMR(400MHz,CDCl3):δ8.76-8.75(m,1H),8.00,7.98(d,d,1H),7.73,7.71(d,d, 1H),7.37(s,1H),5.38-5.33(m,1H),5.32,5.29(d,d,1H),4.41-4.36(m,1H),3.85-3.78(m, 1H),3.69-3.64(m,1H),3.63(s,3H),2.30-1.92(m,5H),1.39,1.36(m,m,12H),0.97,0.95 (m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 5）Compound 5-6 synthesis
By compound 5-5（0.36g,0.72mmol）, compound 1-8（0.24g,0.72mmol）, Pd (PPh3)4（83mg, 0.07mmol）With potassium carbonate（0.3g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, under nitrogen protection, 90 DEG C Reaction 4.0 hours.After reaction completely, EtOAc is added（40mL）After dilute reaction solution, water is used respectively（10mL×3）Eaten with saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（DCM/EtOAc(v/v)=80/1）Obtain product 0.2g, yield：45%.
MS(ESI,pos.ion)m/z:627.7[M+H]+；
1H NMR(400MHz,CDCl3):δ8.77(q,1H),7.82,7.79(d,d,1H),7.67(s,1H),7.60, 7.58(d,d,1H),5.38-5.33(m,1H),5.32,5.29(d,d,1H),4.41-4.35(m,1H),3.85-3.78(m, 1H),3.69-3.64(m,1H),3.63(s,3H),2.87-2.84(m,2H),2.78-2.75(m,2H),2.30-1.92(m, 5H),1.75-1.54(m,4H),1.52-1.42(m,2H),1.30-1.20(m,2H),0.97,0.95(m,m,3H),0.90, 0.89(m,m,3H)ppm。
Step 6）Compound 5-7 synthesis
By compound 5-6（62.5mg,0.1mmol）, compound 1-13（52mg,0.11mmol）, Pd (PPh3)4（12mg, 0.01mmol）And potassium carbonate（35mg,0.25mmol）It is placed in reaction bulb, is injected separately into DME（2.5mL）And pure water（0.5mL）, N2Under protection, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, adds water（10mL）Dilute reaction solution, water layer are used EtOAc（10mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 44mg, yield：50%.
MS(ESI,pos.ion)m/z:445.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.75(q,1H),7.85,7.83(d,d,1H),7.80,7.78(d,d,1H), 7.69(q,1H),7.67(s,1H),7.57,7.55(d,d,1H),7.18,7.16(d,d,1H),5.38-5.33(m,1H), 5.32,5.29(d,d,2H),5.24-5.20(m,1H),4.41-4.35(m,2H),3.85-3.78(m,2H),3.69-3.65 (m,2H),3.63(s,6H),2.81-2.79(m,4H),2.38-1.86(m,10H),1.73-1.52(m,4H),1.49-1.39 (m,2H),1.27-1.17(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 6
Synthetic route：
Step 1）Compound 6-1 synthesis
By compound 3-2（4.0g,10.23mmol）, compound 1-12-2（2.86g,11.3mmol）, Pd (dppf) Cl2·CH2Cl2（0.42g,0.51mmol）And KOAc（2.51g,25.57mmol）It is placed in reaction bulb, N2Under protection, injection DMF（20mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, diatom Soil filtering, filtrate use water respectively（80mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 3.59g, yield：80%.
1H NMR(400MHz,CDCl3):δ7.35(m,4H),7.10(s,1H),4.93(t,1H,J=8.2Hz),3.88- 3.66(m,2H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,9H),1.26 (s,12H)ppm。
Step 2）Compound 6-2 synthesis
By compound 1-8（0.33g,1.0mmol）, compound 6-1（0.44g,1.0mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, is injected separately into DME（10mL）And pure water（2mL）, N2Protect Under shield, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（20mL）Dilute reaction solution, water layer EtOAc （20mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 255mg, yield：45%.
MS(ESI,pos.ion)m/z:569.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51- 7.50,7.49-7.48(m,m,2H),4.98-4.92(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.84- 2.81(m,2H),2.75-2.72(m,2H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.96(m,2H), 1.75-1.54(m,4H),1.53-1.43(m,2H),1.41(s,9H),1.31-1.21(m,2H)ppm。
Step 3）Compound 6-3 synthesis
By compound 6-2（0.57g,1.0mmol）, compound 1-12-2（0.28g,1.1mmol）, Pd (dppf) Cl2· CH2Cl2（81.7mg,0.1mmol）And KOAc（0.25g,2.5mmol）It is placed in reaction bulb, injects DMF（3.0mL）, N2Protection Under, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（30mL）After dilute reaction solution, diatomite mistake Filter, filtrate use water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.34g, yield：55%.
MS(ESI,pos.ion)m/z:616.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23- 7.22,7.21-7.20(m,m,2H),4.98-4.92(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.80- 2.77(m,2H),2.66-2.63(m,2H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.96(m,2H), 1.74-1.54(m,6H),1.52-1.43(m,2H),1.41(s,9H),1.33,1.30(q,q,12H)ppm。
Step 4）Compound 6-4 synthesis
Respectively by compound 6-3（0.42g,0.69mmol）, compound 2-5（0.25g,0.69mmol）, potassium carbonate （0.24g,1.72mmol）With tetra-triphenylphosphine palladium（80mg,0.069mmol）It is placed in reaction bulb, N2Under protection, it is injected separately into DME（8mL）And water（2mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, EtOAc is added（40mL）Dilute reaction solution, use respectively Water and saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 80/1）Obtain yellow solid 275mg, yield：55%.
MS(ESI,pos.ion)m/z:726.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.59-7.57 (m,m,3H),7.47(s,1H),5.24-5.19(m,1H),4.98-4.92(m,1H),3.64-3.58(m,2H),3.31-3.23 (m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.57-2.17(m,5H),2.10-1.96(m,3H),1.73- 1.56(m,4H),1.53(s,9H),1.47-1.42(m,2H),1.41(s,9H),1.27-1.17m,2H)ppm。
Step 5）Compound 6-5 synthesis
By compound 6-4（0.22g,0.3mmol）It is dissolved in EtOAc（4mL）, then instill the ethyl acetate solution of hydrogen chloride （2mL,4M）Afterwards, drop finishes, and reacts at room temperature 8 hours.After reaction completely, concentration of reaction solution, residue ethyl acetate（5mL）Mashing Afterwards, yellow solid 0.18g, yield are filtrated to get：90%.
MS(ESI,pos.ion)m/z:525.,3[M+H]+。
Step 6）Compound 6-6 synthesis
By compound 6-5（0.17g,0.26mmol）, compound 6-5-2（83.8mg,0.57mmol）, EDCI（0.11g, 0.57mmol）And HOAT（0.07g,0.52mmol）It is suspended in DCM（3mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.5mL, 2.6mmol）, drop is complete, reacts at room temperature 3 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, respectively with ammonium chloride water Solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/ v)=40/1）Obtain faint yellow solid 0.13g, yield：65%.
MS(ESI,pos.ion)m/z:783.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57 (m,m,3H),7.40(s,1H),5.44,5.42(m,m,2H),5.31-5.26(m,1H),5.10-5.05(m,1H),4.64- 4.57(m,2H),3.88-3.82(m,2H),3.72-3.65(m,2H),3.64(s,6H),2.95-2.92(m,2H),2.76- 2.73(m,2H),2.36-1.93(m,8H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.36,1.34(d,d,6H), 1.27-1.17(m,2H)ppm。
Embodiment 7
Synthetic route：
Step 1）Compound 7-1 synthesis
By compound 6-5（0.17g,0.26mmol）, compound 7-1-0（0.12g,0.57mmol）, EDCI（0.11g, 0.57mmol）And HOAT（0.07g,0.52mmol）It is suspended in DCM（3mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.5mL, 2.6mmol）, drop is complete, reacts at room temperature 3 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, respectively with ammonium chloride water Solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/ v)=40/1）Obtain faint yellow solid 0.12g, yield：50%.
MS(ESI,pos.ion)m/z:460.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57 (m,m,3H),7.40(s,1H),5.28-5.24(m,1H),5.21,5.19(d,d,2H),5.09-5.04(m,1H),4.47- 4.41(m,2H),3.86-3.80(m,2H),3.70-3.65(m,2H),3.63(s,6H),2.95-2.92(m,2H),2.76- 2.73(m,2H),2.36-1.88(m,10H),1.73-1.51(m,10H),1.49-1.31(m,10H),1.27-1.03(m,8H) ppm。
Embodiment 8
Synthetic route：
Step 1）Compound 8-2 synthesis
By compound 8-1（3.0g,13.1mmol）With compound 3-1-0（3.63g,13.1mmol）It is dissolved in DCM（40mL） In, at 0 DEG C, it is slowly added to TEA（3.9mL,26.3mmol）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, water is added （50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous Na2SO4It is dry It is dry, crude product 3.27g, yield are obtained after concentration：62.9%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:399.3[M+H]+。
Step 2）Compound 8-3 synthesis
By compound 8-2（3.27g,8.2mmol）And ammonium acetate（5.1g,66mmol）It is suspended in toluene（30mL）In, 110 DEG C reaction 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction, water layer EtOAc is quenched（80mL×3）Extraction Take, merge organic phase, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=4/1）Obtain product 2.85g, yield：86%.
MS(ESI,pos.ion)m/z:407.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.45(m,4H),7.20(s,1H),4.93(t,1H,J=8.2Hz),3.88- 3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,7H),1.26 (s,2H),1.12(d,3H,J=6.2Hz)ppm。
Step 3）Compound 8-4 synthesis
By compound 8-3（2.8g,6.9mmol）, compound 1-12-2（1.93g,7.6mmol）, Pd (dppf) Cl2· CH2Cl2（0.28g,0.34mmol）With KOAc（1.7g,17.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected （30mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（200mL）Dilute reaction solution, diatom Soil filtering, filtrate use water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 2.76g, yield：88.2%.
MS(ESI,pos.ion)m/z:454.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35(m,4H),7.10(s,1H),4.93(t,1H,J=8.2Hz),3.88- 3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,9H),1.26 (s,12H),1.02(d,3H,J=6.2Hz)ppm。
Step 4）Compound 8-5 synthesis
By compound 8-4（0.26g,0.58mmol）, compound 1-8（0.19g,0.58mmol）, Pd (PPh3)4（35mg, 0.03mmol）And potassium carbonate（0.08g,1.4mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（4.0mL）With it is pure Water（1.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）After dilute reaction solution, point Water is not used（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 185mg, yield：55%.
MS(ESI,pos.ion)m/z:583.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51- 7.50,7.49-7.48(m,m,2H),4.89-4.84(m,1H),3.80-3.73(m,1H),3.09-3.02(m,1H),2.84- 2.81(m,2H),2.75-2.72(m,2H),2.33-2.18(m,2H),1.75-1.54(m,5H),1.53-1.44(m,2H), 1.42(s,9H),1.31-1.21(m,2H),0.96-0.93(m,3H)ppm。
Step 5）Compound 8-6 synthesis
At 0 DEG C, by DIPEA（1.95mL,11.8mmol）It is added to compound 8-1（2.45g,10.7mmol）With compound HATU（4.88g,12.84mmol）THF（30mL）In solution, after isothermal reaction 0.5 hour, compound 1-9-2 is added portionwise （2.21g,11.9mmol）, after adding, react at room temperature 4.0 hours.After reaction completely, water is added（50mL）Reaction is quenched, removes THF, use EtOAc（50mL×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying will after concentration Residue is dissolved in glacial acetic acid（20mL）In, 40 DEG C of reactions are overnight.After reaction completely, glacial acetic acid, residue EtOAc are removed （100mL）After dissolving, sodium carbonate liquor is used（50mL×3）Washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain product 3.24g, yield：80%.
MS(ESI,pos.ion)m/z:381.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.84(d,1H,J=2.9Hz),7.44(d,1H,J=15.0Hz),7.33(dd, 1H,J=15.0Hz,2.9Hz),4.88(t,1H,J=16.9Hz),4.27(dd,1H,J=24.8Hz,17.3Hz),3.14(dd, 1H,J=24.7Hz,17.3Hz),2.53(dt,1H,J=24.4Hz,17.2Hz),2.21-2.03(m,1H),1.81(dt,1H,J= 24.4Hz,17.2Hz),1.41(s,9H),0.95(d,3H,J=12.7Hz)ppm。
Step 6）Compound 8-7 synthesis
By compound 8-6（4.27g,11.27mmol）, compound 1-12-2（4.29g,16.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.65g,0.8mmol）And KOAc（2.76g,28.17mmol）It is placed in reaction bulb, N2Under protection, DME is added （30mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, DME is removed, adds water（50mL）, use EtOAc（50mL×3）Extraction, Merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=3/1）Obtain buff white solid 2.89g, yield：60%.
MS(ESI,pos.ion)m/z:428.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82(dd,1H),7.65,7.63(d,d,1H),7.27,7.25(d,d,1H), 5.07-5.02(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.51-2.42(m,1H),2.30-2.16(m, 1H),1.86-1.78(m,1H),1.41(s,9H),1.32,1.29(m,m,12H),0.96-0.93(m,3H)ppm。
Step 7）Compound 8-8 synthesis
By compound 8-7（0.25g,0.58mmol）, compound 8-5（0.34g,0.58mmol）, Pd (PPh3)4（35mg, 0.03mmol）And potassium carbonate（80mg,1.4mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（4.0mL）And pure water （1.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）After dilute reaction solution, respectively Use water（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=80/1）Obtain faint yellow solid 0.28g, yield：60%.
MS(ESI,pos.ion)m/z:402.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.79,7.77(d,d,1H),7.66-7.62(m,3H),7.59(s,1H), 7.56,7.54(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.14-5.09(m,1H),4.89-4.84(m, 1H),3.85-3.73(m,2H),3.14-3.02(m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.51-2.42 (m,1H),2.33-2.16(m,3H),1.86-1.78(m,1H),1.74-1.54(m,5H),1.46-1.43(m,2H),1.42 (m,18H),1.28-1.18(m,2H),0.96-0.93(m,6H)ppm。
Step 8）Compound 8-9 synthesis
By compound 8-8（0.24g,0.3mmol）It is dissolved in EtOAc（4.0mL）In, it is slowly dropped into the ethyl acetate of hydrogen chloride Solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （5mL）After mashing, faint yellow solid 0.2g, yield are filtrated to get：90%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:603.3[M+H]+。
Step 9）Compound 8-10 synthesis
By compound 8-9（0.23g,0.31mmol）, compound 1-11-2（0.12g,0.68mmol）, EDCI（0.13g, 0.68mmol）And HOAT（85mg,0.62mmol）It is suspended in DCM（20mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.51mL, 3.1mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, ammonium chloride is used respectively Solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/ v)=50/1）Obtain faint yellow solid 128mg, yield：45%.
MS(ESI,pos.ion)m/z:459.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.79,7.77(d,d,1H),7.66-7.62(m,3H),7.59(s,1H), 7.56,7.54(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.56,5.55(d,d,1H),5.46,5.44(d, d,1H),5.31-5.26(m,1H),5.07-5.02(m,1H),4.41-4.36(m,1H),4.31-4.27(m,1H),3.92- 3.84(m,2H),3.66(s,6H),3.61-3.54(m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.56- 2.47(m,1H),2.37-2.09(m,5H),1.83-1.75(m,1H),1.72-1.52(m,5H),1.50-1.40(m,2H), 1.28-1.18(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94-0.89(m,12H)ppm。
Embodiment 9
Synthetic route：
Step 1）Compound 9-2 synthesis
By compound 9-1（11.0g,44.8mmol）It is dissolved in DCM（200mL）In, at -78 DEG C, it is slowly dropped into Et2NSF3 （8.85mL,67.3mmol）, drop finishes, and after isothermal reaction 2.0 hours, reacts at room temperature 19 hours.After reaction completely, ammonium chloride is added The aqueous solution（100mL）Reaction, water layer DCM is quenched（100mL×3）Extraction, merges organic phase, and saturated common salt water washing is anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Obtain weak yellow liquid 7.75g yield：70%.
MS(ESI,pos.ion)m/z:248.3[M+H]+；
1H NMR(400MHz,CDCl3):δ5.26,5.13(ds,ds,1H),4.55-4.41(m,1H),3.88-3.74(m, 1H),3.73(s,3H),3.64-3.58(m,1H),2.52-2.44(m,1H),2.40-2.32(m,1H),1.42-1.47(d, 9H,J=20Hz)ppm。
Step 2）Compound 9-3 synthesis
By compound 9-2（5.83g,23.6mmol）It is dissolved in THF（30mL）In, at 0 DEG C, it is slowly dropped into the water of lithium hydroxide Solution（1.98g,30mL）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, watery hydrochloric acid is used（1M）Adjust the pH value of reaction solution To 5, after removing THF, water layer watery hydrochloric acid（1M）PH value is adjusted to 2, uses EtOAc（80mL×3）Extraction, merge organic phase, use Saturated common salt water washing, anhydrous Na2SO4Dry, white solid 5.27g, yield are obtained after concentration：96%.
MS(ESI,pos.ion)m/z:234.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.76(brs,1H),5.28-5.12(m,1H),4.56-4.44(m,1H), 3.86-3.58(m,2H),2.77-2.01(m,2H),1.48-1.44(d,9H,J=16Hz)ppm。
Step 3）Compound 9-4 synthesis
By compound 9-3（1.3g,5.57mmol）It is dissolved in THF（20mL）In, at 0 DEG C, it is slowly dropped into borine（8.3mL,1M in THF）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, methanol is used（4.0mL）Reaction is quenched, removes THF, residue Use DCM（50mL）After dissolving, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, obtained after concentration Colorless syrup 1.07g, yield：88%.
MS(ESI,pos.ion)m/z:220.3[M+H]+；
1H NMR(400MHz,CDCl3):δ5.19-5.06(m,1H),4.12-4.04(m,1H),3.99-3.79(m,1H), 3.69-3.63(m,1H),3.60-3.46(m,2H),2.25-2.00(m,2H),1.44(s,9H)ppm。
Step 4）Compound 9-6 synthesis
By compound 9-4（1.15g,5.24mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, by TCCA（1.22g, 5.24mmol）In addition system, then by TEMPO DCM solution（82mg,0.52mmol,3mL）Instill, drop finishes, isothermal reaction After 1.0 hours, react at room temperature 1.0 hours.After reaction completely, solid, filtrate saturated sodium bisulfite solution are filtered to remove（20mL ×3）Washing, anhydrous Na2SO4Dry, residue is dissolved in methanolic ammonia solution after concentration（7mL,7M）, react 0.5 hour at 0 DEG C, After room temperature continues reaction 1.0 hours, it is cooled to again at 0 DEG C, is slowly dropped into glyoxal water solution（1.1mL,40%）, drop is complete, room Temperature reaction 24 hours.After reaction completely, concentration of reaction solution, residue adds DCM（50mL）After dissolving, water is used respectively（30mL× 3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 100/1）Obtain faint yellow solid 0.67g, yield：50%.
MS(ESI,pos.ion)m/z:256.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.98(s,2H),5.36-5.13(m,2H),3.72-3.31(m,2H),2.58- 2.32(m,2H),1.48(s,9H)ppm。
Step 5）Compound 9-7 synthesis
By compound 9-6（0.63g,2.47mmol）It is dissolved in DCM（8.0mL）In, at 0 DEG C, add NIS（1.23g, 5.43mmol）, isothermal reaction 2.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, solid is filtered to remove, filtered Liquid saturated sodium bisulfite solution（20mL×3）Washing, merge organic phase, use anhydrous Na2SO4Dry, obtain yellow after concentration and consolidate Body 1.07g, yield：85.6%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:508.1[M+H]+；
1H NMR(400MHz,CDCl3):δ5.34-5.08(m,2H),3.72-3.28(m,2H),2.58-2.33(m,2H), 1.48(s,9H)ppm。
Step 6）Compound 9-8 synthesis
By compound 9-7（1.07g,2.12mmol）It is dissolved in ethanol（6.0mL）In, add sodium sulfite（2.14g, 17mmol）And water（6.0mL）, 90 DEG C are reacted 30 hours.After reaction completely, solid is filtered to remove, concentrates filtrate, residue adds DCM（40mL）After dissolving, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through post layer after concentration Analysis isolates and purifies（Eluant, eluent：PE/EtOAc(v/v)=1/1）Obtain white solid 0.59g, yield：73%.
MS(ESI,pos.ion)m/z:382.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.04(s,1H),5.35-5.09(m,2H),3.98-3.63(m,1H),3.58- 3.29(m,1H),2.55-2.34(m,2H),1.48(s,9H)ppm。
Step 7）Compound 9-9 synthesis
By compound 9-3（5.0g,21.45mmol）With compound 3-1-0（4.93g,17.87mmol）It is dissolved in DCM （100mL）In, at 0 DEG C, it is slowly dropped into TEA（4.34g,42.9mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, Add water（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merge organic phase, it is anhydrous with saturated common salt water washing Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain product 4.5g, yield： 52.2%。
MS(ESI,pos.ion)m/z:403.3[M+H]+。
Step 8）Compound 9-10 synthesis
By compound 9-9（4.48g,11.19mmol）And ammonium acetate（12.5g,162mmol）It is suspended in toluene（50mL） In, 110 DEG C are flowed back 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction, water layer EtOAc is quenched（80mL ×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=3/1）Obtain product 4.2g, yield：92%.
MS(ESI,pos.ion)m/z:411.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.56-7.51(m,2H),7.47-7.45(m,2H),7.22(s,1H),5.38- 5.29(m,1H),5.25-5.17(m,1H),4.13-4.07,3.62-3.39(m,m,1H),3.68-3.58(m,1H),2.68- 2.38(m,2H),1.38(s,9H)ppm。
Step 9）Compound 9-11 synthesis
By compound 9-10（2.0g,4.87mmol）, compound 1-12-2（1.26g,4.97mmol）, Pd (dppf) Cl2·CH2Cl2（0.07g,0.097mmol）And KOAc（1.19g,12.2mmol）It is placed in reaction bulb, N2Under protection, injection DME（20mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilution, diatomite mistake Filter, filtrate use water respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain product 1.42g, yield：64%.
MS(ESI,pos.ion)m/z:458.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.81-7.79(m,2H),7.65-7.60(m,2H),7.28(s,1H),5.39- 5.26(m,1H),5.20-5.12(m,1H),4.07-3.99,3.59-3.41(m,m,1H),3.69-3.62(m,1H),2.62- 2.51(m,2H),1.34(s,12H),1.28(s,9H)ppm。
Step 10）Compound 9-12 synthesis
By compound 9-11（1.2g,2.62mmol）, compound 1-8（0.88g,2.62mmol）, Pd (PPh3)4（0.15g, 0.13mmol）And potassium carbonate（0.90g,6.55mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（12mL）With it is pure Water（3.0mL）Afterwards, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（120mL）Dilute reaction solution Afterwards, water is used respectively（50mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.77g, yield：50%.
MS(ESI,pos.ion)m/z:586.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.51-7.50,7.49-7.48 (m,m,2H),7.41(s,1H),5.35-5.28,5.23-5.15(m,m,1H),4.85-4.80(m,1H),4.11-3.99(m, 1H),3.73-3.60(m,1H),2.92-2.77(m,3H),2.76-2.72(m,2H),2.27-2.13(m,1H),1.75-1.54 (m,4H),1.53-1.44(m,2H),1.42(s,9H),1.31-1.21(m,2H)ppm。
Step 11）Compound 9-13 synthesis
By compound 9-12（0.94g,1.61mmol）, compound 1-12-2（0.45g,1.77mmol）, Pd (dppf) Cl2·CH2Cl2（66mg,0.081mmol）And KOAc（0.4g,4.03mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （8.0mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（80mL）After dilute reaction solution, Diatomite filters.Filtrate uses water respectively（30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through post layer after concentration Analysis isolates and purifies（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.56g, yield：55%.
MS(ESI,pos.ion)m/z:634.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.41(s,1H),7.23- 7.22,7.21-7.20(m,m,2H),5.35-5.28,5.23-5.15(m,m,1H),4.85-4.80(m,1H),4.11-3.99 (m,1H),3.73-3.60(m,1H),2.92-2.77(m,3H),2.66-2.63(m,2H),2.27-2.13(m,1H),1.74- 1.54(m,6H),1.52-1.45(m,2H),1.42(s,9H),1.33,1.30(q,q,12H)ppm。
Step 12）Compound 9-14 synthesis
By compound 9-13（0.27g,0.42mmol）, compound 9-8（0.16g,0.42mmol）, four triphenyl phosphorus palladiums （25mg,0.02mmol）And potassium carbonate（0.17g,1.27mmol）It is suspended in DME/H2O（v/v=3/1）Mixed solvent（8.0mL） In, under nitrogen protection, 90 DEG C are reacted 2.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate（50mL） After dissolving, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/EtOH (v/v)=80/1）Obtain faint yellow solid 0.14g, yield：45%.
