CN107266529A - One class suppresses the Large cyclic heterocyclic compound and its preparation and use of hepatitis C virus - Google Patents

One class suppresses the Large cyclic heterocyclic compound and its preparation and use of hepatitis C virus Download PDF

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Publication number
CN107266529A
CN107266529A CN201610219170.8A CN201610219170A CN107266529A CN 107266529 A CN107266529 A CN 107266529A CN 201610219170 A CN201610219170 A CN 201610219170A CN 107266529 A CN107266529 A CN 107266529A
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amino
alkyl
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aryl
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王喆
王栋
陈俊杰
许曼
徐海涛
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Tianjin Chang Sen Pharmaceutcal Corp Ltd
Shanghai Longwood Pharmaceutical Co Ltd
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Tianjin Chang Sen Pharmaceutcal Corp Ltd
Shanghai Longwood Pharmaceutical Co Ltd
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Priority to CN201610219170.8A priority Critical patent/CN107266529A/en
Priority to PCT/CN2017/079087 priority patent/WO2017173960A1/en
Priority to CN201780000221.0A priority patent/CN107074876B/en
Publication of CN107266529A publication Critical patent/CN107266529A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • A61K31/435—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
    • 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
    • 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
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The application is related to the compound that a class suppresses HCV, and the formula A is represented.The application further relates to preparation and the pharmaceutical applications of such compound.

Description

One class suppresses the Large cyclic heterocyclic compound and its preparation and use of hepatitis C virus
Technical field
Present invention relates particularly to a kind of Novel macrocyclic shape heterocyclic compound and its intermediate, preparation method and purposes.
Background technology
Infection with hepatitis C virus causes chronic liver disease, such as hepatic sclerosis and liver cancer.Hepatitis c virus infection is Infectious Diseases One of.Counted according to the World Health Organization, the whole world there are 1.7 hundred million hepatitis C victims, China nearly there are 39,000,000 hepatitis C infections Person.In recent years, the treatment of hepatitis C has achieved significant progress, and current approved has listed several products, wherein, Sofosbuvir,Harvoni(Ledipasvir/Sofosbuvir),ViekiraxPak(ombitasvir/paritaprevir And ritonavir/Exviera), the curative effect for HCV-genotype 1b is excellent.However, for other HCV Genotype and its drug-resistant viral curative effect still have much room for improvement.It is therefore necessary to develop more validity and the third of more preferable tolerance Hepatitis virus medicine.
So far every research shows, HCV (HCV) is cause most of non-A non-B hepatitis main Pathogen.HCV is a kind of positive single strand RNA virus of flaviviridae (F1aviviridae), and its genome contains about 10000 nucleotides and the polymeric protein for encoding about 3000 amino acid.It includes a nucleocapsid protein (C) and envelope protein (E1 and E2), and some non-structural proteins (NS1, NS2, NS3, NS4a, NS5a and NS5b).NS3 proteases have silk ammonia Pepsin activity, it is considered to be the required key element of virus replication and infection mechanism.The essential of NS3 proteases can be by Variation flavivirus NS3 protease reduces the fact of viral infection and estimated.In addition, HCV NS3 serine proteases are sent out It is existing to be beneficial to NS3/NS4a, NS4a/NS4b, NS4b/NS5a, the joint protein cleavage such as NS5a/NS5b, and it is responsible for multiple in virus The generation (referring to US 2003/0207861) of four virus proteins during system.Therefore, HCV NS3 serine proteases into For the target for the most attraction for treating infection with hepatitis C virus.
The content of the invention
The invention provides a kind of Novel macrocyclic shape jeterocyclic chemistry using 18-19 circle heterocycles as core different from existing structure Compound, and its intermediate, preparation method and application.The present invention Large cyclic heterocyclic compound to HCV have compared with Good inhibitory activity, can be effective for treatment infection with hepatitis C virus, and has relatively low toxic side effect.
According to the one side of the application, this application provides formula A compound:
Or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt or their mixture；
Wherein,
A-B is singly-bound or carbon-carbon double bond, and when A-B is singly-bound, A is selected from carbon, oxygen, sulphur or nitrogen, and B is selected from carbon；
N=0,1 or 2；
Q is selected from C1-6Alkyl, C2-6Alkenyl or C3-6Cycloalkyl；
L independently is oxygen, sulphur, a C2-C20Alkenyl, C1-C20Alkyl, C3-C20Cycloalkyl, C2-C20Heterocyclic radical, C6-C20 Aryl, C3-C20Heterocyclic aryl, C1-C20Alkylthio group, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C2-C20Heterocyclic radical epoxide, C1- C20Alkyl amino, C1-C20The carbonyl of alkoxy one, C6-C20Aryl or C6-C20Aryloxy group；
L1It is each independently oxygen, sulphur, C2-C20Alkenyl, C1-C20Alkyl, C3-C20Cycloalkyl, C2-C20Heterocyclic radical, C6-C20 Aryl, C3-C20Heterocyclic aryl, C1-C20Alkylthio group, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C2-C20Heterocyclic radical epoxide, C1- C20Alkyl amino, C1-C20Alkoxy carbonyl, C6-C20Aryl or C6-C20Aryloxy group；
X is oxygen, sulphur or nitrogen；
Y is nitrogen or CH；
R1For hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C6-C20Aryl, C3-C20Heterocyclic aryl, C1-C20Alkylsulfonylamino group Base, C2-C20Heterocycle sulfonamido or C1-C20Alkoxycarbonyl amino；
R2For hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy-carbonyl, C3-C20Cycloalkyloxy-carbonyl, C6- C20Aryl, C3-C20Heterocyclic aryl, C6-C20Aryloxy group, C1-C20Alkyl sulphonyl, C3-C20Naphthene sulfamide base, C1-C20Alcoxyl Base sulfonyl, C3-C20Cycloalkyloxy sulfonyl, C6-C20Aryl sulfonyl, C6-C20Aryloxy sulfonyl, C1-C20Alkylamino sulphur Acyl group, C3-C20Naphthene amino sulfonyl or C6-C20Fragrant amino sulfonyl；
R3、R4It is each independently hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy, halogen, hydroxyl, cyano group, Nitro, C1-C20Alkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Arylamino, C1-C20Alkyl sulfonyl amino, C2-C20Heterocycle sulfonamido, C6-C20Arenesulfonyl amino or C1-C20Alkyl sulfonyl amino amino；Wherein, R3With R4Between can be with It is interconnected to cyclic structure；
R5And R6It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkane Epoxide, C1-C20Alkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Arylamino, C1-C20Alkyl sulfonyl amino, C2-C20Heterocycle sulfonamido, C6-C20Arenesulfonyl amino or C1-C20Alkyl sulfonyl amino amino；
R7、R8、R9And R10It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, fluoroform alkyl, C1-C20Alkyl, C1-C20Alkoxy, C1-C20Alkylthio group, C1-C20Alkoxy-carbonyl, amino carbonyl, C1-C20Alkyl amino-carbonyl, carbonylamino, C1-C20Alkyl-carbonyl-amino, C2-C20Heterocyclic radical Epoxide carbonyl, C6-C20Aryl, C6-C20Aryloxy group, C6-C20Aryloxycarbonyl or C2-C20Heterocyclic radical；Wherein, R7With R8、R8With R9、R9With R10Between can be interconnected to 5-6 membered cyclic structures, its optional quilt Alkyl replaces；
J is hydrogen, hydroxyl, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C1-C20Alkyl Amino, C3-C20Cycloalkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Fragrant amino, C4-C20Heterocycle fragrant amino, RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C1-C20Alkyl, C1-C20Alkoxy, C3-C20 Cycloalkyl, C6-C20The C such as aryl, heteroaryl3-C20Cycloalkyloxy, C6-C20Aryloxy group, C1-C20Alkylamino, C3-C20Naphthene amino, C6-C20Fragrant amino, C1-C20Urea groups, C1-C20Ghiourea group, C1-C20Phosphate or C1-C20Borate；If R is substituted, take Dai Ji is selected from C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy.
Heterocycle in above-mentioned each group contains the 1-3 hetero atoms for being selected from nitrogen, oxygen and sulphur.
According to some embodiments of the application, in formula A,
R3、R4It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alcoxyl Base, C1-C6Alkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Arylamino, C1-C6Alkyl sulfonyl amino, C2-C6It is miscellaneous Cyclic sulfonamido, C6-C10Arenesulfonyl amino or C1-C6Alkyl sulfonyl amino amino, wherein the heterocycle contains 1-3 nitrogen, oxygen Or sulphur atom, or, R3With R4It is interconnected to the cyclic structure of 5-7 annular atom；
R5And R6It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alcoxyl Base, C1-C6Alkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Arylamino, C1-C6Alkyl sulfonyl amino, C2-C6It is miscellaneous Cyclic sulfonamido, C6-C10Arenesulfonyl amino or C1-C6Alkyl sulfonyl amino amino, wherein the heterocycle contains 1-3 nitrogen, oxygen Or sulphur atom；
R7、R8、R9And R10In, R7With R8、R8With R9And/or R9With R10Between to be interconnected to oxygen-containing or nitrogen 5-6 members miscellaneous Ring, and the heterocycle optionally replaces by C1-C6 alkyl；Remaining is not into cyclic group independently selected from hydrogen, halogen, hydroxyl, cyano group, nitre Base, fluoroform alkyl, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkylthio group, C1-C6Alkoxy-carbonyl, amino carbonyl, C1-C6 Alkyl amino-carbonyl, carbonylamino, C1-C6Alkyl-carbonyl-amino, C2-C6Heterocyclic radical Epoxide carbonyl, C6-C10Aryl, C6-C10Virtue Epoxide, C6-C10Aryloxycarbonyl or C2-C6Heterocyclic radical, wherein the heterocycle contains 1-3 nitrogen, oxygen or sulphur atom；
J is hydrogen, hydroxyl, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C1-C6Alkyl ammonia Base, C3-C6Cycloalkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Fragrant amino, C4-C10Heterocycle fragrant amino, RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C1-C10Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, C1-C6 Alkoxy, C3-C6Cycloalkyloxy, C6-C10Aryloxy group, C1-C6Alkylamino, C3-C6Naphthene amino, C6-C10Fragrant amino, C1-C6Urea Base, C1-C6Ghiourea group, C1-C6Phosphate-based or C1-C6Boric acid ester group；
L is singly-bound, oxygen, sulphur, C2-C6Alkenyl, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Heterocyclic radical, C6-C10Aryl, C3- C6Heterocyclic aryl, C1-C6Alkylthio group, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C2-C6Heterocyclic radical epoxide, C1-C6Alkyl amino, C1-C6Alkoxy carbonyl, C6-C10Aryl or C6-C10Aryloxy group；
L1Selected from oxygen, sulphur, C2-C6Alkenyl, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Heterocyclic radical, C6-C10Aryl, C3-C6It is miscellaneous Ring C6-C10Aryl, C1-C6Alkylthio group, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C2-C6Heterocyclic radical epoxide, C1-C6Alkyl amino, C1-C6Alkoxy carbonyl, C6-C10Aryl or C6-C10Aryloxy group；
X is oxygen, sulphur or nitrogen；
Y is nitrogen or CH；
R1For hydrogen, C1-C6Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, C3-C6Heterocyclic aryl, C1-C6Alkyl sulfonyl amino, C2-C6Heterocycle sulfonamido or C1-C6Alkoxycarbonyl amino；
R2For hydrogen, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy-carbonyl, C3-C6Cycloalkyloxy-carbonyl, C6-C10Virtue Base, C3-C60Heterocycle C6-C10Aryl, C6-C10Aryloxy group, C1-C6Alkyl sulphonyl, C3-C6Naphthene sulfamide base, C1-C6Alkoxy Sulfonyl, C3-C6Cycloalkyloxy sulfonyl, C6-C10Aryl sulfonyl, C6-C10Aryloxy sulfonyl, C1-C6Alkylamino sulphonyl Base, C3-C6Naphthene amino sulfonyl or C6-C10Fragrant amino sulfonyl.
According to other embodiments of the application, in formula A,
L is singly-bound；
L1Selected from oxygen or sulphur；
X is selected from oxygen, sulphur or nitrogen；
Y is selected from nitrogen or CH；
R1Selected from the tert-butyl group；
R2Selected from hydrogen；
R3And R4It independently is methyl；
R5And R6It independently is hydrogen；
R7、R8、R9And R10In, R7With R8、R8With R9Or R9With R10Between be interconnected to oxygen-containing or nitrogen 5-6 circle heterocycles (such as the five-membered ring containing 2 oxygen atoms), and the heterocycle is optionally by C1-C6Alkyl substitution (if not being substituted or being replaced by methyl)； Remaining is not selected from hydrogen into cyclic group；With
J is selected from RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C3-C6Cycloalkyl.
The formula A compounds of the present invention include Formulas I or II big ring-type polycyclic compound:
Or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt or their mixture；In Formulas I and Formula II The definition of each group is with the definition in formula A.
There is provided the polycyclic compound of Formula V according to the second aspect of the invention:
Wherein,
R7、R8,R9And R10It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, fluoroform alkyl, C1-C20Alkyl, C1-C20Alkoxy, C1-C20Alkylthio group, C1-C20Alkoxy-carbonyl, amino carbonyl, C1-C20The amino carbonyl of alkyl one, carbonyl ammonia Base, C1-C20Alkyl-carbonyl-amino, C2-C20Heterocyclic radical Epoxide carbonyl, C6-C20Aryl, C6-C20Aryloxy group, C6-C20Aryloxy group carbonyl Base or C2-C20Heterocyclic radical；Wherein, R7With R8And/or R8With R9Or R8With R10Between can be interconnected to alkyl-substituted 5-6 Membered cyclic structure；
The third aspect of the present invention includes there is provided a kind of method for preparing compound V of the present invention, this method:It is logical Cross following reaction synthesizing heterocyclic compounds V:
Compound Va-f is made by condensation reaction using raw material SM-2 and raw material SM-2a；Wherein, R7、R8、R9And R10's Definition is with described in claim 1；
Described prepare compound V condensation reaction is under inert gas shielding, to carry out in organic solvent, raw material SM-2a consumption is 1-2 times of SM-2 moles；Reaction temperature is 50-100 DEG C；
In the present invention, optimal, Formula V is following any structure：
There is provided a kind of side of the big ring-type polycyclic compound for the formula A (Formulas I) for preparing the present invention for the fourth aspect of the present invention Method, including following five steps:
1) under inert gas shielding, raw material SM-3 is in anhydrous organic solvent, in triphenyl phosphorus and azodicarboxylate (such as：Diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) in the presence of with another reagent V occur Mitsunobu it is anti- Should, generation compound 3-1；Other each groups in SM-3 and compound V and product 3-1 (including X, Y, R5、R6、R7、R8、R9) determine Justice is with described in claim 1；R11Definition with described in claim 5；
2) under inert gas shielding, by step 1) in obtained compound 3-1 slough protection group R11Afterwards again in coupling examination Agent is (such as：HATU with another amino acid derivativges reagent SM-4 reaction generation compounds 3-2 in the presence of)；It is each in SM-4 and 3-2 Group (including X, Y, R1、R2、R5、R6、R7、R8、R9、R10) definition with described in claim 1；R11Definition with claim 5 It is described；
3) under inert gas shielding, by step 2) obtained compound 3-2 sloughs protection group R11Afterwards again in phosgene or three In the presence of phosgene, react to form compound 3-3 with another reagent SM-5；Each group and parameter (bag in reagent SM-5 and product Include n, L, L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10) definition with described in claim 1；R10The same right of definition It is required that described in 5；
4) under inert gas shielding, by step 3) obtained compound 3-3 is in the presence of palladium catalyst, and reaction is obtained Big cyclic products 3-4；Each group and parameter in product (including n, L, L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10) Definition is with described in claim 1；
5) under inert gas shielding, by step 4) obtained compound 3-4 after hydrolysis acidification again with SM-6 in coupling Reagent is (such as：HATU the final big ring-type polycyclic compound I of reaction generation in the presence of)；Each group and parameter in SM-6 and product (including n, L, L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10, J) definition with described in claim 1；
In step 1) in, under inert gas shielding, SM-3 raw materials are dissolved in organic solvent (such as dichloromethane, tetrahydrochysene furan Mutter or toluene) in, in triphenyl phosphorus and azodicarboxylate (such as：Diethylazodicarboxylate or azo-2-carboxylic acid's diisopropyl Ester) in the presence of occur Mitsunobu reactions, generation compound 3-1 with another reagent V；The reaction temperature is 0-40 DEG C, institute The triphenyl phosphorus consumption stated is 1-2 times of raw material SM-3 moles, and described azodicarboxylate's consumption is SM-3 moles of raw material 1-2 times of amount；
In step 2) in, by step 1 under inert gas shielding) obtained compound 3-1 is in strong acid (such as hydrochloric acid, sulfuric acid Or trifluoroacetic acid) in the presence of, in the case where temperature is 10-50 DEG C, protection group R is sloughed in reaction11(such as Boc) generates amine intermediate afterwards, then In coupling reagent (such as：HATU in the presence of), at 0-80 DEG C of temperature organic solvent (such as dichloromethane, tetrahydrofuran or N, Dinethylformamide) in reagent SM-4 reaction obtain compound 3-2；The consumption of described coupling reagent is compound 3-1 1-2.5 times of mole.
In step 3) in, by step 2 under inert gas shielding) obtained compound 3-2 is in strong acid (such as hydrochloric acid, sulfuric acid Or trifluoroacetic acid) in the presence of, in the case where temperature is 10-50 DEG C, protection group R is sloughed in reaction11Amine intermediate is generated afterwards, then in phosgene Or isocyanate intermediate is generated in the presence of triphosgene, then in organic solvent (such as dichloromethane, four at 0-40 DEG C of temperature Hydrogen furans or toluene) in react to form compound 3-3 with another reagent SM-5；The consumption of described triphosgene is compound 3-2 1-2 times of mole.
