CN103848819B - Spiro compound serving as hepatitis C inhibitor, drug composition and applications of spiro compound and drug composition in drugs - Google Patents

Spiro compound serving as hepatitis C inhibitor, drug composition and applications of spiro compound and drug composition in drugs Download PDF

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CN103848819B
CN103848819B CN201310631650.1A CN201310631650A CN103848819B CN 103848819 B CN103848819 B CN 103848819B CN 201310631650 A CN201310631650 A CN 201310631650A CN 103848819 B CN103848819 B CN 103848819B
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independently
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compound
hcv
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CN103848819A (en
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张英俊
张健存
谢洪明
任青云
巫锡伟
付长萍
胡柏林
李石凤
方清洪
雷勇
罗峰
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YICHANG HEC CHANGJIANG PHARMACEUTICAL Co.,Ltd.
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Guangdong HEC Pharmaceutical
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    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Abstract

The invention provides a spiro compound serving as a hepatitis C inhibitor, a drug composition and applications of the spiro compound and the drug composition in drugs. The compound is a compound shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug of the compound shown in the formula (I). Besides, the invention also provides the drug composition comprising the compound, an application of the compound and the drug composition to inhibiting at least one of HCV (hepatitis C virus) replication and HCV protein functions, and an application of the compound and the drug composition to preventing, disposing, treating or alleviating HCV infection or hepatitis C diseases of patients.

Description

Spiro-compound, pharmaceutical composition as hepatitis c inhibitor and they in medicine Application in thing
Invention field
The invention belongs to drug world and be related to for treat HCV (HCV) infection compound, comprising Composition of the compound and application thereof and using method.Especially, compound of the present invention can be as NS5A The spiro-compound of inhibitor.More particularly it relates to the NS5A albumen work(encoded by HCV can be suppressed The compound of energy, the pharmaceutical composition comprising 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, is human immunodeficiency virus type 1 infection people Several 5 times.And the major part in the middle of these HCV infection individualities can develop into serious progressive hepatopathy, including cirrhosis and liver Cell cancer.Therefore, chronic HCV infection will be the main cause of global patient's premature death because of hepatopathy.
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 combined including pegylated alfa-interferons and Ribavirin, big portion Divide patient also cannot persistently reduce viral load, and many patients often with some side reactions, and can not treat for a long time.Cause This, needed for the method for new effective treatment HCV infection is urgent at present.
HCV is positive chain RNA virus.According to the amino acid sequence to deriving and the ratio of the extensive similitude of 5 ' non-translational regions Compared with HCV is classified in the single category of flaviviridae (Flaviviridae family).All members of flaviviridae All it is the envelope virus particle containing positive chain RNA genome, the genome is turned over by single uninterrupted ORFs (ORF's) Translate, encode all known virus specified proteins.
There is considerable heterogeneity in the nucleotides and coded amino acid sequence of whole HCV genomes. At least 7 main genotype are identified, and discloses more than 50 hypotype.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 in HCV life cycles and weighs very much Want role (see, e.g., Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).
Distribution of the main genotypes of HCV in the whole world is different, although carried out lots of genes type to pathogenesis and treatment The research of effect, but still do not know the clinical importance of HCV genetic heterogeneities.
Single-stranded HCV rna genes group length is about 9500 nucleotides, and with single ORFs, 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, produces structure and non-structural (NS) albumen.For HCV, ripe non-structural protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) be formed by two-strain protease realization.It is generally acknowledged that the first is metal egg White enzyme, is cut in NS2-NS3 contacts；It is included in NS3 (also referred to herein as NS3 protease) N-terminal region for second Serine protease, it mediates all of follow-up cutting in NS3 downstreams, is cis in NS3-NS4A cleavage sites, in remaining NS4A- NS4B, NS4B-NS5A, NS5A-NA5B site is then trans.NS4A albumen seems have several functions, plays NS3 protease cofactors Effect, and may assist NS3 and other rdrp virus components carry out film positioning.The formation of NS3 albumen and NS4A compounds Seemingly process event, improve necessary to proteolytic efficiency on all sites.NS3 albumen also shows ribonucleoside triphosphote Enzyme and DBPA activity.NS5B (also known as HCV polymerases herein) is that the RNA of RNA that depends on for participating in HCV duplications is polymerized Enzyme.
The compounds of this invention is that, for treating patient's HCV infection, the compound optionally suppresses the duplication of HCV virus. Specifically, the compounds of this invention is the compound for effectively suppressing NS5A protein functions.HCV NS5A albumen see, for example, Tan, S.-L.,Katzel,M.G.,Virology 2001,284,1-12;And Park, K.-J.;Choi,S.-H,J.Biological Chemistry,2003。
Abstract of invention
The present invention relates to new spiro-compound and the method for HCV-Ab IgG infection.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 has the structure as shown in formula (I)：
Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolism product Thing, pharmaceutically acceptable salt or prodrug, wherein：
Each A and A ' independently are 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 ' independently be following group：
Wherein, each X1And X2It independently is O, S, NR6Or CR7R7a；
W1For carbocylic radical or heterocyclic radical；
W2For carbocylic radical, heterocyclic radical, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, thick bicyclic group or thick miscellaneous bicyclic group；
Each Y1、Y2、Y1’And Y2’It 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 f and f ' independently are 0,1,2,3 or 4；
Each Q1And Q2It independently is a key, 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 be 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、R2Arbitrarily 3-8 circle heterocycles or 3-8 units carbocyclic ring, C are formed with X-CH5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12 Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4And X '-CH are randomly formed 3-8 circle heterocycles or carbocyclic ring, C5-12Condensed-bicyclic, C5-12 Condense miscellaneous 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 R5aAnd R5a’It 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)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- alkoxyls, R13S (=O)-alkoxyl, R13R13aN-C (=O)-alkoxyl, aryl, heteroaryl Base, alkoxyl, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, 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, alkoxyl 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；Wherein institute The aliphatic for stating group is alkyl；Each R6aIndependently be 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- alkoxyls, R13S (=O)-alkoxyl, R13R13aN-C (=O)-alkane Epoxide, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitre Base, aralkyl, fragrant amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, virtue Base alkoxyl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, Alkoxyacyl, alkyl sulphonyl, alkyloxysulfonyl, alkyl sulphinyl, alkyl sulphonyl epoxide, alkyl sulphinyl oxygen Base, 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, alkoxyl 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；Wherein described base The aliphatic of group is alkyl；Each R8And R8aIt independently is H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, miscellaneous alkyl, ring Alkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkane Base-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 formed with the atom being attached thereto；
With each R13And R13aIt independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl Base；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aIt is first substituted or non-substituted 3-8 to be randomly formed with nitrogen-atoms Ring, 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-N(R5)-C(=O)-O- (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-、-[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-、R13aR13N-, alkyl-OC (= O)-, alkyl-C (=O)-, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-、R13R13aNS(=O)-、R13OS(= O)-、R13S(=O)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxyls, R13S(= O)-alkoxyl, R13R13aN-C (=O)-alkylamino, alkyl, miscellaneous alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Alkyl, a-amino acid group, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic, C5-12The miscellaneous bicyclic, alkoxyl of spiral shell, Aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxyl aliphatic, alkylamino aliphatic, alkylthio group fat Race, aromatic yl aliphat, heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide Aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, alkyl halide Base, thiazolinyl, alkynyl, fragrant amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, Alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, heterocyclic radical alkylamino or fragrant oxygen Base can optionally by one or more selected from deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, Alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, hydroxyl replace Alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O), alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace Alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2- or the substituent of alkoxyl that replaces of carboxyl replaced.
Wherein in some embodiments, wherein W1For C3-8Carbocylic radical or C2-10Heterocyclic radical；
And W2For C3-8Carbocylic radical, C2-10Heterocyclic radical, C5-12Spiral shell bicyclic group, C5-12The miscellaneous bicyclic group of spiral shell, C5-12Thick bicyclic group or C5-12Thick miscellaneous bicyclic group.
Wherein in some embodiments, wherein
Construction unit is following subformula：
Construction unit is following subformula：
Wherein, each X1、X2、X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each Q1And Q2It independently is key, a NR6, O, S, C (=O) or (CR7R7a)e；
Q3For N or CR7；
Each e independently is 0,1,2,3 or 4；
Each R5aAnd R5a’It 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)-、C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl oxygen Base, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro, C1-6Alkane ammonia Base, 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；
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, 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 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
Wherein in some embodiments, wherein,
Construction unit is following subformula：
Construction unit is following group：
Wherein, each Y1、Y2、Y1’And Y2’It independently is N or CH2；
Each f and f ' independently are 0,1,2,3 or 4；
Each R5aAnd R5a’It 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)-、C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl oxygen Base, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro or C1-6Alkane Amino；
With each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alkane Epoxide C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkane Base, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl.
Wherein in some 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 e independently is 0,1,2,3 or 4；
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, C1-6Alkoxyl, 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-C1-6Alkoxyl, R13S(=O)-C1-6Alkoxyl, R13R13aN-C(=O)-C1-6 Alkoxyl, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxyl, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms 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, C1-6Alkoxyl, 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.
Wherein in some 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, each X1It independently is O or S；
Each Y1It independently is N or CH；
Each e independently is 0,1,2 or 3；
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, C1-6Alkoxyl, 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-、-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)-、C1-6Alkoxyl, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, sulfydryl or nitro；
With 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
Wherein in some 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 units 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 units 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 X '-CH form 3-8 circle heterocycles, C5-12It is thick Close bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2The heterocycle formed with Y-X-CH or condensed ring or spiro ring system are selected 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 other embodiments, wherein R3、R4And the heterocycles that 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.
Wherein in some embodiments, it has such as formula（II）Shown structure：
Wherein,Construction unit is following subformula：
Construction unit is following group：
Each Q1And Q2It independently is key, a NR6, O, S, C (=O) or (CH2)e；
Q3For N and CH；
Each X1It independently is O, S, NR6Or CR7R7a；
Each e independently is 0,1,2,3 or 4；
Each f and f ' independently are 0,1,2,3 or 4
Each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each Y1、Y2、Y1’And Y2’It 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, C1-6Alkoxyl, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, amino first Acyl group, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-, alkyl-S (=O)r- or amino-sulfonyl；
Each R5a、R5a’And R6aIt 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)-、C1-6Alkyl acyl, C1-6Alkyl acyl Epoxide, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulfonyl Base epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro, C1-6 Alkylamino, 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 Aliphatic be alkyl, alkyl can be, but be not limited to methyl, ethyl, propyl group, isopropyl, butyl and 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；The aliphatic of wherein described group is alkyl, and alkyl can Think, but be not limited to methyl, ethyl, propyl group, isopropyl, butyl and 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, C1-6Alkoxyl, 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms 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-、- CH2S(=O)r、-CF2-、-CHR5a、-CR5aR6a- or-CH2N(R6)-。
In other embodiments, it has such as formula（III）Shown structure：
Wherein, each Q1、Q2、Q4And Q5It independently is NR6, O, S, C (=O) or (CR7R7a)e；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（IV）Shown structure：
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（V）Shown structure：
Wherein, each Q1、Q2And Q4It independently is O, S, C (=O), NR6Or CH2；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（VI）Shown structure：
Wherein, each Q1And Q2It independently is O, S, C (=O), NR6Or CH2；
I is 0,1,2,3 or 4；
And W3For C3-10Carbocylic radical or C2-10Heterocyclic radical.
In other embodiments, it has such as formula（VII）Shown structure：
Wherein, each Q1、Q3、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（VIII）Shown structure：
Wherein, each Q1、Q3、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（IX）Shown structure：
Wherein, each Q1、Q3And Q4It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（X）Shown structure：
Wherein, each Q1And Q3It independently is O, S, C (=O), NR6Or CH2；
And W3For C3-10Carbocylic radical or C2-10Heterocyclic radical.
Wherein in some embodiments, wherein, Y and Y ' independently is 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.
Wherein in some 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
In other embodiments, wherein,
Each R9、R9a、R10And R11It independently is H, deuterium, 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, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl.
In other embodiments, it has such as formula（XI）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.
In other embodiments, it has such as formula（XII）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 in some embodiments, it has such as formula（XIII）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 in some 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 in some embodiments, it has such as formula（X’）Shown compound
Wherein, each Q1And Q2It independently is O, S, C (=O), NR6Or CH2；
Each R5aAnd R5a’It independently is H, deuterium, C1-4Alkyl, oxo (=O), benzyl, F, Cl, Br or I;
Each R6And R7It independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
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：
Wherein Bn is benzyl；
Construction unit is following group：
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
In other embodiments, wherein
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I;
Each R6And R7It independently is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Substituent replaced.
Wherein in some embodiments, it has such as formula（XI’）Shown compound
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
X1For O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isobutyl group, isopropyl or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from the replacement of deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Base is replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein in some embodiments, it has such as formula（XII’）Shown compound：
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
Each X1It independently is O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Substituent replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein in some embodiments, it has such as formula（XIII’）Shown compound：
Wherein, each Q1、Q2And Q4It independently is O, S, C (=O), NR6Or CH2；
X3For O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from the replacement of deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Base is replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes any of the above described one kindization Compound.
Wherein in some embodiments, the pharmaceutical composition can also further include pharmaceutically acceptable carrier, Excipient, diluent, assistant agent, medium or its combination.
Wherein in some embodiments, it is further comprising the medicine of other HCV-Ab IgGs.
In other embodiments, wherein the medicine of the HCV-Ab IgG is interferon, Ribavirin, interleukin-22, white Interleukin 6, interleukin 12, promote to produce compound, RNA interfering, antisense RNA, miaow quinoline not moral, the flesh of 1 type helper T lymphocyte response Glycosides 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.
In other embodiments, 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.
Wherein in some 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 of the HCV for enter, shell, translate, replicate, assemble, discharging.Described HCV virus albumen is selected from metalloprotein Enzyme, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And HCV virus replicate required internal ribosome inlet point (IRES) With inosine monophosphate dehydrogenase (IMPDH).
On the other hand, compound of the present invention or pharmaceutical composition its be used to suppressing HCV reproduction processes and suppress HCV At least one of virus protein function；The HCV reproduction processes selected from HCV enter, shelling, translation, replicate, assembling, release The complete viral cycle of HCV.Described HCV virus albumen selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And HCV virus replicate required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition can be used to prepare for preventing, processing, control Treat or mitigate the purposes of the medicine of patient's hepatitis C disease, including the compound as described herein for giving patient effective amounts 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), (X), the preparation of the compound that (XI), (XII), (XIII), (IX '), (X '), (XI '), (XII ') or (XIII ') is included, point From the method with purifying.
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 below make more specific complete description.
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 for determining, embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention has expectedly cover all of choice, variant and coordinate, and these may be such as right Require defined like that comprising within the scope of the present invention.Those skilled in the art will recognize 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.Have many documents and similar material to distinguish with the present patent application or contradict, 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 be using defined below unless other aspects show.Purpose of the invention, chemical element is according to unit Plain periodic table, CAS versions and Chemical Physics handbook, 75thEd., 1994 defining.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito, 1999, and " 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 replaced by one or more substituents, such as General formula compound above, or as special example such as embodiment the inside, subclass, and the class compound that the present invention is included. Should be appreciated that " optionally substituted " this term can be exchanged with " substituted or unsubstituted " this term to use.In general, art Language " optionally " is whether located at before term " substituted ", represents that one or more hydrogen atoms given in structure are concrete Substituent is replaced.Unless other aspects show that an optional substituted radical can have a substituent, and each can in group Substituted position is replaced.When more than one position can be selected from one or more of concrete group in given structural formula Substituent is replaced, then substituent can be replaced with identical or different in each position.Wherein described substituent can be, But be not limited to, deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, Alkoxyl, hydroxyl replacement that alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, hydroxyl replace Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl Substituted alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
Terminology used in the present invention " aliphatic " or " fatty group ", represent straight chain (i.e. non-branched) or side chain, replace 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 them embodiment is 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, other reality 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 is included, 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 base " represents that fatty group is replaced by one or more identical or different halogen atoms, its Middle fatty group has implication as described in the present invention, and halogen atom is fluorine, chlorine, bromine or iodine, and such example includes, but does not limit In trifluoromethyl, trifluoroethyl, chloromethyl, 2- chlorovinyls etc..
Term " hydroxyl group aliphatic base " represents that fatty group is replaced by one or more oh groups, wherein fatty group With implication as described in the present invention, such example includes, but is not limited to ethoxy, 2- hydroxypropyls, methylol etc..
Term " amino fatty group " represents that fatty group is replaced by one or more amino groups, wherein fatty group With implication as described in the present invention, it is different that such example includes, but is not limited to amino methyl, 2- amino-ethyls, 2- amino Propyl group 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 saturated straight chain or the univalence hydrocarbyl of side chain of 1-3 carbon atom, wherein alkyl can independently and appoint Selection of land is replaced by one or more substituents described in the invention.The example of alkyl is included, 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 group (- 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 group (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3) C(CH3)3), n-heptyl, n-octyl etc..Term " alkyl " and its prefix " alkane " being used herein as, all comprising straight chain and side chain Saturated carbon chains.Term " alkylene " is being used herein as, and 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 " thiazolinyl " 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 be the C-C of undersaturated condition, i.e., be sp2Double bond, wherein alkene Base group independently and optionally can be replaced 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 thiazolinyl is included, 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, it is the keys of sp tri- that wherein at least one position is the C-C of undersaturated condition, i.e., wherein alkynes Base group independently and optionally can be replaced by one or more substituents described in the invention, and wherein alkynyl is specifically real Example is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH) etc..
Term " alkyl that hydroxyl replaces " represents that alkyl group is replaced by one or more oh groups, wherein alkyl base Group has implication of the present invention.Such example is included, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyls Deng.
Term " haloalkyl " represents that alkyl group is replaced 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 replaced by one or more oh groups, and wherein alkyl group has Implication as described in the present invention, such example includes, but is not limited to ethoxy, 2- hydroxypropyls, methylol etc..
Term " aminoalkyl " represents that alkyl group is replaced by one or more amino groups, and wherein alkyl group has Implication as described in the present invention, such example includes, but is not limited to amino methyl, 2- amino-ethyls, 2- amino isopropyls Deng.
The saturation obtained by two hydrogen atoms is removed in term " alkylidene " expression from the saturated hydrocarbyl of straight or branched 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, alkoxyl, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro or virtue Epoxide.Such example is included, 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 the alkylene group removed from the alkene of straight or branched obtained by two hydrogen atoms. 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, alkoxyl, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro or aryloxy group.Such reality Example is included, 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 is included, but is not limited to, cyclopropylidene, sub- cyclobutyl, cyclopentylene, the amyl- 1- alkenylenes of 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 are independently selected in its middle ring 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, with 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- diyls, 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, piperazine -4- ethyl -1- bases, piperidines -4- methyl isophthalic acids-base, piperidines -4- ethyl -1- bases, pyrrolidines -2- methyl - 1- bases 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 is included, 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 is included, 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 is included, 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 " is represented and condenses miscellaneous bicyclic system with two tie points and molecule remainder phase Even.Such example is included, but is not limited to 3- azabicyclos [3.1.0] hexane -3,6- diyls 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 condenses miscellaneous bicyclic group alkyl " represent condense miscellaneous bicyclic group alkyl with 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 is included, but is not limited to 5- spiral shells [2.4] heptane -5,7- diyls, Spiral shell [4.4] nonane -2,7- diyls etc..
Term " sub- spiral shell miscellaneous bicyclic group " represents that there are the miscellaneous bicyclic system of spiral shell two tie points to be connected with molecule remainder, its The miscellaneous bicyclic group of middle spiral shell has implication as described in the present invention.Such example is included, 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 " sub- spiral shell miscellaneous bicyclic group alkyl " represent the miscellaneous bicyclic group alkyl system of spiral shell 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 " is represented in alkyl chain and may be inserted into one or more hetero atoms, wherein alkyl group and hetero atom With implication as described in the present invention.Unless otherwise detailed instructions, miscellaneous alkyl group contains 1-10 carbon atom, other reality 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 is that miscellaneous alkyl group contains 1-4 carbon atom, and other embodiment is, miscellaneous alkyl group Containing 1-3 carbon atom.Such example is included, but is not limited to, CH3OCH2-、CH3CH2OCH2-、CH3SCH2-、(CH3)2NCH2-、(CH3)2CH2OCH2-、CH3OCH2CH2-、CH3CH2OCH2CH2- etc..
Term " alicyclic group ", " annular aliphatic base ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refer to monovalence or many Valency, non-aromatic, the undersaturated ring of saturation or part, and not comprising hetero atom, including the monocyclic of 3-12 carbon atom or Two rings of 7-12 carbon atom.Bicyclic carbocyclic with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] System, while the bicyclic carbocyclic with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable annular aliphatic Base is included, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of annular aliphatic base includes, but is not limited to, ring Propyl group, cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyls, 1- cyclopenta -2- thiazolinyls, 1- cyclopenta -3- thiazolinyls, cyclohexyl, 1- Cyclohexyl -1- thiazolinyls, 1- cyclohexyl -2- thiazolinyls, 1- cyclohexyl -3- thiazolinyls, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl Base, cyclodecyl, ring undecyl, cyclo-dodecyl etc..And " the annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " cycloalkyl " can be substituted or unsubstituted, and wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyanogen Base, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl replace Alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace Alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
Term " cycloalkyl oxy " or " carbocylic radical epoxide " include optionally substituted cycloalkyl or carbocylic radical, such as institute of the present invention Definition, it is connected on oxygen atom, and be connected with remaining molecule by oxygen atom, such example includes, but is not limited to ring Cyclopropyl epoxide that propyl group epoxide, cyclopentyloxy, cyclohexyl epoxide, hydroxyl replace etc..
Term " cycloalkyl amino " represents that amino group is replaced by one or two optionally substituted group of naphthene base, its Middle cycloalkyl has implication as described in the present invention, and such example includes, but is not limited to cyclopropylamino, cyclopenta ammonia Cyclopropylamino, dicyclohexyl amino, Bicyclopropyl amino that base, Cyclohexylamino, hydroxyl replace etc..
Term " carbocylic radical epoxide alkoxyl " represents that alkoxyl is replaced by one or more carbocylic radical epoxide groups, wherein Alkoxyl 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 fatty group " represents fatty group by one or more optionally substituted cycloalkyl oxies Group is replaced, and wherein fatty group and cycloalkyl oxy group have implication as described in the present invention, and such example includes, But it is not limited to cyclopropyl epoxide methyl, cyclopropyl epoxide ethyl, cyclopentyloxymethyl, cyclopentyloxy ethyl, cyclohexyl Epoxide ethyl, halogenated cyclopropyl epoxide ethyl etc..
Term " cycloalkyl amino fatty group " represents fatty group by one or more optionally substituted cycloalkyl aminos Group is replaced, and wherein fatty group and cycloalkylamino group have implication as described in the present invention, and such example includes, But it is not limited to Cyclopropylaminomethyl, cyclopropylaminoethyl, clopentylamino methyl, clopentylamino ethyl, cyclohexyl Amino-ethyl, halogenated cyclopropyl amino-ethyl etc..
Term " cycloalkyl fatty group " represents that fatty group can be replaced by one or more groups of naphthene base, its middle ring Alkyl and fatty group have implication as described in the present invention, and such example includes, but is not limited to Cvclopropvlmethvl, ring third Base ethyl, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc..
Term " cycloalkyl alkoxy " (" carbocyclylalkoxy ") represents alkoxy base by one or more cycloalkyl (" carbocylic radical ") group is replaced, and wherein cycloalkyl (" carbocylic radical ") group and alkoxy base have and contain as described in the present invention Justice, such example includes, 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 herein, all referring to it is monocyclic, Bicyclic or three-ring system, one or more carbon atoms are independent in its middle ring and optionally replaced 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 one of which tie point is 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 replaced.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " heterolipid Ring race " or " heterocycle " group are monocyclic (1-6 carbon atom and the 1-3 hetero atom selected from N, O, P, S, the heres of 3-7 yuan of rings S or P are optionally replaced by one or more oxygen atoms and obtain such as SO, SO2、PO、PO2Group, when described ring be ternary During ring, only one of which hetero atom), or bicyclic (4-9 carbon atom and the 1-3 miscellaneous original selected from N, O, P, S of 7-10 units Son, is optionally replaced by one or more oxygen atoms in this S or P and obtains such as SO, SO2、PO、PO2Group).
Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group with saturation or part insatiable hunger With ring or heterocycle and the formed group of conjunction.The example of heterocycle is included, 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- dioxy amyl groups, 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- hydroxyl -1- (piperazine - 1- yls) ethyl ketone -4- bases, 2- hydroxyl -1- ((the 4H)-yl of 5,6- dihydro -1,2,4- triazines -1) ethyl ketone -4- bases, 5,6- dihydro -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyl -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 that two carbon atoms are replaced such as pyrimidine by oxygen atom on 1,1- dioxothiomorpholinyl and its middle ring Diketo.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, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitre Base, aryloxy group, hydroxyl replace alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkane Base-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
Term " cycloheteroalkylalkyl " includes the alkyl that heterocyclic radical replaces；Term " heterocyclylalkoxy " replaces including heterocyclic radical Alkoxyl, wherein oxygen atom is connected with the remainder of molecule；Term " heterocyclic radical alkylamino " includes the alkane that heterocyclic radical replaces Amino, wherein nitrogen-atoms are connected with the remainder of molecule.Wherein heterocyclic radical, alkyl, alkoxyl and alkylamino have such as this Bright described implication, such example includes, but is not limited to pyrroles's -2- ylmethyls, morpholine -4- base ethyls, morpholine -4- base second Epoxide, piperazine -4- base oxethyls, piperidin-4-yl ethylamino etc..
Term " heterocyclic radical fatty group " represents the fatty group that heterocyclic radical replaces, and wherein heterocyclic radical and fatty group has Implication as described in the present invention, such example includes, but is not limited to pyrroles's -2- methyl, piperidines -2- ethyls, piperazine -2- second Base, piperidines -2- methyl etc..
Term " heterocyclic radical epoxide " includes optionally substituted heterocyclic radical, 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's -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 replaced 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 does not limit In, pyrroles's -2- amino, pyrroles's -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine -2- amino, two Pyrroles's -2- amino etc..
Term " heterocyclic radical epoxide alkoxyl " represents that alkoxyl is replaced by one or more heterocyclic radical epoxide groups, wherein Alkoxyl and heterocyclic radical epoxide group have implication as described in the present invention, and such example is included, but is not limited to, and pyrroles- 2- Oxymethoxies, pyrroles's -3- epoxide ethyoxyls, piperidines -2- epoxide ethyoxyls, piperidines -3- epoxide ethyoxyls, piperazine -2- oxygen Ylmethoxy, piperidines -4- epoxide ethyoxyls etc..
Term " heterocyclic radical epoxide fatty group " represents that fatty group is replaced by one or more heterocyclic radical epoxide groups, Wherein fatty group and heterocyclic radical epoxide group have implication as described in the present invention, and such example is included, but is not limited to, Pyrroles's-2- epoxide methyl, piperazine-3- epoxide ethyls, piperazine-2- epoxide ethyls, morpholine -2-epoxide methyl, piperidines-2- epoxide second Base etc..
Term " heterocyclylamino group fatty group " represents that fatty group is replaced by one or more heterocyclylamino group groups, Wherein fatty group and heterocyclylamino group group have implication as described in the present invention, and such example is included, but is not limited to Pyrroles's-2- amino methyls, piperazine-3- amino-ethyls, piperazine-2- amino-ethyls, piperidines-2- amino-ethyls, morpholine -2-amino first Base etc..
Term " hetero atom " represents one or more O, S, N, P and Si atoms, including 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 the NH in pyrrolidinyl) or NR (such as the NR in the pyrrolidinyl that N- replaces).
Term " halogen " refers to F, Cl, Br or I.
" undersaturated " the expression structure division of term for being used in the present invention contains one or more degrees of unsaturation.
Term " alkoxyl " used in the present invention, is related to alkyl, as defined herein, is connected by oxygen atom To in 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 alkoxyl, and wherein substituent can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyanogen Base, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfydryl, nitro etc..
Term " alkoxyl that hydroxyl replaces " represents that alkoxy base is replaced 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 replaced by one or more amino groups, wherein alkoxyl tool 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 alkoxyl " represents that alkoxyl is replaced by one or more azido groups, wherein alkoxyl tool Have an implication as described in the present invention, such example include, but is not limited to 2- nitrine base oxethyls, 3- azido propoxyl group, 2- azido propoxyl group etc..
Term " alkyloxy-alkoxy " represents that alkoxy base is replaced 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 " alkoxyl fatty group " represents that fatty group is replaced by one or more alkoxy bases, wherein fat Race's base and alkoxy base have implication as described in the present invention, and such example includes, but is not limited to methoxy, second Epoxide methyl, ethoxyethyl group, ethoxy-c thiazolinyl etc..
Term " alkylamino fatty group " represents that fatty group is replaced by one or more alkylamino radicals, wherein fat Race's base and alkylamino radicals have an implication as described in the present invention, such example include, but is not limited to dimethylaminoethyl, Methylaminoethyl, Diethylaminomethyl, diethyllaminoethyl etc..
Term " alkylthio group fatty group " represents that fatty group is replaced by one or more alkylthio radicals, wherein fat Race's base and alkylthio radicals have implication as described in the present invention, and such example includes, but is not limited to methylmercaptoethyl, first Mercaptopropyl, ethylthio-ethyl, methyl mercapto acrylic etc..