MS(ESI,pos.ion)m/z:761.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57 (m,m,2H),7.51(s,1H),7.41(s,1H),5.35-5.28,5.23-5.15(m,m,2H),5.08-5.03(m,1H), 4.85-4.80(m,1H),4.11-3.99(m,2H),3.73-3.60(m,2H),3.01-2.73(m,6H),2.34-2.13(m, 2H),1.72-1.52(m,4H),1.47-1.43(m,2H),1.42(s,9H),1.41(s,9H),1.27-1.17(m,2H)ppm。
Step 13）Compound 9-15 synthesis
By compound 9-14（0.39g,0.51mmol）It is dissolved in ethyl acetate（4.0mL）In, the acetic acid second of hydrogen chloride is added dropwise Ester solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （4.0mL）After mashing, faint yellow solid 0.32g, yield are filtrated to get：90%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:561.3[M+H]+。
Step 14）Compound 9-16 synthesis
By compound 9-15（0.2g,0.29mmol）, compound 1-11-2（0.11g,0.65mmol）, EDCI（0.12g, 0.65mmol）And HOAT（80mg,0.59mmol）It is suspended in DCM（5mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.49mL, 2.97mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, chlorination is used respectively Ammonium salt solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH (v/v)=40/1）Obtain white solid foam 0.15g, yield：60%.
MS(ESI,pos.ion)m/z:875.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57 (m,m,2H),7.51(s,1H),7.44(s,1H),7.38(s,1H),5.32,5.29(d,d,2H),5.29-5.24(m,1H), 5.19-5.11(m,2H),4.99-4.94(m,1H),4.46-4.40(m,2H),4.13-4.01(m,2H),3.75-3.64(m, 2H),3.63(s,6H),3.04-2.73(m,6H),2.36-2.12(m,4H),1.73-1.52(m,4H),1.49-1.38(m, 2H),1.27-1.17(m,2H),1.41(s,9H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 10
Synthetic route：
Step 1）Compound 10-2 synthesis
At 0 DEG C, by DMAP（0.55g,4.5mmol）It is added to compound 10-1（7.08g,45.06mmol）MeCN （50mL）In solution, after stirring 10 minutes, then di-tert-butyl dicarbonate is instilled（10.82g,49.56mmol）, drop is complete, and constant temperature is anti- After answering 30 minutes, react at room temperature 2.0 hours.After reaction completely, concentration of reaction solution is through column chromatographic isolation and purification（Eluant, eluent：PE/ EtOAc(v/v)=1/1）Obtain colourless liquid 7.54g, yield：65%.
MS(ESI,pos.ion)m/z:157.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ4.29-4.26(m,1H),3.71(s,3H),3.25-3.18(m,1H),3.16- 3.10(m,1H),2.25-2.20(m,1H),1.84-1.79(m,1H),1.46(s,9H),1.01-0.99(m,3H),0.86- 0.84(m,3H)ppm。
Step 2）Compound 10-3 synthesis
By compound 10-2（4.85g,18.86mmol）It is dissolved in THF（40mL）In, at 0 DEG C, by a hydronium(ion) lithia water Solution（1.5g,20mL）In addition system, react at room temperature 2.0 hours.After reaction completely, THF is removed, adds water（50mL）, use EtOAc（30mL×3）Washing, after liquid separation, water layer watery hydrochloric acid（1M）PH value is adjusted to use EtOAc to after 1（50mL×3）Extraction, close And organic phase, with saturated common salt water washing, anhydrous Na2SO4Dry, white solid 4.35g, yield are obtained after concentration：95%.
MS(ESI,pos.ion)m/z:244.5[M+H]+；
1H NMR(400MHz,CDCl3):δ4.34-4.31(m,1H),3.28-3.22(m,1H),3.20-3.13(m,1H), 2.23-2.18(m,1H),1.85-1.80(m,1H),1.46(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H) ppm。
Step 3）Compound 10-4 synthesis
By compound 10-3（3.18g,13.1mmol）With compound 3-1-0（3.63g,13.1mmol）It is dissolved in DCM （40mL）In, at 0 DEG C, it is slowly dropped into Et3N（3.9mL,26.3mmol）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, Add water（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merge organic phase, it is anhydrous with saturated common salt water washing Na2SO4Dry, crude product 3.27g is obtained after concentration, be directly used in and react in next step.
MS(ESI,pos.ion)m/z:413.3[M+H]+。
Step 4）Compound 10-5 synthesis
By compound 10-4（3.37g,8.2mmol）And ammonium acetate（5.1g,66mmol）It is suspended in toluene（30mL）In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction, water layer EtOAc is quenched（80mL× 3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=2/1）Obtain product 2.75g, yield：80%.
MS(ESI,pos.ion)m/z:421.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.63-7.60(m,2H),7.49-7.45(m,2H),7.31(s,1H),5.04- 4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.25-2.19(m,1H),1.87-1.81(m,1H), 1.53(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 5）Compound 10-6 synthesis
By compound 10-5（2.89g,6.9mmol）, compound 1-12-2（1.93g,7.6mmol）, Pd (dppf) Cl2· CH2Cl2（0.28g,0.34mmol）With KOAc（1.7g,17.25mmol）It is placed in reaction bulb, N2Protection, inject DME（30mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（200mL）Dilute reaction solution, diatomite filtering, Filtrate uses water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=1/1）Obtain faint yellow solid 2.74g, yield：85%.
MS(ESI,pos.ion)m/z:468.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.23-8.20(m,2H),7.79-7.76(m,2H),7.23(s,1H),5.04- 4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.25-2.19(m,1H),1.87-1.81(m,1H), 1.53(s,9H),1.35,1.32(m,m,12H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 6）Compound 10-7 synthesis
By compound 10-6（0.23g,0.5mmol）, compound 1-8（0.17g,0.5mmol）, Pd (PPh3)4（0.12g, 0.05mmol）And potassium carbonate（0.17g,1.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（5.0mL）With it is pure Water（1.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, point Water is not used（10mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 178mg, yield：60%.
MS(ESI,pos.ion)m/z:597.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(m,m,2H),7.72-7.71,7.70-7.69 (m,m,2H),7.39(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.84-2.81 (m,2H),2.75-2.72(m,2H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.74-1.54(m,4H),1.53- 1.43(m,2H),1.41(s,9H),1.30-1.21(m,2H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 7）Compound 10-8 synthesis
By compound 10-7（0.96g,1.61mmol）, compound 1-12-2（0.45g,1.77mmol）, Pd (dppf) Cl2·CH2Cl2（66mg,0.081mmol）And KOAc（0.4g,4.03mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （8.0mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（80mL）After dilute reaction solution, Diatomite filters.Filtrate uses water respectively（30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through post layer after concentration Analysis isolates and purifies（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.52g, yield：50%.
MS(ESI,pos.ion)m/z:644.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.77-7.76,7.75-7.74(m,m,2H),7.44-7.43,7.42-7.41 (m,m,2H),7.39(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.80-2.77 (m,2H),2.66-2.63(m,2H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.74-1.54(m,6H),1.52- 1.44(m,2H),1.41(s,9H),1.33,1.30(q,q,12H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 8）Compound 10-9 synthesis
By compound 10-3（1.13g,4.66mmol）It is dissolved in THF（10mL）In, under 0 DEG C of nitrogen protection, by borine （10mL,1M in THF）It is slowly dropped into reaction bulb, drop finishes, isothermal reaction 3 hours.After reaction completely, methanol is used（10mL）Quench Go out reaction, through column chromatographic isolation and purification after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain colorless oil 0.8g, yield：75%.
1H NMR(400MHz,CDCl3):δ4.37(brs,1H),4.20-4.12(m,1H),3.84-3.73(m,2H), 3.06-2.94(m,2H),1.84-1.78(m,1H),1.48(s,9H),1.44-1.38(m,1H),1.01-0.99(m,3H), 0.86-0.84(m,3H)ppm。
Step 9）Compound 10-10 synthesis
By compound 10-9（0.8g,3.48mmol）It is dissolved in DCM（10mL）In, at 0 DEG C, by Dai Si-Martin's oxidant （2.07g,4.88mmol）It is added portionwise in reaction bulb, after adding, reacts at room temperature 2.0 hours.After reaction completely, water is added （20mL）And DCM（50mL）Dilute reaction solution, filter, after filtrate layered, organic layer saturated common salt water washing, anhydrous sodium sulfate Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/2）Colorless oil 0.39g is obtained, is produced Rate：50%.
1H NMR(400MHz,CDCl3):δ9.69-9.68(m,1H),4.48-4.45(m,1H),3.32-3.15(m,1H), 3.01-2.94(m,1H),2.30-2.28,2.27-2.25(m,m,1H),1.76-1.74,1.72-1.71(m,m,1H),1.43 (s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 10）Compound 10-11 synthesis
By compound 10-10（0.4g,1.76mmol）And ammoniacal liquor（2mL）It is dissolved in methanol（3mL）In, at 0 DEG C, by glyoxal （40%,1mL）The aqueous solution slowly instill in reaction bulb, drop finish, room temperature reaction overnight.After reaction completely, passed through after concentration of reaction solution Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 0.22g, yield：47%.
MS(ESI,pos.ion)m/z:266.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.96(s,2H),5.01-4.96(m,1H),3.41-3.35(m,1H),3.31- 3.24(m,1H),2.26-2.20(m,1H),1.85-1.79(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86- 0.84(m,3H)ppm。
Step 11）Compound 10-12 synthesis
By compound 10-11（0.22g,0.84mmol）It is dissolved in DCM（5mL）In, at 0 DEG C, by N- N-iodosuccinimides （0.38g,1.68mmol）It is added portionwise in reaction bulb, isothermal reaction 1.5 hours.After reaction completely, DCM is added（20mL）Dilution After reaction solution, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=3/2）Obtain white solid 0.27g, yield：63%.
MS(ESI,pos.ion)m/z:518.2[M+H]+；
1H NMR(400MHz,CDCl3):δ5.14-5.10(m,1H),3.41-3.34(m,1H),3.30-3.23(m,1H), 2.37-2.31(m,1H),2.02-1.96(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H) ppm。
Step 12）Compound 10-13 synthesis
By compound 10-12（0.17g,0.33mmol）It is suspended in second alcohol and water（v/v=3/7）Mixed solvent（5mL） In, by sodium sulfite（0.37g,2.9mmol）Add in mixed liquor and flow back 17 hours.After reaction completely, ethanol, residue are removed Add water（10mL）, use ethyl acetate（10mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are dense Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 0.11g, yield：84%.
MS(ESI,pos.ion)m/z:392.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.33(s,1H),4.87-4.83(m,1H),3.41-3.34(m,1H),3.30- 3.24(m,1H),2.29-2.24(m,1H),1.92-1.86(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86- 0.84(m,3H)ppm。
Step 13）Compound 10-14 synthesis
By compound 10-13（0.16g,0.42mmol）, compound 10-8（0.27g,0.42mmol）, four triphenyl phosphorus palladiums （25mg,0.02mmol）And potassium carbonate（0.17g,1.27mmol）It is suspended in DME/H2O（v/v=3/1）Mixed solvent（8mL）In, Under nitrogen protection, 90 DEG C are reacted 5.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate（20mL）Dissolving Afterwards, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/EtOH(v/ v)=80/1）Obtain faint yellow solid 147mg, yield：45%.
MS(ESI,pos.ion)m/z:782.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.80-7.79(m,m,2H),7.76-7.75,7.74-7.73(m,m,2H), 7.46(s,1H),7.39(s,1H),5.12-5.08(m,1H),5.04-4.99(m,1H),3.41-3.34(m,2H),3.30- 3.24(m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.31-2.19(m,2H),1.91-1.81(m,2H), 1.73-1.52(m,4H),1.49-1.42(m,2H),1.41(s,18H),1.27-1.17(m,2H),1.01-0.99(m,3H), 0.86-0.84(m,3H)ppm。
Step 14）Compound 10-15 synthesis
By compound 10-14（0.39g,0.5mmol）It is dissolved in ethyl acetate（4.0mL）In, the acetic acid second of hydrogen chloride is added dropwise Ester solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （4.0mL）Mashing, obtains faint yellow solid 0.33g, yield after filtering：90%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:581.8[M+H]+。
Step 15）Compound 10-16 synthesis
By compound 10-15（0.21g,0.29mmol）, compound 1-11-2（0.11g,0.65mmol）, EDCI （0.12g,0.65mmol）And HOAT（80mg,0.59mmol）It is suspended in DCM（5mL）In, at 0 DEG C, it is slowly dropped into DIPEA （0.49mL,2.97mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, point Not Yong ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=40/1）Obtain yellow foamy solid 0.14g, yield：55%.
MS(ESI,pos.ion)m/z:896.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57 (m,m,3H),7.39(s,1H),5.32,5.29(d,d,2H),5.23-5.16(m,2H),4.40-4.35(m,2H),3.63(s, 6H),3.57-3.50(m,2H),3.45-3.39(m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.34-2.22 (m,2H),2.18-2.08(m,2H),1.91-1.81(m,2H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27- 1.17(m,2H),1.01-0.99(m,6H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H),0.86-0.84(m, 6H)ppm。
Embodiment 11
Synthetic route：
Step 1）Compound 11-2 synthesis
At room temperature, by the ethyl acetate solution of hydrogen chloride（5.0mL,4M）It is added drop-wise to compound 11-1（1.72g, 4.13mmol）EtOAc（10mL）In solution, drop finishes, and reacts 8.0 hours.After reaction completely, concentration of reaction solution, residue adds Enter EtOAc（5.0mL）After mashing, solid 1.38g, yield are filtrated to get：86%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:317.5[M+H]+。
Step 2）Compound 11-3 synthesis
By compound 11-2（1.4g,3.6mmol）, compound 1-11-2（0.69g,3.9mmol）And EDCI（0.75g, 3.9mmol）It is suspended in DCM（10mL）In, at 0 DEG C, it is slowly dropped into DIPEA（2.38mL,14.4mmol）, drop is complete, room temperature reaction 2.0 hour.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase are washed with saturated ammonium chloride solution, anhydrous sulphur Sour sodium is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Faint yellow solid 1.45g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:474.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.96(brs,1H),7.68-7.67(m,1H),7.55-7.52(m,1H), 7.35-7.32(m,1H),7.14-7.10(m,1H),5.32,5.29(d,d,1H),4.55-4.51(m,1H),4.31-4.26 (m,1H),3.63(s,3H),3.62-3.55(m,1H),3.47-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82 (m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 3）Compound 11-4 synthesis
By compound 11-3（0.76g,1.61mmol）, compound 1-12-2（0.45g,1.77mmol）, Pd (dppf) Cl2·CH2Cl2（66mg,0.081mmol）And KOAc（0.4g,4.03mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （4.0mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（40mL）After dilute reaction solution, Diatomite filters.Filtrate uses water respectively（30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through post layer after concentration Analysis isolates and purifies（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.42g, yield：55%.
MS(ESI,pos.ion)m/z:474.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.96(m,1H),7.94-7.93(m,1H),7.65-7.64,7.63-7.62 (m,m,1H),7.41-7.34(m,2H),5.32,5.30(d,d,1H),4.71-4.66(m,1H),4.31-4.26(m,1H), 3.63(s,3H),3.62-3.55(m,1H),3.48-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H), 1.32,1.29(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4）Compound 11-5 synthesis
By compound 11-4（0.21g,0.44mmol）, compound 1-8（70mg,0.21mmol）, four triphenyl phosphorus palladiums （25mg,0.02mmol）And potassium carbonate（87mg,0.63mmol）It is suspended in DME/H2O（v/v=3/1）Mixed solvent（4.0mL） In, under nitrogen protection, 90 DEG C are reacted 5.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate（20mL） Afterwards, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/EtOH(v/ v)=40/1）Obtain faint yellow solid 82mg, yield：45%.
MS(ESI,pos.ion)m/z:435.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.96(m,1H),8.90(m,1H),7.68-7.67,7.66-7.65(m,m, 4H),7.53-7.52,7.51-7.49(m,m,4H),5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),4.61-4.57 (m,1H),4.33-4.28(m,2H),4.27-4.22(m,1H),3.66(s,3H),3.63(s,3H),3.61-3.55(m,1H), 3.47-3.35(m,3H),2.77-2.75(m,4H),2.26-1.86(m,8H),1.75-1.42(m,8H),1.22-1.20(m, 2H),1.02-0.89(m,12H)ppm。
Embodiment 12
Synthetic route：
Step 1）Compound 12-2 synthesis
At 0 DEG C, by thionyl chloride（5.5mL,75.8mmol）It is slowly dropped to compound 12-1（10g,77.5mmol）'s MeOH（50mL）In solution, after isothermal reaction 1.0 hours, react at room temperature 2.0 hours.After reaction completely, NaHCO is added3Solution （50mL）Reaction is quenched, removes methanol, residue DCM（35mL×3）Extraction, merge organic phase, with saturated common salt water washing, Anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：EtOAc）Obtain colourless liquid 7.5g, yield： 67.6%。
MS(ESI,pos.ion)m/z:144.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.38(br,1H),4.20-4.16(m,1H),3.67(s,3H),2.39-2.23 (m,3H),2.14-2.07(m,1H)ppm。
Step 2）Compound 12-3 synthesis
At 0 DEG C, by DMAP（0.55g,4.5mmol）It is added to compound 12-2（6.45g,45.06mmol）MeCN （30mL）In solution, after stirring 10 minutes, then di-tert-butyl dicarbonate is instilled（10.82g,49.56mmol）, drop is complete, and constant temperature is anti- After answering 30 minutes, react at room temperature 2.0 hours.After reaction completely, concentration of reaction solution is through column chromatographic isolation and purification（Eluant, eluent：PE/ EtOAc(v/v)=1/1）Obtain colourless liquid 5.0g, yield：45.6%.
MS(ESI,pos.ion)m/z:144.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ4.60-4.57(m,1H),3.75(s,3H),2.65-2.55(m,1H),2.50- 2.42(m,1H),2.36-2.24(m,1H),2.04-1.96(m,1H),1.45(s,9H)ppm。
Step 3）Compound 12-4 synthesis
At -78 DEG C, by lithium triethylborohydride（1.79g,16.9mmol）It is slowly dropped to compound 12-3（3.74g, 15.4mmol）Toluene（50mL）In solution, after isothermal reaction 70 minutes, DIPEA is sequentially added（3.2mL,19.4mmol）, DMAP（0.19g,1.54mmol）And TFAA（3mL,40.4mmol）, after adding, react at room temperature 2.0 hours.It is dense after reaction completely Through column chromatographic isolation and purification after contracting reaction solution（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain yellow liquid 2.26g, yield： 64.8%。
MS(ESI,pos.ion)m/z:128.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ6.65-6.52(br,1H),4.96-4.91(br,1H),4.68-4.57(m, 1H),3.76(s,3H),3.12-3.00(m,1H),2.71-2.61(m,1H),1.49-1.44(br,9H)ppm。
Step 4）Compound 12-5 synthesis
At 0 DEG C, by chloroiodomethane（1.40g,7.9mmol）It is slowly dropped to diethyl zinc（0.49g,3.94mmol）First Benzene（6mL）In solution, after reacting 45 minutes, then compound 12-4 is instilled（0.3g,1.32mmol）Toluene（4mL）Solution, drop Finish, isothermal reaction 18 hours.After reaction completely, saturation NH is added4Cl solution（15mL）Reaction, water layer EtOAc is quenched（25mL ×3）Extraction, merge organic phase, use anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/ v)=10/1）Obtain yellow liquid 0.19g, yield：59.7%.
MS(ESI,pos.ion)m/z:142.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ4.64-4.51(m,1H),3.70(s,3H),3.56-3.45(m,1H),2.64- 2.54(m,1H),2.05-2.01(m,1H),1.50,1.41(s,s,9H),0.75-0.65(m,3H)ppm。
Step 5）Compound 12-6 synthesis
At 0 DEG C, by a hydronium(ion) lithia（0.89g,21.2mmol）The aqueous solution（10mL）It is slowly dropped to compound 12-5（1.02g,4.23mmol）THF（20mL）In solution, drop finishes, and 40 DEG C are reacted 12 hours.After reaction completely, THF is removed, Add water（10mL）, then use EtOAc（25mL×3）Extraction, water layer hydrochloric acid after liquid separation（10%）PH value is adjusted to 1, then uses EtOAc （25mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, white solid is obtained after concentration 0.84g, yield：87.5%.
MS(ESI,neg.ion)m/z:226.2[M-H]-；
1H NMR(400MHz,CD3OD):δ4.53-4.46(m,1H),3.48-3.42(m,1H),2.70-2.57(m,1H), 2.05-2.01(m,1H),1.60-1.54(m,1H),1.48,1.41(s,s,9H),0.89-0.80(m,1H),0.73-0.66 (m,1H)ppm。
Step 6）Compound 12-7 synthesis
By compound 12-6（3.91g,17.22mmol）With compound 3-1-0（5.47g,19.81mmol）It is dissolved in DCM （60mL）In, at 0 DEG C, it is slowly dropped into DIPEA（3.4mL,20.67mmol）, drop is complete, reacts at room temperature 3.0 hours.Reaction is complete Afterwards, water is added（50mL）Reaction, water layer DCM is quenched（100mL×3）Extraction, merge organic phase, with saturated common salt water washing, Anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain white solid 4.5g, yield：61.7%.
MS(ESI,pos.ion)m/z:425.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.77-7.73(m,2H),7.64-7.62(m,2H),5.53-5.09(m,2H), 4.78-4.67(m,1H),3.59-3.46(m,1H),2.69-2.62(m,1H),2.43-2.40(m,1H),1.42(s,9H), 1.00-0.96(m,1H),0.76-0.69(m,2H)ppm。
Step 7）Compound 12-8 synthesis
Compound 12-7（4.5g,10.64mmol）And ammonium acetate（16.4g,212.73mmol）It is suspended in dimethylbenzene （50mL）In, 120 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction is quenched, water layer is used EtOAc（100mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain product 2.14g, yield：50%.
MS(ESI,pos.ion)m/z:404.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.62-7.52(br,2H),7.49-7.46(d,2H,J=12Hz),7.21(s, 1H),5.27-5.24(d,1H,J=10.0Hz),3.31-3.27(m,1H),1.71-1.67(m,2H),1.52(s,9H),0.89- 0.86(m,1H),0.64-0.69(m,2H)ppm。
Step 8）Compound 12-9 synthesis
By compound 12-8（2.1g,5.2mmol）, compound 1-12-2（1.59g,6.25mmol）, Pd (dppf) Cl2· CH2Cl2（0.43g,0.52mmol）And KOAc（1.54g,15.63mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （20mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil filtering, filtrate use water respectively（60mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 2.27g, yield：97%.
MS(ESI,pos.ion)m/z:452.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.81-7.79(d,2H,J=8.04Hz),7.60(br,2H),7.26(s,1H), 5.28-5.26(d,1H,J=8.0Hz),3.53(br,1H),3.30-3.27(br,1H),1.67-1.66(m,2H),1.52(s, 9H),1.34(s,12H),0.89-0.86(m,1H),0.69-0.64(m,2H)ppm。
Step 9）Compound 12-10 synthesis
At room temperature, by the ethyl acetate solution of hydrogen chloride（5.0mL,4M）It is added drop-wise to compound 12-9（0.9g,2mmol）'s EtOAc（10mL）In solution, drop finishes, and reacts 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （5.0mL）After mashing, solid 0.94g, yield are filtrated to get：95%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:425.2[M+H]+。
Step 10）Compound 12-11 synthesis
By compound 12-10（0.37g,0.75mmol）, compound 1-11-2（0.13g,0.75mmol）And EDCI （0.3g,1.58mmol）It is suspended in DCM（5.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA（1.0mL,6.01mmol）, drop is complete, room Temperature reaction 2.0 hours.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase are washed with saturated ammonium chloride solution, Anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 324mg, yield：85%.