In step 4) in, under inert gas shielding, by step 3) obtained compound 3-3 is dissolved in anhydrous organic solvent In (such as Isosorbide-5-Nitrae-dioxane, tetrahydrofuran or toluene), in palladium catalyst (such as palladium or tetra-triphenylphosphine palladium), phosphorus part In the presence of (such as 2- (di-t-butyl phosphorus) -1,1 '-dinaphthalene) and inorganic strong alkali (such as cesium carbonate), reacted at 0-100 DEG C of temperature, Obtain big cyclic products 3-4；The consumption of palladium catalyst is the 0.2-5% of raw material SM-1 moles；The consumption of phosphorus part is raw material The 0.3-10% of SM-1 moles；The consumption of inorganic base is 1-3 times of raw material SM-1 moles；
In step 5) in, by step 4) obtained compound 3-4 in inorganic strong alkali (such as：Lithium hydroxide or sodium hydroxide) Under effect, in solvent (such as water, methanol, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane), it is hydrolyzed in 10-60 DEG C and sloughs protection group Acidifying generation carboxylic acid after methoxyl group, then in coupling reagent (such as：HATU in the presence of), in organic solvent (such as dichloromethane, tetrahydrochysene Furans or N, N dimethyl formamide) in, the polycyclic product I of big ring-type is obtained by amidation process with SM-6；Described coupling The consumption of reagent is 1-2.5 times of compound 3-4 moles；The temperature of amidation process is 0-80 DEG C；
There is provided a kind of side of the big ring-type polycyclic compound for the formula A (Formula II) for preparing the present invention for the fifth aspect of the present invention Method, including following six step:
1) under inert gas shielding, raw material SM-3 is in anhydrous organic solvent, in triphenyl phosphorus and azodicarboxylate (such as：Diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) in the presence of with another reagent V occur Mitsunobu it is anti- Should, generation compound 3-1；Other each groups in SM-3 and compound V and product 3-1 (including X, Y, R5、R6、R7、R8、R9、R10) Definition with described in claim 1；R11Definition with described in claim 5；
2) under inert gas shielding, by step 1) in obtained compound 3-1 with the potassium fluoborate of ethene three in palladium chtalyst Agent (such as Pd (dppf) Cl2) in the presence of, compound 4-1 is obtained by Suzuki reactions；Each group in product (including X, Y, R5、 R6、R7、R8、R9、R10) definition with described in claim 1；R11Definition with described in claim 5；
3) under inert gas shielding, by step 2) in obtained compound 4-1 slough protection group R11Afterwards again in coupling examination With another amino acid derivativges reagent SM-4 reaction generation compounds 4-2 in the presence of agent；Each group in product (including X, Y, R1、R2、R5、R6、R7、R8、R9、R10) definition with described in claim 1；R11Definition with described in claim 5；
4) under inert gas shielding, by step 3) obtained compound 4-2 sloughs protection group R11Afterwards again with another reagent SM-7 reacts to form compound 4-3；Each group and parameter in reagent SM-7 and product (including n, L, L1、X、Y、R1、R2、R3、R4、 R5、R6、R7、R8、R9、R10) definition with described in claim 1；R11Definition with described in claim 5；
5) under inert gas shielding, by step 4) obtained bifunctional vinyl compound 4-3 in ruthenium catalyst (such as:Zhan Shi is catalyzed Agent or Grubbs catalyst etc.) in the presence of, big cyclic products 4-4 is obtained by olefin metathesis cyclization；It is each in product Group and parameter (including n, L, L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10) definition with described in claim 1；
6) under inert gas shielding, by step 5) obtained compound 4-4 after hydrolysis acidification again with SM-6 in coupling Reagent is (such as：HATU the final Macrocyclic compound II of reaction generation in the presence of)；Each group and parameter in SM-6 and product (including n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10, J) definition with described in claim 1；
In step 1) in, under inert gas shielding, SM-3 raw materials are dissolved in organic solvent (such as dichloromethane, tetrahydrochysene furan Mutter or toluene) in, in triphenyl phosphorus and azodicarboxylate (such as：Diethylazodicarboxylate or azo-2-carboxylic acid's diisopropyl Ester) in the presence of occur Mitsunobu reactions, generation compound 3-1 with another reagent V；The reaction temperature is 0-40 DEG C, institute The triphenyl phosphorus consumption stated is 1-2 times of raw material SM-3 moles, and described azodicarboxylate's consumption is SM-3 moles of raw material 1-2 times of amount；
In step 2) in, under inert gas shielding, by step 1) in obtained compound 3-1 be dissolved in organic solvent (such as Ethanol, toluene or tetrahydrofuran) in, with the potassium fluoborate of ethene three in palladium catalyst (such as Pd (dppf) Cl2) and alkali (such as three second Amine) in the presence of, compound 4-1 is obtained by Suzuki reactions at 20-100 DEG C of temperature；The described potassium fluoborate of ethene three Consumption is 1-4 times of raw material SM-3 moles；Described palladium catalyst consumption is 0.03-5% times of raw material SM-3 moles；Institute The base amount stated is 1-4 times of raw material SM-3 moles.
In step 3) in, by step 2 under inert gas shielding) obtained compound 4-1 is in strong acid (such as hydrochloric acid, sulfuric acid Or trifluoroacetic acid) in the presence of, in the case where temperature is 10-50 DEG C, protection group R is sloughed in reaction11(such as Boc) generates amine intermediate afterwards, then In coupling reagent (such as：HATU in the presence of), at 0-80 DEG C of temperature organic solvent (such as dichloromethane, tetrahydrofuran or N, Dinethylformamide) in reagent SM-4 reaction obtain compound 4-2；The consumption of described coupling reagent is compound 4-1 1-2.5 times of mole.
In step 4) in, by step 3 under inert gas shielding) obtained compound 4-2 is in strong acid (such as hydrochloric acid, sulfuric acid Or trifluoroacetic acid) in the presence of, in the case where temperature is 10-50 DEG C, protection group R is sloughed in reaction11Amine intermediate is generated afterwards, then in alkali (such as Triethylamine) in the presence of, in organic solvent (such as dichloromethane, tetrahydrofuran or toluene), in 10-30 DEG C and another reagent SM-7 reacts to form bifunctional vinyl compound 4-3；The consumption of described alkali is 1-5 times of compound 4-2 moles.
In step 5) in, by step 4 under inert gas shielding) obtained bifunctional vinyl compound 4-3 be dissolved in it is anhydrous organic molten In agent (such as dichloromethane, dichloroethanes or toluene), in ruthenium catalyst (such as:Zhan Shi catalyst or Grubbs catalyst etc.) work Under, reacted at 0-100 DEG C of temperature, by olefin metathesis cyclization, obtain big cyclic products 4-4；Described ruthenium is urged Agent consumption is the 0.2-10% of bifunctional vinyl compound 4-3 moles；Described consumption of organic solvent is bifunctional vinyl compound 4-3 weight 15-40 times of ratio；
In step 6) in, by step 5) obtained compound 4-4 in inorganic strong alkali (such as：Lithium hydroxide or sodium hydroxide) Under effect, in solvent (such as water, methanol, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane), it is hydrolyzed in 10-60 DEG C and sloughs protection group Acidifying generation carboxylic acid after methoxyl group, then in coupling reagent (such as：HATU in the presence of), in organic solvent (such as dichloromethane, tetrahydrochysene Furans or N, N dimethyl formamide) in, the polycyclic product II of big ring-type is obtained by amidation process with SM-6；Described idol The consumption for closing reagent is 1-2.5 times of compound 3-4 moles；The temperature of amidation process is 0-80 DEG C；
There is provided a kind of compound of the present invention, its stereoisomer, dynamic isomer, ester for the sixth aspect of the present invention Change or the purposes of amidated pro-drug, pharmaceutically acceptable salt or its mixture, it is used to suppress HCV；Or for making The standby medicine for suppressing HCV.
The seventh aspect of the present invention there is provided a kind of pharmaceutical composition, comprising:One or more formula A of the present invention are (such as Formulas I or II) compound or its stereoisomer, dynamic isomer, esterification or amidated pro-drug or its pharmaceutically may be used The salt of receiving, and pharmaceutically acceptable excipient.
The eighth aspect of the present invention there is provided a kind of composition, including:One or more following medicines and one or more Formula A (such as Formulas I or II) compounds of the present invention or its stereoisomer, dynamic isomer, esterification or amidated precursor Medicine or its pharmaceutically acceptable salt:(1) immunomodulator；(2) HCV (HCV) protease inhibitors；(3) HCV (HCV) AG14361；(4) nucleosides and nucleoside derivates of (2)-(3) are not belonging to；(5) hepatitis B Viral (HBV) inhibitor；(6) human immune deficiency virus (HIV) inhibitor；(7) cancer therapy drug；(8) anti-inflammatory drug；Or (9) It is not belonging to other compounds of above-mentioned (1)-(8).
The pharmaceutical composition of the application includes but is not limited to peroral dosage form, parenteral dosage forms, exterior-applied formulation and rectum Form of administration.In some embodiments, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release Preparation, solution and suspension, sterile solution, suspension or emulsion for parental injection.In other embodiments, it is described Pharmaceutical composition is to be adapted to the unit dosage forms that single bestows exact dose.In other embodiments, the amount of the compound exists In the range of about 0.001mg/kg body weight/days-about 1000mg/kg body weight/days.In other embodiments, the compound The scope of amount is about 0.5mg/kg body weight/days-about 50mg/kg body weight/days.In some embodiments, the amount of the compound It is about 0.001g/ days-about 7g/ days.In other embodiments, the amount of the compound is about 0.002g/ days-about 6g/ days. In other embodiment, the amount of the compound is about 0.005g/ days-about 5g/ days.In other embodiments, the chemical combination The amount of thing is about 0.01g/ days-about 5g/ days.In other embodiments, the amount of the compound is about 0.02g/ days-about 5g/ My god.In other embodiments, the amount of the compound is about 0.05g/ days-about 2.5g/ days.In other embodiments, institute The amount for stating compound is about 0.1g/ days-about 1g/ days.In other embodiments, the dosage level less than above range lower limit can Can be enough.In other embodiments, it may be necessary to higher than the dosage level of the above range upper limit.In some implementations In mode, the compound is applied with single dose, once a day.In other embodiments, the chemical combination is applied with multiple dose Thing, daily more than once.In some embodiments, the compound twice is applied daily.In other embodiments, daily Using three compounds.In other embodiments, four compounds are applied daily.In other embodiments, The compound that administration daily is more than four times.In some embodiments, the individual that described pharmaceutical composition is applied to is the food in one's mouth Newborn animal.In other embodiments, the mammal is people.In other embodiments, described pharmaceutical composition is also wrapped Containing at least one therapeutic agent (a kind of formulation is made).In some embodiments, described pharmaceutical composition and at least one are controlled Agent is treated respectively with independent dosage form combination into combination product, such as set containing medicines (kit of part).
Wherein, described immunomodulator includes interferon or interferon derivative.Wherein described interferon can be poly- Ethylene glycol interferon.
Described hiv inhibitor is including but not limited to Ritonavir medicine (Ritonavir).
Described hepatitis type B virus (HBV) inhibitor including but not limited to:Lamivudine, Sebivo, adefovirdipivoxil, Emtricitabine, Entecavir, tenofovir or clevudine.
The ninth aspect of the present invention answering in suppression HCV is prepared there is provided any of the above-described pharmaceutical composition With.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and produce the present invention each preferably Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is:
1) Large cyclic heterocyclic compound of the invention not only has preferably inhibitory activity to NS3 HCVs, and And it is substantially better than the inhibitory activity of the Macrocyclic compound of the own clinical test of other different types；
2) present invention have extensively studied the structure of different Large cyclic heterocyclic compounds and be imitated with suppressing the structure of hepatitis C virus activity Relation, and it was found that some effectively suppress the Large cyclic heterocyclic compound structures of hepatitis C virus；
3) present invention optimizes the preparation of Novel macrocyclic shape polycyclic compound and its polycyclic small molecule intermediates of different type Method, largely reduces preparation cost, is the industrialization of the polycyclic hepatitis C virus inhibitors medicine of Novel macrocyclic shape Production provides an effective practical new method.
4) some Large cyclic heterocyclic compounds of the invention have very low toxic side effect or substantially nontoxic, it is possible to Further successfully research and develop the anti-hepatitis c virus new drug of a high effect nontoxic.
Next, the preparation method to compound of the present invention is described further：
The present invention not only designs and synthesized the Novel macrocyclic shape polycyclic compound for suppressing HCV, also enters One step has deeply probed into difference by the research to the Macrocyclic compound suppression hepatitis C virus cytotoxic activity containing polycyclic functional group The new Macrocyclic compound containing polycyclic functional group of structure and the relation for suppressing hepatitis C virus cytotoxic activity, are further researched and developed excellent Changed effective for treat infection with hepatitis C virus Novel macrocyclic shape polycyclic compound, and preparation method thereof.
The crux innovative point of the present invention is to have synthesized novel multi-cyclic compounds Va-Vi first, and synthesizes general key Intermediate 7 and 13, has then synthesized Formulas I-II Macrocyclic compounds.
The English of chemical reagent and solvent during Macrocyclic compound of the synthesizing new of the present invention containing polycyclic functional group Abbreviation annotation, which all collects, is listed in embodiment Instrumental and raw material declaratives.
In following reaction scheme 1, raw material SM-2 or SM-2 ' and raw material SM-2a is respectively adopted in organic solvent (such as：Methanol, Ethanol, DMF etc.) in reacted, (50-100 DEG C) is made respectively by condensation reaction in a heated condition Compound Va-Vf；
Reaction scheme 1:Intermediate Va, Vb, Vc, Vd, Ve, Vf synthesis
Reaction scheme 2:Intermediate Vg, Vh, Vi synthesis
The method shown in 1 and 2 obtains novel multi-cyclic compounds Va-Vf, Vg-Vi crucial in the present invention from the reactions above Afterwards, in order to carry out structural behaviour optimization innovation from different perspectives, the present invention devises following synthetic route and is prepared in key Mesosome 7 (reaction scheme 3) and 13 (reaction schemes 4).Followed by shared intermediate 7 or 13 be raw material, synthesized it is a series of most Finished product LW100201-LW100224 (i.e. I) and LW100225-LW100226 (i.e. II).Specific each step reaction experiment and Detailed conditions and product analysis result are listed in embodiment respectively.
Reaction scheme 3：
In above-mentioned synthetic reaction route 3, SM-3 raw materials are dissolved in anhydrous organic solvent (such as dichloromethane, tetrahydrochysene furan first Mutter or toluene) in, in the presence of triphenyl phosphorus and azodicarboxylate, occur Mitsunobu with another reagent Va-Vf respectively Reaction, generates compound 4；Then Boc protection groups are removed with hydrochloric acid and generates amine intermediate, then in the presence of coupling reagent HATU Compound 5 is generated with the amino acid derivativges SM-4 of another protection；5 remove Boc protection groups with hydrochloric acid generates amine intermediate, then Isocyanate intermediate is generated in the presence of phosgene or triphosgene, then reacts to form compound 6 with neopentyl glycol；6 anhydrous In organic solvent, in the presence of palladium catalyst, reaction obtains big ring-type key intermediate 7；Effect of the product 7 in lithium hydroxide Lower hydrolysis generation carboxylic acid 8；Last 8 pass through amidatioon with another carbamate raw material SM-6 in the presence of coupling reagent HATU The final big ring-type polycyclic compound LW100201-LW100224 (i.e. I) of reaction generation.
Following structural formula series 1 for the present invention by reaction scheme it is 2-in-1 into key intermediate compound 6a-6f, 7a-7f And 8a-8f specific example, they have structural formula 1 as follows：
Structural formula 1：
Reaction scheme 4：
In above-mentioned reaction scheme 3, compound 4 (being obtained in reaction scheme 3) and the potassium fluoborate of ethene three are urged in palladium first Agent is (such as：Pd(dppf)Cl2) in the presence of, compound 10 is obtained by Suzuki reactions；Then with hydrochloric acid removing Boc protections Base generates amine intermediate, then the amino acid derivativges SM-4 generation compounds in the presence of coupling reagent HATU with another protection 11；11 remove Boc protection groups with hydrochloric acid generates amine intermediate, then in the presence of alkali (such as triethylamine), is reacted with acyl chlorides SM-7 Form compound 12；12 in anhydrous organic solvent (such as dichloromethane, dichloroethanes or toluene), in ruthenium catalyst (such as:0.2- 10%mol Zhan Shi catalyst or Grubbs catalyst etc.) in the presence of, pass through olefin metathesis cyclization (RCM:ring Closing metathesis, 0-100 DEG C), obtain the big cyclic products 13 of trans cycloolefin；13 in the presence of lithium hydroxide water Solution generation carboxylic acid intermediate；Last carboxylic acid intermediate is with another carbamate raw material SM-6 in the presence of coupling reagent HATU Final big ring-type polycyclic compound LW100225-LW100226 (i.e. II) is generated by amidation process.
The cyclization of olefines reaction of midbody compound 12 of two terminals containing diene Zhan used in above-mentioned synthetic reaction route 4 Family name's catalyst (Zhan Catalyst-1＆1B) structure is as shown in following structural series 2:
Structural formula series 2：
The key intermediate compound 12a's and 13a that following structural formula series 3 is synthesized for the present invention by reaction scheme 3 Specific example, they have structural formula as follows：
Structural formula series 3：
In above-mentioned reaction scheme 2-3, required raw material amino acid derivativges SM-6 is most preferably selected from serial 4 institutes of following structural The structure (SM-6a, SM-6b and SM-6c) shown:
In a word, through the multistep reaction in above-mentioned reaction scheme 2 and 3, the various heterocycles rolled into a ball containing different new functions have been synthesized Intermediate Va-Vi and final Macrocyclic compound I-II, the Novel macrocyclic shape final compound I-II's that table 1 synthesizes for the present invention Specific example, they have structural formula LW100201-LW100224 (I) and LW100225-LW100226 (II)：
The new HCV-Ab IgG inhibitor of table 1.
Detailed description of the invention
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme System.All documents or literature department quoted in the application point include but is not limited to patent, patent application, article, books, manipulator Volume and paper, are integrally incorporated herein by reference.
The technical terms of chemistry
Unless otherwise defined, the connotation that otherwise all scientific and technical terminologies have herein and claim theme art technology The connotation that personnel are generally understood that is identical.Unless otherwise indicated, all patents, patent application, the open material quoted in full herein It is integrally incorporated by reference herein.If there are multiple definition to term herein, it is defined by this chapter definition.
It should be understood that above-mentioned summary and being specified as hereafter are exemplary and be only used for explaining, without appointing to subject matter What is limited.In this application, unless otherwise expressly specified, it is otherwise plural using also including during odd number.It shall yet further be noted that unless another It is described, otherwise "or" used, "or" represent "and/or".In addition, term " comprising " used and other forms, such as " bag Containing ", it is " containing " and " containing " and non-limiting.
Can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method in the range of art technology, such as mass spectrum, NMR, IR and UV/Vis spectroscopic methodology and Pharmacological method.Unless proposed to be specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemistry Relevant description in the term that uses be known in the art.In chemical synthesis, chemical analysis, medicine preparation, preparation and it can pass Send, and to using standard technique in the treatment of patient.For example, using operation instruction of the manufacturer to kit, or according to The explanation of mode or the application well known in the art is implemented to react and purified.Generally can according in this specification quote and Description in the multiple summary discussed and more specific document, according to conventional method well known in the art implement above-mentioned technology and Method.In this manual, group and its substituent can be selected by those skilled in the art with provide stable structure division and Compound.
When the conventional chemical formulas by writing from left to right describes substituent, the substituent is similarly included from right to left Write substituent equivalent in chemistry resulting during structural formula.For example, CH2O is equal to OCH2。
Unless otherwise stated, general chemical terms used, such as, but not limited to, " alkyl ", " amine ", " aryl " etc. It is same as its optionally substituted form.For example, " alkyl " used herein includes optionally substituted alkyl.
Term " optionally/any " or " optionally/arbitrarily " refer to that the event or situation that then describe may occur or can Can not occur, the description includes occurring the event or situation and do not occur the event or situation.For example, according to determining hereafter Justice, " optionally substituted alkyl " refers to " unsubstituted alkyl " (alkyl of unsubstituted base substitution) or " substituted alkyl " (quilt The alkyl of substituent substitution).
C used herein1-CnIncluding C1-C2、C1-C3、……C1-Cn.For example, described " C1-C4" group refers to the portion There is 1-4 carbon atom, i.e. group to include 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms in point.Therefore, For example " C1-C4Alkyl " refers to that in the alkyl for having 1-4 carbon atom that is, described alkyl is selected from methyl, ethyl, propyl group, isopropyl Base, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.Digital scope herein, such as " 1-10 " refer to each in given range Individual integer, such as " 1-10 carbon atom " refer to that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon Atom, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
The term " alkyl " being used alone or in combination herein refers to the full of optionally substituted straight chain or optionally substituted side chain And aliphatic hydrocarbon.This paper " alkyl " can preferably have about 20 carbon atoms of 1-, such as, with about 10 carbon atoms of 1-, have About 8 carbon atoms of 1-, or about 6 carbon atoms of 1-, or about 3 carbon atoms of about 4 carbon atoms of 1- or 1-.This paper alkyl embodiment Including but not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl-l- propyl group, 2- methyl-2-propyls, 2-methyl-1-butene Base, 3- methyl-l- butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- propyl group, 2- methyl-1-pentenes base, 3- methyl-1-pentenes base, 4- methyl-l- amyl groups, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 2,2- dimethyl-l- butyl, 3, 3- dimethyl -1- butyl, 2- ethyl -1- butyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, new penta Base, tertiary pentyl and hexyl, and longer alkyl group, such as heptyl and octyl group.Group defined herein, such as " alkyl " occur During digital scope, such as " C1-C6Alkyl " or " C1-6Alkyl " refer to can by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 The alkyl that carbon atom, 5 carbon atoms or 6 carbon atoms are constituted, this paper alkyl also includes the situation of not specified digital scope.
" alkyl " that is applied in combination herein refers to alkyl, alkane sulphur in the alkyl linked with other groups, such as alkoxy " alkyl " in alkyl, hydroxy alkyl, haloalkyl, cyanogen substituted alkyl, alkyl monosubstituted amino, dialkyl amido in base etc..