Term " haloalkyl ", " haloalkenyl group " and " halogenated alkoxy " expression alkyl, thiazolinyl or alkoxyl can be by one The situation that individual or multiple halogen atoms are replaced, 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 as a big portion of " 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 one of which attachment point is connected with the remainder of molecule.Term " virtue Base " can be exchanged with term " aromatic rings " and used, and such 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 Alkoxyl, hydroxyl that aryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl replace Base replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (= O)-, hydroxyl replace alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
Term " aromatic yl aliphat base " represents that fatty group is replaced by one or more optionally substituted aromatic yl groups, its Middle fatty group and aromatic yl group have implication as described in the present invention, and such example includes, but is not limited to phenethyl, benzene Methyl, to methylphenylethyl, styryl etc..
Term " aryloxy group " includes optionally substituted aryl, 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 amino group is replaced by one or two optionally substituted aromatic yl group, 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 alkoxyl is replaced by one or more optionally substituted aryloxy groups, its Middle alkoxyl 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 fatty group " represents that fatty group is taken by one or more optionally substituted aryloxy groups In generation, wherein aryloxy group and fatty group, have implication as described in the present invention, and such example includes, but is not limited to phenoxy group Methyl, Phenoxyethyl, tolyloxyethyl, phenoxy propyl etc..
Term " fragrant amino fatty group " represents fatty group by one or more optionally substituted fragrant amino groups Replaced, wherein fragrant amino and fatty group have implication as described in the present invention, such example includes, but is not limited to benzene Amino methyl, phenylaminoethyl, toluidino ethyl, phenylamino propyl group, phenylamino pi-allyl etc..
Term " alkoxy aryl " represents that alkoxy base is replaced by one or more optionally substituted aryl, wherein virtue Base and alkoxyl 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 replaced by one or more optionally substituted aromatic yl groups, 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 " heteroaryl alkyl " or " heteroarylalkoxy " most, Monocyclic, the bicyclic and three-ring system containing 5-14 yuan of rings altogether is represented, wherein at least one member ring systems are aromatic, 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 It is connected with molecule remainder comprising 3-7 yuan of rings, and only one of which attachment point.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, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, miscellaneous Ring group, sulfydryl, nitro, aryloxy group, hydroxyl replace alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkane Base-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2-, carboxyl replace Alkoxyl 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 biphosphole bases, 1,3,4- thio biphosphole bases, 1,2,5- thio biphosphole bases, 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 are (such as 1- Isoquinolyl, 3- isoquinolyls or 4- isoquinolyls).
Term " heteroaryl epoxide " includes optionally substituted heteroaryl, as defined herein, is connected on oxygen atom, And it is connected with molecule remainder by oxygen atom, 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 fatty group " represents fatty group by one or more optionally substituted heteroaryl epoxides Group is replaced, and wherein fatty group and heteroaryl epoxide group have implication as described in the present invention, and such example includes, But it is not limited to pyridine -2- epoxide ethyls, thiazole -2- epoxide methyl, imidazoles -2- epoxide ethyls, pyrimidine -2- epoxide propyl group etc..
No matter term " sulfonyl ", be single use or be 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 that amino replaces, and forms ammonia Sulfonyl (- SO2NH2)。
No matter term " carboxyl ", be single use or be used in conjunction (such as " carboxyalkyl "), expression-CO with other terms2H；
No matter term " carbonyl ", be single use or be used in conjunction (such as " amino carbonyl " or " acyloxy ") with other terms, Represent-(C=O)-.
Term " alkoxyl that carboxyl replaces " represents that alkoxy base is replaced 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 that aryl replaces.Some of them embodiment is that aromatic alkyl group is referred to " aralkyl of lower level " group, i.e. aromatic yl group is connected to C1-6Alkyl group on.Other embodiment is, aralkyl Base group is referred to containing C1-3Alkyl " benzene alkylene ".Wherein instantiation includes benzyl, diphenyl methyl, phenethyl.Aralkyl On aryl further can be replaced by halogen, alkyl, alkoxyl, 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 includes, but is not limited to methyl mercapto (CH3S-)。
Term " halogenated alkylthio " includes C1-10Haloalkyl be connected on bivalent sulfur atom.Some of them embodiment It is that halogenated alkylthio is the C of lower level1-3Halogenated alkylthio, such example includes, but is not limited to trifluoromethylthio.
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amine groups separately Replaced by one or two alkyl group.Some of them embodiment is that alkyl amino is one or two C1-6Alkyl connects The alkylamino group of the lower level on 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 and 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 replaced 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 replaced by one or two heteroaryl, and wherein heteroaryl is with this Bright described implication, such example includes, but is not limited to N- thienyl amino etc..Some of them embodiment is, heteroaryl Hetero-aromatic ring on base amino can further be substituted.
Term " heteroarylaliphatic " represent fatty group replaced by one or more heteroaryls, wherein heteroaryl and Fatty group has implication of the present invention, and such example includes, but is not limited to thiophene -2- acrylic, pyridine -4- second Base, imidazoles -2- methyl, furans -2- ethyls, indoles -3- methyl etc..
Term " heteroaryl alkyl " represents that alkyl group is replaced 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 " includes that the heteroarylalkyl group containing nitrogen-atoms is connected to other 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- base ethylaminos, the amino of pyrimidine -2-base third, pyrimidine -2-base methylamino etc..
Term " aminoalkyl " includes the C replaced by one or more amino1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the C replaced by one or more amino groups1-6" aminoalkyl of lower level ", this The example of sample is included, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " alkylaminoalkyl group " includes the alkyl group replaced by alkylamino.Some of them embodiment is, 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 replace, and such example includes, but and It is not limited to, N- Methylaminomethyls, N, N- dimethyl aminoethyls, N, N- diethylamino methyl etc..
Term " carboxyalkyl " includes the C that can be replaced 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 " include optionally substituted aryl, as defined herein as be connected on oxygen atom, and And be connected with molecule remainder by oxygen atom, such example includes, but is not limited to phenoxy group etc..
Term " heteroarylalkoxy " includes that the heteroarylalkyl group containing oxygen atom is connected to other 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 that optionally substituted cycloalkyl replaces, and such example includes, but It is not limited to cyclohexyl methyl.Described cycloalkyl further can be replaced by deuterium, halogen, alkyl, alkoxyl and hydroxyl.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " represents 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 has a key, One alkane chain or a miscellaneous alkane chain, wherein j is 0,1,2,3 or 4.Such system can include independent or conjugation unsaturation State, but its core texture is not comprising aromatic rings or heteroaromatic (but aromatic series can be used as substituent thereon).Condense double Each ring in ring is either carbocyclic ring or is miscellaneous alicyclic, and such example is included, 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 replace or Unsubstituted, wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, miscellaneous Alkoxyl, hydroxyl that aryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl replace Base replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (= O)-, hydroxyl replace alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
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 Comprising aromatic rings or heteroaromatic (but aromatic series can be used as substituent thereon).And at least one member ring systems comprising one or Multiple hetero atoms, each of which member ring systems include 3-7 yuan of rings, i.e., comprising 1-6 carbon atom and selected from 1-3 of N, O, P, S Hetero atom, is optionally replaced by one or more oxygen atoms in this S or P and obtains such as SO, SO2、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 described to condense miscellaneous bicyclic group 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, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, mercapto Base, nitro, aryloxy group, hydroxyl replace alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (= O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2-, carboxyl replace alkoxyl Etc..
Term " volution base ", " volution ", " spiral shell bicyclic group ", that " spiral shell is bicyclic " represents that ring originates from is 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 be referred to as " volution ".Volution 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, alkoxyl, alkylamino, alkyl, thiazolinyl, Alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl replace alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (= O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2-, carboxyl Substituted alkoxyl 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 that a ring originates from particularly ring-shaped carbon on another ring.For example, such as institute above Description, ring A and ring B shares a carbon atom in the member ring systems of two saturations, then be referred to as " volution ".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 The 1-3 hetero atom of N, O, P, S, is optionally replaced by one or more oxygen atoms in this S or P and obtains such as SO, SO2、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 the spiral shell can be replaced or unsubstituted , wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkane Alkoxyl, hydroxyl replacement that epoxide, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, hydroxyl replace Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace alkyl-S (=O)-, hydroxyl Substituted alkyl-S (=O)2-, the alkoxyl etc. that replaces of carboxyl.
A-amino acid group of the present invention removes the group that hydroxyl is formed by the carboxyl of a-amino acid, its with X or X ' connects, 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 replaced.For example
As described in the present invention, substituent draws one and is bonded the member ring systems formed on the ring at the center of being connected to (such as formula (a) institute Show) represent substituent (R5a)fCan be replaced 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 The E ends and E' ends of ring W3 can be connected with other groups, and in the present invention, the group that E and E' two ends are connected is can With what is exchanged.
As described in the present invention, member ring systems the inside dotted line key represents a double bond or singly-bound.For example, the structure of formula (c) Represent any one structure elected from formula (d) the inside.
Unless other aspects show, structural formula described in the invention includes all of isomeric forms (as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism))：R, S configuration for example 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 pointed out, the describing mode for adopting 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 affect mutually between expressed concrete option between same-sign, it is also possible to represent identical Group in, do not affect mutually between expressed concrete option between same-sign, with R9As a example 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 two9Concrete 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 R9Concrete option it is unaffected from each other.
Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. It is such conversion by pro-drug hydrolyze in blood or in blood or tissue Jing enzymatic conversions are affected for precursor structure.This 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.One for example in the present invention Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include Phosphate, such as these phosphate compounds are that the di on Jing parents is obtained.Beg for regard to pro-drug is complete 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 other aspects show that all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless showing in terms of other, 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 pass through the present invention such as and retouch by technology known to art Adopt as stating and experimentally characterized.Such product can be by the way that compound is administered through oxidation, reduction, water Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the metabolite being fully contacted compound and the mammal of the present invention produced by a period of time.
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 There are different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture, constitute the part of the present invention.Very Many organic compounds are all with optical active forms presence, the i.e. 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 name compound linearly polarized light rotation, (-) 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 enantiomeric mixture.50:50 mixture of enantiomers It is referred to as racemic mixture or racemic modification, this may cause in chemical reaction process without stereoselectivity or stereotaxis 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 being migrated by proton Change, the such as isomerization of keto-enol and imine-enamine.Valence (chemical valence) dynamic isomer includes The change of restructuring 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, react 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 additive 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 acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4's Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any group comprising N 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 is further included 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 one or more solvent molecules are formed with the compound of the present invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, 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, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or protection compound in amino feature, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl Base is used for blocking or protect the feature of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl-protecting group Group " refers to the substituent of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- are (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl etc..For protection group The general description of group 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 including suppress HCV virus albumen activity level, virus assembling and emission levels.Its In, HCV protein expression levels are included but is not limited to：The translation skill of viral protein gene, the posttranslational modification level of albumen, son Levels of replication for inhereditary material, etc..
The description of the compounds of this invention
Spiro-compound according to the present invention and its pharmaceutical preparation, 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 the compound shown in formula (I) or the compound shown in formula (I) Its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
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 X1And X2It independently is O, S, NR6Or CR7R7a；
W1For carbocylic radical or heterocyclic radical；
W2For carbocylic radical, heterocyclic radical, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, thick bicyclic group or thick miscellaneous bicyclic group；
Each Y1、Y2、Y1’And Y2’It 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 f and f ' independently are 0,1,2,3 or 4；
Each Q1And Q2It independently is a key, 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 be 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 units carbocyclic ring, C are randomly formed with X-CH5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12 Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4And X '-CH are randomly formed 3-8 circle heterocycles or carbocyclic ring, C5-12Condensed-bicyclic, C5-12 Condense miscellaneous 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 R5aAnd R5a’It 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)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- alkoxyls, R13S (=O)-alkoxyl, R13R13aN-C (=O)-alkoxyl, aryl, heteroaryl Base, alkoxyl, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, 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, alkoxyl 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- alkoxyls, R13S (=O)-alkoxyl, R13R13aN-C (=O)-alkoxyl, aryl, heteroaryl Base, alkoxyl, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, fragrant ammonia Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl Alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, 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, alkoxyl 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, alkoxyl, 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 formed with the atom being attached thereto；
With each R13And R13aIt independently is H, deuterium, alkyl, miscellaneous alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl Base；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aIt is first substituted or non-substituted 3-8 to be randomly formed with nitrogen-atoms Ring, 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-N(R5)-C(=O)-O- (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-、-[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-、R13aR13N-, alkyl-OC (= O)-, alkyl-C (=O)-, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-、R13R13aNS(=O)-、R13OS(= O)-、R13S(=O)-、R13aR13N- alkyl, R13S (=O)-alkyl, R13R13aN-C (=O)-alkyl, R13aR13N- alkoxyls, R13S(= O)-alkoxyl, R13R13aN-C (=O)-alkylamino, alkyl, miscellaneous alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Alkyl, a-amino acid group, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic, C5-12The miscellaneous bicyclic, alkoxyl of spiral shell, Aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxyl aliphatic, alkylamino aliphatic, alkylthio group fat Race, aromatic yl aliphat, heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclic radical epoxide Aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, alkyl halide Base, thiazolinyl, alkynyl, fragrant amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, Alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, heterocyclic radical alkylamino or fragrant oxygen Base can optionally by one or more selected from deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, Alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, hydroxyl replace Alkoxyl, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O), alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl replace Alkyl-S (=O)-, hydroxyl replace alkyl-S (=O)2- or the substituent of alkoxyl that replaces of carboxyl replaced.
Wherein in some embodiments, wherein W1For C3-8Carbocylic radical or C2-10Heterocyclic radical；
And W2For C3-8Carbocylic radical, C2-10Heterocyclic radical, C5-12Spiral shell bicyclic group, C5-12The miscellaneous bicyclic group of spiral shell, C5-12Thick bicyclic group or C5-12Thick miscellaneous bicyclic group.
Wherein in some embodiments, wherein
Construction unit is following subformula：
Construction unit is following subformula：
Wherein, each X1、X2、X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each Q1And Q2It independently is key, a NR6, O, S, C (=O) or (CR7R7a)e；
Q3For N or CR7；
Each e independently is 0,1,2,3 or 4；
Each R5aAnd R5a’It 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)-、C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl oxygen Base, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro, C1-6Alkane ammonia Base, 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；
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, 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 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
Wherein in some embodiments, wherein,
Construction unit is following subformula：
Construction unit is following group：
Wherein, each Y1、Y2、Y1’And Y2’It independently is N or CH2；
Each f and f ' independently are 0,1,2,3 or 4；
Each R5aAnd R5a’It 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)-、C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl oxygen Base, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro or C1-6Alkane Amino；
With each R6It independently is hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alkane Epoxide C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl C1-6Alkane Base, C2-10Heterocyclic radical C1-6Alkyl or C3-8Cycloalkyl C1-6Alkyl.
Wherein in some 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 e independently is 0,1,2,3 or 4；
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, C1-6Alkoxyl, 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-C1-6Alkoxyl, R13S(=O)-C1-6Alkoxyl, R13R13aN-C(=O)-C1-6 Alkoxyl, C6-10Aryl, C1-9Heteroaryl, C1-6Alkoxyl, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms 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, C1-6Alkoxyl, 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.
Wherein in some 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(R6)-、-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, each X1It independently is O or S；
Each Y1It independently is N or CH；
Each e independently is 0,1,2 or 3；
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, C1-6Alkoxyl, 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-、-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)-、C1-6Alkoxyl, C1-6Alkylamino, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, sulfydryl or nitro；
With 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
Wherein in some 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 units 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 units 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 X '-CH form 3-8 circle heterocycles, C5-12It is thick Close bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic.
In other embodiments, wherein R1、R2The heterocycle formed with Y-X-CH or condensed ring or spiro ring system are selected from Following subformula：
Wherein, each R15It independently is H, deuterium, oxo（O）, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Alkyl halide Base, C1-3Alkoxyl, 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 formed of Y '-X '-CH or condensed ring or spiro ring system choosing From following subformula：
Wherein, each R15It independently is H, deuterium, oxo（O）, F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Alkyl halide Base, C1-3Alkoxyl, 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.
Wherein in some embodiments, it has such as formula（II）Shown structure：
Wherein,Construction unit is following subformula：
Construction unit is following group：
Each Q1And Q2It independently is key, a NR6, O, S, C (=O) or (CH2)e；
Q3For N and CH；
Each X1It independently is O, S, NR6Or CR7R7a；
Each e independently is 0,1,2,3 or 4；
Each f and f ' independently are 0,1,2,3 or 4
Each X3And X5It independently is O, S, NR6, C (=O) or CR7R7a；
Each Y1、Y2、Y1’And Y2’It 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, C1-6Alkoxyl, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, amino first Acyl group, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-, alkyl-S (=O)r- or amino-sulfonyl；
Each R5a、R5a’And R6aIt 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)-、C1-6Alkyl acyl, C1-6Alkyl acyl Epoxide, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alkyloxysulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulfonyl Base epoxide, C1-6Alkyl sulphinyl epoxide, C1-6Alkoxyl, C1-6Alkyl, C6-10Aryl ,-CF3、-OCF3, sulfydryl, nitro, C1-6 Alkylamino, 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, C1-6Alkoxyl, 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms 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-、- CH2S(=O)r、-CF2-、-CHR5a、-CR5aR6a- or-CH2N(R6)-。
In other embodiments, it has such as formula（III）Shown structure：
Wherein, each Q1、Q2、Q4And Q5It independently is NR6, O, S, C (=O) or (CR7R7a)e；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（IV）Shown structure：
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（V）Shown structure：
Wherein, each Q1、Q2And Q4It independently is O, S, C (=O), NR6Or CH2；
0,1,2,3 or 4 independently are with each i and e.
In other embodiments, it has such as formula（VI）Shown structure：
Wherein, each Q1And Q2It independently is O, S, C (=O), NR6Or CH2；
I is 0,1,2,3 or 4；
And W3For C3-10Carbocylic radical or C2-10Heterocyclic radical.
In other embodiments, it has such as formula（VII）Shown structure：
Wherein, each Q1、Q3、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（VIII）Shown structure：
Wherein, each Q1、Q3、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（IX）Shown structure：
Wherein, each Q1、Q3And Q4It independently is O, S, C (=O), NR6Or CH2；
It is 0,1,2,3 or 4 with e.
In other embodiments, it has such as formula（X）Shown structure：
Wherein, each Q1And Q3It independently is O, S, C (=O), NR6Or CH2；
And W3For C3-10Carbocylic radical or C2-10Heterocyclic radical.
Wherein in some embodiments, wherein, Y and Y ' independently is 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- dimethylglycine, 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.
Wherein in some 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；Or work as R13And R13aIt is connected on same nitrogen-atoms, R13、R13aAppoint with nitrogen-atoms Meaning ground forms that substituted or non-substituted 3-8 yuan of rings, spiral shell be bicyclic or condensed-bicyclic.
In other embodiments, wherein,
Each R9、R9a、R10And R11It independently is H, deuterium, 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, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl.
In other embodiments, it has such as formula（XI）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.
In other embodiments, it has such as formula（XII）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 ,-NR13R13a, benzyl, piperazinyl, cyclopenta, ring third Base, cyclohexyl or C1-9Heteroaryl.
Wherein in some embodiments, it has such as formula（XIII）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 in some 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 in some embodiments, it has such as formula（X’）Shown structure,
Wherein, each Q1And Q2It independently is O, S, C (=O), NR6Or CH2；
Each R5aAnd R5a’It independently is H, deuterium, C1-4Alkyl, oxo (=O), benzyl, F, Cl, Br or I;
Each R6And R7It independently is H, deuterium, C1-4Alkyl, C6-10Aryl, C2-10Heterocyclic radical or C3-8Cycloalkyl；
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：
Wherein Bn is benzyl；
Construction unit is following group：
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
In other embodiments, wherein
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I;
Each R6And R7It independently is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Substituent replaced.
Wherein in some embodiments, it has such as formula（XI’）Shown structure,
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
X1For O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isobutyl group, isopropyl or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from the replacement of deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Base is replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein in some embodiments, it has such as formula（XII’）Shown structure：
Wherein, each Q1、Q2、Q4And Q5It independently is O, S, C (=O), NR6Or CH2；
Each X1It independently is O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Substituent replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein in some embodiments, it has such as formula（XIII’）Shown compound：
Wherein, each Q1、Q2And Q4It independently is O, S, C (=O), NR6Or CH2；
X3For O, S, NR6, C (=O) or CR7R7a；
Each R6、R7And R7aIt independently is hydrogen, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl；
Each R5aAnd R5a’It independently is H, deuterium, methyl, ethyl, oxo (=O), benzyl, F, Cl, Br or I；
Each Y1、Y2、Y1’And Y2’It independently is N or CR7；
Each f and f ' independently are 0,1,2,3 or 4；
Each i and e independently are 0,1,2,3 or 4；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or tertiary fourth Base；
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, benzyl, tert-butoxy or the tert-butyl group optionally can be selected from the replacement of deuterium, F, Cl, Br, hydroxyl, cyano group by one or more Base is replaced；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein in some embodiments, the structure comprising one of：
Or its stereoisomer, geometric isomer, change Isomers, nitrogen oxides, hydrate, solvate or pharmaceutically 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 producing the product of HCV-Ab IgG.Thus, compound of the invention can be used for life A kind of pharmaceuticals are produced for the illness that mitigates, prevent, control or treat HCV to be mediated, particularly HCV NS5A are protein mediated Disease.Thus, compound of the invention can serve as the active component of pharmaceutical composition, and the pharmaceutical composition can include formula （I）Representative compound, can also further comprising at least one pharmaceutically acceptable carrier, assistant agent or diluent.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " is meant that, the thing for being adopted Matter or composition must be adapted on chemistry or toxicity be matched with the other components of composition preparation and the mammal for treating 's.Those skilled in the art can according to using other components and the object of used treatment such as people, come specifically chosen " medicine The material or composition of acceptable on ".
The salt of the compound of the present invention is also included for preparing or purifying the intermediate of compound shown in formula (I) or formula (I) The salt of the detached enantiomter of shown compound, 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., Using inorganic base or organic base, such as ammonia（Primaquine, parahelium, tertiary ammonia）, alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt is included, but is not limited to, ammonia, such as primaquine, secondary from the organic salt that amino acid is obtained, such as glycine and arginine Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain 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
Compound of the described pharmaceutical composition comprising 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 to have suppress well to HCV NS5A albumen makees With.
Described pharmaceutical composition further includes the medicine of HCV-Ab IgG.The medicine of the HCV-Ab IgG can for 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 compound, RNA interfering, antisense RNA, miaow quinoline not moral, the inosine of 1 type helper T lymphocyte response 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 wraps 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, shelling, translation, replicate, assembling, the intact virus of the HCV of release Cycle；Described HCV virus albumen is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And HCV virus Internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for replicating.
When can be used for treatment, the compounds of this invention of therapeutically effective amount, especially formula（I）Compound and its pharmaceutically may be used The salt of acceptance can give as unprocessed chemicals, and the active component for being alternatively arranged as pharmaceutical composition is provided.Therefore, this 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 carrier, diluent or excipient.Herein The term " therapeutically effective amount " for being used refers to and be enough to show significant patient benefit（For example 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, is 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, the method is included the compounds of this invention, especially formula（I）Change Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent or excipient are mixed.This The used term " pharmaceutically acceptable " of invention refers to such compound, raw material, composition and/or formulation, they Rational medicine judge in the range of, it is adaptable to 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 UD 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 are used to prevent or treat between about 0.05mg/kg body weight/days and about 100mg/kg body weight/days, usually with monotherapy The disease of HCV mediations.Generally the drug regimen of present invention can be given by daily about 1 to about 5 time or as continuous infusion Thing.This kind of dose regimen can be used as long-term or short-term therapy.Mix to prepare the amount of the active component of single formulation with carrier material 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.Preferred unit dosage forms are the days containing hereinbefore active component The unit dosage forms of dosage or divided dose or its appropriate fraction.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 comprising present invention compound and one or more other treatment medicine 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 accounts for the about 10-80% of normal dosage.Pharmaceutical preparation is suitable to by any suitable approach Administration, such as by oral（Including oral cavity or sublingual）, rectum, nose, local（Including oral cavity, sublingual or percutaneous）, vagina or stomach It is parenteral（Including in subcutaneous, intracutaneous, intramuscular, joint, in intrasynovial, breastbone, in intrathecal, focus, intravenous or intradermal injection Or infusion）Approach.This kind of preparation can be prepared by any known method of art of pharmacy, such as by by active component and carrier Or excipient mixing.It is preferred that being administered orally or drug administration by injection.
The pharmaceutical preparation for being suitable to be administered orally is provided by independent unit, such as capsule or tablet；Powder or granule； Solution or supensoid agent in aqueous 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, for oral administration in the form of a tablet or capsule, active medicine component can with pharmaceutically can connect The oral, non-toxic inert carrier received（Such as ethanol, glycerine, water etc.）Mix.By the way that compound powder is broken into into suitable fine chi It is very little, and with the pharmaceutical carrier equally crushed（The edible carbohydrate such as such as starch or mannitol）Mix to prepare powder.Also There may be flavouring, preservative, dispersant and colouring agent.
By preparing pulverulent mixture as above, and it is loaded in the gelatin shell of shaping to prepare capsule.In dress Before filling out operation, can be by glidant and lubricant（Such as colloidal silica, talcum powder, magnesium stearate, calcium stearate or solid-state Polyethylene glycol）In being added to pulverulent mixture.Can also add when capsule is taken 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, it is natural and synthesis Natural gum（Such as gum arabic, tragacanth or mosanom）, carboxymethylcellulose calcium, 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 making pulverulent mixture, granulation or pre- compressing tablet, lubricant and disintegrant are added, it is tabletted, so as to make Piece agent.By the appropriate compound crushed and diluent as described above or base-material, optionally and adhesive（For example carboxymethyl is fine Dimension element, alginates, gelatin or polyvinylpyrrolidone）, dissolving inhibitor（Such as paraffin）, absorbsion accelerator（Quaternary salt）And/or Absorbent（Such as bentonite, kaolin or Dicalcium Phosphate）Mix to prepare pulverulent mixture.Useful binders（Such as syrup, shallow lake Slurry, mucialga of arabic gummy（acadiamucilage）Or cellulosic material or polymeric material solution）Pressurization after wetting is sieved, by powder Shape granulating mixture.One alternative of granulation is, as a result can be will to form not good by pulverulent mixture by tablet press machine Agglomerate smashes make particle again.Can make particle lubrication to prevent from gluing by adding stearic acid, stearate, talcum powder or mineral oil To on the punch die of tablet press machine.Then the mixture for Jing being lubricated is tabletted.The compound of present invention can also be with free stream Dynamic inert carrier mixing, just can be tabletted without the need for passing through 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 UDs.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, so as to specified rate contains There is the compound of scheduled volume.Syrup can be prepared by the way that compound is dissolved in the suitably seasoned aqueous solution, 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 being administered orally.Also preparation can be made and prolongs When or sustained release, such as by coating or be 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 gives, for example small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be by various phosphatide（For example courage is consolidated Alcohol, octadecylamine or phosphatid ylcholine）Constitute.
The compounds of this invention, especially formula（I）Compound and its pharmaceutically acceptable salt also can be by using monoclonals Antibody is used 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 replaced by palmitoyl residues.Additionally, compound can Be coupled with a class Biodegradable polymeric, for reaching the controlled release of medicine, this kind of polymer such as PLA, poly- ε-oneself in The cross-linked copolymer of ester, poly butyric, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel or Amphipathic nature block polymer.
The pharmaceutical preparation for being suitable to percutaneous dosing can be as discrete patch (discrete patch) to protect in a long time Hold and recipient's epidermis close contact.For example, active component can pass medicine by by electro-ionic osmosis patch, generally can be found in Pharmaceutical Research 1986,3(6),318。
The pharmaceutical preparation for being suitable to local administration can be made into ointment, cream, supensoid agent, lotion, powder, solution, paste Agent, gel, spray, aerosol, oil formulation or transdermal patch.
Being suitable to the pharmaceutical preparation of rectally can provide as suppository or as enema.
The pharmaceutical preparation (wherein carrier is solid) for being suitable to nose administration is such as 20-500 micrometer ranges including particle diameter Dust base, by being administered in snuffing mode, i.e., is quickly sucked by nasal passage from the meal agent container of close nose.Wherein carry Body is liquid, is adapted as nasal mist or the aqueous solution agent or oil of the appropriate formulation including active component of nasal drop administration Property solution.
It is suitable to include minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation, can be with not Dosage compresed gas aerosol, nebulizer, insufflator or other matters that same type is measured deliver the device of aerosol sprays Middle preparation.
The pharmaceutical preparation for being suitable to vagina administration can be with vaginal plug, vagina plug, cream, creme, gel, paste, foam Agent or spray are provided.
Being suitable to the pharmaceutical preparation of parenteral includes aqueous and non-aqueous sterile injection solution agent and aqueous and non-aqueous Sterile suspensions, aqueous and non-aqueous sterile injection solution agent can contain antioxidant, buffer, bacteriostatic agent and make the preparation The solute isotonic with receptor's blood waiting, aqueous and non-aqueous sterile suspensions may include suspending agent and thickener.Preparation can be with UD or multi-dose container are provided, and the peace of such as sealing is triumphant and bottle, and can be stored under the conditions of freeze-drying (lyophilized), Only need to before use add sterile liquid carrier, such as water for injection.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
The invention provides the purposes in medicine is prepared of compound or pharmaceutical composition of the present invention, 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 of the HCV for enter, shell, translate, replicate, assemble, discharging.Described HCV virus albumen is selected from metalloprotein Enzyme, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And HCV virus replicate required internal ribosome inlet point (IRES) With inosine monophosphate dehydrogenase (IMPDH).Arbitrary compound of the present invention or pharmaceutical composition can be used for treating the third type liver Scorching virus (HCV) infection or hepatitis C disease, especially, it has good inhibiting effect to HCV NS5A albumen.
Comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered, further include that other are administered to patient HCV medicines, thus, it is possible to the compound of the present invention and other anti-HCV medicaments are carried out into therapeutic alliance, wherein the HCV-Ab IgG Medicine is interferon, Ribavirin, interleukin-22, interleukin 6, interleukin 12, the change of promotion 1 type helper T lymphocyte response of generation Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, three Ribavirin, Ba Wei former times monoclonal antibodies（Bavituximab）、CivacirTM, EBP520 (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- 9190th, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.It is wherein described dry Disturb element for Interferon Alpha-2b, the interferon-' alpha ' of Pegylation, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound α- Interferon, interferon gamma 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 used as single formulation, or separate compound or pharmaceutical composition are used as a part for 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 to be carried out As carried out within 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 process 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 Thing can be any dosage and any method of administration being efficiently used for processing or mitigating the order of severity of disease.Required standard True amount changes the situation according to patient, this depend on race, 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 is used to that this to be further illustrated The content of invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods for preparing the compound of the present invention are considered as the model in the present invention Within enclosing.For example, can 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 reagents 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 of temperature is 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 not through being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Rise imperial chemistry examination 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 is commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain through metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain through calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is that in advance drying is used Jing anhydrous sodium sulfates.
Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.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 (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, by using following abbreviation：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, is represented with hertz (Hz).
By outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determining, G1329A automatic samplers and G1315B DAD detectors Analysis is applied to, 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 determining, 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；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength is recording 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 the series of high efficiency liquid chromatograies (HPLC) of Agilent 1100, wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, and 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, 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 methyl alcohol
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 NaOH
NaClO2Sodium chlorite
NaCl sodium chloride
NaH2PO4Sodium dihydrogen phosphate
NaH sodium hydrides
NaI sodium iodides
Na2SO4Sodium sulphate
TBTU O- BTA-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester
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- azo BTAs)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
NIS N- N-iodosuccinimides
TFAA TFAAs
SEMCl 2- (TMS) 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
SbCl3Trichloride antimony
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- phosphine 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 1
Target compound 18 can be prepared by synthetic method 1, wherein X5For leaving groups such as F, Cl, Br, I, OTf Group, also, each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、Y4、W1、W2、R14And R16With implication as described in the present invention, Pg is Amino protecting group, such as Boc, Fmoc, Cbz.The cyclization in the presence of alkali of compound 1 obtains compound 2, and compound 2 is in reduction Compound 3 is obtained in the presence of agent, compound 3 occurs halogenating reaction and obtains compound 4, and the demethylation of compound 4 obtains compound 5, compound 5 obtains compound 6 under the catalysis of palladium with connection boric acid pinacol ester reaction, and compound 6 is urged with compound 5 ' in palladium Coupling reaction is carried out under change and obtains compound 7, compound 7 obtains compound 8 with TFMS anhydride reactant in the basic conditions, Compound 8 obtains compound 9 under the catalysis of palladium with connection boric acid pinacol ester reaction.Compound 10 occurs in the presence of borine Reduction reaction obtains compound 11, and compound 12 is subsequently obtained under the oxidation of Dai Si-Martin, and compound 12 is in ammoniacal liquor and second two Cyclization in the presence of aldehyde obtains compound 13, and compound 13 carries out reaction and obtains compound 14 with NIS, and compound 14 is in sulfurous acid An iodine is sloughed in the reaction system of sodium and obtains compound 15.Compound 15 carries out coupling reaction with compound 9 under palladium chtalyst Compound 16 is obtained, compound 17 is obtained after the deprotection of compound 16, compound 17 carries out condensation reaction and obtains with compound 17-1 To target compound 18.
Synthetic method 2
Target compound 31 can be prepared by synthetic method 2, wherein, each A1、A2And A3Independently selected from N or CR7、X5For leaving groups such as F, Cl, Br, I, OTf, also, each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、Y4、Y4’、W1、W2、R14 And R16With implication as described in the present invention, Pg is amino protecting group, such as Boc, Fmoc, Cbz etc..Compound 19 and compound There is the mixture that condensation reaction obtains compound 20 and 21 in 19-1, subsequently cyclization is heated in acetate system and obtain compound 22, compound 22 obtains compound 23 under the catalysis of palladium with connection boric acid pinacol ester reaction.Compound 5 ' is in the basic conditions Compound 24 is obtained with TFMS anhydride reactant, compound 24 occurs coupling reaction and obtains under the catalysis of palladium with compound 6 Compound 26, compound obtained and further coupling reaction with compound 23 under the catalysis of palladium in compound 25, compound 25 there is 26 obtain in the basic conditions compound 27 with TFMS anhydride reactant, compound 27 under the catalysis of palladium with connection boric acid frequency that Alcohol ester reaction obtains compound 28, and compound 28 carries out coupling reaction under palladium chtalyst and obtains compound 29 with compound 15, changes Compound 30 is obtained after the deprotection of compound 29, compound 30 carries out condensation reaction and obtains target compound 31 with compound 17-1.
Synthetic method 3
Compound 35 can be prepared by synthetic method 3.Wherein, X5For leaving groups such as F, Cl, Br, I, OTf, and And, each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’, W and W1With implication as described in the present invention.Compound 32 is under the action of an acid Compound 34 is obtained with the reaction of compound 33.Compound 34 carries out coupling reaction under palladium chtalyst and obtains targeted with compound 6 Compound 35.
Synthetic method 4
Target compound 43 can be prepared by synthetic method 4, wherein, each R5a、R5a’、f、f’、Y1、Y2、Y1’、Y2’、 Y4、W1、W2、R14And R16With implication as described in the present invention, Pg is amino protecting group, such as Boc, Fmoc, Cbz.Compound 36 obtain compound 37 under palladium chtalyst with TMSA reactions, and compound 37 takes off TMS under the catalysis of alkali and obtains compound 38.Change There is coupling reaction and obtain compound 39 in compound 25, compound 39 is in the basic conditions with three under the catalysis of palladium with compound 15 The reaction of fluorine methanesulfonic acid acid anhydride obtains compound 40, and compound 40 carries out coupling reaction under palladium chtalyst and obtains compound with compound 38 41, compound 42 is obtained after the deprotection of compound 41, compound 42 carries out condensation reaction and obtains target chemical combination with compound 17-1 Thing 43.
Synthetic method 5
Target compound 54 can be prepared by synthetic method 5, wherein, each A1、A2And A3Independently selected from N or CR7, also, each R5a、R5a’、f、f’、Y1、Y2、Y4、Y4’、W1、R14And R16With implication as described in the present invention, Pg is amino guarantor Shield base, such as Boc, Fmoc, Cbz.Benzoquinones and conjugated diene obtain compound 44, compound 44 by Diels-Alder reactions There is rearrangement reaction in the presence of alkali and obtain compound 45, compound 45 is reduced in the presence of Pd/C hydrogen and obtains compound 46, compound 46 reacts in the presence of alkali and trifluoromethanesulfanhydride anhydride and obtains target compound 47.Compound 47 is in palladium Catalysis is lower to obtain compound 48 with the generation of compound 6 coupling reaction, compound 48 under the catalysis of palladium further with compound 23 Generation coupling reaction obtains compound 49, and compound 49 obtains compound 50 with TFMS anhydride reactant in the basic conditions, Compound 50 obtains compound 51 under the catalysis of palladium with connection boric acid pinacol ester reaction, and compound 51 is urged with compound 15 in palladium Coupling reaction is carried out under change and obtains compound 52, compound 53, compound 53 and compound 17- are obtained after the deprotection of compound 52 1 carries out condensation reaction obtains target compound 54.
Synthetic method 6
Target compound 61 can be prepared by synthetic method 6, wherein each R5a、R5a’、f、f’、Y1、Y2And W1Have Implication as described in the present invention.Compound 55 obtained and Diels-Alder reactions in butine dicarboxylic acid dimethyl ester and conjugated diene there is, Compound 55 obtains compound 56 under the reduction of Pd/C hydrogen, and compound 56 obtains compound 57, chemical combination in the presence of alkali There is ring-closure reaction and obtain compound 58 in thing 57, the heating response under conditions of hydrazine hydrate/acetic acid of compound 58 obtains compound 59, compound 59 reacts in the presence of POCl3 and obtains compound 60, and compound 60 and compound 6 are issued in the catalysis of palladium Raw coupling reaction obtains compound 61.
Synthetic method 7
Target compound 71 can be prepared by synthetic method 7, wherein, X5For leaving groups such as F, Cl, Br, I, OTf Group, also, each w, R5a、R5a’、f、f’、Y1、Y2、Y2’、Y4、W、W1、R14And R16With implication as described in the present invention, Pg is ammonia Base protection group, such as Boc, Fmoc, Cbz.The Jing halos of compound 62 obtain compound 63, and after removing methyl compound 64 is obtained, Compound 64 obtains in the basic conditions compound 65 with TFMS anhydride reactant, and compound 65 is with compound 6 in palladium chtalyst Under carry out coupling reaction and obtain compound 66, compound 66 obtains compound with TFMS anhydride reactant in the basic conditions 67, compound 67 obtains compound 68 under the catalysis of palladium with connection boric acid pinacol ester reaction.Compound 68 exists with compound 15 Coupling reaction is carried out under palladium chtalyst and obtains compound 69, compound 70, compound 70 and chemical combination are obtained after the deprotection of compound 69 Thing 17-1 carries out condensation reaction and obtains target compound 71.
Embodiment
Embodiment 1
Synthetic route：
Step 1）The synthesis of compound 1-2
By compound 1-1（5.0g,33.7mmol）With K2CO3（23.4g,168.5mmol）It is suspended in acetone（50mL）In, It is slowly dropped into iodomethane（3.15mL,50.55mmol）, drip and finish, 60 DEG C are reacted 5.0 hours.After reaction completely, concentration of reaction solution, Residue adds water（150mL）And EtOAc（150mL）, diatomite is filtered, after filtrate layered, water layer EtOAc（150mL×2） Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： PE/EtOAc(v/v)=10/1）Obtain yellow solid 2.46g, yield：45%.
MS(ESI,pos.ion)m/z:163.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.51-7.48(m,1H),7.30-7.26(m,1H),6.91-6.87(m,1H), 3.90(s,3H),3.08-3.05(m,2H),2.70-2.67(m,2H)ppm。
Step 2）The synthesis of compound 1-3
By t-BuOK（3.7g,32.6mmol）It is suspended in toluene（20mL）In, 0 DEG C of N2Under protection, compound is slowly dropped into 1-2（2.3g,14.2mmol）With 1,4- dibromobutanes（3.6g,15.6mmol）Toluene（30mL）Solution, drop finishes, 80 DEG C of reactions 3.5 hour.After reaction completely, it is cooled to room temperature, adds water（30mL）Reaction, water layer EtOAc is quenched（50mL×3）Extraction, closes And organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc (v/v)=8/1）Obtain weak yellow liquid 2.2g, yield：72%.
MS(ESI,pos.ion)m/z:217.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.37-7.31(m,2H),7.03(dd,1H,J=6.2,2.5Hz),3.91(s, 3H),2.93(s,2H),1.83-1.64(m,6H),1.52-1.42(m,4H)ppm。
Step 3）The synthesis of compound 1-4
At 0 DEG C, by trifluoroacetic acid（4.0mL,54mmol）It is slowly dropped into compound 1-3（9.73g,45mmol）With triethyl group Silane（28.8mL,180mmol）Mixture in, drop finish, 40 DEG C reaction overnight.After reaction completely, concentration of reaction solution, residue It is dissolved in DCM（100mL）In, Na is used respectively2CO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, Jing posts layer after concentration Analysis is isolated and purified（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain colorless oil 7.1g, yield：78%.
MS(ESI,pos.ion)m/z:203.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.13-7.10(m,1H),6.81-6.80(m,1H),6.67-6.65(m,1H), 3.83(s,1H),2.85(s,2H),2.80(s,2H),1.72-1.57(m,8H)ppm。
Step 4）The synthesis of compound 1-5
By compound 1-4（14.1g,69.8mmol）And NIS（17.2g,76.8mmol）It is suspended in acetonitrile（200mL）In, 0 At DEG C, trifluoroacetic acid is slowly dropped into（1.55mL,20.9mmol）, dripping and finish, room temperature reaction is overnight.After reaction completely, concentration reaction Liquid, residue adds water（100mL）, use EtOAc（100mL×3）Extraction, merges organic phase, molten with saturated sodium sulfite respectively Liquid（50mL×2）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/ DCM(v/v)=20/1）Obtain colorless oil 19.2g, yield：84%.
MS(ESI,pos.ion)m/z:329.2[M+H]+；
1HNMR(400MHz,CDCl3):δ7.45(d,1H),6.43(d,1H),3.77(s,3H),2.90(s,2H),2.81 (s,2H),1.73-1.69(m,4H),1.63-1.59(m,4H)ppm。
Step 5）The synthesis of compound 1-6
At -78 DEG C, by BBr3（74.7g,298.8mmol）It is slowly dropped into compound 1-5（19.6g,59.7mmol）DCM （150mL）In solution, drop finishes, after isothermal reaction 20 minutes, room temperature reaction 1.0 hours.After reaction completely, reactant liquor is slowly fallen In entering frozen water, water layer DCM（100mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dried, concentration By column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain pale solid 17.24g, yield：92%.
MS(ESI,pos.ion)m/z:315.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.36(d,1H),6.41(d,1H),4.91(s,1H),2.89(s,2H),2.82 (s,2H),1.73-1.69(m,4H),1.67-1.63(m,4H)ppm。
Step 6）The synthesis of compound 1-7
By compound 1-6（0.5g,1.59mmol）, compound 1-6-2（0.60g,2.36mmol）With Pd (dppf) Cl2· CH2Cl2（64.9mg,0.08mmol）With acetic anhydride potassium（0.62g,6.32mmol）In reaction bulb, N2Under protection, inject anhydrous DMF（5mL）Afterwards, 100 DEG C are reacted 1.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）Dilute reaction solution, silicon Diatomaceous earth is filtered, and filtrate uses respectively water（25mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographies point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain white solid 0.48g, yield：96%.
MS(ESI,pos.ion)m/z:315.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.51(d,1H,J=8.0Hz),6.60(d,1H,J=8.0Hz),5.29(s, 1H),3.07(s,2H),2.72(s,2H),1.72-1.62(m,8H),1.31(s,12H)ppm。
Step 7）The synthesis of compound 1-8
By compound 1-7（0.15g,0.48mmol）, compound 1-6（0.18g,0.57mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）After dilute reaction solution, saturation is used Brine It, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1） To white solid 107.7mg, yield：60%.
MS(ESI,pos.ion)m/z:375.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.90(d,2H,J=8.1Hz),6.65(d,2H,J=8.1Hz),4.64(br., 2H),2.82(s,4H),2.66(s,4H),1.60-1.68(m,16H)ppm。
Step 8）The synthesis of compound 1-9
At 0 DEG C, by triethylamine（0.3mL,2.16mmol）It is slowly dropped into compound 1-8（80mg,0.21mmol）DCM （5mL）In solution, after stirring 10 minutes, then trifluoromethanesulfanhydride anhydride is instilled（0.3mL,2.16mmol）, drip and finish, room temperature reaction 1.0 Hour.After reaction completely, frozen water is added（25mL）Reaction, water layer DCM is quenched（25mL×3）Extraction, merges organic phase, uses full And brine It, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain yellow liquid 130.5mg, yield：97.4%.
1H NMR(400MHz,CDCl3):δ7.09(d,2H,J=8.4Hz),7.04(d,2H,J=8.4Hz),2.99(s, 4H),2.66(s,4H),1.62-1.70(m,16H)ppm。
Step 9）The synthesis of compound 1-10
By compound 1-9（0.14g,0.22mmol）, compound 1-6-2（0.16g,0.63mmol）With Pd (dppf) Cl2·CH2Cl2（17.4mg,0.021mmol）With acetic anhydride potassium（0.17g,1.73mmol）In being placed in reaction bulb, N2Protection Under, inject DMF（5mL）Afterwards, 100 DEG C are reacted 1.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）Dilution is anti- Liquid, diatomite is answered to filter, filtrate uses respectively water（25mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=50/1）Obtain white solid 92.58mg, yield：70.8%.
1H NMR(400MHz,CDCl3):δ7.64(d,2H,J=7.5Hz),7.00(d,2H,J=7.5Hz),3.13(s, 4H),2.59(s,4H),1.62-1.58(m,16H),1.35(s,24H)ppm。
Step 10）The synthesis of compound 1-12
By compound 1-11（10.0g,46.6mmol）It is dissolved in THF（100mL）In, under 0 DEG C of nitrogen protection, by borine （100mL,1M in THF）Slowly it is added drop-wise in reaction bulb, drop finishes, isothermal reaction 3.0 hours.After reaction completely, methyl alcohol is used （80mL）Reaction is quenched, Jing column chromatographic isolation and purifications after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain colourless Grease 7.0g, 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 11）The synthesis of compound 1-13
By compound 1-12（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 dividedly in some parts in reaction bulb, after adding, room temperature reaction 2.0 hours.After reaction completely, water is added （250mL）Dilute reaction solution, filters, after filtrate layered, organic layer saturated common salt water washing, and 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 12）The synthesis of compound 1-14
By compound 1-13（3.5g,17.6mmol）And ammoniacal liquor（13mL）It is dissolved in methyl alcohol（30mL）In, at 0 DEG C, by second two Aldehyde（40%,8mL）The aqueous solution slowly instill in reaction bulb, drop finish, room temperature reaction is overnight.After reaction completely, after concentration of reaction solution Jing column chromatographic isolation and purifications（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 13）The synthesis of compound 1-15
By compound 1-14（2.0g,8.4mmol）It is dissolved in DCM（60mL）, at 0 DEG C, by N- N-iodosuccinimides （3.8g,16.8mmol）In being dividedly in some parts reaction bulb, isothermal reaction 1.5 hours.After reaction completely, reactant liquor saturated aqueous common salt Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white Solid 2.6g, yield：63.1%.
MS(ESI,pos.ion)m/z:490.0[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 14）The synthesis of compound 1-16
By compound 1-15（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 is added Water（50mL）, use ethyl acetate（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, after concentration Jing column chromatographic isolation and purifications（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 15）The synthesis of compound 1-17
By compound 1-10（61.8mg,0.104mmol）, compound 1-16（112.5mg,0.31mmol）, potassium carbonate （71.8mg,0.52mmol）With Pd (PPh3)4（12mg,0.0104mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into （6mL）And water（1.5mL）, 90 DEG C are reacted 2 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）Dilute reaction solution Afterwards, saturated common salt water washing, anhydrous Na are used2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v) =1/2）Obtain white solid 59.2mg, yield：70%.
MS(ESI,pos.ion)m/z:407.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ10.60(br.,2H),7.08-7.22(m,6H),5.01(br,2H),3.42 (m,4H),3.07-3.04(m,4H),2.70-2.68(m,4H),2.18(m,4H),2.05(m,4H),1.64-1.58(m, 16H),1.51(s,18H)ppm。
Step 16）The synthesis of compound 1-18
By compound 1-17（38.2mg,0.047mmol）It is dissolved in DCM（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（3mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（10mL）After washing, mistake Filter obtains white solid 34.46mg, yield：96.7%.
MS(ESI,pos.ion)m/z:613.5[M+H]+；
1H NMR(400MHz,CD3OD):δ7.85(s,2H),7.64(d,2H,J=7.9Hz),7.22(d,2H,J= 7.9Hz),5.25-5.20(m,2H),3.62-3.58(m,4H),3.12(s,4H),2.75-2.73(m,2H),2.71(s,4H), 2.60-2.54(m,2H),2.45-2.35(m,2H),2.28-2.22(m,2H),1.73-1.63(m,16H)ppm。
Step 17）The synthesis of compound 1-19
By compound 1-18（60.6mg,0.08mmol）, compound 1-18-2（29.43mg,0.168mmol）And EDCI （32.2mg,0.168mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA（0.10mL,0.64mmol）, drip and finish, room temperature Reaction 3.0 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, is washed respectively with ammonium chloride solution and saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/MeOH(v/v)=60/1）Obtain white solid Body 58.03mg, yield：78.3%.
MS(ESI,pos.ion)m/z:464.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ10.58(br,2H),7.22-7.06(m,6H),5.41(br,2H),5.29 (br.,2H),4.33(m,2H),3.70(s,6H),3.66(m,4H),3.07-3.01(m,4H),2.69-2.67(m,4H), 2.35-1.97(m,10H),1.64(m,16H),0.94-0.88(m,12H)ppm。
Embodiment 2
Synthetic route：
Step 1）The synthesis of compound 2-1
By compound 1-18（0.57g,0.75mmol）, compound 2-1-0（0.34g,1.58mmol）, EDCI（0.30g, 1.58mmol）And HOAT（0.20g,1.50mmol）It is suspended in DCM（4mL）In, 0℃Under, it is slowly dropped into DIPEA（1.05mL, 6.01mmol）, drip and finish, room temperature reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, uses respectively chlorination Ammonium salt solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc (v/v)=1/10）Obtain pale yellow powder 0.42g, yield：55%.
MS(ESI,pos.ion)m/z:506.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,2H),7.35-7.34(m,2H),7.32(m,2H),5.56,5.55 (d,d,1H),5.46,5.44(d,d,1H),5.32-5.28(m,2H),4.40-4.35(m,2H),3.85-3.78(m,2H), 3.69-3.61(m,2H),3.03-3.00(m,4H),2.97-2.94(m,4H),2.30-1.92(m,10H),1.70-1.50(m, 12H),1.45(s,9H),1.41(s,9H),1.40-1.33(m,4H),1.02-0.89(m,12H)ppm。
Embodiment 3
Synthetic route：
Step 1）The synthesis of compound 3-2
At 0 DEG C, by DIPEA（1.95mL,11.8mmol）It is added to compound 3-1（2.45g,10.7mmol）With HATU （4.88g,12.84mmol）THF（30mL）In solution, after isothermal reaction 0.5 hour, compound 3-1-2 is dividedly in some parts （2.22g,11.9mmol）, after adding, room temperature reaction 4.0 hours.After reaction completely, add water（50mL）Reaction is quenched, is removed THF, uses EtOAc（50mL×3）Extraction, merges organic phase, uses saturated common salt water washing, and 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）Dissolving, uses sodium carbonate liquor（50mL×3）Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain product 3.24g, yield：80%.
MS(ESI,pos.ion)m/z:380.5[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 2）The synthesis of compound 3-3
By compound 3-2（4.27g,11.27mmol）, compound 1-6-2（4.29g,16.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.65g,0.8mmol）And KOAc（2.09g,21.3mmol）In being placed in reaction bulb, N2Under protection, DME 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 Filter, filtrate uses respectively water（60mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 2.9g, yield：60%.
MS(ESI,pos.ion)m/z:428.5[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 3）The synthesis of compound 3-4
By compound 3-1（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）, drip and finish, room temperature reaction 2.0 hours.After reaction completely, methyl alcohol is used（4.0mL）Reaction is quenched, THF is removed, it is remaining Thing DCM（50mL）Dissolving, uses respectively water（20mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing posts after concentration Chromatography is purified（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain colorless syrup 1.03g, 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 4）The synthesis of compound 3-6
By compound 3-4（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, finishes, and after isothermal reaction 1.0 hours, room temperature is anti- Answer 1.0 hours.After reaction completely, solids removed by filtration, filtrate is washed with saturated sodium bisulfite solution（30mL×3）, organic phase Use anhydrous Na2SO4It is dried, compound 3-5 is obtained after concentration for colorless syrup.
Compound 3-5 is dissolved in into methanolic ammonia solution（10mL,7M）, after reacting 0.5 hour at 0 DEG C, room temperature reaction 1.0 hours Afterwards, at 0 DEG C, it is slowly dropped into the aqueous solution of glyoxal（1.2mL,40%）, drip and finish, room temperature reaction 24 hours.It is dense after reaction completely Contracting reactant liquor, residue DCM（100mL）After dissolving, water is used respectively（30mL×3）With saturated common salt water washing, anhydrous Na2SO4 It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/MeOH(v/v)=100/1）Faint yellow solid 0.51g is obtained, is produced Rate：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 5）The synthesis of compound 3-7
By compound 3-6（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, solids removed by filtration, filtrate is molten with saturated sodium sulfite Liquid（30mL×3）Washing, anhydrous Na2SO4It is dried, yellow solid 0.9g, yield is obtained after concentration：90%.It is directly used in next step Reaction.
MS(ESI,pos.ion)m/z:504.1[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 6）The synthesis of compound 3-8
By compound 3-7（0.9g,1.8mmol）It is dissolved in ethanol（10mL）In, add sodium sulfite（2.0g,16mmol）With Water（10mL）, 90 DEG C are reacted 30 hours.After reaction completely, solids removed by filtration concentrates filtrate, and residue adds DCM（50mL） After dissolving, water is used respectively（20mL×2）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration （Eluant, eluent：PE/EtOAc(v/v)=6/1）Obtain white solid 0.38g, 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 7）The synthesis of compound 3-9
By compound 1-6（5.0g,15.92mmol）It is dissolved in DCM（50mL）In, at 0 DEG C, add pyridine（6.5mL, 79.62mmol）, after stirring 10 minutes, it is slowly dropped into Tf2O（8.0mL,47.77mmol）, after isothermal reaction 20 minutes, room temperature is anti- Answer 3 hours.After reaction completely, frozen water is instilled（50mL）Reaction, water layer DCM is quenched（60mL×3）Extraction, merges organic phase, Use saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)= 6/1）Obtain pale yellow oily liquid 5.98g.
1H NMR(400MHz,CDCl3):δ7.57(d,1H),6.79(d,1H),3.07(s,2H),2.88(s,2H), 1.75-1.72(m,4H),1.65-1.63(m,4H)ppm。
Step 8）The synthesis of compound 3-10
By compound 3-9（0.21g,0.48mmol）, compound 1-7（0.18g,0.57mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（50mL）After dilute reaction solution, saturation is used Brine It, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain White solid 145.7mg, yield：60%.
1H NMR(400MHz,CDCl3):δ7.19-7.18(dd,dd,1H),6.97,6.95(dd,dd,1H),6.94, 6.92(dd,dd,1H),6.67,6.64(dd,dd,1H),4.81(brs,1H),2.94-2.82(m,8H),1.74-1.38(m, 16H)ppm。
Step 9）The synthesis of compound 3-11
By compound 3-10（3.90g,7.7mmol）, compound 3-3（3.29g,7.7mmol）, Pd (PPh3)4（0.45g, 0.38mmol）And potassium carbonate（2.1g,15.4mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（32mL）And pure water （8.0mL）, 90 DEG C are reacted 5.0 hours.After reaction completely, it is cooled to room temperature, plus EtOAc（250mL）After dilute reaction solution, use respectively Water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/ EtOAc(v/v)=2/1）Obtain faint yellow solid 2.02g, yield：40%.
1H NMR(400MHz,CDCl3):δ7.77,7.75(dd,dd,1H),7.58-7.57(q,1H),7.50,7.48 (dd,dd,1H),7.47,7.45(dd,dd,1H),7.39,7.36(d,d,1H),7.02,6.99(dd,dd,1H),6.67, 6.64(dd,dd,1H),5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.93-2.82(m, 8H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.70-1.49(m,12H),1.42(s, 9H),1.41-1.38(m,4H),0.96-0.93(m,3H)ppm。
Step 10）The synthesis of compound 3-12
By compound 3-11（1.05g,1.59mmol）It is dissolved in DCM（10mL）In, at 0 DEG C, add pyridine（0.65mL, 7.96mmol）, after stirring 10 minutes, it is slowly dropped into Tf2O（0.8mL,4.78mmol）, after isothermal reaction 20 minutes, room temperature reaction 3 hours.After reaction completely, frozen water is instilled（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses Saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/ 1）Obtain pale yellow oily liquid 1.0g, yield：80%.
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57(q,1H), 7.47-7.46(m,2H),7.39,7.37-7.36(d,d,1H),7.21-7.20,7.19-7.18(d,d,1H),6.97-6.96, 6.95-6.94(dd,dd,1H),5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.95-2.90 (m,4H),2.89-2.86(m,4H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.75- 1.45(m,16H),1.41(s,9H),0.96-0.93(m,3H)ppm。
Step 11）The synthesis of compound 3-13
By compound 3-12（1.28g,1.62mmol）, compound 1-6-2（0.42g,1.7mmol）, Pd (dppf) Cl2· CH2Cl2（67mg,0.08mmol）And KOAc（0.4g,4.05mmol）In being placed in reaction bulb, N2Under protection, DMF is injected（10mL）, 90 DEG C are reacted 6.0 hours.After reaction completely, it is cooled to room temperature, plus ethyl acetate（100mL）After dilute reaction solution, diatomite is filtered, Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Wash De- agent：PE/EtOAc(v/v)=1/1）Obtain faint yellow solid 0.62g, yield：50%.
MS(ESI,pos.ion)m/z:768.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(d,d,1H),7.64,7.62(dd,dd,1H), 7.58-7.57(m,2H),7.47,7.45(dd,dd,1H),7.43,7.41(dd,dd,1H),7.39,7.36(d,d,1H), 5.14-5.09(m,1H),3.85-3.78(m,1H),3.14-3.05(m,3H),2.93-2.86(m,6H),2.51-2.42(m, 1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.72-1.44(m,14H),1.41(s,9H),1.32,1.29(q, q,12H),1.28-1.19(m,2H),0.96-0.93(m,3H)ppm。
Step 12）The synthesis of compound 3-14
By compound 3-13（0.44g,0.58mmol）, compound 3-8（0.24g,0.63mmol）, Pd (PPh3)4（35mg, 0.03mmol）And potassium carbonate（0.08g,1.4mmol）In being 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（30mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.28g, yield：55%.