MS(ESI,pos.ion)m/z:509.3[M+H]+；
1H NMR(400MHz,CDCl3):δ8.96(brs,1H),7.68-7.67(m,1H),7.55-7.52(m,1H), 7.35-7.32(m,1H),7.14-7.10(m,1H),5.32,5.29(d,d,1H),4.55-4.51(m,1H),4.31-4.26 (m,1H),3.63(s,3H),3.62-3.55(m,1H),3.47-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82 (m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 11）Compound 12-12 synthesis
By compound 12-11（0.54g,1.07mmol）, compound 1-8（0.36g,1.07mmol）, Pd (PPh3)4 （0.12g,0.11mmol）And potassium carbonate（0.37g,2.67mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into （5.0mL）And pure water（1.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（50mL）It is dilute After releasing reaction solution, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.41g, yield：60%.
MS(ESI,pos.ion)m/z:638.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.62(s,1H),7.51- 7.50,7.49-7.48(m,2H),5.32,5.30(d,d,1H),4.89-4.85(m,1H),4.09-4.04(m,1H),3.63 (s,3H),3.45-3.38(m,1H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.46-2.39(m,1H),2.22- 2.09(m,1H),2.00-1.98,1.97-1.94(m,m,1H),1.75-1.54(m,4H),1.53-1.36(m,3H),1.30- 1.21(m,2H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 12）Compound 12-13 synthesis
By compound 12-10（0.15g,0.36mmol）, compound 4-2-2（68mg,0.36mmol）And EDCI（69mg, 0.36mmol）It is suspended in DCM（10mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.24mL,1.44mmol）, drop is complete, room temperature reaction 3.0 hour.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase are washed with saturated ammonium chloride solution, anhydrous sulphur Sour sodium is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Faint yellow solid 0.16g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:523.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.64-7.61,7.60-7.57(m,m,4H),7.29(s,1H),5.30,5.28 (d,d,1H),4.85-4.82(m,1H),4.09-4.04(m,1H),3.63(s,3H),3.37-3.31(m,1H),2.44-2.36 (m,1H),1.97-1.86(m,2H),1.62-1.51(m,1H),1.47-1.40(m,1H),1.35,1.32(q,q,12H), 1.27-1.13(m,1H),0.94-0.89(m,7H),0.51-0.47(m,1H)ppm。
Step 13）Compound 12-14 synthesis
By compound 12-13（0.26g,0.5mmol）, compound 12-12（0.32g,0.5mmol）, Pd (PPh3)4 （57.8mg,0.05mmol）And potassium carbonate（0.17g,1.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into （4.0mL）And pure water（1.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（50mL）It is dilute After releasing reaction solution, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 0.26g, yield：55%.
MS(ESI,pos.ion)m/z:477.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.62(m,m,6H),7.48-7.47,7.46-7.45 (m,m,4H),5.99,5.97(d,d,1H),5.32,5.30(d,d,1H),4.89-4.82(m,2H),4.13-4.04(m,2H), 3.65(s,3H),3.63(s,3H),3.45-3.38(m,1H),3.37-3.31(m,1H),2.77-2.75(m,4H),2.46- 2.36(m,2H),2.22-2.09(m,1H),2.00-1.98,1.97-1.94,1.93-1.91(m,m,2H),1.90-1.80(m, 1H),1.73-1.52(m,4H),1.50-1.32(m,5H),1.28-1.18(m,2H),1.12-1.02(m,1H),0.98-0.82 (m,14H),0.51-0.46(m,2H)ppm。
Embodiment 13
Synthetic route：
Step 1）Compound 13-2 synthesis
By compound 13-1（10.68g,46.6mmol）It is dissolved in THF（100mL）In, under 0 DEG C of nitrogen protection, it is slowly dropped into Borine（100mL,1M in THF）, drop is complete, isothermal reaction 3.0 hours.After reaction completely, methanol is used（80mL）Reaction is quenched, it is dense Through column chromatographic isolation and purification after contracting reaction solution（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain colorless oil 7.52g, yield： 75%。
1H NMR(400MHz,CDCl3):δ4.20-4.11(m,1H),3.91-3.85(m,2H),3.72-3.65(m,1H), 3.34-3.26(m,1H),2.69(brs,1H),2.43-2.33(m,1H),1.52-1.48(m,1H),1.45(s,9H),1.35- 1.04(m,3H),0.94-0.80(m,1H)ppm。
Step 2）Compound 13-3 synthesis
By compound 13-2（7.49g,34.8mmol）It is dissolved in DCM（250mL）In, at 0 DEG C, by Dai Si-Martin（20.7g, 48.8mmol）Oxidant is added portionwise in reaction bulb, after adding, is reacted at room temperature 2.0 hours.After reaction completely, into reaction solution Add water（250mL）, filter, after filtrate layered, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, passed through after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain colorless oil 3.71g, yield：50%.
1H NMR(400MHz,CDCl3):δ9.69-9.66(m,1H),4.07-4.02(m,1H),3.90-3.83(m,1H), 3.04-2.94(m,1H),1.93-1.71(m,2H),1.44(s,9H),1.29-1.05(m,4H)ppm。
Step 3）Compound 13-4 synthesis
By compound 13-3（3.75g,17.6mmol）And ammoniacal liquor（13.0mL）It is dissolved in methanol（30mL）In, at 0 DEG C, slowly Instill glyoxal（40%,8.0mL）The aqueous solution, drop finish, room temperature reaction overnight.After reaction completely, through post layer after concentration of reaction solution Analysis isolates and purifies（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain white solid 1.99g, yield：45%.
MS(ESI,pos.ion)m/z:252.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.99(s,2H),4.91-4.84(m,1H),4.06-3.98(m,1H),2.97- 2.88(m,1H),2.11-2.02(m,1H),1.86-1.74(m,1H),1.73-1.65(m,1H),1.63-1.52(m,1H), 1.50(s,9H),1.25-1.03(m,2H)ppm。
Step 4）Compound 13-5 synthesis
By compound 13-4（2.11g,8.4mmol）It is dissolved in DCM（60mL）In, at 0 DEG C, by N- N-iodosuccinimides （3.8g,16.8mmol）It is added portionwise in reaction bulb, after adding, isothermal reaction 1.5 hours.After reaction completely, reaction solution is used full And brine It, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/1） Obtain white solid 2.66g, yield：63%.
MS(ESI,pos.ion)m/z:504.2[M+H]+；
1H NMR(400MHz,CDCl3):δ4.69-4.63(m,1H),4.62-4.18(m,1H),2.97-2.87(m,1H), 2.21-2.12(m,1H),1.85-1.72(m,2H),1.64-1.52(m,1H),1.50(s,9H),1.25-1.06(m,2H) ppm。
Step 5）Compound 13-6 synthesis
By compound 13-5（1.64g,3.27mmol）It is suspended in second alcohol and water（v/v=3/7）Mixed solvent（50mL） In, by sodium sulfite（3.7g,29mmol）Add in mixed liquor and flow back 17 hours.After reaction completely, ethanol is removed, residue adds Enter water（50mL）, aqueous phase EtOAc（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are dense Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 0.99g, yield：80.5%.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.34(s,1H),4.75-4.68(m,1H),4.06-3.99(m,1H),2.97- 2.87(m,1H),2.16-2.07(m,1H),1.86-1.69(m,2H),1.64-1.53(m,1H),1.50(s,9H),1.25- 1.02(m,2H)ppm。
Step 6）Compound 13-7 synthesis
By compound 13-1（3.96g,17.28mmol）With compound 13-7-0（5.82g,19.81mmol）It is dissolved in CH3CN （60mL）In, at 0 DEG C, it is slowly dropped into DIPEA（3.4mL,20.67mmol）, drop is complete, reacts at room temperature 3.0 hours.Reaction is complete Afterwards, frozen water is used（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merge organic phase, with saturated common salt water washing, nothing Water Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain white solid 4.67g yield：61%.
MS(ESI,pos.ion)m/z:445.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.90-7.89,7.88-7.87(dd,dd,1H),7.84,7.82,7.80(d, dd,d,1H),7.69-7.68,7.67-7.66(q,q,1H),5.26(s,2H),4.79-4.74(m,1H),3.96-3.89(m, 1H),3.09-3.00(m,1H),2.15-2.06(m,2H),1.42(s,9H),1.27-1.02(m,4H)ppm。
Step 7）Compound 13-8 synthesis
By compound 13-7（4.71g,10.64mmol）And ammonium acetate（16.4g,212.73mmol）It is suspended in toluene （50mL）In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction is quenched, water layer is used EtOAc（100mL×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography after concentration Isolate and purify（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain product 2.25g, yield：50%.
MS(ESI,pos.ion)m/z:425.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.61(s,1H),7.59,7.57,7.55(d,dd,d,1H),7.22,7.20 (d,d,1H),7.11,7.09(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H), 2.12-2.03(m,1H),1.87-1.74(m,1H),1.72-1.53(m,2H),1.50(s,9H),1.25-1.02(m,2H) ppm。
Step 8）Compound 13-9 synthesis
By compound 13-8（2.2g,5.2mmol）, compound 1-12-2（1.59g,6.25mmol）, Pd (dppf) Cl2· CH2Cl2（0.43g,0.52mmol）And KOAc（1.54g,15.63mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （30mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）After dilute reaction solution, diatom Soil filtering, filtrate use water respectively（50mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 2.08g, yield：85%.
MS(ESI,pos.ion)m/z:472.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.79,7.77,7.75(d,dd,d,1H),7.52,7.50(d,d,1H),7.26 (s,1H),6.95-6.94,6.92-6.91(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97- 2.87(m,1H),2.12-2.03(m,1H),1.87-1.74(m,1H),1.72-1.53(m,2H),1.50(s,9H),1.32, 1.29(q,q,12H),1.25-1.02(m,2H)ppm。
Step 9）Compound 13-10 synthesis
By compound 13-9（1.23g,2.62mmol）, compound 1-8（0.88g,2.62mmol）, Pd (PPh3)4 （0.15g,0.13mmol）And potassium carbonate（0.90g,6.55mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into （12mL）And pure water（3.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, reaction solution adds EtOAc （100mL）After dilution, water is used respectively（50mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography after concentration Isolate and purify（Eluant, eluent：DCM/MeOH(v/v)=150/1）Obtain faint yellow solid 0.94g, yield：60%.
MS(ESI,pos.ion)m/z:601.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.60(s,1H),7.56,7.54(d,d,1H),7.46,7.45,7.44,7.43 (d,d,d,d,1H),7.14-7.13,7.11(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97- 2.87(m,1H),2.85-2.81(m,2H),2.76-2.72(m,2H),2.12-2.03(m,1H),1.87-1.52(m,11H), 1.50(s,9H),1.28-1.06(m,2H)ppm。
Step 10）Compound 13-11 synthesis
By compound 13-10（0.96g,1.61mmol）, compound 1-12-2（0.45g,1.77mmol）, Pd (dppf) Cl2·CH2Cl2（80mg,0.096mmol）And KOAc（0.4g,4.02mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （10mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（100mL）After dilute reaction solution, silicon Diatomaceous earth filters.Filtrate uses water respectively（20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography after concentration Isolate and purify（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain faint yellow solid 0.73g, yield：70%.
MS(ESI,pos.ion)m/z:648.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.62,7.60(d,d,1H),7.59(s,1H),7.18-7.12(m,2H), 4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H),2.81-2.77(m,2H),2.66-2.63(m, 2H),2.12-2.03(m,1H),1.87-1.53(m,9H),1.50(s,9H),1.49-1.42(m,2H),1.33,1.30(q,q, 12H),1.25-1.20(m,2H)ppm。
Step 11）Compound 13-12 synthesis
By compound 13-6（0.16g,0.42mmol）, compound 13-11（0.27g,0.42mmol）, four triphenyl phosphorus palladiums （25mg,0.02mmol）And potassium carbonate（0.15g,1.12mmol）The EtOH/H being suspended in2O（v/v=3/1）Mixed solvent （8.0mL）In, under nitrogen protection, 90 DEG C are reacted 6.0 hours.After reaction completely, ethyl acetate is added（50mL）Dilute reaction solution Afterwards, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/EtOH(v/ v)=80/1）Obtain faint yellow solid 0.21g, yield：65%.
MS(ESI,pos.ion)m/z:771.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.60(s,1H),7.56,7.55,7.54,7.53(d,d,d,d,1H),7.52, 7.49(d,d,1H),7.51(s,1H),7.14-7.13,7.11(dd,dd,1H),4.86-4.79(m,2H),4.28-4.20(m, 2H),2.97-2.87(m,4H),2.75-2.72(m,2H),2.12-1.94(m,2H),1.88-1.74(m,2H),1.72-1.51 (m,8H),1.50(s,18H),1.48-1.38(m,2H),1.27-1.02(m,6H)ppm。
Step 12）Compound 13-13 synthesis
By compound 13-12（0.39g,0.51mmol）It is dissolved in ethyl acetate（4.0mL）In, the acetic acid second of hydrogen chloride is added dropwise Ester solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （10mL）After mashing, pale yellow powder shape solid 0.33g, yield are filtrated to get：90%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:571.7[M+H]+。
Step 13）Compound 13-14 synthesis
By compound 13-13（0.21g,0.29mmol）, compound 6-5-2（96mg,0.65mmol）, EDCI（0.12g, 0.65mmol）And HOAT（80mg,0.59mmol）It is suspended in DCM（5.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.41mL, 2.32mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, chlorination is used respectively Ammonium salt solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH (v/v)=60/1）Obtain faint yellow solid 0.13g, yield：56%.
MS(ESI,pos.ion)m/z:415.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.60(s,1H),7.56,7.55,7.54,7.53(d,d,d,d,1H),7.52, 7.49(d,d,1H),7.43(s,1H),7.14-7.13,7.11(dd,dd,1H),5.44,5.42(m,m,2H),4.99-4.90 (m,2H),4.72-7.65(m,2H),3.87-3.81(m,2H),3.64(s,6H),2.96-2.92(m,2H),2.89-2.80 (m,2H),2.75-2.72(m,2H),2.26-2.18(m,1H),2.02-1.93(m,1H),1.84-1.51(m,10H),1.49- 1.39(m,2H),1.35,1.33(d,d,6H),1.27-1.14(m,4H),1.12-0.99(m,2H)ppm。
Embodiment 14
Synthetic route：
Step 1）Compound 14-2 synthesis
By compound 1-8（0.63g,1.88mmol）, compound 14-1（0.63g,1.88mmol）, four triphenyl phosphorus palladiums （0.22g,0.188mmol）And potassium carbonate（0.78g,5.64mmol）It is suspended in DME/H2O（v/v=3/1）Mixed solvent （12mL）In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, EtOAc is added（40mL）Dilute reaction solution, respectively Use water（20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.43g, yield：50%.
1H NMR(400MHz,CDCl3):δ8.14-8.13(m,1H),7.98-7.97(m,1H),7.87-7.86,7.85- 7.84(m,m,1H),7.83,7.81(m,m,1H),7.74,7.72(m,m,1H),7.55,7.53(m,m,1H),2.85-2.82 (m,2H),2.74-2.71(m,2H),1.75-1.54(m,4H),1.53-1.43(m,2H),1.31-1.21(m,2H)ppm。
Step 2）Compound 14-3 synthesis
By compound 14-2（0.46g,1.0mmol）, compound 1-12-2（0.26g,1.02mmol）, Pd (dppf) Cl2·CH2Cl2（81.6mg,0.1mmol）And KOAc（0.25g,2.5mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （3.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（30mL）After dilute reaction solution, diatom Soil filtering, filtrate use water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 278mg, yield：50%.
MS(ESI,pos.ion)m/z:557.4[M+H]+；
1H NMR(400MHz,CDCl3):δ8.28,8.25(m,m,1H),8.23-8.22(m,1H),8.10-7.99, 7.98-7.97(m,m,1H),7.85,7.83(m,m,1H),7.57-7.56(m,1H),7.18-7.17,7.16-7.15(m,m, 1H),2.81-2.78(m,2H),2.64-2.61(m,2H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33- 1.32,1.30-1.29(m,m,24H)ppm。
Step 3）Compound 14-4 synthesis
By compound 14-3（0.56g,1.0mmol）, compound 2-7（0.88g,2.1mmol）, four triphenyl phosphorus palladiums （0.12g,0.1mmol）And potassium carbonate（0.35g,2.5mmol）It is suspended in EtOH/H2O（v/v=3/1）Mixed solvent（12mL） In, under nitrogen protection, 90 DEG C are reacted 6.0 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, eaten with saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（DCM/EtOH(v/v)=50/1）Obtain faint yellow Solid 0.36g, yield：40.5%.
MS(ESI,pos.ion)m/z:445.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.33-8.32(m,1H),8.14-8.13(m,1H),8.01-8.00,7.99- 7.98(m,m,1H),7.93,7.90(m,m,1H),7.84(m,2H),7.60(s,1H),7.40(s,1H),6.08,6.05(d, d,1H),5.46,5.44(d,d,1H),5.43-5.36(m,2H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.85- 3.78(m,2H),3.66(s,3H),3.65(s,3H),3.64-3.61(m,2H),3.03-3.00(m,2H),2.96-2.93(m, 2H),2.32-1.92(m,10H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.02, 1.00(m,m,3H),0.97,0.95(m,m,3H),0.94,0.91(m,m,3H),0.90.0.89(m,m,3H)ppm。
Embodiment 15
Synthetic route：
Step 1）Compound 15-2 synthesis
By compound 15-1（2.0g,15.3mmol）It is dissolved in MeOH（20mL）In, it is slowly dropped into thionyl chloride at 0 DEG C （3.4mL,46.9mmol）, drop is complete, and 80 DEG C are reacted 3.5 hours.After reaction completely, concentration of reaction solution obtains white solid 2.76g, Yield：99.5%, it is directly used in and reacts in next step.
1H NMR(400Hz,CDCl3):δ3.68(s,3H),3.58(t,1H),3.56(s,1H),3.32(m,1H),3.02 (m,1H),2.77(m,1H),2.52(s,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 2）Compound 15-3 synthesis
By compound 15-2（3.1g,17.1mmol）Disposably it is added to the benzyl chloroformate being stirred vigorously（3.7mL, 26.3mmol）With potassium carbonate（10.6g,76.7mmol）THF/H2O（20mL/10mL）Mixed liquor in, after adding, room temperature is anti- It should stay overnight.After reaction completely, watery hydrochloric acid is used（1M）The pH value of reaction solution is adjusted to after 3, uses EtOAc（50mL×3）Extraction, merge Organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc (v/v)=4/1）Obtain pale yellow oily liquid 3.0g, yield：62.8%.
1H NMR(400Hz,CDCl3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m, 1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.63(m,1H),3.58(s,1H),3.38(m,1H),3.32(m, 1H),2.21(m,1H),1.96(m,1H)ppm。
Step 3）Compound 15-4 synthesis
By compound 15-3（1.0g,3.6mmol）It is dissolved in DCM（20mL）In, Dai Si-Martin's oxidation is added portionwise at 0 DEG C Agent（3.0g,7.1mmol）, after adding, react at room temperature 1.0 hours.After reaction completely, concentration of reaction solution is through column chromatographic isolation and purification （Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain yellow oily liquid 0.79g, yield：79.5%.
1H NMR(400Hz,CDCl3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m, 1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m, 1H)ppm。
Step 4）Compound 15-5 synthesis
By compound 15-4（1.0g,3.6mmol）It is dissolved in toluene（20mL）In, sequentially add ethylene glycol（0.8mL, 15.7mmol）With TsOH（0.14g,0.8mmol）, after adding, backflow is overnight.After reaction completely, EtOAc is used（50mL）Dilution is anti- Liquid is answered, uses saturated sodium bicarbonate solution respectively（30mL）And saturated nacl aqueous solution（30mL）Washing, anhydrous sodium sulfate drying are dense Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=6/1）Obtain colourless liquid 0.54g, yield：46.7%.
1H NMR(400Hz,CDCl3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m, 1H),5.09(s,2H),4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38(m,1H),3.32(m, 1H),2.21(m,1H),1.96(m,1H)ppm。
Step 5）Compound 15-6 synthesis
By compound 15-5（0.58g,1.8mmol）It is dissolved in MeOH（10mL）In, add the Pd/C of catalytic amount（0.5g）, room Warm hydrogenation is stayed overnight.After reaction completely, filtering, product 0.33g, yield are obtained after filtrate concentration：98.9%.It is directly used in down Single step reaction.
1H NMR(400Hz,CDCl3):δ4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38 (m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 6）Compound 15-7 synthesis
By compound 15-6（3.48g,18.6mmol）, compound 1-11-2（3.26g,18.6mmol）With EDCI（7.1g, 37mmol）It is suspended in DCM（50mL）In, at 0 DEG C, it is slowly dropped into DIPEA（12.3mL,74.4mmol）, drop is complete, reacts at room temperature Night.After reaction completely, reaction solution saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=3/1）Obtain pale yellow oily liquid 2.5g, yield：39.1%.
1H NMR(400Hz,CDCl3):δ9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m, 4H),3.76(m,2H),3.50(s,3H),3.45(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m, 3H)ppm。
Step 7）Compound 15-8 synthesis
By compound 15-7（0.9g,2.6mmol）It is dissolved in THF（5.0mL）In, add LiOH（0.12g,5.0mmol）'s The aqueous solution（5.0mL）, after adding, room temperature reaction is overnight.After reaction completely, watery hydrochloric acid is used（1M）The pH value of reaction solution is adjusted to 2 Afterwards, EtOAc is used（50mL×3）Extraction, merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate drying, obtained after concentration White solid 0.85g, yield：99%, it is directly used in and reacts in next step.
1H NMR(400Hz,CDCl3):δ9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m, 4H),3.76(m,2H),3.50(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m,3H)ppm。
Step 8）Compound 15-9 synthesis
By compound 15-8（1.78g,5.4mmol）With compound 3-1-0（1.64g,5.9mmol）It is dissolved in MeCN（30mL） In, it is slowly dropped into DIPEA at 0 DEG C（1.1mL,6.7mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, concentration reaction Through column chromatographic isolation and purification after liquid（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain faint yellow solid 2.76g, yield：97.3%.
1H NMR(400Hz,CDCl3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.32,5.29(d,d, 1H),5.22(s,2H),5.06-5.02(m,1H),4.36-4.31(m,1H),4.02-4.00(m,4H),3.81-3.77(m, 1H),3.63(s,3H),3.56-3.51(m,1H),2.79-2.73(m,1H),2.41-2.34(m,1H),2.18-2.06(m, 1H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 9）Compound 15-10 synthesis
By compound 15-9（3.0g,5.7mmol）With ammonium acetate（4.4g,57.1mmol）It is suspended in dimethylbenzene（20mL） In, 130 DEG C of reactions are overnight.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, organic phase are eaten with saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain Yellow solid 2.6g, yield：89.9%.
1H NMR(400Hz,CDCl3):δ7.45-7.41(m,2H),7.29-7.26(m,3H),5.40-5.36(m,1H), 5.32,5.29(d,d,1H),4.42-4.38(m,1H),3.98-3.92(m,5H),3.71-3.69(m,1H),3.63(s,3H), 2.83-2.77(m,1H),2.45-2.39(m,1H),2.24-2.11(m,1H),0.97-0.95(m,3H),0.91-0.89(m, 3H)ppm。
Step 10）Compound 15-11 synthesis
By compound 15-10（4.0g,7.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.64g,0.8mmol）, anhydrous vinegar Sour potassium（1.94g,19.8mmol）With compound 1-12-2（3.11g,12.2mmol）It is placed in reaction bulb, adds DME（50mL）, Under nitrogen protection, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, point Water is not used（100mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/DCM(v/v)=4/1）Obtain white solid 4.15g, yield：94.7%.
1H NMR(400Hz,CDCl3):δ7.64-7.57(m,4H),7.22(s,1H),5.40-5.36(m,1H),5.32, 5.29(d,d,1H),4.42-4.38(m,1H),3.98-3.96(m,5H),3.71-3.69,3.67-3.66(m,1H),3.63 (s,3H),2.83-2.77(m,1H),2.45-2.39(m,1H),2.24-2.11(m,1H),1.35,1.32(m,m,12H), 0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 11）Compound 15-12 synthesis
By compound 15-11（0.13g,0.234mmol）, compound 1-8（78mg,0.234mmol）, four triphenyl phosphorus palladiums （0.14g,0.12mmol）And potassium carbonate（0.8g,5.85mmol）It is suspended in DME/H2O（v/v=3/1）Mixed solvent （4.0mL）In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, EtOAc is added（20mL）Dilute reaction solution, use Saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 100/1）Obtain faint yellow solid 0.13g, yield：81%.