The term " alkoxy " being used alone or in combination herein refers to alkylether radicals (O- alkyl), alkoxy it is non-limiting Embodiment includes methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tertiary fourth oxygen Base etc..
The term " alkenyl " being used alone or in combination herein refers to the one of optionally substituted straight chain or optionally substituted side chain Valency alkyl, it has at least one C=C double bond.The alkenyl has but is not limited to about 18 carbon atoms of 2-, for example, with 2- About 10 carbon atoms, or with about 8 carbon atoms of 2-, about 6 carbon atoms of 2-, about 4 carbon atoms of 2-.Double bond in these groups It can be cis or trans conformation, and should be understood to include described two isomers.Embodiment includes but is not limited to vinyl (CH=CH2), 1- acrylic (CH2CH=CH2), isopropenyl (C (CH3)=CH2), cyclobutenyl and 1,3- butadienyls etc..This When there is digital scope in the alkenyl of text definition, such as " C2-C6Alkenyl " or " C2-6Alkenyl " refers to can be by 2 carbon atoms, 3 carbon originals The alkenyl that son, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms are constituted, this paper alkenyl is also covered by not specified digital scope Situation.
The term " alkynyl " being used alone or in combination herein refers to the monovalent hydrocarbon of optionally substituted straight or branched, and it has There is at least one key of C ≡ C tri-.The alkynyl has but is not limited to about 18 carbon atoms of 2-, and for example it has about 10 carbon originals of 2- Son, or with about 8 carbon atoms of 2-, or about 6 carbon atoms of 2-, or about 4 carbon atoms of 2-.This paper alkynyl embodiment include but It is not limited to acetenyl, 2-propynyl, 2- butynyls and 1,3- diacetylene bases etc..When there is digital scope in alkynyl defined herein, Such as " C2-C6Alkynyl " or " C2-6Alkynyl " refers to can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 The alkynyl group that carbon atom is constituted, this paper alkynyl is also covered by the situation of not specified digital scope.
The term " halo " or " halogen substitution " being used alone or in combination herein refer to optionally substituted group (such as alkane Base, alkenyl and alkynyl) wherein at least one hydrogen atom be replaced by halogen (such as fluorine, chlorine, bromine, iodine or its combination).At some In embodiment, two or more hydrogen (such as difluoromethyl, trifluoromethyl) are replaced using mutually the same halogen；In other realities Apply in mode using not fully identical halogen replaces two or more hydrogen (such as the fluoro- 1- iodine ethyls of the chloro- 1- of 1-) each other.Halogen The nonlimiting examples of substituted alkyl are methyl fluoride and bromoethyl.The nonlimiting examples of haloalkenyl group are bromo vinyl.Halogen Nonlimiting examples for alkynyl are chloroethene alkynyl.
The term " aromatic radical/aryl " being used alone or in combination herein refers to optionally substituted aryl radical, and it has 6- About 20, such as 6-12 or 6-10 ring carbons, it can be monocyclic aryl, bicyclic aryl or more cyclophane base.It is bicyclic Aryl or more cyclophane base can be a monocyclic aryl and other free rings, and such as alicyclic ring, heterocycle, aromatic ring, heteroaromatic are mutually condensed. The nonlimiting examples of monocyclic aryl include the monocyclic virtue of 6 to about 12,6 to about 10 or 6 to about 8 ring carbons Base, such as phenyl；Bicyclic aryl is, for example, naphthyl；Polyaromatic is, for example, phenanthryl, anthryl, azulenyl.
The term " heterocyclic aryl or heteroaryl " being used alone or in combination herein refers to any substituted heteroaryl, and it is included About 5 to about 20, such as 5 to 12 or 5 to 10 skeleton ring member nitrogen atoms, wherein at least one (such as 1-4,1-3,1-2) Ring member nitrogen atoms are hetero atom, hetero atom of the hetero atom in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but are not limited to This.The ring of the group does not include two adjacent O or S atom.Heteroaryl includes bicyclic heteroaryl (have a ring), bicyclic Heteroaryl (there are two rings) or polyheteroaromatic (there are more than two rings).Occur two or more in ring heteroatomic In embodiment, described two or more hetero atoms can be mutually the same, or in described two or more hetero atom some or It is all different from each other.Bicyclic heteroaryl or more ring heteroaryl can be a bicyclic heteroaryl and other free rings, such as alicyclic ring, Heterocycle, aromatic ring, heteroaromatic mutually condense and (can be collectively referred to as fused ring heteroaryl).The nonlimiting examples of bicyclic heteroaryl include 5 To about 12,5 to about 10,5 to about 7 or the bicyclic heteroaryl of 6 skeleton ring member nitrogen atoms, such as its nonlimiting examples Including pyridine radicals；Fused ring heteroaryl includes benzimidazolyl (benzimidazolyl), quinolyl (quinolinyl), a word used for translation Piperidinyl (acridinyl).The other embodiments of heteroaryl include but is not limited to：Pyridine, pyrimidine, pyrazine, pyridazine, triazine, furans, Thiophene, imidazoles, triazole, tetrazolium, thiazole, isothiazole, 1,2,4- thiadiazoles, pyrroles, pyrazoles, oxazole, isoxazole, oxadiazoles, benzene And furans, benzothiophene, benzothiazole, indoles, indazole, quinoline, isoquinolin, purine, carbazole, benzimidazole, pyrrolopyridine, Pyrrolopyrimidine, Pyrazolopyridine, pyrazolopyrimidine etc..Acridinyl, phenazinyl, benzoxazolyl, diazosulfide base, benzo Oxadiazolyl, BTA base, isoquinolyl, benzazole base (indolizinyl), isothiazolyl (isothiazolyl), different nitrogen Miscellaneous indenyl (isoindolyl), oxadiazolyls (oxadiazolyl), purine radicals (purinyl), phthalazinyl (phthalazinyl), pteridyl (pteridinyl), quinazolyl (quinazolinyl), quinoxalinyls (quinoxalinyl), triazine radical (triazinyl) and thiadiazolyl group (thiadiazolyl) etc., and its oxide, such as pyrrole Piperidinyl-N- oxides (pyridyl-N-oxide) etc..
The term " heterocycle " being used alone or in combination herein or " heterocyclic radical " refer to nonaromatic heterocycles, and it includes saturated heterocyclic Or unsaturated heterocycle (containing unsaturated bond).The atom of one or more (such as 1-4,1-3,1-2) cyclization is miscellaneous Atom, such as oxygen, nitrogen or sulphur atom.Heterocycle can include single heterocycle (having a ring) or double heterocycles (ring that there are two bridges to close) Or many heterocycles (ring that there is two or more bridge to close)；Also loop coil is included.Heterocyclic radical can have 3 to about 20, such as 3- about 10,3- About 8,4-8,4-7, about 6 ring member nitrogen atoms of 5- about 8 or 5-.The non-limiting example of heterocyclic radical includes azine (azinyl), azetidinyl (azetidinyl), oxetanylmethoxy (oxetanyl), thietanyl (thietanyl), Homopiperidinyl (homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, Thiazepinyl, 1,2,3,6- tetrahydro pyridyl (1,2,3,6-tetrahydropyridinyl), 2- pyrrolinyls (2- Pyrrolinyl), 3- pyrrolinyls (3-pyrrolinyl), indoline base (indolinyl), 2H- pyranoses (2H- Pyranyl), 4H- pyranoses (4H-pyranyl), dioxane hexyl (dioxanyl), 1,3- dioxolanyls (1,3- Dioxolanyl), pyrazolinyl (pyrazolinyl), two sulphur cyclohexyl (dithianyl), two sulphur cyclopenta (dithiolanyl), dihydro pyranyl (dihydropyranyl), dihydro-thiophene base (dihydrothienyl), dihydrofuran Base (dihydrofuranyl), pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazoles piperidinyl (imidazolidinyl), 3- azabicyclos [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3- azabicyclos [4.1.0] heptyl (3-azabicyclo [4.1.0] heptyl), 3H- indyls (3H-indolyl) and quinolyl (quinolizinyl) etc..The term also includes all annular forms of carbohydrate, including but not limited to monose, disaccharides and oligosaccharides. Embodiment also includes but is not limited to, aziridine, tetrahydrofuran, thiophane, pyrrolidines, oxazolidines, thiazolidine, imidazolidine, different Oxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidyl etc..Heterocyclic radical is also included with one or more The heterocycle of aromatic rings fusion (having a common key), such as 2,3- Dihydrobenzofuranes, 1,3- benzodioxolanes, benzene And-the dioxane of Isosorbide-5-Nitrae-, BIDA, naphthalimide.Heterocyclic radical with one or more fragrance fusions can lead to Cross aromatic rings or non-aromatic ring part is connected with other groups.Other groups can be combined by hetero atom or carbon atom with heterocycle (i.e. heterocycle is connected or is further substituted with parent molecule).
The term cycloalkyl being used alone or in combination herein can be monocyclic cycloalkyl or bicyclic cycloalkyl, ring Between can be bridge close or loop coil.Cycloalkyl can have 3 to 20 carbon atoms, such as with about 15 ring carbons of 3- or About 10 ring carbons of 3- or 3-6 ring carbons.Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloheptyl Base, adamantyl etc..
Alkoxy is represented by " alkyl-O- "；Cycloalkyloxy is represented by " cycloalkyl-O- "；Aryloxy group is represented by " virtue Base-O- "；Alkylamino is represented by " alkyl-N- "；Naphthene amino is represented by " cycloalkyl-N- "；Fragrant amino is represented by " virtue Base-N- ", alkyl therein, cycloalkyl and aryl are defined as above.
" halogen " refers to fluorine, chlorine, bromine, iodine.First choice is fluorine, chlorine and bromine.Cyano group refers to "-CN "；Hydroxyl refers to "-OH "；Mercapto Base refers to "-SH "；Amino refers to "-NH2”。
Sulfonamido refers to " RSO2NH- " andAmino-sulfonyl refers to "-SO2NH2" or "-SO2NHR ", its Middle R can be alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, aryloxy group, alkylamino, naphthene amino, fragrant ammonia Base, urea groups, ghiourea group, phosphate or borate, these groups are defined as above.It is appreciated that alkyl sulfonyl amino refers to sulphur R is the situation of alkyl in the structural formula that acylamino- is represented, alcoxyl ylsulfonylamino refers to that R is in the structural formula that sulfonamido is represented The situation of alkoxy, by that analogy.
Term " substituted " means that one or more appointed groups of hydrogen on a specific atom are replaced Generation, if the normal chemical valence for the atom specified in the case of existing without departing from, then result is a stabilization after substitution Compound.
Technical term of pharmacology
Some technical term of pharmacology relevant term " subject ", " patient " or " individual " used herein refers to suffer from disease, disease The individual of disease or the patient's condition etc., including mammal and nonmammalian.The embodiment of mammal includes but is not limited to lactation and moved Any member of thing guiding principle：People, inhuman primate (such as chimpanzee and other apes and monkey)；Domestic animal, such as ox, horse, Sheep, goat, pig；Domestic animal, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and Cavy etc..The embodiment of non-human mammal includes but is not limited to birds and fish etc..Provided herein is a method In the embodiment of composition, the mammal is behaved.
Term " treatment " used herein includes alleviating, mitigate or improving disease or illness disease with other similar synonyms Shape, prevents other symptoms, improves or prevention causes the potential metabolism reason of symptom, suppress disease or illness, for example, prevent disease Or the development of illness, alleviate disease or illness, disease or illness is taken a turn for the better, alleviate the symptom caused by disease or illness, or Stop the symptom of disease or illness, in addition, the term includes the purpose of prevention.The term also include obtain therapeutic effect and/or Preventive effect.The therapeutic effect refers to cure or improves treated potential disease.In addition, pair related to potential disease one Plant or the healing or improvement of a variety of physiological signs are also therapeutic effect, although for example patient may nevertheless suffer from the shadow of potential disease Ring, but observe that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk Compound, even if or not yet make medical diagnosis on disease, but apply institute to the patient for one or more physiological signs of the disease occur State composition.
Term " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with certain At least one medicament or the amount of compound of one or more symptoms of the treated disease of alleviation or illness in degree.Its result Can be sign, the abatement of symptom or the cause of disease and/or alleviation, or biosystem it is any other needed for change.For example, for controlling " effective dose " treated is clinically to provide the composition for including compound disclosed herein needed for significant remission effect Amount.The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.
Terms used herein " taking ", " administration ", " administration " etc. are to refer to compound or composition being delivered to progress The method in the required site of biological agent.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Art technology Personnel know the application technique available for Compounds and methods for described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, Discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa Those.In a preferred embodiment, the compound and composition being discussed herein are by orally administering.
Refer to dock the one of treated subject herein for term " acceptable " used in preparation, composition or composition As health condition there is no long-term adverse effect.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity for not influenceing the application compound or property Material (such as carrier or diluent), and relative nontoxic, the i.e. material can be applied to individual without causing bad biological respinse Or interacted with any component included in bad mode and composition.
Terms used herein " carrier " refers to the chemical compound or reagent of relative nontoxic, and it helps to introduce compound Into cell or tissue.
Terms used herein " pharmaceutically acceptable salt " refers to the free acid for remaining appointed compound and free alkali Biopotency, and there is no on biology or other side the salt of ill-effect.The application compound also includes pharmaceutically may be used With the salt of receiving.Pharmaceutically acceptable salt refers to the form for the base group in parent compound being converted into salt.Pharmaceutically Acceptable salt is include but not limited to, the inorganic or organic acid salt of base group such as amine (ammonia) base.The application is pharmaceutically Acceptable salt can be synthesized by parent compound, i.e. the acid of basic group in parent compound and 1-4 equivalents is molten at one Reacted in agent system.Suitable salt is set forth in Remingtong ' s Pharmaceutical Scicences, 17th ed.,Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, In 66,2 (1977).
In addition to special instructions, the salt in the application refers to the acid salt with the formation of organic acid/inorganic acid, and with organic base/ The basic salt of inorganic base formation.In addition, when the basic functionality of compound of formula I be pyridine or imidazoles (but be not restricted to pyridine or Imidazoles), acidic functionality will form amphion (inner salt) when being carboxylic acid (but being not restricted to carboxylic acid), inner salt is also included within this In salt in application.
" stereoisomer " used herein refers to as different produced by the spatially arrangement mode difference of atom in molecule Structure body.Compound of formula I contains asymmetric or chiral centre, and accordingly, there exist different stereoisomeric forms in any ratio.Molecular formula I's is all Stereochemical structure is as mixture, including racemic mixture, is used as the part applied at present.Non-enantiomer mixture can Single diastereomer is separated into, based on their different physicochemical properties, using well-known means, for example, mapping Isomers split can by with appropriate optically active substance (such as chiral alcohol or Mosher`s Mohs acyl chlorides) reaction conversions For diastereoisomer, it is corresponding single isomers to be isolated and convert (as hydrolyzed).Some compounds in formula 1 It is probably that atropisomer (such as substituted aryl) is also a part in the application.Chiral chromatographic column can also be used in enantiomter Separation.Compound in Formulas I there may be different tautomeric forms, and these forms are included in the range of the application. For example, the compound of keto-enol and imine-enamine forms.
" suppressing HCV (Hepatitis C Virus, HCV) " as described herein refers to directly act on hepatitis Each target spot of virus replication, such as NS3/4A protease, NS5A protease, NS5B polymerases, it includes preventing hepatitis C virus Duplication, suppress the function of GAP-associated protein GAP, killing etc. to virus.
Embodiment：
Raw material involved in the present invention and reagent (including reference compound ABT-450) it is commercially available unless otherwise specified or Customized processing is commercially available.
Compound in the present invention can contain a non-aromatic double bond and one or more asymmetric centers.Therefore, this is Row compound can be racemization and racemic mixture, single enantiomer, dynamic isomer, suitable or trans isomer form.This hair Bright prepared compound (formula I-II) is natural ammonia in the big ring-type polycyclic compound of chirality of the purity higher than 98%, product The sour and non-natural amino acid optical purity of base is determined by optical activity and chiral chromatographic column respectively, the structure of each final product Characterize respectively by LC-MS or/and hydrogen compose nuclear magnetic resonance (1HNMR) analysis is determined.
Because autonomous replication level is extremely low in HCV in vitro common liver cell, and its uniquely can infection animal be black orangutan Orangutan, therefore the preclinical drug efficacy study of anti hepatitis C virus drug does not have suitable animal test model at present, someone's research will Infection in Vitro HCV human liver tissue is implanted into immunodeficient mouse and set up in body mouse model, but this mouse of raising has skill Art difficulty, model is unstable, and lacks normal immune response, and the pathogenic process difference with hepatitis C is too big, thus not by Animal model for evaluating hepatitis drug efficacy study.HCV cell culture system, nothing are replicated before 1999 without effectively breeding Method understands fully HCV mechanism of causing a disease and the vial life cycle so that the progress of antiviral drugs is slow.Researchers are carried out It is substantial amounts of to attempt, until 1999 have just overcome difficulties breakthrough progress, establish an effective cell culture model- Replicon (replicon) system, the basis of this system is the HCVRNA of the subgenome built using genetic engineering, is being turned Can be with autonomous replication in Bel7402's Huh-7 cells of dye.
Using oneself above-mentioned effective cell culture model-replicon (replicon) system through receiving in the industry, enter Isolated experiment is gone, medicine has been evaluated according to experimental result, wherein to NS3/4A ammonia of HCV target spot HCV The main isolated experiment result data of pepsin inhibitor includes:
Inhibitory action (EC of the compound to hepatitis C virus replicon (Replicon)50)。
So far external preclinical and clinical test results, which are studied, to be shown, such isolated test result and related activity in vivo Result of the test has uniformity.
Compound prepared by the present invention can be screened by inhibitory activity test experiments Preliminary Determination outside following clinical precursor Its curative effect to infection with hepatitis C virus, is then further confirmed by clinical test.Other method is in this area Also it is obvious for the personnel of tool general technology.
The compounds of this invention or its stereoisomer, dynamic isomer, esterification or amidated pro-drug or its medicine Acceptable salt and its mixture on, through measuring, have preferable curative effect, with obvious to infection with hepatitis C virus Suppression HCV effect, inhibitory action (EC of the compound to hepatitis C virus replicon (Replicon)50) test As a result 2 (TMC432 is reference compound) are listed in the table below；Wherein, field of activity (EC50) be denoted as " A " in 100-1000nM, it is living Property scope is denoted as " B " in 100-10nM, and field of activity≤10nM is denoted as " C ".
Table 2:The compound of the part present invention suppresses the active testing result of HCV
Method of testing：
HCV protease (HCV NS3/4A) inhibitory activity method of testing:
The inhibitory activity of HCV protease (HCV NS3/4A) is to be quenched fluorescing system to determine by an inside.EDANS and DABCYL groups are connected to the opposite end of a peptide.In protein cleavage, DABCYL is surveyed to EDANS fluorescent quenchings Amount.That is, HCV NS3-4A protease inhibitors high flux screening models are used, by reagent sets 5 concentration dilution degree respectively, together When set positive control and negative control.In the reaction system of optimization, with Polarstar fluorescence detectors in ex=355, em= Under the conditions of 520, fluorescent value is determined.The inhibiting rate of each concentration is calculated, sample is calculated to protease with Reed-Muench methods Half-inhibition concentration (IC50)。
Material：HCV protease:HCV NS3-4A are voluntarily prepared, -70 DEG C of preservations.HCV protease substrates (FRET-S):Ac- Asp-Glu-Asp (EDANS)-Glu-Glu-Abu- ψ-[COO]-Ala-Ser-Lys- (DABCYL)-NH2 is purchased from the U.S. AnaSpec companies, 100 μM are made into DMSO, and -20 DEG C are kept in dark place after packing.Reaction buffer:30mM NaCl, 5mMCaC12, 10mM DTT, 50mM Tris (pH7.8).Instrument:Polarstar fluorescence detectors are Germany's BMG Products.