MS(ESI,pos.ion)m/z:446.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57(q,1H),7.56 (s,1H),7.53,7.51-7.50(dd,dd,1H),7.49-7.48,7.46(dd,dd,1H),7.47,7.45(dd,dd,1H), 7.39,7.37(d,d,1H),7.34,7.32(d,d,1H),5.14-5.09(m,1H),5.06-5.01(m,1H),3.85-3.73 (m,2H),3.14-3.00(m,4H),2.97-2.86(m,6H),2.51-2.42(m,1H),2.35-2.18(m,3H),1.86- 1.49(m,14H),1.42(s,9H),1.41(s,9H),1.40-1.34(m,4H),0.96-0.93(m,6H)ppm。
Step 13）The synthesis of compound 3-15
By compound 3-14（0.36g,0.4mmol）It is dissolved in EtOAc（4.0mL）In, the ethyl acetate that hydrogen chloride is added dropwise is molten Liquid（3.0mL,4M）, drip and finish, room temperature reaction 8.0 hours.After reaction completely, concentration of reaction solution, residue adds ethyl acetate （5.0mL）After beating, pale yellow powder shape solid 0.30g, yield are filtrated to get：90%.It is directly used in next step reaction.
MS(ESI,pos.ion)m/z:691.5[M+H]+。
Step 14）The synthesis of compound 3-16
By compound 3-15（0.26g,0.31mmol）, compound 3-15-2（0.15g,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）, drip and finish, room temperature reaction 3 hours.After reaction completely, DCM is added（20mL）Dilute reaction solution, it is molten with ammonium chloride respectively Liquid and saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/MeOH(v/v) =50/1）Obtain white solid 0.15g, yield：45%.
MS(ESI,pos.ion)m/z:543.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.84(s,1H),7.78-7.77,7.76-7.75(d,d,1H),7.58-7.57 (q,1H),7.53,7.51-7.50(dd,dd,1H),7.49-7.48,7.46(dd,dd,1H),7.47,7.45(dd,dd,1H), 7.39,7.37(d,d,1H),7.34,7.32(d,d,1H),5.90,5.88(d,d,1H),5.21,5.19(d,d,1H),5.17- 5.13(m,1H),5.10-5.05(m,1H),4.53-4.41(m,2H),3.94-3.85(m,2H),3.65(s,3H),3.63(s, 3H),3.62-3.55(m,2H),3.04-3.00(m,2H),2.97-2.94(m,2H),2.93-2.90(m,2H),2.89-2.86 (m,2H),2.51-2.41(m,1H),2.35-2.21(m,5H),1.77-1.49(m,28H),1.45-1.34(m,4H),1.28- 1.07(m,6H),0.92-0.89(m,6H)ppm。
Embodiment 4
Synthetic route：
Step 1）The synthesis of compound 4-2
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, -5 DEG C reaction 30 minutes after, add compound 4-1（1.72g, 7.07mmol）, after adding, room temperature reaction 1.0 hours.After reaction completely, frozen water is added（50mL）Reaction is quenched, THF, water is removed Layer uses EtOAc（50mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, Jing posts layer after concentration Analysis is isolated and purified（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain pale yellow oily liquid 1.07g, yield：62.9%.
MS(ESI,pos.ion)m/z:242.1[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）The synthesis of compound 4-3
At 0 DEG C, by chloroiodomethane（6.57g,37.24mmol）It is slowly dropped to diethyl zinc（2.30g,18.60mmol） Toluene（30mL）In solution, drop finishes, isothermal reaction 45 minutes, then is slowly dropped into compound 4-2（1.5g,6.22mmol）First Benzene（15mL）Solution, isothermal reaction 18 hours.After reaction completely, saturated ammonium chloride solution is added（20mL）Reaction, water layer is quenched Use EtOAc（25mL×3）Extraction, merges organic phase, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： 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),3.37-3.29(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）The synthesis of compound 4-4
By compound 4-3（0.69g,2.7mmol）It is dissolved in EtOAc（6.0mL）, add the ethyl acetate solution of hydrogen chloride （5.0mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, colourless oil liquid 0.5g, yield are obtained after concentration of reaction solution： 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）The synthesis of compound 4-5
By compound 4-4（0.53g,2.77mmol）, compound 4-4-2（0.87g,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 Hour.After reaction completely, DCM is added（20mL）Dilute reaction solution, it is anhydrous respectively with ammonium chloride solution and saturated common salt water washing Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/1）White liquid 0.61g is obtained, Yield：70.2%.
MS(ESI,pos.ion)m/z:347.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35-7.27(m,3H),7.19-7.14(m,2H),5.91,5.89(s,s, 1H),5.33-5.30(m,1H),4.66-4.64(m,1H),3.72(s,3H),3.64(s,3H),3.47-3.41(m,1H), 3.31-3.25(m,1H),2.18-2.11(m,1H),1.81-1.74(m,1H),0.49-0.37(m,4H)ppm。
Step 5）The synthesis of compound 4-6
At 0 DEG C, by lithium hydroxide（0.14g,3.2mmol）The aqueous solution（5.0mL）It is slowly dropped into compound 4-5 （0.22g,0.64mmol）THF solution（5.0mL）In, drop finishes, and 40 DEG C are reacted 12 hours.After reaction completely, THF is removed, plus Enter water（30mL）, then use EtOAc（10mL×3）Extraction, collects water phase, uses hydrochloric acid（10%）The pH value of solution is adjusted to into 1, water layer EtOAc is used again（25mL×3）Extraction, merges organic phase, anhydrous Na2SO4It is dried, white solid 0.17g, yield is obtained after concentration： 80%。
MS(ESI,pos.ion)m/z:333.5[M+H]+。
Step 6）The synthesis of compound 4-7
At 0 DEG C, by DIPEA（0.195mL,1.18mmol）It is added to compound 4-6（0.35g,1.07mmol）With HATU （0.49g,1.284mmol）THF（10mL）In solution, after isothermal reaction 0.5 hour, compound 3-1-2 is dividedly in some parts （0.22g,1.19mmol）, after adding, room temperature reaction 4.0 hours.After reaction completely, add water（10mL）Reaction is quenched, is removed THF, uses EtOAc（20mL×3）Extraction, merges organic phase, uses saturated common salt water washing, and anhydrous sodium sulfate drying will after concentration Residue is dissolved in glacial acetic acid（5.0mL）In, 40 DEG C of reactions are overnight.After reaction completely, glacial acetic acid, residue EtOAc are removed （20mL）Dissolving, uses sodium carbonate liquor（10mL×3）Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Wash De- agent：PE/EtOAc(v/v)=1/2）Obtain product 0.33g, yield：65%.
MS(ESI,pos.ion)m/z:483.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.71-7.70(dd,1H),7.35-7.27(m,4H),7.20-7.15(m, 3H),5.91,5.89(s,s,1H),5.46-5.43(m,1H),5.22-5.18(m,1H),3.64(s,3H),3.52-3.46(m, 1H),3.19-3.13(m,1H),2.59-2.52(m,1H),2.27-2.19(m,1H),0.54-0.41(m,4H)ppm。
Step 7）The synthesis of compound 4-8
By compound 4-7（0.24g,0.5mmol）, compound 1-6-2（0.15g,0.6mmol）, Pd (dppf) Cl2· CH2Cl2（20.4mg,0.025mmol）And KOAc（0.12g,1.25mmol）In being placed in reaction bulb, N2Under protection, DMF is added （3.0mL）, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, diatom Soil is filtered, and filtrate uses respectively water（10mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographies point after concentration From purifying（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain buff white solid 0.17g, yield：65%.
MS(ESI,pos.ion)m/z:531.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.84-7.83(q,1H),7.65,7.63(d,d,1H),7.36-7.27(m, 4H),7.19-7.15(m,2H),5.91,5.89(s,s,1H),5.46-5.43(m,1H),5.20-5.16(m,1H),3.64(s, 3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.59-2.52(m,1H),2.27-2.19(m,1H),1.32(q, 6H),1.29(q,6H),0.54-0.41(m,4H)ppm。
Step 8）The synthesis of compound 4-9
By compound 4-8（0.31g,0.58mmol）, compound 3-10（0.29g,0.58mmol）, Pd (PPh3)4（35mg, 0.03mmol）And potassium carbonate（80mg,1.4mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8.0mL）And water （2.0mL）, 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 Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.22g, yield：50%.
MS(ESI,pos.ion)m/z:381.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.78,7.75(dd,dd,1H),7.56-7.55(q,1H),7.51-7.48 (dd,dd,1H),7.47-7.44(m,4H),7.38-7.33(m,2H),7.23-7.19(m,1H),7.02,6.99(dd,dd, 1H),6.66,6.94(dd,dd,1H),6.13,6.11(s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H), 3.64(s,3H),3.52-3.46(m,1H),3.19-3.13(m,1H),2.93-2.82(m,8H),2.59-2.52(m,1H), 2.27-2.19(m,1H),1.70-1.50(m,12H),1.48-1.35(m,4H),0.54-0.41(m,4H)ppm。
Step 9）The synthesis of compound 4-10
By compound 4-9（1.21g,1.59mmol）It is dissolved in DCM（10mL）In, at 0 DEG C, add pyridine（0.65mL, 7.96mmol）, after stirring 10 minutes, it is slowly dropped into Tf2O（0.8mL,4.78mmol）, after isothermal reaction 20 minutes, room temperature reaction 3 hours.After reaction completely, frozen water is instilled（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses Saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/ 1）Obtain pale yellow oily liquid 1.2g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(d,d,1H),7.56-7.55(q,1H), 7.48-7.44(m,5H),7.38-7.33(m,2H),7.23-7.18(m,2H),6.97,6.94(dd,dd,1H),6.13,6.11 (s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H),3.64(s,3H),3.52-3.46(m,1H),3.19- 3.13(m,1H),2.95-2.90(m,4H),2.89-2.86(m,4H),2.59-2.52(m,1H),2.27-2.19(m,1H), 1.74-1.35(m,16H),0.54-0.41(m,4H)ppm。
Step 10）The synthesis of compound 4-11
By compound 4-10（2.23g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （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 Filter.Filtrate uses respectively water（30mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation is pure after concentration Change（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 1.41g, yield：65%.
1H NMR(400MHz,CDCl3):δ7.78-7.77,7.76-7.75(d,d,1H),7.64,7.62(dd,dd,1H), 7.57-7.55(m,2H),7.48-7.44(m,4H),7.43,7.41(dd,dd,1H),7.37-7.33(m,2H),7.23-7.19 (m,1H),6.13,6.11(s,s,1H),5.48,5.46(m,m,1H),5.21-5.17(m,1H),3.64(s,3H),3.52- 3.46(m,1H),3.19-3.13(m,1H),3.08-3.05(m,2H),2.93-2.90(m,4H),2.89-2.86(m,2H), 2.59-2.52(m,1H),2.27-2.19(m,1H),1.72-1.36(m,14H),1.32,1.29(q,q,12H),1.27-1.19 (m,2H),0.54-0.41(m,4H)ppm。
Step 11）The synthesis of compound 4-12
By compound 4-6（1.55g,4.66mmol）It is dissolved in THF（20mL）In, under 0 DEG C of nitrogen protection, by borine（10mL, 1M in THF）Slowly it is added drop-wise in reaction bulb, drop finishes, isothermal reaction 3.0 hours.After reaction completely, methyl alcohol is used（10mL）It is quenched Reaction, Jing column chromatographic isolation and purifications after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain colorless oil 0.96g, yield：65%.
1H NMR(400MHz,CDCl3):δ7.35-7.27(m,3H),7.19-7.14(m,2H),5.91,5.89(s,s, 1H),5.34-5.31(m,1H),4.98(brs,1H),4.41-4.33(m,1H),3.74-3.66(m,2H),3.64(s,3H), 3.13-2.99(m,2H),1.64-1.56(m,1H),1.49-1.41(m,1H),0.48-0.45(m,4H)ppm。
Step 12）The synthesis of compound 4-13
By compound 4-12（1.10g,3.48mmol）It is dissolved in DCM（25mL）In, at 0 DEG C, by Dai Si-Martin（2.07g, 4.88mmol）Oxidant is dividedly in some parts in reaction bulb, after adding, room temperature reaction 2.0 hours.After reaction completely, water is added （20mL）Dilute reaction solution, filters, after filtrate layered, organic layer saturated common salt water washing, and anhydrous sodium sulfate drying, after concentration Jing column chromatographic isolation and purifications（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain colorless oil 0.55g, yield：50%.
1H NMR(400MHz,CDCl3):δ9.63-9.62(m,1H),7.35-7.27(m,3H),7.19-7.14(m,2H), 5.91,5.89(s,s,1H),5.33-5.30(m,1H),4.44-4.41(m,1H),3.64(s,3H),3.50-3.44(m,1H), 3.18-3.12(m,1H),2.42-2.35(m,1H),1.70-1.64(m,1H),0.50-0.38(m,4H)ppm。
Step 13）The synthesis of compound 4-14
By compound 4-13（0.56g,1.76mmol）And ammoniacal liquor（2.0mL）It is dissolved in methyl alcohol（5.0mL）In, at 0 DEG C, by second Dialdehyde（40%,1.0mL）The aqueous solution slowly instill in reaction bulb, drop finish, room temperature reaction is overnight.After reaction completely, concentration reaction Jing column chromatographic isolation and purifications after liquid（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain white solid 0.31g, yield：50%.
MS(ESI,pos.ion)m/z:355.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.48-7.45(m,2H),7.38-7.33(m,2H),7.23-7.19(m,1H), 6.97(s,2H),6.23,6.21(s,s,1H),5.49-5.46(m,1H),5.19-5.14(m,1H),3.62(s,3H),3.61- 3.56(m,1H),3.44-3.38(m,1H),2.24-2.17(m,1H),1.90-1.82(m,1H),0.53-0.40(m,4H) ppm。
Step 14）The synthesis of compound 4-15
By compound 4-14（2.97g,8.4mmol）It is dissolved in DCM（60mL）, at 0 DEG C, by N- N-iodosuccinimides （3.8g,16.8mmol）In being dividedly in some parts reaction bulb, isothermal reaction 1.5 hours.After reaction completely, reactant liquor saturated aqueous common salt Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain white Solid 3.05g, yield：60%.
MS(ESI,pos.ion)m/z:607.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.48-7.45(m,2H),7.38-7.33(m,2H),7.23-7.19(m,1H), 6.23,6.21(s,s,1H),5.49-5.46(m,1H),5.07-5.03(m,1H),3.75-3.69(m,1H),3.62(s,3H), 3.48-3.41(m,1H),2.39-2.31(m,1H),2.06-1.98(m,1H),0.54-0.41(m,4H)ppm。
Step 15）The synthesis of compound 4-16
By compound 4-15（1.98g,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）, use ethyl acetate（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration By column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain white solid 1.25g, yield：70%.
MS(ESI,pos.ion)m/z:481.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.48-7.45(m,2H),7.38-7.33(m,3H),7.23-7.19(m,1H), 6.23,6.21(s,s,1H),5.49-5.46(m,1H),4.85-4.81(m,1H),3.69-3.63(m,1H),3.62(s,3H), 3.46-3.40(m,1H),2.32-2.24(m,1H),2.00-1.92(m,1H),0.53-0.41(m,4H)ppm。
Step 16）The synthesis of compound 4-17
By compound 4-16（0.35g,0.72mmol）, compound 4-11（0.63g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（4.0mL）And water（1.0mL）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, uses respectively water （20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =50/1）Obtain product 0.47g, yield：60%.
MS(ESI,pos.ion)m/z:549.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.78,7.75(d,d,1H),7.56-7.55(q,1H),7.54(s,1H), 7.53,7.51(d,d,1H),7.49-7.44(m,5H),7.37-7.27(m,6H),7.23-7.15(m,3H),6.13,6.11 (s,s,1H),5.91,5.89(s,s,1H),5.49-5.43(m,2H),5.21-5.17(m,1H),5.06-5.02(m,1H), 3.64(s,6H),3.61-3.55(m,1H),3.52-3.46(m,1H),3.40-3.34(m,1H),3.19-3.13(m,1H), 3.03-3.00(m,2H),2.97-2.94(m,2H),2.93-2.90(m,2H),2.89-2.86(m,2H),2.59-2.52(m, 1H),2.28-2.19(m,2H),1.96-1.88(m,1H),1.70-1.49(m,12H),1.46-1.34(m,4H),0.54- 0.41(m,8H)ppm。
Embodiment 5
Synthetic route：
Step 1）The synthesis of compound 5-1
By 1,2-dimethoxy benzene（40.0g,0.29mol）It is added to n-hexane（100mL）And tetramethylethylenediamine（40mL）It is molten In liquid.Under room temperature, n-BuLi is slowly dropped into（1.6M n-hexanes, 200mL, 0.32mol）, dripping and finish, room temperature reaction drops after 28 hours Temperature is slowly dropped into Me to _ 78 DEG C3SiCl（45mL）, drip and finish, slowly it is raised to room temperature reaction.After reaction completely, water is added （100mL）Reaction is quenched, n-hexane is used（100mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：hexane/DCM(v/v)=10/1）Obtain colorless oil 51.8g, yield： 85%。
1H NMR(400MHz,CDCl3):δ7.06-7.02(m,1H),6.97-6.93(m,2H),3.86(s,6H),0.28 (s,9H)ppm。
Step 2）The synthesis of compound 5-2
By compound 5-1（69.33g,0.33mol）It is dissolved in tetramethylethylenediamine（60mL）In, at 0 DEG C, it is slowly dropped into n- BuLi（1.6M n-hexanes, 250mL, 0.40mol）, dripping and finish, room temperature reaction is cooled to _ 78 DEG C, by Me after 25 hours3SiCl （60mL）In being slowly dropped into reaction system, drop finishes, and reaction is warmed to room temperature at leisure.After reaction completely, frozen water is added（150mL）Quench Go out reaction, use n-hexane（100mL×3）Extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, concentration By column chromatographic isolation and purification（Eluant, eluent：hexane/DCM(v/v)=10/1）Obtain colorless oil 82.86g, yield：89%.
1H NMR(400MHz,CDCl3):δ7.11(s,2H),3.83(s,6H),0.29(s,18H)ppm。
Step 3）The synthesis of compound 5-3
By compound 5-2（19.2g,68.1mmol）It is dissolved in DCM（100mL）In, at 0 DEG C, it is slowly dropped into ICl（23.1g, 0.14mol）DCM（100mL）Solution, drop finishes, room temperature reaction 30 minutes.After reaction completely, Na is used2S2O3Solution（100mL）Quench Go out reaction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： hexane/DCM(v/v)=10/1）Obtain faint yellow solid 21.5g, yield：81%.
1H NMR(400MHz,CDCl3):δ7.24(s,2H),3.87(s,6H)ppm。
Step 4）The synthesis of compound 5-4
By compound 5-3（1.80g,4.62mmol）It is dissolved in DCM（20mL）In, at -78 DEG C, it is slowly dropped into BBr3 （2.0mL,21.2mmol）, drop finishes, room temperature reaction 1.0 hours after isothermal reaction 10 minutes.After reaction completely, reactant liquor is poured into Frozen water（50mL）In, use DCM（30mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, after concentration Jing column chromatographic isolation and purifications（Eluant, eluent：DCM）Obtain white solid 1.50g, yield：90%.
1H NMR(400MHz,CDCl3):δ7.00(s,2H),5.66(s,2H)ppm。
Step 5）The synthesis of compound 5-5
By compound 5-4（0.36g,1.0mmol）, cyclopentanone（0.25g,3.0mmol）And p-methyl benzenesulfonic acid（19mg, 0.1mmol）It is dissolved in n-hexane（20mL）In, flow back 5.0 hours.After reaction completely, reactant liquor is poured into water（25mL）In, water layer Use EtOAc（20mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：hexane/DCM(v/v)=1/1）Obtain beige solid 0.20g, yield：46%.
1H NMR(400MHz,CDCl3):δ6.84(s,1H),2.17(m,4H),1.87(m,4H)ppm。
Step 6）The synthesis of compound 5-6
By compound 1-7（0.15g,0.48mmol）, compound 5-5（0.20g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain white solid Body 0.14g, yield：60%.
MS(ESI,pos.ion)m/z:489.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.75,7.73(s,s,1H),7.00,6.98(s,s,1H),6.88,6.86 (dd,dd,1H),6.70,6.68(dd,dd,1H),4.81(brs,1H),2.89-2.83(m,4H),2.12-1.77(m,8H), 1.71-1.38(m,8H)ppm。
Step 7）The synthesis of compound 5-8
At 0 DEG C, by DMAP（0.55g,4.5mmol）It is added to compound 5-7（8.43g,45.06mmol）MeCN （30mL）In solution, then by di-tert-butyl dicarbonate（10.82g,49.56mmol）In dropping to reactant liquor, isothermal reaction 30 minutes, Room temperature reaction 2.0 hours afterwards.After reaction completely, Jing column chromatography for separation after concentration of reaction solution（Eluant, eluent：PE/EtOAc(v/v)=2/ 1）Obtain colourless liquid 5.9g, yield：45.6%.
MS(ESI,pos.ion)m/z:188.2[M-Boc]+；
1H NMR(400MHz,CDCl3):δ4.71-4.67(m,1H),4.02-4.01(m,4H),3.77-3.76,3.74- 3.73(m,m,1H),3.70(s,3H),3.52-3.51,3.49-3.48(m,m,1H),2.77-2.75,2.73-2.71(m,m, 1H),2.35-2.28(m,1H),1.43(s,9H)ppm。
Step 8）The synthesis of compound 5-9
By compound 5-8（5.40g,18.86mmol）It is dissolved in THF（40mL）In, at 0 DEG C, by lithium hydroxide aqueous solution （1.5g,20mL）In addition system, 40 DEG C are reacted 12 hours.After reaction completely, THF is removed, add water（30mL）, use EtOAc （25mL×3）Extraction, water layer watery hydrochloric acid（1M）Adjust pH value to 2, use EtOAc（50mL×3）Extraction, organic phase is with anhydrous Na2SO4It is dried, white solid 4.84g, yield is obtained after concentration：94%.
MS(ESI,pos.ion)m/z:274.5[M+H]+。
Step 9）The synthesis of compound 5-10
At 0 DEG C, by DIPEA（1.95mL,11.8mmol）It is added to compound 5-9（2.92g,10.7mmol）With HATU （4.88g,12.84mmol）THF（30mL）In solution, after isothermal reaction 0.5 hour, compound 3-1-2 is dividedly in some parts （2.22g,11.9mmol）, after adding, room temperature reaction 4.0 hours.After reaction completely, add water（50mL）Reaction is quenched, is removed THF, uses EtOAc（50mL×3）Extraction, merges organic phase, uses saturated common salt water washing, and 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）Dissolving, uses sodium carbonate liquor（50mL×3）Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain product 3.62g, yield：80%.
MS(ESI,pos.ion)m/z:424.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.71-7.70(dd,1H),7.33,7.30(d,d,1H),7.20,7.17(d, d,1H),5.14-5.10(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m, m,1H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),1.53(s,9H)ppm。
Step 10）The synthesis of compound 5-11
By compound 5-10（4.77g,11.27mmol）, compound 1-6-2（4.29g,16.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.65g,0.8mmol）And KOAc（2.09g,21.3mmol）In being 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（250mL）Dilute reaction solution, diatomite Filter, filtrate uses respectively water（100mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 3.18g, yield：60%.
MS(ESI,pos.ion)m/z:472.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.84-7.83(q,1H),7.67,7.65(d,d,1H),7.36,7.34(d,d, 1H),5.13-5.09(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m, 1H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),1.53(s,9H),1.32,1.29(q,q,12H) ppm。
Step 11）The synthesis of compound 5-12
By compound 5-11（0.27g,0.58mmol）, compound 5-6（0.28g,0.58mmol）, Pd (PPh3)4（35mg, 0.03mmol）And potassium carbonate（80mg,1.4mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8.0mL）And water （2.0mL）, 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 Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=100/1）Obtain faint yellow solid 0.20g, yield：50%.
MS(ESI,pos.ion)m/z:706.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.65-7.64(m,1H),7.51-7.48(m,2H),7.47,7.44(s,s, 1H),7.11,7.09(s,s,1H),6.92,6.90(dd,dd,1H),6.70,6.88(dd,dd,1H),5.22-5.18(m, 1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66,3.64-3.63(m,m,1H),2.89-2.83(m, 4H),2.82-2.79,2.78-2.76(m,m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m, 6H),1.70-1.54(m,6H),1.53(s,9H),1.49-1.38(m,2H)ppm。
Step 12）The synthesis of compound 5-13
By compound 5-12（1.13g,1.6mmol）It is dissolved in DCM（50mL）In, at 0 DEG C, add pyridine（0.65mL, 8.0mmol）, after stirring 10 minutes, it is slowly dropped into Tf2O（0.8mL,4.78mmol）, after isothermal reaction 20 minutes, room temperature reaction 3 Hour.After reaction completely, frozen water is instilled（50mL）Reaction, water layer DCM is quenched（60mL×3）Extraction, merges organic phase, uses full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1） Obtain pale yellow oily liquid 1.20g, yield：90%.
1H NMR(400MHz,CDCl3):δ7.65-7.64(m,1H),7.51-7.46(m,2H),7.41,7.39(s,s, 1H),7.13-7.12,7.10(dd,dd,1H),7.11,7.09(s,s,1H),6.89-6.88,6.87-6.86(dd,dd,1H), 5.22-5.18(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),2.93-2.88(m,4H),2.82-2.79, 2.78-2.76(m,m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m,4H),1.73-1.54 (m,6H),1.53(s,9H),1.51-1.42(m,2H)ppm。
Step 13）The synthesis of compound 5-14
By compound 5-13（2.09g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 1.22g, yield：60%.
1H NMR(400MHz,CDCl3):δ7.64-7.62(m,2H),7.52-7.46(m,3H),7.25,7.23(dd,dd, 1H),7.11,7.09(s,s,1H),5.22-5.18(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68- 3.66,3.64-3.63(m,m,1H),3.07-3.04(m,2H),2.88-2.85(m,2H),2.82-2.79,2.78-2.76(m, m,1H),2.26-2.19(m,1H),2.14-2.04(m,2H),1.98-1.74(m,6H),1.72-1.54(m,4H),1.53(s, 9H),1.51-1.41(m,4H),1.32,1.29(q,q,12H)ppm。
Step 14）The synthesis of compound 5-15
By compound 5-14（0.59g,0.72mmol）, compound 1-16（0.26g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is added（40mL）Dilute reaction solution, uses respectively water（30mL×3）With it is full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v)=100/1）Produced Thing 0.40g, yield：60%.
MS(ESI,pos.ion)m/z:463.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.65-7.64(m,1H),7.51,7.49(d,d,1H), 7.48,7.47(d,d,1H),7.46,7.43(s,s,1H),7.38,7.36(dd,dd,1H),7.13-7.09(m,2H),5.22- 5.18(m,1H),5.14-5.09(m,1H),3.96-3.94(m,4H),3.91-3.89(m,1H),3.68-3.66(m,1H), 3.64-3.58(m,1H),3.31-3.24(m,1H),3.10-3.06(m,2H),2.92-2.88(m,2H),2.82-2.79, 2.78-2.76(m,m,1H),2.47-2.38(m,1H),2.28-2.17(m,2H),2.14-1.74(m,10H),1.70-1.55 (m,8H),1.53(s,9H),1.41(s,9H)ppm。
Step 15）The synthesis of compound 5-16
By compound 5-15（0.37g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 0.33g, yield：95%.
MS(ESI,pos.ion)m/z:725.5[M+H]+。
Step 16）The synthesis of compound 5-17
By compound 5-16（70mg,0.08mmol）, compound 4-4-2（35.1mg,0.17mmol）, EDCI（32.2mg, 0.17mmol）And HOAT（21.8mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA（0.10mL, 0.64mmol）, drip and finish, room temperature reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, uses respectively chlorination Ammonium salt solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/MeOH (v/v)=60/1）Obtain white solid 66.4mg, yield：75%.
MS(ESI,pos.ion)m/z:554.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.65-7.64(m,1H),7.51,7.43(m,5H),7.38- 7.27(m,6H),7.23-7.15(m,3H),7.13-7.09(m,2H),6.13-6.11(s,s,1H),5.91-5.89(s,s, 1H),5.42-5.32(m,3H),5.25-5.20(m,1H),4.03-4.01,3.99-3.98(m,m,1H),3.97-3.96(m, 4H),3.91-3.85(m,1H),3.76-3.67(m,1H),3.64(s,6H),3.10-3.06(m,2H),2.92-2.88(m, 2H),2.80-2.77,2.76-2.74(m,m,1H),2.35-1.74(m,14H),1.70-1.50(m,6H),1.45-1.34(m, 2H)ppm。
Embodiment 6
Synthetic route：
Step 1）The synthesis of compound 6-1
At 0 DEG C, by triethylamine（5.4mL）It is slowly dropped to formic acid（3.7mL）In, sequentially add 2,5- dimethoxy benzenes Formaldehyde（2.0g,12mmol）With Maxwell acid（1.73g,12mmol）Afterwards, 100 DEG C are reacted 2.0 hours.After reaction completely, ice is added Water（20mL）Reaction is quenched, then uses hydrochloric acid（2M）The pH value of solution is adjusted to into 1, water layer EtOAc（25mL×3）Extraction, it is organic Mutually use anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain white solid Body 2.1g, yield：83%.
MS(ESI,pos.ion)m/z:211.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.78-6.70(m,6H),3.78(s,3H),3.75(s,3H),2.91(t,2H, J=7.8Hz),2.65(t,2H,J=7.8Hz)ppm。
Step 2）The synthesis of compound 6-2
By compound 6-1（4.68g,22.3mmol）With PPA（50.87g,24.8mL）In being placed in reaction bulb, 80 DEG C of reactions 4.0 hour.After reaction completely, frozen water is added（250mL）, aqueous layer with ethyl acetate（100mL×5）Extraction, organic phase is used respectively Sodium bicarbonate solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/ EtOAc(v/v)=3/1）Obtain light yellow solid 3.0g, yield：70%.
