CN103732613B

CN103732613B - Hepatitis c virus inhibitors

Info

Publication number: CN103732613B
Application number: CN201280039845.0A
Authority: CN
Inventors: R.拉贾马尼; K.V.伦杜钱塔拉; K.萨库纳姆; P.纳贾拉克什米; N.A.米恩威尔; P.M.斯科拉
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2011-06-15
Filing date: 2012-06-12
Publication date: 2016-11-30
Anticipated expiration: 2032-06-12

Abstract

The open hepatitis C virus inhibitors with logical formula (I) of the present invention, the present invention also open compositions comprising described compound and the method using described compound suppression HCV.

Description

Hepatitis C virus inhibitors

Cross reference to related applications

This application claims the rights and interests of the U.S. Provisional Application Serial No. 61/497,141 submitted on June 15th, 2011.

The disclosure relates generally to antiviral compound, and relates more particularly to suppress to be encoded by hepatitis C virus (HCV) NS3 protease (also referred herein as " serine protease ") function compound, comprise the combination of such compound Thing and the method being used for suppressing the function of NS3 protease.

HCV is a main human pathogen, the infection estimation whole world 1.7 hundred million people-be about by human immunodeficiency 5 times of the quantity that poison 1 type infects.An individual sizable part for these HCV infection, develops into serious Progressive symmetric erythrokeratodermia liver Disease, including liver cirrhosis and hepatocarcinoma.

At present, maximally effective HCV therapy uses alpha-interferon and the associating of ribavirin, causes holding in the patient of 40% Continuous effect.Nearest clinical effectiveness proves, the interferon-alpha of Pegylation is better than the unmodified α as monotherapy-dry Disturb element.But, even if using alpha-interferon and the experimental therapy scheme of ribavirin combination including Pegylation, the most greatly The viral load of a part of patient the most persistently reduce.Therefore, the effective therapy of exploitation treatment HCV infection is existed clearly And unmet needs.

HCV is a kind of positive chain RNA virus.Based on the extensive similarity in the aminoacid sequence derived and 5 ' untranslated regions Relatively, HCV has been classified as a single genus in flaviviridae (Flaviviridae family).Flaviviridae family All members there is the virion (virions) of encapsulation, it comprises one by single, continual, open reading The translation of frame encodes the positive chain RNA genome of all known viruse specific proteinses.

Sizable heterogeneity is found in the aminoacid sequence of the nucleotide and coding that run through HCV genome.To 6 Individual main genotype has carried out characterized, and has been described with more than 50 kinds of hypotypes.Although existing genotype is to morbidity Mechanism and the numerous studies that may affect for the treatment of, but the main genotypes of HCV is different in distribution all over the world, and HCV The clinical meaning of genetic heterogeneity remain unintelligible.

The length of strand HCV rna gene group about 9500 nucleotide, and have a single open reading frame (ORF), about 3000 amino acid whose single big polyproteins of coding.In the cell infected, this polyprotein is in multiple positions By cell and virus protease cracking on Dian, produce structure and non-structural (NS) albumen.In the case of HCV, ripe non-knot The generation of structure albumen (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is carried out by two virus proteases.First splits Solution is at NS2-NS3 node, second is serine protease, and it is included in the N-end region of NS3, and mediate all subsequently The cracking in NS3 downstream, both are cis (cis), at NS3-NS4A cracking site, and for remaining NS4A-NS4B, NS4B, NS5A, NS5A-NS5B site, for trans.NS4A albumen seem play multi-functional, as NS3 protease auxiliary because of Son, and the film location of NS3 and other rdrp virus components may be assisted.The formation of the complex of NS3 albumen and NS4A, for Effective polyprotein processing, the proteolytic cleavage of raising all sites are requisite.NS3 albumen also represents nucleoside three phosphorus Acid enzyme and the activity of DBPA.NS5B is a kind of RNA polymerase depending on RNA, and it participates in the duplication of HCV.

The disclosure provides peptide compounds, and it can suppress NS3 protease, as combined the function of performance with NS4A protease.This Outward, the disclosure illustrates and gives combination treatment to patient, thus effectively suppresses the compound of the foundation disclosure of HCV NS3 protease Can give together with other compound with anti-HCV activity.

At its first aspect, the disclosure provides formula (I) compound:

Or its pharmaceutically acceptable salt, wherein

Q is 1 or 2；

-----It is singly-bound or double bond；

R^pIt is selected from

With

Wherein R^pIt is connected to parent molecular moiety by commutable carbon atom arbitrary in group；

N is 0,1,2,3,4,5 or 6；

X⁰Selected from CH and N；

X¹Selected from CH and N；

X²And X³Independently selected from CH, C (R^a) and N；Condition is X¹、X²And X³In at least one be not N；

Each R^aIndependently selected from thiazolinyl epoxide, alkoxyl, alkyloxy-alkoxy, alkyl, benzodioxane base, carboxylic acid amides Base (carboxamido), carboxyl, Carboxyalkoxy, cyano group, cycloalkyl alkoxy, cycloalkyl oxy, deuterated alkoxyl, dioxane Base amino, halogen, haloalkyl, halogenated alkoxy, halo alkoxy carbonyl, hydroxyl, morpholinyl, phenyl, piperazinyl, pyrazoles Base, pyridine radicals and pyrrolidinyl, wherein morpholinyl, phenyl, piperazinyl, pyridine radicals and pyrrolidinyl are optionally independent by one or two Ground replaces selected from the group of alkoxyl, alkyl, alkyl sulphonyl, halogen, halogenated alkoxy, haloalkyl and morpholinyl；And its In two adjacent R^aMay be optionally formed selected from dioxane base, dioxolanes together with the carbon atom that group is connected with it The ring of base, morpholinyl, pyranose and phenyl, wherein this ring is optionally taken independently selected from the group of alkyl and halogen by one or two Generation；

R^bIt it is alkyl；

R^xSelected from methyl and ethyl；

R^yAnd R^zIndependently selected from hydrogen and hydroxyl；Condition is to work as-----During for double bond, R^yAnd R^zIt is respectively hydrogen；

R²Selected from hydrogen, alkyl, halogen, halogenated alkoxy, haloalkyl and hydroxy alkyl；And

R³Selected from hydrogen, alkoxyalkoxycarbonyl, alkoxy carbonyl, alkyl amino-carbonyl, alkyl-carbonyl, cycloalkyl alcoxyl Base carbonyl, naphthene base carbonyl, cycloalkyloxycarbonyl, deuterated alkoxy carbonyl, deuterated halo alkoxy carbonyl, dialkyl amido Carbonyl, dialkyl amino carbonyl carbonyl, halo alkoxy carbonyl, haloalkylamino carbonyl, halogenated alkyl carbonyl, heterocyclic radical carbonyl Base, heterocyclic radical epoxide carbonyl, phenylcarbonyl group and phenyloxycarbonyl, wherein cycloalkyl alkoxy carbonyl, naphthene base carbonyl and ring The cycloalkyl moiety of alkyloxycarbonyl, Heterocyclylcarbonyl and the heterocyclyl moieties of heterocyclic radical epoxide carbonyl and phenylcarbonyl group and The phenyl moiety of phenyloxycarbonyl optionally by one, two or three independently selected from alkyl, alkyl amino, alkyl-carbonyl, The group of cycloalkyl, dialkyl amido, halogen, halogenated alkoxy and haloalkyl replaces.

In the first embodiment of first aspect, the disclosure provides formula (I) compound or its pharmaceutically acceptable salt, Wherein:

Q is 1；

-----It it is double bond；

R^xIt it is methyl；And

R^yAnd R^zIt is individually hydrogen.

In the second embodiment of first aspect, the disclosure provides formula (I) compound or its pharmaceutically acceptable salt, Wherein R^pIt is:

In the 3rd embodiment, the disclosure provides formula (I) compound or its pharmaceutically acceptable salt, wherein:

R^pIt is

N is 0,1,2 or 3；

Each R^aIndependently selected from alkoxyl and halogen；And

R³Selected from alkoxy carbonyl and halo alkoxy carbonyl.

In second aspect, the disclosure provides formula (II) compound

Or its pharmaceutically acceptable salt, wherein

N is 0,1,2,3,4,5 or 6；

Each R¹Independently selected from alkoxyl, alkyl, carboxamide groups, carboxyl, cyano group, cycloalkyl oxy, dialkyl amido, halogen Element, haloalkyl, halogenated alkoxy and phenyl, wherein phenyl optionally by one or two independently selected from alkoxyl, alkyl, halogen The group of element, halogenated alkoxy and haloalkyl replaces；

R²Selected from hydrogen, alkyl, halogen and haloalkyl；And

R³Selected from alkoxy carbonyl, alkyl-carbonyl, halo alkoxy carbonyl, halogenated alkyl carbonyl and phenylcarbonyl group, wherein Phenyl is optionally replaced independently selected from the group of alkyl and halogen by one or two.

In the third aspect, the disclosure provides and comprises formula (I) compound or its pharmaceutically acceptable salt and pharmaceutically can connect The compositions of the carrier being subject to.In the first embodiment of the third aspect, the disclosure provides and comprises formula (I) compound or its pharmacy Upper acceptable salt, at least one other compound with anti-HCV activity and compositions of pharmaceutical carrier.The second embodiment party In case, at least one in other compound is interferon or ribavirin.In the 3rd embodiment, interferon is selected from interference Element α 2B, glycol interferon alpha, Interferon Alfacon-1, interferon-ALPHA 2A and lymphoblastoid (lymphoblastiod) are done Disturb element τ.In the 4th embodiment of the third aspect, disclosure offer comprises formula (I) compound or it is pharmaceutically acceptable Salt, at least one other compound with anti-HCV activity and compositions of pharmaceutical carrier, wherein in other compound at least One selected from interleukin-22, interleukin 6, interleukin 12, imiquimod, ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, Amantadine (amantadine) and rimantadine.In the 5th embodiment of the third aspect, the disclosure provides and comprises formula (I) Compound or its pharmaceutically acceptable salt, at least one there is other compound of anti-HCV activity, and the combination of pharmaceutical carrier Thing, wherein the effectively suppression of at least one in other compound is used for treating HCV infection selected from the function of following target: HCV Metalloproteases, HCV serine protease, HCV polymerase, HCV unwindase, HCV NS4B albumen, HCV enter, HCV assembles, HCV abjection (HCV egress), HCV NS5A albumen and IMPDH.