Prepare and operation：First be made into DMSO after 10mg/mL, be diluted to 10000 with buffer solution, 2000,400,80, 16ng/mL tested concentration, adds 20 μ L/ holes, and overall reaction system is 200 μ L, make final concentration of 1000,200,40,8, 1.6ng/mL.The μ L of buffer solution 140, the μ L of 20 μ L, HCV protease of decoction 20 are separately added into 96 hole fluorescence enzyme reaction plates, most Add afterwards and start reaction after the final concentration of μ L of FRET-S substrates 20 O.25 μM at 37 DEG C, and set protease and substrate reactions control Hole and independent substrate and protease control wells, fluorescence detector determine fluorescence signal (ex=355, em=520).Various kinds sample wells Fluorescent value fluorescent value compareed with enzyme compare the inhibiting rate for calculating each concentration samples, sample pair is calculated using the Muench methods of Reed mono- Half-inhibition concentration (the IC of HCV protease50)。
Hepatitis C virus replicon (Replicon) system Antiviral breeding:
Completed with the double reporter gene Replicon systems newly built, virus replication level is by report in infection cell Gene renilla luciferase (Renilla luciferase) detection is realized.The expression of reporter gene and HCV RNA are multiple Good linear relationship in level processed and viral protein expression level.The concentration gradient of 82 times of dilutions, 3 multiple holes, 3 weights It is multiple, if 1 to 2 kinds of positive drug controls.The final EC for calculating compound50。
Toxicity of compound screening test
In order to test the toxicity of above-claimed cpd of the invention, the present invention uses 18-22g healthy mices, using single Dosage 10000mg/kg, gavages administration 1 time, and the toxic reaction in continuous 7 days produced by observation experiment animal is tested to assess Thing carries out acute toxicity (Acute Toxocity Study, MTD) and investigated to the toxicity size of body, as a result shows that such is changed Overall toxicity very little (the LD of compound50>10000), survival rate is 80%-100% after mouse administration, wherein there is 1/3rd mouse It is 100% to gavage survival rate after dosage 10000mg/kg noval chemical compound.Therefore, the compounds of this invention is through measuring, not only There is preferable curative effect to infection with hepatitis C virus, the effect of HCV is suppressed with obvious, and have three/ The higher noval chemical compound overall toxicity of one activity is very low, and (mouse survival rate is 100%, LD50>15000) nothing, is typically regarded as Poison.
Illustrate classes of compounds of the present invention and synthesis and the effect of intermediate by the following examples.
The instrument and raw material being related in embodiment are described as follows:
Proton nmr spectra is that the analysis of Bruker AV-400 (400MHz) nuclear magnetic resonance spectrometer is obtained.Chemical shift is with tetramethylsilane Alkane is recorded for internal standard, and (CHC1 is represented in units of ppm3:δ7.26ppm).The data message of record is as follows:Chemical shift And its split point and coupling constant (s:Singlet；d:Doublet；t：Triplet；q：Quartet；br：Broad peak；m：Multiplet).
Mass spectrometric data needs except other, all using the liquid of the senior LCQ companies of Finnigan (Finnigan LCQAdvantage) Matter combined instrument is analyzed, and all reactions are all operated under the conditions of the anhydrous and oxygen-free that dry argon gas is protected.Solid metal has Machine compound is stored in argon gas protection drying box.
Tetrahydrofuran and ether are obtained by distillation, add metallic sodium and benzophenone during distillation wherein.Dichloromethane Alkane (DCM), pentane and hexane are handled with calcium hydride.The special material and intermediate being related in the present invention are by the gloomy medicine of Tianjin length The customized processing such as industry Co., Ltd is provided, and other all chemical reagent are from Tianjin chemical reagents corporation, A Er get Ritchies company (Aldrich), the reagent suppliers such as Acker sieve company (Acros) are bought.Intermediate or production as needed for being reacted in building-up process Inadequate next step of thing etc. is tested, then untill being repeatedly blended into sufficient amount.The HCV protease of prepared compound of the invention (HCVNS3-4A) inhibitory activity test experiments are completed by Shanghai Yaoming Kangde New Medicine Development Co., Ltd.
SM-3：N-Boc- allohydroxyproline methyl esters
SM-4：N-Boc-L- Terleus
Alcalase 2.4L：Subtilopeptidase A-karr Si Baige (Subtilisin-Carlsberg) protein hydrolysate Enzyme
Boc：Tert-butoxycarbonyl
(Boc)2O：Di-tert-butyl dicarbonate
CDI：N, N '-carbonyl dimidazoles
DBU：Carbon -7- the alkene of 1,8- diazabicyclos [5.4.0] 11
HATU：2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester
NBS：N- bromo-succinimides
DMAP：DMAP
DIEA：N, N- diisopropylethylamine
DIAD:Diisopropyl azodiformate
SOC12：Thionyl chloride
POCl3：POCl3
Pd/C：Palladium charcoal
HMPA：Hexa
HOAc：Glacial acetic acid
HBr：Hydrobromic acid
HCl:Hydrochloric acid
TFA：Trifluoroacetic acid
TsOH：P-methyl benzenesulfonic acid
NaOH：Sodium hydroxid
ACN:Acetonitrile
DCM:Dichloromethane
DCE：Dichloroethanes
DMF：N,N-dimethylformamide
DMSO：Dimethyl sulfoxide
Et20：Diethyl ether
EA：Ethyl acetate
PE：Petroleum ether
THF:Tetrahydrofuran
TBME：Methyl tertiary butyl ether(MTBE)
Embodiment 1
Compound SM-2a synthesis
3-bromobenzaldehyde (93g, 0.5mol), BnNEt3Cl (5.72g, 25.13mmol) is dissolved in CHCl3In (125mL). 50%NaOH and keeping temperature (65-70 DEG C) are slowly added dropwise at 55 DEG C, rear 55 DEG C of stirrings of keeping temperature are finished.Raw material after 3 hours Fundamental reaction is complete.The dilution of 930mL water is added, insoluble matter dissolving, separates aqueous phase, use 50%H after stirring fully2SO4Adjust pH to 2 ~3,180mL EA are extracted, and are dried, are spin-dried for obtaining carboxylic acid 58.3g, yield 50.5%.
The said goods (58.3g, 0.266mol) are dissolved in EtOH (615mL), dense H is added2SO4(63.5mL, 1.118mol), back flow reaction is carried out under nitrogen protection, detection is sampled after 2 hours, and reaction is finished.Evaporated under reduced pressure solvent, is added 1.5L EA are diluted, and saturation Na is used successively2CO3Solution and the washing of saturation NaCl solution, anhydrous sodium sulfate drying, filtering, filtrate rotation Dry, column chromatography purifies to obtain SM-2a 17.75g, yield 26.1%.
Embodiment 2
Compound Va synthesis
Benzo [1,3] dioxolane (40g, 0.327mol) is dissolved in DCM (2.44L) and glacial acetic acid (2.277L), it is cold But to 15 DEG C, dense HNO is added dropwise3(325.2mL), keeping temperature is less than 40 DEG C, and stirring 30 minutes is warmed to room temperature after completion of dropping, cold But to 0-5 DEG C, the dense HNO of smoke is added dropwise3Normal-temperature reaction is risen to after (813mL), completion of dropping to be stirred overnight.
Add 9.6L frozen water in reaction solution to stir 10 minutes, stratification, aqueous phase uses 800mL DCM and 800mL successively EA respectively extraction 1 time, merges organic phase, is washed 2 times with 640mL successively, 640mL saturations NaHCO3Wash 2 times, anhydrous sodium sulfate is done Dry, filtering is spin-dried for obtaining crude product 24g, yield 34.7%.
Above-mentioned crude product is dissolved in MeOH (850mL), SnCl is added2·2H2In O (255g, 1.13mol), oil bath heating is returned Stream reaction is stayed overnight.Reaction solution is spin-dried for solvent, adds the dilution of 500mL EA and 200mL water, is adjusted with 1N NaOH after pH to 13, is used Diatomite is filtered, and filter cake is washed 3 times with 200mL EA.Filtrate layered, aqueous phase is extracted 3 times with 500mL EA, and aqueous phase adds NaCl extremely Extracted 1 time with 500mL EA again after saturation, the rear organic phase that merges is washed with saturation NaCl, anhydrous sodium sulfate drying, filtering, filtrate It is spin-dried for obtaining o-phenylenediamine SM-2 10g, yield 58%.
By above-mentioned o-phenylenediamine SM-2 (8.28g, 32.2mmol), alpha-carbonyl acid esters SM-2a (7g, 46mmol) is dissolved in anhydrous In EtOH (100mL), the lower back flow reaction of nitrogen protection stops reaction, placed for the weekend after 6 hours.Reacting liquid filtering, filter cake is used EtOH is washed, and filter cake dries to obtain Va 6.7g, yield 60%.ESI-MS[(M+H+)]:m/z 344.93,346.93.
Embodiment 3
Compound Vb synthesis
Catechol (22g, 0.2mol) is dissolved in 824mL ether, 0 DEG C is cooled to, fuming nitric aicd 8.8mL, drop is added dropwise Add after finishing, recover to being stirred overnight at room temperature.System is poured into 250mL frozen water, stirring divides liquid after 20 minutes, aqueous phase is used 150mL ether is extracted 6 times, merges organic phase, with saturated sodium carbonate and after organic phase, divides liquid, anhydrous sodium sulfate drying, mistake Filter, filtrate is spin-dried for obtaining 38.2g crude products, and silica gel column chromatography obtains nitration product 9.6g, yield 31.2%.1NMR(CDCl3, 400MHz) and δ 10.65(s,1H),7.68(d,1H),7.28(d,1H),6.93(t,1H),5.82(s,1H).
Above-mentioned product (42.45g, 0.273mol) is dissolved in DMF (842mL), CH is added2I2(205mL, 2.545mol), CuO (8.7g, 0.109mol) and K2CO3(159g,1.149mol).After being replaced 3 times with argon gas, reaction solution is heated to 160- Detection is sampled after 170 DEG C, 2 hours, reaction is finished.Reaction solution is concentrated, and is poured into 9L water, is extracted 3 times, is associated with 2.5L EA Machine phase, dries after saturated common salt washing, is spin-dried for obtaining 114g, column chromatography purifies to obtain cyclization product 35g, yield 75%.
The said goods (35g, 0.206mol) are dissolved in 267mL glacial acetic acid, smoke HNO is slowly added dropwise under stirring3 (133mL), completion of dropping, reaction solution is stirred overnight at room temperature.Reaction solution adds 1.25L DCM dilutions, and 1.25L ice is poured under stirring In water, point liquid, aqueous phase is extracted to no product with 1.25L, merges organic phase, is washed 1 time with 1.5L successively, 1.5L saturations NaHCO3 Wash 1 time, saturation NaCl is washed 1 time, anhydrous sodium sulfate drying, filter, filtrate is spin-dried for obtaining double nitration product 43.95g, yield 71.1%.
The said goods (31.5g, 0.147mol) are dissolved in 1.1L MeOH, SnCl is added2·H2O(332g, 1.47mol).The lower heated overnight at reflux of reaction solution stirring.Reaction solution is cooled down, concentration, adjusts pH extremely with about 4L1N NaOH solutions afterwards 10-11, aqueous phase filtering, is extracted 3 times with 3L EA, is merged organic phase, is washed 1 time with 3L saturations NaCl, anhydrous sodium sulfate drying, Filtering, filtrate is spin-dried for obtaining SM-2 ' 11.07g, yield 49.9%.
SM-2 ' (11g, 72mmol) and SM-2a (18.6g, 72mmol) are dissolved in anhydrous EtOH, argon gas protection is lower to flow back Reaction, question response is cooled to room temperature after terminating, separate out a large amount of yellow solids, and filtering, filter cake is washed with EtOH, filter cake dry in Mesosome Vb 25.5g, yield 70%.1H NMR (DMSO-d6,400MHz) δ 12.54 (s, 1H), 8.50 (s, 1H), 8.33-8.31 (m, 1H), 7.74-7.73 (m, 1H), 7.48 (t, 1H), 7.23 (d, 1H), 6.79 (d, 1H), 6.23 (s, 2H) .ESI-MS [(M+ H+)]:m/z 345.11,347.02。
Embodiment 4
Compound Vc synthesis
2-ketoacid (15.3g, 67.2mmol) is dissolved in anhydrous DCM, argon gas is replaced three times, is cooled to 0 DEG C, and protochloride is added dropwise Sulfone, drop, which finishes to be warmed to room temperature, stirs 0.5h, stand-by.Nitroaniline (6.0g, 33.6mmol) is dissolved in anhydrous DCM, TEA, argon is added Gas is replaced three times, and the gained DCM solution before 0 DEG C of dropwise addition, drop finishes, and is warmed to room temperature stirring 0.5h, and addition saturated sodium bicarbonate is washed Wash, point liquid is dried, is spin-dried for, plus filtered after EA dissolvings, filtrate is spin-dried for, column chromatography (PE-PE:EA50:1 to 1:1.5) yellow is obtained Solid 4g, yield 23%.1H-NMR((d6-DMSO,400MHz)δ6.33(s,2H),7.10(m,1H),7.58-7.62(m, 1H), (s, the 1H) .MS (ESI) of 7.76 (d, J=8.6Hz, 1H), 7.97-8.05 (m, 2H), 8.17 (s, 1H), 11.24:m/z 447(M+H).
Under nitrogen protective condition, above-mentioned product (2.5g, 25.0mmol), zinc powder and ammonium chloride are added to ethanol successively The aqueous solution in, be heated to reflux after 1h, reaction is complete, reaction solution is concentrated under reduced pressure into dry, and gained concentrate is directly crossed to post purifying (PE:EA 3:1) product Vc 1.55g, yield 75%, are obtained.1H-NMR (d6-DMSO, 400MHz) δ 6.24 (s, 2H), 7.03 (d, J=8.24Hz, 1H), 7.43-7.47 (m, 2H), 7.69 (d, J=9.04Hz, 1H), 8.26 (d, J=7.84Hz, 1H), 8.43 (s,1H),12.65(s,-OH,1H).MS(ESI):m/z 343
Embodiment 5
Compound Vd synthesis
In 250mL round-bottomed flask, 11g (10mmol) catechol, 100mL acetone, 100mL benzene and 5mg pairs are added Connect on benzene methanesulfonic acid, flask and the water that molecular sieve is produced with absorbing reaction is placed in apparatus,Soxhlet's, extractor.It is heated to reflux 24 small When, the molecular sieve more renewed continues to be heated to reflux 24 hours.Be concentrated under reduced pressure reaction solution, residue petroleum ether extraction three times, closes And petroleum ether extraction liquid, it is colourless to be washed till aqueous phase with 2N sodium hydroxide solutions, and organic addition anhydrous magnesium sulfate is dried, filtering, filtrate It is spin-dried for, obtains a weak yellow liquid (3.6g, yield 24%).1H NMR(CDCl3,400MHz)δ6.80-6.82(m,4H),1.72 (s,6H).
100mL nitric acid (70%) and 50mL are added in the 250mL there-necked flasks equipped with thermometer and constant pressure funnel 10 DEG C are cooled in glacial acetic acid, ice bath, above-mentioned product 24.75g (0.165mol), controlling reaction temperature are added dropwise from dropping funel After 15-20 DEG C, completion of dropping, 45min is stirred in continuation in ice bath, and TLC detects no raw material.It is under agitation that reaction solution is slow Slowly pour into 500mL cold water, obtain a yellow solid, stir 10min, use Buchner funnel suction filtration, water washing filter cake twice, is taken out It is dry, (40 DEG C) are dried in vacuum drying chamber and are stayed overnight, 30.12g (93.5%) is obtained.1H NMR(CDCl3,400MHz)δ7.87(d, 1H),7.60(s,1H),6.79(d,1H),1.75(s,6H)。
122mL fuming nitric aicds (98%) and 61mL glacial acetic acid, ice bath are added in the 250mL there-necked flasks equipped with thermometer In be cooled to 10 DEG C, a small amount of mononitrated products (used time 80min) for adding 30g (0.153mol) in batches, controlling reaction temperature exists 15-20 DEG C, after adding, 45min is stirred in continuation in ice bath, and TLC detects no raw material.Reaction solution is slowly toppled under agitation In the cold water for entering 550mL, a yellow solid is obtained, 10min is stirred, uses Buchner funnel suction filtration, water washing filter cake twice, is drained, very (40 DEG C) are dried in empty drying box to stay overnight, and obtain 33.72g (98%).1HNMR(CDCl3,400MHz)δ7.23(s,2H),1.81 (s,6H)。
Above-mentioned product (5g, 21mmol) is dissolved in ethyl acetate (100mL), Pd/C (150mg) is added, instrument pressure will be hydrogenated Reaction bulb is put into the corresponding position of hydrogenation instrument by regulation to 0.1MPa, device good seal is replaced 5 times with hydrogen, stirring 20h, HPLC monitoring reaction are complete.Filtered with diatomite, filtrate decompression is evaporated to obtain crude product 4.6g.Silicagel column purifies (PE:EA 15: 1 to 5:1) SM-2 " (2.6g, yield 69%) is obtained.Its hydrochloride1HNMR(D2O,ppm)δ6.68(s,2H),1.64(s,6H, 2CH3).
SM-2 " (4.4g, 24.4mmol) and SM-2a (6.3g, 24.4mmol) are dissolved in EtOH (185mL), changed with argon gas Gas three times, reaction solution is heated to backflow, stirs 1.5h, and HPLC monitoring reactions are complete, stop reaction.Reaction solution is put into refrigerator 2h, there is crystal precipitation, collected by suction solid, and is washed with ice-cold ethanol, obtains Vd (5.43g, yield 59.5%),1HNMR (CDCl3,400MHz)δ8.59(s,1H),8.44(d,1H),7.60(d,1H),7.38(t,1H),7.26(s,1H),6.72(s, 1H),1.79(s,6H,2CH3)；MS(ESI):m/z 373.28(M+H).
Embodiment 6
Compound Ve-Vf synthesis
Catechol (22g, 0.2mol) is dissolved in 824mL ether, 0 DEG C is cooled to, fuming nitric aicd 8.8mL, drop is added dropwise Add after finishing, recover to being stirred overnight at room temperature.System is poured into 250mL frozen water, stirring divides liquid after 20 minutes, aqueous phase is used 150mL ether is extracted 6 times, is merged in organic phase, saturated sodium carbonate and organic phase, is dried to obtain 38.2g crude products, silica gel column layer Analyse to obtain nitro-pyrocatechol 9.6g, yield 31.2%.
Nitro-pyrocatechol (0.5g, 3.23mmol) and phosphorus pentoxide (0.053g) are dissolved in toluene (2mL), heated It is warming up to after 75 DEG C, stirring 10min, acetone (0.275mL) is added dropwise.Phosphorus pentoxide (0.053g), Zong Gongjia are added per 30min 4 times, add within 2 hours.Continue to react 1 hour after adding.Reaction solution is down to room temperature temperature, by solution topple over for NaOH (20mL, In 1mol/l), point liquid is organic to be added to anhydrous sodium sulfate drying, and filtering is spin-dried for, obtains solid 0.15g (yield 23.8%).1HNMR(CDCl3,400MHz)δ7.60(d,1H),7.00(d,1H),6.88(t,1H),1.82(s,6H,2CH3)。
In 25mL there-necked flasks, fuming nitric aicd (1.6mL), ice bath cooling are added.(0.15g, 0.77mmol) is dissolved in In HOAc (0.8mL), treat that temperature is down to 0 DEG C, configuration solution is added dropwise, T≤5 DEG C are kept.After completion of dropping, reaction solution is in ice bath Continue to react 15min, TLC display reactions are complete.Reaction solution is poured into 20mL frozen water, filtered after stirring 10min, filter cake is with greatly Clear water cleaning is measured, dinitro compound solid 100mg, yield 54.2%. is obtained1HNMR(CDCl3,400MHz)δ7.69(d, 1H),6.88(d,1H),1.82(s,6H,2CH3)。
Dinitro substrate (2.3g, 9.58mmol) and catalyst Pd (0) (0.7g, 5.72mmol) are dissolved in EtOH In (34.1mL), by device good seal, replaced 5 times with hydrogen, reaction is stirred at room temperature and stays overnight.HPLC is detected without raw material, by solution After being spin-dried for, DCM (20mL) dissolvings are added, hydrochloric acid dioxane solution is added dropwise and is separated out to without solid, reddish black solid is filtered to obtain, uses Petroleum ether is rinsed.Solid is poured into saturated sodium bicarbonate and DCM solution, point liquid retains organic phase, add anhydrous sodium sulfate and do Dry, filtering, filtrate is spin-dried for obtaining solid o-phenylenediamine (0.94g), yield 54.57%.