MS(ESI,pos.ion)m/z:193.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.98(d,1H,J=8.7Hz),6.73(d,1H,J=8.7Hz),3.90(s, 3H),3.85(s,3H),2.97-3.00(m,2H),2.65-2.68(m,2H)ppm。
Step 3）The synthesis of compound 6-3
By compound 6-2（1.31g,6.82mmol）, compound 6-2-2（1.64g,7.15mmol）And TEBAC （0.3g,1.36mmol）It is suspended in DMSO（30mL）In, at 0 DEG C, it is slowly dropped into the NaOH aqueous solution（50%,2mL）, drip and finish, 50 DEG C Reaction 2.0 hours.After reaction completely, water is added（50mL）, water layer EtOAc（50mL×3）Extraction, organic phase saturated common salt Water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain Huang Color grease 1.07g, yield：60%.
MS(ESI,pos.ion)m/z:263.5[M+H]+；
1H NMR(400MHz,CDCl3):δ6.84,6.82(m,m,1H),6.77,6.75(m,m,1H),3.97-3.90(m, 2H),3.84(d,3H),3.81(d,3H),3.70-3.62(m,2H),2.83-2.81(m,2H),2.01-1.93(m,2H), 1.80-1.71(m,2H)ppm。
Step 4）The synthesis of compound 6-4
By compound 6-3（1.0g,3.8mmol）And triethyl silicane（3.7mL,23mmol）In being mixed in reaction bulb, 0 DEG C Under, it is slowly dropped into trifluoroacetic acid（8.0mL）, 40 DEG C are reacted 7 hours.After reaction completely, concentration of reaction solution, residue EtOAc （50mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain pale yellow oily liquid 0.80g, yield：85%.
MS(ESI,pos.ion)m/z:249.5[M+H]+；
1H NMR(400MHz,CDCl3):δ6.67-6.66(m,2H),3.77(d,6H),3.71-3.66(m,4H),2.77- 2.74(m,4H),1.76-1.70(m,4H)ppm。
Step 5）The synthesis of compound 6-5
By compound 6-4（0.69g,2.77mmol）It is dissolved in DCM（20mL）In, at -78 DEG C, it is slowly dropped into BBr3 （0.36mL,3.88mmol）, drop finishes, after isothermal reaction 10 minutes, room temperature reaction 1.0 hours.After reaction completely, frozen water is used （20mL）Reaction is quenched, DCM is used（25mL×3）Extraction, organic phase saturated common salt water washing, anhydrous Na2SO4It is dried, after concentration Jing column chromatographic isolation and purifications（Eluant, eluent：PE/EtOAc(v/v)=12/1）Obtain 0.61g colourless liquids, yield：100%.
MS(ESI,pos.ion)m/z:221.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.45(m,2H),4.97(brs,2H),3.74-3.70(m,4H),2.75- 2.72(m,4H),1.79-1.72(m,4H)ppm。
Step 6）The synthesis of compound 6-6
By compound 6-5（1.70g,7.7mmol）It is dissolved in DCM（50mL）In, N2Protection, at 0 DEG C, adds pyridine （3.1mL,38.6mmol）, after stirring 10 minutes, then it is slowly dropped into trifluoromethanesulfanhydride anhydride（3.9mL,23.1mmol）, after dripping off, Room temperature reaction 1.0 hours.After reaction completely, frozen water is used（50mL）Reaction is quenched, DCM is used（60mL×3）Extraction, merges organic Phase, saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)= 8/1）Obtain pale yellow oily liquid 3.17g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.28(m,2H),3.71-3.66(m,4H),2.78-2.76(m,4H),1.90- 1.84(m,4H)ppm。
Step 7）The synthesis of compound 6-7
By compound 1-7（0.15g,0.48mmol）, compound 6-6（0.23g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 175mg, yield：65%.1H NMR(400MHz,CDCl3):δ7.21-7.19(dd,dd,1H),6.98,6.95(dd,dd,1H), 6.94,6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),3.70-3.65(m,4H),2.92- 2.86(m,4H),2.85-2.82(m,2H),2.75-2.72(m,2H),1.85-1.79(m,4H),1.70-1.50(m,6H), 1.49-1.38(m,2H)ppm。
Step 8）The synthesis of compound 6-9
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 it is slowly added dropwise glyoxylic acid ethyl ester（1mL,10.1mmol）Afterwards, room temperature reaction 1.0 hours.After reaction completely, Filter, after filtrate concentration yellow liquid 1.9g, yield are obtained：91.8%.Need not be further purified, be directly used in next step reaction.
Step 9）The synthesis of compound 6-10
By TFA（0.75mL,10.1mmol）It is added to compound 6-9（2.0g,9.7mmol）DMF（15mL）In solution, After stirring 10 minutes, 1, the 3- cyclopentadiene of new steaming is sequentially added（1.29g,19.5mmol）Drip with two, after adding, room temperature Reaction 12 hours.After reaction completely, DMF is removed, residue adds NaHCO3Solution（10%,20mL）, use Na2CO3By solution PH value is adjusted to 8, then uses petroleum ether（25mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dried, it is dense Jing column chromatographic isolation and purifications after contracting（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain light yellow liquid 2.38g, yield： 90.0%。
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 10）The synthesis of compound 6-11
By Pd/C（0.2g）It is added to compound 6-10（2.0g,7.37mmol）Ethanol（60mL）In solution, at 20 Atmospheric pressure H2Under atmosphere, room temperature reaction 24 hours.After reaction completely, Pd/C is filtered to remove, after filtrate concentration yellow liquid is obtained 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 11）The synthesis of compound 6-12
By compound 6-11（1.69g,10mmol）It is dissolved in MeOH（20mL）In, at 0 DEG C, it is respectively dropped into Et3N（1.67mL, 12mmol）And Boc2O（2.41mL,10.5mmol）, dripping and finish, room temperature reaction is overnight.After reaction completely, methyl alcohol, residue are removed Use DCM（50mL）After dissolving, water is used respectively（20mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, obtains after concentration Colorless syrup 2.37g, yield：88%.
Step 12）The synthesis of compound 6-13
At 0 DEG C, by a hydronium(ion) lithia（0.48g,11.35mmol）The aqueous solution（10mL）It is slowly dropped to compound 6-12（0.61g,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（50mL）, water layer EtOAc（25mL×3）Washing, after point liquid, water mutually uses hydrochloric acid（10%）Adjust pH value to 1, use EtOAc（25mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dried, white is obtained after concentration Solid 0.44g, yield：80%.
MS(ESI,pos.ion)m/z:242.3[M+H]+。
Step 13）The synthesis of compound 6-14
By compound 6-13（1.34g,5.57mmol）It is dissolved in THF（20mL）In, at 0 DEG C, it is slowly dropped into borine（8.3mL, 1M in THF）, drip and finish, room temperature reaction 2.0 hours.After reaction completely, methyl alcohol is used（4.0mL）Reaction is quenched, THF is removed, it is remaining Thing DCM（50mL）Dissolving, uses respectively water（20mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, obtains after concentration Colorless syrup 1.01g, yield：80%.
MS(ESI,pos.ion)m/z:228.3[M+H]+。
Step 14）The synthesis of compound 6-16
By compound 6-14（1.19g,5.24mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, add TCCA（1.22g, 5.24mmol）Afterwards, it is slowly dropped into the DCM solution of TEMPO（82mg,0.52mmol,3mL）, drop finishes, after isothermal reaction 1.0 hours, Room temperature reaction 1.0 hours.After reaction completely, filter, filtrate saturated sodium bisulfite solution（20mL×3）Washing, anhydrous Na2SO4 It is dried, residue is dissolved in into methanolic ammonia solution after concentration（7.0mL,7M）.After said mixture is reacted 0.5 hour in 0 DEG C, room Temperature reaction 1.0 hours.After above-mentioned system is cooled to again into 0 DEG C, glyoxal water solution is slowly added dropwise（1.1mL,40%）, drip and finish, Room temperature reaction 24 hours.After reaction completely, concentration of reaction solution, residue adds DCM（60mL）Dissolving, uses respectively water（20mL× 3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)= 1/1）Obtain faint yellow solid 0.59g, yield：50%.
MS(ESI,pos.ion)m/z:264.3[M+H]+；
1H NMR(400MHz,CDCl3):δ6.99(s,2H),4.88-4.85(m,1H),4.49-4.44(m,1H),2.57- 2.53(m,1H),2.04-1.96(m,1H),1.89-1.84(m,1H),1.74-1.62(m,2H),1.59-1.46(m,2H), 1.44(s,9H)ppm。
Step 15）The synthesis of compound 6-17
By compound 6-16（0.65g,2.47mmol）It is dissolved in DCM（8.0mL）In, at 0 DEG C, it is slowly added to NIS（1.23g, 5.43mmol）, after adding, isothermal reaction 2.0 hours.After reaction completely, DCM is added（30mL）Dilute reaction solution, filters, filtrate Use saturated sodium bisulfite solution（20mL×3）Washing, anhydrous Na2SO4It is dried, yellow solid 1.27g is obtained after concentration, directly uses In next step reaction.
MS(ESI,pos.ion)m/z:516.3[M+H]+；
1H NMR(400MHz,CDCl3):δ5.33-5.30(m,1H),4.39-4.35(m,1H),2.76-2.72(m,1H), 2.04-1.92(m,2H),1.83-1.71(m,2H),1.61-1.51(m,2H),1.44(s,9H)ppm。
Step 16）The synthesis of compound 6-18
By compound 6-17（1.12g,2.12mmol）It is dissolved in ethanol（6.0mL）And water（6.0mL）In, add sodium sulfite （2.14g,17mmol）, 90 DEG C are reacted 30 hours.After reaction completely, filter, after filtrate concentration, residue adds DCM（80mL） Dissolving, uses respectively water（20mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration （Eluant, eluent：PE/EtOAc(v/v)=1/1）Obtain white solid 0.58g, yield：70%.
MS(ESI,pos.ion)m/z:390.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.36(s,1H),4.81-4.78(m,1H),4.47-4.43(m,1H),2.65- 2.61(m,1H),2.04-1.96(m,1H),1.93-1.88(m,1H),1.79-1.67(m,2H),1.59-1.48(m,2H), 1.44(s,9H)ppm。
Step 17）The synthesis of compound 6-19
By compound 6-18（0.55g,1.4mmol）, compound 6-7（0.73g,1.4mmol）, four triphenyl phosphorus palladiums （0.16g,0.14mmol）And potassium carbonate（0.58g,4.2mmol）It is suspended in DME and H2O（v/v=3/1）Mixed solvent（16mL） In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, EtOAc is added（40mL）Dilute reaction solution, uses saturated common salt Water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain white Color solid 0.35g, yield：40%.
MS(ESI,pos.ion)m/z:636.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.52(brs,2H),7.49,7.46(dd,dd,1H), 7.37,7.35(dd,dd,1H),7.02,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),4.85-4.81(m,1H), 4.50-4.46(m,1H),3.70-3.65(m,4H),2.98-2.89(m,6H),2.85-2.82(m,2H),2.54-2.50(m, 1H),2.04-1.96(m,1H),1.88-1.79(m,5H),1.73-1.41(m,12H),1.40(s,9H)ppm。
Step 18）The synthesis of compound 6-20
Just compound 6-19（3.17g,5.0mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, instill pyridine（2.4mL, 30mmol）, after stirring 10 minutes, instill trifluoromethanesulfanhydride anhydride（3.37mL,20mmol）, drop finishes, after isothermal reaction 20 minutes, room Temperature reaction 1.0 hours.After reaction completely, frozen water is added（25mL）Reaction is quenched, DCM is used（30mL×3）Extraction, merges organic Phase, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain colourless liquid 3.26g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.49,7.47(dd,dd,1H),7.39,7.37(dd,dd, 1H),7.20,7.18(dd,dd,1H),6.96,6.94(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H), 3.70-3.65(m,4H),2.98-2.91(m,6H),2.89-2.86(m,2H),2.54-2.50(m,1H),2.04-1.96(m, 1H),1.88-1.79(m,5H),1.74-1.43(m,12H),1.40(s,9H)ppm。
Step 19）The synthesis of compound 6-21
By compound 6-20（1.92g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 1.12g, yield：60%.
1H NMR(400MHz,CDCl3):δ7.64,7.62(dd,dd,1H),7.56(s,1H),7.54,7.52(dd,dd, 1H),7.48,7.46(dd,dd,1H),7.43,7.41(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H), 3.70-3.65(m,4H),3.08-3.05(m,2H),2.98-2.93(m,4H),2.89-2.86(m,2H),2.54-2.50(m, 1H),2.04-1.96(m,1H),1.88-1.79(m,5H),1.73-1.43(m,10H),1.40(s,9H),1.32,1.29(q, q,12H),1.28-1.19(m,2H)ppm。
Step 20）The synthesis of compound 6-22
By compound 6-21（0.54g,0.72mmol）, compound 1-16（0.26g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =100/1）Obtain product 0.37g, yield：60%.
MS(ESI,pos.ion)m/z:428.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.56(s,1H),7.49,7.47(dd,dd,1H),7.40, 7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),5.15-5.08(m,1H),4.85- 4.81(m,1H),4.50-4.46(m,1H),3.70-3.65(m,4H),3.64-3.58(m,1H),3.31-3.24(m,1H), 3.03-3.00(m,4H),2.98-2.93(m,4H),2.54-2.50(m,1H),2.47-2.38(m,1H),2.29-2.17(m, 1H),2.10-1.96(m,3H),1.88-1.79(m,5H),1.73-1.43(m,12H),1.41(s,9H),1.40(s,9H) ppm。
Step 21）The synthesis of compound 6-23
By compound 6-22（0.34g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 0.30g, yield：95%.
MS(ESI,pos.ion)m/z:655.5[M+H]+；
Step 22）The synthesis of compound 6-24
By compound 6-23（64mg,0.08mmol）, compound 1-18-2（29.4mg,0.17mmol）, EDCI （32.2mg,0.17mmol）And HOAT（21.8mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA （0.10mL,0.64mmol）, drip and finish, room temperature reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, point Not Yong ammonium chloride solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=60/1）Obtain white solid 38.74mg, yield：50%.
MS(ESI,pos.ion)m/z:485.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.57(s,1H),7.49,7.47(dd,dd,1H),7.40, 7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),6.08,6.05(d,d,1H), 5.32-5.28(m,2H),5.01-4.97(m,1H),4.80-4.75(m,1H),4.41-4.36(m,1H),4.21-4.17(m, 1H),3.85-3.78(m,1H),3.69-3.66(m,5H),3.65(s,3H),3.63(s,3H),3.04-3.00(m,4H), 2.98-2.93(m,4H),2.50-2.46(m,1H),2.30-1.92(m,7H),1.85-1.78(m,5H),1.70-1.49(m, 9H),1.47-1.34(m,3H),1.02-0.89(m,12H)ppm。
Embodiment 7
Synthetic route：
Step 1）The synthesis of compound 7-1
By compound 6-2（2.75g,14.34mmol）With compound 7-0（5.23g,21.51mmol）It is dissolved in DMF（15mL） In, add NaH under 0 DEG C of nitrogen protection（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 frozen water（100mL）Reaction, aqueous layer with ethyl acetate is quenched（100mL×3）Extraction, organic phase is used respectively Water and saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v) =8/1）Obtain product 0.79g, yield：20%.
MS(ESI,pos.ion)m/z:276.5[M+H]+；
1H NMR(400MHz,CDCl3):δ6.84,6.82(m,m,1H),6.77,6.75(m,m,1H),3.84(s,3H), 3.81(s,3H),2.81-2.79(m,2H),2.73-2.65(m,2H),2.51-2.39(m,2H),2.35-2.34(m,3H), 1.84-1.74(m,4H)ppm。
Step 2）The synthesis of compound 7-2
By compound 7-1（1.05g,3.8mmol）And triethyl silicane（3.7mL,23mmol）In being mixed in reaction bulb, 0 ℃N2Under protection, trifluoroacetic acid is slowly injected into（8.0mL）, 40 DEG C are reacted 7 hours.After reaction completely, trifluoroacetic acid is removed, it is remaining Thing EtOAc（50mL）Dissolving, respectively with sodium carbonate liquor and saturated common salt water washing, anhydrous sodium sulfate drying, Jing after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain pale yellow oily liquid 0.84g, yield：85%.
MS(ESI,pos.ion)m/z:262.5[M+H]+；
1H NMR(400MHz,CDCl3):δ6.62-6.61(m,2H),3.77(s,6H),2.77-2.69(m,6H),2.56- 2.45(m,2H),2.30-2.29(m,3H),1.89-1.79(m,4H)ppm。
Step 3）The synthesis of compound 7-3
By compound 7-2（1.12g,4.3mmol）It is dissolved in glacial acetic acid（40mL）In, add hydrobromic acid（9.6mL, 85mmol）, after adding, flow back 12 hours.After reaction completely, saturated sodium bicarbonate solution is added（50mL）Reaction, water layer is quenched Use ethyl acetate（50mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, Jing posts layer after concentration Analysis is isolated and purified（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain white solid 0.45g, yield：45%.
1H NMR(400MHz,CDCl3):δ6.45(m,2H),4.97(brs,2H),2.81-2.69(m,6H),2.60- 2.48(m,2H),2.30-2.29(m,3H),1.91-1.81(m,4H)ppm。
Step 4）The synthesis of compound 7-4
By compound 7-3（0.35g,1.5mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, add trifluoromethanesulfanhydride anhydride （1.2mL,7.1mmol）, after stirring 10 minutes, it is slowly dropped into triethylamine（2.4mL,17.27mmol）, room temperature reaction 2.0 hours. After reaction completely, frozen water is added（20mL）Reaction, aqueous layer with ethyl acetate is quenched（30mL×3）Extraction.Merge organic phase, use full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1） Obtain product 0.56g, yield：75%.
1H NMR(400MHz,CDCl3):δ7.28(m,2H),2.79-2.69(m,6H),2.56-2.44(m,2H),2.30- 2.29(m,3H),2.04-1.92(m,4H)ppm。
Step 5）The synthesis of compound 7-5
By compound 1-7（0.15g,0.48mmol）, compound 7-4（0.24g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 128mg, yield：50%.1H NMR(400MHz,CDCl3):δ7.21,7.19(dd,dd,1H),6.98,6.95(dd,dd,1H), 6.94,6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),2.92-2.89(m,2H),2.88- 2.82(m,4H),2.77-2.69(m,4H),2.56-2.44(m,2H),2.30-2.29(m,3H),1.98-1.88(m,4H), 1.71-1.50(m,6H),1.49-1.38(m,2H)ppm。
Step 6）The synthesis of compound 7-6
By compound 6-18（0.55g,1.4mmol）, compound 7-5（0.75g,1.4mmol）, four triphenyl phosphorus palladiums （0.16g,0.14mmol）And potassium carbonate（0.58g,4.2mmol）It is suspended in DME and H2O（v/v=3/1）Mixed solvent（16mL） In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, it is warm to be cooled to, and adds EtOAc（40mL）Diluting reaction Liquid, uses saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/ v)=1/3）Obtain white solid 0.45g, yield：50%.
MS(ESI,pos.ion)m/z:649.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.52(brs,2H),7.38,7.35(dd,dd,1H), 7.14,7.11(dd,dd,1H),7.01,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),4.85-4.81(m,1H), 4.50-4.46(m,1H),2.94-2.87(m,4H),2.85-2.82(m,4H),2.76-2.68(m,2H),2.55-2.43(m, 3H),2.30-2.29(m,3H),2.04-1.83(m,7H),1.73-1.41(m,11H),1.40(s,9H)ppm。
Step 7）The synthesis of compound 7-7
Just compound 7-6（0.32g,0.5mmol）It is dissolved in DCM（5mL）In, at 0 DEG C, instill pyridine（0.24mL, 3mmol）, after stirring 10 minutes, instill trifluoromethanesulfanhydride anhydride（0.34mL,2mmol）, drip and finish, room temperature reaction 1.0 hours.Reaction After completely, frozen water is added（10mL）Reaction is quenched, DCM is used（20mL×3）Extraction, merges organic phase, anhydrous Na2SO4It is dried, it is dense Jing column chromatographic isolation and purifications after contracting（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain colourless liquid 0.31g, yield：80%.
1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.39,7.37(dd,dd,1H),7.20,7.18(dd,dd, 1H),7.14,7.11(dd,dd,1H),6.96,6.94(dd,dd,1H),4.85-4.81(m,1H),4.50-4.46(m,1H), 2.95-2.86(m,8H),2.76-2.68(m,2H),2.55-2.43(m,3H),2.30-2.29(m,3H),2.04-1.83(m, 7H),1.74-1.43(m,11H),1.40(s,9H)ppm。
Step 8）The synthesis of compound 7-8
By compound 7-7（1.95g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.85g, yield：45%.
1H NMR(400MHz,CDCl3):δ7.64,7.62(dd,dd,1H),7.56(s,1H),7.43,7.41(dd,dd, 1H),7.16-7.15,7.13,7.11(dd,m,dd,2H),4.85-4.81(m,1H),4.50-4.46(m,1H),3.08-3.05 (m,2H),2.94-2.86(m,6H),2.76-2.68(m,2H),2.54-2.44(m,3H),2.30-2.29(m,3H),2.04- 1.83(m,6H),1.73-1.43(m,10H),1.40(s,9H),1.32,1.29(q,q,12H),1.27-1.19(m,2H)ppm。
Step 9）The synthesis of compound 7-10
By compound 7-9（10.68g,46.6mmol）It is dissolved in THF（100mL）In, under 0 DEG C of nitrogen protection, it is slowly dropped into boron Alkane（100mL,1M in THF）, drip and finish, isothermal reaction 3.0 hours.After reaction completely, methyl alcohol is used（80mL）Reaction is quenched, is concentrated Jing column chromatographic isolation and purifications after reactant liquor（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 10）The synthesis of compound 7-11
By compound 7-10（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 dividedly in some parts in reaction bulb, after adding, room temperature reaction 2.0 hours.After reaction completely, in reactant liquor Add water（250mL）, filter, after filtrate layered, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, Jing 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 11）The synthesis of compound 7-12
By compound 7-11（3.75g,17.6mmol）And ammoniacal liquor（13.0mL）It is dissolved in methyl alcohol（30mL）In, at 0 DEG C, slowly Instill glyoxal（40%,8.0mL）The aqueous solution, drop finish, room temperature reaction is overnight.After reaction completely, Jing posts layer after concentration of reaction solution Analysis is isolated and purified（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain white solid 1.99g, yield：45%.
MS(ESI,pos.ion)m/z:252.5[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 12）The synthesis of compound 7-13
By compound 7-12（2.11g,8.4mmol）It is dissolved in DCM（60mL）In, at 0 DEG C, by N- N-iodosuccinimides （3.8g,16.8mmol）In being dividedly in some parts reaction bulb, after adding, isothermal reaction 1.5 hours.After reaction completely, reactant liquor is used full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/1） Obtain white solid 2.66g, yield：63%.
MS(ESI,pos.ion)m/z:504.3[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 13）The synthesis of compound 7-14
By compound 7-13（1.65g,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）, water mutually uses EtOAc（50mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying is dense Jing column chromatographic isolation and purifications after contracting（Eluant, eluent：PE/EtOAc(v/v)=3/2）Obtain white solid 0.99g, yield：80%.
MS(ESI,pos.ion)m/z:378.1[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 14）The synthesis of compound 7-15
By compound 7-8（0.55g,0.72mmol）, compound 7-14（0.27g,0.72mmol）, Pd (PPh3)4（83mg, 0.07mmol）With potassium carbonate（0.30g,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, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v)=80/1）Product 0.38g is obtained, is produced Rate：60%.
MS(ESI,pos.ion)m/z:441.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.53(s,1H),7.48,7.46(dd,dd,1H),7.41, 7.38(dd,dd,1H),7.34,7.32(dd,dd,1H),7.13,7.11(dd,dd,1H),4.85-4.77(m,2H),4.50- 4.46(m,1H),4.28-4.20(m,1H),3.04-3.00(m,2H),2.97-2.87(m,8H),2.76-2.684(m,2H), 2.55-2.43(m,3H),2.30-2.29(m,3H),2.12-1.52(m,21H),1.50(s,9H),1.40(s,9H),1.25- 1.02(m,2H)ppm。
Step 15）The synthesis of compound 7-16
By compound 7-15（0.35g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 0.30g, yield：90%.
MS(ESI,pos.ion)m/z:682.5[M+H]+；
Step 16）The synthesis of compound 7-17
By compound 7-16（66mg,0.08mmol）, compound 1-18-2（29.4mg,0.17mmol）, EDCI （32.2mg, 0.17mmol）And HOAT（21.8mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA （0.10mL,0.64mmol）, drip and finish, room temperature reaction 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 Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=60/1）Obtain white solid 39.8mg, yield：50%.
MS(ESI,pos.ion)m/z:498.8[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.57(s,1H),7.54(s,1H),7.49,7.47(dd,dd,1H),7.40, 7.38(dd,dd,1H),7.34,7.33(dd,dd,1H),7.13,7.11(dd,dd,1H),6.08,6.05(d,d,1H), 5.32,5.29(d,d,1H),5.03-4.97(m,2H),4.80-4.75(m,1H),4.40-4.35(m,1H),4.21-4.17 (m,1H),3.77-3.69(m,1H),3.65(s,3H),3.63(s,3H),3.03-3.00(m,2H),2.97-2.87(m,6H), 2.54-2.43(m,5H),2.30-2.29(m,3H),2.26-2.13(m,2H),2.08-1.88(m,6H),1.83-1.49(m, 14H),1.47-1.34(m,3H),1.21-1.03(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 8
Synthetic route：
Step 1）The synthesis of compound 8-1
By t-BuOK（1.17g,10.41mmol）It is suspended in toluene（10mL）In, 0 DEG C of N2Under protection, by compound 6-2 （0.80g,4.16mmol）And pentamethylene bromide（0.62mL,4.58mmol）It is mixed in toluene（20mL）In, it is slowly dropped into In stating reaction bulb, drop finishes, and 110 DEG C are reacted 2.5 hours.After reaction completely, it is cooled to room temperature, in reactant liquor frozen water is added （50mL）, use EtOAc（30mL×3）Extraction, merges organic phase, uses saturated common salt water washing, anhydrous sodium sulfate drying, after concentration Jing column chromatographic isolation and purifications（Eluant, eluent：PE/EtOAc(v/v)=4/1）Obtain faint yellow solid 0.63g, yield：58%.
MS(ESI,pos.ion)m/z:261.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.98(d,1H,J=8.7Hz),6.73(d,1H,J=8.7Hz),3.89(s, 3H),3.86(s,3H),2.88(s,2H),1.82-1.68(m,5H),1.51-1.26(m,5H)ppm。
Step 2）The synthesis of compound 8-2
By compound 8-1（0.99g,3.8mmol）And triethyl silicane（3.7mL,23mmol）In being mixed in reaction bulb, 0 ℃N2Under protection, trifluoroacetic acid is slowly dropped into（8.0mL）, drip and finish, 40 DEG C are reacted 7.0 hours.After reaction completely, trifluoro second is removed Acid, residue EtOAc（50mL）Dissolving, respectively with saturated sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate is done It is dry, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=5/1）Pale yellow oily liquid 0.81g is obtained, is produced Rate：87%.
MS(ESI,pos.ion)m/z:247.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.61(s,2H),3.79(s,6H),2.74(s,4H),1.58-1.40(m, 10H)ppm。
Step 3）The synthesis of compound 8-3
By compound 8-2（0.78g,3.17mmol）It is dissolved in DCM（20mL）In, at -78 DEG C, it is slowly dropped into BBr3 （1.20mL,12.67mmol）, drop finishes, after isothermal reaction 10 minutes, room temperature reaction 1.0 hours.After reaction completely, frozen water is added （50mL）Reaction is quenched, water layer is extracted with DCM（30mL×3）, merging organic phase, saturated common salt water washing, anhydrous sodium sulfate is done It is dry, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=5/1）Pale yellow oily liquid 0.69g is obtained, is produced Rate：100%.
MS(ESI,pos.ion)m/z:219.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.49(s,2H),5.07-4.53(br,2H),2.68(s,4H),1.59-1.37 (m,10H)ppm。
Step 4）The synthesis of compound 8-4
By compound 8-3（0.69g,3.16mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, it is slowly dropped into pyridine（2.03mL, 25.29mmol）, after stirring 10 minutes, instill Tf2O（3.19mL,19.97mmol）, drip and finish, room temperature reaction 1.0 hours.Reaction After completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（30mL×3）Extraction, merges organic phase, saturated common salt washing Wash, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/DCM(v/v)=6/1）Obtain colorless oil Liquid 1.11g, yield：73%.1H NMR(400MHz,CDCl3):δ7.13(s,2H),2.92(s,4H),1.59-1.41(m, 10H)ppm。
Step 5）The synthesis of compound 8-5
By compound 1-7（0.15g,0.48mmol）, compound 8-4（0.23g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 125mg, yield：50%.
1H NMR(400MHz,CDCl3):δ7.21,7.19(dd,dd,1H),6.98,6.96(dd,dd,1H),6.94, 6.92(dd,dd,1H),6.66,6.64(dd,dd,1H),4.81(brs,1H),2.92-2.89(m,3H),2.87-2.82(m, 3H),2.71-2.68(m,2H),1.77-1.38(m,16H),1.29-1.21(m,2H)ppm。
Step 6）The synthesis of compound 8-6
By compound 8-5（0.73g,1.4mmol）, compound 1-16（0.51g,1.4mmol）, four triphenyl phosphorus palladiums （0.16g,0.14mmol）And potassium carbonate（0.58g,4.2mmol）It is suspended in DME and H2O（v/v=3/1）Mixed solvent（16mL） In, under nitrogen protection, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, Use saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)= 1/3）Obtain white solid 0.38g, yield：45%.