In fourth aspect, the disclosure provides the method for the HCV infection for the treatment of patient, and it comprises and gives treatment to this patient and have Formula (I) compound of effect amount or its pharmaceutically acceptable salt.In the first embodiment of fourth aspect, the method is further It is included in before giving formula (I) compound or its pharmaceutically acceptable salt, gives at least one afterwards or simultaneously and have Other compound of anti-HCV activity.In the second embodiment of fourth aspect, at least one in other compound is interference Element or ribavirin.In the 3rd embodiment, interferon is selected from interferon-ALPHA 2B, glycol interferon alpha, composite interference Element, interferon-ALPHA 2A and lymphoblastoid interferon-tau.In the 4th embodiment of fourth aspect, the disclosure provides treatment to suffer from The method of the HCV infection of person, it formula (I) compound including giving therapeutically effective amount to this patient, or it is pharmaceutically acceptable Salt and before giving formula (I) compound or its pharmaceutically acceptable salt, give at least one afterwards or simultaneously Having other compound of anti-HCV activity, wherein at least one in other compound is selected from interleukin-22, interleukin 6, Bai Jie Element 12, imiquimod, ribavirin, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.In four directions In 5th embodiment in face, the disclosure provides the method for HCV infection for the treatment of patient, and it comprises and gives treatment to this patient and have Formula (I) compound of effect amount, or its pharmaceutically acceptable salt, and giving formula (I) compound or it is pharmaceutically acceptable Salt before, give at least one other compound with anti-HCV activity afterwards or simultaneously, wherein in other compound At least one effectively suppression be used for treating HCV infection selected from function of following target: HCV metalloproteases, HCV serine Protease, HCV polymerase, HCV unwindase, HCV NS4B albumen, HCV enter, HCV assembles, HCV deviates from, HCV NS5A albumen And IMPDH.

The other side of the disclosure can include the proper combination of embodiment disclosed herein.

Other aspect and embodiment is can be also found that in description provided herein.

Description in this disclosure should meet the law of chemical bonded refractory and principle is explained.In some cases, may be used Can need to remove hydrogen atom to accommodate substituent group in arbitrary given position.

Should be understood that the compound that the disclosure is contained is that those are for the chemical combination as medicine with suitable stability Thing.

In molecule, arbitrary substituent group of specific location or the definition of variable are intended to independent of it in this molecule at other Definition.Such as, when n is 2, two R¹Each in group may be the same or different.

List of references cited in all patents, patent application and this specification is incorporated by this most by reference Wen Zhong.Inconsistent when, will be as the criterion with the disclosure (including definition).

Unless the context clearly dictates otherwise, singulative the most used herein " " (" a ", " an ") and " being somebody's turn to do " include Plural referents.

Term used herein " thiazolinyl " refers to the straight chain of 2-6 the carbon atom containing at least one carbon-to-carbon double bond or props up Chain group.

Term used herein " thiazolinyl epoxide " refers to be connected to the thiazolinyl of parent molecular moiety by oxygen atom.

Term used herein " alkoxyl " refers to be connected to the alkyl of parent molecular moiety by oxygen atom.

Term used herein " alkyloxy-alkoxy " refers to be connected to the alkoxyl of parent molecular moiety by oxygen atom Alkyl.

Term used herein " alkoxyalkoxycarbonyl " refers to be connected to the alcoxyl of parent molecular moiety by carbonyl Base alkoxyl.

Term used herein " alkoxyalkyl " refers to the alkyl replaced by one, two or three alkoxyl.

Term used herein " alkoxy carbonyl " refers to be connected to the alkoxyl of parent molecular moiety by carbonyl.

Term used herein " alkyl " refers to the base derived from the straight or branched saturated hydrocarbons containing 1 to 10 carbon atom Group.

Term used herein " alkyl-carbonyl " refers to be connected to the alkyl of parent molecular moiety by carbonyl.

Term used herein " alkyl amino " refers to-NHR^q, wherein R^qIt it is alkyl.

Term used herein " alkyl amino-carbonyl " refers to be connected to the alkyl amino of parent molecular moiety by carbonyl.

Term used herein " alkyl sulphonyl " refers to be connected to the alkyl of parent molecular moiety by sulfonyl.

Term used herein " carbonyl " refer to-C (O)-.

Term used herein " carboxamide groups " refers to-C (O) NR^xR^y, wherein R^xAnd R^yIndependently selected from hydrogen and alkyl.

Term used herein " carboxyl " refers to-CO₂H。

Term used herein " Carboxyalkoxy " refers to be connected to the carboxyalkyl of parent molecular moiety by oxygen atom.

Term used herein " carboxyalkyl " refers to the alkyl replaced by one, two or three carboxyl.

Term used herein " cyano group " refers to-CN.

Term used herein " cycloalkyl " refers to have 3 to 7 carbon atoms and 0 heteroatomic saturated monocycle or bicyclo- Hydrocarbon ring system.The representative example of cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl and cyclopenta.

Term used herein " cycloalkyl alkoxy " refers to be connected to (the cycloalkanes of parent molecular moiety by oxygen atom Base) alkyl.

Term used herein " cycloalkyl alkoxy carbonyl " refers to be connected to the cycloalkanes of parent molecular moiety by carbonyl Base alkoxyl.

Term used herein " (cycloalkyl) alkyl " refers to by the alkyl of one, two or three cycloalkyl substituted.

Term used herein " naphthene base carbonyl " refers to be connected to the cycloalkyl of parent molecular moiety by carbonyl.

Term used herein " cycloalkyl oxy " refers to be connected to the cycloalkyl of parent molecular moiety by oxygen atom.

Term used herein " cycloalkyloxycarbonyl " refers to be connected to the cycloalkyl of parent molecular moiety by carbonyl Epoxide.

Term used herein " deuterated alkoxyl " refers to that alkoxyl, at least one of which hydrogen atom are substituted by D-atom.

Term used herein " deuterated alkoxy carbonyl " refers to be connected to the deuterated alkane of parent molecular moiety by carbonyl Epoxide.

Term used herein " deuterated halogenated alkoxy " refers to halogenated alkoxy, and at least one of which hydrogen atom is former by deuterium Son substitutes.

Term used herein " deuterated halo alkoxy carbonyl " refers to be connected to the deuterium of parent molecular moiety by carbonyl For halogenated alkoxy.

Term used herein " dialkyl amido " refers to-NR^pR^q, wherein R^pAnd R^qIt it is alkyl.Described alkyl can identical or Different.

Term used herein " dialkyl amino carbonyl " refers to be connected to the dialkyl group of parent molecular moiety by carbonyl Amino.

Term used herein " dialkyl amino carbonyl carbonyl " refers to be connected to the two of parent molecular moiety by carbonyl Alkyl amino-carbonyl.

Term used herein " halo " and " halogen " refer to F, Cl, Br and I.

Term used herein " halogenated alkoxy " refers to be connected to the haloalkyl of parent molecular moiety by oxygen atom.

Term used herein " halo alkoxy carbonyl " refers to be connected to the alkyl halide of parent molecular moiety by carbonyl Epoxide.

Term used herein " haloalkyl " refers to the alkyl replaced by, two, three or four halogen atoms.

Term used herein " halogenated alkyl carbonyl " refers to be connected to the haloalkyl of parent molecular moiety by carbonyl.

Term used herein " haloalkylamino " refers to-NHR^q, wherein R^qIt it is haloalkyl.

Term used herein " haloalkylamino carbonyl " refers to be connected to the halo of parent molecular moiety by carbonyl Alkyl amino.

Term used herein " heterocyclic radical " refers to containing miscellaneous independently selected from nitrogen, oxygen and sulfur of one, two or three Five members of atom, six Yuans or seven Yuans rings.Five-membered ring has 0 to 2 double bond, and six Yuans and seven Yuans rings have 0 to 3 double Key.Term " heterocyclic radical " also include wherein heterocyclic ring to be fused to phenyl, monocyclic cycloalkenyl, monocyclic cycloalkyl or another monocycle miscellaneous The bicyclic groups of ring group；And wherein second cycle line system is fused to phenyl, monocyclic cycloalkenyl, monocyclic cycloalkyl or another monocyclic heterocycles base Three cyclic groups.The heterocyclic radical of the present invention can be connected to parent molecular moiety by the carbon atom in group or nitrogen-atoms.Heterocycle The example of base includes, but is not limited to benzothienyl, furyl, imidazole radicals, indoline base, indyl, isothiazolyl, different Oxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidyl, pyrazolyl, pyridine radicals, pyrrolidinyl, pyrrolopyridinyl, pyrrole radicals, Thiazolyl, thienyl and tetrahydro-1,4-thiazine base.

Term used herein " Heterocyclylcarbonyl " refers to be connected to the heterocyclic radical of parent molecular moiety by carbonyl.

Term used herein " heterocyclic radical epoxide " refers to be connected to the heterocyclic radical of parent molecular moiety by oxygen atom.

Term used herein " heterocyclic radical epoxide carbonyl " refers to be connected to the heterocyclyloxy of parent molecular moiety by carbonyl Base.

Term used herein " hydroxyl " refers to-OH.

Term used herein " hydroxy alkyl " refers to the alkyl replaced by one, two or three hydroxyl.

Term used herein " phenylcarbonyl group " refers to be connected to the phenyl of parent molecular moiety by carbonyl.

Term used herein " phenyl epoxide " refers to be connected to the phenyl of parent molecular moiety by oxygen atom.

Term used herein " phenyloxycarbonyl " refers to be connected to the phenyl epoxide of parent molecular moiety by carbonyl.

Term used herein " sulfonyl " refers to-SO₂-。

The compound of the disclosure can exist as pharmaceutically acceptable salt form.Term used herein " pharmaceutically may be used The salt accepted " represent salt or the zwitterionic form of the compound of the disclosure, it is water solublity or oil-soluble or dispersible, its Be suitable in scope of sound medical judgment contact tissue with patient use and without excessive toxicity, zest, anaphylaxis or its Its problem or complication, match with reasonable benefit/Hazard ratio, and effective to its desired use.Described salt can at compound Separate eventually and during purification or separately through making suitable basic functionality prepare with suitable acid reaction.Representative acid-addition salts Including acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, Butyrate, Camphora hydrochlorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, caproate, first Hydrochlorate, fumarate, hydrochlorate, hydrobromate, hydriodate (hydroiodide), 2-hydroxyethanesulfonic acid salt, lactate, Maleate, mesitylene sulfonate, methane sulfonates, naphthalenesulfonates, nicotinate, 2-naphthalene sulfonate, oxalates, palm fibre Palmitic acid hydrochlorate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, wine Stone hydrochlorate, trichloroacetate, trifluoroacetate, phosphate, glutamate, Glu, bicarbonate, tosilate and hendecanoic acid Salt.The example that can be used for being formed the acid of pharmaceutically acceptable addition salt includes such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid etc. The organic acid such as mineral acid and such as oxalic acid, maleic acid, succinic acid and citric acid.

Base addition salts can be by making acidic-group and suitable alkali (such as gold during the final separation of compound and purification Belong to the hydroxide of cation, carbonate or bicarbonate) or react prepared with ammonia or organic primary, secondary or tertiary amine.Pharmaceutically may be used The cation of salt accepted includes lithium, sodium, potassium, calcium, magnesium and aluminum, and avirulence quaternary ammonium cation, such as ammonium, tetramethyl-ammonium, Tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethamine, tri-n-butylamine, pyridine, DMA, N- Methyl piperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzyl amine, N, N-dibenzyl phenethyl amine, and N, N '-two Benzyl ethylenediamine.Other the representative organic amine that can be used for being formed base addition salts includes ethylenediamine, ethanolamine, diethanolamine, piperazine Pyridine and piperazine.