Contracting acetone o-phenylenediamine (1.6g, 9.44mmol) and alpha-carbonyl acid esters SM-2a (2.18g, 7.64mmol) are dissolved in In EtOH (30mL), device good seal is replaced 3 times with argon gas, heating reflux reaction 16h (outer 90 DEG C of temperature).HPLC detects nothing After raw material, room temperature is down to, reaction solution is spin-dried for, brown solid is obtained, silica gel column chromatography (DCM fills post, DCM elution) is isolated and purified Two parts faint yellow solid:
A sample) is first gone out for Ve (LW1002-19-107-1), 1.64g, yield 49.59%；HPLC:98.19% is pure, (protects Stay time t=8.8min, method：Methanol：Water=30：70).1HNMR(CDCl3,400MHz)δ8.56(s,1H,6’-H),8.37 (d,1H,4’-H),7.61(d,1H,2’-H),7.47(d,1H,5-H/7-H),7.37(t,1H,3’-H),6.86(d,1H,6-H/ 8-H),1.81(s,6H,2CH3).MS(ESI):m/z 373,375.30(M+H)。
B sample is gone out after) for Vf (LW1002-19-107-2), 1.2g, yield 36.29%；HPLC：97.87% is pure, (retains Time t=8.3min, method：Methanol:Water 30:70),1HNMR(CDCl3,400MHz)δ10.76(br s,1H,OH),8.56 (s,1H,6’-H),8.37(d,1H,4’-H),7.64(d,1H,2’-H),7.38(t,1H,3’-H),7.01(d,1H,5-H/7- H),6.68(d,1H,6-H/8-H),1.84(s,6H,2CH3).MS(ESI):m/z 373,375.28(M+H)。
Embodiment 7
Compound 4a synthesis
By raw material SM-3 (0.24g, 0.96mmol), compound Va (0.33g, 0.96mmol) and triphenyl phosphorus (0.456g, 1.7mmol) is dissolved in anhydrous THF (7mL), is cooled to 0 DEG C after argon gas displacement, DIAD is then added dropwise dropwise (0.35g,1.7mmol).Recover to being stirred at room temperature after 18h.Concentration of reaction solution obtains crude product, and column chromatography purifies to obtain product 4a (0.52g, yield 95%).ESI-MS[(M+H+)]:m/z 572.09.
Embodiment 8
Compound 5a synthesis
Compound 4a (0.52g, 0.9mmol) is dissolved in the anhydrous DCM of 3mL, 3.5mL 4N HCl Isosorbide-5-Nitrae-dioxy six is added Ring solution.1h is stirred at room temperature, concentration of reaction solution obtains the hydrochloride of amine.This hydrochloride and SM-4 (0.23g, 1mmol) are dissolved in nothing In water DMF, 0 DEG C is then cooled to.Argon gas protection under, add DIEA (0.85mL, 4.9mmol) and HATU (0.45g, 1.2mmol).Reaction solution is stirred at room temperature one hour, then adds EA dilutions, and 5% aqueous citric acid solution is washed, and is washed, 1M carbonic acid Hydrogen sodium water solution is washed, and saturated common salt is washed 4 times.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, column chromatography Purify to obtain product 5a (0.5g), two step yields 81%.HNMR(CDCl3)δ8.18(s,1H),7.91(d,1H),7.55(d,1H), 7.39(s,1H),7.33(t,1H),7.28(s,1H),7.16(s,1H),6.17(s,2H,OCH2O),5.31(m,1H),4.99 (t,1H),4.21(m,3H),3.78(s,3H,OCH3),2.36(m,1H),2.06(m, 1H),1.28(s,9H,3CH3),1.08 (s,9H,3CH3)ppm.ESI-MS[(M+H+)]:m/z 685.11.
Embodiment 9
Compound 6a synthesis
Compound 5a (4.96g, 7.2mmol) is dissolved in the anhydrous DCM of 30mL, 35mL 4N HCl Isosorbide-5-Nitrae-dioxy six is added Ring solution.Concentration of reaction solution after 1h is stirred at room temperature and obtains amine intermediate.
Amine intermediate is dissolved in the anhydrous DCM of 126mL, 0 DEG C is cooled to after argon gas displacement, then sequentially adds triphosgene (3.25g, 11mmol) and pyridine (9.4mL).Reaction solution is diluted after stirring half an hour at 0 DEG C with EA, is then washed with water, saturation food Salt is washed twice.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains inter-mediate isocyanate.
Inter-mediate isocyanate is dissolved in the anhydrous THF of 188mL, neopentyl glycol (2.28g, 22mmol) and 4A is sequentially added Molecular sieve.It is stirred at room temperature after half an hour, adds DBU (1.42mL, 9.5mmol), continues to stir that EA dilutions, diatomite are added after 1h Filtering, mother liquor is washed with water successively, saturated common salt washing.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, post Chromatographic purifying obtains product 6a (2.78g, two step gross production rates 53%).ESI-MS[(M+H+)]:m/z 715.19.
Embodiment 10
Compound 7a synthesis
Substrate 6a (2.78g, 3.9mmol), cesium carbonate (3.17g, 9.7mmol) and dry toluene (250mL) are added anti- Device is answered, palladium (0.22g, 0.97mmol) and 2- (di-t-butyl phosphorus) -1 is then sequentially added, 1 '-dinaphthalene (0.49g, 1.24mmol).90 DEG C are heated to after argon gas displacement to be stirred overnight.Question response liquid is cooled to after room temperature, is filtered with diatomite, and EA is washed Wash filter cake.Mother liquor obtains crude product after being concentrated under reduced pressure, column chromatography obtains macrocyclic products 7a (1.1g, yield after purification：45%).ESI-MS [(M+H+)]:m/z 635.22.
Embodiment 11
Compound 8a synthesis
7a (0.3g, 0.47mmol) is dissolved in THF/MeOH (13mL/6.5mL), 1N lithium hydroxides are then slowly added into The aqueous solution (7.2mL), is stirred at room temperature after 2h and is concentrated under reduced pressure after organic solvent, and pH to 4~5 is adjusted with 1N HCl.EA is extracted three times, is closed And organic phase, saturated common salt washing, after organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains product 8a (0.25g, yield 86%).ESI-MS[(M-H-)]:m/z 619.24.
Embodiment 12
Compound L W100202 synthesis
8a (46mg, 0.074mmol) and SM-6a (30mg, 0.13mmol) are dissolved in dry DMF (3mL), Ran Houleng But to 0 DEG C.Under argon gas protection, DIEA (0.083mL, 0.476mmol) and HATU (42.4mg, 0.11mmol) is added.Reaction Liquid is stirred at room temperature one hour, then adds EA dilutions, and 5% aqueous citric acid solution is washed, and is washed, and 1M sodium bicarbonate aqueous solutions are washed, Semi-saturation salt is washed 4 times.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, and column chromatography purifies finally Big ring product LW100202 (44mg, yield 71%).ESI-MS[(M+H+)]:m/z 833.67.
Embodiment 13
Compound L W100201 synthesis
According to above-mentioned prepare compound LW100202 embodiment 12, the present embodiment raw material 8a (0.074mmol) and SM- 6b (0.098mmol) reacts (reaction scheme 2), and the final macrocyclic products LW100201 of 48mg are obtained after purification.ESI-MS[(M+H+)]:m/z 835.68.
Embodiment 14
Compound SM-6c synthesis
Substrate (2g, 6.1mmol) is dissolved in anhydrous methylene chloride (24mL), triethylamine (0.85mL) is slowly added into, reacted Liquid becomes viscous；Then Boc is added2O (1.4g, 6.1mmol), reaction solution is stirred at room temperature 17 hours, and LTC display reactions are complete. Reaction solution is transferred in separatory funnel, successively with water (4mL), saturated sodium bicarbonate solution (4mL), and saturated aqueous common salt (4mL) Wash, organic phase anhydrous sodium sulfate drying, filter, obtain yellow oil 1.84g after filtrate concentration, column chromatography obtains pure products 1.32g (84.6%), colorless oil.1HNMR(CDCl3,400MHz)δ5.79(m,1H),5.28(d,1H),5.10(dd, 1H),4.17(m,2H),2.14(m,1H),1.79(m,1H),1.45(m,10H),1.26(t,3H,CH3).
In 100mL round-bottomed flask, substrate (0.3g, 1mmol) is dissolved in absolute ether (10mL), by reaction bulb third Cooled down in ketone-ice bath (- 15 DEG C), with vigorous stirring, disposably add diazomethane (10mmol) and catalytic amount palladium (0.1mmol), opens wide bottleneck, and continuation is stirred vigorously 30 minutes at -15 DEG C.Reaction solution is concentrated after being filtered with diatomite, obtains one Brown oil.1HNMR(CDCl3,400MHz)δ5.13(brs,1H),4.19-4.23(m,2H),1.60-1.65(m,2H), 1.46(s,9H),1.28(t,3H),1.07-1.13(m,1H),0.86-0.89(m,1H),0.50-0.58(m,2H),0.28- 0.36(m,2H).
Above-mentioned product (1.52g, 6.2mmol) is dissolved in the anhydrous THF of 60mL, CDI (1.13g, 6.9mmol) is added, used Argon gas is replaced 3 times, after reaction solution is heated to 60 DEG C of reactions 4 hours, is cooled to room temperature, add cyclopropanesulfonamide (0.84g, 6.9mmol), DBU (1.05g, 6.9mmol), is stirred overnight at room temperature.Reactant mixture is added after the dilution of 80mL ethyl acetate, according to Secondary 10% lemon pickling of use 30mL 2 times, the washing of 30mL saturated common salts, organic phase anhydrous sodium sulfate drying, filtering, filtrate rotation It is dry, silica gel column chromatography (PE:EA 50:1 to 1:1) product 0.43g, is obtained.Yield is 20.1%.MS(ESI):m/z 343.10 (M-H).
0.3g the said goods are dissolved in 100mL 4N hydrochloric acid Isosorbide-5-Nitrae dioxane solutions, are stirred overnight, TCL monitoring reactions, Reaction is spin-dried for solvent after terminating, and obtains SM-6c (0.25g), yield is 97%.
Embodiment 15
Compound L W100203 synthesis
According to above-mentioned prepare compound LW100202 embodiment 12, the present embodiment raw material 8a (0.065mmol) and SM- 6c (0.13mmol) is reacted, and the final macrocyclic products LW100203 of 50mg are obtained after purification.MS(ESI):m/z 847.2(M+H)
Embodiment 16
Compound 8b synthesis
According to above-mentioned prepare compound 4a-8a embodiment 6- embodiments 11, the present embodiment is from raw material SM-3 (4.8mmol) And Vb (4.8mmol) starts to obtain 0.3g products 8b after five step reaction purifications by reaction scheme 2.ESI-MS[(M-H-)]:m/z 619.45.
Embodiment 17
Compound L W100205 synthesis
According to above-mentioned prepare compound LW100202 embodiment 11, the present embodiment raw material 8b (0.10mmol) and SM- 6a (0.10mmol) is reacted, and 68mg final products LW100205 is obtained after purification.ESI-MS[(M+H+)]:m/z 833.71.
Embodiment 18
Compound L W100204 synthesis
According to above-mentioned prepare compound LW100202 embodiment 11, the present embodiment raw material 8b (0.08mmol) and SM- 6b (0.08mmol) is reacted, and 52mg final products LW100204 is obtained after purification.ESI-MS[(M+H+)]:m/z 835.70.
Embodiment 19
Compound L W100206 synthesis
The addition substrate carboxylic acid (about 80mg, 0.130mmol) in 50mL there-necked flasks, dry DMF (3mL), stirring and dissolving, plus Enter SM-6c (55mg, 0.098mmol), replaced 3 times with argon gas, be placed in ice-water bath and be cooled to 0-5 DEG C, stir 10min, about DIEA (0.25mL) is added in 10min, and 5min is stirred in ice-water bath, HATU (140mg) is added, reaction solution is warmed to room temperature, Stirring reaction HPLC after 1.5 hours, shows reacted complete.Plus after people's ethyl acetate (40mL) dilution, use semi-saturation salt Water washing 4 times, anhydrous magnesium sulfate is dried, and filtering, filtrate is spin-dried for obtaining about 100-150mg crude products, and prep-HPLC separates to obtain 3mg LW100206, MS (ESI):m/z 847.2(M+H).
Embodiment 20
Compound 8c synthesis
Under nitrogen protective condition, successively by Vc (1.55g, 8.88mmol), SM-3 (1.66g, 17.8mmol) and triphen Base phosphine is added in the anhydrous THF of 155mL, DIAD (1.82g, 22.2mmol) is added under frozen water protective condition, stirring reaction is stayed overnight, TLC detection reactions are complete.It is concentrated under reduced pressure into dry, the direct column chromatography of gained concentrate obtains target product 4c 2.0g, yield 80%.1H-NMR ((d6-DMSO, 400MHz) δ 1.33 (s, 5H), 1.39 (s, 4H), 2.28-2.32 (m, 1H), 2.60-2.65 (m, 1H), 3.63-3.69 (m, 4H), 3.72-3.75 (m, 1H), 4.32 (t, J=8Hz, 1H), 4.47-4.76 (m, 1H), 6.27 (d, J=1.2Hz, 2H), 7.37-7.44 (m, 2H), 7.59-7..67 (m, 2H), 7.94 (d, J=7.04Hz, 1H), 8.10 (d, J=1.2Hz, 1H) .MS (ESI):m/z 594(M+23)
4c (1.32g, 1.81mmol) is added in THF, then the HCl solution (9N) of 2mL dioxane is added into reaction In liquid, it is stirred at room temperature 30 minutes, after TLC points plate is determined without raw material, solvent is evaporated off, obtains white solid hydrochloride 0.92g, is dissolved in In dry DMF (3mL), add SM-4 (0.42g, 1.81mmol), argon gas replace 3 times, reaction solution is cooled to 0 DEG C, under stirring according to Secondary addition DIEA (1.17g, 9.05mmol) and HATU (0.83g, 2.17mmol), recover to being stirred overnight at room temperature.Add EA After (40mL) dilution, washed, anhydrous sodium sulfate drying, filtered with water and saturated sodium-chloride successively, filtrate concentration obtains crude product 2g, Silica gel column chromatography (PE:EA 40:1 to 1:1) yellow solid 5c 400mg, two step yields 40%, are obtained.1H-NMR((CDCl3, 400MHz) δ 1.08 (s, 9H), 1.33 (s, 5H), 1.39 (s, 4H), 2.3-2.32 (m, 1H), 2.62-2.64 (m, 1H), 3.63- 3.69 (m, 3H), 4.09-4.12 (m, 1H), 4.18 (d, J=9.8Hz, 1H), 4.33 (d, J=11.76Hz, 1H), 4.72 (t, J =9.04Hz, 1H), 4.95-4.98 (m, 1H), 5.19-5.21 (m, 1H), 6.25-6.29 (m, 2H), 7.25-7.34 (m, 2H), 7.55-7.57(d,1H),7.66-7.68(d,1H),7.82-7.84(d,1H),8.11(d,1H).
In 25mL single port bottles, 5c (700mg, 1.02mmol), anhydrous DCM (0.8mL) and hydrochloric acid dioxy six are sequentially added Ring solution (4N, 4mL), is stirred at room temperature 1h, and HPLC shows no raw material.After reaction solution is concentrated under reduced pressure, continued to take out with vacuum oil pump 5min, obtains 5c hydrochloride.Anhydrous DCM (10.6mL) is dissolved in, is replaced 3 times with argon gas, reaction solution is cooled to 0 DEG C, stirring is lower to be added Enter triphosgene, pyridine is then added dropwise, reaction solution is after 0 DEG C is stirred 0.5h, and room temperature continues to stir 15min.Add EA After (53mL) dilution, washed (13mL*2), anhydrous sodium sulfate drying, filtered with water (13mL) and saturated sodium-chloride successively, filtrate rotation It is dry, inter-mediate isocyanate is obtained, oil pump is drained.Inter-mediate isocyanate is dissolved in anhydrous THF (15mL), add neopentyl glycol and 4A molecular sieves (1.75g), were stirred at room temperature after 0.5 hour, added DBU, continued to stir 4 hours, HPLC shows no raw material.Add EA (53mL) is diluted, and is filtered through diatomite, and filtrate uses water (11mL) successively, and saturated sodium-chloride is washed (11mL*4), and anhydrous sodium sulfate is done Dry, filtering, filtrate is spin-dried for obtaining crude product 1g, silica gel column chromatography (PE:EA40:1 to 1:1) yellow foamy solid 6c, is obtained 450mg, yield 40%.1H-NMR (CDCl3,400MHz) δ 0.96 (s, 6H), 1.08 (s, 9H), 2.33-2.34 (m, 1H), 2.62-2.64 (m, 1H), 3.08-3.1 (m, 2H), 3.37-3.43 (m, 2H), 3.74-3.77 (m, 3H), 4.07-4.08 (m, 1H), 4.09-4.15 (m, 1H), 4.22-4.25 (d, J=9.4Hz, 1H), 4.72 (t, J=9.04Hz, 1H), 4.32-4.35 (m,1H),4.72-4.77(m,1H),5.41-5.43(m,1H),5.98(s,1H),6.27-6.29(m,2H),7.25-7.34 (m, 2H), 7.56-7.58 (d, H), 7.66-7.7 (M, 1H), 7.83-7.85 (d, H), 8.13 (s, 1H)
In 50mL single port bottles, 6c (340mg, 0.14mmol), dry toluene (15mL), cesium carbonate are sequentially added (114mg, 0.35mmol), logical argon gas 5min, addition palladium (8mg, 0.0176mmol), PLn (18.8mg, 0.046mmol), Argon gas is replaced 3 times, and reaction solution oil bath heating is to 90 DEG C, and hour is stayed overnight in reaction, and TLC monitoring raw materials disappear.Silica gel column chromatography (PE:EA 40:1 to 2:1) yellow foamy solid 7c 125mg, are obtained.1H-NMR(CDCl3,400MHz)δ1.08(s,9H), 1.26 (s, 6H), 2.05-2.06 (m, 1H), 2.23-2.25 (m, 1H), 2.51-2.55 (m, 1H), 2.78-2.80 (m, 1H), 3.34-3.36 (m, 1H), 3.54-3.57 (m, 1H), 3.70-3.72 (m, 3H), 4.00-4.02 (m, 1H), 4.09-4.15 (m, 1H), 4.22-4.25 (m, 2H), 4.49-4.52 (m, 1H), 4.77-4.80 (m, 1H), 5.23-5.26 (m, 1H), 6.27-6.29 (m, 2H), 7.0-7.06 (m, 1H), 7.27-7.29 (m, 1H), 7.35-7.38 (m, 2H), 7.40-7.42 (m, 1H), 7.66- 7.69(m,1H).
Under nitrogen protective condition, compound 7c (20mg, 0.0135mmol) is added in THF/ methanol 1.6mL successively, Nitrogen displacement 3 times, is then added dropwise 1N LiOH solution, and 2h is reacted under the conditions of RT, and TLC detection reactions are complete.Reaction solution is concentrated into It is dry, 1N salt acid for adjusting pH 1-2 are added, are extracted 3 times with EA, then filtering and concentrating is carried out next to dry after anhydrous sodium sulfate drying Step reaction.