MS(ESI,pos.ion)m/z:683.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.51-7.50,7.49-7.48 (m,m,2H),7.35(s,1H),6.07,6.05(d,d,1H),5.40-5.36(m,1H),4.35-4.31(m,1H),3.98- 3.96,3.94-3.92(m,m,5H),3.71-3.69(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.84-2.77 (m,3H),2.75-2.72(m,2H),2.45-2.39(m,1H),2.28-2.16(m,1H),1.75-1.54(m,4H),1.53- 1.43(m,2H),1.31-1.21(m,2H),1.02,1.00(m,m,3H),0.94,0.91(m,m,3H)ppm。
Step 12）Compound 15-13 synthesis
By compound 15-12（0.34g,0.5mmol）, Pd (dppf) Cl2·CH2Cl2（20.4mg,0.025mmol）, nothing Water acetic acid potassium（0.12g,1.25mmol）With compound 1-12-2（0.15g,0.6mmol）It is placed in reaction bulb, adds DMF （2.0mL）, under nitrogen protection, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）Dilution is anti- After answering liquid, water is used respectively（10mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.24g, yield：66%.
1H NMR(400Hz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.35(s,1H),7.23-7.22, 7.21-7.20(m,m,2H),6.08,6.05(d,d,1H),5.40-5.36(m,1H),4.35-4.31(m,1H),3.98- 3.96,3.94-3.92(m,m,5H),3.71-3.69(m,1H),3.65(s,3H),2.83-2.77(m,3H),2.66-2.63 (m,2H),2.45-2.39(m,1H),2.28-2.16(m,1H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33, 1.30(q,q,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 13）Compound 15-14 synthesis
By compound 15-13（0.15g,0.2mmol）, compound 2-7（84mg,0.2mmol）, four triphenyl phosphorus palladiums （12mg,0.01mmol）And potassium carbonate（69mg,0.5mmol）It is suspended in EtOH/H2O（v/v=3/1）Mixed solvent（4.0mL） In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, EtOAc is added（20mL）Dilute reaction solution, use saturated common salt Water washing, anhydrous sodium sulfate drying,
Through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 98.6mg yield：55%.
MS(ESI,pos.ion)m/z:449.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57 (m,m,2H),7.40(s,1H),7.35(s,1H),6.07,6.05(d,d,1H),5.44-5.36(m,2H),5.32,5.29(d, d,1H),4.41-4.37(m,1H),4.35-4.31(m,1H),3.98-3.96,3.94-3.92(m,m,5H),3.86-3.80 (m,1H),3.71-3.66(m,1H),3.65(s,3H),3.63(s,3H),2.95-2.92(m,2H),2.83-2.73(m,3H), 2.45-2.39(m,1H),2.32-2.04(m,6H),2.03-1.92(m,1H),1.73-1.52(m,4H),1.49-1.39(m, 2H),1.27-1.17(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94,0.92(m,m,3H), 0.90,0.89(m,m,3H)ppm。
Embodiment 16
Synthetic route：
Step 1）Compound 16-1 synthesis
At 0 DEG C, by DIPEA（1.95mL,11.8mmol）It is added to compound 12-6（2.43g,10.7mmol）With chemical combination Thing HATU（4.88g,12.84mmol）THF（25mL）In solution, after isothermal reaction 0.5 hour, compound 1-7- is added portionwise 2（2.21g,11.9mmol）, after adding, react at room temperature 4.0 hours.After reaction completely, water is added（50mL）Reaction is quenched, removes THF, water layer EtOAc（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying will be surplus after concentration Excess is dissolved in glacial acetic acid（20mL）In, 40 DEG C of reactions are overnight.After reaction completely, glacial acetic acid is removed, residue is dissolved in EtOAc （100mL）In, use sodium carbonate liquor（50mL×3）Washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=1/2）Obtain product 2.02g, yield：50%.
MS(ESI,pos.ion)m/z:378.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H), 5.03-5.00(m,1H),3.31-3.24(m,1H),2.56-2.49(m,1H),2.12-2.07(m,1H),1.53-1.48(m, 1H),1.46(s,9H),1.42-1.38(m,1H),1.00-0.97(m,1H)ppm。
Step 2）Compound 16-2 synthesis
By compound 16-1（1.03g,2.74mmol）It is dissolved in EtOAc（5.0mL）, the acetic acid second of hydrogen chloride is instilled at 0 DEG C Ester solution（6.0mL,4M）Afterwards, react at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （10mL）Stirring to pulp, faint yellow solid 0.82g, yield are obtained after filtering：85.5%.
MS(ESI,pos.ion)m/z:278.2[M+H]+。
Step 3）Compound 16-3 synthesis
By compound 16-2（0.66g,1.88mmol）, compound 1-11-2（0.49g,2.82mmol）And EDCI （0.54g,2.82mmol）It is suspended in DCM（10mL）, at 0 DEG C, it is slowly dropped into DIPEA（1.86mL,11.28mmol）Afterwards, room temperature Reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, water is used respectively（20mL×3）And saturated aqueous common salt Washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain solid 0.69g, yield：85%.
MS(ESI,pos.ion)m/z:435.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H), 5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H), 2.62-2.55(m,1H),2.21-2.09(m,2H),1.53-1.45(m,1H),0.97-0.89(m,7H),0.50-0.46(m, 1H)ppm。
Step 4）Compound 16-4 synthesis
By compound 16-3（3.08g,7.1mmol）, compound 1-12-2（2.72g,10.7mmol）, Pd (dppf) Cl2·CH2Cl2（0.0.57g,0.7mmol）And KOAc（2.09g,21.3mmol）It is placed in reaction bulb, N2Under protection, injection DMF（30mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, diatom Soil filtering, filtrate use water respectively（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 2.22g, yield：65%.
MS(ESI,pos.ion)m/z:483.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82(dd,1H),7.65,7.63(d,d,1H),7.45,7.42(d,d,1H), 5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H), 2.62-2.55(m,1H),2.22-2.09(m,2H),1.53-1.45(m,1H),1.32,1.29(m,12H),0.97-0.89(m, 7H),0.50-0.46(m,1H)ppm。
Step 5）Compound 16-5 synthesis
By compound 16-4（0.24g,0.5mmol）, compound 12-12（0.32g,0.5mmol）, Pd (PPh3)4（58mg, 0.05mmol）And potassium carbonate（0.17g,1.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（6mL）And pure water （2mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）After dilute reaction solution, use respectively Water（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/ MeOH(v/v)=50/1）Obtain faint yellow solid 0.23g, yield：50.4%.
MS(ESI,pos.ion)m/z:457.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.80,7.78(d,d,1H),7.66-7.65,7.64-7.62(m,m,2H), 7.61(s,1H),7.59(q,1H),7.57,7.55(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.32,5.29 (d,d,2H),5.14-5.10(m,1H),4.89-4.85(m,1H),4.13-4.04(m,2H),3.63(s,6H),3.45-3.36 (m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.62-2.55(m,1H),2.46-2.39(m,1H),2.2- 2.09(m,3H),2.00-1.98,1.97-1.94(m,m,1H),1.73-1.36(m,8H),1.28-1.18(m,2H),0.97, 0.95(m,m,6H),0.90-0.92(m,2H),0.91,0.89(m,m,6H),0.50-0.46(m,2H)ppm。
Embodiment 17
Synthetic route：
Step 1）Compound 17-1 synthesis
By compound 11-4（0.24g,0.5mmol）, compound 3-6（0.31g,0.5mmol）, Pd (PPh3)4（58mg, 0.05mmol）And potassium carbonate（0.17g,1.25mmol）It is placed in reaction bulb, N2Under protection, EtOH is injected separately into（6mL）With it is pure Water（2mL）, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）After dilute reaction solution, respectively Use water（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=50/1）Obtain faint yellow solid 0.22g, yield：50%.
MS(ESI,pos.ion)m/z:446.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.90(m,1H),7.66-7.65,7.64-7.62(m,m,2H),7.59(s, 1H),7.58-7.57(m,1H),7.48-7.47,7.46(m,m,2H),7.45-7.44,7.43-7.42(m,m,1H),7.37- 7.36,7.35-7.34(m,m,1H),7.21,7.19,7.17(m,m,m,1H),5.46,5.44(d,d,1H),5.32,5.29 (d,d,1H),5.23-5.19(m,1H),4.62-4.57(m,1H),4.41-4.36(m,1H),4.31-4.26(m,1H), 3.85-3.78(m,1H),3.66(s,3H),3.65-3.64(m,1H),3.63(s,3H),3.47-3.35(m,2H),2.79- 2.74(m,4H),2.30-1.85(m,10H),1.72-1.52(m,4H),1.50-1.39(m,2H),1.28-1.18(m,2H), 0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 18
Synthetic route：
Step 1）Compound 18-2 synthesis
By NBS（2.16g,12mmol）With compound 18-1（2.51g,10mmol）It is dissolved in CCl4（20mL）In, at 0 DEG C, It is slowly dropped into dibenzoyl peroxide（0.24g,1.0mmol）, drop finishes, and after being stirred at room temperature 15 minutes, flows back 7.0 hours.Reaction After completely, CCl is removed4, residue EtOAc（100mL）Dissolving, uses water respectively（50mL×3）With saturated common salt water washing, nothing Aqueous sodium persulfate is dried, and crude product 3.2g is obtained after concentration, is directly used in and is reacted in next step.
MS(ESI,pos.ion)m/z:330.8[M+H]+；
1H NMR(400MHz,CDCl3):δ8.18-8.17(m,1H),7.79(m,1H),4.66-4.65(m,2H)ppm。
Step 2）Compound 18-3 synthesis
By NaH（60%,3.13g,78mmol）It is suspended in DMF（100mL）In, it is slowly dropped into diethyl malonate （12.54g,78mmol）, drop finish, 100 DEG C reaction 40 minutes after be down to room temperature reaction.Add compound 18-2（11.74g, 35.60mmol）, finish, after reacting at room temperature 30 minutes, 75 DEG C are reacted 1.0 hours.After reaction completely, saturated ammonium chloride solution is used （50mL）Reaction is quenched, adds EtOAc（150mL）, organic phase is separated, respectively with water and saturated common salt water washing, anhydrous slufuric acid Sodium is dried, and product 13.0g is obtained after concentration, is directly used in and is reacted in next step.
1H NMR(400MHz,CDCl3):δ8.14(m,1H),7.75(m,1H),4.18-4.13(q,4H),3.83-3.80 (m,1H),3.55-3.54,3.53-3.52(m,m,2H),1.23-1.19(t,6H)ppm。
Step 3）Compound 18-4 synthesis
By compound 18-3（13g）It is dissolved in DMSO（100mL）In, at room temperature, it is slowly added to NaCl（4.10g,70mmol） And water（0.64g,35.6mmol）, after adding, 100 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc （200mL）Dilute reaction solution, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=20/1）Obtain product 8.5g.
1H NMR(400MHz,CDCl3):δ8.08-8.07(m,1H),7.75(m,1H),4.08-4.03(q,2H),2.98- 2.97,2.96,2.94(m,m,m,2H),2.75,2.74,2.72(d,d,d,2H),1.22-1.19(t,3H)ppm。
Step 4）Compound 18-5 synthesis
By compound 18-4（3.37g,10mmol）It is dissolved in methanol（20mL）In, the NaOH aqueous solution is instilled at 0 DEG C（0.8g, 20mL）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, watery hydrochloric acid is used（1M）PH to 5 is adjusted, removes methanol, water layer is with dilute salt Acid（1M）PH to 2 is adjusted, uses EtOAc（50mL×3）Extraction, organic phase anhydrous Na2SO4Dry, white solid is obtained after concentration 2.78g yield：90%.
MS(ESI,pos.ion)m/z:309.5[M+H]+；
1H NMR(400MHz,CDCl3):δ10.32(brs,1H),8.08-8.07(m,1H),7.78(m,1H),3.02- 3.01,3.00-2.99,2.98-2.97(m,m,m,2H),2.88,2.86,2.84(d,d,d,2H)ppm。
Step 5）Compound 18-6 synthesis
At -10 DEG C, by oxalyl chloride（0.93mL,11mmol）It is slowly dropped into compound 18-5（3.09g,10mmol）And DMF （0.05mL）DCM solution（40mL）In, drop finishes, stand-by without handling after reacting at room temperature 1.0 hours.
At -15 DEG C, by freshly prepd above-claimed cpd（3.27g,10mmol）It is slowly dropped into AlCl3（1.73g,13mmol） DCM（30mL）In suspension, drop finishes, isothermal reaction 2.0 hours.After reaction completely, reaction solution is poured slowly into frozen water, will Organic layer separates, water layer DCM（30mL×3）Extraction, merge organic phase, washed respectively with clear water and saturated sodium carbonate solution, Anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain yellowish toner Last 2.33g, yield：80.5%.
MS(ESI,pos.ion)m/z:292.1[M+H]+；
1H NMR(400MHz,CDCl3):δ8.38(s,1H),3.22-3.20(m,2H),2.80-2.78(m,2H)ppm。
Step 6）Compound 18-7 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 18-6（2.91g, 10mmol）, Isosorbide-5-Nitrae-dibromobutane（1.31mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（30mL）Suspension In, 60 DEG C are reacted 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（100mL）In, separate out solid.Filtering, Gu Body EtOAc（50mL）Dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=10/1）Obtain product 2.59g, yield：75%.
MS(ESI,pos.ion)m/z:346.1[M+H]+；
1H NMR(400MHz,CDCl3):δ8.38(s,1H),3.07-3.06(q,2H),2.03-1.91(m,2H),1.82- 1.62(m,4H),1.34-1.24(m,2H)ppm。
Step 7）Compound 18-8 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 18-7（3.45g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.81g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:332.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.08(dd,1H),3.23-3.20(m,2H),3.04-3.01(m,2H), 1.77-1.45(m,8H)ppm。
Step 8）Compound 18-9 synthesis
By compound 18-8（0.33g,1.0mmol）, compound 1-13（0.99g,2.1mmol）, compound Pd (PPh3)4 （0.12g,0.1mmol）With potassium carbonate（0.35g,2.5mmol）It is dissolved in DME（8mL）And water（2mL）In, under nitrogen protection, 90 DEG C Reaction 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）After dilute reaction solution, water is used respectively（20mL×3） With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 50/1）Obtain product 0.43g, yield：50%.
MS(ESI,pos.ion)m/z:858.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.70-8.69(dd,1H),7.87-7.86(q,1H),7.76,7.73(d,d, 1H),7.66,7.64(d,d,1H),7.62-7.61(q,1H),7.57,7.55(d,d,1H),7.53,7.51(d,d,1H), 6.08,6.05(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78 (m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.14-3.11(m,2H),2.94-2.91(m,2H), 2.38-2.10(m,8H),2.01-1.86(m,2H),1.71-1.51(m,6H),1.49-1.39(m,2H),1.02,1.00(m, m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 19
Synthetic route：
Step 1）Compound 19-1 synthesis
By compound 8-1（1.12g,4.88mmol）It is dissolved in THF（10mL）In, at 0 DEG C, it is slowly dropped into borine（7.3mL, 1M in THF）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, methanol is used（4.0mL）Reaction is quenched, removes THF, it is remaining Thing DCM（50mL）Dissolving, uses water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through post after concentration Chromatography purifies（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain colorless syrup 1.05g, yield：100%.
MS(ESI,pos.ion)m/z:216.3[M+H]+；
1H NMR(400MHz,CDCl3):δ4.02(s,1H),3.99-3.87(m,1H),3.75-3.68(m,1H),3.66 (dd,1H,J=11.6Hz,2.0Hz),3.57(dd,1H,J=11.6Hz,7.4Hz),2.76(t,1H,J=10.5Hz),2.19- 2.06(m,2H),1.46(s,9H),1.01(d,3H,J=6.2Hz)ppm。
Step 2）Compound 19-3 synthesis
By compound 19-1（1.0g,4.64mmol）It is dissolved in DCM（12mL）In, at 0 DEG C, it is separately added into TCCA（1.08g, 4.64mmol）And TEMPO（64mg,0.46mmol）DCM（5.0mL）Solution, finish, after isothermal reaction 1.0 hours, room temperature is anti- Answer 1.0 hours.After reaction completely, solid, filtrate saturated sodium bisulfite solution are filtered to remove（30mL×3）Washing, organic phase Use anhydrous Na2SO4Dry, it is colorless syrup that compound 19-2 is obtained after concentration.
Compound 19-2 is dissolved in methanolic ammonia solution（10mL,7M）, after reacting 0.5 hour at 0 DEG C, room temperature continues to react 1.0 hours, after being cooled to 0 DEG C again, it is slowly dropped into the aqueous solution of glyoxal（1.2mL,40%）, drop is complete, and room temperature reaction 24 is small When.After reaction completely, concentration of reaction solution, residue DCM（100mL）Dissolving, uses water respectively（30mL×3）And saturated aqueous common salt Washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=100/1）Obtain yellowish Color solid 0.51g, yield：44%.
MS(ESI,pos.ion)m/z:252.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.97(s,2H),4.90(t,1H,J=8.0Hz),3.76(dd,1H,J=10Hz, 7.2Hz),2.83(t,1H,J=8.0Hz),2.64-2.33(m,2H),2.32-2.12(m,1H),1.47(s,9H),1.09(d, 3H,J=6.4Hz)ppm。
Step 3）Compound 19-4 synthesis
By compound 19-3（0.51g,2.03mmol）It is dissolved in DCM（10mL）In, at 0 DEG C, add NIS（1.0g, 4.46mmol）, after adding, isothermal reaction 2.0 hours.After reaction completely, solid is filtered to remove, filtrate is molten with saturated sodium sulfite Liquid（30mL×3）Washing, anhydrous Na2SO4Dry, yellow solid 0.92g, yield are obtained after concentration：90%.It is directly used in next step Reaction.
MS(ESI,pos.ion)m/z:504.2[M+H]+；
1H NMR(400MHz,CDCl3):δ4.85(t,1H,J=8.0Hz),3.75(dd,1H,J=10Hz,7.2Hz),2.84 (t,1H,J=10Hz),2.52-2.29(m,2H),2.21(d,1H,J=6.6Hz),1.48(s,9H),1.08(d,3H,J= 6.4Hz)ppm。
Step 4）Compound 19-5 synthesis
By compound 19-4（0.91g,1.8mmol）It is dissolved in ethanol（10mL）In, add sodium sulfite（2.0g,16mmol） And water（10mL）, 90 DEG C are reacted 30 hours.After reaction completely, solid is filtered to remove, concentrates filtrate, residue adds DCM （50mL）After dissolving, water is used respectively（20mL×2）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=6/1）Obtain white solid 0.41g, yield：60%.
MS(ESI,pos.ion)m/z:378.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.04(s,1H),4.85(t,1H,J=8.4Hz),3.75(dd,1H,J= 10.3Hz,7.3Hz),2.82(t,1H,J=10.4Hz),2.58-2.36(m,2H),2.29-2.11(m,1H),1.08(d,3H,J =6.4Hz)ppm。
Step 5）Compound 19-6 synthesis
By compound 19-5（0.63g,1.66mmol）, compound 1-12-2（0.46g,1.82mmol）, Pd (dppf) Cl2·CH2Cl2（68mg,0.083mmol）With KOAc（0.41g,4.14mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （5.0mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（40mL）After dilute reaction solution, silicon Diatomaceous earth filters, and filtrate uses water respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.53g, yield：85%.
MS(ESI,pos.ion)m/z:378.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.69(s,1H),4.90-4.85(m,1H),3.75-3.68(m,1H),3.04- 2.97(m,1H),2.44-2.34(m,1H),2.33-2.20(m,1H),1.83-1.75(m,1H),1.41(s,9H),1.38, 1.36(m,m,12H),0.96-0.93(m,3H)ppm。
Step 6）Compound 19-7 synthesis
By compound 8-4（0.75g,1.66mmol）, compound 18-8（0.55g,1.66mmol）, Pd (PPh3)4（96mg, 0.083mmol）And potassium carbonate（0.57g,4.14mmol）It is placed in reaction bulb, N2Under protection, EtOH is injected separately into（5mL）With it is pure Water（1.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）After dilute reaction solution, point Water is not used（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.48g, yield：50%.
MS(ESI,pos.ion)m/z:578.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.75, 7.73-7.72(m,m,2H),7.59(s,1H),4.89-4.84(m,1H),3.80-3.73(m,1H),3.25-3.22(m,2H), 3.09-3.02(m,1H),2.82-2.79(m,2H),2.33-2.16(m,2H),1.74-1.53(m,7H),1.52-1.43(m, 2H),1.41(s,9H),0.96-0.93(m,3H)ppm。
Step 7）Compound 19-8 synthesis
By compound 19-7（0.33g,0.58mmol）, compound 19-6（0.22g,0.58mmol）, Pd (PPh3)4 （35mg,0.03mmol）And potassium carbonate（0.08g,1.4mmol）It is placed in reaction bulb, N2Under protection, EtOH is injected separately into （8.0mL）And pure water（2.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilution After reaction solution, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：DCM/MeOH(v/v)=80/1）Obtain faint yellow solid 0.19g, yield：45%.
MS(ESI,pos.ion)m/z:748.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.44(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.75, 7.73-7.72(m,m,2H),7.67(s,1H),7.59(s,1H),5.22-5.17(m,1H),4.89-4.84(m,1H),3.80- 3.73(m,2H),3.18-3.15(m,2H),3.09-3.02(m,2H),2.86-2.83(m,2H),2.35-2.16(m,4H), 1.76-1.51(m,8H),1.46-1.42(m,2H),1.41(s,18H),0.96-0.93(m,6H)ppm。
Step 8）Compound 19-9 synthesis
By compound 19-8（0.3g,0.4mmol）It is dissolved in EtOAc（4.0mL）In, it is slowly dropped into the ethyl acetate of hydrogen chloride Solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （10mL）After mashing, faint yellow solid 0.25g, yield are filtrated to get：90%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:548.5[M+H]+。
Step 9）Compound 19-10 synthesis
By compound 19-9（0.22g,0.31mmol）, compound 1-11-2（0.12g,0.68mmol）, EDCI（0.13g, 0.68mmol）And HOAT（85mg,0.62mmol）It is suspended in DCM（10mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.51mL, 3.1mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, ammonium chloride is used respectively Solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/ v)=50/1）Obtain faint yellow solid 0.15g, yield：55%.
MS(ESI,pos.ion)m/z:862.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.44(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.75, 7.73-7.72(m,m,2H),7.59(s,1H),7.57(s,1H),5.56,5.55(d,d,1H),5.48-5.43(m,1H), 5.32,5.29(d,d,1H),5.07-5.02(m,1H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m,1H), 4.31-4.27(m,1H),3.92-3.85(m,2H),3.66(s,3H),3.63(s,3H),3.61-3.54(m,2H),3.18- 3.15(m,2H),2.86-2.83(m,2H),2.38-2.09(m,6H),1.73-1.51(m,8H),1.48-1.38(m,2H), 1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94-0.89(m,12H)ppm。
Embodiment 20
Synthetic route：
Step 1）Compound 20-1 synthesis
By compound 18-8（0.16g,0.5mmol）, compound 3-5（0.25g,0.5mmol）, Pd (PPh3)4（58mg, 0.05mmol）And potassium carbonate（0.17g,1.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（8.0mL）With it is pure Water（2.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）After dilute reaction solution, point Water is not used（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.14g, yield：45%.
MS(ESI,pos.ion)m/z:621.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.75, 7.73-7.72(m,m,2H),7.59(s,1H),6.08,6.05(d,d,1H),5.23-5.19(m,1H),4.34-4.33, 4.32-4.31,4.30(m,m,m,1H),3.85-3.78(m,1H),3.69-3.66(m,1H),3.65(s,3H),3.25-3.22 (m,2H),2.82-2.79(m,2H),2.30-2.16(m,3H),2.13-1.92(m,2H),1.73-1.54(m,6H),1.52- 1.42(m,2H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 2）Compound 20-2 synthesis
By compound 20-1（0.24g,0.39mmol）, compound 2-9（0.15g,0.468mmol）, PdCl2(PPh3)2 （14.1mg,0.02mmol）, CuI（33mg,0.172mmol）, PPh3（0.23g,0.86mmol）It is added in reaction bulb, nitrogen Under protection, DMF is added（10mL）, it is slowly dropped into triethylamine（5.0mL）, drop finishes, and after being stirred at room temperature 10 minutes, 90 DEG C of reactions 10 are small When.After reaction completely, diatomite is filtered, and water is added in filtrate（20mL）, use EtOAc（20mL×3）Extraction, merge organic phase, With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 60/1）Obtain product 0.1g, yield：30%.