MS(ESI,pos.ion)m/z:608.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.52(brs,2H),7.37,7.35(dd,dd,1H), 7.13,7.10(dd,dd,1H),7.02,6.99(dd,dd,1H),6.66,6.64(dd,dd,1H),5.14-5.08(m,1H), 3.64-3.58(m,1H),3.31-3.24(m,1H),2.93-2.89(m,4H),2.88-2.82(m,4H),2.47-2.38(m, 1H),2.28-2.17(m,1H),2.10-1.97(m,2H),1.77-1.54(m,12H),1.53(s,9H),1.52-1.40(m, 4H),1.29-1.21(m,2H)ppm。
Step 7）The synthesis of compound 8-7
By compound 8-6（0.30g,0.5mmol）It is dissolved in DCM（5mL）In, at 0 DEG C, instill pyridine（0.24mL, 3mmol）, after stirring 10 minutes, instill trifluoromethanesulfanhydride anhydride（0.34mL,2mmol）, drip and finish, room temperature reaction 1.0 hours.Reaction After completely, frozen water is added（10mL）Reaction is quenched, DCM is used（20mL×3）Extraction, merges organic phase, anhydrous Na2SO4It is dried, it is dense Jing column chromatographic isolation and purifications after contracting（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain colourless liquid 295mg, yield：80%.
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.39,7.37(dd,dd,1H),7.20,7.18(dd,dd, 1H),7.13,7.10(dd,dd,1H),6.96,6.94(dd,dd,1H),5.14-5.08(m,1H),3.64-3.58(m,1H), 3.31-3.23(m,1H),2.95-2.90(m,4H),2.89-2.85(m,4H),2.47-2.38(m,1H),2.28-2.17(m, 1H),2.10-1.97(m,2H),1.77-1.54(m,12H),1.53(s,9H),1.52-1.44(m,4H),1.29-1.21(m, 2H)ppm。
Step 8）The synthesis of compound 8-8
By compound 1-16（0.50g,1.38mmol）, PdCl2(PPh3)2（98mg,0.14mmol）, tetra-n-butyl iodate Ammonium（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 Ethamine（2.0mL）, after being stirred at room temperature 10 minutes, it is slowly dropped into TMSA（0.98mL,6.89mmol）, to drip and finish, 70 DEG C of reactions are overnight. After reaction completely, diatomite is filtered, and filtrate adds water（20mL）Dilution, water layer EtOAc（20mL×3）Extraction, merges organic Phase, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain product 0.25g, yield：55%.
MS(ESI,pos.ion)m/z:334.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.24(s,1H),4.95-4.90(m,1H),3.72-3.66(m,1H),3.38- 3.30(m,1H),2.56-2.48(m,1H),2.40-2.30(m,1H),2.28-2.19(m,1H),2.07-1.97(m,1H), 1.41(s,9H),0.32(s,9H)ppm。
Step 9）The synthesis of compound 8-9
By compound 8-8（0.30g,0.87mmol）And K2CO3（0.60g,4.35mmol）It is dissolved in MeOH（2mL）And THF （2mL）Mixed solvent in, room temperature reaction 6.0 hours.After reaction completely, EtOAc is added（20mL）Dilute reaction solution, filters, Jing column chromatographic isolation and purifications after filtrate concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1）Obtain product 0.18g, yield：80%.
MS(ESI,pos.ion)m/z:262.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.25(s,1H),4.99-4.94(m,1H),3.72-3.66(m,1H),3.38- 3.30(m,1H),2.56-2.48(m,1H),2.40-2.30(m,1H),2.28-2.19(m,1H),2.07-1.97(m,1H), 1.41(s,9H)ppm。
Step 10）The synthesis of compound 8-10
By compound 8-7（0.29g,0.39mmol）, compound 8-9（0.11g,0.43mmol）, PdCl2(PPh3)2 （14.1mg,0.02mmol）, CuI（33mg,0.172mmol）, PPh3（0.23g,0.86mmol）In being added to reaction bulb, nitrogen Under protection, DMF is added（10mL）, it is slowly dropped into triethylamine（5.0mL）, drop finishes, after being stirred at room temperature 10 minutes, 90 DEG C of reactions 5.0 Hour.After reaction completely, EtOA is addedc（50mL）Dilute reaction solution, diatomite is filtered, and filtrate uses respectively water（20mL×3）With Saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/MeOH(v/v)=80/ 1）Obtain compound 8-10（165mg, yield：50%）.
MS(ESI,pos.ion)m/z:426.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.52(s,1H),7.49,7.46(dd,dd,1H),7.41, 7.39(dd,dd,1H),7.35,7.33(dd,dd,1H),7.13,7.10(dd,dd,1H),5.18-5.08(m,2H),3.72- 3.66(m,1H),3.64-3.58(m,1H),3.38-3.24(m,2H),3.22-3.18(m,2H),3.09-3.06(m,2H), 2.93-2.90(m,2H),2.88-2.85(m,2H),2.56-2.30(m,3H),2.28-2.17(m,2H),2.10-1.97(m, 3H),1.77-1.56(m,16H),1.53(s,9H),1.41(s,9H),1.29-1.21(m,2H)ppm。
Step 11）The synthesis of compound 8-11
By compound 8-10（0.34g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 286mg, yield：90%.
MS(ESI,pos.ion)m/z:651.5[M+H]+；
Step 12）The synthesis of compound 8-12
By compound 8-11（63.7mg,0.08mmol）, compound 8-11-2（39.8mg,0.17mmol）, EDCI （32.2mg,0.17mmol）And HOAT（21.8mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA （0.10mL,0.64mmol）, drip and finish, room temperature reaction 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 Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=60/1）Obtain white solid 43.5mg, yield：50%.
MS(ESI,pos.ion)m/z:545.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ10.23(brs,2H),7.88(s,1H),7.49,7.46(dd,dd,1H), 7.48(s,1H),7.42,7.40(dd,dd,1H),7.36-7.30(m,5H),7.24-7.19(m,2H),7.13-7.10(m, 5H),5.71,5.69(dd,dd,1H),5.51-5.46(m,2H),5.32-5.28(m,1H),4.51-4.43(m,2H),3.89- 3.78(m,2H),3.73-3.61(m,2H),3.22-3.18(m,2H),3.09-3.06(m,2H),2.93-2.90(m,2H), 2.88-2.85(m,2H),2.33-1.92(m,10H),1.77-1.48(m,14H),1.47-1.37(m,2H),1.29-1.21 (m,2H),1.02-0.89(m,12H)ppm。
Embodiment 9
Synthetic route：
Step 1）The synthesis of compound 9-1
At -10 DEG C, by new 1, the 3- cyclopentadiene for steaming（9.20g,138.8mmol）Instill benzoquinones（10g,92.5mmol）'s DCM（100mL）In solution, room temperature reaction 0.5 hour after isothermal reaction 1 hour.After reaction completely, remove solvent, add just oneself Alkane（500mL）, filtering after stirring, filtrate concentrate drying obtains faint yellow solid 10.5g, yield：65.2%.Need not be further purified It is directly used in next step reaction.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.57(s,2H),6.68(s,2H),3.55(s,2H),3.22-3.21(m, 2H),1.56-1.42(m,2H)ppm。
Step 2）The synthesis of compound 9-2
By compound 9-1（5.50g,31.6mmol）With sodium acetate（7.77g,94.7mmol）It is dissolved in methyl alcohol（100mL）, nitrogen Under gas shielded, 50 DEG C are reacted 3 hours.After reaction completely, Jing column chromatographic isolation and purifications after concentration of reaction solution（Eluant, eluent：DCM） To white solid 5.10g, yield：92.7%.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.80-6.79(m,2H),6.35(s,2H),3.55(s,2H),4.10-4.09 (m,2H),2.25-2.18(m,2H)ppm。
Step 3）The synthesis of compound 9-3
By compound 9-2（4.70g,27.0mmol）With the palladium carbon of catalytic amount（0.47g）It is suspended in methyl alcohol（50mL）In, often Room temperature reaction 1.5 hours under pressure hydrogen system.After reaction completely, filter, Jing recrystallization purifyings after filtrate concentration obtain white solid Body 3.55g, yield：74.6%.
1H NMR(400MHz,d6-DMSO):δ8.27(s,2H),6.29(s,2H),3.47(s,2H),1.79-1.77(m, 2H),1.48-1.46(m,1H),1.36-1.34(m,1H),1.01-0.99(m,2H)ppm。
Step 4）The synthesis of compound 9-4
At 0 DEG C, by pyridine（9.0g,114mmol）It is added drop-wise to compound 9-3（3.35g,19mmol）DCM（50mL）It is molten In liquid, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（21g,76mmol）In instilling reaction bulb, drop finishes, room temperature reaction 1 hour. After reaction completely, DCM is added（50mL）Dilute reaction solution, saturated common salt water washing, anhydrous sodium sulfate drying, Jing posts layer after concentration Analysis is isolated and purified（Eluant, eluent：PE/DCM(v/v)=10/1）Obtain colorless oil 8.2g, yield：98.0%.
1H NMR(400MHz,CDCl3):δ7.05(s,2H),3.71-3.70(m,2H),2.05-2.02(m,2H),1.90- 1.87(m,1H),1.69-1.68(m,1H),1.38-1.34(m,2H)ppm。
Step 5）The synthesis of compound 9-5
By compound 1-7（0.15g,0.48mmol）, compound 9-4（0.21g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 0.11g, yield：50%.
1H NMR(400MHz,CDCl3):δ7.30,7.28(s,s,1H),7.11,7.09(s,s,1H),6.96,6.94 (dd,dd,1H),6.49,6.47(dd,dd,1H),4.81(brs,1H),3.79-3.76(m,1H),3.52-3.50(m,1H), 2.90-2.84(m,4H),2.08-2.02(m,1H),1.98-1.92(m,1H),1.87-1.83(m,1H),1.71-1.50(m, 7H),1.49-1.38(m,2H),1.35-1.29(m,1H),1.25-1.19(m,1H)ppm。
Step 6）The synthesis of compound 9-6
At 0 DEG C, by DIPEA（19.5mL,118mmol）It is added to compound 1-11（23g,107mmol）With compound HATU（48.82g,128.4mmol）THF（250mL）In solution, after isothermal reaction 0.5 hour, compound 3-1- is dividedly in some parts 2（22.13g,119mmol）, after adding, room temperature reaction 4.0 hours.After reaction completely, add water（100mL）Reaction is quenched, is removed THF, uses EtOAc（200mL×3）Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying obtains thick after concentration Product, is directly used in next step reaction.Product obtained above is dissolved in into glacial acetic acid（100mL）In, 40 DEG C of reactions are overnight.Reaction After completely, concentration of reaction solution, residue EtOAc（400mL）Dissolving, sodium carbonate liquor（150mL×3）Washing, anhydrous slufuric acid Sodium is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain compound 9-6（31.64g, 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 7）The synthesis of compound 9-7
By compound 9-6（4.11g,11.27mmol）, compound 1-6-2（4.29g,16.9mmol）, Pd (dppf) Cl2·CH2Cl2（0.65g,0.8mmol）And KOAc（2.09g,21.3mmol）In being placed in reaction bulb, N2Under protection, DMF is added （30mL）, 90 DEG C are reacted 3 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（200mL）Dilute reaction solution, uses water（60mL ×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（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 8）The synthesis of compound 9-8
By compound 9-5（99.0mg, 0.207mmol), compound 9-7（85.5mg,0.207mmol）, Pd (PPh3)4 （24.0mg,0.021mmol）And potassium carbonate（85.9mg,0.62mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into （4.0mL）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 reactant liquor, water is used respectively（10mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：DCM/EtOH(v/v)=100/1）Obtain yellow solid 82.8mg, yield：65%.
MS(ESI,pos.ion)m/z:616.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.62-7.59(m,2H),7.46,7.44(s,s,1H),7.33,7.31(s,s, 1H),7.23,7.21(d,d,1H),7.03,7.01(dd,dd,1H),6.49,6.47(dd,dd,1H),5.04-4.99(m, 1H),3.86-3.76(m,3H),3.64-3.57(m,1H),2.90-2.84(m,4H),2.63-2.53(m,1H),2.47-2.35 (m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.70-1.50(m,7H),1.49- 1.43(m,2H),1.41(s,9H),1.28-1.21(m,2H)ppm。
Step 9）The synthesis of compound 9-9
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 9-8（1.17g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1） To colorless oil 1.2g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.62-7.59(m,2H),7.41,7.39(s,s,1H),7.33,7.31(s,s, 1H),7.23,7.21(d,d,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.04-4.99(m, 1H),3.86-3.76(m,3H),3.64-3.57(m,1H),2.92-2.86(m,4H),2.63-2.53(m,1H),2.47-2.35 (m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.74-1.43(m,9H),1.41 (s,9H),1.28-1.21(m,2H)ppm。
Step 10）The synthesis of compound 9-10
By compound 9-9（1.87g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.82g, yield：45%.
1H NMR(400MHz,CDCl3):δ7.80,7.78(dd,dd,1H),7.62-7.59(m,2H),7.53,7.51(s, s,1H),7.40,7.38(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),5.04-4.99(m, 1H),3.86-3.76(m,3H),3.64-3.57(m,1H),3.03-3.00(m,2H),2.91-2.87(m,2H),2.63-2.53 (m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,3H),1.89-1.85(m,1H),1.72- 1.42(m,7H),1.41(s,9H),1.32,1.29(q,q,12H),1.27-1.19(m,4H)ppm。
Step 11）The synthesis of compound 9-11
By compound 9-10（0.52g,0.72mmol）, compound 1-16（0.26g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）After dilute reaction solution, water is used respectively （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =100/1）Obtain product 0.37g, yield：60%.
MS(ESI,pos.ion)m/z:428.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.62-7.59(m,2H),7.49,7.46(s,s,1H), 7.42,7.40(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.06,7.03(dd,dd,1H), 5.15-5.08(m,2H),5.04-4.99(m,1H),3.86-3.76(m,3H),3.64-3.57(m,2H),3.31-3.23(m, 1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.63-2.53(m,1H),2.47-2.35(m,2H),2.29-2.15 (m,2H),2.10-1.93(m,5H),1.89-1.85(m,1H),1.70-1.49(m,7H),1.41(s,18H),1.40-1.34 (m,2H),1.28-1.21(m,2H)ppm。
Step 12）The synthesis of compound 9-12
By compound 9-11（0.33g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 0.28g, yield：90%.
MS(ESI,pos.ion)m/z:635.5[M+H]+。
Step 13）The synthesis of compound 9-13
By compound 9-12（62.43mg,0.08mmol）, compound 9-12-2（24.7mg,0.168mmol）, EDCI （32.2mg,0.168mmol）And HOAT（21.78mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA （0.10mL,0.64mmol）, drip and finish, room temperature reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, point Not Yong ammonium chloride solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=60/1）Obtain white solid 35.69mg, yield：50%.
MS(ESI,pos.ion)m/z:447.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.62-7.59(m,2H),7.49,7.46(s,s,1H), 7.42,7.40(dd,dd,1H),7.33,7.31(s,s,1H),7.23,7.21(d,d,1H),7.06,7.03(dd,dd,1H), 5.48-5.42(m,2H),5.18-5.10(m,2H),4.64-4.53(m,2H),3.88-3.79(m,4H),3.72-3.66(m, 2H),3.65,3.64(s,s,6H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.42-2.06(m,6H),2.04- 1.90(m,4H),1.89-1.85(m,1H),1.70-1.51(m,7H),1.48,1.46(d,d,3H),1.44-1.37(m,2H), 1.36,1.34(d,d,3H),1.28-1.21(m,2H)ppm。
Embodiment 10
Synthetic route：
Step 1）The synthesis of compound 10-1
Under room temperature, by the ethyl acetate solution of hydrogen chloride（5mL,4M）It is added drop-wise to compound 1-16（1.50g,4.13mmol） EtOAc（10mL）In solution, drop finishes, and reacts 8.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （10mL）After beating, solid 1.2g, yield are filtrated to get：86.45%.It is directly used in next step reaction.
MS(ESI,pos.ion)m/z:264.1[M+H]+。
Step 2）The synthesis of compound 10-2
By compound 10-1（1.2g,3.6mmol）, compound 1-18-2（0.69g,3.9mmol）And EDCI（0.75g, 3.9mmol）It is suspended in DCM（20mL）In, after reacting 5 minutes at 0 DEG C, it is slowly dropped into DIPEA（2.38mL,14.4mmol）, drop Finish, room temperature reaction 2.0 hours.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase saturated ammonium chloride solution Washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain yellowish Color 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 3）The synthesis of compound 10-3
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 9-5（0.91g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1） To colorless oil 0.93g, yield：80%.
1H NMR(400MHz,CDCl3):δ7.30,7.28(s,s,1H),7.07,7.05(s,s,1H),7.01-6.96(m, 2H),3.79-3.76(m,1H),3.52-3.50(m,1H),2.92-2.86(m,4H),2.08-2.02(m,1H),1.98-1.92 (m,1H),1.87-1.83(m,1H),1.74-1.42(m,9H),1.35-1.29(m,1H),1.25-1.19(m,1H)ppm。
Step 4）The synthesis of compound 10-4
By compound 10-3（1.53g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain faint yellow solid 0.64g, yield：45%.
1H NMR(400MHz,CDCl3):δ7.88,7.86(s,s,1H),7.80,7.78(dd,dd,1H),7.48-7.46 (m,2H),3.92-3.89(m,1H),3.78-3.75(m,1H),3.03-3.00(m,2H),2.91-2.87(m,2H),1.96- 1.90(m,1H),1.85-1.79(m,2H),1.72-1.41(m,7H),1.32,1.29(q,q,24H),1.28-1.17(m, 3H),1.12-1.06(m,1H)ppm。
Step 5）The synthesis of compound 10-5
By compound 10-4（0.41g,0.72mmol）, compound 10-2（0.64g,1.512mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =100/1）Obtain product 0.39g, yield：60%.
MS(ESI,pos.ion)m/z:450.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.81(s,1H),7.42,7.40(dd,dd,1H),7.38, 7.36(s,s,1H),7.31,7.29(s,s,1H),7.06,7.04(dd,dd,1H),6.08,6.05(d,d,1H),5.32- 5.25(m,3H),4.41-4.30(m,2H),3.85-3.76(m,4H),3.68-3.66(m,1H),3.65(s,3H),3.63(s, 3H),3.62-3.61(m,1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.30-1.88(m,13H),1.70- 1.49(m,7H),1.44-1.34(m,2H),1.30-1.21(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 11
Synthetic route：
Step 1）The synthesis of compound 11-1
By butine dicarboxylic acid dimethyl ester（2.0g,14mmol）With 1,3-cyclohexadiene（1.2g,15.48mmol）It is dissolved in new steaming THF（10.0mL）In, system moves to 60 DEG C and reacts 18 hours.After reaction completely, concentration of reaction solution Jing column chromatographic isolation and purifications（Wash De- agent：PE/EtOAc(v/v)=30/1）Obtain colorless oil 2.36g, yield：76%.
MS(ESI,pos.ion)m/z:223.2[M+H]+；
1H NMR(400MHz,CDCl3):δ6.35(dd,2H,J=3.2Hz,4.4Hz),4.00(m,2H),3.74(s,6H), 1.45(m,2H),1.38(m,2H)ppm。
Step 2）The synthesis of compound 11-2
By compound 11-1（0.8g,3.6mmol）It is dissolved in ethyl acetate（10.0mL）In, add the palladium carbon of catalytic amount （0.04g）, react 2 hours in nitrogen atmosphere under room temperature.After reaction completely, diatomite is filtered, and after filtrate concentration colourless liquid is obtained 0.77g, without the need for purifying.Yield：95%.
MS(ESI,pos.ion)m/z:225.2[M+H]+；
1H NMR(400MHz,CDCl3):δ3.78(s,6H),3.02(s,2H),1.62(m,2H),1.40(m,2H)ppm。
Step 3）The synthesis of compound 11-3
By compound 11-2（0.78g,3.5mmol）It is dissolved in methyl alcohol（10mL）In, add sodium hydrate aqueous solution（10%, 3.5mL）, 60 DEG C are reacted 8 hours.After reaction completely, methyl alcohol is removed, with hydrochloric acid（1M）Adjust pH to 1, use EtOAc（30mL×3）Extraction Take, anhydrous sodium sulfate drying, white solid 0.67g, yield are obtained after concentration：98%.
MS(ESI,pos.ion)m/z:197.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ8.62(brs,2H),3.37(s,2H),1.66(m,4H),1.38(m,4H) ppm。
Step 4）The synthesis of compound 11-4
By compound 11-3（3.7g,18.88mmol）With acetic anhydride（20mL）Mixing, 100 DEG C are reacted 1.5 hours.Reaction After completely, it is cooled to room temperature, white solid 3.09g, yield is obtained after concentration of reaction solution：92%.
MS(ESI,pos.ion)m/z:179.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.26(m,2H),1.85(d,4H,J=8.0Hz),1.35(d,4H,J=8.0Hz) ppm。
Step 5）The synthesis of compound 11-5
By compound 11-4（0.31g,1.74mmol）, sodium acetate（0.22g,2.6mmol）With hydrazine hydrate（0.13mL, 2.6mmol）In being mixed in acetic acid aqueous solution（10mL,50%）, 100 DEG C are reacted 16 hours.After reaction completely, it is cooled to room temperature, filters White solid is obtained, is washed, after MTBE washings, be dried to obtain product 0.28g, yield：85%.
MS(ESI,pos.ion)m/z:193.2[M+H]+；
1H NMR(400MHz,CDCl3):δ3.17(s,2H),1.69(d,4H,J=8.0Hz),1.15(d,4H,J=8.0Hz) ppm。
Step 6）The synthesis of compound 11-6
By compound 11-5（69mg,0.36mmol）With POCl3（3.0mL）Mixing, 110 DEG C are reacted 5 hours.Reaction After completely, it is cooled to room temperature, white solid 78mg, yield is obtained after concentration of reaction solution：95%.
MS(ESI,pos.ion)m/z:230.1[M+H]+；
1H NMR(400MHz,CDCl3):δ3.46(s,2H),1.90(d,4H,J=8.0Hz),1.37(d,4H,J=8.0Hz) ppm.
Step 7）The synthesis of compound 11-7
By compound 1-7（0.15g,0.48mmol）, compound 11-6（0.11g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain white solid Body 0.11g, yield：60%.
MS(ESI,pos.ion)m/z:381.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.50,7.48(dd,dd,1H),6.44,6.42(dd,dd,1H),4.81 (brs,1H),3.37-2.26(m,2H),3.00-2.97(m,2H),1.71-1.16(m,16H)ppm。
Step 8）The synthesis of compound 11-8
By compound 9-6（10g,27.39mmol）It is dissolved in EtOAc（50mL）, the ethyl acetate of instillation hydrogen chloride is molten at 0 DEG C Liquid（60mL,4M）Afterwards, room temperature reaction 8.0 hours, after reaction completely, concentration of reaction solution, residue EtOAc（30mL）Beating Afterwards, faint yellow solid 8.0g, yield are filtrated to get：86.5%.
MS(ESI,pos.ion)m/z:267.2[M+H]+；
1H NMR(400MHz,CDCl3):δ8.01(s,1H),7.70-7.76(m,2H),5.27-5.25(m,1H),3.31- 3.30(m,2H),2.77-2.74(m,1H),2.54-2.52(m,1H),2.40-2.37(m,1H),2.30-2.10(m,1H) ppm。
Step 9）The synthesis of compound 11-9
By compound 11-8（6.35g,18.8mmol）, compound 1-18-2（4.93g,28.2mmol）And EDCI（5.4g, 28.2mmol）It is dissolved in DCM（100mL）, at 0 DEG C, it is slowly added dropwise DIPEA（18.64mL,112.8mmol）Afterwards, room temperature reaction 3.0 Hour.After reaction completely, DCM is added（100mL）After dilute reaction solution, washed with saturated ammonium chloride solution and saturated common salt respectively Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Obtain solid 6.74g, yield：85%.
MS(ESI,pos.ion)m/z:423.3[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 10）The synthesis of compound 11-10
By compound 11-9（3.0g,7.1mmol）, compound 1-6-2（2.72g,10.7mmol）, Pd (dppf) Cl2· CH2Cl2（0.65g,0.8mmol）And KOAc（2.09g,21.3mmol）In being placed in reaction bulb, N2Protection, injects 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, diatomite is filtered, filter Liquid uses respectively water（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Wash De- agent：PE/EtOAc(v/v)=1/2）Obtain buff white solid 2.1g, yield：62.87%.
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）The synthesis of compound 11-11
By compound 11-7（41.8mg,0.11mmol）, compound 11-10（51.7mg,0.11mmol）, Pd (PPh3)4 （25mg,0.02mmol）And K2CO3（91mg,0.66mmol）It is suspended in DME（2.0mL）And water（0.4mL）In, nitrogen protection Under, 90 DEG C are reacted 3.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（20mL）After dilute reaction solution, water is used respectively （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/ MeOH(v/v)=100/1）Obtain faint yellow solid 60.57mg, yield：80%.
MS(ESI,pos.ion)m/z:689.5[M+H]+；
1H NMR(400MHz,CDCl3):δ8.08,8.06(d,d,1H),7.95(q,1H),7.57(brs,2H),7.50- 7.47(dd,dd,1H),7.06,7.03(d,d,1H),6.44,6.42(dd,dd,1H),5.32,5.29(d,d,1H),5.24- 5.20(m,1H),4.40-4.35(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),3.47- 3.30(m,2H),3.00-2.97(m,2H),2.90-2.87(m,2H),2.38-2.28(m,1H),2.25-2.10(m,3H), 2.01-1.86(m,1H),1.77-1.51(m,10H),1.47-1.35(m,6H),0.97,0.95(m,m,3H),0.90,0.89 (m,m,3H)ppm。
Step 13）The synthesis of compound 11-12
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 11-11（1.3g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2） To colorless oil 1.32g, yield：85%.
1H NMR(400MHz,CDCl3):δ8.08,8.06(d,d,1H),8.01,7.99(d,d,1H),7.95(q,1H), 7.05,7.04(d,d,1H),7.00,6.97(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H),4.40- 4.35(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),3.47-3.30(m,2H),3.02- 2.99(m,2H),2.98-2.94(m,2H),2.39-2.27(m,1H),2.24-2.10(m,3H),2.01-1.86(m,1H), 1.77-1.35(m,10H),1.51-1.35(m,6H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 14）The synthesis of compound 11-13
By compound 11-12（2.05g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.90g, yield：45%.
1H NMR(400MHz,CDCl3):δ8.08,8.06(d,d,1H),7.95(q,1H),7.84,7.82(dd,dd, 1H),7.63,7.61(dd,dd,1H),7.06,7.03(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,1H), 4.40-4.35(m,1H),3.84-3.78(m,1H),3.68-3.65(m,1H),3.63(s,3H),3.47-3.30(m,2H), 2.99-2.96(m,2H),2.91-2.87(m,2H),2.39-2.27(m,1H),2.25-2.10(m,3H),2.01-1.86(m, 1H),1.77-1.51(m,8H),1.50-1.36(m,6H),1.32,1.29(q,q,12H),1.27-1.18(m,2H),0.97, 0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 15）The synthesis of compound 11-14
By compound 11-13（0.57g,0.72mmol）, compound 10-2（0.30g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is added（40mL）After dilute reaction solution, water is used respectively（30mL×3）With Saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v)=100/1）Obtain Product 0.39g, yield：60%.
MS(ESI,pos.ion)m/z:483.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.08,8.06(d,d,1H),7.95(q,1H),7.88(s,1H),7.46, 7.43(dd,dd,1H),7.06,7.03(d,d,1H),6.87,6.85(dd,dd,1H),6.08,6.05(d,d,1H),5.32- 5.28(m,2H),5.24-5.20(m,1H),4.41-4.32(m,2H),3.85-3.78(m,2H),3.68-3.66(m,2H), 3.65(s,3H),3.63(s,3H),3.47-3.30(m,2H),3.10-3.07(m,2H),2.99-2.96(m,2H),2.39- 1.86(m,10H),1.77-1.50(m,10H),1.45-1.34(m,6H),1.02-0.89(m,12H)ppm。
Embodiment 12
Synthetic route：
Step 1）The synthesis of compound 12-1
By compound 9-5（1.2g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=3/1）Obtain faint yellow solid 0.74g, yield：65%.
1H NMR(400MHz,CDCl3):δ7.88,7.86(s,s,1H),7.35,7.33(s,s,1H),7.02,7.00 (dd,dd,1H),6.49,6.47(dd,dd,1H),4.81(brs,1H),3.92-3.89(m,1H),3.78-3.75(m,1H), 2.90-2.84(m,4H),1.96-1.90(m,1H),1.85-1.79(m,2H),1.70-1.50(m,7H),1.48-1.38(m, 2H),1.32,1.29(q,q,12H),1.23-1.17(m,1H),1.12-1.06(m,1H)ppm。
Step 2）The synthesis of compound 12-2
By compound 12-1（0.33g,0.72mmol）, compound 10-2（0.30g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =100/1）Obtain product 0.27g, yield：60%.