Embodiment 21
Compound L W00208 synthesis
In 25mL there-necked flasks, sequentially add 8c (20mg, 0.065mmol) and SM-6b (27.5mg, 0.098mmol) is arrived Dry DMF (3mL), reaction bulb is replaced 3 times with argon gas, and ice-water bath is cooled to 0 DEG C, adds HATU (37.3mg, 0.098mmol), DIEA is added dropwise, then is replaced 3 times with argon gas, removes ice bath, is warmed to room temperature reaction 1 hour, HPLC is monitored to without raw material.Add EA After (200mL) dilution, washed 4 times with semi-saturation salt, anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for, and obtains crude product 20mg, silicon Plastic column chromatography (PE:EA 40:1 to 2:1) LW100208 10mg, are obtained.1H-NMR(CDCl3,400MHz)δ1.00-1.04(m, 14H),1.11-1.14(m,4H),1.26-1.29(m,6H),1.31-1.43(m,1H),1.91-1.95(m,1H),1.91- 1.95(m,1H),2.37-2.39(m,1H),2.90-2.95(m,1H),3.47-3.55(m,1H),3.71(s,1H),3.92- 3.96 (m, 1H), 4.06-4.12 (m, 1H), 4.31-4.39 (m, 2H), 5.11 (d, J=9.8Hz, 1H), 5.20 (d, J= 16.8Hz, 1H), 5.33-5.36 (m, 1H), 6.26 (d, J=1.56Hz, 2H), 7.00-7.03 (m, 1H), 7.27-7.30 (m, 1H),7.36-7.40(m,2H),7.55-7.56(m,1H),7.66-7.69(m,1H).MS(ESI):m/z 831.3(M+H)。
Embodiment 22
Compound L W00207 synthesis
Double bond substrate LW100208 (20mg, 0.139mmol) is dissolved in 5mL ethyl acetate, 10%Pd/C is added (4mg), room temperature is hydrogenated 30 minutes, and TLC monitoring reactions are complete, and reactant mixture is filtered through diatomite, and filter cake is washed with ethyl acetate Wash three times, merging filtrate is spin-dried for, and obtains crude product, pure products 5.5mg yellow solids LW100207 is obtained through preparing after TLC is isolated and purified. 1H-NMR(CDCl3,400MHz)δ1.00-1.04(m,13H),1.11-1.14(m,4H),1.25-1.29(m,10H),1.59- 1.64(m,3H),2.36-2.38(m,1H),2.92-2.96(m,2H),3.48-3.53(m,1H),3.71(s,1H),3.94- 3.95 (m, 1H), 4.09-4.15 (m, 2H), 4.31-4.37 (m, 2H), 6.26 (d, J=1.56Hz, 2H), 7.00-7.03 (m, 1H),7.27-7.30(m,1H),7.36-7.40(m,2H),7.42-7.54(m,1H),7.66-7.68(m,1H).MS(ESI): m/z 833.2(M+H)。
Embodiment 23
Compound L W00209 synthesis
In 25mL there-necked flasks, sequentially add 8c (12mg, 0.032mmol) and SM-6c (14mg, 0.05mmol) and arrive anhydrous DMF (3mL), reaction bulb is replaced 3 times with argon gas, and ice-water bath is cooled to 0 DEG C, adds HATU (20mg, 0.05mmol), is added dropwise DIEA, is warmed to room temperature 20 DEG C and reacts 1 hour, and HPLC monitors, EA (200mL) dilution complete to reaction, the washing of semi-saturation salt, nothing Aqueous sodium persulfate is dried, and filtering, filtrate is spin-dried for obtaining crude product 20mg, silica gel column chromatography (PE:EA 40:1 to 2:1) LW100209, is obtained 8mg。1H-NMR(CDCl3,400MHz)δ1.00-1.04(m,12H),1.11-1.13(m,4H),1.19-1.36(m,10H), 1.70-1.72(m,1H),2.05-2.06(m,1H),2.35-2.36(m,1H),2.70-2.75(m,1H),2.95-2.98(m, 1H),3.45-3.52(m,1H),3.71(s,1H),4.08-4.10(m,2H),4.31-4.40(m,3H),5.28-5.35(m, 1H),5.95-5.98(m,1H),6.26(m,2H),6.95-7.03(m,1H),7.27-7.30(m,1H),7.34-7.40(m, 2H),7.50-7.54(m,1H),7.56-7.69(m,1H).MS(ESI):m/z 845.3(M+H)。
Embodiment 24
Compound 8d synthesis
By Vd (5.4g, 14.52mmol), cis-N-Boc-L- proline methyl esters (3.92g, 15.97mmol), PPh3 (7.62g, 29.04mmol) is dissolved in anhydrous THF (25mL), is replaced three times with argon gas, is cooled to after 0 DEG C, DIAD is added dropwise (5.72mL, 29.04mmol) (is diluted) with 5mL THF, is recovered to 18h is stirred at room temperature, HPLC monitors, decompression complete to reaction It is evaporated after reaction solution and obtains crude product 26.68g, silicagel column purifying (PE:EA 20:1 to7:1) 4d (9.23g, weak yellow foam shape are obtained Solid), yield 106%.1HNMR(CDCl3,400MHz)δ8.23(s,1H),8.01(d,1H),7.59(d,1H),7.37(t, 1H),7.28(s,1H),7.08(s,1H),5.08(m,1H),4.50(m,1H),3.94(m,2H),3.80(s,3H,CH3), 2.63(m,1H),2.41(m,1H),1.86(s,6H,2CH3),1.45(s,9H,3CH3,Boc)；MS(ESI):m/z 602.42(M +H)。
The said goods 4d (9.2g, 15.32mmol) is dissolved in anhydrous DCM (12.5mL), 4N HCl Isosorbide-5-Nitrae-dioxy is added Six ring solution (62mL).2h is stirred at room temperature in reaction solution, and HPLC monitoring reactions are complete.Reaction solution evaporated under reduced pressure obtains faint yellow solid. This product (8.87g, 16.52mmol), Boc-L- Terleus (3.82g, 16.52mmol) are dissolved in DMF (26.6mL), argon is changed Gas three times, reaction solution is cooled to 0 DEG C with ice bath, sequentially add DIEA (14.4mL, 82.6mmol), HATU (7.54g, 19.83mmol).Recover to 16.5h is stirred at room temperature, HPLC monitoring reactions are complete.Added in reaction solution after 355mL EA dilutions, according to Secondary addition 70mL washing, 70mL saturated common salts washing (4 times), is filtered, is spin-dried for obtaining crude product 17.09g anhydrous sodium sulfate drying.Silicon Glue post purifies (PE:EA 15:1 to 1:1) 5d (9.37g), yield 79.5%. are obtained1HNMR(CDCl3,400MHz)δ8.16 (s,1H),7.90(d,1H),7.58(d,1H),7.44(s,1H),7.34(t,1H),7.10(s,1H),4.77(t,1H), 4.11-4.25(m,3H),3.80(s,3H,CH3),2.65(m,1H),2.39(m,1H),1.86(s,6H,2CH3),1.28(s, 9H,3CH3),1.11(s,9H,3CH3)；MS(ESI):m/z 715.60(M+H).
The said goods 5d (9.37g, 13.13mmol) is dissolved in anhydrous DCM (10.2mL), 4N HCl Isosorbide-5-Nitrae-dioxy is added Six ring solution (50.8mL), are stirred at room temperature after 1h, stop reaction.Concentration of reaction solution obtains product 6d (9.59g), yield 112.4% 。1HNMR(DMSO-d6,400MHz)δ9.73(s,0.3H),8.24(s,1H),8.09(d,1H),7.69(d,1H),7.48(t, 1H),7.43(s,1H),7.22(s,1H),4.88(m,1H),4.55(t,1H),4.21(d,1H),4.06(d,1H),3.93(s br,1H),3.70(s,3H,CH3),2.61(m,1H),2.38(m,1H),1.77(d,6H,2CH3),1.05(s,9H,3CH3)；MS (ESI):m/z 615.52(M+H)。
6d (5g, 7.69mmol) is dissolved in DCM (133mL), reaction solution is cooled to after 0 DEG C, addition triphosgene (3.24g, 11.54mmol).Pyridine (9.9mL, 123.04mmol) is added dropwise.Reaction solution continues at 0 DEG C after stirring 0.5h, and HPLC monitorings are anti- Should be complete.Added in reaction solution after 400mL EA dilutions, successively with 95mL washings once, 95mL saturated common salts are washed twice, Anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for obtaining inter-mediate isocyanate, drained with oil pump.Inter-mediate isocyanate is dissolved in In 198mL THF, neopentyl glycol (2.4g, 23.07mmol) and 4A molecular sieves (13.2g) are added, is stirred at room temperature after 0.5h, added DBU (1.5mL, 10mmol), continues to stir 1h, HPLC monitoring reactions are complete.Added in reaction solution after 396mL EA dilutions, according to Secondary to be washed once with 79mL, 79mL saturated common salts are washed 4 times, plus anhydrous sodium sulfate drying, and filtering is spin-dried for obtaining crude product 8.2g, mistake Silicagel column purifies (PE:EA 15:1 to 2:1) product 7d (3.8468g), yield 67.3% are obtained.1HNMR(CDCl3, 400MHz)δ8.11(s,1H),7.90(d,1H),7.69(s,1H),7.60(d,1H),7.38(m,2H),7.14(s,1H), 5.38(d,1H),4.79(t,1H),4.35(m,1H),4.18(m,1H),4.05(m,1H),3.81(s,3H,CH3),3.71(d, 1H),3.32(d,1H),3.08(m,2H),2.69(m,1H),2.31(m,1H),1.86(s,6H,2CH3),1.31(s,6H, 2CH3),1.07(s,9H,3CH3)；MS(ESI):m/z 743.64(M+H).
7d (500mg, 0.67mmol), cesium carbonate (546mg, 1.675mmol), the logical argon gas 15min of toluene (42mL) is standby With) will be replaced through argon gas after mentioned reagent add after reaction bulb, then logical argon gas 5min, add palladium (38.2mg, 0.17mmol) with PdLn (85.4mg, 0.2144mmol), argon gas is replaced 3 times.90 DEG C are heated to, 16h is reacted, HPLC monitorings are anti- Should be complete.Reaction solution is filtered through diatomite, and EA washing filter cakes, merging filtrate is spin-dried for, and obtains crude product 0.6947g.Cross silicagel column purifying (PE:EA 40:1 to 4:1) macrocyclic products (181.1mg), yield 40.4%, are obtained.1HNMR(CDCl3,400MHz)δ7.41- 7.49(m,4H),7.09(m,2H),5.29(d,1H),4.51(m,1H),4.31(m,3H),4.14(m,2H),4.05(m,1H), 3.75(s,2H),3.71(s,3H,CH3),2.51(m,1H),2.18(m,1H),1.81(s,6H,2CH3),1.32(s,6H, 2CH3),1.08(s,9H,3CH3)；MS(ESI):m/z 663.70(M+H).
Macrocyclic products (180mg, 0.27mmol) are dissolved in THF/MeOH (7.4mL/3.7mL), 1N lithium hydroxide water is added 2h is stirred at room temperature in solution (4.1mL), reaction solution, and HPLC monitoring reactions are complete.Reaction solution is spin-dried for organic phase, and aqueous phase is adjusted with 1N HCl PH to 4~5.EA is extracted three times, is merged organic phase, is washed with saturated common salt, anhydrous sodium sulfate drying, is filtered, is spin-dried for obtaining product 8d (lw1002-42-37-1,158.6mg), yield 90%.1HNMR(DMSO-d6,400MHz)δ7.68(s,1H),7.20-7.45 (m,3H),7.09(s,1H),6.98(s,1H),4.60(d,1H),4.11-4.30(m,4H),4.02(m,3H),3.71(m, 2H),2.31(m,1H),2.18(m,1H),1.76(s,6H,2CH3),1.34(s,6H,2CH3),0.98(d,9H,3CH3)；MS (ESI):m/z 649.70(M+H)。
Embodiment 25
Compound L W100210 synthesis
Double bond substrate LW100210 (120mg, 0.139mmol) is dissolved in 10mL ethyl acetate, is carefully added into palladium carbon (10% Pd/C) (50mg), after being replaced 5 times with hydrogen, under hydrogen balloon hydrogenation, is stirred at room temperature 30 minutes, HPLC monitoring reactions are complete, stop Only react, reactant mixture is filtered through diatomite, filter cake is washed three times with ethyl acetate, and merging filtrate is spin-dried for, and obtains crude product 112.5mg, pure products LW100211 23mg, yellow solid are obtained through preparing after TLC is isolated and purified.1HNMR(CDCl3,400MHz) δ10.15(s,1H),9.90(s,1H),7.60(d,1H),7.40(m,3H),7.10(m,1H),7.00(m,1H),5.40(s br,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m,1H),2.95 (m,1H),2.60(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,2H),1.40(m,1H),1.30(s,6H),1.26 (m,2H),1.15(s,9H),0.90(m,3H)；MS(ESI):m/z 863.90(M+H).
Embodiment 26
Compound L W100211 synthesis
By 8d (50mg, 0.077mmol), SM-6a (30.8mg, 0.1155mmol) is dissolved in DMF (3.1mL), and reaction bulb is used After argon gas is replaced three times, 0 DEG C is cooled in ice bath, DIEA (0.085mL, 0.4928mmol), and HATU are added dropwise successively (44mg, 0.1155mmol), argon gas is replaced three times, is warmed to room temperature, and stirs 1.5h, and HPLC monitoring reactions are complete, stop reaction. 25mL EA dilution is added in reaction solution, with semi-saturation brine It four times, organic phase anhydrous sodium sulfate drying, suction filtration, filter Liquid is spin-dried for obtaining crude product 153.4mg, crosses silicagel column purifying (PE:EA 10:1~8:1~6:15:1) crude product 76.7mg, is obtained, is made Slave board, which is further purified, obtains sterling LW100211 49mg, yield 73.8%.1HNMR(CDCl3,400MHz)δ10.15(s, 1H),9.90(s,1H),7.80(d,1H),7.38(m,3H),7.12(m,1H),6.98(m,1H),5.78(m,1H),5.25(m, 1H),5.12(m,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m, 1H),2.90(m,1H),2.30(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.40(m,1H),1.30(s, 6H),1.26(m,2H),1.15(s,9H),0.90(m,2H)；MS(ESI):m/z 861.91(M+H).
Embodiment 27
Compound L W100212 synthesis
By 8d (50mg, 0.077mmol), SM-6c (32.4mg, 0.1155mmol) is dissolved in DMF (3.1mL), and reaction bulb is used After argon gas is replaced three times, it is placed in ice bath and is cooled to 0 DEG C, DIEA (0.085mL, 0.4928mmol), and HATU is added dropwise successively (44mg, 0.1155mmol), under argon gas protection, is warmed to room temperature, and stirs 1.5h, and HPLC monitoring reactions are complete, stop reaction.Instead Answer liquid to add after 25mL EA dilutions, washed four times with semi-saturation salt, anhydrous sodium sulfate drying, suction filtration, filtrate is spin-dried for obtaining crude product 108.7mg, silicagel column purifies to obtain crude product 165mg, prepares plate and is further purified and obtains sterling LW100212 49.7mg, yield 73.7%.1HNMR(CDCl3,400MHz)δ10.20(s,1H),9.90(s,1H),7.90(d,1H),7.50(m,4H),7.18 (m,1H),4.68(m,1H),4.35(m,2H),4.16(m,3H),4.09(m,1H),3.69(m,2H),3.50(m,1H),3.42 (m,1H),3.02(m,1H),2.30(m,2H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.56(m,1H),1.40 (m,1H),1.30(s,6H),1.26(m,2H),1.15(m,10H),0.90(m,2H)；MS(ESI):m/z 875.99(M+H).
Embodiment 28
Compound 8e synthesis
By Ve (1g, 2.7mmol), triphenylphosphine (1.4g, 5.38mmol), cis-N-Boc-4- OH-L-prolines first Ester (0.74g, 3mmol) is dissolved in THF (46mL).Reaction bulb is replaced three times with argon gas, is cooled to 0 DEG C, be added dropwise DIAD (1.1mL, 5.38mmol), temperature is held essentially constant.Ice-water bath is removed, is continued after stirring reaction 4h, HPLC detections fundamental reaction is complete. It is spin-dried for reaction solution, silica gel column chromatography purifying (PE:EA 30:1 to 20:1) 4e (1.4g), yield 87.5% are obtained.1HNMR (CDCl3,400MHz)δ8.22(s,1H),7.99(d,1H),7.60(d,1H),7.35(m,2H),7.27(s,1H),4.48(m, 1.5H),4.30(m,0.5),3.95(m,1.5H),3.80(s,3H,CH3),3.78(m,0.5H),2.62(m,1H),2.43(m, 1H),1.85(s,6H,2CH3),1.46(s,9H,3CH3)；MS(ESI)m/z 600.49(M+H).
4e (1.4g, 2.33mmol) is dissolved in 12mL DCM, 4mL 4N HCl-dioxane are added dropwise, 2h is stirred at room temperature, HPLC detection reactions are complete.It is spin-dried for obtaining hydrochloride 1.35g.By this hydrochloride (1.35g, 2.6mmol), Boc-L- Terleus (0.6g, 2.6mmol) is dissolved in 8mL DMF, after argon gas ventilation twice, and reaction solution is cooled to 0 DEG C, and stirring is lower to be added dropwise DIEA (2.3mL, 13mmol) (temperature change is not obvious), then adds HATU (1.2g, 3.12mmol), then with argon gas ventilation twice, 6h is stirred at room temperature, HPLC detection reactions are complete.Added in reaction solution after 25mL EA dilutions, (8*2mL), saturation are washed with water successively Salt washes (8*2mL), anhydrous sodium sulfate drying, and filtering, filtrate is spin-dried for obtaining crude product 2.6g.Cross 30 times of silicagel column purifying (PE:EA 20:1~15:1~12:1) faint yellow solid sterling 5e 0.65g, yield 36%., are obtained1NMR(CDCl3,400MHz)δ8.15 (s,1H),7.87(d,1H),7.56(d,1H),7.36(m,3H),6.30(s br,1H),4.73(m,1H),4.18(m,2H), 4.02(m,1H),3.79(s,3H,OCH3),2.61(m,1H),2.35(m,1H),1.86(d,6H,2CH3),1.59(s,9H, 3CH3),1.06(s,9H,3CH3)；MS(ESI):m/z 713.67(M+H).
Substrate 5e (1.15g, 1.15mmol) is dissolved in DCM, the lower Isosorbide-5-Nitrae-dioxane that 6mL 4N HCl are added dropwise of stirring is molten Liquid.Continue that reaction 3h, HPLC detection reaction is stirred at room temperature completely.It is spin-dried for reaction solution solvent and obtains hydrochloride 1.4g, is dissolved in 30mL DCM, reaction solution is cooled to after 0 DEG C, and stirring is lower to add triphosgene (0.71g, 2.4mmol), and reaction bulb argon gas is taken a breath twice, Add pyridine (2.1mL, 25.8mmol).0 DEG C of stirring 0.5h, is then warmed to room temperature, and continues to stir 0.5h.HPLC detections have been reacted Entirely.Added in reaction solution after 80mL EA dilutions, successively with 15mL water and the washing of 15mL saturated common salts twice, anhydrous sodium sulfate is done It is dry, filtering, after filtrate is spin-dried for, continuation takes out 1h with oil pump and obtains isocyanate intermediate, is dissolved in THF, add neopentyl glycol (0.5g, 4.83mmol) and 4A molecular sieves (2.75g), 0.5h is stirred at room temperature in reactant mixture, add DBU (0.31mL, 2.1mmol), continue after stirring reaction 1h, HPLC detections find that reaction is complete.Added in reaction solution after 80mL EA dilutions, successively Washed with 15mL saturated common salts, obtain crude product 2g.Silicagel column purifies (PE:EA 10:1 to 2:1) sterling 6e 0.8g, yield are obtained 66.7%.1HNMR(CDCl3,400MHz)δ8.14(s,1H),7.83(d,1H),7.55(d,1H),7.41(m,3H),5.90 (s,1H),4.73(m,1H),4.21(m,2H),4.13(m,1H),3.80(m,3H,OCH3),3.52(s,2H,),3.11(m, 2H),2.65(m,1H),2.30(m,2H),1.82(d,6H,2CH3),0.98(s,15H,5CH3)；MS(ESI):m/z 743.68, 745.68(M+H)。
6e (0.4g, 0.54mmol) is dissolved in 30mL dry toluenes (with preceding logical argon gas 15min), cesium carbonate is added (0.44g, 1.35mmol), reaction mixed argon gas-liquid is led to after 5min, add palladium (30mg, 0.135mmol), PLn (70mg, 0.173mmol), then with argon gas take a breath three times, reaction solution is heated to 90 DEG C, is stirred overnight.Second day, HPLC detections were reacted Entirely.Reaction mixture is filtered through diatomite, EA washing filter cakes, merging filtrate is spin-dried for, and obtains crude product 0.65g.Silicagel column is purified (PE:EA 15:1 to 5:1) macrocyclic compound 7e 70mg, yield 19.5%,1HNMR(CDCl3,400MHz)δ7.40(m, 3H),7.28(m,2H),6.98(m,1H),6.15(s,1H),5.30(m,1H),4.80(d,1H),4.50(m,1H),4.31(m, 1H),4.20(m,1H),4.02(m,1H),3.75(m,1H),3.71(s,3H,OCH3),3.31(d,1H),2.50(m,1H), 2.31(m,1H),2.20(m,1H),1.81(m,6H,2CH3),1.25(s,6H,2CH3),1.06(s,9H,3CH3)；MS(ESI): m/z 663.83(M+H).