MS(ESI,pos.ion)m/z:429.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.78(s,1H),7.99-7.98,7.97-7.96(m,m,2H),7.76- 7.75,7.73-7.72(m,m,2H),7.59(s,1H),7.56(s,1H),6.08,6.06(d,d,1H),5.51-5.47(m, 1H),5.46,5.44(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.89- 3.78(m,2H),3.73-3.67(m,2H),3.66(s,3H),3.63(s,3H),3.17-3.14(m,2H),2.79-2.76(m, 2H),2.32-1.92(m,10H),1.74-1.54(m,6H),1.51-1.41(m,2H),1.02,1.00(m,m,3H),0.97, 0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 21
Synthetic route：
Step 1）Compound 21-2 synthesis
By PPh3MeBr（5.05g,14.2mmol）It is suspended in THF（50mL）In, at -20 DEG C, it is slowly dropped into potassium tert-butoxide （14.9mL,14.9mmol,1.0M）THF solution, drop finish, and after being warming up to -5 DEG C of reactions 30 minutes, add compound 21-1 （1.72g,7.07mmol）, after adding, react at room temperature 1.0 hours.After reaction completely, frozen water is added（50mL）Reaction is quenched, removes Remove THF, water layer EtOAc（50mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentration By column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain pale yellow oily liquid 1.07g, yield： 62.9%。
MS(ESI,pos.ion)m/z:242.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ5.01(d,2H,J=10.8Hz),4.36(t,1H,J=11.2Hz),3.95 (s,2H),3.64(s,3H),3.01(q,1H,J=14.6Hz),2.57-2.50(m,1H),1.38(s,9H)ppm。
Step 2）Compound 21-3 synthesis
At 0 DEG C, by chloroiodomethane（6.6g,37.24mmol）It is slowly dropped to diethyl zinc（2.3g,18.6mmol）First Benzene（30mL）In solution, drop finishes, isothermal reaction 45 minutes, then is slowly dropped into compound 21-2（1.5g,6.22mmol）Toluene （15mL）Solution, drop finish, isothermal reaction 18 hours.After reaction completely, saturation NH is added4Cl solution（20mL）Reaction, water is quenched Layer EtOAc（25mL×3）Extraction, merge organic phase, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=10/1）Obtain white liquid 0.58g, yield：36.5%.
MS(ESI,pos.ion)m/z:156.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ4.47-4.33(m,1H),3.71(s,3H),3.29-3.37(m,2H),2.25- 2.17(m,1H),1.86-1.75(m,1H),1.44,1.40(s,s,9H),0.62-0.50(m,4H)ppm。
Step 3）Compound 21-4 synthesis
By compound 21-3（0.69g,2.7mmol）It is dissolved in EtOAc（6.0mL）, add the ethyl acetate solution of hydrogen chloride （5.0mL,4M）Afterwards, react at room temperature 8.0 hours.After reaction completely, colourless oil liquid 0.5g is obtained after concentration of reaction solution, is produced Rate：96.5%.
MS(ESI,pos.ion)m/z:156.2[M+H]+；
1H NMR(400MHz,CD3OD):δ4.66-4.62(m,1H),4.45-4.44(m,1H),3.86(s,3H),3.61- 3.60(m,1H),2.39-2.34(m,1H),2.19-2.14(m,1H),1.49-1.46(m,1H),1.19-1.16(m,1H), 0.88-0.87(m,1H),0.81-0.79(m,1H)ppm。
Step 4）Compound 21-5 synthesis
By compound 21-4（0.53g,2.77mmol）, compound 1-11-2（0.73g,4.16mmol）And EDCI （1.06g,5.55mmol）It is suspended in DCM（10mL）In, at 0 DEG C, it is slowly dropped into DIPEA（2.4mL,14.52mmol）Afterwards, room temperature Reaction 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, washed respectively with ammonium chloride solution and saturated common salt Wash, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/1）Obtain white liquid 0.60g, yield：70%.
MS(ESI,pos.ion)m/z:313.2[M+H]+；
1H NMR(400MHz,CDCl3):δ5.44-5.42(br,1H),4.71-4.68(m,1H),4.29-4.20(m, 1H),3.73(s,3H),3.72-3.69(m,1H),3.67(s,3H),3.59-3.54(m,1H),2.20-2.15(m,1H), 2.06-2.01(m,1H),1.95-1.90(m,1H),1.05-0.93(m,6H),0.66-0.61(m,4H)ppm。
Step 5）Compound 21-6 synthesis
At 0 DEG C, by lithium hydroxide（0.14g,3.2mmol）The aqueous solution（5mL）It is slowly dropped into compound 21-5（0.2g, 0.64mmol）THF solution（5.0mL）In, drop finishes, and 40 DEG C are reacted 12 hours.After reaction completely, THF is removed, adds water （30mL）, then use EtOAc（10mL×3）Extraction, aqueous phase is collected, uses hydrochloric acid（10%）The pH value of solution is adjusted to 1, water layer is used again EtOAc is extracted（25mL×3）, merge organic phase, anhydrous Na2SO4Dry, white solid 0.16g, yield are obtained after concentration： 82.8%。
MS(ESI,pos.ion)m/z:299.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.06(br,1H),5.76(br,1H),4.73-4.69(m,1H),4.23- 4.18(m,1H),3.79(d,1H,J=9.7Hz),3.66(s,3H),3.49(d,1H,J=9.7Hz),2.26-2.18(m,1H), 2.07-1.93(m,2H),1.00-0.94(m,6H),0.68-0.64(m,4H)ppm。
Step 6）Compound 21-7 synthesis
By compound 3-1-0（0.31g,1.11mmol）With compound 21-6（0.3g,1.0mmol）It is dissolved in MeCN（10mL） In, at 0 DEG C, it is slowly dropped into DIPEA（0.21mL,1.27mmol）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, to anti- Answer and water is added in liquid（10mL）, remove MeCN, residue EtOAc（30mL）Dissolving, eaten respectively with ammonium chloride solution and saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/1）Obtain Faint yellow solid 0.37g, yield：66.7%.
MS(ESI,pos.ion)m/z:495.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.32,5.29(br,br, 1H),5.31(s,2H),4.72-4.70(m,1H),4.35-4.30(m,1H),3.67(s,3H),3.61-3.59(m,1H), 3.55-3.49(m,1H),2.20-2.07(m,2H),1.83-1.76(m,1H),0.97,0.96(m,m,3H),0.91,0.89 (m,m,3H),0.52-0.39(m,4H)ppm。
Step 7）Compound 21-8 synthesis
By compound 21-7（0.33g,0.67mmol）With NH4OAc（1.04g,13.43mmol）It is suspended in dimethylbenzene （10mL）In, reacted 5.0 hours at 120 DEG C.After reaction completely, it is cooled to room temperature, adds water（20mL）Reaction is quenched, water layer is used EtOAc（20mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain yellow solid 0.19g, yield：60%.
MS(ESI,pos.ion)m/z:475.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.58(s,1H),7.45-7.41(m,2H),7.29-7.26(m,2H),5.46, 5.44(br,br,1H),4.93-4.89(m,1H),4.41-4.37(m,1H),3.71-3.67(m,1H),3.67(s,3H), 3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),0.97,0.95(m, m,3H),0.91,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 8）Compound 21-9 synthesis
By compound 21-8（0.19g,0.4mmol）, compound 1-12-2（0.15g,0.6mmol）, Pd (dppf) Cl2· CH2Cl2（33mg,0.04mmol）And KOAc（0.12g,1.19mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （5.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）Dilute reaction solution, diatomite Filtering, filtrate use water respectively（20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 0.16g, yield：80%.
MS(ESI,pos.ion)m/z:523.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.64-7.57(m,4H),7.21(s,1H),5.46,5.44(br,br,1H), 4.93-4.89(m,1H),4.42-4.37(m,1H),3.71-3.67(m,1H),3.66(s,3H),3.50-3.44(m,1H), 2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),1.35(m,6H),1.32(m,6H),0.97, 0.95(m,m,3H),0.91,0.89(m,m,3H),0.55-0.42(m,4H)ppm。
Step 9）Compound 21-10 synthesis
By compound 18-8（0.17g,0.52mmol）, compound 21-9（0.57g,1.10mmol）, Pd (PPh3)4 （60.29mg,0.052mmol）And potassium carbonate（0.22g,1.57mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into （6.0mL）And water（1.5mL）, 90 DEG C are reacted 3.0 hours, after reaction completely, are cooled to room temperature, are added ethyl acetate（30mL）Dilution After reaction solution, water is used respectively（10mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：DCM/EtOH(v/v)=50/1）Obtain faint yellow solid 0.25g, yield：50%.
MS(ESI,pos.ion)m/z:481.8[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.52-8.51(dd,1H),7.91-7.90,7.89-7.88(m,m,2H), 7.75-7.74,7.73-7.72(m,m,2H),7.71,7.69-7.68(m,m,2H),7.60-7.59,7.58-7.57(m,m, 4H),5.32,5.30(d,d,2H),4.93-4.89(m,2H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m, 2H),3.72-3.66(m,2H),3.63(s,6H),3.50-3.44(m,2H),3.04-3.01(m,2H),2.85-2.81(m, 2H),2.39-2.32(m,2H),2.23-2.11(m,2H),2.05-1.97(m,2H),1.71-1.50(m,6H),1.49-1.39 (m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H),0.55-0.42(m,8H)ppm。
Embodiment 22
Synthetic route：
Step 1）Compound 22-2 synthesis
By anhydrous sodium sulfate（3.48g,24.5mmol）It is added to（R）- 1- phenyl ethylamines（1.3mL,10.1mmol）Toluene （15mL）In solution, then glyoxylic acid ethyl ester is slowly added dropwise（1mL,10.1mmol）Afterwards, react at room temperature 1.0 hours.After reaction completely, Filtering, yellow liquid 1.9g, yield are obtained after filtrate concentration：91.8%.It need not be further purified, be directly used in and react in next step.
Step 2）Compound 22-3 synthesis
By TFA（0.75mL,10.1mmol）It is added to compound 22-2（2.0g,9.7mmol）DMF（15mL）Solution In, after stirring 10 minutes, sequentially add 1, the 3- cyclopentadiene newly steamed（1.29g,19.5mmol）Dripped with two, after adding, Room temperature reaction 12 hours.After reaction completely, DMF is removed, residue adds NaHCO3Solution（10%,20mL）, use Na2CO3Will be molten The pH value of liquid is adjusted to 8, then uses petroleum ether（25mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4It is dry It is dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain light yellow liquid 2.38g, yield： 90%。
1H NMR(400MHz,CDCl3):δ7.35-7.17(m,5H),6.42(br,1H),6.28-6.26(br,1H), 4.34-4.30(m,2H),3.82-3.78(m,2H),3.04-3.02(m,1H),2.90(br,1H),2.20(br,1H),2.13 (m,1H),1.41(d,3H,J=6.6Hz),0.95(t,3H,J=7.2Hz)ppm。
Step 3）Compound 22-4 synthesis
By Pd/C（0.2g）It is added to compound 22-3（2.0g,7.37mmol）Methanol（20mL）In solution, at 20 Atmospheric pressure H2Under atmosphere, react at room temperature 24 hours.After reaction completely, Pd/C is filtered to remove, yellow liquid is obtained after filtrate concentration 1.2g, yield：96.2%.
MS(ESI,pos.ion)m/z:170.2[M+H]+；
1H NMR(400MHz,CDCl3):δ4.21-4.15(m,2H),3.55(br,1H),3.33(br,1H),2.63(br, 1H),2.32(br,1H),1.64-1.60(m,2H),1.53-1.47(m,2H),1.42-1.36(m,2H),1.28(t,3H,J= 7.1Hz)ppm。
Step 4）Compound 22-5 synthesis
By compound 22-4 (0.68g, 4.02mmol）, compound 1-11-2（1.06g,6.03mmol）And EDCI （1.54g,8.05mmol）It is suspended in DCM（25mL）, at 0 DEG C, it is slowly dropped into DIPEA（2.1mL,12.7mmol）Afterwards, room temperature is anti- It should stay overnight.After reaction completely, water is added（30mL）Reaction, water layer DCM is quenched（35mL×3）Extraction, merge organic phase, with full And brine It, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1） To white solid 0.74g, yield：56.4%.
MS(ESI,pos.ion)m/z:327.3[M+H]+；
1H NMR(400MHz,CDCl3):δ5.44(br,1H),4.40(br,1H),4.33-4.30(m,1H),4.19- 4.14(m,2H),4.02(br,1H),3.66(s,3H),2.74(br,1H),2.04(br,1H),1.91-1.88(m,2H), 1.80-1.74(m,2H),1.56-1.54(m,1H),1.43-1.38(m,1H),1.26(t,3H,J=7.1Hz),1.07(d,3H, J=6.8Hz),0.97(d,3H,J=6.8Hz)ppm。
Step 5）Compound 22-6 synthesis
At 0 DEG C, by a hydronium(ion) lithia（0.48g,11.35mmol）The aqueous solution（10mL）It is slowly dropped to compound 22-5（0.74g,2.27mmol）THF（25mL）In solution, drop finishes, and 40 DEG C are reacted 12 hours.After reaction completely, THF is removed, Residue adds water（20mL）, water layer EtOAc（15mL×3）Washing, after liquid separation, aqueous phase hydrochloric acid（10%）Adjust pH value to 1, then use EtOAc（25mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, obtained after concentration white Color solid 0.55g, yield：81.3%.
MS(ESI,pos.ion)m/z:299.2[M+H]+；
1H NMR(400MHz,CD3OD):δ4.52(br,1H),4.20(d,1H,J=7.8Hz),3.93(br,1H),3.63 (s,3H),2.73(br,1H),2.01-1.98(m,4H),1.85-1.75(m,2H),1.54-1.46(m,2H),1.05(d,3H, J=6.8Hz),0.98(d,3H,J=6.8Hz)ppm。
Step 6）Compound 22-7 synthesis
By compound 3-1-0（0.31g,1.11mmol）With compound 22-6（0.3g,1.0mmol）It is dissolved in DCM（30mL） In, at 0 DEG C, it is slowly dropped into DIPEA（0.2mL,1.21mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, water is added （20mL）, use EtOAc（30mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, passed through after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain faint yellow solid 0.33g, yield：66.7%.
MS(ESI,pos.ion)m/z:495.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.75(d,2H,J=8.52Hz),7.68(d,2H,J=8.56Hz),5.45(d, 1H,J=9.4Hz),5.24(d,1H,J=16.56Hz),4.55-4.59(m,1H),3.67(s,3H),3.57(m,1H),2.73- 2.65(m,2H),2.27-2.19(m,1H),2.04(s,1H),1.84-1.77(m,2H),1.49-1.46(m,1H),1.27- 1.24(m,1H),1.08-1.07(br,1H),1.05-1.03(m,1H),0.91-0.89(m,6H)ppm。
Step 7）Compound 22-8 synthesis
By compound 22-7（0.33g,0.67mmol）And NH4OAc（1.04g,13.43mmol）It is suspended in toluene （8.0mL）In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（20mL）Reaction is quenched, water layer is used EtOAc（20mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain yellow solid 188mg, yield：58.9%.
MS(ESI,pos.ion)m/z:476.3[M+H]+；
1H NMR(400MHz,CDCl3):δ10.35(s,1H),7.64-7.62(d,2H,J=8.52Hz),7.55-7.45 (d,2H,J=1.84Hz),7.16(s,1H),5.54-5.46(br,2H),4.57-4.53(m,1H),3.70(s,3H),3.58 (m,1H),2.69(m,1H),2.54-2.48(m,1H),1.87-1.76(m,4H),1.47-1.45(m,2H),0.85-0.81 (m,6H)ppm。
Step 8）Compound 22-9 synthesis
By compound 22-8（0.19g,0.40mmol）, compound 1-12-2（0.15g,0.59mmol）, Pd (dppf) Cl2·CH2Cl2（33mg,0.039mmol）And KOAc（0.12g,1.19mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （5.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）, diatomite filtering, filtrate point Water is not used（20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=1/2）Obtain buff white solid 0.17g, yield：80.3%.
MS(ESI,pos.ion)m/z:523.3[M+H]+；
1H NMR(400MHz,CDCl3):δ10.48(s,1H),7.81-7.75(m,4H),7.43-7.41(d,1H,J= 8.0Hz),5.49-5.39(m,2H),4.58-4.53(m,2H),3.67(s,3H),3.57(m,1H),2.65(m,1H),2.54- 2.47(m,1H),2.10-2.04(m,2H),1.83-1.79(m,1H),1.49-1.46(m,2H),1.38(s,12H),0.85- 0.81(m,6H)ppm。
Step 9）Compound 22-10 synthesis
By compound 22-9（1.37g,2.62mmol）, compound 18-8（0.86g,2.62mmol）, Pd (PPh3)4 （0.12g,0.1mmol）And potassium carbonate（0.9g,6.55mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（12mL） And pure water（3.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）Dilute reaction solution Afterwards, water is used respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.84g, yield：50%.
MS(ESI,pos.ion)m/z:646.2[M+H]+；
1H NMR(400MHz,CDCl3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.76- 7.75,7.74-7.73(m,m,2H),7.60(s,1H),5.32,5.30(d,d,1H),5.06-5.02(m,1H),4.80-4.75 (m,1H),4.45,4.43,4.41(m,m,m,1H),3.63(s,3H),3.25-3.22(m,2H),2.82-2.79(m,2H), 2.55-2.50(m,1H),2.22-2.10(m,1H),2.08-2.00(m,1H),1.83-1.78(m,1H),1.74-1.54(m, 9H),1.52-1.37(m,3H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 10）Compound 22-11 synthesis
By compound 22-6（0.58g,1.95mmol）With HATU（0.78g,2.06mmol）It is suspended in THF（20mL）In, 0 At DEG C, DIPEA is slowly dropped into（0.41mL,2.48mmol）, drop finishes, and after isothermal reaction 0.5 hour, is slowly dropped into compound 1-9- 2（0.4g,2.15mmol）THF（10mL）Solution, drop finish, and react at room temperature 2.0 hours.After reaction completely, THF is removed, it is remaining Thing adds water（20mL）, use EtOAc（30mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are dense Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain brown oil liquid 0.77g, yield：85%.
Step 11）Compound 22-12 synthesis
By compound 22-11（1.34g,2.87mmol）It is dissolved in glacial acetic acid（20mL）In, 40 DEG C of reactions are overnight.Reaction is complete Afterwards, glacial acetic acid, residue EtOAc are removed（50mL）Dissolving, uses sodium carbonate liquor（50mL×3）Washing, anhydrous sodium sulfate are done It is dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/1）Obtain brown solid 0.87g, yield： 68%。
MS(ESI,pos.ion)m/z:450.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.59-7.52(m,1H),7.32-7.21(m,2H),5.41-5.38(m,2H), 4.35-4.32(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),2.67-2.65(m,1H), 2.20-2.13(m,1H),1.85-1.73(m,4H),1.46-1.43(m,2H),0.88-0.84(m,6H)ppm。
Step 12）Compound 22-13 synthesis
By compound 22-12（0.15g,0.33mmol）, compound 1-12-2（0.13g,0.49mmol）, Pd (dppf) Cl2·CH2Cl2（27mg,0.033mmol）And KOAc（97mg,0.99mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （5.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40.0mL）Dilute reaction solution, diatom Soil filtering, filtrate use water respectively（30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 90mg, yield：55.5%.
MS(ESI,pos.ion)m/z:497.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.85-7.80(m,1H),7.72-7.68(m,2H),5.45-5.41(m,2H), 4.56-4.48(m,1H),4.33-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H), 3.04-2.98(m,1H),2.25-2.20(m,1H),2.20-2.13(m,2H),1.87-1.76(m,1H),1.46-1.49(m, 2H),1.35(s,12H),0.88-0.84(m,6H)ppm。
Step 13）Compound 22-14 synthesis
By compound 22-13（50mg,0.1mmol）, compound 22-10（65mg,0.1mmol）, Pd (PPh3)4（12mg, 0.01mmol）And potassium carbonate（34.5mg,0.25mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（5.0mL）With Pure water（1.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（25mL）After dilute reaction solution, Water is used respectively（10mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Elution Agent：DCM/MeOH(v/v)=50/1）Obtain buff white solid 47mg, yield：50%.
MS(ESI,pos.ion)m/z:468.8[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.49(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.76- 7.75,7.74-7.73(m,m,3H),7.60(s,1H),7.56-7.55(q,1H),7.48,7.44(d,d,1H),5.39-5.35 (m,1H),5.32,5.29(d,d,2H),5.06-5.02(m,1H),4.80-4.75(m,1H),4.73-4.69(m,1H), 4.45-4.40(m,2H),3.63(s,6H),2.96-2.93(m,2H),2.85-2.82(m,2H),2.58-2.50(m,2H), 2.22-2.10(m,2H),2.08-2.00(m,1H),1.83-1.35(m,18H),1.31-1.24(m,1H),0.97,0.95(m, m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 23
Synthetic route：
Step 1）Compound 23-2 synthesis
By compound 3-1-0（2.98g,10.79mmol）And compound 23-1（2.69g,11.87mmol）It is dissolved in MeCN （250mL）In, at 0 DEG C, it is slowly dropped into DIPEA（2.14mL,12.95mmol）, drop is complete, reacts at room temperature 3.0 hours.Reaction is complete Afterwards, MeCN is removed, residue adds water（100mL）, then use EtOAc（100mL×3）Extraction, merge organic phase, saturated aqueous common salt Washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain white Solid 4.1g, yield：90%.
MS(ESI,pos.ion)m/z:425.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.61-5.59(m,1H), 5.33(s,2H),4.73-4.69(m,1H),4.35-4.28(m,1H),3.99-3.92(m,1H),1.76-1.74(m,3H), 1.42(s,9H)ppm。
Step 2）Compound 23-3 synthesis
By compound 23-2（1.54g,3.64mmol）And ammonium acetate（4.2g,5.46mmol）It is suspended in toluene（30mL） In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（50mL）Reaction, water layer EtOAc is quenched（50mL ×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=6/1）Obtain faint yellow solid 1.25g, yield：85%.
MS(ESI,pos.ion)m/z:404.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.64(s,1H),7.45-7.41(m,2H),7.35-7.32(m,2H),5.78- 5.75(m,1H),5.55-5.52(m,1H),4.24-4.17(m,1H),3.77-3.69(m,1H),1.78-1.77(m,3H), 1.39(s,9H)ppm。
Step 3）Compound 23-4 synthesis
By compound 23-3（4.12g,10.23mmol）, compound 1-12-2（2.86g,11.25mmol）, Pd (dppf) Cl2·CH2Cl2（0.42g,0.51mmol）And KOAc（2.51g,25.57mmol）It is placed in reaction bulb, N2Under protection, injection DMF（40mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（100mL）Dilute reaction solution Afterwards, diatomite filters, and filtrate uses water respectively（80mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through post after concentration Chromatography purifies（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 3.69g, yield：80%.
1H NMR(400MHz,CDCl3):δ7.75-7.72(m,2H),7.61-7.58(m,2H),7.28(s,1H),5.78- 5.75(m,1H),5.55-5.52(m,1H),4.24-4.17(m,1H),3.77-3.69(m,1H),1.78-1.77(m,3H), 1.39(s,9H)ppm。
Step 4）Compound 23-5 synthesis
By compound 23-4（0.45g,1.0mmol）It is dissolved in EtOAc（4mL）, then instill the ethyl acetate solution of hydrogen chloride （3.0mL,4M）Afterwards, drop finishes, and reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue ethyl acetate（5mL） After mashing, yellow solid 0.38g, yield are filtrated to get：90%.
MS(ESI,pos.ion)m/z:352.5[M+H]+。
Step 5）Compound 23-6 synthesis
By compound 23-5（0.11g,0.26mmol）, compound 1-11-2（50mg,0.286mmol）, EDCI（0.11g, 0.57mmol）And HOAT（0.07g,0.52mmol）It is suspended in DCM（3.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA （0.5mL,2.6mmol）, drop is complete, reacts at room temperature 3 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, use respectively Aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=2/1）Obtain faint yellow solid 0.11g, yield：83%.