MS(ESI,pos.ion)m/z:623.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.81(s,1H),7.52(brs,2H),7.35,7.33(s,s,1H),7.31, 7.28(s,s,1H),7.03,7.01(dd,dd,1H),6.49,6.47(dd,dd,1H),5.32,5.29(d,d,1H),5.28- 5.25(m,1H),4.41-4.37(m,1H),3.85-3.76(m,3H),3.69-3.65(m,1H),3.63(s,3H),2.90- 2.84(m,4H),2.30-1.93(m,7H),1.92-1.88(m,1H),1.70-1.50(m,7H),1.48-1.38(m,2H), 1.30-1.21(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 3）The synthesis of compound 12-3
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 12-2（1.18g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2） To colorless oil 1.22g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.81(s,1H),7.35,7.33(s,s,1H),7.31,7.28(s,s,1H), 7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H), 4.41-4.37(m,1H),3.85-3.76(m,3H),3.68-3.64(m,1H),3.63(s,3H),2.92-2.86(m,4H), 2.30-1.93(m,7H),1.92-1.88(m,1H),1.74-1.42(m,9H),1.30-1.21(m,2H),0.97,0.95(m, m,3H),0.90,0.89(m,m,3H)ppm。
Step 4）The synthesis of compound 12-4
By compound 12-3（1.89g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.82g, yield：45%.
1H NMR(400MHz,CDCl3):δ7.81(s,1H),7.80,7.78(dd,dd,1H),7.49,7.47(s,s, 1H),7.40,7.38(dd,dd,1H),7.31,7.29(s,s,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H), 4.41-4.37(m,1H),3.85-3.76(m,3H),3.69-3.64(m,1H),3.63(s,3H),3.03-3.00(m,2H), 2.91-2.87(m,2H),2.30-1.93(m,7H),1.93-1.88(m,1H),1.72-1.52(m,5H),1.51-1.41(m, 2H),1.32,1.29(q,q,12H),1.27-1.19(m,4H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H) ppm。
Step 5）The synthesis of compound 12-6
Under room temperature, by the ethyl acetate solution of hydrogen chloride（10mL,4M）It is added drop-wise to compound 12-5（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（10mL）After beating, solid 1.37g, yield are filtrated to get：85%.It is directly used in next step reaction.
MS(ESI,pos.ion)m/z:317.5[M+H]+。
Step 6）The synthesis of compound 12-7
By compound 12-6（1.4g,3.6mmol）, compound 1-18-2（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）, drip and finish, room temperature reaction 2.0 hour.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sulphur Sour sodium is dried, Jing column chromatographic isolation and purifications 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:474.5[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 7）The synthesis of compound 12-8
By compound 12-7（1.61g,3.4mmol）, compound 12-4（2.49g,3.4mmol）, Pd (PPh3)4（0.20g, 0.17mmol）And potassium carbonate（1.41g,10.22mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（24mL）And water （6mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, use respectively Water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/ MeOH(v/v)=60/1）Obtain faint yellow solid 1.29g, yield：40%.
MS(ESI,pos.ion)m/z:476.7[M+2H]2+；
1H NMR(400MHz,CDCl3):δ8.96(m,1H),7.81(s,1H),7.73-7.72(m,1H),7.55-7.52 (m,1H),7.44,7.42(dd,dd,1H),7.40-7.36(m,3H),7.31,7.29(s,s,1H),7.14-7.10(m,1H), 6.07,6.05(d,d,1H),5.32,5.29(d,d,1H),5.28-5.25(m,1H),4.41-4.37(m,1H),4.33-4.29 (m,1H),4.28-4.23(m,1H),3.86-3.80(m,2H),3.79-3.76(m,1H),3.69-3.66(m,1H),3.65 (s,3H),3.63(s,3H),3.60-3.55(m,1H),3.44-3.36(m,1H),3.03-3.00(m,2H),2.94-2.90 (m,2H),2.30-1.88(m,11H),1.74-1.49(m,9H),1.46-1.35(m,2H),1.30-1.21(m,2H),1.02- 0.89(m,12H)ppm。
Embodiment 13
Synthetic route：
Step 1）The synthesis of compound 13-2
By compound 13-1（2.06g,10.0mmol）It is dissolved in DCM（50mL）In, at -78 DEG C, it is slowly added dropwise Boron tribromide （7.7mL,80.0mmol）, drop finishes, after isothermal reaction 10 minutes, room temperature reaction 1.0 hours.After reaction completely, frozen water is used （50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dry It is dry, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1）Obtain 1.6g oily liquids, yield：90%.
MS(ESI,pos.ion)m/z:179.5[M+H]+;
1H NMR(400MHz,CDCl3):δ6.55(s,2H),6.51(br,2H),5.51-5.45(m,2H),1.78-1.65 (m,2H),1.00-0.87(m,2H)ppm。
Step 2）The synthesis of compound 13-3
At 0 DEG C, by pyridine（4.8mL,60mmol）It is slowly dropped into compound 13-2（1.78g,10mmol）DCM（20mL） In solution, after stirring 10 minutes, trifluoromethanesulfanhydride anhydride is slowly added dropwise（6.73mL,40mmol）, drip and finish, room temperature reaction 1.0 hours. After reaction completely, frozen water is added（25mL）Reaction, water layer DCM is quenched（30mL×3）Extraction, merges organic phase, saturated common salt Water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=40/1）Obtain nothing Color oily liquid 3.98g, yield：90%.
1H NMR(400MHz,CDCl3):δ7.36(s,2H),5.53-5.47(m,2H),1.69-1.56(m,2H),0.91- 0.78(m,2H)ppm。
Step 3）The synthesis of compound 13-4
By compound 1-7（0.15g,0.48mmol）, compound 13-3（0.21g,0.48mmol）, potassium carbonate（0.16g, 1.12mmol）With Pd (PPh3)4（27.6mg,0.024mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 0.115g, yield：50%.
1H NMR(400MHz,CDCl3):δ7.35,7.33(s,s,1H),7.24,7.22(s,s,1H),6.97,6.95 (dd,dd,1H),6.52,6.50(dd,dd,1H),5.61-5.56(m,1H),5.21-5.17(m,1H),4.81(brs,1H), 2.91-2.87(m,4H),1.77-1.51(m,8H),1.49-1.38(m,2H),0.99-0.88(m,2H)ppm。
Step 4）The synthesis of compound 13-5
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 13-4（0.91g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1） To colorless oil 0.87g, yield：75%.
1H NMR(400MHz,CDCl3):δ7.35,7.33(s,s,1H),7.19,7.17(s,s,1H),7.04,7.02 (dd,dd,1H),6.99,6.97(dd,dd,1H),5.61-5.55(m,1H),5.21-5.17(m,1H),2.93-2.89(m, 4H),1.77-1.42(m,10H),0.99-0.88(m,2H)ppm。
Step 5）The synthesis of compound 13-6
By compound 13-5（1.53g,2.5mmol）, compound 1-6-2（1.34g,5.25mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain faint yellow solid 0.57g, yield：40%.
1H NMR(400MHz,CDCl3):δ7.87,7.85(s,s,1H),7.86,7.84(dd,dd,1H),7.57,7.55 (s,s,1H),7.49,7.47(dd,dd,1H),5.75-5.72(m,1H),5.38-5.34(m,1H),3.03-3.00(m,2H), 2.93-2.90(m,2H),1.83-1.41(m,8H),1.32,1.29(q,q,24H),1.27-1.19(m,2H),1.05-0.92 (m,2H)ppm。
Step 6）The synthesis of compound 13-7
By compound 13-6（0.41g,0.72mmol）, compound 10-2（0.64g,1.512mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is added（40mL）Dilute reaction solution, uses respectively water（30mL×3）With it is full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v)=80/1）Produced Thing 0.39g, yield：60%.
MS(ESI,pos.ion)m/z:451.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.79(s,1H),7.48,7.46(s,s,1H),7.39, 7.36(dd,dd,1H),7.38,7.36(s,s,1H),7.15,7.13(dd,dd,1H),6.07,6.05(d,d,1H),5.57- 5.53(m,1H),5.41-5.38(m,1H),5.32-5.25(m,3H),4.41-4.36(m,1H),4.34-4.30(m,1H), 3.85-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.07-3.03(m,2H),2.99- 2.96(m,2H),2.30-1.49(m,18H),1.44-1.34(m,2H),1.11-1.04(m,1H),1.02-0.89(m,13H) ppm。
Embodiment 14
Synthetic route：
Step 1）The synthesis of compound 14-2
By alchlor（90g,676mmol）And sodium chloride（25g,432mmol）In being placed in reaction bulb, 150 are warming up to DEG C, thing to be mixed is slowly dropped into compound 14-1 in after molten（20g,135mmol）, drip and finish, 200 DEG C are warming up to, constant temperature is anti- Answer 1.0 hours.After reaction completely, it is cooled to room temperature, pours reactant liquor into frozen water（500mL）In, after filtration, filter cake is beaten with methyl alcohol After obtain gray solid 19g, yield：95%.
MS(ESI,pos.ion)m/z:149.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.41-7.38(m,1H),7.24-7.19(m,1H),6.80-6.79,6.78- 6.77(d,d,1H,J=4.0Hz),5.46(br,1H),3.06-3.03(m,2H),2.69-2.66(m,2H)ppm。
Step 2）The synthesis of compound 14-3
By compound 14-2（5.0g,33.7mmol）With K2CO3（23.4g,168.5mmol）It is suspended in acetone（50mL）In, It is slowly dropped into iodomethane（3.15mL,50.55mmol）, drip and finish, 60 DEG C are reacted 5.0 hours.After reaction completely, concentration of reaction solution, Residue adds water（150mL）And EtOAc（150mL）, diatomite is filtered, after filtrate layered, water layer EtOAc（150mL×2） Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： PE/EtOAc(v/v)=10/1）Obtain yellow solid 2.46g, yield：45%.
MS(ESI,pos.ion)m/z:163.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.51-7.48(m,1H),7.30-7.26(m,1H),6.91-6.87(m,1H), 3.90(s,3H),3.08-3.05(m,2H),2.70-2.67(m,2H)ppm。
Step 3）The synthesis of compound 14-4
By compound 14-3（20.0g,123.3mmol）It is suspended in methyl alcohol（250mL）In, at 0 DEG C, it is dividedly in some parts NaBH4 （2.8g,74.0mmol）, after adding, room temperature reaction 1.0 hours.After reaction completely, methyl alcohol is removed, residue adds EtOAc （400mL）Dissolving, uses respectively water（100mL×2）And saturated aqueous common salt（100mL）Washing, anhydrous Na2SO4It is dried, Jing after concentration Column chromatographic isolation and purification（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain faint yellow solid 17.6g, yield：87%.
MS(ESI,pos.ion)m/z:165.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.13-7.09(m,1H),7.08-7.05(m,1H),6.75-6.72(m,1H), 5.29-5.25(m,1H),3.84(d,3H),3.70(brs,1H),2.84-2.80(m,2H),2.49-2.40(m,1H),1.96- 1.88(m,1H)ppm。
Step 4）The synthesis of compound 14-5
By compound 14-4（2.0g,12.2mmol）It is dissolved in THF（20mL）In, at 0 DEG C, add p-TSA（1.0g, 6.1mmol）, after adding, back flow reaction 3.0 hours.After reaction completely, THF is removed, residue adds EtOAc（100mL）It is molten Solution, uses respectively water（50mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Wash De- agent：PE）Obtain colourless liquid 1.23g, yield：69%.
MS(ESI,pos.ion)m/z:147.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.29(t,1H,J=7.8Hz),7.09(d,1H,J=7.4Hz),6.90-6.86 (m,1H),6.77(d,1H,J=8.0Hz),6.61-6.57(m,1H),3.92(s,3H),3.39(s,2H)ppm。
Step 5）The synthesis of compound 14-6
By compound 14-5（5.0g,34.2mmol）It is dissolved in absolute ether（35mL）In, add activated zinc powder（2.5g, 37.6mmol）, after stirring 10 minutes, N2Under protection, trichloro-acetic chloride is slowly dropped into（4.0mL,35.9mmol）And POCl3 （3.3mL,35.9mmol）Diethyl ether solution（35mL）, to drip and finish, backflow is overnight.After reaction completely, filter, filtrate adds water （50mL）, use EtOAc（60mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, Jing after concentration Column chromatographic isolation and purification（Eluant, eluent：PE）Obtain faint yellow solid 6.5g, yield：74%.
MS(ESI,pos.ion)m/z:257.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.28(t,1H,J=7.8Hz),7.02(d,1H,J=7.6Hz),6.79(d,1H, J=8.0Hz),4.53-4.45(m,2H),3.82(s,3H),3.36(d,1H,J=17.2Hz),3.09-3.00(m,1H)ppm。
Step 6）The synthesis of compound 14-7
By compound 14-6（6.45g,25.2mmol）It is dissolved in methyl alcohol（80mL）In, add zinc powder（8.2g,126mmol）With Ammonium chloride（6.7g,126mmol）, N2Under protection, 45 DEG C of reactions are overnight.After reaction completely, diatomite is filtered, after filtrate concentration, Residue adds water（50mL）, use EtOAc（60mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=60/1）Colorless oil 3.69g is obtained, is produced Rate：78%.
MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.22(t,1H,J=7.8Hz),6.89(d,1H,J=7.6Hz),6.71(d,1H, J=8.0Hz),4.11-3.99(m,2H),3.82(s,3H),3.63-3.52(m,1H),3.27(d,1H,J=17.2Hz),3.03- 2.93(m,1H),2.92-2.84(m,1H)ppm。
Step 7）The synthesis of compound 14-8
By compound 14-7（2.3g,12.2mmol）It is dissolved in triethylene-glycol（30mL）In, add KOH（2.1g, 36.7mmol）And hydrazine hydrate（4.8mL,97.8mmol）, 130 DEG C are reacted 20 minutes, plus water knockout drum, are warming up to 200 DEG C of reactions 50 Minute.After reaction completely, it is cooled to room temperature, reactant liquor adds water（100mL）, use PE（150mL×3）Extraction, merges organic phase, satisfies And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain colourless liquid 1.42g, yield：67%.
MS(ESI,pos.ion)m/z:175.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.19(t,1H,J=7.7Hz),6.84(d,1H,J=7.5Hz),6.71(d,1H, J=8.0Hz),3.84(s,3H),3.78-3.70(m,1H),3.20-3.08(m,1H),3.04-2.94(m,1H),2.80-2.70 (m,1H),2.60-2.46(m,1H),2.30-2.17(m,1H),1.86-1.70(m,2H)ppm。
Step 8）The synthesis of compound 14-9
By compound 14-8（9.92g,57.0mmol）It is dissolved in THF（80mL）And acetonitrile（40mL）In, add NIS （14.2g,63.0mmol）, after stirring 10 minutes, then the trifluoroacetic acid of catalytic amount is instilled, room temperature reaction 5.0 hours.Reaction is complete Afterwards, concentration of reaction solution, residue adds EtOAc（200mL）, saturation sulfurous acid solution is used respectively（50mL×3）Washing, it is anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain colourless liquid 12.8g, yield：75%.
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.52(d,1H,J=8.4Hz),6.49(d,1H,J=8.4Hz),3.81(s, 3H),3.70-3.62(m,1H),3.17-3.08(m,1H),3.08-3.00(m,1H),2.94-2.85(m,1H),2.60-2.48 (m,1H),2.32-2.20(m,1H),1.94-1.84(m,1H),1.82-1.68(m,1H)ppm。
Step 9）The synthesis of compound 14-10
By compound 14-9（2.16g,7.2mmol）It is dissolved in DCM（20mL）In, at -78 DEG C, it is slowly dropped into BBr3 （2.7mL,28.8mmol）, drop finishes, after isothermal reaction 10 minutes, room temperature reaction 4.0 hours.After reaction completely, reactant liquor is delayed Slowly frozen water is poured into（100mL）In, water layer DCM（50mL×3）Extraction, merges organic phase, and saturated common salt water washing is anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Colourless liquid 1.85g is obtained, Yield：90%.
MS(ESI,pos.ion)m/z:287.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.43(d,1H,J=8.3Hz),6.46(d,1H,J=8.3Hz),5.05(s, 1H),3.70-3.62(m,1H),3.17-3.08(m,1H),3.08-3.00(m,1H),2.94-2.85(m,1H),2.60-2.48 (m,1H),2.32-2.20(m,1H),1.94-1.84(m,1H),1.82-1.68(m,1H)ppm。
Step 10）The synthesis of compound 14-11
By compound 14-10（1.55g,5.4mmol）It is dissolved in DCM（20mL）In, at 0 DEG C, it is slowly dropped into pyridine（1.1mL, 13.5mmol）, after constant temperature is stirred 10 minutes, slowly instill Tf2O（1.4mL,8.1mmol）, drip and finish, room temperature reaction 1.0 hours. After reaction completely, frozen water is added（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merges organic phase, saturated common salt Water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain colourless liquid 2.21g, yield： 98%。
MS(ESI,pos.ion)m/z:419.0[M+H]+；
1H NMR(400MHz,CDCl3):δ7.64(d,1H,J=8.5Hz),6.86(d,1H,J=8.5Hz),3.76-3.67 (m,1H),3.30-3.14(m,2H),3.12-3.00(m,1H),2.65-2.50(m,1H),2.35-2.23(m,1H),1.94- 1.84(m,1H),1.83-1.72(m,1H)ppm。
Step 11）The synthesis of compound 14-12
By compound 1-7（0.3g,0.96mmol）, compound 14-11（0.40g,0.96mmol）, potassium carbonate（0.33g, 2.4mmol）With Pd (PPh3)4（55.5mg,0.048mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 0.23g, yield：50%.
1H NMR(400MHz,CDCl3):δ7.27,7.25(s,s,1H),7.01-6.97(m,2H),6.67,6.65(dd, dd,1H),4.81(brs,1H),4.01-3.94(m,1H),3.08-2.97(m,1H),2.93-2.83(m,5H),2.63-2.48 (m,2H),2.19-2.08(m,2H),1.70-1.50(m,7H),1.49-1.38(m,2H)ppm。
Step 12）The synthesis of compound 14-13
At 0 DEG C, by pyridine（1.8g,22.8mmol）It is added drop-wise to compound 14-12（1.82g,3.8mmol）DCM （10mL）In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（4.2g,15.2mmol）In instilling reaction bulb, drop finishes, room temperature Reaction 1 hour.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（30mL×3）, merge organic phase, use Saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/ 1）Obtain colorless oil 1.62g, yield：70%.
1H NMR(400MHz,CDCl3):δ7.27,7.25(s,s,1H),7.18,7.16(dd,dd,1H),7.03,7.01 (dd,dd,1H),6.92,6.90(t,t,1H),4.01-3.94(m,1H),3.08-2.97(m,1H),2.93-2.85(m,5H), 2.63-2.48(m,2H),2.19-2.08(m,2H),1.74-1.42(m,9H)ppm。
Step 13）The synthesis of compound 14-14
By compound 14-13（1.22g,2.0mmol）, compound 1-6-2（1.07g,4.2mmol）, Pd (dppf) Cl2· CH2Cl2（81.7mg,0.1mmol）And KOAc（0.49g,5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain faint yellow solid 0.45g, yield：40%.
1H NMR(400MHz,CDCl3):δ7.67,7.65(dd,dd,1H),7.64,7.62(s,s,1H),7.48,7.46 (dd,dd,1H),7.35,7.32(t,t,1H),4.12-4.05(m,1H),3.19-3.08(m,1H),3.03-3.00(m,2H), 2.93,2.91(m,m,1H),2.90-2.86(m,2H),2.50-2.40(m,2H),2.19-2.09(m,1H),2.06-1.96 (m,1H),1.72-1.40(m,7H),1.32,1.29(q,q,24H),1.27-1.20(m,2H)ppm。
Step 14）The synthesis of compound 14-15
By compound 14-14（0.28g,0.5mmol）, compound 10-2（0.42g,1.0mmol）, Pd (PPh3)4 （57.8mg,0.05mmol）With potassium carbonate（0.17g,1.25mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen is protected Under shield, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =80/1）Obtain product 0.25g, yield：55%.
MS(ESI,pos.ion)m/z:450.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.59(s,1H),7.38,7.36(dd,dd,1H),7.35, 7.33(t,t,1H),7.22,7.20(s,s,1H),7.05,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32- 5.28(m,3H),4.41-4.37(m,1H),4.35-4.28(m,2H),3.85-3.78(m,2H),3.68-3.66(m,2H), 3.65(s,3H),3.63(s,3H),3.23-3.12(m,2H),3.07-3.03(m,2H),2.97-2.93(m,2H),2.77- 2.65(m,2H),2.32-1.92(m,12H),1.70-1.49(m,7H),1.45-1.34(m,2H),1.02-0.89(m,12H) ppm。
Embodiment 15
Synthetic route：
Step 1）The synthesis of compound 15-1
By compound 14-7（1.07g,5.7mmol）And NIS（1.42g,6.3mmol）It is dissolved in）Acetonitrile（20mL）In, then drip Enter the trifluoroacetic acid of catalytic amount, room temperature reaction 5.0 hours.After reaction completely, concentration of reaction solution, residue adds EtOAc （100mL）Afterwards, saturated sodium bisulfite solution is used（20mL×3）Washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation is pure after concentration Change（Eluant, eluent：PE）Obtain colourless liquid 1.34g, yield：75%.
MS(ESI,pos.ion)m/z:315.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35,7.33(t,t,1H),6.51,6.49(m,m,1H),3.99-3.95(m, 1H),3.91(s,3H),3.85-3.78(m,1H),3.74-3.66(m,1H),3.20-3.14(m,1H),3.00,2.94(m,m, 1H),2.88-2.85,2.83-2.81(m,m,1H)ppm。
Step 2）The synthesis of compound 15-2
By compound 15-1（2.26g,7.2mmol）It is dissolved in DCM（20mL）In, at -78 DEG C, it is slowly dropped into BBr3 （2.7mL,28.8mmol）, drop finishes, after isothermal reaction 10 minutes, room temperature reaction 4.0 hours.After reaction completely, reactant liquor is instilled Frozen water（100mL）In be quenched, water layer DCM（50mL×3）Extraction, merges organic phase, uses saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=20/1）Colourless liquid 1.94g is obtained, Yield：90%.
MS(ESI,pos.ion)m/z:301.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.26,7.24(t,t,1H),6.45,6.42(s,s,1H),4.81(brs, 1H),4.36-4.32(m,1H),3.88-3.81(m,1H),3.74-3.66(m,1H),3.19,3.13(m,1H),3.00,2.96 (m,m,1H),2.87-2.80(m,1H)ppm。
Step 3）The synthesis of compound 15-3
By compound 15-2（1.62g,5.4mmol）It is dissolved in DCM（15mL）In, at 0 DEG C, it is slowly dropped into pyridine（1.1mL, 13.5mmol）, after constant temperature is stirred 10 minutes, slowly instill Tf2O（1.4mL, 8.1mmol), drop finishes, room temperature reaction 1.0 hours. After reaction completely, frozen water is added（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merges organic phase, saturated common salt Water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain colourless liquid 2.29g, yield： 98%。
MS(ESI,pos.ion)m/z:432.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.47,7.45(t,t,1H),6.83,6.81(s,s,1H),4.33-4.29(s, 1H),3.83-3.76(m,1H),3.70-3.63(m,2H),3.28-3.21(m,1H),2.96-2.89(m,1H)ppm。
Step 4）The synthesis of compound 15-4
By compound 1-7（0.16g,0.5mmol）, compound 15-3（0.22g,0.5mmol）, potassium carbonate（0.17g, 1.25mmol）With Pd (PPh3)4（57.8mg,0.05mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（4mL）With Water（1mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 123mg, yield：50%.
1H NMR(400MHz,CDCl3):δ7.17,7.15(s,s,1H),6.99,6.97(dd,dd,1H),6.93,6.91 (q,q,1H),6.67,6.65(dd,dd,1H),4.81(brs,1H),4.46-4.42(m,1H),3.75-3.68(m,1H), 3.66-3.59(m,1H),3.50-3.47,3.46-3.43(m,m,1H),3.17-3.14,3.12-3.10(m,m,1H),2.92- 2.83(m,5H),1.70-1.51(m,6H),1.49-1.38(m,2H)ppm。
Step 5）The synthesis of compound 15-5
At 0 DEG C, by pyridine（1.8g,22.8mmol）It is added drop-wise to compound 15-4（1.87g,3.8mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（4.2g,15.2mmol）In instilling reaction bulb, drop finishes, room temperature reaction 1 Hour.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=10/1） Obtain colorless oil 1.66g, yield：70%.
1H NMR(400MHz,CDCl3):δ7.18,7.16(dd,dd,1H),7.17,7.15(s,s,1H),7.03,7.00 (dd,dd,1H),6.87,6.84(q,q,1H),4.46-4.42(m,1H),3.75-3.68(m,1H),3.66-3.59(m,1H), 3.50-3.47,3.46-3.43(m,m,1H),3.17-3.14,3.12-3.10(m,m,1H),2.92-2.83(m,5H),1.74- 1.42(m,8H)ppm。
Step 6）The synthesis of compound 15-6
By compound 15-5（1.25g,2.0mmol）, compound 1-6-2（1.07g,4.2mmol）, Pd (dppf) Cl2· CH2Cl2（81.66mg,0.1mmol）And KOAc（0.49g,5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=5/1）Obtain faint yellow solid 0.58g, yield：50%.
1H NMR(400MHz,CDCl3):δ7.67,7.65(dd,dd,1H),7.60,7.58(s,s,1H),7.48,7.46 (dd,dd,1H),7.30,7.28(t,t,1H),4.02-3.98(m,1H),3.86-3.79(m,1H),3.58-3.50(m,1H), 3.33-3.31,3.29-3.27(m,m,1H),3.03-3.00(m,2H),2.90-2.78(m,4H),1.74-1.40(m,6H), 1.32,1.29(q,q,24H),1.27-1.20(m,2H)ppm。
Step 7）The synthesis of compound 15-7
By compound 15-6（0.29g,0.5mmol）, compound 10-2（0.42g,1.0mmol）, Pd (PPh3)4 （57.8mg,0.05mmol）With potassium carbonate（0.17g,1.25mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen is protected Under shield, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （30mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =80/1）Obtain product 0.25g, yield：55%.
MS(ESI,pos.ion)m/z:457.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.57(s,1H),7.36,7.33(dd,dd,1H),7.31, 7.29(t,t,1H),7.26,7.24(s,s,1H),7.05,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32- 5.28(m,3H),4.82-4.78(m,1H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.90-3.78(m,3H), 3.68-3.65(m,3H),3.65(s,3H),3.63(s,3H),3.41-3.39,3.37-3.35(m,m,1H),3.07-3.03 (m,2H),2.99-2.88(m,4H),2.30-1.92(m,10H),1.70-1.49(m,6H),1.44-1.34(m,2H),1.02- 0.89(m,12H)ppm。
Embodiment 16
Synthetic route：
Step 1）The synthesis of compound 16-1
By compound 10-1（1.21g,3.6mmol）, compound 16-0（0.74g,3.9mmol）And EDCI（0.75g, 3.9mmol）It is suspended in DCM（20mL）In, at 0 DEG C, it is slowly dropped into DIPEA（2.38mL,14.4mmol）, drip and finish, room temperature reaction 2.0 hour.After reaction completely, DCM is added（40mL）Dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sulphur Sour sodium is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2）Faint yellow solid 1.33g is obtained, Yield：85%.
MS(ESI,pos.ion)m/z:435.1[M+H]+；
1H NMR(400MHz,CDCl3):δ7.35(s,1H),5.31,5.28(d,d,1H),5.08-5.03(m,1H), 4.47-4.42(m,1H),3.84-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),2.32-1.92(m,5H), 1.60-1.48(m,1H),1.24-1.11(m,1H),0.92-0.88(m,6H)ppm。
Step 2）The synthesis of compound 16-2
By compound 9-2（5.0g,28.7mmol）And K2CO3（15g,108.7mmol）It is suspended in acetone（100mL）In, 0 Under the protection of DEG C nitrogen, iodomethane is slowly dropped into（10mL,160.5mmol）, to drip and finish, 60 DEG C of reactions are overnight.After reaction completely, mistake Filter, concentrates filtrate, and residue adds DCM（100mL）After dissolving, water is used respectively（50mL×2）With saturated common salt water washing, it is anhydrous Sodium sulphate is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/DCM(v/v)=6/1）White solid 3.2g is obtained, is produced Rate：55%.
MS(ESI,pos.ion)m/z:203.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.67-6.65(m,2H),6.56(m,2H),4.25-4.21(m,2H),3.81 (d,6H),1.85-1.81(m,1H),1.78-1.74(m,1H)ppm。
Step 3）The synthesis of compound 16-3
By compound 16-2（3.0g,14.83mmol）With N- methyl-N morpholine oxides（NMO）（2.1g,18mmol）It is dissolved in THF/H2O（50mL）Mixed solvent（(v/v)=3/2）In, add the OsO of catalytic amount4, after adding, room temperature reaction is overnight.Reaction After completely, excessive sodium thiosulfate is added, after stirring 1 hour, remove THF, residue is dissolved in EtOAc（150mL）In, respectively With water and saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/EtOH(v/ v)=100/1）Obtain white solid 3.0g, yield：86%.