Term used herein " anti-HC V activity " means that this compound can effectively treat HCV virus.

Term " compound of the disclosure " and equivalents are intended to formula (I) compound and pharmaceutically acceptable mapping Body, diastereomer, and salt.Similarly, if context allows completely, then when mentioning intermediate, it is intended to cover its salt.

Term " patient " includes the mankind and other both mammal.

Term " Pharmaceutical composition " means that other pharmaceutical carrier of the compound and at least one that comprise the disclosure (i.e. assists Agent, excipient or vehicle) compositions that combines, described carrier be such as diluent, preservative, filler, flux-regulating agent, Disintegrating agent, wetting agent, emulsifying agent, suspending agent, sweeting agent, correctives, fumet, antibacterial agent, antifungal, lubricant and point Powder, this depends on the character of the pattern that gives and dosage form.Such as, Remington ' s Pharmaceutical can be used Sciences, the 18th edition, Mack Publishing Company, composition listed in Easton, PA (1999).

Phrase " pharmaceutically acceptable " employed herein refers to those compounds, material, compositions and/or dosage form, it In scope of sound medical judgment, be applicable to the contact tissue with patient and without excessive toxicity, zest, anaphylaxis or its Its problem or complication, match with reasonable risk/benefit ratio.

Term " therapeutically effective amount " means to be enough to show the every of meaning patient benefit (such as viral load persistently reduces) The total amount of one active component.When being applied to the indivedual active component individually given, this term refers to this separate constituent.When being applied to During combination, this term refers to produce the merging amount of the active component of response to treatment, either combines continuously the most simultaneously and gives.

Term " is treated " and " process " refers to: (i) prevention can susceptible disease, disorder and/or disease but N-Y-D- for suffering from There is this disease, disorder or disease in the patient of disease, disorder and/or disease；(ii) suppress this disease, disorder or disease, i.e. hold back Make its development；And/or (iii) alleviate this disease, disorder or disease, even if this disease, disorder and/or disease disappear.

When for naming the compound of the disclosure, title P1 ' used herein, P1, P2, P2^*, P3 and P4 draw relative to The relative position of the amino acid residue that the protease inhibitor of native peptides cracking substrate combines.In natural substrate, cracking occurs Between P1 and P1 ', wherein the position designated amino acid without upper right corner apostrophe (nonprime) is last from the C-of peptide natural cleavage sites End initiates and extends to N end；But, the N-end of autothermic cracking site, the position title in band upper right corner apostrophe (prime) starts and prolongs Extend C-end.Such as, P1 ' refers to first position (i.e. first position of N end) of right hand end of the C end away from cracking site；So And P1 system is from the left-hand side open numbering of C end cracking site, P2: from the second position etc. of C end).(see Berger A. and Schechter I., Transactions of the Royal Society London book series (1970), B257,249- 264]。

There is asymmetric center in the compound of the disclosure.Such as, described compound can include that the P1 cyclopropyl of following formula becomes Point

Wherein C₁And C₂Each represent the asymmetric carbon atom at the position 1 and 2 of cyclopropyl rings.

Should be understood that the disclosure contains all stereochemical forms or its mixture, it has the energy of suppression HCV protease Power.

Some compound of the disclosure can also exist by different stable conformational forms, and described form is separable.By Can allow to separate not in limited rotation, the torsion unsymmetry that such as exists owing to steric hindrance or ring strain around asymmetric singly-bound Isomorphic map isomer.The disclosure includes each conformer and the mixture thereof of these compounds.

Some compound of the disclosure can exist with zwitterionic form and the disclosure includes every the one or two of these compounds Property ionic species and mixture thereof.

When giving formula (I) compound of therapeutically effective amount as thick chemicals and its pharmaceutically acceptable salt is used for Time in therapy, the active component existence as Pharmaceutical composition is possible.Therefore, the disclosure further provides for pharmaceutical compositions Thing, it formula (I) compound including therapeutically effective amount or its pharmaceutically acceptable salt, and one or more is pharmaceutically acceptable Carrier, diluent or excipient.Formula (I) compound and pharmaceutically acceptable salt system thereof are as described above.Carrier, diluent or Excipient is necessary for acceptable in adaptive with other composition of preparation and harmless to its receiver meaning.According to the disclosure On the other hand, also providing for the method for preparing pharmaceutical preparation, it includes formula (I) compound or it is pharmaceutically acceptable Salt, mixes with one or more pharmaceutically acceptable carrier, diluent or excipient.

Pharmaceutical preparation can exist with the unit dosage forms of the active component that per unit dosage contains scheduled volume.The chemical combination of the disclosure Thing between about 150 mgs/kg of (" mg/kg ") body weight/day of about 0.01-, preferably in the range of about 0.05-about 100mg/kg body Dosage level between weight/sky is for preventing and treat in the disease mediated monotherapy of HCV to be typical.Normally, these public affairs The Pharmaceutical composition opened will give about 1 to about 5 every day, or as selecting, give with continuous infusion.Such administration can be used as Chronic or acute therapy.Can with support material be combined to produce single dosage form active component amount by according to just treating disease, The seriousness of this disease, give the time, give approach, the drainage rate of compound used therefor, the persistent period for the treatment of, and patient Age, sex, body weight and disease and change.Preferably unit dose formulations is that those contain hereinbefore daily dose or point agent The preparation of the active component of amount or its suitable mark.Normally, the optimal dose of substantially less than this compound is started with Low dose for the treatment of.Thereafter, dosage is increased with little increment, until it reaches the optimum effect in the case of described.It is said that in general, expect most The concentration level not producing any injury or harmful side effect generally will provide the effective result of antiviral gives compound.

The compound comprising the disclosure when the compositions of the disclosure is treated and/or the group of preventive with one or more other Closing, this compound and other medicines all can exist less than or equal to the dosage generally giving dosage in monotherapy scheme. The compositions of the disclosure can (such as) be treated or preventive with one or more other with the form of monolithic and/or double/multilayer tablet Prepare together, or separately can give with treatment or preventive.

Pharmaceutical preparation may be adapted to be given by arbitrary suitable approach, such as by per os (including buccal or Sublingual), rectum, Nose, locally (include buccal, Sublingual or percutaneous), vagina or parenteral (include subcutaneous, Intradermal, intramuscular, intraarticular, intrasynovial, breast In bone, in sheath, intralesional, intravenous or intradermal or infusion) approach.Such preparation can be by known in pharmacy neighborhood Either method (such as) prepare by making active component be combined with carrier or excipient.

Being suitable to pharmaceutical preparation that per os gives can be as the discrete unit of such as capsule or tablet；Powder or granule；It is stored in Solution in aqueous or non-aqueous liquid or suspension；Edible foams or foamed (whips)；Or oil-in-water liq breast Liquid or water-in-oil emulsion exist.

Such as, giving for per os in the form of tablets or capsules, active medicine component can with oral, non-toxic pharmaceutically Acceptable inert carrier (such as ethanol, glycerol, water etc.) combines.Powder is by being broken to suitable fine size also by compound powder It is mixed to prepare with the pharmaceutical carrier (such as edible carbohydrate, such as starch or mannitol) of similar pulverizing.Also can exist Correctives, preservative, dispersant and coloring agent.

Capsule system is by preparing mixture of powders as described above and being filled into the gelatin shell of molding and prepare.Can fill out Fill and the forward direction mixture of powders of operation adds fluidizer and lubricant, such as colloidal silicon dioxide, Talcum, magnesium stearate, hard Fat acid calcium or solid polyethylene glycol.Also disintegrating agent or solubilizing agent (such as agar, calcium carbonate or sodium carbonate) can be added to take in The utilizability of medicine is improved during capsule.

Additionally, when being desired or needed for, it is possible to suitable binding agent, lubricant, disintegrating agent and coloring agent are mixed mixing In thing.Suitable binding agent includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and conjunction Plastic (such as arabic gum, Tragacanth or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol etc..Described dosage form uses Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes, but is not limited to starch, methylcellulose, agar, bentonite, Huang Virgin rubber etc..Tablet is by such as preparing mixture of powders, granulation or slugging, interpolation lubricant and disintegrating agent and being pressed into tablet Prepare.Mixture of powders by the compound that will suitably pulverize and diluent mentioned above or substrate and optionally with binding agent (such as carboxymethyl cellulose, alginate (aliginate), gelatin or polyvinylpyrrolidone), solution retarding agents (such as stone Wax), re-absorption accelerator (such as quaternary ammonium salt) and/or absorbent (such as bentonite, Kaolin or dicalcium phosphate) be mixed to prepare. Mixture of powders can be by with binding agent (such as syrup, gelatinized corn starch, Acadia's (acadia) mucus or cellulose or polymer The solution of raw material) moistening be pressed through mesh screen and pelletize.As the replacement scheme pelletized, mixture of powders can be made to pass through tabletting Machine and result system are broken for the briquetting of the imperfect shaping of granule.Can be by adding stearic acid, stearate, Talcum or mineral oil Carry out lubricated granules, to prevent the mould sticking to form tablet.Then tablet will be pressed into through the mixture of lubrication.Also can be by these public affairs The compound opened does not suffers from pelletizing or hitting pressure step with flowing freely inert carrier combination direct pressing piece agent.Can provide The clarification being made up of the coating of the seal coating of Lac, sugar or polymer raw material and the polishing coating of wax or opaque protectiveness bag Clothing.Can be added to dyestuff in these coating materials distinguish different unit dose.

Liquid oral such as solution, syrup and elixir can be prepared with dosage unit form, from so that quantitatively containing pre- Quantitative compound.Syrup can be prepared by being dissolved in suitably seasoned aqueous solution by compound, and elixir can pass through Prepared by use non-toxic vehicle.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol Ether), preservative, taste masking additive (such as Oleum menthae or natural sweetener or saccharin or other artificial sweetener) etc..

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

Formula (I) compound and pharmaceutically acceptable salt thereof can give with liposome delivery systems, the least monolayer fat Plastid, big unilamellar liposome and multilamellar liposome.Liposome can be by multiple phospholipid (such as cholesterol, octadecylamine or phospholipid Phatidylcholine) constitute.

Formula (I) compound and pharmaceutically acceptable salt thereof also can be by using monoclonal antibody as single carrier (compound molecule is coupled) passs medicine.Compound also can with as can the soluble polymer coupling of target medicine carrier.This Base polymer can include polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide phenol, poly-hydroxyethyl Radix Asparagi BS-749 or the polyethylene-oxide polylysine replaced by palmitoyl residues.Additionally, compound can be with a class biodegradable Polymer coupling, for reaching the controlled release of medicine, such as polylactic acid, poly-epsilon-caprolactone (polepsilon as a example by this base polymer Caprolactone), poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and hydrogel Cross-linked copolymer or amphipathic nature block polymer.

The pharmaceutical preparation being suitable to percutaneous dosing can exist as discrete patch (discrete patches), with when long Between keep and receiver's epidermis close contact in section.Such as, active component can be transmitted by ionotherapy by patch, typically As at Pharmaceutical Research, 3 (6), described in 318 (1986).