MS(ESI,pos.ion)m/z:509.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.72-7.69(m,2H),7.60-7.58(m,2H),7.23(s,1H),6.08, 6.06(d,d,1H),5.74-5.70(m,1H),5.45-5.42(m,1H),4.70-4.67,4.66-4.63(m,m,1H), 4.29-4.25(m,1H),4.16-4.13,4.12-4.09(m,m,1H),3.65(s,3H),2.34-2.22(m,1H),1.66- 1.65(m,3H),1.35,1.32(q,q,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 6）Compound 23-7 synthesis
By compound 23-6（0.51g,1.0mmol）, compound 18-8（0.33g,1.0mmol）, Pd (PPh3)4（58mg, 0.05mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（9.0mL）With it is pure Water（3.0mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（80mL）After dilute reaction solution, Water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：DCM/MeOH(v/v)=100/1）Obtain white solid 0.38g, yield：60%.
MS(ESI,pos.ion)m/z:632.2[M+H]+；
1H NMR(400MHz,CDCl3):δ8.58(dd,1H),7.92-7.91,7.90-7.89(m,m,2H),7.77- 7.76,7.74-7.73(m,m,2H),7.34(s,1H),5.74-5.70(m,1H),5.45-5.42(m,2H),5.32,5.30 (d,d,1H),4.70-4.67,4.66-4.63(m,m,1H),4.45-4.44,4.42,4.40(m,m,m,1H),4.16-4.13, 4.12-4.09(m,m,1H),3.63(s,3H),3.25-3.22(m,2H),2.82-2.78(m,2H),2.29-2.17(m,1H), 1.73-1.53(m,9H),1.52-1.42(m,2H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 7）Compound 23-8 synthesis
By compound 23-1（10.58g,46.6mmol）It is dissolved in tetrahydrofuran（100mL）In, under 0 DEG C of nitrogen protection, slowly Instill the tetrahydrofuran solution of borine（100mL,1M）, drop is complete, isothermal reaction 3 hours.After reaction completely, methanol is used（80mL）Quench Go out reaction, through column chromatographic isolation and purification after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain colorless oil 7.45g yield：75%.
1H NMR(400MHz,CDCl3):δ5.32-5.29(m,1H),4.63-4.54(m,1H),4.16-4.09(m,1H), 3.97-3.92(m,1H),3.88-3.82(m,1H),3.80-3.79(m,1H),3.22(br,1H),1.62-1.61(m,3H), 1.43(s,9H)ppm。
Step 8）Compound 23-9 synthesis
By compound 23-8（7.42g,34.8mmol）It is dissolved in DCM（250mL）In, at 0 DEG C, by Dai Si-Martin（20.7g, 48.8mmol）Oxidant is added portionwise in reaction bulb, after adding, is reacted at room temperature 2.0 hours.After reaction completely, water is added （150mL）Reaction is quenched, filters, filtrate is pure through column chromatography for separation after concentration with saturated common salt water washing, anhydrous sodium sulfate drying Change（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain colorless oil 3.72g, yield：50.7%.
1H NMR(400MHz,CDCl3):δ9.77-9.75(m,1H),5.41-5.38(m,1H),4.64-4.59(m,1H), 4.24-4.17(m,1H),3.96-3.89(m,1H),1.65-1.64(m,3H),1.44(s,9H)ppm。
Step 9）Compound 23-10 synthesis
By compound 23-9（3.71g,17.6mmol）And ammoniacal liquor（13mL）It is dissolved in methanol（30mL）In, at 0 DEG C, slowly drip Enter glyoxal（40%,8mL）The aqueous solution, drop finish, room temperature reaction overnight.After reaction completely, concentration of reaction solution is through column chromatography for separation Purifying（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain white solid 2.08g, yield：47.6%.
MS(ESI,pos.ion)m/z:250.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.05(s,2H),6.32-6.28(m,1H),5.38-5.35(m,1H),4.23- 4.17(m,1H),3.86-3.80(m,1H),1.68-1.67(m,3H),1.40(s,9H)ppm。
Step 10）Compound 23-11 synthesis
By compound 23-10（2.09g,8.4mmol）It is dissolved in DCM（30mL）In, at 0 DEG C, by N- N-iodosuccinimides （3.8g,16.8mmol）It is added portionwise in reaction bulb, isothermal reaction 1.5 hours.After reaction completely, reaction solution saturated aqueous common salt Washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white Solid 2.65g, yield：63%.
MS(ESI,pos.ion)m/z:502.1[M+H]+；
1H NMR(400MHz,CDCl3):δ5.52-5.45(m,2H),4.35-4.29(m,1H),3.94-3.88(m,1H), 1.67-1.66(m,3H),1.40(s,9H)ppm。
Step 11）Compound 23-12 synthesis
By compound 23-11（1.64g,3.27mmol）It is suspended in second alcohol and water（v/v=3/7）Mixed solvent（50mL） In, add sodium sulfite（3.7g,29mmol）, flow back 17 hours.After reaction completely, ethanol is removed, residue adds water （50mL）, use ethyl acetate（50mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentration By column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 1.03g, yield：84%.
MS(ESI,pos.ion)m/z:376.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.18(s,1H),5.35-5.32(m,1H),5.28-5.24(m,1H),4.29- 4.23(m,1H),3.91-3.85(m,1H),1.67-1.66(m,3H),1.40(s,9H)ppm。
Step 12）Compound 23-13 synthesis
By compound 23-12（0.38g,1.0mmol）It is dissolved in EtOAc（4mL）, then instill the ethyl acetate solution of hydrogen chloride （3.0mL,4M）Afterwards, drop finishes, and reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue ethyl acetate（5mL） After mashing, yellow solid 0.31g, yield are filtrated to get：90%.
MS(ESI,pos.ion)m/z:276.1[M+H]+。
Step 13）Compound 23-14 synthesis
By compound 23-13（90mg,0.26mmol）, compound 1-11-2（50mg,0.29mmol）, EDCI（0.11g, 0.57mmol）And HOAT（0.07g,0.52mmol）It is suspended in DCM（3.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA （0.5mL,2.6mmol）, drop is complete, reacts at room temperature 3 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, use respectively Aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=2/1）Obtain faint yellow solid 90mg, yield：80%.
MS(ESI,pos.ion)m/z:433.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.31(s,1H),5.59-5.55(m,1H),5.52-5.50(m,1H),5.32, 5.29(d,d,1H),4.67-4.65,4.63-4.61(m,m,1H),4.45-4.44,4.42,4.40(m,m,m,1H),4.15- 4.13,4.11-4.09(m,m,1H),3.63(s,3H),2.29-2.17(m,1H),1.66-1.65(m,3H),0.97,0.95 (m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 14）Compound 23-15 synthesis
By compound 23-14（43mg,0.1mmol）, compound 1-12-2（28mg,0.11mmol）, Pd (dppf) Cl2· CH2Cl2（8.2mg,0.01mmol）And KOAc（25mg,0.25mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （1.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（10mL）After dilute reaction solution, silicon Diatomaceous earth filters, and filtrate uses water respectively（10mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 34.6mg, yield：80%.
1H NMR(400MHz,CDCl3):δ7.61(s,1H),5.81-5.77(m,1H),5.46-5.44(m,1H),5.32, 5.29(d,d,1H),4.61-4.59,4.57-4.55(m,m,1H),4.44,4.42,4.40(m,m,m,1H),4.07-4.04, 4.03-4.00(m,m,1H),3.63(s,3H),2.29-2.17(m,1H),1.66-1.65(m,3H),1.39,1.36(m,m, 12H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 15）Compound 23-16 synthesis
By compound 23-15（0.43g,1.0mmol）, compound 23-7（0.63g,1.0mmol）, Pd (PPh3)4（58mg, 0.05mmol）And potassium carbonate（0.35g,2.5mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（9.0mL）With it is pure Water（3.0mL）, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, adds ethyl acetate（80mL）After dilute reaction solution, Water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：DCM/MeOH(v/v)=50/1）Obtain white solid 0.34g, yield：40%.
MS(ESI,pos.ion)m/z:429.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.42(dd,1H),7.91-7.90,7.89-7.88(m,m,2H),7.77- 7.76,7.74-7.73(m,m,2H),7.64(s,1H),7.34(s,1H),6.02-5.97(m,1H),5.74-5.70(m,1H), 5.56,5.55(d,d,1H),5.45-5.42(m,2H),5.32,5.30(d,d,1H),4.70-4.67(m,1H),4.66-4.63 (m,1H),4.44,4.42,4.40(m,m,m,1H),4.28,4.27,4.25(m,m,m,1H),4.16-4.13,4.12-4.09 (m,m,2H),3.66(s,3H),3.63(s,3H),3.18-3.15(m,2H),2.86-2.82(m,2H),2.34-2.17(m, 2H),1.70-1.51(m,12H),1.48-1.39(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H), 0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 24
Synthetic route：
Step 1）Compound 24-1 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 1-6（2.96g, 10mmol）, 1, pentamethylene bromide（1.5mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（20mL）In suspension, 60 DEG C are reacted 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（80mL）In, separate out solid.Filtering, solid are used EtOAc（50mL）Dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=10/1）Obtain product 2.53g, yield：70%.
MS(ESI,pos.ion)m/z:365.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.66-2.65(m,2H),1.71-1.63(m,2H),1.61-1.53(m,1H), 1.51-1.43(m,2H),1.37-1.26(m,5H)ppm。
Step 2）Compound 24-2 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 24-1（3.62g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.96g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:349.5[M+H]+；
1H NMR(400MHz,CDCl3):δ2.73-2.71(m,4H),1.77-1.65(m,4H),1.63-1.55(m,4H), 1.29-1.21(m,2H)ppm。
Step 3）Compound 24-3 synthesis
By compound 24-2（0.35g,1.0mmol）, compound 1-13（0.99g,2.1mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And K2CO3（0.35g,2.5mmol）It is suspended in DME（5.0mL）And water（1.0mL）In, under nitrogen protection, 90 DEG C Reaction 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, eaten respectively with water and saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=50/1）Obtain Faint yellow solid 0.39g, yield：45%.
MS(ESI,pos.ion)m/z:439.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.79,7.77(d,d,2H),7.70-7.69(q,2H),7.18,7.16(d,d, 2H),6.08,6.06(d,d,1H),5.32,5.30(d,d,1H),5.25-5.20(m,2H),4.40-4.32(m,2H),3.84- 3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),2.99-2.97(m,4H),2.39-2.10(m, 8H),2.00-1.89(m,2H),1.71-1.60(m,4H),1.30-1.22(m,6H),1.02,1.00(m,m,3H),0.97, 0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 25
Synthetic route：
Step 1）Compound 25-1 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 1-6（2.96g, 10mmol）, 1,3- dibromopropane（1.1mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（30mL）In suspension, 60 DEG C are reacted 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（100mL）In, separate out solid.Filtering, solid are used EtOAc（50mL）Dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=10/1）Obtain product 2.35g, yield：70%.
MS(ESI,pos.ion)m/z:337.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.99-2.98(m,2H),2.39-2.29(m,2H),2.13-2.04(m,2H), 1.79-1.57(m,2H)ppm。
Step 2）Compound 25-2 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 25-1（3.34g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.08g is obtained, Yield：65%.
MS(ESI,pos.ion)m/z:323.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.74-2.73(m,4H),2.28-2.18(m,2H),1.87-1.78(m,2H), 1.52-1.29(m,2H)ppm。
Step 3）Compound 25-3 synthesis
By compound 25-2（0.32g,1.0mmol）, compound 3-5（0.50g,1.0mmol）, Pd (PPh3)4（0.12g, 0.1mmol）And K2CO3（0.35g,2.5mmol）It is suspended in DME（5.0mL）And water（1.0mL）In, under nitrogen protection, 90 DEG C Reaction 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, eaten respectively with water and saturation Salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=100/1） To faint yellow solid 0.27g, yield：45%.
MS(ESI,pos.ion)m/z:612.6[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51- 7.50,7.49-7.48(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.36(m,1H), 3.85-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),2.77-2.75(m,2H),2.68-2.67(m,2H), 2.30-1.92(m,7H),1.86-1.77(m,2H),1.59-1.36(m,2H),0.97,0.95(m,m,3H),0.90,0.89 (m,m,3H)ppm。
Step 4）Compound 25-4 synthesis
By compound 25-3（0.3g,0.5mmol）, compound 16-4（0.24g,0.5mmol）, Pd (PPh3)4（57.8mg, 0.05mmol）And K2CO3（0.17g,1.25mmol）It is suspended in DME（5.0mL）And water（1.0mL）In, under nitrogen protection, 90 DEG C reaction 5.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, respectively with water and saturation Brine It, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)=50/1） To faint yellow solid 0.18g, yield：40.5%.
MS(ESI,pos.ion)m/z:444.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.79,7.77(d,d,1H),7.66-7.65,7.64-7.62(m,m,2H), 7.59(m,2H),7.57,7.55(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.32,5.29(m,m,2H), 5.23-5.19(m,1H),5.14-5.10(m,1H),4.41,4.39,4.37(m,m,m,1H),4.12,4.11-4.10,4.08 (m,m,m,1H),3.85-3.78(m,1H),3.68-3.65(m,1H),3.63(s,6H),3.42-3.36(m,1H),3.00- 2.98(m,2H),2.72-2.70(m,2H),2.62-2.55(m,1H),2.30-1.92(m,9H),1.85-1.76(m,2H), 1.65-1.44(m,3H),0.97,0.95(m,m,6H),0.94-0.92(m,1H),0.91,0.89(m,m,6H),0.50-0.46 (m,1H)ppm。
Embodiment 26
Synthetic route：
Step 1）Compound 26-1 synthesis
By compound 1-6（2.0g,6.82mmol）, 2,2 '-two bromodiethyl ethers（1.64g,7.15mmol）, TEBAC （0.3g,1.36mmol）It is suspended in DMSO（20mL）In, at 0 DEG C, it is slowly dropped into the NaOH aqueous solution（50%,2.0mL）, drop is complete, 50 DEG C are reacted 2.0 hours.After reaction completely, water is added（50mL）Reaction, water layer EtOAc is quenched（50mL×3）Extraction, merge Organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc (v/v)=15/1）Obtain yellow oil 1.49g, yield：60%.
MS(ESI,pos.ion)m/z:367.1[M+H]+；
1H NMR(400MHz,CDCl3):δ4.19-4.13(m,2H),3.73-3.68(m,2H),2.70-2.69(m,2H), 2.10-2.02(m,2H),1.82-1.73(m,2H)ppm。
Step 2）Compound 26-2 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 26-1（3.64g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.27g is obtained, Yield：65%.
MS(ESI,pos.ion)m/z:353.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.75-3.71(m,4H),2.76-2.74(m,4H),1.85-1.79(m,4H) ppm。
Step 3）Compound 26-3 synthesis
By compound 9-1（6.86g,27.97mmol）It is dissolved in DCM（70mL）In, at 0 DEG C, by Dai Si-Martin reagent （23.7g,56mmol）It is added portionwise in reaction system, after adding, reacts at room temperature 7.0 hours.After reaction completely, thiosulfuric acid is used Sodium water solution（100mL）Reaction, diatomite filtering is quenched, filtrate uses DCM（100mL×3）Extraction, merge organic phase, it is anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=6/1）Obtain weak yellow liquid 5.78g yield：85%.
Step 4）Compound 26-4 synthesis
By compound 26-3（5.81g,23.9mmol）It is dissolved in DCM（70mL）In, at -78 DEG C, by Et2NSF3（4.85mL, 35.9mmol）Slowly in instillation system, drop finishes, and after isothermal reaction 2.0 hours, reacts at room temperature 19 hours.After reaction completely, chlorine is used Change aqueous ammonium（50mL）Reaction, water layer DCM is quenched（100mL×3）Extraction, merge organic phase, anhydrous Na2SO4Dry, it is dense Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=20/1）Obtain weak yellow liquid 5.0g, yield：79%.
MS(ESI,pos.ion)m/z:266.3[M+H]+；
1H NMR(400MHz,CDCl3):δ9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.93- 3.84(m,2H),3.77(s,3H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 5）Compound 26-5 synthesis
By compound 26-4（5.0g,18.86mmol）It is dissolved in THF（40mL）In, at 0 DEG C, by lithium hydroxide aqueous solution （1.5g,20mL）In addition system, react at room temperature 2.0 hours.After reaction completely, watery hydrochloric acid is used（1M）Adjust the pH value of reaction solution To 5, THF, water layer watery hydrochloric acid are removed（1M）PH value is adjusted to use EtOAc to after 2（80mL×3）Extraction, merge organic phase, with full And brine It, anhydrous Na2SO4Dry, white solid 4.54g, yield are obtained after concentration：94%.
MS(ESI,pos.ion)m/z:252.3[M+H]+；
1H NMR(400MHz,CDCl3):δ9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.89- 3.74(m,2H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 6）Compound 26-6 synthesis
By compound 26-5（2.37g,9.43mmol）It is dissolved in THF（30mL）In, at 0 DEG C, it is molten to instill borine tetrahydrofuran Liquid（14.2mL,1M）, drop is complete, reacts at room temperature 2.0 hours.After reaction completely, methanol is used（4.0mL）Reaction is quenched, removes THF, Residue DCM（100mL）After dissolving, water is used respectively（40mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, concentration After obtain colorless syrup 1.79g, yield：80%.
1H NMR(400MHz,CDCl3):δ4.43-4.27(m,1H),3.59-3.34(m,2H),3.60-3.46(m,2H), 2.48-2.18(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 7）Compound 26-8 synthesis
By compound 26-6（1.8g,7.59mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, by TCCA（1.77g, 7.59mmol）In addition system, then by TEMPO DCM solution（0.12g,0.76mmol,5.0mL）In instillation system, drop Finish, after isothermal reaction 1.0 hours, react at room temperature 1.0 hours.After reaction completely, solid is filtered to remove, filtrate is with saturation sulfurous acid Sodium solution（40mL×3）Washing, anhydrous Na2SO4Dry, residue is dissolved in ammonia methanol after concentration（20mL,7M）In, it is anti-at 0 DEG C After answering 0.5 hour, then react at room temperature 1.0 hours.After being cooled to 0 DEG C again, the aqueous solution of glyoxal is added dropwise（2.0mL,40%）, Drop finishes, and reacts at room temperature 24 hours.After reaction completely, concentration of reaction solution, residue DCM（150mL）After dissolving, water is used respectively （50mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/ MeOH(v/v)=60/1）Obtain faint yellow solid 1.04g, yield：50%.
MS(ESI,pos.ion)m/z:274.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.00(s,2H),5.83-5.80(m,1H),4.05-3.79(m,1H),3.74- 3.52(m,1H),3.11-2.33(m,2H),1.51(s,9H)ppm。
Step 8）Compound 26-9 synthesis
By compound 26-8（0.93g,3.4mmol）It is dissolved in DCM（30mL）In, at 0 DEG C, by NIS（1.7g,7.5mmol） It is added portionwise in system, after adding, isothermal reaction 2.0 hours.After reaction completely, filtering, filtrate saturated sodium bisulfite solution （50mL×3）Washing, anhydrous Na2SO4Dry, yellow solid 1.07g, yield are obtained after concentration：60%.It is directly used in anti-in next step Should.
MS(ESI,pos.ion)m/z:526.1[M+H]+；
1H NMR(400MHz,CDCl3):δ5.13-5.08(m,1H),3.91-3.87(m,1H),3.58-3.46(m,2H), 2.74-2.72(m,1H),1.51(s,9H)ppm。
Step 9）Compound 26-10 synthesis
By compound 26-9（1.03g,1.96mmol）It is dissolved in EtOH（10mL）In, add sodium sulfite（2.47g, 19.6mmol）And water（10mL）, 90 DEG C are reacted 30 hours.After reaction completely, filtering, filtrate, residue DCM are concentrated（80mL） After dissolving, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=6/1）Obtain white solid 0.26g, yield：33%.
MS(ESI,pos.ion)m/z:400.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.08(s,1H),5.33-4.95(m,1H),3.91-3.87(m,1H),3.78- 3.36(m,2H),2.96-2.55(m,1H),1.49(s,9H)ppm。
Step 10）Compound 26-11 synthesis
By compound 3-1-0（2.41g,8.66mmol）With compound 26-5（2.17g,8.66mmol）It is dissolved in DCM （30mL）In, at 0 DEG C, it is slowly dropped into TEA（2.5mL,17.32mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, Add water（50mL）Reaction is quenched, uses DCM（30mL×3）Extraction, merge organic phase, anhydrous Na2SO4Dry, slightly produced after concentration Thing 3.6g, yield：99%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:421.3[M+H]+。
Step 11）Compound 26-12 synthesis
By compound 26-11（3.6g,8.6mmol）And ammonium acetate（7.0g,86mmol）It is suspended in toluene（30mL）In, 110 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, adds water（60mL）Reaction, water layer EtOAc is quenched（80mL× 3）Extraction, merge organic phase, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)= 6/1）Obtain product 1.47g, yield：40%.
MS(ESI,pos.ion)m/z:429.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.54-7.52(m,2H),7.48-7.46(m,2H),7.26-7.25(m,1H), 5.19-5.18(m,1H),3.70-3.52(m,2H),2.78-2.65(m,2H),1.48(s,9H)ppm。
Step 12）Compound 26-13 synthesis
By compound 26-12（1.4g,3.27mmol）, compound 1-12-2（0.92g,3.6mmol）, Pd (dppf) Cl2·CH2Cl2（0.13g,1.16mmol）And KOAc（0.81g,8.17mmol）It is placed in reaction bulb, N2Under protection, DME is injected （25mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, ethyl acetate is added（80mL）Dilute reaction solution, diatomite filtering, filter Liquid uses water respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=1/2）Obtain solid 1.49g, yield：96%.
MS(ESI,pos.ion)m/z:476.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.54-7.52(m,2H),7.48-7.46(m,2H),7.26-7.25(m,1H), 5.19-5.18(m,1H),3.70-3.52(m,2H),2.78-2.65(m,2H),1.48(s,9H),1.35(s,12H)ppm。
Step 13）Compound 26-14 synthesis
By compound 26-13（2.14g,4.5mmol）, compound 26-2（1.57g,4.5mmol）, Pd (PPh3)4 （0.26g,0.225mmol）And potassium carbonate（1.24g,9.0mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into （20mL）And pure water（4.0mL）, 90 DEG C are reacted 2.0 hours.After reaction completely, ethyl acetate is added（100mL）Dilute reaction solution Afterwards, water is used respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=6/1）Obtain faint yellow solid 1.67g, yield：60%.
MS(ESI,pos.ion)m/z:620.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(m,m,2H),7.72-7.71,7.70-7.69 (m,m,2H),7.46(s,1H),4.93-4.88(m,1H),4.18-4.17,4.15-4.13,4.11-4.08,4.06-4.05 (m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80-3.79(m,m,m,m,1H),3.75-3.70(m, 4H),2.86-2.67(m,5H),2.47-2.26(m,1H),1.82-1.76(m,4H),1.41(s,9H)ppm。
Step 14）Compound 26-15 synthesis
By compound 26-14（1.42g,2.3mmol）, compound 1-12-2（0.64g,2.53mmol）, Pd (dppf) Cl2·CH2Cl2（90mg,0.115mmol）And KOAc（0.6g,5.75mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （15mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is used（100mL）Dilute reaction solution, diatomite filtering, filtrate point Water is not used（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=4/1）Obtain faint yellow solid 1.07g, yield：70%.
MS(ESI,pos.ion)m/z:668.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.77-7.76,7.75-7.74(m,m,2H),7.46(s,1H),7.44- 7.43,7.42-7.41(m,m,2H),4.93-4.88(m,1H),4.18-4.17,4.15-4.13,4.11-4.08,4.06- 4.05(m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80-3.79(m,m,m,m,1H),3.67- 3.63(m,4H),2.86-2.68(m,3H),2.61-2.58(m,2H),2.47-2.26(m,1H),1.79-1.73(m,4H), 1.41(s,9H),1.33,1.30(m,m,12H)ppm。
Step 15）Compound 26-16 synthesis
By compound 26-15（0.37g,0.55mmol）, compound 26-10（0.22g,0.55mmol）, four triphenyl phosphorus Palladium（32mg,0.027mmol）And potassium carbonate（0.19g,1.37mmol）It is suspended in EtOH/H2O（v/v=4/1）Mixed solvent （7.5mL）In, under nitrogen protection, 90 DEG C are reacted 2.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （50mL）Dissolving, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/ MeOH(v/v)=100/1）Obtain faint yellow solid 0.24g, yield：55%.