MS(ESI,pos.ion)m/z:237.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.62-6.61(m,2H),4.12-4.10(m,2H),3.86(d,6H),3.77- 3.76(m,2H),3.60(brs,2H),2.24-2.20(m,1H),1.99-1.95(m,1H)ppm。
Step 4）The synthesis of compound 16-4
By compound 16-3（0.51g,2.16mmol）It is dissolved in DCM（15mL）In, at -78 DEG C, it is slowly dropped into DAST （0.7mL,5.2mmol）, drop finishes, after isothermal reaction 2.0 hours, room temperature reaction 36 hours.After reaction completely, add ammonium chloride molten Liquid（20mL）Reaction, water layer DCM is quenched（20mL×2）Extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：DCM/PE(v/v)=1/5）Obtain white solid 0.24g, yield： 46%。
MS(ESI,pos.ion)m/z:241.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.57(m,2H),4.95-4.73(m,2H),3.92(d,6H),3.70-3.66 (m,2H),2.23-2.15(m,1H),1.95-1.67(m,1H)ppm。
Step 5）The synthesis of compound 16-5
At -78 DEG C, by BBr3（7.47g,29.88mmol）It is slowly dropped into compound 16-4（1.43g,5.97mmol）'s DCM（15mL）In solution, drop finishes, after isothermal reaction 20 minutes, room temperature reaction 1.0 hours.It is after reaction completely, reactant liquor is slow Pour frozen water into（50mL）In, water layer DCM（50mL×3）Extraction, merges organic phase, saturated common salt water washing, anhydrous Na2SO4It is dry It is dry, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=6/1）Obtain pale solid 1.01g, yield： 80%。
MS(ESI,pos.ion)m/z:213.5[M+H]+；
1H NMR(400MHz,CDCl3):δ6.50(s,2H),5.77(brs,2H),5.01-4.97,4.94-4.87, 4.81-4.80(m,m,m,2H),3.55-3.51(m,2H),2.31-2.24(m,1H),2.03-1.95(m,1H)ppm。
Step 6）The synthesis of compound 16-6
By compound 16-5（1.15g,5.4mmol）It is dissolved in DCM（15mL）In, at 0 DEG C, it is slowly dropped into pyridine（1.1mL, 13.5mmol）, after constant temperature is stirred 10 minutes, slowly instill Tf2O（1.4mL, 8.1mmol), drop finishes, room temperature reaction 1.0 hours. After reaction completely, frozen water is added（50mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merges organic phase, saturated common salt Water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE）Obtain colourless liquid 2.18g, yield： 85%。
1H NMR(400MHz,CDCl3):δ7.32(s,2H),5.00-4.95,4.93-4.85,4.83-4.78(m,m,m, 2H),3.65-3.63(m,2H),2.32-2.24(m,1H),2.04-1.96(m,1H)ppm。
Step 7）The synthesis of compound 16-7
By compound 1-7（0.3g,0.96mmol）, compound 16-6（0.46g,0.96mmol）, potassium carbonate（0.33g, 2.4mmol）With Pd (PPh3)4（55.5mg,0.048mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into（8mL）With Water（2mL）, 90 DEG C are reacted 12 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, washed with saturated common salt Wash, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=8/1）Obtain colourless liquid 0.25g, yield：50%.
1H NMR(400MHz,CDCl3):δ7.42,7.40(s,s,1H),7.12,7.10(s,s,1H),7.04,7.02 (dd,dd,1H),6.49,6.47(dd,dd,1H),5.00-4.78(m,2H),3.90-3.87(m,1H),3.82-3.79(m, 1H),2.90-2.84(m,4H),2.26-2.19(m,1H),1.98-1.90(m,1H),1.70-1.50(m,6H),1.49-1.38 (m,2H)ppm。
Step 8）The synthesis of compound 16-8
By compound 16-7（0.26g,0.5mmol）, compound 16-1（0.22g,0.5mmol）, Pd (PPh3)4 （57.8mg,0.05mmol）With potassium carbonate（0.17g,1.25mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen is protected Under shield, 90 DEG C are reacted 4.0 hours.After reaction completely, EtOAc is added（50mL）After dilute reaction solution, saturated common salt water washing is used, Anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v)=100/1）Obtain product 0.19g, yield： 55%。
MS(ESI,pos.ion)m/z:673.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.95(s,1H),7.40,7.37(s,s,1H),7.36,7.34(s,s,1H), 7.11,7.09(dd,dd,1H),6.51,6.50(dd,dd,1H),6.49,6.47(dd,dd,1H),5.22-5.18(m,1H), 5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.23-4.21 (m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.90-2.84 (m,4H),2.34-2.26(m,1H),2.23-2.08(m,4H),1.99-1.80(m,2H),1.70-1.50(m,6H),1.49- 1.31(m,3H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 9）The synthesis of compound 16-9
At 0 DEG C, by pyridine（1.8g,22.8mmol）It is added drop-wise to compound 16-8（2.55g,3.8mmol）DCM（20mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（4.2g,15.2mmol）In instilling reaction bulb, drop finishes, room temperature reaction 1 Hour.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（50mL×3）Extraction, merges organic phase, uses full And brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=1/2） Obtain colorless oil 2.14g, yield：70%.
1H NMR(400MHz,CDCl3):δ7.95(s,1H),7.39,7.37(s,s,1H),7.36,7.34(s,s,1H), 7.06,7.03(dd,dd,1H),7.01,6.99(dd,dd,1H),6.51,6.49(d,d,1H),5.22-5.18(m,1H), 5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.24-4.21 (m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.92-2.86 (m,4H),2.34-2.26(m,1H),2.23-2.08(m,4H),2.00-1.89(m,1H),1.88-1.80(m,1H),1.73- 1.31(m,9H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 10）The synthesis of compound 16-10
By compound 16-9（1.6g,2.0mmol）, compound 1-6-2（0.76g,3.0mmol）, Pd (dppf) Cl2· CH2Cl2（81.7mg,0.1mmol）And KOAc（0.49g,5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.63g, yield：40%.
1H NMR(400MHz,CDCl3):δ7.95(s,1H),7.79,7.77(dd,dd,1H),7.51,7.49(s,s, 1H),7.42,7.40(dd,dd,1H),7.36,7.34(s,s,1H),6.51,6.49(d,d,1H),5.22-5.18(m,1H), 5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m,2H),4.40-4.35(m,1H),4.24-4.21 (m,1H),4.05-4.02(m,1H),3.84-3.78(m,1H),3.68-3.66(m,1H),3.65(s,3H),3.03-3.00 (m,2H),2.91-2.88(m,2H),2.34-2.26(m,1H),2.23-2.08(m,4H),1.99-1.89(m,1H),1.86- 1.80(m,1H),1.72-1.53(m,4H),1.50-1.43(m,2H),1.40-1.33(m,1H),1.32,1.29(q,q, 12H),1.28-1.19(m,2H),1.12-0.99(m,1H),0.88-0.81(m,6H)ppm。
Step 11）The synthesis of compound 16-11
By compound 16-10（0.39g,0.5mmol）, compound 10-2（0.21g,0.5mmol）, Pd (PPh3)4 （57.8mg,0.05mmol）With potassium carbonate（0.17g,1.25mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen is protected Under shield, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =50/1）Obtain product 0.26g, yield：55%.
MS(ESI,pos.ion)m/z:475.2[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.95(s,1H),7.88(s,1H),7.45,7.43(dd,dd,1H),7.42, 7.39(s,s,1H),7.36,7.34(s,s,1H),7.04,7.02(dd,dd,1H),6.07,6.05(d,d,1H),5.32- 5.26(m,2H),5.22-5.18(m,1H),5.10-5.09,5.05-5.04,4.96-4.95,4.91-4.90(m,m,m,m, 2H),4.47-4.41(m,1H),4.34-4.30(m,1H),4.24-4.21(m,1H),4.05-4.02(m,1H),3.85-3.78 (m,2H),3.68-3.66(m,2H),3.65(s,6H),3.07-3.03(m,2H),2.98-2.94(m,2H),2.35-1.80 (m,12H),1.70-1.49(m,7H),1.44-1.34(m,2H),1.22-1.11(m,1H),1.02,1.00(m,m,3H), 0.94,0.91(m,m,3H),0.87-0.81(m,6H)ppm。
Embodiment 17
Synthetic route：
Step 1）The synthesis of compound 17-1
At -10 DEG C, by 1,3- cyclohexadiene（11.12g,138.8mmol）Instill benzoquinones（10.0g,92.5mmol）DCM （90mL）In solution, after isothermal reaction 1 hour, room temperature reaction 48 hours.After reaction completely, solvent is removed, add n-hexane （500mL）, filtering after stirring, filtrate anhydrous sodium sulfate drying obtains faint yellow solid 12.5g, yield after concentration：71.8%, It is directly used in next step reaction.MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.59(s,2H),6.47(s,2H),3.42(s,2H),3.20-3.18(m, 2H),1.52-1.39(m,4H)ppm。
Step 2）The synthesis of compound 17-2
By compound 17-1（5.0g,26.6mmol）With sodium acetate（6.54g,79.7mmol）It is dissolved in methyl alcohol（100mL）In, Lower 50 DEG C of nitrogen protection is reacted 4 hours.After reaction completely, concentration of reaction solution Jing column chromatographic isolation and purifications（Eluant, eluent：DCM）Obtain White solid 4.56g, yield：91.2%.
MS(ESI,pos.ion)m/z:189.1[M+H]+；
1H NMR(400MHz,CDCl3):δ6.43-6.39(m,2H),6.28(s,2H),3.65(s,2H),3.45-3.41 (m,2H),2.48-2.44(m,2H),2.09-2.01(m,2H)ppm。
Step 3）The synthesis of compound 17-3
By compound 17-2（4.0g,21.3mmol）With the palladium carbon of catalytic amount（0.4g）It is suspended in methyl alcohol（50mL）In, Room temperature reaction 1.5 hours in atmospheric hydrogen system.After reaction completely, filter, Jing recrystallization purifyings obtain white after filtrate concentration Solid 3.06g, yield：75.6%.
MS(ESI,pos.ion)m/z:191.1[M+H]+；
1H NMR(400MHz,d6-DMSO):δ7.18(s,2H),6.21(s,2H),3.47-3.44(m,2H),1.61- 1.54(m,4H),1.42-1.38(m,4H)ppm。
Step 4）The synthesis of compound 17-4
At 0 DEG C, by pyridine（9.0g,114mmol）It is added drop-wise to compound 17-3（3.61g,19.0mmol）DCM（20mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（21.0g,76.0mmol）In instilling reaction bulb, drop finishes, room temperature reaction 1 Hour.After reaction completely, DCM is added（50mL）Dilute reaction solution, saturated common salt water washing, anhydrous sodium sulfate drying, after concentration Jing column chromatographic isolation and purifications（Eluant, eluent：PE/DCM(v/v)=10/1）Obtain colorless oil 8.4g, yield：97.3%.
1H NMR(400MHz,CDCl3):δ7.15(s,2H),3.69-3.67(m,2H),1.75-1.71(m,4H),1.36- 1.32(m,4H)ppm。
Step 5）The synthesis of compound 17-5
By compound 17-4（7.99g,17.6mmol）, compound 1-7（5.65g,18.0mmol）, four triphenyl phosphorus palladiums （1.02g,0.88mmol）And potassium carbonate（9.73g,70.4mmol）It is suspended in 80mL DME/H2O（v/v=3/1）Mixed solvent In, lower 90 DEG C of nitrogen protection is reacted 3 hours.After reaction completely, ethyl acetate is added（250mL）After dilute reaction solution, saturation is used Brine It, anhydrous sodium sulfate drying, Jing Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/DCM(v/v)=8/1） To white solid 4.85g, yield：56%.
MS(ESI,pos.ion)m/z:493.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.38,7.36(s,s,1H),7.07,7.05(s,s,1H),6.96,6.94 (dd,dd,1H),6.52,6.50(dd,dd,1H),4.81(brs,1H),3.24-3.14(m,1H),2.90-2.83(m,4H), 2.75-2.65(m,1H),1.92-1.81(m,2H),1.70-1.49(m,10H),1.48-1.38(m,2H),1.37-1.27(m, 2H)ppm。
Step 6）The synthesis of compound 17-6
By compound 17-5（101.8mg, 0.21mmol), compound 9-7（85.5mg,0.21mmol）, Pd (PPh3)4 （23.9mg,0.021mmol）And potassium carbonate（85.9mg,0.62mmol）In being placed in reaction bulb, N2Under protection, DME is injected separately into （4.0mL）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 reactant liquor, water is used respectively（10mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：DCM/EtOH(v/v)=100/1）Obtain yellow solid 84.7mg, yield：65%.
MS(ESI,pos.ion)m/z:630.5[M+H]+；
1H NMR(400MHz,CDCl3):δ7.59-7.57(m,2H),7.45,7.43(s,s,1H),7.32,7.30(s,s, 1H),7.28-7.26(m,1H),7.03,7.01(dd,dd,1H),6.52,6.50(dd,dd,1H),5.04-4.99(m,1H), 3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),2.90-2.83(m,4H),2.63-2.53(m, 1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.72-1.52(m,10H),1.48- 1.42(m,2H),1.41(s,9H),1.40-1.29(m,4H)ppm。
Step 7）The synthesis of compound 17-7
At 0 DEG C, by pyridine（0.9g,11.4mmol）It is added drop-wise to compound 17-6（1.2g,1.9mmol）DCM（10mL） In solution, after stirring 10 minutes, by trifluoromethanesulfanhydride anhydride（2.1g,7.6mmol）In instilling reaction bulb, drop finishes, and room temperature reaction 1 is little When.After reaction completely, frozen water is added（20mL）Reaction, water layer DCM is quenched（20mL×3）Extraction, merges organic phase, uses saturation Brine It, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent：PE/EtOAc(v/v)=2/1） To colorless oil 1.23g, yield：85%.
1H NMR(400MHz,CDCl3):δ7.59-7.57(m,2H),7.41,7.39(s,s,1H),7.32,7.30(s,s, 1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H),6.99,6.97(dd,dd,1H),5.04-4.99(m,1H), 3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),2.92-2.88(m,4H),2.63-2.53(m, 1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.74-1.44(m,12H),1.41(s, 9H),1.39-1.29(m,4H)ppm。
Step 8）The synthesis of compound 17-8
By compound 17-7（1.90g,2.5mmol）, compound 1-6-2（0.96g,3.8mmol）, Pd (dppf) Cl2· CH2Cl2（0.11g,0.13mmol）And KOAc（0.74g,7.5mmol）In being mixed in reaction bulb, under nitrogen protection, DMF is added （12mL）, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（100mL）After dilute reaction solution, diatom Soil is filtered.Filtrate uses respectively water（50mL×3）With saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatography for separation after concentration Purifying（Eluant, eluent：PE/EtOAc(v/v)=1/3）Obtain faint yellow solid 0.83g, yield：45%.
1H NMR(400MHz,CDCl3):δ7.82,7.80(dd,dd,1H),7.59-7.57(m,2H),7.51,7.49(s, s,1H),7.39-7.37(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),5.04-4.99(m,1H), 3.82-3.76(m,1H),3.64-3.57(m,1H),3.38-3.21(m,2H),3.03-3.00(m,2H),2.89-2.85(m, 2H),2.63-2.53(m,1H),2.47-2.35(m,1H),2.25-2.15(m,1H),2.04-1.93(m,1H),1.72-1.44 (m,10H),1.41(s,9H),1.40-1.33(m,4H),1.32,1.29(q,q,12H),1.25-1.19(m,2H)ppm。
Step 9）The synthesis of compound 17-9
By compound 17-8（0.53g,0.72mmol）, compound 1-16（0.26g,0.72mmol）, Pd (PPh3)4 （83mg,0.07mmol）With potassium carbonate（0.30g,2.12mmol）It is suspended in DME（6.0mL）And water（1.5mL）In, nitrogen protection Under, 90 DEG C are reacted 4.0 hours.After reaction completely, it is cooled to room temperature, adds EtOAc（40mL）Dilute reaction solution, uses respectively water （20mL×3）With saturated common salt water washing, anhydrous sodium sulfate drying, Jing column chromatographic isolation and purifications after concentration（DCM/MeOH(v/v) =80/1）Obtain product 0.37g, yield：60%.
MS(ESI,pos.ion)m/z:425.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.97(s,1H),7.59-7.57(m,2H),7.48,7.46(s,s,1H), 7.36,7.34(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H), 5.14-5.08(m,1H),5.04-4.99(m,1H),3.82-3.76(m,1H),3.64-3.57(m,2H),3.38-3.21(m, 3H),3.07-3.03(m,2H),2.94-2.90(m,2H),2.63-2.53(m,1H),2.47-2.35(m,2H),2.29-2.15 (m,2H),2.10-1.93(m,3H),1.72-1.54(m,10H),1.53(s,9H),1.41(s,9H),1.40-1.29(m,6H) ppm。
Step 10）The synthesis of compound 17-10
By compound 17-9（0.34g,0.4mmol）It is dissolved in EtOAc（5mL）In, the ethyl acetate for adding hydrogen chloride is molten Liquid（5mL,4M）Afterwards, room temperature reaction 8 hours.After reaction completely, concentration of reaction solution, residue EtOAc（5mL）After beating, mistake Filter obtains white solid 0.29g, yield：90%.
MS(ESI,pos.ion)m/z:649.5[M+H]+。
Step 11）The synthesis of compound 17-11
By compound 17-10（63.6mg,0.08mmol）, compound 9-12-2（24.7mg,0.17mmol）, EDCI （32.2mg,0.17mmol）And HOAT（21.8mg,0.16mmol）It is dissolved in DCM（5mL）, at 0 DEG C, it is slowly dropped into DIPEA （0.10mL,0.64mmol）, drip and finish, room temperature reaction 3.0 hours.After reaction completely, DCM is added（50mL）Dilute reaction solution, point Not Yong ammonium chloride solution and saturated common salt water washing, anhydrous Na2SO4It is dried, Jing column chromatographic isolation and purifications after concentration（Eluant, eluent： DCM/MeOH(v/v)=60/1）Obtain white solid 36.3mg, yield：50%.
MS(ESI,pos.ion)m/z:454.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.59-7.57(m,2H),7.48,7.46(s,s,1H), 7.36,7.34(dd,dd,1H),7.32,7.30(s,s,1H),7.28-7.26(m,1H),7.04,7.02(dd,dd,1H), 5.48,5.46(m,m,1H),5.44,5.42(m,m,1H),5.18-5.10(m,2H),4.64-4.53(m,2H),3.88-3.81 (m,2H),3.72-3.66(m,2H),3.65(s,3H),3.64(s,3H),3.38-3.21(m,2H),3.07-3.03(m,2H), 2.94-2.90(m,2H),2.42-1.89(m,8H),1.72-1.51(m,10H),1.48,1.46(d,d,3H),1.44-1.29 (m,9H)ppm。
Embodiment 18
Synthetic route：
Embodiment 18 is prepared according to the synthetic method of similar embodiment 1.
Compound 18-2：1H 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。
Compound 18-3：1H 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 18-4：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 18-5：MS(ESI,pos.ion)m/z:490.0[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 18-6：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 18-7：MS(ESI,pos.ion)m/z:407.4[M+2H]2+；
1H NMR(400MHz,CDCl3):δ10.60(br.,2H),7.08-7.22(m,6H),5.01(br,2H),3.42 (m,4H),3.07-3.04(m,4H),2.70-2.68(m,4H),2.18(m,4H),2.05(m,4H),1.64-1.58(m, 16H),1.51(s,18H)ppm。
Compound 18-8：MS(ESI,pos.ion)m/z:307.3[M+2H]2+；
1H NMR(400MHz,CD3OD):δ7.85(s,2H),7.64(d,2H,J=7.9Hz),7.22(d,2H,J= 7.9Hz),5.25-5.20(m,2H),3.62-3.58(m,4H),3.12(s,4H),2.75-2.73(m,2H),2.71(s,4H), 2.60-2.54(m,2H),2.45-2.35(m,2H),2.28-2.22(m,2H),1.73-1.63(m,16H)ppm。
Compound 18-9：MS(ESI,pos.ion)m/z:464.5[M+2H]2+；
1H NMR(400MHz,CDCl3):δ10.58(br,2H),7.22-7.06(m,6H),5.41(br,2H),5.29 (br.,2H),4.33(m,2H),3.70(s,6H),3.66(m,4H),3.07-3.01(m,4H),2.69-2.67(m,4H), 2.35-1.97(m,10H),1.64(m,16H),0.94-0.88(m,12H)ppm。
Embodiment 19
Synthetic route：
Embodiment 19 is prepared according to the synthetic method of similar embodiment 10.
Compound 19-1：MS(ESI,pos.ion)m/z:264.1[M+H]+。
Compound 19-2：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 19-3：MS(ESI,pos.ion)m/z:450.3[M+2H]2+；
1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.81(s,1H),7.42,7.40(dd,dd,1H),7.38, 7.36(s,s,1H),7.31,7.29(s,s,1H),7.06,7.04(dd,dd,1H),6.08,6.05(d,d,1H),5.32- 5.25(m,3H),4.41-4.30(m,2H),3.85-3.76(m,4H),3.68-3.66(m,1H),3.65(s,3H),3.63(s, 3H),3.62-3.61(m,1H),3.07-3.03(m,2H),2.96-2.93(m,2H),2.30-1.88(m,13H),1.70- 1.49(m,7H),1.44-1.34(m,2H),1.30-1.21(m,2H),1.02-0.89(m,12H)ppm。
BA
In order to verify effect of the compound as herein described to HCV, inventor adopts HCV Replicate Sub-system (HCV Replicon System) as evaluation model.HCV replicon reported firsts are in Science.1999Jul2;285 (5424), 110-3.HCV Replicate Sub-systems have become research HCV rna replicons, pathogenic and viral persistence most important instrument it One, for example using replicon successfully demonstrate 5'-NCR Minimum Areas necessary to HCV rna replicons, and HCV is multiple 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 expressly incorporated herein）Described method is verified.
In short, inventor is thin using the human liver cancer of stable transfection HCV genotype GT1a, GT1b or GT2a replicons respectively Born of the same parents system Huh-7 is tested compound as herein described, and Y93H, L31F, P32L, I302V resistant mutation is respectively adopted Body and wild type HCV1b are tested compound as herein described.The HCV Replicate Sub-systems for being used herein are included G418 resistant genes NEO and luciferase reporter gene, can be by NEO genes with levels of replication of the HCV in host cell Expression or luciferase gene expression characterizing, and then the effect effect that compound described herein is replicated to HCV virus Fruit can be assessed.Herein, detect to detect the expression of NEO genes by realtime quantitative inspection (qPCR) Amount, by chemoluminescence method the expression of luciferase gene is detected.
Operating process brief introduction：
1. compound EC is determined based on uciferase activity50：
The Huh-7 cells of transfection HCV Replicate Sub-systems are seeded in 96 orifice plates, 8000 cells are contained in each hole. Carry out 5 times of gradient dilutions to compound as herein described respectively, obtain 10 concentration gradients.Compound as herein described 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 substrates Bright-Glo (Promega companies), after 5 minutes, using chemiluminescence detection system Topcount microwell plates liquid dodges luminescence counter and is 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 arranges hole without compound as negative control.
2.qPCR detects antibiotic G418 resistant gene NEO genetic testing compound EC50：
The Huh-7 cells of transfection HCV Replicate Sub-systems are seeded in 96 orifice plates, 8000 cells are contained in each hole. Carry out 5 times of gradient dilutions to compound as herein described respectively, obtain 10 concentration gradients.Compound as herein described is added To the hole of the Huh-7 cells containing transfection HCV Replicate Sub-systems, it is incubated 72 hours in CO2gas incubator.By qPCR Reaction determines the expression 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 Testing carries out two batches, and arrange without compound hole as negative control.
3. result
The EC based on determined by above50, it may be determined that compound as herein described can effectively suppress HCV genotype 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a.Wherein, for the EC of HCV genotype 1b50Scope is 1pm～99nM.Table 2 is provided EC of the present invention representative compound for HCV1a and HCV1b genotype50Value (nM), the EC50Value is 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 80 0.033 8 75 7.28 15 41 0.33
2 142 1.422 9 2.73 0.06 16 29 0.72
3 12 0.026 10 10.52 0.34 17 0.99 0.12
4 4.27 0.088 11 7.53 0.28 18 87 0.042
5 2.58 0.103 12 92 1.63 19 6.82 0.13
6 43 0.084 13 31 2.07
7 >100 3.67 14 36 0.73
According to Y93H, L31F, P32L, I302V resistant mutants and the experimental result of wild type HCV1b, built by molecule Mould, with reference to CAD analog result, it was demonstrated that the compound of present invention by suppress HCV NS5A albumen machine System, has played superior anti-hepatitis C virus effect.
It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and And can be embodied in other concrete 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, should refer to appended claims, rather than previous embodiment, 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 the mechanism that suppresses different from NS5A suppressing HCV.In one embodiment, the compound of present invention suppresses HCV replicons, in another embodiment, this The compound of bright content suppresses NS5A.The compound of present invention can suppress the Multi-genotype of HCV.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or feature that the embodiment or example are described In being contained at least one embodiment of the present invention or example.In this manual, the schematic representation of above-mentioned term is differed Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any Combine 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 in the principle and objective without departing from 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 (21)

1. a kind of compound, it has the structure as shown in formula (X '), or the stereoisomer or medicine of the structure shown in formula (X ') Acceptable salt on,
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：
Construction unit is following group：
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
2. compound according to claim 1, wherein
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or the tert-butyl group；
Each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy.
3. compound according to claim 1, it has the structure as shown in formula (XI ')
Wherein, each Q1And Q2It independently is CH2；
Each Q4And Q5It independently is CH2；
Each f and f ' independently are 1；
Each i independently is 1,2,3 or 4
Each e independently is 0,1 or 2；
Each R5aAnd R5a’It independently is H；
Each Y1And Y2It independently is CR7；
Each Y1’And Y2’It independently is CR7；
Each X1It independently is CR7R7a；
Each R7And R7aIt independently is hydrogen；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isobutyl group, isopropyl or the tert-butyl group；
Each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
4. compound according to claim 1, it has the structure as shown in formula (XII ')：
Wherein, each Q1And Q2It independently is CH2；
Each Q4And Q5It independently is CH2；
Each X1It independently is CR7R7a；
Each R7And R7aIt independently is hydrogen；
Each R5aAnd R5a’It independently is H；
Each Y1And Y2It independently is CR7；
When e is 1, Y1’And Y2’It independently is N or CR7, when e is 2, Y1’And Y2’It is CR7；
Each f and f ' independently are 1；
Each i independently is 1,2,3 or 4
Each e independently is 1 or 2；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or the tert-butyl group；
Each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
5. compound according to claim 1, it has the structure as shown in formula (XIII ')：
Wherein, each Q1And Q2It independently is CH2；
Q4For CH2；
X3For CR7R7a；
Each R7And R7aIt independently is hydrogen；
Each R5aAnd R5a’It independently is H；
Each Y1And Y2It independently is CR7；
Each Y1’And Y2’It independently is CR7；
Each f and f ' independently are 1；
Each i independently is 1,2,3 or 4；
E independently is 0 or 1；
Each R14And R14aIt independently is methyl, ethyl, phenyl, cyclohexyl, 1- methyl-propyls, isopropyl, isobutyl group or the tert-butyl group；
Each R16And R16aIndependently be hydroxyl, methoxyl group, ethyoxyl, phenoxy group,Or tert-butoxy；
Following group independently is with each A and A '：
Wherein R1、R2The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
Wherein R3、R4The heterocycle being individually formed with N-CH or condensed ring or spiro ring system are selected from following subformula：
6. a kind of compound, it includes the structure of one of：
Or its stereoisomer or pharmaceutically acceptable salt.
7. a kind of pharmaceutical composition, wherein described pharmaceutical composition include the chemical combination according to any one of claim 1-6 Thing.
8. pharmaceutical composition according to claim 7, further comprising pharmaceutically acceptable assistant agent, medium or its group Close.
9. pharmaceutical composition according to claim 8, wherein, the assistant agent includes carrier, excipient.
10. pharmaceutical composition according to claim 9, wherein, the excipient includes diluent.
11. pharmaceutical compositions according to claim 7, it is further comprising the medicine of other HCV-Ab IgGs.
12. pharmaceutical compositions according to claim 11, wherein the medicine of the HCV-Ab IgG is interferon, Ribavirin, white Interleukin 2, interleukin 6, interleukin 12, compound, RNA interfering, antisense RNA, the miaow for promoting 1 type helper T lymphocyte response of generation Quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibodies (Bavituximab), CivacirTM, EBP520 (boceprevir), TVR (telaprevir), Erlotinib (erlotinib), Dacca he Wei (daclatasvir), Division A League Matches of Spanish Football Wei (simeprevir), asunaprevir, vaniprevir, faldaprevir, ABT- 450th, Dan Nuopuwei (danoprevir), sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, that drawing Wei (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, Xi Luruiwei (ciluprevir)、BMS-650032、ACH-1625、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX- 1766、PHX-2054、IDX-136、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- 837093rd, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.
13. pharmaceutical compositions according to claim 12, 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.
14. pharmaceutical compositions according to any one of claim 7-13, it further presses down comprising at least one HCV Preparation.
15. pharmaceutical compositions according to claim 14, wherein the HCV inhibitor be used for suppress HCV reproduction processes and Suppress at least one of HCV virus protein function.
16. pharmaceutical compositions according to claim 15, wherein the HCV reproduction processes are entered, shell, turned over selected from HCV The complete viral cycle of the HCV for translating, replicate, assemble or discharging.
17. pharmaceutical compositions according to claim 15, wherein described HCV virus albumen selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And HCV virus replicate required internal ribosome inlet point and inosine list Phosphate dehydrogenase.
Medicine group any one of 18. compounds or claim 7-17 according to any one of claim 1-6 Purposes of the compound in medicine is prepared, the medicine be used for suppress HCV replicate and suppress HCV virus protein function at least it One.
19. purposes according to claim 18, the HCV reproduction processes are entered selected from HCV, shelled, translating, replicating, group The complete viral cycle of dress or the HCV for discharging.
20. purposes according to claim 18, wherein described HCV virus albumen selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A and NS5B；And the internal ribosome inlet point required for HCV virus duplication and inosine monophosphate dehydrogenation Enzyme.
Medicine group any one of 21. compounds or claim 7-17 according to any one of claim 1-6 Purposes of the compound in medicine is prepared, the medicine is used to preventing, process, treat or mitigating HCV infection or the third type liver of patient Scorching disease.
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