Be suitable for the pharmaceutical preparation of topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, Paste, gel, spray, aerosol or oil preparation.

For treatment eye or other outside organization, such as oral cavity and skin, preparation is preferably as topical ointments or cream Use.When preparing ointment, can use described active component with or paraffin or water-miscible ointment base.Or, Active component Oil-in-water creams substrate or Water-In-Oil substrate can be made cream.

The pharmaceutical preparation being applicable to administer locally to eyes includes eye drop, wherein active component dissolve or be suspended in suitable In carrier, particularly aqueous solvent.

It is applicable to the pharmaceutical preparation of topical in oral cavity and includes lozenge, pastille and mouth wass.

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

The pharmaceutical preparation (wherein carrier is solid) being suitable for nose administration includes pulvis grossus, and it is by nasal inhalation mode It is administered, i.e. by quickly being sucked by nasal passage from close to the dust container of nose.It is adapted as nasal mist or drips The appropriate formulation (wherein carrier is liquid) that nose agent is administered includes aqueous solution agent or the oily solution agent of active component.

The pharmaceutical preparation being adapted to pass through inhalation includes minuteness particle powder (dusts) or mist agent (mists), its Prepared by dosage compresed gas aerosol, nebulizer or the insufflator of available dissimilar metering.

Be suitable for vagina administration pharmaceutical preparation can with vaginal suppository, vagina plug, ointment, gel, paste, foam or Spray provides.

Be suitable to the pharmaceutical preparation of parenteral and include aqueous and non-aqueous sterile injection solution and aqueous and non-aqueous Sterile suspensions, aqueous and non-aqueous sterile injection solution can contain antioxidant, buffer agent, antibacterial, and make preparation with The solute that receptor's blood waiting is isotonic；Aqueous and non-aqueous sterile suspensions can include suspending agent and thickening agent.Preparation can be single Position dosage or multi-dose container provide, the ampoule such as sealed and bottle, and under the conditions of freeze-dried (lyophilizing) can be saved in, Sterile liquid carrier such as water for injection only need to be added the most at once.The injection solution and the suspensoid that face used time preparation can Prepared by sterile powder injection, granule and tablet.

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

Table 1 below lists the example of some exemplary compounds can being administered together with the compound of the disclosure.At connection Closing in therapy, the compound of the disclosure jointly or can separate administration with other anti-HCV activity compound, or is mixed by compound In compositions.

Table 1

The compound of the disclosure also acts as laboratory reagent.Compound can move for design virus replication experiment, checking Thing experimental system and structure biology research provide research tool aspect to play a role, to deepen HCV disease mechanisms further Understanding.Additionally, the compound of the disclosure can be used for being set up or determine other antiviral chemical combination by such as competitive inhibition The binding site of thing.

The compound of the disclosure may further be used to process or prevent virus contaminated materials, thus reduces the reality contacting this kind of material Testing room personnel or medical worker or patient infects viral risk, described material is such as blood, tissue, operating theater instruments and clothing Thing, Laboratory Instruments and medicated clothing and blood sampling or blood transfusion apparatus and material.

When being prepared by synthetic method, or (include occurring in human or animal's health (internal) by metabolic process Those processes) or external generating process produce time, the disclosure is intended to the compound including having formula (I).

Originally describe the disclosure in conjunction with some embodiment, but be not intended to make these embodiments limit its scope.Phase Instead, the disclosure will contain all replacements, modification and the equivalent that may be included in right.Therefore, it is included in spy Determine the following example in embodiment and will illustrate the enforcement of the disclosure, it should be clear that be these embodiment purposes be for Some embodiment of exemplary illustration, and provide to provide be considered most useful and should be readily appreciated that its method and conceptual The explanation of aspect.

For the abbreviation of the application, including being abbreviated as art technology in following exemplary flow process and embodiment especially Known to personnel.Some abbreviations used are as follows: Et₂O represents ether；H or hr or hrs representative hour；Min or mins represents Minute；THF represents oxolane；TBME represents methyl tertiary butyl ether(MTBE)；DMAP represents N, N-dimethyl aminopyridine；LiHMDS generation Table hexamethylsilazide；DCM represents dichloromethane；DIPEA represents diisopropylethylamine；Boc represents tertiary fourth oxygen Base carbonyl；Petroleum ether (pet ether) represents petroleum ether (petroleum ether)；DMSO represents dimethyl sulfoxide；Rt or RT or Rt represents room temperature or holdup time (context will specify that)；IPA represents isopropanol；T-BuO represents tert-butoxy；HATU represents Hexafluorophosphoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea；EtOAc represents ethyl acetate；TMS generation Table trimethyl silyl；DPPA represents diphenyl phosphoryl azide；Me represents methyl；OAc represents acetate；N-Bu generation Table normal-butyl；DAST represents borontrifluoride (diethylamino) sulfur；And TFA represents trifluoroacetic acid.

Known to those skilled in the art and can easily prepare for synthesizing the initiation material of the compound of the disclosure Or can be through commercially available acquisition.

There is provided the following methods being set forth below presented for purposes of illustration and be not intended to limit the category of claim. Will be appreciated that, it may be necessary to prepare such compound, wherein use the blocking group of routine to protect functional group, remove this subsequently Blocking group is to provide the compound of the disclosure.Known to those skilled in the art about according to the disclosure use blocking group detailed Thin content.

The preparation of step 1:3-methylpent-obtusilic acid ethyl ester

At room temperature to (E)-but-2-ene-1-alcohol (50g, 693mmol) 1,1,1-triethoxy ethane (890mL, 4854mmol) solution adds acetic acid (5g, 83mmol).Reaction is heated to 125 DEG C through 4h.Pair is distilled out by conventional distil-lation Product ethanol, obtains the crude compound 3-methylpent-obtusilic acid ethyl ester (70g, 71.0%) in colorless oil.This product without It is further purified i.e. in next step；¹H NMR(DMSO-d₆) δ ppm 5.82-5.73 (m, 1H), 5.03-4.92 (m, 2H), 4.08-4.02 (m, 2H), 2.50 (m, 1H), 2.31-2.26 (m, 2H), 1.17 (t, J=8Hz, 3H), 1.00 (d, J= 8Hz, 3H).

The preparation of step 2:3-methylpent-obtusilic acid

In methanol (500mL) solution of 3-methylpent-obtusilic acid ethyl ester (70g, 492mmol), at room temperature add KOH (41.4g, 738mmol).Reacting by heating material is with the 18h that refluxes.Under reduced pressure distillation reaction material.Ether (750ml) is added To residue, wash with saturated solution of sodium bicarbonate (350mL × 3).Dense HC l (250mL) is used to make the water layer acid of merging Change, extract with D CM (500mL × 3).The organic layer of merging is dried through anhydrous sodium sulfate and under reduced pressure concentrates, obtains in brown The crude compound 3-methylpent-obtusilic acid (52g, 93%) of color grease；¹H NMR (DMSO-d₆) δ ppm 12.04 (s, br, 1H), 5.84-5.75 (m, 1H), 5.03-4.92 (m, 2H), 2.56-2.50 (m, 1H), 2.28-2.22 (m, 2H), 1.00 (d, J =8Hz, 3H).

The preparation of step 3:3-methylpent-4-alkene-1-alcohol

To lithium aluminium hydride (6.03g, 0.159mol) at the anhydrous Et of 150mL at 0 DEG C₂Suspension in O is added dropwise over The anhydrous Et of 100mL of 3-methylpent-obtusilic acid (17.4g, 0.122mol)₂O solution.After having added, reaction is made to be warming up to room Temperature also stirs 2h.Reacting substance is poured onto in 1L beaker.Lower carefully add water (6.03mL) through the 30min time being sufficiently stirred for With 15%NaOH (6.03mL).The white solid separated is removed by filtration and uses Et₂O fully washs.The filter that will merge Liquid is dried and under atmospheric pressure passes through distillation and concentration.Bottoms, thus obtain desired compound 9.04g (74%)；

¹H NMR(CDCl₃) δ ppm 5.65 (m, 1H), 4.90 (m, 2H), 3.55 (m, 2H), 3.30 (m, 1H), 2.25 (m, 1H), 1.50 (q, J=7Hz, 2H), 1.00 (d, J=7Hz, 3H).

The preparation of step 4:5-bromo-3-methylpent-1-alkene

At 0 DEG C to stirring the 4.504g (44.97mmol) in the dichloromethane of 100mL 3-methylpent-4-alkene- 1-alcoholic solution sequentially adds mesyl chloride and the triethylamine of 6.91mL (49.6mmol) of 3.8mL (49.1mmol), and at 0 DEG C Lower by gained mixture stirring 15min.Then reactant mixture is poured onto saturated aqueous NaHCO of 100mL₃In, and by institute Obtain mixture and be stirred vigorously 10min.Organic facies is separated, is dried (Na₂SO₄), the most under reduced pressure concentrate, obtain thick methanesulfonic acid Salt compound.Crude compound is dissolved in the anhydrous THF of 130mL, and in this solution, adds the nothing of 5.87g (67.6mmol) Water lithium bromide.Reflux 4h by gained mixture.Reacting substance is cooled to room temperature and dilutes with the pentane of 300mL.With two The saturated NaHCO of 100-mL part₃And the water washing organic facies of five 100-mL parts, then it is dried (Na₂SO₄).Under atmospheric pressure lead to Cross 30-cm Vigreux post and remove solvent through distillation.Evaporative distillation goes out residue (70 DEG C, 80mmHg), obtains 6.28g (86%) Bromide.

¹H NMR(CDCl₃) δ ppm 1.01 (d, J=5Hz, 3H), 1.80 (dt, J=J '=5Hz, 2H), 2.35 (m, J =5Hz, 1H), 3.36 (t, J=5Hz, 2H), 5.02 (m, 2H), 5.64 (m, 1H).

Step 5:(2R) preparation of-6-methyl octyl-7-alkene-2-alcohol

Magnesium chips (1.3g, 55.2mmol) is suspended in anhydrous THF (50mL), and at room temperature adds in this mixture (a pinch of) iodine (20mg) a little.In this reacting substance, add 5-'s bromo-3-methylpent-1-alkene (6g, 36.8mmol) THF (200mL) solution.Utilize hot-air syringe reacting by heating material to start reaction.When the reaction is adjudged complete, will at-78 DEG C This solution imports in the THF (50mL) of (S)-expoxy propane (3.21g, 55.2mmol) and copper bromide (0.528g, 3.68mmol) Solution in.Reacting substance is made to be back to room temperature and be stirred overnight.With ammonium chloride saturated solution quencher reacting substance and use ether (200mL × 3) extract.By the organic layer of merging through anhydrous Na₂SO₄It is dried and at room temperature concentrates, thus obtaining crude compound. By column chromatography (silica gel, 10% TBME is in petroleum ether) purifying crude compound, obtain (the 2R)-6-first in oil-based liquid Base octyl-7-alkene-2-alcohol (12.4g, 92%).¹H NMR (400MHz, CDCl₃): δ ppm 5.82-5.69 (m, 1H), 4.98-4.91 (m, 2H), 4.27-4.26 (m, 1H), 3.65-3.39 (m, 1H), 2.15-1.98 (m, 1H), 1.36-1.19 (m, 5H), 1.18- 1.1 (m, 1H), 1.08-0.95 (m, 5H), 0.89-0.78 (m, 1H).