MS(ESI,pos.ion)m/z:813.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82-7.81,7.80-7.79(m,m,2H),7.78-7.75,7.74-7.73 (m,m,2H),7.53(s,1H),7.46(s,1H),5.20-5.15(m,1H),4.93-4.88(m,1H),4.18-4.17, 4.15-4.13,4.11-4.08,4.06-4.05(m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80- 3.79(m,m,m,m,1H),3.74-3.69(m,4H),3.00-2.97(m,2H),2.92-2.68(m,4H),2.53-2.26(m, 2H),1.84-1.78(m,4H),1.53(s,9H),1.41(s,9H)ppm。
Step 16）Compound 26-17 synthesis
By compound 26-16（0.24g,0.3mmol）It is dissolved in EtOAc（4.0mL）In, the ethyl acetate that hydrogen chloride is added dropwise is molten Liquid（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （4.0mL）After mashing, pale yellow powder shape solid 0.18g, yield are filtrated to get：80%.It is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:613.3[M+H]+。
Step 17）Compound 26-18 synthesis
By compound 26-17（0.20g,0.26mmol）, compound 1-11-2（100mg,0.57mmol）, EDCI （0.11g,0.57mmol）With HOAT（70mg,0.52mmol）It is suspended in DCM（6.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA （0.43mL,2.6mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, respectively With ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： DCM/MeOH(v/v)=40/1）Obtain faint yellow solid 0.19g, yield：80%.
MS(ESI,pos.ion)m/z:464.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57 (m,m,2H),7.46(s,1H),7.41(s,1H),5.32,5.30(d,d,2H),5.29-5.26(m,1H),5.16-5.11(m, 1H),4.47,4.45,4.43(m,m,m,2H),4.21-4.19,4.17-4.15,4.13-4.11,4.09-4.07(m,m,m,m, 2H),3.94-3.93,3.91-3.88,3.87-3.84,3.82-3.81(m,m,m,m,2H),3.74-3.69(m,4H),3.63 (s,6H),3.00-2.72(m,6H),2.55-2.29(m,2H),2.23-2.11(m,2H),1.84-1.78(m,4H),0.97, 0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 27
Synthetic route：
Step 1）Compound 27-1 synthesis
By compound 1-6（4.2g,14.34mmol）With compound 10-0（5.23g,21.51mmol）It is dissolved in DMF（15mL） In, under 0 DEG C of nitrogen protection, add NaH（60%,1.43g,35.85mmol）, after adding, 50 DEG C are reacted 18 hours.Reaction is complete Afterwards, it is cooled to room temperature, adds water（100mL）Reaction, aqueous layer with ethyl acetate is quenched（100mL×3）Extraction, organic phase use water respectively With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)= 8/1）Obtain product 1.08g, yield：20%.
MS(ESI,pos.ion)m/z:377.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.78-2.70(m,2H),2.65-2.64(m,2H),2.55-2.45(m,2H), 2.35-2.34(m,3H),1.93-1.83(m,4H)ppm。
Step 2）Compound 27-2 synthesis
By compound 27-1（1.43g,3.8mmol）And triethyl silicane（3.7mL,23mmol）It is mixed in reaction bulb, 0 ℃N2Under protection, trifluoroacetic acid is slowly injected into（8.0mL）, drop is complete, and 40 DEG C are reacted 7 hours.After reaction completely, trifluoro second is removed Acid, residue EtOAc（50mL）Dissolving, it is dense with sodium carbonate liquor and saturated common salt water washing, anhydrous sodium sulfate drying respectively Through column chromatographic isolation and purification after contracting（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain pale yellow oily liquid 1.1g, yield： 80%。
MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(400MHz,CDCl3):δ2.82-2.70(m,6H),2.53-2.41(m,2H),2.30-2.29(m,3H), 1.99-1.87(m,4H)ppm。
Step 3）Compound 27-3 synthesis
By compound 27-2（1.63g,4.5mmol）, compound 6-1（1.97g,4.5mmol）, Pd (PPh3)4（0.26g, 0.225mmol）And potassium carbonate（1.24g,9.0mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（20mL）With it is pure Water（4.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, ethyl acetate is added（100mL）After dilute reaction solution, water is used respectively （30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/ EtOAc(v/v)=6/1）Obtain faint yellow solid 1.61g, yield：60%.
MS(ESI,pos.ion)m/z:597.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51- 7.50,7.49-7.48(m,m,2H),4.97-4.93(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.81- 2.74(m,4H),2.69-2.66(m,2H),2.51-2.38(m,3H),2.30-2.29(m,3H),2.28-2.16(m,1H), 2.10-1.97(m,2H),1.93-1.87(m,4H),1.53(s,9H)ppm。
Step 4）Compound 27-4 synthesis
By compound 27-3（1.37g,2.3mmol）, compound 1-12-2（0.64g,2.53mmol）, Pd (dppf) Cl2·CH2Cl2（90mg,0.115mmol）And KOAc（0.6g,5.75mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （10mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is used（100mL）Dilute reaction solution, diatomite filtering, filtrate point Water is not used（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=4/1）Obtain faint yellow solid 0.89g, yield：60%.
MS(ESI,pos.ion)m/z:645.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23- 7.22,7.21-7.20(m,m,2H),4.97-4.93(m,1H),3.64-3.58(m,1H),3.31-3.23(m,1H),2.74- 2.66(m,4H),2.59-2.56(m,2H),2.47-2.33(m,3H),2.30-2.29(m,3H),2.27-2.16(m,1H), 2.10-1.97(m,2H),1.92-1.82(m,4H),1.53(s,9H),1.33,1.30(m,m,12H)ppm。
Step 5）Compound 27-5 synthesis
By compound 27-4（0.35g,0.55mmol）, compound 2-5（0.2g,0.55mmol）, four triphenyl phosphorus palladiums （32mg,0.027mmol）And potassium carbonate（0.19g,1.37mmol）It is suspended in EtOH/H2O（v/v=4/1）Mixed solvent （7.5mL）In, under nitrogen protection, 90 DEG C are reacted 2.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （50mL）Dissolving, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/ MeOH(v/v)=50/1）Obtain faint yellow solid 0.21g, yield：50%.
MS(ESI,pos.ion)m/z:754.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.59-7.57 (m,m,3H),7.47(s,1H),5.24-5.19(m,1H),4.97-4.93(m,1H),3.64-3.58(m,2H),3.31-3.24 (m,2H),2.99-2.95(m,2H),2.88-2.85(m,2H),2.81-2.73(m,2H),2.56-2.31(m,5H),2.30- 2.29(m,3H),2.27-2.16(m,2H),2.10-1.87(m,7H),1.53(s,18H)ppm。
Step 6）Compound 27-6 synthesis
By compound 27-5（0.23g,0.3mmol）It is dissolved in EtOAc（4.0mL）In, the ethyl acetate that hydrogen chloride is added dropwise is molten Liquid（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （4.0mL）After mashing, pale yellow powder shape solid 0.19g, yield are filtrated to get：90%.It is directly used in and reacts in next step.
Step 7）Compound 27-7 synthesis
By compound 27-6（0.18g,0.26mmol）, compound 27-6-2（0.12g,0.57mmol）, EDCI（0.11g, 0.57mmol）With HOAT（70mg,0.52mmol）It is suspended in DCM（6.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.43mL, 2.6mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, ammonium chloride is used respectively Solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/ v)=40/1）Obtain faint yellow solid 0.19g, yield：78%.
MS(ESI,pos.ion)m/z:468.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57 (m,m,3H),7.47-7.45(m,2H),7.40(s,1H),7.37-7.27(m,5H),7.23-7.15(m,3H),6.13,6.11 (s,s,1H),5.91,5.89(s,s,1H),5.38-5.29(m,3H),5.18-5.13(m,1H),3.91-3.84(m,2H), 3.91-3.84(m,2H),3.75-3.67(m,2H),3.64(s,6H),2.99-2.95(m,2H),2.88-2.85(m,2H), 2.81-2.73(m,2H),2.51-2.39(m,2H),2.36-2.08(m,9H),2.03-1.87(m,6H)ppm。
Embodiment 28
Synthetic route：
Step 1）Compound 28-1 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 1-6（2.96g, 10mmol）, 1,5- bis- bromo- 3- methylpentanes（1.7mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（30mL）It is outstanding In turbid, 60 DEG C are reacted 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（100mL）In, separate out solid.Cross Filter, solid EtOAc（50mL）Dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain product 2.63g, yield：70%.
MS(ESI,pos.ion)m/z:379.2[M+H]+；
1H NMR(400MHz,CDCl3):δ2.68-2.67(m,2H),1.65-1.57(m,2H),1.46-1.33(m,5H), 1.10-1.01(m,2H),0.82-0.80(m,3H)ppm。
Step 2）Compound 28-2 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 28-1（3.78g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.02g is obtained, Yield：56%.
MS(ESI,pos.ion)m/z:365.2[M+H]+；
1H NMR(400MHz,CDCl3):δ2.74-2.67(m,4H),1.64-1.32(m,7H),1.03-1.00(m,3H), 0.89-0.79(m,2H)ppm。
Step 3）Compound 28-4 synthesis
By compound 28-3（5.91g,29mmol）, NBS（5.76g,32mmol）And p-TSA（1.0g,5.2mmol）It is mixed Together in reaction bulb, 100 DEG C are reacted 0.5 hour.After reaction completely, it is cooled to room temperature, is separately added into DCM（100mL）And water （50mL）Dilute reaction solution, after liquid separation, water layer DCM（50mL×3）Extraction, merges organic phase, and saturated common salt water washing is anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/DCM(v/v)=5/1）Yellow slurry 5.72g is obtained, Yield：70%.
MS(ESI,pos.ion)m/z:285.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.55(d,1H,J=4.0Hz),7.14(d,1H,J=4.0Hz),4.29(s,2H) ppm。
Step 4）Compound 28-5 synthesis
By compound 28-4（5.58g,19.8mmol）With compound 1-9（4.7g,21.8mmol）It is dissolved in DCM（100mL） In, at 0 DEG C, it is slowly dropped into DIPEA（3.62mL,21.9mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, add Water（50mL）Reaction is quenched, removes DCM, water layer EtOAc（50mL×3）Extraction, merging organic phase, saturated common salt water washing, Anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain yellow solid 5.78g yield：70%.
MS(ESI,pos.ion)m/z:418.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.49(d,1H,J=4.0Hz),7.13(t,1H,J=4.0Hz),5.23-5.02 (m,2H),4.48-4.37(m,1H),3.60-3.38(m,2H),2.29-2.26(m,2H),2.11-1.92(m,2H),1.44 (s,9H)ppm。
Step 5）Compound 28-6 synthesis
By compound 28-5（7.92g,19mmol）And NH4OAc（22.2g,288mmol）It is suspended in dimethylbenzene （100mL）In, reacted 5.0 hours at 140 DEG C.After reaction completely, it is cooled to room temperature, adds water（100mL）Reaction is quenched, water layer is used EtOAc（100mL×3）Extraction, merge organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain yellow solid 6.94g, yield：92%.
MS(ESI,pos.ion)m/z:398.3[M+H]+；
1H NMR(400MHz,CDCl3):δ10.51(br,1H),7.07(s,1H),6.94(s,2H),4.91-4.90(m, 1H),3.39(s,2H),2.98(s,1H),2.12(s,2H),1.95(s,1H),1.48(s,9H)ppm。
Step 6）Compound 28-7 synthesis
By compound 28-6（1.0g,2.5mmol）, compound 1-12-2（0.96g,3.8mmol）, PdCl2(dppf) .CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）It is mixed in reaction bulb, under nitrogen protection, adds DMF （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（60mL）After dilute reaction solution, diatomite Filtering.Filtrate uses water respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4Dry, it is pure through column chromatography for separation after concentration Change（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain white solid 0.89g, yield：80%.
1H NMR(400MHz,CDCl3):δ10.51(br,1H),7.53(s,1H),7.27(s,1H),7.15(s,1H), 4.94-4.93(m,1H),3.39(s,2H),2.99(s,1H),2.12-1.94(m,4H),1.49(s,9H),1.34(s,12H), 1.24(m,8H)ppm。
Step 7）Compound 28-8 synthesis
By compound 28-7（0.23g,0.51mmol）It is dissolved in ethyl acetate（4.0mL）In, it is slowly dropped into the second of hydrogen chloride Acetate solution（3.0mL,4M）, drop is complete, reacts at room temperature 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc（5.0mL）After mashing, faint yellow solid 0.21g, yield are filtrated to get：100%.
MS(ESI,pos.ion)m/z:346.2[M+H]+。
Step 8）Compound 28-9 synthesis
By compound 28-8（0.12g,0.29mmol）, compound 1-11-2（0.11g,0.65mmol）, EDCI（0.12g, 0.65mmol）And HOAT（80mg,0.59mmol）It is suspended in DCM（5.0mL）In, at 0 DEG C, it is slowly dropped into DIPEA（0.6mL, 3.63mmol）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, chlorination is used respectively Ammonium salt solution and saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc (v/v)=2/1）Obtain white solid foam 0.12g, yield：80%.
MS(ESI,pos.ion)m/z:503.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.68,7.67(s,s,1H),7.27(d,1H),7.11(dd,1H),5.56, 5.55(d,d,1H),5.42-5.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,1H),3.66(s,3H),3.65- 3.61(m,1H),2.32-1.92(m,5H),1.33,1.30(m,m,12H),1.02,1.00(m,m,3H),0.93,0.91(m, m,3H)ppm。
Step 9）Compound 28-10 synthesis
By compound 28-9（1.70g,3.4mmol）, compound 28-2（1.23g,3.4mmol）, Pd (PPh3)4（0.20g, 0.17mmol）And potassium carbonate（1.41g,10.22mmol）It is placed in reaction bulb, N2Under protection, DME is injected separately into（24mL）With it is pure Water（6mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）Dilute reaction solution, use respectively Water and saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 100/1）Obtain faint yellow solid 1.0g, yield：45%.
MS(ESI,pos.ion)m/z:660.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.04,7.03(d,d,1H),7.01,7.00(s,s,1H), 5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64 (m,1H),3.63(s,3H),2.71-2.65(m,4H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.45-1.26 (m,7H),1.03-1.00(m,3H),0.97-0.85(m,8H)ppm。
Step 10）Compound 28-11 synthesis
By compound 28-10（1.51g,2.3mmol）, compound 1-12-2（0.64g,2.53mmol）, Pd (dppf) Cl2·CH2Cl2（90mg,0.115mmol）And KOAc（0.6g,5.75mmol）It is placed in reaction bulb, N2Under protection, DMF is injected （10mL）, 120 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is used（100mL）Dilute reaction solution, diatomite filtering, filtrate point Water is not used（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent： PE/EtOAc(v/v)=4/1）Obtain faint yellow solid 0.97g, yield：60%.
MS(ESI,pos.ion)m/z:707.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.04,7.03(d,d,1H),6.73,6.72(s,s,1H), 5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64 (m,1H),3.63(s,3H),2.66-2.63(m,2H),2.59-2.56(m,2H),2.31-2.05(m,4H),2.02-1.92 (m,1H),1.42-1.23(m,19H),1.03-0.95(m,8H),0.90-0.89(m,m,3H)ppm。
Step 11）Compound 28-12 synthesis
By compound 28-11（0.43g,0.61mmol）, compound 2-7（0.25g,0.61mmol）, Pd (PPh3)4 （70mg,0.05mmol）And potassium carbonate（0.25g,1.83mmol）It is suspended in EtOH（5mL）With water（1mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）Dilute reaction solution, water is used respectively （20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：EtOAc） Obtain product 0.32g, yield：60%.
MS(ESI,pos.ion)m/z:437.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.33(s,1H),7.26,7.25(s,s,1H),7.03, 7.02(d,d,1H),5.56,5.55(d,d,1H),5.44-5.37(m,2H),5.32,5.29(d,d,1H),4.41-4.37(m, 1H),4.34-4.30(m,1H),3.86-3.79(m,2H),3.69-3.67(m,2H),3.66(s,3H),3.63(s,3H), 2.98-2.95(m,2H),2.81-2.78(m,2H),2.31-2.05(m,8H),2.02-1.92(m,2H),1.47-1.32(m, 5H),1.28-1.22(m,2H),1.03-0.89(m,17H)ppm。
Embodiment 29
Synthetic route：
Step 1）Compound 29-2 synthesis
By NBS（2.16g,12mmol）With compound 29-1（2.5g,10mmol）It is dissolved in CCl4（20mL）In, at 0 DEG C, delay It is slow to instill dibenzoyl peroxide（0.24g,1.0mmol）, drop finishes, after being stirred at room temperature 15 minutes, back flow reaction 7.0 hours.Instead After answering completely, CCl is removed4, residue EtOAc（100mL）Dissolving, uses water respectively（50mL×3）With saturated common salt water washing, Anhydrous sodium sulfate drying, crude product 3.2g is obtained after concentration, be directly used in and react in next step.
MS(ESI,pos.ion)m/z:331.8[M+H]+；
1H NMR(400MHz,CDCl3):δ7.87(s,1H),4.68(s,2H)ppm。
Step 2）Compound 29-3 synthesis
By NaH（60%,3.13g,78mmol）It is suspended in DMF（100mL）In, it is slowly dropped into diethyl malonate （12.54g,78mmol）, drop finish, 100 DEG C reaction 40 minutes after be down to room temperature reaction.Add compound 29-2（11.77g, 35.6mmol）, finish, after reacting at room temperature 30 minutes, 75 DEG C are reacted 1.0 hours.After reaction completely, saturated ammonium chloride solution is used （50mL）Reaction is quenched, adds EtOAc（150mL）, organic phase is separated, respectively with water and saturated common salt water washing, anhydrous slufuric acid Sodium is dried, and product 14g is obtained after concentration, is directly used in and is reacted in next step.
1H NMR(400MHz,CDCl3):δ7.86(m,1H),4.18-4.13(m,4H),3.91,3.89,3.87(s,d,s, 1H),3.57,3.55(dd,dd,2H),1.23,1.21,1.19(s,s,s,6H)ppm。
Step 3）Compound 29-4 synthesis
By compound 29-3（14g）It is dissolved in DMSO（100mL）In, at room temperature, it is slowly added to NaCl（4.10g,70mmol） And water（0.64g,35.6mmol）, after adding, 100 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc （200mL）Dilute reaction solution, with saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Elution Agent：PE/EtOAc(v/v)=20/1）Obtain product 8.0g.
1H NMR(400MHz,CDCl3):δ7.72(t,1H),4.08,4.06,4.05,4.03(s,s,s,s,2H),2.96, 2.94,2.92(m,m,m,2H),2.75,2.73,2.71(d,m,d,2H),1.22,1.21,1.19(s,s,s,3H)ppm。
Step 4）Compound 29-5 synthesis
By compound 29-4（3.38g,10mmol）It is dissolved in methanol（20mL）In, the NaOH aqueous solution is instilled at 0 DEG C（0.8g, 20mL）, drop is complete, reacts at room temperature 3.0 hours.After reaction completely, watery hydrochloric acid is used（1M）PH to 5 is adjusted, removes methanol, water layer is with dilute salt Acid（1M）PH to 2 is adjusted, uses EtOAc（50mL×3）Extraction, organic phase anhydrous Na2SO4Dry, white solid is obtained after concentration 2.79g yield：90%.
MS(ESI,pos.ion)m/z:312.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.75(t,1H),3.01,2.99,2.97(m,m,m,2H),2.91,2.89, 2.87(d,m,d,2H)ppm。
Step 5）Compound 29-6 synthesis
At -10 DEG C, by oxalyl chloride（0.93mL,11mmol）It is slowly dropped into compound 29-5（3.1g,10mmol）And DMF （0.05mL）DCM（40mL）In solution, drop finishes, stand-by without handling after reacting at room temperature 1.0 hours.
At -15 DEG C, by freshly prepd above-claimed cpd（3.32g,10mmol）It is slowly dropped into AlCl3（1.73g,13mmol） DCM（30mL）In suspension, drop finishes, isothermal reaction 2.0 hours.After reaction completely, reaction solution is poured slowly into frozen water, will Organic layer separates, water layer DCM（30mL×3）Extraction, merge organic phase, washed respectively with clear water and saturated sodium carbonate solution, Anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain yellowish toner Last 2.33g, yield：80%.
MS(ESI,pos.ion)m/z:293.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.32,3.30,3.28(d,m,d,2H),2.88,2.86,2.85(d,m,d, 2H)ppm。
Step 6）Compound 29-7 synthesis
At -5 DEG C, by sodium hydroxide（1.6g,40mmol）The aqueous solution（1.6mL）It is slowly dropped into compound 29-6（2.92g, 10mmol）, Isosorbide-5-Nitrae-dibromobutane（1.31mL,11mmol）With TEBAC（0.46g,2.0mmol）DMSO（30mL）Suspension In, 60 DEG C are reacted 8.0 hours.After reaction completely, reaction solution is poured slowly into frozen water（100mL）In, separate out solid.Filtering, Gu Body EtOAc（50mL）Dissolving, with saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatographic isolation and purification after concentration（Wash De- agent：PE/EtOAc(v/v)=10/1）Obtain product 1.72g, yield：50%.
MS(ESI,pos.ion)m/z:347.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.20-3.18(m,2H),2.06-1.94(m,2H),1.84-1.64(m,4H), 1.37-1.27(m,2H)ppm。
Step 7）Compound 29-8 synthesis
At -5 DEG C, by CF3COOH（9.0mL,120mmol）It is slowly dropped into compound 29-7（3.46g,10mmol）, NH4F （1.11g,30mmol）With Et3SiH（4.79mL,30mmol）Suspension in, drop finish, 50 DEG C react 15 hours.Reaction is complete Afterwards, trifluoroacetic acid, residue EtOAc are removed（100mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, nothing Aqueous sodium persulfate is dried, through column chromatographic isolation and purification after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Product 2.15g is obtained, Yield：65%.
MS(ESI,pos.ion)m/z:333.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.07-3.04(m,4H),1.81-1.49(m,8H)ppm。
Step 8）Compound 29-9 synthesis
By compound 29-8（33mg,0.1mmol）, compound 3-5（104mg,0.21mmol）, Pd (PPh3)4（12mg, 0.01mmol）And potassium carbonate（34.5mg,0.25mmol）It is suspended in DME（2mL）With water（0.4mL）In, under nitrogen protection, 90 DEG C reaction 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）Dilute reaction solution, water is used respectively（10mL×3） With saturated common salt water washing, anhydrous sodium sulfate drying, through column chromatographic isolation and purification after concentration（Eluant, eluent：DCM/MeOH(v/v)= 50/1）Obtain product 45.5mg, yield：50%.
MS(ESI,pos.ion)m/z:456.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.07-8.06,8.04-8.03(m,m,4H),7.87-7.86,7.85-7.84 (m,m,4H),7.59(s,2H),5.32,5.29(d,d,2H),5.23-5.19(m,1H),4.41-4.40,4.39-4.38, 4.37-4.36(m,m,m,2H),3.85-3.78(m,2H),3.69-3.64(m,2H),3.63(s,6H),2.87-2.85(m, 4H),2.30-1.92(m,10H),1.75-1.43(m,8H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 30
Synthetic route：
Embodiment 30 is prepared according to the synthetic method of similar embodiment 1.
Compound 30-2：MS(ESI,pos.ion)m/z:367.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.68(s,1H),7.42-7.40(m,1H),7.30-7.28(m,1H),5.11- 5.09(m,1H),3.45-3.43(m,2H),2.94-2.93(m,1H),2.21-2.18(m,2H),2.01-1.91(m,1H), 1.49(s,9H)ppm。
Compound 30-3：MS(ESI,pos.ion)m/z:266.1[M+H]+。
Compound 30-4：MS(ESI,pos.ion)m/z:423.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.59-7.51(m,1H),7.34-7.21(m,2H),5.42-5.38(m,2H), 4.34-4.30(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),3.04-2.98(m,1H), 2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),0.88-0.84(m,6H)ppm。
Compound 30-5：MS(ESI,pos.ion)m/z:471.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.87-7.80(m,1H),7.71-7.66(m,2H),5.47-5.42(m,2H), 4.34-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H), 2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),1.35(s,12H),0.88-0.84(m,6H) ppm。
Compound 30-6：MS(ESI,pos.ion)m/z:864.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.67(q,2H),7.59,7.57(d,d,2H),7.40,7.38(d,d,2H), 5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78 (m,2H),3.66(s,3H),3.65-3.64(m,2H),3.63(s,3H),2.84-2.82(m,4H),2.39-2.10(m,8H), 2.01-1.86(m,4H),1.73-1.52(m,4H),1.50-1.40(m,2H),1.28-1.18(m,2H),1.02-0.89(m, 12H)ppm。
Embodiment 31
Synthetic route：
Embodiment 31 is prepared according to the synthetic method of similar embodiment 2.