7e (100mg, 0.15mmol) is dissolved in THF/MeOH (4mL/2mL), stirring is lower to add the 1N LiOH aqueous solution 1.5h is stirred at room temperature in (2.3mL), reaction solution, and HPLC detection reactions are complete.Organic phase is spin-dried for, aqueous phase is adjusted with the 1N HCl aqueous solution After pH to 4-5, it is extracted with ethyl acetate three times (15x3mL), merges organic phase, plus anhydrous sodium sulfate drying, filtering, filtrate rotation Do to obtain 8e 130mg, yield 128%.MS (ESI) m/z 649.69.
Embodiment 29
Compound L W100214 synthesis
Carboxylic acid 8e (70mg, 0.11mmol) and sulfonamide SM-6a (44.6mg, 0.165mg) are dissolved in 5mL DMF, argon is used Gas is taken a breath twice, and reaction solution is cooled to 0 DEG C, and stirring is lower to be added dropwise DIEA (0.12mL, 0.72mmol), then add HATU (63mg, 0.165mmol), then take a breath twice, after room temperature reaction 1.5h, send HPLC detection reactions complete.
Reaction solution adds after 15mL EA dilutions, and (10*4mL) is washed with semi-saturation salt, and anhydrous sodium sulfate drying is filtered, filter Liquid is spin-dried for obtaining 140mg.Silica gel column chromatography (PE:EA 15:1 to 4:1) LW100214 14mg are obtained,1HNMR(CDCl3) δ7.35 (m,5H,ArH),6.98(m,1H),5.67(m,1H),5.35(m,1H),5.19(m,1H),5.10(m,1H),4.31(m,3H), 4.01(m,2H),3.67(s,1H)3.43(m,2H),2.88(m,1H),2.60(m,1H),2.00(m,1H),,1.83(s,3H, CH3),1.78(s,3H,CH3),1.62(m,4H),1.11(s,6H,2CH3),1.01(s,9H,3CH3),0.91(m,2H).LCMS (ESI):m/z 861.87(M+H).
Embodiment 30
Compound L W100213 synthesis
With reference to embodiment 22, LW100214 (10mg) normal temperature Pd/C hydrogenations obtain LW100213 7mg.
1HNMR(CDCl3)δ7.35(m,5H,ArH),6.98(m,1H),5.67(m,1H),5.35(m,1H),5.19(m, 1H),5.10(m,1H),4.31(m,3H),4.01(m,2H),3.67(s,1H)3.43(m,2H),2.88(m,1H),2.60(m, 1H),2.00(m,1H),,1.83(s,3H,CH3),1.78(s,3H,CH3),1.62(m,4H),1.11(s,6H,2CH3),1.01 (s,9H,3CH3),0.91(m,2H).MS(ESI)m/z 863.90(M+H).
Embodiment 31
Compound L W100215 synthesis
Sour 8e (35mg, 0.054mmol), sulfonamide SM-6c (23.2mg, 0.081mmol) are dissolved in DMF, put with argon gas Change twice, reaction solution is cooled to 0 DEG C.Stirring is lower to be added dropwise DIEA, then adds HATU, then with argon gas ventilation twice.Reaction solution room After temperature stirring 1.5h, send HPLC detection reactions complete.Reaction solution adds after 15mL EA dilutions, is washed with semi-saturation salt (5x4mL), organic addition anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for obtaining 70mg, column chromatography purifying (PE:EA 10:1 to 5:1) LW100215 43mg are obtained, yield 67% prepares chromatographic separation and purification, HPLC (220/254nm):96.26%/ 99.03%；1HNMR(CDCl3,400MHz)δ7.41(m,6H,ArH),7.29(m,1H),6.18(s,1H),5.88(s,1H), 4.49(d,1H),4.42(m,2H),4.27(m,1H),4.13(m,2H),3.78(m,2H),3.48(m,1H),3.38(m,1H), 2.95(m,2H),2.60(m,1H),2.29(m,2H),2.20(m,2H),1.79(s,3H,CH3),1.76(s,3H,CH3),1.69 (m,1H),1.25(m,3H),1.16(s,6H,2CH3),1.08(s,9H,3CH3),0.80(m,2H),0.51(m,3H),0.45 (m,3H).LCMS(ESI):m/z 875.6.
Embodiment 32
Compound 8f synthesis
By Vf (1.5g, 4.03mmol), the cis hydroxyproline methyl esters of N-Boc- (1.104g, 4.5mmol), PPh3 (2.13g, 8.12mmol) is dissolved in anhydrous THF (70mL), and device good seal is replaced 3 times, reaction bulb is placed in ice bath with argon gas In be cooled to 0 DEG C, DIAD (1.65mL, 8.12mmol) is added dropwise.After completion of dropping, ice bath is removed, makes its clear-cutting forestland to room temperature, Reaction 4 hours, reaction solution is spin-dried for, silica gel column chromatography (PE:EA 15:1~10:1~5:1) yellow fluorescent solid 4f, is obtained (3.52g)。1HNMR(CDCl3,400MHz)δ8.20(s,1H),7.93(m,1H),7.58(m,2H),7.32(m,1H),7.16 (d,1H),5.02-5.05(m,1.5H),4.48(m,0.5H),3.92-3.95(m,1.5H),3.80(s,3H,CH3),3.73 (m,0.5H),2.64(m,1H),2.37(m,1H),1.75(s,6H,2CH3),1.41(s,9H,3CH3)；MS(ESI):m/z 600.42(M+H)。
4f (3.47g, 5.8mmol) is dissolved in DCM (30mL), hydrochloric acid dioxane solution (10mL, 40mmol) is added dropwise, Solution becomes blood red, almost without heat release, and gradually separates out red solid.HPLC is sent in reaction after 3 hours, detection reaction is complete, It is transferred in eggplant bottle and is spin-dried for reaction solution, obtains yellow hydrochloride solid (3.39g).By this solids and N-Boc-L Terleus (1.405g, 6.24mmol) is dissolved in dry DMF (45mL), and device good seal is replaced 3 times with argon gas, dropped in ice salt bath DIEA (8.3mL, 30.6mmol) is slowly added dropwise to 0 DEG C in temperature.Drop finishes, and adds HATU (2.8g, 7.37mmol), and 3 are replaced with argon gas Secondary, normal-temperature reaction is stayed overnight.HPLC detection reactions are complete, add EA (200mL) dilutions, organic phase washed with water (75mL) and saturation After saline solution (75mL) washing, with anhydrous sodium sulfate drying, filtering is spin-dried for, silica gel column chromatography (PE:EA 20:1 to 5:1) Faint yellow solid 5f (3.3g), yield 74.23%.MS(ESI):m/z 713.53(M+H).
5f (3.3g, 4.63mmol) is dissolved in DCM (50mL), hydrochloric acid dioxane solution (10mL, 40mmol) is added dropwise, Solution becomes blood red.HPLC is sent in reaction after 3 hours, detection reaction is complete, is transferred in eggplant bottle and is spin-dried for reaction solution, obtains yellow and consolidates Body hydrochloride 3.24g, is dissolved in anhydrous DCM (87.8mL), adds triphosgene (2.26g, 7.61mmol), is stoppered plug, will be anti- Answer bottle to change after argon gas 3 times, be placed in ice-water bath and be cooled to T≤5 DEG C, stirring is lower to be added dropwise pyridine solution (6.5 mL), reaction solution by Crossfade into and continue to stir 30min in ice bath after emerald green, the big calorimetric of releasing, completion of dropping, color reverses back is orange red, then removes Ice bath is gone to continue to react 15min at room temperature.Send HPLC reactions complete.The rear pump or output pump being spin-dried for is drained, and is dissolved in anhydrous THF In (130.68mL), 4A molecular sieves (8.72g pulverizes) are added, neopentyl glycol (1.58g, 15.24mmol), good seal will react After bottle ventilation 3 times, DBU (1mL) is added dropwise in stirring at room temperature, and reactionless phenomenon, stirring reaction is stayed overnight.HPLC is sent to react within second day Entirely, by reacting liquid filtering, it is spin-dried for, silica gel column chromatography (PE:EA 20:1 to 3:1) product 6f 1.2g.MS (ESI) are obtained:m/z 743.67(M+H).
By 6f (0.6g, 0.74mmol), CsCO3(0.6g, 1.85mmol) is dissolved in treated toluene (45mL), reaction Liquid continues logical argon gas 5 minutes.Add Pd (OAc)2(42mg, 0.185mmol), PLn (94mg, 0.24mmol), loads onto condenser pipe, After good seal, argon gas is changed 3 times, stirring is warming up to 90 DEG C, and reaction is stayed overnight.HPLC is sent within second day, when product point retains with raw material point Between it is about the same, reaction solution is crossed into diatomite, is spin-dried for, crude product 1.1g, silica gel column chromatography (PE is obtained:EA 20:1to 2:1), by institute Obtain after solution is spin-dried for and drained with oil pump, obtain faint yellow solid 7f 185mg, yield 34.6%.MS(ESI):m/z 663.74(M+ H).
7f is dissolved in THF/MeOH solution (7.175mL/3.605mL), the LiOH/H prepared is instilled2O solution (4mL, 1N) it is stirred at room temperature after reaction 2h, TLC, HPLC monitoring reaction are complete, stop reaction.Organic phase is spin-dried for, HCl solution is instilled (1N) adjusts solution PH between 4~5, with EA aqueous phase extracteds three times, merges organic phase, saturated common salt water washing 3 times, organic phase Middle addition anhydrous sodium sulfate drying 30min, filtering, faint yellow solid 8f 201mg.MS (ESI) are spin-dried for obtaining by organic phase:m/z 649.69。
Embodiment 33
Compound L W100217 synthesis
Contracting carboxylic acid 8f (50mg, 0.082mmol) and sulfonamide SM-6a (32.68mg, 0.1224mmol) are dissolved in DMF molten In liquid (5mL), by reaction bulb good seal, replaced 3 times with argon gas, reaction bulb is placed in ice bath and cools to T≤5 DEG C, under stirring DIEA (0.092mL, 0.525mmol) is added dropwise, without obvious heat release, HATU (46.54mg, 0.1224mmol) is added, good seal is anti- Bottle is answered, then is replaced 3 times with argon gas, 90 DEG C, after 20min is heated to, is down to room temperature, continues to react 1.5hr.TLC monitor to Raw material reaction is complete, and reaction solution adds 50mL EA dilutions, goes in separatory funnel, adds saturated common salt water washing 3 times, separates Organic phase, adds anhydrous sodium sulfate drying, and filtering, organic phase is spin-dried for obtaining crude product 121mg.Silica gel column chromatography, obtains sterling LW100217 light green solid 37mg, yield 63.3%；1HNMR(CDCl3,400MHz)δ10.20(s,1H),9.90(s,1H), 7.70(d,1H),7.60(m,1H),7.50(m,1H),7.28(m,1H),7.20(d,1H),7.01(m,1H),5.78(m,1H), 5.25(m,1H),5.12(m,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.00(m,1H),3.79(m,2H), 3.52(m,1H),3.35(m,1H),2.90(m,1H),2.35(m,1H),1.82(m,7H),1.68(m,1H),1.40(m,1H), 1.30(s,6H),1.26(m,2H),1.15(s,9H),0.90(m,2H)； MS(ESI):m/z 861.95(M+H).
Embodiment 34
Compound L W100216 synthesis
Double bond substrate LW100217 (21mg, 0.0343mmol) is dissolved in EA solution (1.5mL), Pd/C (5mg) is added Reaction bulb good seal, hydrogen is replaced 5 times, normal-temperature reaction 1h, and discovery has 1/3 starting material left, continues replacing hydrogen reaction 1h, residue Few raw material, continues replacing hydrogen 30min, finds new HPLC peaks occur, thus it is speculated that overreact, stops reaction, reaction solution warp It is spin-dried for after diatomite filtering.Solid is dissolved in DCM (10mL), is uniformly applied to and prepares on plate TLC, with solvent (DCM: MeOH 30:1) deploy, taking-up prepares plate after 2h, scrapes silica gel, dissolved with DCM (15mL), ultrasound, filtering, filtrate is spin-dried for light Yellow solid LW100216 9mg (yield 42.76%).1HNMR (CDCl3,400MHz) δ 10.15 (s, 1H), 9.90 (s, 1H), 7.66(d,1H),7.56(m,1H),7.40(m,1H),7.28(m,1H),7.21(d,1H),7.00(m,1H),6.28(s,1H), 5.40(s br,1H),4.80(d,1H),4.46(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m, 1H),2.95(m,1H),2.60(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,2H),1.40(m,1H),1.30(s, 6H),1.26(m,2H),1.15(s,9H),0.90(m,3H)；MS(ESI):m/z 863.90(M+H).
Embodiment 35
Compound L W100218 synthesis
Carboxylic acid 8f (30mg, 0.049mmol) and sulfonamide SM-6c (20.64mg, 0.0735mmol) are dissolved in DMF solution In (3.1mL), by reaction bulb good seal, replaced 3 times with argon gas, reaction bulb is placed in ice bath and cools to T≤5 DEG C, be added dropwise DIEA (0.055mL, 0.317mmol), without obvious heat release, adds HATU (27.95mg, 0.0735mmol), good seal reaction bulb, Replaced 3 times with argon gas again, be warming up to 90 DEG C, after 20min, be down to room temperature, continue to react 1.5h.
Extract reaction solution and monitored with TLC, it is found that raw material has reacted complete, add after 30mL EA dilutions, reaction solution is transferred to In separatory funnel, saturated common salt water washing is added 3 times, separate organic phase, add anhydrous sodium sulfate drying, filtering, organic phase rotation Do to obtain crude product 80mg, silicagel column purifying (PE:EA 20:1 to 2:1) sterling LW100218, light green solid 32mg, are obtained, is received Rate 93.03%.1HNMR(CDCl3,400MHz)δ10.30(s,1H),9.90(s,1H),7.80(d,1H),7.50(m,4H), 7.05(m,1H),5.32(m,1H),4.84(m,1H),4.35(m,2H),4.16-4.09(m,4H),3.71(m,2H),3.50 (m,1H),3.32(m,1H),2.98(m,1H),2.30(m,2H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.56 (m,1H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(m,10H),0.90(m,2H)；MS(ESI):m/z 875.88(M+H).
Embodiment 36
The synthesis of compound 13
By compound 4 (0.86g, 1.5mmol), the potassium fluoborate of ethene three (0.61g, 4.5mmol) and triethylamine (0.63mL, 4.5mmol) is dissolved in 15mL absolute ethyl alcohols, then adds Pd (dppf) Cl2(44mg, 0.06mmol), argon gas is put Return stirring is heated to after changing to stay overnight.Question response liquid is cooled to after room temperature, and 10%KHSO is added into mixed liquor4The aqueous solution is quenched Reaction, then with EA aqueous phase extracteds three times.Merge organic phase, after anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, post layer Analysis purifies to obtain product 10 (0.62g, yield 80%).ESI-MS[(M+H+)]:m/z 520.28.
Compound 10 (0.62g, 1.2mmol) is dissolved in the anhydrous DCM of 4mL, 4mL 4N HCl Isosorbide-5-Nitrae-dioxane is added Solution.Concentration of reaction solution after 1h is stirred at room temperature and obtains amine intermediate.Amine intermediate and SM-4 (0.30g, 1.3mmol) are dissolved in nothing In water DMF, 0 DEG C is then cooled to.Argon gas protection under, add DIEA (0.85mL, 4.9mmol) and HATU (0.49g, 1.3mmol).Reaction solution is stirred at room temperature one hour, then adds EA dilutions, and 5% aqueous citric acid solution is washed, and is washed, 1M carbonic acid Hydrogen sodium water solution is washed, and saturated common salt is washed 4 times.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, column chromatography Purify to obtain product 11 (0.64g), two step yields 85%.ESI-MS[(M+H+)]:m/z 633.41.
Compound 11 (0.64g, 1.0mmol) is dissolved in the anhydrous DCM of 4mL, 4mL 4N HCl Isosorbide-5-Nitrae-dioxane is added Solution.Concentration of reaction solution after 1h is stirred at room temperature and obtains amine intermediate.Amine intermediate is dissolved in the anhydrous DCM of 10mL, is cooled to after 0 DEG C, Triethylamine (0.56mL, 4.0mmol) and raw material SM-7 (0.3g, 2.0mmol) are added, is stirred at room temperature after half an hour, it is dilute with EA Reaction solution is released, organic phase is washed twice with semi-saturation salt, dried, and crude product is done to obtain in filtering, decompression, and column chromatography purifies to obtain product 12 (0.51g), two step yields 78%.ESI-MS[(M+H+)]:m/z 645.45.
Under argon gas protection Zhan Shi is added into substrate 12 (0.51g, 0.79mmol) anhydrous methylene chloride (158mL) solution 1B catalyst (30mg, 0.04mmol), then by reaction solution heated overnight at reflux.Question response liquid is cooled to after room temperature, is depressurized dense Contracting obtains crude product, and column chromatography purifying obtains big ring product 13 (0.42g, yield 86%).ESI-MS[(M+H+)]:m/z 617.55.
Embodiment 37
Compound L W100225 synthesis
Substrate 13 (0.42g, 0.68mmol) is dissolved in THF/MeOH (19mL/9.5mL), 1N hydrogen-oxygens are then slowly added into Change the lithium aqueous solution (10mL), be stirred at room temperature after 2h and be concentrated under reduced pressure after organic solvent, pH to 4~5 is adjusted with 1N HCl.EA extractions three It is secondary, merge after organic phase, saturated common salt washing, organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains Intermediate carboxylic acids (0.37g, yield 90%).ESI-MS[(M-H-)]:m/z 601.11.
Intermediate carboxylic acids (89mg, 0.15mmol) and SM-6a (60mg, 0.26mmol) are dissolved in dry DMF (6mL) In, then it is cooled to 0 DEG C.Under argon gas protection, DIEA (0.17mL, 0.95mmol) and HATU (85mg, 0.22mmol) is added. Reaction solution is stirred at room temperature one hour, then adds EA dilutions, and 5% aqueous citric acid solution is washed, and is washed, 1M sodium bicarbonate aqueous solutions Wash, semi-saturation salt is washed 4 times.After organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure obtains crude product, and column chromatography purifies most The whole big polycyclic product LW100225 of ring-type (106mg, yield 88%).ESI-MS[(M+H+)]:m/z 815.64.
Embodiment 38
Compound L W100226 synthesis
According to above-mentioned prepare compound LW100225 embodiment 45, the present embodiment with identical intermediate carboxylic in upper example Sour (0.15mmol) and SM-6b (0.26mmol) reactions, obtain 105mg final products LW100226 after purification.ESI-MS[(M+H+)]:m/z 817.69.