Step 6:(2R) preparation of-4-toluene sulfonic acide 6-methyl octyl-7-alkene-2-base ester

DMAP is added in pyridine (16mL) solution of (2R)-6-methyl octyl-7-alkene-2-alcohol (12g, 84mmol) (0.51g, 4.22mmol), and by solution stirring 10min.At 0 DEG C, paratoluensulfonyl chloride (18.5g, 97mmol) is added extremely In reacting substance.Reacting substance is made to be back to room temperature and be stirred overnight.Under reduced pressure remove pyridine, and with ethyl acetate (200mL) Dilution residue.By organic solution 1.5N HCl/water solution, bicarbonate saturated solution, aqueous salt solu-tion, through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining crude compound (14.5g, 32%).Crude compound without be further purified i.e. for Next step.

Step 7:(3R) preparation of-2-(diphenylmethylene amino)-3,7 dimethyl nonyl-8-olefin(e) acid ethyl ester

To (2R)-4-toluene sulfonic acide 6-methyl octyl-7-alkene-2-base ester (15g, 50.6mmol) and N-(hexichol at 0 DEG C Methylene) glycine ethyl ester (13.53g, 50.6mmol) the solution being stored in toluene (120mL) in add LiHMDS (60.7mL, 60.7mmol, the 1M solution in T HF).Make reacting substance be back to room temperature, at 110 DEG C, heat 2h.Will reaction Material is cooled to room temperature, extracts with water quencher and by ethyl acetate (200mL × 3).By the organic layer of merging through anhydrous Na₂SO₄Dry Dry and under reduced pressure concentrate, obtain crude compound (14.5g).Crude compound is without being further purified i.e. for next step.MS: MS m/z 392.1(M⁺+1)。

Step 8:(3R)-2-amino-3, the preparation of 7-dimethyl nonyl-8 olefin(e) acid ethyl ester

Second to (3R)-2-(diphenylmethylene amino)-3,7 dimethyl nonyl-8-olefin(e) acid ethyl ester (14.5g, 37mmol) Ether (25mL) solution adds 1.5N HCl/water solution (125mL), and at room temperature reacting substance is stirred overnight.Use ether (100mL) washing reaction material.Saturated solution of sodium bicarbonate is used to make aqueous solution alkalize and use ethyl acetate (100mL × 3) to extract Take.By the organic layer of merging through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining crude compound (2.1g, 23%).Roughening is closed Thing is without being further purified i.e. for next step.

¹H NMR (400MHz, CDCl₃): δ ppm 5.85-5.60 (m, 1H), 4.98-4.85 (dd, J=1.6,2.8Hz, 2H), 4.10-4.06 (m, 2H), 3.15-3.14 (m, 1H), 2.15-2.02 (m, 1H), 1.94-1.75 (m, 3H), 1.32-1.17 (m, 9H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H) .MS:MS m/z 227.7 (M⁺+1)。

Step 9:(3R) preparation of-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8 olefin(e) acid ethyl ester

At room temperature to (3R)-2-amino-3, the DCM (20mL) of 7-dimethyl nonyl-8 olefin(e) acid ethyl ester (2.0g, 8.8mmol) Solution adds DIPEA (1.7g, 13.2mmol), adds (Boc) subsequently₂O (2.4g, 11.4mmol).At room temperature will reaction Material is stirred overnight.Reacting substance D CM is diluted and washes with water.By organic layer through anhydrous Na₂S O₄It is dried and in decompression Lower concentration, thus obtain crude compound.By column chromatography (silica gel, 20% ethyl acetate is in petroleum ether) purification of crude chemical combination Thing, obtains 2.7g (84%) (3R)-2-(tertbutyloxycarbonylamino)-3 in oil-based liquid, 7-dimethyl nonyl-8-olefin(e) acid second Ester.

¹H NMR (400MHz, CDCl₃): δ ppm 5.85-5.60 (m, 1H), 4.98-4.85 (dd, J=1.6,2.8Hz, 2H), 4.10-4.06 (m, 2H), 2.15-2.02 (m, 1H), 1.55-1.44 (m, 8H), 1.39-1.30 (s, 9H), 1.27-1.21 (m, 4H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H).

Step 10:(3R) preparation of-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-olefin(e) acid

At room temperature to (3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-olefin(e) acid ethyl ester (2.7g, In the solution of THF/ water (40mL, 1: 1) 8.25mmol) add methanol (20mL), add subsequently LiOH (0.987g, 41.2mmole).At room temperature reacting substance is stirred overnight.Under reduced pressure evaporate solvent, and remaining with water (100mL) dilution Thing.Make described aqueous solution be acidified to p H～3 with 1.5N HCl/water solution, and extract by ethyl acetate (100mL × 3).To merge Organic layer through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining crude compound.By column chromatography, (silica gel is stored in D C 3% methanol in M) purifying crude compound, obtain the 2.1g (85%) required compound in glue liquid.

¹H NMR (400MHz, DMSO-D₆): δ ppm 12.2-12.02 (bs, 1H), 6.92-6.85 (m, 1H) 5.72- 5.66 (m, 1H), 4.98-4.85 (dd, J=1.6,2.8Hz, 2H), 4.03-3.95 (m, 1H), 2,58-2.56 (m, 1H) 2.15- 2.02 (m, 1H), 1.45-1.36 (m, 10H), 1.27-1.21 (m, 5H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H).

Step 1:(2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)- The preparation of 4-hydroxyl pyrrolidine-2-methyl formate

To (3R)-2-((tert-butoxycarbonyl) amino)-3 at 0 DEG C, 7-dimethyl nonyl-8-olefin(e) acid (6.5g, 21.7mmol), L-4-L-Hydroxyproline methyl ester hydrochlorate (3.9g, 21.7mmol) and hexafluorophosphoric acid O-(7-azepine benzotriazole- 1-yl)-N, N, N ', N '-tetramethylureaIn (8.36g, 21.7mmol) serosity in DCM (50mL), it is added dropwise over N, N- Diisopropylethylamine (11.5mL, 66.6mmol).At room temperature gained light yellow mixture is stirred overnight, uses 1M HCl (35ml) wash, through Na with saline₂SO₄It is dried, filters, concentrate in a vacuum.By conventional column chromatography (60-120g silica gel Post) purification residual oil thing (12g), with 4% to 8%IPA-Hex, it is provided that the expectation product of white foaming body (2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)-4-hydroxyl pyrrolidine-2-first Acid methyl ester (9a, 4.3g, 46% productivity) and unexpected diastereomer (2S, 4R)-1-((2R, 3R)-2-of tacky grease (tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)-4-hydroxyl pyrrolidine-2-methyl formate (9b, 1.9g, 20% productivity).

¹H NMR (400MHz, CDCl₃): δ ppm 5.73-5.64 (m, 1H), 5.19-5.17 (m, 1H), 4.97-4.88 (m, 2H), 4.70-4.66 (t, J=8.4Hz, 1H), 4.53 (bs, 1H), 4.29-4.25 (m, 1H), 3.99-3.96 (d, J= 10.8Hz, 3H), 3.72 (s, 3H), 3.70-3.66 (m, 1H), 2.34-2.11 (m, 1H), 2.10-2.00 (m, 2H), 1.85- 1.81 (m, 1H), 1.49-1.41 (m, 9H), 1.39-1.14 (m, 3H), 0.98-0.86 (m, 7H) MS:MS m/z 427.2 (M⁺+ 1)

Step 2:(2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)- The preparation of 4-hydroxyl pyrrolidine-2-formic acid

At room temperature to (2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-alkene acyl Base)-4-hydroxyl pyrrolidine-2-methyl formate (4.3g, 10mmol) THF/ water (30mL, 1: 1) solution in add methanol (10mL) LiOH (1.3g, 0.030 mole), is added subsequently.At room temperature reacting substance is stirred overnight.Under reduced pressure evaporate molten Agent, and dilute residue with water (100mL).Make described aqueous solution be acidified to pH～3 with 1.5N HCl/water solution, and use acetic acid second Ester (100mL × 3) extracts.By the organic layer of merging through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining white solid Expect product (2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)-4-hydroxyl Pyrrolidine-2-formic acid (3.2g, 78% productivity).

¹H NMR (400MHz, CDCl₃): δ ppm 5.70-5.61 (m, 1H), 5.14-5.12 (d, J=8.8Hz, 1H), 4.96-4.88 (m, 2H), 4.82-4.78 (t, J=8.4Hz, 1H), 4.52 (bs, 1H), 4.27-4.23 (m, 1H), 3.57- 3.53 (m, 3H), 2.48-2.42 (m, 1H), 2.33-2.28 (m, 1H), 1.88-1.82 (m, 2H), 1.45-1.42 (s, 9H), 1.29-1.21 (m, 3H), 0.98-0.93 (m, 7H) MS:MS m/z 411.2 (M⁺+1)。

Step 3:(2S, 4R)-1-((2S, 3R)-2-(tertbutyloxycarbonylamino)-3,7-dimethyl nonyl-8-enoyl-)- The preparation of 4-(4-methoxyisoquinoliae-1-base epoxide) pyrrolidine-2-formic acid

Under room temperature, nitrogen atmosphere, to (2S, 4R)-1-((3R)-2-((tert-butoxycarbonyl) amino)-3,7-dimethyl Nonyl-8-enoyl-)-4-hydroxyl pyrrolidine-2-formic acid (1.5g, 3.6mmo l) DMS O solution in add 1-chloro-4-methoxy Isoquinolin (840mg, 4.4mmol), adds t-BuOK (the 1M solution in THF, 18mL) subsequently.At room temperature by reacting substance Stirring 4h.By reacting substance aqueous citric acid solution quencher and be extracted with ethyl acetate.By the organic layer of merging through anhydrous Na₂S O₄It is dried and under reduced pressure concentrates, obtaining crude compound.By combiflash purifying crude compound, obtain in pale solid Expectation product (800mg, 40%).¹H NMR (400MHz, CDCl₃): δ ppm 8.11-8.09 (m, 2H), 7.70-7.66 (t, J=7.4Hz, 1H), 7.56-7.51 (t, J=8.0Hz, 1H), 7.47 (s, 1H), 5.78 (bs, 1H), 5.69-5.65 (m, 1H), 5.14-5.11 (m, 1H), 4.96-4.88 (m, 3H), 4.43-4.41 (m, 1H), 4.27-4.24 (m, 1H), 3.99 (s, 4H), 2.75-2.73 (m, 1H), 2.67-2.65 (m, 1H), 2.10 (bs, 1H), 1.88-1.85 (m, 2H), 1.31 (s, 9H), 1.24 (s, 2H), 0.98-0.96 (m, 4H), 0.91-0.86 (m, 4H) MS:MS m/z 568.2 (M⁺+1)。