Compound 31-1：1H NMR(400MHz,CDCl3):δ3.99-3.87(br,1H),3.68-3.51(m,2H), 3.48-3.39(m,1H),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H) ppm。
Compound 31-2：1H NMR(400MHz,CDCl3):δ9.46(d,1H,J=2.8Hz),4.08-4.03(m,1H), 3.51-3.42(m,2H),2.01-1.93(m,2H),1.91-1.84(m,2H),1.43(s,9H)ppm。
Compound 31-3：MS(ESI,pos.ion)m/z:238.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t, 2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Compound 31-4：MS(ESI,pos.ion)m/z:490.1[M+H]+；
1H NMR(400MHz,CDCl3):δ4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02 (m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Compound 31-5：MS(ESI,pos.ion)m/z:364.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz), 3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Compound 31-6：MS(ESI,pos.ion)m/z:264.1[M+H]+。
Compound 31-7：MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m, 1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m, 3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Compound 31-8：MS(ESI,pos.ion)m/z:391.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H), 4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H), 0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Compound 31-9：MS(ESI,pos.ion)m/z:319.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J= 4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H), 2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Compound 31-10：MS(ESI,pos.ion)m/z:811.4[M+H]+；
1H NMR(400MHz,CDCl3):δ7.48(s,2H),5.51-5.47(m,2H),5.32,5.30(d,d,2H), 4.41-4.36(m,1H),3.89-3.83(m,2H),3.73-3.66(m,2H),3.63(s,6H),3.12-3.10(m,4H), 2.32-1.92(m,10H),1.79-1.58(m,4H),1.53-1.43(m,2H),1.32-1.22(m,2H),0.97,0.95(m, m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 32
Synthetic route：
Embodiment 32 is prepared according to the synthetic method of similar embodiment 18.
Compound 31-1：MS(ESI,pos.ion)m/z:858.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.70-8.69(dd,1H),7.87-7.86(q,1H),7.76,7.73(d,d, 1H),7.66,7.64(d,d,1H),7.62-7.61(q,1H),7.57,7.55(d,d,1H),7.53,7.51(d,d,1H), 6.08,6.05(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78 (m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.14-3.11(m,2H),2.94-2.91(m,2H), 2.38-2.10(m,8H),2.01-1.86(m,2H),1.71-1.51(m,6H),1.49-1.39(m,2H),1.02,1.00(m, m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 33
Synthetic route：
Embodiment 33 is prepared according to the synthetic method of similar embodiment 28.
Compound 33-1：MS(ESI,pos.ion)m/z:418.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.49(d,1H,J=4.0Hz),7.13(t,1H,J=4.0Hz),5.23-5.02 (m,2H),4.48-4.37(m,1H),3.60-3.38(m,2H),2.29-2.26(m,2H),2.11-1.92(m,2H),1.44 (s,9H)ppm。
Compound 33-2：MS(ESI,pos.ion)m/z:398.3[M+H]+；
1H NMR(400MHz,CDCl3):δ10.51(br,1H),7.07(s,1H),6.94(s,2H),4.91-4.90(m, 1H),3.39(s,2H),2.98(s,1H),2.12(s,2H),1.95(s,1H),1.48(s,9H)ppm。
Compound 33-3：1H NMR(400MHz,CDCl3):δ10.51(br,1H),7.53(s,1H),7.27(s,1H), 7.15(s,1H),4.94-4.93(m,1H),3.39(s,2H),2.99(s,1H),2.12-1.94(m,4H),1.49(s,9H), 1.34(s,12H),1.24(m,8H)ppm。
Compound 33-4：MS(ESI,pos.ion)m/z:346.2[M+H]+。
Compound 33-5：MS(ESI,pos.ion)m/z:503.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.68,7.67(s,s,1H),7.27(d,1H),7.11(dd,1H),5.56, 5.55(d,d,1H),5.42-5.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,1H),3.66(s,3H),3.65- 3.61(m,1H),2.32-1.92(m,5H),1.33,1.30(m,m,12H),1.02,1.00(m,m,3H),0.93,0.91(m, m,3H)ppm。
Compound 33-6：MS(ESI,pos.ion)m/z:660.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.04,7.03(d,d,1H),7.01,7.00(s,s,1H), 5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64 (m,1H),3.63(s,3H),2.71-2.65(m,4H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.45-1.26 (m,7H),1.03-1.00(m,3H),0.97-0.85(m,8H)ppm。
Compound 33-7：MS(ESI,pos.ion)m/z:707.7[M+H]+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.04,7.03(d,d,1H),6.73,6.72(s,s,1H), 5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64 (m,1H),3.63(s,3H),2.66-2.63(m,2H),2.59-2.56(m,2H),2.31-2.05(m,4H),2.02-1.92 (m,1H),1.42-1.23(m,19H),1.03-0.95(m,8H),0.90-0.89(m,m,3H)ppm。
Compound 33-8：MS(ESI,pos.ion)m/z:437.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.40(s,1H),7.33(s,1H),7.26,7.25(s,s,1H),7.03, 7.02(d,d,1H),5.56,5.55(d,d,1H),5.44-5.37(m,2H),5.32,5.29(d,d,1H),4.41-4.37(m, 1H),4.34-4.30(m,1H),3.86-3.79(m,2H),3.69-3.67(m,2H),3.66(s,3H),3.63(s,3H), 2.98-2.95(m,2H),2.81-2.78(m,2H),2.31-2.05(m,8H),2.02-1.92(m,2H),1.47-1.32(m, 5H),1.28-1.22(m,2H),1.03-0.89(m,17H)ppm。
Biological activity
In order to verify effect of the compound as described herein to HCV, inventor uses HCV Replicate Sub-systems (HCV Replicon System) it is used as evaluation model.HCV replicons are reported in Science.1999Jul2 first;285 (5424), 110-3.HCV Replicate Sub-systems have become research HCV rna replicons, pathogenic and viral persistence most important instrument it One, such as 5'-NCR Minimum Areas necessary to successfully demonstrating HCV rna replicons using replicon, and HCV is answered Subsystem has been successfully used as the evaluation model of antiviral drugs.The present inventor according to Science.1999Jul2;285 (5424), 110-3, and J.Virol.2003Mar;77 (5), 3007-19（By referring to general It is incorporated herein）Described method is verified.
In short, inventor is thin using stable transfection HCV genotype GT1a, GT1b respectively or the human liver cancer of GT2a replicons Born of the same parents system Huh-7 is tested compound as described herein, and Y93H, L31F, P32L, I302V resistant mutation is respectively adopted Body and wild type HCV1b are tested compound as described herein.HCV Replicate Sub-systems used in herein include G418 resistant genes NEO and luciferase reporter gene, levels of replication of the HCV in host cell can be by the tables of NEO genes Characterized up to the expression quantity of amount or luciferase gene, and then the action effect that compound described herein replicates to HCV virus can To be assessed.Herein, detected by realtime quantitative inspection (qPCR) to detect the expression quantity of NEO genes, The expression quantity of luciferase gene is detected by chemoluminescence method.Operating process brief introduction：
1. based on uciferase activity measure compound EC50：
The Huh-7 cells for transfecting HCV Replicate Sub-systems are seeded in 96 orifice plates, 8000 cells are contained in each hole. 5 times of gradient dilutions are carried out to compound as described herein respectively, obtain 10 concentration gradients.Compound as described herein is added To the hole of the Huh-7 cells containing transfection HCV Replicate Sub-systems, it is incubated 72 hours in CO2gas incubator.To Kong Zhongjia Enter 40 microlitres of luciferase luminous substrate Bright-Glo (Promega companies), after 5 minutes, utilize chemiluminescence detection system Topcount microwell plates liquid dodges luminescence counter and detected, and is utilized respectively GraphPad Prism softwares and determines each chemical combination The EC of thing50（Half-maximal effect concentration, concentration for50%of maximal effect）.Herein, for every The experiment of individual compound carries out two batches, and sets the hole for not adding compound as negative control.
2.qPCR detection antibiotic G418 resistant gene NEO genetic testing compounds EC50：
The Huh-7 cells for transfecting HCV Replicate Sub-systems are seeded in 96 orifice plates, 8000 cells are contained in each hole. 5 times of gradient dilutions are carried out to compound as described herein respectively, obtain 10 concentration gradients.Compound as described herein is added To the hole of the Huh-7 cells containing transfection HCV Replicate Sub-systems, it is incubated 72 hours in CO2gas incubator.Pass through qPCR Reaction determines the expression quantity of NEO genes, and is utilized respectively the EC that GraphPad Prism softwares determine each compound50（Partly most Big effective concentration, concentration for50%of maximal effect）.Herein, for the reality of each compound Carry out two batches are tested, and the hole for not adding compound is set as negative control.
3. result
Based on above identified EC50, it may be determined that compound as described herein can effectively suppress HCV genotype 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a.Wherein, for HCV genotype 1b EC50Scope is 1pm~99nM.Table 2 provides Present invention representative compound is directed to the EC of HCV1a and HCV1b genotype50It is worth (nM), the EC50Value is to be based on fluorescence Plain enzymatic activity and determine.
Table 2
Embodiment 1a(nM) 1b(nM) Embodiment 1a(nM) 1b(nM) Embodiment 1a(nM) 1b(nM)
1 0.103 0.025 12 23.763 0.775 23 0.332 0.084
2 1.602 0.073 13 18.643 0.679 24 0.858 0.094
3 3.687 0.039 14 2.875 0.274 25 0.116 0.062
4 0.082 0.021 15 1.682 0.362 26 15.682 0.438
5 0.206 0.051 16 0.306 0.058 27 9.679 0.783
6 2.937 0.089 17 0.083 0.030 28 26.835 1.667
7 5.726 0.182 18 0.217 0.044 29 2.784 0.532
8 0.032 0.009 19 0.429 0.036 30 0.658 0.094
9 7.580 0.231 20 0.068 0.015 31 3.685 0.103
10 10.562 0.355 21 1.672 0.408 32 0.062 0.028
11 9.524 0.624 22 0.068 0.023 33 15.682 0.438
According to the experimental result of Y93H, L31F, P32L, I302V resistant mutants and wild type HCV1b, built by molecule Mould, the result simulated with reference to CAD, it was demonstrated that the compound of present invention is by suppressing HCV NS5A albumen Mechanism, superior anti-hepatitis C virus effect is played.
It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and And it can be embodied in other concrete forms without departing from its essential characteristics.Therefore, it is contemplated that each embodiment is in all respects all It is considered illustrative and nonrestrictive, appended claims, rather than this preceding embodiment is should refer to, therefore, appended All changes in the implication and scope of claims equivalents are included in herein.
The compound of present invention can by suppressing except NS5A in addition to or suppress different from the NS5A mechanism suppressed HCV.In one embodiment, the compound of present invention suppresses HCV replicons, in another embodiment, this hair The compound of bright content suppresses NS5A.The compound of present invention can suppress HCV Multi-genotype.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the feature for combining the embodiment or example description It is contained at least one embodiment or 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.Moreover, specific features, structure, material or the feature of description can be any Combined in an appropriate manner in one or more embodiments or example.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art is not departing from the principle and objective of the present invention In the case of above-described embodiment can be changed within the scope of the invention, change, replace and modification, the scope of the present invention Limited by claim and its equivalent.

Claims (47)

1. a kind of compound, it is stereoisomer, the tautomerism of compound shown in compound or formula (I) shown in formula (I) Body pharmaceutically acceptable salt,
Each Y and Y ' independently are following construction unit：-[U-(CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-N (R11)-(CR9R9a)t-R12、-U-(CR9R9a)t-R12Or-[U- (CR9R9a)t-N(R10)-(CR9R9a)t]k-U-(CR9R9a)t-O- (CR9R9a)t-R12；
Each U independently be-C (=O)-,-C (=S)-,-S (=O)-or-S (=O)2-；
Each R9、R9a、R10And R11It independently is H, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
Each R12It independently is R13aR13N- ,-C (=O) R13,-C (=S) R13,-C (=O)-O-R13,-C (=O) NR13R13a、-OC (=O) NR13R13a,-OC (=O) OR13、-N(R13) C (=O) NR13R13a、-N(R13) C (=O) OR13a、-N(R13) C (=O)- R13a、R13R13aN-S (=O)2-、R13S (=O)2-、R13S (=O)2N(R13a)-、R13OS (=O)2-、C1-6Alkyl, C2-6Miscellaneous alkane Base, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl or C6-10Aryl C1-6Alkyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
Each R13And R13aIt independently is H, C1-6Alkyl, C2-6Miscellaneous alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9It is miscellaneous Aryl or C6-10Aryl C1-6Alkyl；Work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aCan any landform with nitrogen-atoms Into non-substituted 3-8 yuan of rings, spiral shell is bicyclic or condensed-bicyclic；
Each t independently is 0,1,2,3 or 4；
0,1 or 2 independently are with each k；
Construction unit is selected from following subformula：
Wherein, X6For O, S ,-Y1=N-, NR6；
Each Y1It independently is N or CH；
Each f independently is 0,1,2,3 or 4；
Each R5aIt independently is H, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkyl acyl-oxygen Base, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl Epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro or C1-6 Alkylamino；
Each A and A ' independently are following group：
Wherein, the X in A and A '1For O or S；
Each R6It independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkane Base, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl；
Each R6aIt independently is H, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), C1-6Alkoxy, C1-6Alkylamino, C1-6 Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, sulfydryl or nitro；
Wherein R1、R2Following subformula is selected from the Y-X-CH heterocycles formed or condensed ring or spiro ring system：
Wherein R3、R4And the heterocycles that are formed of Y '-X '-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein, each R15It independently is H, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl, C1-3Alkoxy, C1-3 Alkylamino, C1-3Alkylthio group, C6-10Fragrant amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryloxy, C1-9Heteroaryl C1-3Alkyl Or C2-10Heterocyclic radical；
R1、R2And the heterocycle or condensed ring or spiro ring system and R that Y '-X '-CH are formed3、R4And the heterocycles that are formed of Y '-X '-CH or Each R in condensed ring or spiro ring system6It independently is hydrogen, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Carbocylic radical；
With each n1And n2It independently is 1,2,3 or 4.
2. compound according to claim 1, it has the structure as shown in formula (II)：
Wherein,Construction unit is following subformula：
Each Q1And Q2It independently is (CH2)e；
E is 1；
Each f independently is 0,1,2,3 or 4；
Each X3And X5It independently is CR7R7a；
Each X6It independently is-Y1=N-, O, S or NR6；
Each Y1It independently is N or CR7；
Each A and A ' independently are following group：
Each R5aIt independently is H, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl acyl, C1-6Alkyl acyl-oxygen Base, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl Epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxy, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro, C1-6Alkane Amino；
R6aIt independently is H, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkoxy, C1-6Alkyl ,-CF3, mercapto Base, nitro, C1-6Alkylamino；
Each R6It independently is hydrogen；
Each R7And R7aIt independently is H；
Each n independently is 1,2；With each Y4And Y4' it independently is a key, S ,-(CH2)n-、-CF2-、-CHR5a-、-CR5aR6a；
Wherein each Y4And Y4' each R5aAnd R6aIt independently is H, hydroxyl, F, Cl, Br, I, cyano group, C1-3Alkoxy, C1-3Alkyl ,- CF3、-OCF3、C1-3Alkylamino.
3. compound according to claim 2, it has the structure as shown in formula (III)：
4. compound according to claim 2, it has the structure as shown in formula (IV)：
Wherein, each Q2And Q3It independently is O, S, C (=O), NR6。
5. compound according to claim 2, it has the structure as shown in formula (V)：
Wherein e is 1,2,3 or 4.
6. according to the compound described in claim any one of 1-5, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N (R10)-(CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
7. compound according to claim 6, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)-(CR9R9a)t- U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
8. compound according to claim 6, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R11)-(CR9R9a)t- R12。
9. compound according to claim 6, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
10. compound according to claim 9, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t-U-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
11. compound according to claim 9, wherein each Y and Y ' independently are-[C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t]k- C (=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
12. compound according to claim 11, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t- C (=O)-(CR9R9a)t-N(R11)-(CR9R9a)t-R12。
13. compound according to claim 9, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t-R12。
14. compound according to claim 13, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t- C (=O)-R13。
15. compound according to claim 14, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C (=O)-R13。
16. compound according to claim 13, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)- (CR9R9a)t- C (=O)-O-R13。
17. compound according to claim 16, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R11)-C (=O)-O-R13。
18. according to the compound described in claim any one of 1-5, wherein each Y and Y ' independently are-U- (CR9R9a)t-R12。
19. compound according to claim 18, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-R12。
20. according to the compound described in claim any one of 1-5, wherein each Y and Y ' independently are-[U- (CR9R9a)t-N (R10)-(CR9R9a)t]k-U-(CR9R9a)t-O-(CR9R9a)t-R12。
21. compound according to claim 20, wherein each Y and Y ' independently are-U- (CR9R9a)t-N(R10)- (CR9R9a)t-U-(CR9R9a)t-O-(CR9R9a)t-R12。
22. compound according to claim 21, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N(R10)- (CR9R9a)t- C (=O)-(CR9R9a)t-O-(CR9R9a)t-R12。
23. compound according to claim 20, wherein each Y and Y ' independently are-U- (CR9R9a)t-O-(CR9R9a)t- R12。
24. compound according to claim 23, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-O- (CR9R9a)t-R12。
25. according to the compound described in claim any one of 1-5, wherein each Y and Y ' independently are-C (=O)-(CR9R9a)t-N (R11)-R12, wherein R11、R124-7 yuan of rings can be formed with the atom being attached thereto.
26. according to the compound described in claim any one of 1-5, wherein,
Each R9、R9a、R10And R11It independently is H, methyl, ethyl, isopropyl, cyclohexyl, isobutyl group or phenyl；
Each R12It independently is-C (=O) R13,-C (=O)-O-R13,-C (=O) NR13R13a, methyl, ethyl, propyl group, phenyl, ring Hexyl, morpholinyl or piperidyl；
Or R11、R124-7 yuan of rings can be formed with the atom being attached thereto；
With each R13And R13aIt independently is H, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl.
27. the compound according to claim 2, it has the structure as shown in formula (VI)：
Wherein, each R14And R14aIt independently is H, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Virtue Base, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl.
28. compound according to claim 27, it has the structure as shown in formula (VII)：
Wherein, each R14And R14aIt independently is H, C1-3Hydroxy alkyl, methyl, ethyl, isopropyl, isobutyl group, the tert-butyl group, allyl Base, propargyl, trifluoroethyl, phenyl, pyranose, morpholinyl, benzyl, piperazinyl, cyclopenta, cyclopropyl, cyclohexyl or C1-9It is miscellaneous Aryl.
29. compound according to claim 1, it has the structure as shown in formula (VIII)：
Wherein, each R14And R14aIt independently is H, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Virtue Base, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n2It independently is 1,2,3 or 4.
30. compound according to claim 1, it has the structure as shown in formula (IX)：
Wherein, each R14And R14aIt independently is H, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C2-6Miscellaneous alkyl, C6-10Virtue Base, C1-9Heteroaryl, C2-10Heterocyclic radical, C3-8Cycloalkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl；
With each n1It independently is 1,2,3 or 4.
31. compound according to claim 1, it has the structure as shown in formula (X)
Wherein, each R5aIt independently is H, C1-4Alkyl, F, Cl, Br or I；
F is 0,1,2,3 or 4；
Each R6It independently is H, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical, C3-8Cycloalkyl or benzyl；
Each R14And R14aIt independently is H, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
WhereinConstruction unit is following subformula：
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
32. compound according to claim 1, it has the structure as shown in formula (XI)
Wherein, each R5aIt independently is H, C1-4Alkyl, F, Cl, Br or I；
F is 0,1,2,3 or 4；
Each Q1And Q2It independently is (CR7R7a)e；
X6For-Y1=N-, O, S or NR6；
Each Y1It independently is N or CR7；
Each i independently is 1,2,3 or 4；
Each e independently is 1；
Each R6、R7And R7aIt independently is H；
Each R14And R14aIt independently is H, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each R16And R16aIt independently is hydroxyl, C1-4Alkyl oxy, C6-10Aryloxy, C2-10Heterocyclic radical or C3-8Cycloalkyl；
Each A or A ' are independently selected from following group：
Wherein R1、R2Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
Wherein R3、R4Following subformula is selected from the N-CH heterocycles being individually formed or condensed ring or spiro ring system：
33. according to the compound described in any one of claim 31 or 32, wherein
Each R5aIt independently is H, methyl, ethyl, F, Cl, Br or I；
Each R6、R7And R7aIt independently is hydrogen；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl or the tert-butyl group；
With each R16And R16aIt independently is hydroxyl, methoxyl group, ethyoxyl, phenoxy group or tert-butoxy.
34. compound according to claim 1, the structure comprising one of：
Or its stereoisomer, dynamic isomer or pharmaceutically acceptable salt.
A kind of 35. pharmaceutical composition, wherein described pharmaceutical composition is included according to any one of claim 1-34 Compound.
36. pharmaceutical composition according to claim 35, further comprising pharmaceutically acceptable carrier, excipient, dilute Release agent, medium or its combination.
37. pharmaceutical composition according to claim 35, it further includes the medicine of other HCV-Ab IgGs.
38. the pharmaceutical composition according to claim 37, wherein the medicine of the HCV-Ab IgG be interferon, it is Ribavirin, white Interleukin 2, interleukin 6, interleukin 12, the compound for promoting 1 type helper T lymphocyte response of generation, RNA interfering, antisense RNA, miaow Quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody, CivacirTM, POP it is auspicious Wei, TVR, Erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir、ABT-450、danoprevir、sovaprevir、MK-5172、vedroprevir、BZF-961、GS- 9256、narlaprevir、ANA975、ABT-267、EDP239、PPI-668、GS-5816、samatasvir、MK-8742、MK- 8325、GSK-2336805、PPI-461、TMC-435、MK-7009、BI-2013335、ciluprevir、BMS-650032、 ACH-1625、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX- 316、EP-013420、VBY-376、TMC-649128、R-7128、PSI-7977、INX-189、IDX-184、IDX102、 R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、HCV-371、VCH-916、VCH-222、ANA- 598、MK-3281、ABT-333、ABT-072、PF-00868554、BI-207127、GS-9190、A-837093、JKT-109、 Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.
39. the pharmaceutical composition according to claim 38, wherein the interferon is Interferon Alpha-2b, Pegylation Interferon-' alpha ', Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or its combination.
40. according to the pharmaceutical composition any one of claim 35-39, it further includes at least one HCV Inhibitor.
41. pharmaceutical composition according to claim 40, wherein the HCV inhibitor be used to suppressing HCV reproduction processes and Suppress at least one of HCV virus protein function.
42. pharmaceutical composition according to claim 41, wherein the HCV reproduction processes enter, shell, turned over selected from HCV The complete viral cycle for the HCV for translating, replicate, assembling or discharging.
43. pharmaceutical composition according to claim 41, described HCV virus albumen be selected from metalloproteinases, NS2, NS3、NS4A、NS4B、NS5A、NS5B；And HCV virus replicates required internal ribosome inlet point and inosine monophosphate takes off Hydrogen enzyme.
44. the medicine any one of compound or claim 35-43 according to any one of claim 1-34 Purposes of the composition in medicine is prepared, the medicine be used for suppress HCV replicate and suppress HCV virus protein function at least it One.
45. purposes according to claim 44, the HCV reproduction processes are selected from HCV and enter, shell, translate, replicate, group The complete viral cycle of dress or the HCV of release.
46. purposes according to claim 45, described HCV virus albumen be selected from metalloproteinases, NS2, NS3, NS4A, NS4B、NS5A、NS5B；And HCV virus replicates required internal ribosome inlet point and inosine monophosphate dehydrogenase.
47. the medicine any one of compound or claim 35-43 according to any one of claim 1-34 Purposes of the composition in medicine is prepared, the medicine are used for the HCV infection or the third type for preventing, handle, treating or mitigating patient Hepatitis disease.
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