Claims (16)

1. formula A compound:
Or its stereoisomer, dynamic isomer, pharmaceutically acceptable salt or their mixture；
Wherein,
A-B is singly-bound or carbon-carbon double bond, and when A-B is singly-bound, A is selected from carbon, oxygen, sulphur or nitrogen, and B is selected from carbon；
N=0,1 or 2；
Q is selected from C1-6Alkyl, C2-6Alkenyl or C3-6Cycloalkyl；
L independently is oxygen, sulphur, a C2-C20Alkenyl, C1-C20Alkyl, C3-C20Cycloalkyl, C2-C20Heterocyclic radical, C6-C20Aryl, C3-C20Heterocyclic aryl, C1-C20Alkylthio group, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C2-C20Heterocyclic radical epoxide, C1-C20Alkyl Amino, C1-C20The carbonyl of alkoxy one, C6-C20Aryl or C6-C20Aryloxy group；
L1It is each independently oxygen, sulphur, C2-C20Alkenyl, C1-C20Alkyl, C3-C20Cycloalkyl, C2-C20Heterocyclic radical, C6-C20Aryl, C3-C20Heterocyclic aryl, C1-C20Alkylthio group, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C2-C20Heterocyclic radical epoxide, C1-C20Alkyl Amino, C1-C20Alkoxy carbonyl, C6-C20Aryl or C6-C20Aryloxy group；
X is oxygen, sulphur or nitrogen；
Y is nitrogen or CH；
R1For hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C6-C20Aryl, C3-C20Heterocyclic aryl, C1-C20Alkyl sulfonyl amino, C2- C20Heterocycle sulfonamido or C1-C20Alkoxycarbonyl amino；
R2For hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy-carbonyl, C3-C20Cycloalkyloxy-carbonyl, C6-C20Virtue Base, C3-C20Heterocyclic aryl, C6-C20Aryloxy group, C1-C20Alkyl sulphonyl, C3-C20Naphthene sulfamide base, C1-C20Alkoxy sulphur Acyl group, C3-C20Cycloalkyloxy sulfonyl, C6-C20Aryl sulfonyl, C6-C20Aryloxy sulfonyl, C1-C20Alkylamino sulfonyl, C3-C20Naphthene amino sulfonyl or C6-C20Fragrant amino sulfonyl；
R3、R4It is each independently hydrogen, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy, halogen, hydroxyl, cyano group, nitro, C1-C20Alkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Arylamino, C1-C20Alkyl sulfonyl amino, C2-C20It is miscellaneous Cyclic sulfonamido, C6-C20Arenesulfonyl amino or C1-C20Alkyl sulfonyl amino amino；Wherein, R3With R4Between can mutually interconnect It is connected into cyclic structure；
R5And R6It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alcoxyl Base, C1-C20Alkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Arylamino, C1-C20Alkyl sulfonyl amino, C2- C20Heterocycle sulfonamido, C6-C20Arenesulfonyl amino or C1-C20Alkyl sulfonyl amino amino；
R7、R8、R9And R10It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, fluoroform alkyl, C1-C20Alkyl, C1-C20 Alkoxy, C1-C20Alkylthio group, C1-C20Alkoxy-carbonyl, amino carbonyl, C1-C20Alkyl amino-carbonyl, carbonylamino, C1-C20 Alkyl-carbonyl-amino, C2-C20Heterocyclic radical Epoxide carbonyl, C6-C20Aryl, C6-C20Aryloxy group, C6-C20Aryloxycarbonyl or C2-C20 Heterocyclic radical；Wherein, R7With R8、R8With R9、R9With R10Between can be interconnected to 5-6 membered cyclic structures, it is optionally taken by alkyl Generation；
J is hydrogen, hydroxyl, C1-C20Alkyl, C3-C20Cycloalkyl, C1-C20Alkoxy, C3-C20Cycloalkyloxy, C1-C20Alkyl amino, C3-C20Cycloalkyl amino, C2-C20Heterocyclic amino group, C6-C20Aryl, C6-C20Fragrant amino, C4-C20Heterocycle fragrant amino, RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C1-C20Alkyl, C1-C20Alkoxy, C3-C20Cycloalkyl, C6-C20The C such as aryl, heteroaryl3-C20Cycloalkyloxy, C6-C20Aryloxy group, C1-C20Alkylamino, C3-C20Naphthene amino, C6-C20Virtue Amino, C1-C20Urea groups, C1-C20Ghiourea group, C1-C20Phosphate or C1-C20Borate；
Heterocycle in above-mentioned each group contains the 1-3 hetero atoms for being selected from nitrogen, oxygen and sulphur.
2. compound according to claim 1, it is characterised in that:In formula A,
A-B is singly-bound or carbon-carbon double bond, and when A-B is singly-bound, A is selected from oxygen, sulphur or nitrogen, and B is selected from carbon；
N=0,1 or 2；
Q is selected from C1-6Alkyl, C2-6Alkenyl or C3-6Cycloalkyl；
R3、R4It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy, C1-C6Alkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Arylamino, C1-C6Alkyl sulfonyl amino, C2-C6Heterocycle Sulfonamido, C6-C10Arenesulfonyl amino or C1-C6Alkyl sulfonyl amino amino, wherein the heterocycle contain 1-3 nitrogen, oxygen or Sulphur atom, or, R3With R4It is interconnected to the cyclic structure of 5-7 annular atom；
R5And R6It is each independently hydrogen, halogen, hydroxyl, cyano group, nitro, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy, C1-C6Alkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Arylamino, C1-C6Alkyl sulfonyl amino, C2-C6Heterocycle Sulfonamido, C6-C10Arenesulfonyl amino or C1-C6Alkyl sulfonyl amino amino, wherein the heterocycle contain 1-3 nitrogen, oxygen or Sulphur atom；
R7、R8、R9And R10In, R7With R8、R8With R9And/or R9With R10Between be interconnected to oxygen-containing or nitrogen 5-6 circle heterocycles, and The heterocycle is optionally replaced by C1-C6 alkyl；Remaining is not into cyclic group independently selected from hydrogen, halogen, hydroxyl, cyano group, nitro, three Fluoromethane base, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkylthio group, C1-C6Alkoxy-carbonyl, amino carbonyl, C1-C6Alkyl ammonia Base carbonyl, carbonylamino, C1-C6Alkyl-carbonyl-amino, C2-C6Heterocyclic radical Epoxide carbonyl, C6-C10Aryl, C6-C10Aryloxy group, C6- C10Aryloxycarbonyl or C2-C6Heterocyclic radical, wherein the heterocycle contains 1-3 nitrogen, oxygen or sulphur atom；
J is hydrogen, hydroxyl, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C1-C6Alkyl amino, C3- C6Cycloalkyl amino, C2-C6Heterocyclic amino group, C6-C10Aryl, C6-C10Fragrant amino, C4-C10Heterocycle fragrant amino, RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C1-C10Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, C1-C6 Alkoxy, C3-C6Cycloalkyloxy, C6-C10Aryloxy group, C1-C6Alkylamino, C3-C6Naphthene amino, C6-C10Fragrant amino, C1-C6Urea Base, C1-C6Ghiourea group, C1-C6Phosphate-based or C1-C6Boric acid ester group；
L is singly-bound, oxygen, sulphur, C2-C6Alkenyl, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Heterocyclic radical, C6-C10Aryl, C3-C6Heterocycle Aryl, C1-C6Alkylthio group, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C2-C6Heterocyclic radical epoxide, C1-C6Alkyl amino, C1-C6Alkane Epoxide carbonyl, C6-C10Aryl or C6-C10Aryloxy group；
L1Selected from oxygen, sulphur, C2-C6Alkenyl, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Heterocyclic radical, C6-C10Aryl, C3-C6Heterocycle C6-C10Aryl, C1-C6Alkylthio group, C1-C6Alkoxy, C3-C6Cycloalkyloxy, C2-C6Heterocyclic radical epoxide, C1-C6Alkyl amino, C1- C6Alkoxy carbonyl, C6-C10Aryl or C6-C10Aryloxy group；
X is oxygen, sulphur or nitrogen；
Y is nitrogen or CH；
R1For hydrogen, C1-C6Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, C3-C6Heterocyclic aryl, C1-C6Alkyl sulfonyl amino, C2-C6 Heterocycle sulfonamido or C1-C6Alkoxycarbonyl amino；
R2For hydrogen, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxy-carbonyl, C3-C6Cycloalkyloxy-carbonyl, C6-C10Aryl, C3-C60Heterocycle C6-C10Aryl, C6-C10Aryloxy group, C1-C6Alkyl sulphonyl, C3-C6Naphthene sulfamide base, C1-C6Alkoxy sulphur Acyl group, C3-C6Cycloalkyloxy sulfonyl, C6-C10Aryl sulfonyl, C6-C10Aryloxy sulfonyl, C1-C6Alkylamino sulfonyl, C3-C6Naphthene amino sulfonyl or C6-C10Fragrant amino sulfonyl.
3. compound according to claim 2, it is characterised in that:In formula A,
L is singly-bound；
L1Selected from oxygen or sulphur；
X is selected from oxygen, sulphur or nitrogen；
Y is selected from nitrogen or CH；
R1Selected from the tert-butyl group；
R2Selected from hydrogen；
R3And R4It independently is methyl；
R5And R6It independently is hydrogen；
R7、R8、R9And R10In, R7With R8、R8With R9Or R9With R10Between be interconnected to oxygen-containing or nitrogen 5-6 circle heterocycles, and should Heterocycle is optionally by C1-C6Alkyl replaces；Remaining is not selected from hydrogen into cyclic group；
J is selected from RSO2NH-、-SO2NH2Or-SO2NHR, wherein R are selected from optionally substituted C3-C6Cycloalkyl.
4. a kind of compound I method in formula A prepared any one of claims 1 to 3, including following five steps:
1) under inert gas shielding, raw material SM-3 is in anhydrous organic solvent, in triphenyl phosphorus and the work of azodicarboxylate Reacted with lower with another reagent V generations Mitsunobu, generation compound 3-1；Compound V is as follows：
R11For C1-C6Alkyl-carbonyl, C1-C6Alkoxy carbonyl or C1-C6Amino carbonyl；Its in SM-3 and compound V and product 3-1 The definition of its each group is with described in claim 1；
2) under inert gas shielding, by step 1) in obtained compound 3-1 slough protection group R11Afterwards again in coupling reagent Effect is lower to generate compound 3-2 with another amino acid derivativges reagent SM-4 reactions；The definition of each group and parameter is with power in 3-2 Profit is required described in 1；
3) under inert gas shielding, by step 2) obtained compound 3-2 sloughs protection group R11Afterwards again in phosgene or triphosgene In the presence of, react to form compound 3-3 with another reagent SM-5；The definition of each group and parameter is same in reagent SM-5 and product Described in claim 1；
4) under inert gas shielding, by step 3) obtained compound 3-3 is in the presence of palladium catalyst, and reaction obtains big ring Shape product 3-4；The definition of each group and parameter is with described in claim 1 in product；
5) under inert gas shielding, by step 4) obtained compound 3-4 after hydrolysis acidification again with SM-6 in coupling reagent (such as：HATU the final Macrocyclic compound I of reaction generation in the presence of)；The definition of each group and parameter is with weighing in SM-6 and product Profit is required described in 1；
In step 1) in, under inert gas shielding, SM-3 raw materials are dissolved in organic solvent, in triphenyl phosphorus and azodicarboxy Occur Mitsunobu reactions, generation compound 3-1 in the presence of acid esters with another reagent V；The reaction temperature is 0-40 DEG C, Described triphenyl phosphorus consumption is 1-2 times of raw material SM-3 moles, and described azodicarboxylate's consumption rubs for raw material SM-3 1-2 times of that amount；
In step 2) in, by step 1 under inert gas shielding) obtained compound 3-1 in the presence of strong acid, is in temperature Protection group R is sloughed in reaction at 10-50 DEG C11Generate amine intermediate afterwards, then in the presence of coupling reagent, at 0-80 DEG C of temperature In organic solvent compound 3-2 is obtained with reagent SM-4 reactions；The consumption of described coupling reagent is compound 3-1 moles 1-2.5 again.
In step 3) in, by step 2 under inert gas shielding) obtained compound 3-2 in the presence of strong acid, is in temperature Protection group R is sloughed in reaction at 10-50 DEG C11Amine intermediate is generated afterwards, then generates isocyanates in the presence of phosgene or triphosgene Intermediate, then reacts to form compound 3-3 with another reagent SM-5 in organic solvent at 0-40 DEG C of temperature；Described three The consumption of phosgene is 1-2 times of compound 3-2 moles.
In step 4) in, under inert gas shielding, by step 3) obtained compound 3-3 is dissolved in anhydrous organic solvent, In the presence of palladium catalyst, phosphorus part and inorganic strong alkali, reacted at 0-100 DEG C of temperature, obtain big cyclic products 3-4；Palladium is urged The consumption of agent is the 0.2-5% of raw material SM-1 moles；The consumption of phosphorus part is the 0.3-10% of raw material SM-1 moles；Nothing The consumption of machine alkali is 1-3 times of raw material SM-1 moles；
In step 5) in, by step 4) obtained compound 3-4 in the presence of inorganic strong alkali, in a solvent, enters in 10-60 DEG C Acidifying generation carboxylic acid after deprotection ylmethoxy is freed in water-filling, then in the presence of coupling reagent, in organic solvent, with SM-6 The polycyclic product I of big ring-type is obtained by amidation process；The consumption of described coupling reagent is the 1- of compound 3-4 moles 2.5 again；The temperature of amidation process is 0-80 DEG C.
5. a kind of compound II method in formula A prepared any one of claims 1 to 3, including following six step:
1) under inert gas shielding, raw material SM-3 is in anhydrous organic solvent, in triphenyl phosphorus and the work of azodicarboxylate Reacted with lower with another reagent V generations Mitsunobu, generation compound 3-1；Compound V structure is as described above；R10For C1-C6 Alkyl-carbonyl, C1-C6Alkoxy carbonyl or C1-C6Amino carbonyl；Other each groups determines in SM-3 and compound V and product 3-1 Justice is with described in claim 1；
2) under inert gas shielding, by step 1) in obtained compound 3-1 with the potassium fluoborate of ethene three in palladium catalyst Under effect, compound 4-1 is obtained by Suzuki reactions；The definition of each group and parameter is with described in claim 1 in product；
3) under inert gas shielding, by step 2) in obtained compound 4-1 slough protection group R11Afterwards again in coupling reagent Effect is lower to generate compound 4-2 with another amino acid derivativges reagent SM-4 reactions；The definition of each group and parameter is same in product Described in claim 1；
4) under inert gas shielding, by step 3) obtained compound 4-2 sloughs protection group R11Afterwards again with another reagent SM-7 Reaction forms compound 4-3；The definition of each group and parameter is with described in claim 1 in reagent SM-7 and product；
5) under inert gas shielding, by step 4) obtained bifunctional vinyl compound 4-3 in the presence of ruthenium catalyst, passes through alkene Double decomposition cyclization obtains big cyclic products 4-4；The definition of each group and parameter is with described in claim 1 in product；
6) under inert gas shielding, by step 5) obtained compound 4-4 after hydrolysis acidification again with SM-6 in coupling reagent (such as：HATU the final Macrocyclic compound II of reaction generation in the presence of)；The definition of each group and parameter is same in SM-6 and product Described in claim 1；
In step 1) in, under inert gas shielding, SM-3 raw materials are dissolved in organic solvent, in triphenyl phosphorus and azodicarboxy Occur Mitsunobu reactions, generation compound 3-1 in the presence of acid esters with another reagent V；The reaction temperature is 0-40 DEG C, Described triphenyl phosphorus consumption is 1-2 times of raw material SM-3 moles, and described azodicarboxylate's consumption rubs for raw material SM-3 1-2 times of that amount；
In step 2) in, under inert gas shielding, by step 1) in obtained compound 3-1 be dissolved in organic solvent, with second The potassium fluoborate of alkene three obtains compound 4- at 20-100 DEG C of temperature in the presence of palladium catalyst and alkali by Suzuki reactions 1；The described potassium fluoborate consumption of ethene three is 1-4 times of raw material SM-3 moles；Described palladium catalyst consumption is raw material SM- 0.03-5% times of 3 moles；Described base amount is 1-4 times of raw material SM-3 moles.
In step 3) in, by step 2 under inert gas shielding) obtained compound 4-1 in the presence of strong acid, is in temperature Protection group R is sloughed in reaction at 10-50 DEG C11Generate amine intermediate afterwards, then in the presence of coupling reagent, at 0-80 DEG C of temperature In organic solvent compound 4-2 is obtained with reagent SM-4 reactions；The consumption of described coupling reagent is compound 3-1 moles 1-2.5 again.
In step 4) in, by step 3 under inert gas shielding) obtained compound 4-2 in the presence of strong acid, is in temperature Protection group R is sloughed in reaction at 10-50 DEG C11Amine intermediate is generated afterwards, then in the presence of alkali, in 10-30 DEG C and another reagent SM- 7 reactions form compound 4-3；The consumption of described alkali is 1-5 times of compound 4-2 moles.
In step 5) in, by step 4 under inert gas shielding) obtained bifunctional vinyl compound 4-3 is dissolved in anhydrous organic solvent, In the presence of ruthenium catalyst, reacted at 0-100 DEG C of temperature, by olefin metathesis cyclization, obtain big cyclic products 4-4；Described ruthenium catalyst consumption is the 0.2-10% of bifunctional vinyl compound 4-3 moles；Described consumption of organic solvent is double Ene compound 4-3 weight than 15-40 times；
In step 6) in, by step 5) obtained compound 4-4 in the presence of inorganic strong alkali, in a solvent, enters in 10-60 DEG C Acidifying generation carboxylic acid after deprotection ylmethoxy is freed in water-filling, then in the presence of coupling reagent, in organic solvent, with SM-6 The polycyclic product II of big ring-type is obtained by amidation process；The consumption of described coupling reagent is the 1- of compound 4-4 moles 2.5 again；The temperature of amidation process is 0-80 DEG C.
6. it is compound described in any one in claim 1-3, its stereoisomer, dynamic isomer, pharmaceutically acceptable Application of the salt in the medicine for suppressing HCV is prepared.
7. a kind of pharmaceutical composition, comprising:Compound, its solid any one of one or more claim 1-3 is different Structure body, dynamic isomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
8. a kind of composition, including:In one or more following medicines and one or more claim 1-3 described in any one Compound, its stereoisomer, dynamic isomer or its pharmaceutically acceptable salt:(1) immunomodulator；(2) third type livers Scorching hiv protease inhibitor；(3) hepatitis C virus polymerase inhibitor；(4) nucleosides and nucleosides for being not belonging to (2)-(3) spread out It is biological；(5) hepatitis type B virus (HBV) inhibitor；(6) human immune deficiency virus (HIV) inhibitor；(7) cancer drug； (8) anti-inflammatory drug；(9) other compounds of above-mentioned (1)-(8) are not belonging to.
9. composition as claimed in claim 8, wherein described immunomodulator includes interferon or interferon derivative.
10. composition as claimed in claim 9, wherein described interferon is Peg-IFN alpha-2b.
11. composition as claimed in claim 8, wherein described hiv inhibitor is Ritonavir.
12. composition as claimed in claim 8, wherein described hepatitis type B virus (HBV) inhibitor is:Lamivudine, Sebivo, adefovirdipivoxil, emtricitabine, Entecavir, tenofovir or clevudine.
13. the composition any one of a kind of claim 8-12 is preparing the application in being used to suppress HCV medicine.
14. a kind of suppression HCV method, it include compound in the claim 1-5 by effective dose described in any one, its Stereoisomer, dynamic isomer, pharmaceutically acceptable salt are applied to the individual of this demand.
15. method as claimed in claim 14, wherein the individual is mammal, it is for example people.
16. it is compound described in any one in claim 1-5, its stereoisomer, dynamic isomer, pharmaceutically acceptable Salt, it is used to suppress HCV.
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