Step 4:(2S, 3R)-1-((2S, 4R)-2-((1R, 2S)-1-(Cyclopropylsulfonyl carbamoyl)-2-ethylene Cyclopropyl carbamoyl)-4-(4-methoxyisoquinoliae-1-base epoxide) pyrrolidin-1-yl)-3,7-dimethyl-1-oxo The preparation of nonyl-8-alkene-2-ylcarbamate

At room temperature to (2S, 4R)-1-((3R)-2-((tert-butoxycarbonyl) amino)-3,7-dimethyl nonyl-8-alkene acyl Base) dichloromethane of-4-((4-methoxyisoquinoliae-1-base) epoxide) pyrrolidine-2-formic acid (800mg, 1.4 mMs) (30mL) solution adds DIPEA (0.73mL, 4.2mmol), HATU (530m g, 1.4 mMs), interpolation (1R, 2S) subsequently- 1-amino-N-(Cyclopropylsulfonyl)-2-vinylcyclopropane carboxamide hydrochloride (according to WO 03/,099,274 the 53-59 page, Prepared by the program illustrated in the 74-76 page) (600m g, 1.5 mMs).At room temperature reactant mixture is stirred 2h.Will Reacting substance D CM dilutes and washes with water.By organic layer through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining roughening and close Thing.By combiflash purifying crude compound, obtain the expectation product (900mg, 90%) in pale solid.¹H NMR (400MHz, CDCl₃): δ ppm8.13-8.07 (m, 2H), 7.72-7.67 (t, J=7.2Hz, 1H), 7.57-7.53 (t, J= 7.2Hz, 1H), 7.47 (s, 1H), 6.80 (bs, 1H), 5.84-5.79 (m, 2H), 5.73--5.64 (m, 1H), 5.39-5.38 (m, 1H), 5.28-5.23 (d, J=17.2Hz, 1H), 5.15-5.12 (d, J=10.4Hz, 1H) 4.97-4.88 (m, 2H), 4.49-4.45 (m, 2H), 4.19-4.17 (m, 2H), 4.00 (s, 3H), 2.90-2.81 (m, 1H), 2.54-2.48 (m, 1H), 2.23-2.07 (m, 2H), 2.05-1.99 (m, 2H), 1.49-1.42 (m, 1H), 1.33 (s, 12H), 1.22-1.15 (m, 2H), 1.07-1.02 (m, 2H), 0.98-0.96 (d, J=6.8Hz, 4H), 0.86-0.81 (d, J=6.8Hz, 4H), MS:MS m/ z782.2(M⁺+1)。

Step 5: compound 1 and the preparation of compound 2

Under room temperature, nitrogen atmosphere, to (2S, 3R)-1-((2S, 4R)-2-((1R, 2S)-1-(Cyclopropylsulfonyl amino Formoxyl)-2-vinyl cyclopropylcarbamoyl)-4-(4-methoxyisoquinoliae-1-base epoxide) pyrrolidin-1-yl)-3, 7-dimethyl-1-oxo nonyl-8-alkene-2-ylcarbamate (900mg, 0.3 mM) is at dichloroethanes (100mL) In de gassed solution in add Grubbs ii for catalyst (24mg, 10%w/w).At 95 DEG C reacting substance is heated Night.Under reduced pressure evaporate solvent, and by combi-flash purification residue, obtain (500mg, 58%) mixed in diastereomer The expectation product of compound.Use preparative-HPL C to separate non-enantiomer mixture, obtain compound 1 (12mg, 8%) and chemical combination Thing 2 (8mg, 3%).

Compound 1:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)- 2-(4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino Carboxylate.

¹H NMR (400MHz, CD₃OD): δ ppm¹H NMR (400MHz, CD₃OD): δ ppm 8.17-8.15 (d, J= 8.4Hz, 1H), 8.13-8.11 (d, J=8.4Hz, 1H), 7.75-7.71 (t, J=8.0Hz, 1H), 7.58-7.54 (m, 2H), 7.30-7.28 (d, J=7.6Hz, 1H), 5.83 (bs, 1H), 5.37-5.32 (t, J=11.2Hz, 1H), 5.05-5.01 (m, 1H), 4.77-4.74 (d, J=11.2Hz, 1H), 4.67-4.63 (m, 1H), 4.04-4.02 (m, 1H), 3.96 (s, 3H), 3.87-3.83 (m, 1H), 2.97-2.96 (m, 1H), 2.76-2.65 (m, 3H), 2.45-2.38 (m, 1H), 1.82-1.81 (m, 1H), 1.78-1.72 (m, 1H), 1.64-1.61 (m, 3H), 1.45-1.32 (m, 5H), 1.13-1.11 (m, 13H), 0.99- 0.98 (d, J=6.4Hz3H), 0.95-0.93 (d, J=6.4Hz, 3H), MS:MS m/z 754.4 (M⁺+1)。

Compound 2:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)- 2-(4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino Carboxylate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.17-8.15 (d, J=8.0Hz, 1H), 8.13-8.10 (d, J= 8.4Hz, 1H), 7.75-7.71 (dt, J=6.8&1.2Hz, 1H), 7.58-7.54 (m, 2H), 5.83 (m, 1H), 5.38-5.33 (t, J=10.4Hz, 1H), 5.06-5.04 (m, 1H), 4.74-4.71 (d, J=11.2Hz, 1H), 4.69-4.64 (m, 1H), 4.03-4.01 (m, 1H), 3.96 (s, 3H), 3.89-3.84 (t, J=9.6Hz, 1H), 3.28-3.18 (m, 1H), 2.96-2.88 (m, 1H), 2.72-2.57 (m, 2H), 2.35-2.32 (m, 1H), 1.98-1.95 (m, 1H), 1.75-1.69 (m, 2H), 1.64- 1.61 (m, 3H), 1.40-1.38 (m, 1H), 1.30-1.26 (m, 3H), 1.19-1.12 (m, 3H), 1.07 (s, 9H), 0.99- 0.91 (m, 6H), MS:MS m/z 752.4 (M⁺-1)。

Compound 3 and the preparation of compound 4

(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-6-amino-N-(Cyclopropylsulfonyl)-2-(4-methoxyl group isoquinoline Quinoline-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16, The preparation of 16a-ten hexahydro ring third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-14a-carboxamide hydrochloride

At room temperature by (2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)-2- (4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-aminocarbamic acid The tertiary butyl ester (500mg, 0.66 mM) solution stirring 30min in dioxane .HCl.Under reduced pressure evaporate solvent, To crude compound (350mg, 77%).By the washing of crude compound ether and i.e. it is used in next step without being further purified. MS:MS m/z 652.2 (M⁺-1)。

The preparation of carbonic acid pyridine-2-base ester 1,1,1-tri-fluoro-2-methyl-prop-2-base ester

1,1,1-tri-fluoro-2-methyl-prop-2-is added in the NaH (1.03g, 25.8mmol) serosity in THF (70mL) Alcohol (3g, 23.42mmol).At 0 DEG C, 20min is stirred in reaction.Then by carbonic acid two pyridine-2-base ester (5.06g, THF (30mL) solution 23.42mmol) adds to this mixture.By gained solution stirring overnight at room temperature.Filter gained Solid by-product also washs with EtOAc (2 × 20mL).The organic layer of merging is washed with water, through anhydrous Na₂SO₄It is dried, filters And under reduced pressure concentrate.By gained white carbonic acid pyridine-2-base ester (1,1,1-tri-fluoro-2-methyl-prop-2-base) ester (1.24g, 21%) it is directly used as reagent.

Compound 3 and the preparation of compound 4:

At room temperature to (2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-6-amino-N-(Cyclopropylsulfonyl)-2-(4-first Epoxide isoquinolyl-1 epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14, 14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-14a-Methanamide hydrochloric acid DCM (4mL) solution of salt (350mg, 0.53mmol) adds DIPEA (0.3mL, 1.8 mMs), adds carbonic acid pyrrole subsequently Pyridine-2-base ester 2,2,2-tri-fluoro-1,1-dimethyl-ethyl ester (180mg, 0.72 mM).At room temperature reactant mixture is stirred Mix 30min.Reacting substance DCM is diluted and washes with water.By organic layer through anhydrous Na₂SO₄It is dried and under reduced pressure evaporates, Obtain the crude compound in non-enantiomer mixture.Use preparative-HPLC to separate non-enantiomer mixture, obtain white solid The compound 3 (50mg, 12%) of body and compound 4 (30mg, 7%).

Compound 3:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)- 2-(4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino Formic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.17-8.15 (d, J=8.4Hz, 1H), 8.13-8.11 (d, J= 8.4Hz, 1H), 7.75-7.71 (t, J=8.0Hz, 1H), 7.58-7.54 (m, 2H), 7.30-7.28 (d, J=7.6Hz, 1H), 5.82 (m, 1H), 5.38-5.32 (t, J=10.4Hz, 1H), 5.04-4.98 (m, 1H), 4.79-4.77 (d, J=10.8Hz, 1H), 4.79-4.77 (m, 1H), 4.02 (s, 3H), 4.00-3.99 (m, 1H), 3.85-3.79 (m, 1H), 3.98-2.94 (m, 1H), 2.77-2.66 (m, 3H), 2.42-2.38 (m, 1H), 1.88-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.64-1.57 (m, 3H), 1.44-1.40 (m, 1H), 1.36-1.31 (m, 6H), 1.17-1.11 (m, 4H), 0.99-0.93 (m, 9H),¹⁹FNMR: δppm-85.12(3F)；MS:MS m/z 808.1 (M⁺+1)。

Compound 4:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)- 2-(4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino Formic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.MS:MS m/z 808.3 (M⁺+1).Compound 5 and the preparation of compound 6

Step 1:(2S, 3R)-1-((2S, 4R)-2-((1R, 2S)-1-Cyclopropylsulfonyl carbamoyl)-2-ethylene Cyclopropyl carbamoyl)-4-hydroxyl pyrrolidine-1-base)-3,7-dimethyl-1-oxo nonyl-8-alkene-2-aminocarbamic acid The preparation of tertiary butyl ester

At room temperature to (2S, 4R)-1-((2S, 3R)-2-((tert-butoxycarbonyl) amino)-3,7-dimethyl nonyl-8-alkene Acyl group)-4-hydroxyl pyrrolidine-2-formic acid (2g, 4.9mmol) dichloromethane (15mL) solution in add HATU (1.86g, 4.9mmol), DIPEA (4.2mL, 24.5 mMs) is added subsequently.At the same temperature reacting substance is stirred 10min.Will (1R, 2S)-1-amino-N-(Cyclopropylsulfonyl)-2-vinylcyclopropane carboxamide hydrochloride is (according to WO 03/,099,274 53-59 page, prepared by the program illustrated in the 74-76 page) (2g, 5.3 mMs) add to reacting substance, and at room temperature Stirring 3hr.By reacting substance dchloromethane and wash with water.By organic layer through anhydrous Na₂SO₄Be dried and under reduced pressure Concentrate, obtain crude compound.By Combiflash (in CHCl₃In 3%MeOH) purifying crude compound, obtain 1.9g (62%) the expectation product of white solid.MS:MS m/z 623.5 (M⁺-1)。

Step 2:(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)-2-hydroxyl Base-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydros The preparation of ring third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-ylcarbamate

Under room temperature, nitrogen atmosphere, to (2S, 3R)-1-((2S, 4R)-2-((1R, 2S)-1-Cyclopropylsulfonyl amino Formoxyl)-2-vinyl cyclopropylcarbamoyl)-4-hydroxyl pyrrolidine-1-base)-3,7-dimethyl-1-oxo nonyl-8- The alkene-2-ylcarbamate (0.9g, 1.4mmol) de gassed solution in dichloroethanes (150mL) adds Grubbs ii is for catalyst (90mg, 10%w/w).By reacting substance heated overnight at 95 DEG C.Under reduced pressure evaporate solvent, And by ISCO purification residue, obtain expecting compound (600mg, 69%).MS:MS m/z 595.2 (M⁺-1)。

Step 3:(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 epoxide)- 14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino The preparation of carboxylate

Under room temperature, nitrogen atmosphere, to ((2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-14a-((Cyclopropylsulfonyl) Carbamoyl)-2-hydroxyl-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base) the carbamic acid tert-butyl group Ester (500mg, 0.8mmol) and 1, adds in DMSO (5mL) solution of 5-bis-chloro-4-methoxyisoquinoliae (230mg, 1.0mmol) Add t-BuOK (the 1M solution in THF, 450mg, 4.0mmol).At room temperature reactant mixture is stirred 2h.By reacting substance Extract with aqueous citric acid solution quencher and by ethyl acetate (150mL × 3).By the organic layer use water merged, aqueous salt solu-tion, Through anhydrous Na₂SO₄It is dried and under reduced pressure concentrates, obtaining the crude compound in non-enantiomer mixture.MS:MS m/z 789.3 (M⁺+1)。

Step 4: compound 5 and the preparation of compound 6

(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinoline is separated by preparative-HPLC Quinoline-1-base epoxide)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6, 7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo ten The non-enantiomer mixture of pentaene-6-aminocarbamic acid ester, obtains desired compound 5 and compound 6.

Compound 5:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 oxygen Base)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate (230mg, 35%).

¹H NMR (400MHz, CD₃OD): δ ppm 8.18-8.16 (d, J=7.6Hz, 1H), 7.78-7.76 (d, J= 6.8Hz, 1H), 7.70 (s, 1H), 7.48-7.44 (t, J=8.0Hz, 1H), 6.67-6.64 (d, J=8.4Hz, 1H), 5.83 (bs, 1H), 5.37-5.32 (t, J=11.2Hz, 1H), 5.05-5.01 (m, 1H), 4.77-4.74 (d, J=11.2Hz, 1H), 4.67-4.63 (m, 1H), 4.04-4.02 (m, 1H), 3.96 (s, 3H), 3.87-3.83 (m, 1H), 2.97-2.96 (m, 1H), 2.76-2.65 (m, 3H), 2.45-2.38 (m, 1H), 1.82-1.81 (m, 1H), 1.78-1.72 (m, 1H), 1.64-1.61 (m, 3H), 1.45-1.32 (m, 5H), 1.13-1.11 (m, 13H), 0.99-0.98 (d, J=6.4Hz3H), 0.95-0.93 (d, J= 6.4Hz, 3H), MS:MS m/z 789.2 (M⁺+1)。

Compound 6:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 oxygen Base)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.18-8.16 (d, J=8.4Hz, 1H), 7.76-7.74 (d, J= 7.6Hz, 1H), 7.70 (s, 1H), 7.48-7.44 (d, J=7.6Hz, 1H), 6.59-6.57 (d, J=8.4Hz, 1H) 5.83 (bs, 1H), 5.38-5.33 (t, J=10.4Hz, 1H), 5.06-5.04 (m, 1H), 4.74-4.71 (d, J=11.2Hz, 1H), 4.69-4.64 (m, 1H), 4.03-4.01 (m, 1H), 3.96 (s, 3H), 3.89-3.84 (t, J=9.6Hz, 1H), 3.28-3.18 (m, 1H), 2.96-2.88 (m, 1H), 2.72-2.57 (m, 2H), 2.35-2.32 (m, 1H), 1.98-1.95 (m, 1H), 1.75- 1.69 (m, 2H), 1.64-1.61 (m, 3H), 1.40-1.38 (m, 1H), 1.30-1.26 (m, 3H), 1.19-1.12 (m, 3H), 1.07 (s, 9H), 0.99-0.91 (m, 6H), MS:MS m/z 787.8 (M⁺-1)。

Compound 7 and the preparation of compound 8

(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-6-amino-2-(5-chloro-4-methoxy isoquinolyl-1 epoxide)- N-(Cyclopropylsulfonyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15, The preparation of 16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-14a-carboxamide hydrochloride

(2R, 6S, 7R, 13aS, 14aR, 16aS, Z)-2-(the chloro-4-of 5-being at room temperature stored in dioxane .HCl Methoxyisoquinoliae-1-base epoxide)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo- 1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] Diaza cyclopentadecylene-6-ylcarbamate (300mg, 3.3mmol) solution stirring 30min.Under reduced pressure evaporate Solvent, obtains crude compound (250mg, 96%).By the washing of crude compound ether and i.e. it is used for next without being further purified In step.MS:MS m/z 688.2 (M⁺-36)。

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 3 Thing 7 and compound 8.Non-enantiomer mixture is separated by preparative-HPLC.

Compound 7:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 oxygen Base)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD3OD): δ ppm 8.18-8.15 (d, J=7.6Hz, 1H), 7.78-7.76 (d, J= 6.4Hz, 1H), 7.70 (s, 1H), 7.49-7.45 (t, J=8.0Hz, 1H), 5.81 (m, 1H), 5.37-5.35 (t, J= 10.8Hz, 1H), 5.04-4.94 (m, 1H), 4.78-4.75 (d, J=11.2Hz, 1H), 4.70-4.66 (m, 1H), 4.01- 3.97 (m, 1H), 3.96 (s, 3H), 3.80-3.77 (d, J=10.4Hz, 1H), 2.98-2.94 (m, 1H), 2.77-2.64 (m, 3H), 2.45-2.38 (m, 1H), 1.84-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.65-1.60 (m, 3H), 1.43-1.29 (m, 8H), 1.17-1.05 (m, 4H), 0.98-0.91 (m, 9H),¹⁹F NMR: δ ppm-85.11 (3F)；MS:MS m/z 843.1 (M⁺+1)。

Compound 8:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 oxygen Base)-14a-(Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.MS:MS m/z 843.3 (M⁺+1)。

Compound 9 and the preparation of compound 10

Use intermediate described herein and by following the general program illustrated for synthesis compound 7 and compound 8 Prepare compound 9 and 10.

Compound 9:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamoyl)- 2-(6-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11, 13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base amino Formic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.10-8.08 (d, J=8.8Hz, 1H), 7.92-7.91 (d, J= 6.0Hz, 1H), 7.26-7.25 (d, J=5.6Hz, 1H), 7.23 (bs, 1H), 7.20 (s, 1H), 7.12-7.11 (dd, J= 2.4&6.4Hz, 1H) 5.88-5.87 (m, 1H), 5.39-5.33 (t, J=10.8Hz, 1H), 5.04-5.00 (m, 1H), 4.74- 4.68 (m, 2H), 4.02-3.99 (m, 1H), 3.99 (s, 3H), 3.88-3.84 (m, 1H), 3.23-3.21 (m, 1H), 2.96- 2.90 (m, 1H), 2.72-2.58 (m, 2H), 2.37-2.34 (m, 1H), 1.80-1.76 (m, 1H), 1.72-1.68 (m, 1H), 1.65-1.57 (m, 3H), 1.40-1.28 (m, 6H), 1.2I-1.02 (m, 5H), 0.99-0.89 (m, 10H),¹⁹F NMR: δ ppm -85.15(3F)；MS:MS m/z 806.2 (M⁺-1)。

Compound 10:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(6-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.MS:MS m/z 806.2 (M⁺+1).1-fluoro-4-methoxyisoquinoliae Preparation

The preparation of step 1:1-chloro-4-methoxy isoquinolin

In acetonitrile (50mL) solution of 1-chlorine isoquinolin-4-alcohol (5.0g, 27.8mmol), TMS-diazonium is added at 0 DEG C Methane (12.73g, 111.2mmol).Reactant mixture is made to be back to room temperature and stir 2h.Under reduced pressure evaporate solvent, be roughened Compound.By silica gel chromatography purifying crude compound, obtain 1-chloro-4-methoxy isoquinolin in pale solid (2.5g, 46.4%).

¹H NMR (400MHz, CD3OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H)；MS:MS m/z 194.7 (M⁺+1)。

The preparation of step 2:1-fluoro-4-methoxyisoquinoliae

In the DMSO solution of 1-chloro-4-methoxy isoquinolin (2.5g, 12.91mmol), at room temperature add cesium fluoride (4.01g, 25.82mmol).Reaction vessel (manometer tube) is sealed and at 145 DEG C, heats 18h.By reacting substance dilute with water And be extracted with ethyl acetate.By organic layer through anhydrous Na₂S O₄It is dried and under reduced pressure evaporates, obtaining crude compound.Pass through silica gel Purification by chromatography crude compound, obtains the expectation compound (700mg, 62%) of white solid.

¹H NMR (400MHz, CD₃OD):

δ ppm8.10 (m, 1H), 8.08 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.49 (m, 1H), 4.04 (s, 3H)；¹⁹F NMR: δ ppm-78.66 (1F)；MS:MS m/z 178.1 (M⁺+1)。

The preparation of 1,5-bis-chloro-4-methoxyisoquinoliae

Step 1:(E) preparation of-3-(2-chlorphenyl) acryloyl group azide

At room temperature add in benzene (100ml) solution of (E)-3-(2-chlorphenyl) acrylic acid (13g, 71.2mmo l) Triethylamine (14.4g, 141mmo l), adds DPPA (19.5g, 71.2mmol) subsequently.At the same temperature reacting substance is stirred Mix 18h.Under reduced pressure evaporate solvent, and extract by residue diluted with water and with dichloromethane.By organic layer through anhydrous slufuric acid Sodium is dried, and filters and evaporates, obtaining crude compound.Used in petroleum ether by conventional column chromatography (silica gel, 60-120 mesh) 10% ethyl acetate, as flowing phase purifying crude compound, obtains the expectation compound (14g, 95%) in light yellow solid.¹H NMR (400MHz, CDCl₃): δ ppm 8.19-8.15 (d, J=16Hz, 1H), 7.63-7.61 (d, J=8Hz, 1H), 7.44- 7.42 (m, 1H), 7.36-7.26 (m, 2H), 6.44-6.40 (d, J=16Hz, 1H).

The preparation of step 2:5-chlorine isoquinolin-1 (2H)-one

Thermotropism (125 DEG C) diphenyl ether (10ml) adds (E)-3-(2-chlorphenyl) acryloyl group azide portionwise (2g, 9.63mmol).At 250 DEG C, 2h is heated in reaction.Reacting substance is cooled to room temperature and dilutes with petroleum ether.Will precipitation Solid filter, by petroleum ether, obtain the crude compound (1.1g, 63.6%) in yellow solid.Crude compound is without entering One step purification is i.e. for next step.

¹H NMR (400MHz, CD₃OD): δ ppm 8.29-8.27 (d, J=8Hz, 1H), 7.84-7.82 (d, J=8Hz, 1H), 7.49 (t, J=8Hz, 1H), 7.32-7.30 (d, J=8Hz, 1H), 6.98-6.96 (d, J=8Hz, 1H)；MS:MS m/z 180.7(M⁺+1)。

The preparation of step 3:5-chloro-4-methoxy isoquinolin-1-(2H)-one

In methanol (70ml) solution of 5-chlorine isoquinolin-1 (2H)-one (3.8g, 21.2mmol), at room temperature add two Acetic acid iodosobenzene (7.5g, 23.4mmol), adds methanesulfonic acid (2.45g, 25.5mmol) subsequently.Under reflux by reacting substance Heating 3h.Evaporation solvent also dilutes residue with cold water.The solid of precipitation is filtered, washes with water, obtain in pale red solid Crude compound (3.9g, 88%).

¹H NMR (400MHz, CDCl₃): δ ppm 8.06-8.03 (d, J=12Hz, 1H), 7.60-7.57 (d, J= 12Hz, 1H), 7.42 (d, J=8Hz, 1H), 7.01-6.99 (br s, 1H), 3.51 (s, 3H)；MS:MS m/z 209.1 (M⁺+ 1)。

Step 4:1, the preparation of 5-bis-chloro-4-methoxyisoquinoliae

POCl by 5-chloro-4-methoxy isoquinolin-1-(2H)-one (6.4g, 30.5mmol)₃(45ml) solution backflow 18h.Under reduced pressure evaporate solvent and dilute residue with cold water.The solid of precipitation is filtered, washes with water, obtain in light brown The crude compound (4g, 57.4%) of solid.

¹H NMR (400MHz, CDCl₃): δ ppm 8.28-8.25 (d, J=12Hz, 1H), 7.87 (s, 1H), 7.79- 7.76 (d, J=12Hz, 1H), 7.58-7.54 (m, 1H), 4.03 (s, 3H)；MS:MS m/z 228.0 (M⁺+1)。

1,7-bis-fluoro-4, the preparation of 6-dimethoxy-isoquinoline

Step 1:7-fluoro-4, the preparation of 6-dimethoxy-isoquinoline-1 (2H)-one

At room temperature to methanol (70ml) solution of 7-fluoro-6-methoxyisoquinoliae-1 (2H)-one (6.3g, 32.6mmol) Middle interpolation iodosobenzen ediacetate (10.5g, 32.6mmol), adds methanesulfonic acid (3.76g, 39.1mmol) subsequently.Under reflux Reacting substance is heated 3h.Evaporation solvent also dilutes residue with cold water.Will precipitation solid filter, wash with water, obtain in The crude compound (6.6g, 91%) of pale red solid.MS:MS m/z 224.0 (M⁺+1)。

The chloro-7-of step 2:1-fluoro-4, the preparation of 6-dimethoxy-isoquinoline

By fluoro-for 7-4, the POCl of 6-dimethoxy-isoquinoline-1 (2H)-one (7.6g, 34.1mmol)₃(50ml) solution returns Stream 18h.Under reduced pressure evaporate solvent and dilute residue with cold water.Make aqueous solution alkalize by solid sodium carbonate, and use acetic acid Ethyl ester extracts.Organic layer is dried through anhydrous sodium sulfate, filters and under reduced pressure evaporate, obtaining crude compound.Pass through layer of silica gel Analysis method (20% ethyl acetate in petroleum ether) purifying crude compound, obtain expectation compound in light yellow solid (2g, 24.3%).

¹H NMR (400MHz, CDCl₃): δ ppm 7.88-7.85 (d, J=12Hz, 1H), 7.75 (s, 1H), 7.54- 7.52 (d, J=8Hz, 1H), 4.05 (s, 3H)；MS:MS m/z 242.0 (M⁺+1)。

Step 3:1,7-bis-fluoro-4, the preparation of 6-dimethoxy-isoquinoline

At room temperature to the chloro-7-of 1-fluoro-4, in DMSO (5ml) solution of 6-dimethoxy-isoquinoline (2g, 8.28mmol) Add cesium fluoride (2.51g, 16.55mmol).Reaction vessel (manometer tube) is sealed and at 145 DEG C, heats 18h.By reactant Matter dilute with water is also extracted with ethyl acetate.By the organic layer of merging through anhydrous Na₂SO₄It is dried and under reduced pressure evaporates, obtaining thick Compound.By silica gel chromatography purifying crude compound, obtain the expectation compound (475mg, 25.5%) of white solid.¹H NMR (400MHz, CDCl₃): δ ppm 7.69-7.67 (d, J=8Hz, 1H), 7.53-7.51 (d, J=8Hz, 1H), 7.45- 7.44 (m, 1H), 4.05 (s, 3H), 4.03 (s, 3H)；¹⁹F NMR: δ ppm-129.58 (1F) ,-79.2 (1F)；MS:MS m/z 226.0(M⁺+1)。

1-fluoro-4, the preparation of 6-dimethoxy-isoquinoline

Step 1:(E) preparation of-3-(3-methoxyphenyl) acryloyl group azide

At room temperature add in benzene (200ml) solution of (E)-3-(3-methoxyphenyl) acrylic acid (20g, 112mmol) Add triethylamine (22.72g, 224mmol), add DPPA (30.9g, 112mmol) subsequently.At the same temperature reacting substance is stirred Mix 18h.Under reduced pressure evaporate solvent, and extract by residue diluted with water and with dichloromethane.By the organic layer of merging through nothing Aqueous sodium persulfate is dried, and filters and evaporates, obtaining crude compound.Oil is used by conventional column chromatography (silica gel, 60-120 mesh) 10% ethyl acetate in ether as flowing phase purifying crude compound, obtain white solid expectation compound (18g, 79%).¹H NMR (400MHz, CDCl3): δ ppm 7.73-7.69 (d, J=16Hz, 1H), 7.33-7.29 (t, J=8Hz, 1H), 7.26 (s, 1H), 7.14-7.12 (d, J=8Hz, 1H), 7.05 (s, 1H) 6.98-6.96 (d, J=4Hz, 1H), 6.43- 6.39 (d, J=16Hz, 1H), 3.86 (s, 3H).

The preparation of step 2:6-methoxyisoquinoliae-1 (2H)-one

To the 1 of (E)-3-(3-methoxyphenyl) acryloyl group azide (7g, 34.4mmol), 2-dichloro-benzenes (70ml) Solution adds mercuric acetate (0.11g, 0.34mmol).At 150 DEG C, 10min is heated in reaction, and elevate the temperature to 180 DEG C 1h.Reacting substance is cooled to room temperature and dilutes with petroleum ether.The solid of precipitation is filtered, by petroleum ether, obtains in Huang The crude compound (3.5g, 58%) of color solid.Crude compound is without being further purified i.e. for next step.

¹H NMR (400MHz, DMSO): δ ppm 8.09-8.06 (d, J=12Hz, 1H), 7.14-7.11 (m, 2H), 7.05-7.03 (d, J=8Hz, 1H), 6.48-6.46 (d, J=4Hz, 1H), 3.86 (s, 3H)；MS:MS m/z 176.0 (M⁺+ 1)。

Step 3:4, the preparation of 6-dimethoxy-isoquinoline-1 (2H)-one

At room temperature in methanol (70ml) solution of 7-fluoro-6-methoxyisoquinoliae-1 (2H)-one (7g, 40.0mmol) Add iodosobenzen ediacetate (14.16g, 40.0mmol), add methanesulfonic acid (11.52g, 120mmol) subsequently.Under reflux will Reacting substance heating 3h.Evaporation solvent also dilutes residue with cold water.The solid of precipitation is filtered, washes with water, obtain in shallow The crude compound (4g, 48.8%) of red solid.¹H NMR (400MHz, DMSO): δ ppm 8.11-8.09 (d, J=8Hz, 1H), 7.19 (s, 1H), 7.13-7.11 (d, J=8Hz, 1H), 6.72-6.71 (d, J=12Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H)；MS:MS m/z 206.1 (M⁺+1)。

Step 4:1-chloro-4, the preparation of 6-dimethoxy-isoquinoline

By 4, the POCl of 6-dimethoxy-isoquinoline-1 (2H)-one (4g, 19.49mmol)₃(40mL) solution backflow 18h. Under reduced pressure evaporate solvent and dilute residue with cold water.Make aqueous solution alkalize by solid sodium carbonate, and extract by ethyl acetate Take.Organic layer is dried through anhydrous sodium sulfate, filters and under reduced pressure evaporate, obtaining crude compound.By silica gel chromatography (in 20% ethyl acetate in petroleum ether) purifying crude compound, obtain expectation compound in light yellow solid (1.2g, 27.5%).

¹H NMR (400MHz, CDCl₃): δ ppm 8.16-8.13 (d, J=12Hz, 1H), 7.74 (s, 1H), 7.44- 7.43 (d, J=4Hz, 1H), 7.30-7.27 (d, J=12Hz, 1H), 7.26 (s, 1H), 4.05 (s, 3H), 3.97 (s, 3H)； MS:MS m/z 224.2 (M⁺+1)。

Step 5:1-fluoro-4, the preparation of 6-dimethoxy-isoquinoline

At room temperature to 1-chloro-4, DMSO (15ml) solution of 6-dimethoxy-isoquinoline (1.5g, 6.71mmol) adds Add cesium fluoride (4g, 26.8mmol).Reaction vessel (manometer tube) is sealed and at 145 DEG C, heats 18h.By reacting substance water Dilute and be extracted with ethyl acetate.By the organic layer of merging through anhydrous Na₂SO₄It is dried and under reduced pressure evaporates, obtaining roughening and close Thing.By silica gel chromatography purifying crude compound, obtain the expectation compound (280mg, 20.15%) of white solid.¹H NMR (400MHz, CDCl₃): δ ppm 7.99-7.97 (d, J=8Hz, 1H), 7.44-7.39 (m, 2H), 7.27-7.11 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H)；¹⁹F NMR: δ ppm-79.32 (1F)；MS:MS m/z 208.0 (M⁺+1)。

The preparation of the chloro-7-of 1-fluoro-4-methoxyisoquinoliae

Step 1:(E) preparation of-3-(4-fluorophenyl) acryloyl group azide

In benzene (120mL) solution of (E)-3-(4-fluorophenyl) acrylic acid (25g, 150mmol), at room temperature add three Ethamine (30.5g, 301mmol), adds DPPA (41.4g, 150mmol) subsequently.At the same temperature reacting substance is stirred 18h.Under reduced pressure evaporate solvent, and extract by residue diluted with water and with dichloromethane.By organic layer through anhydrous sodium sulfate It is dried, filters and evaporate, obtaining crude compound.Used in petroleum ether by conventional column chromatography (silica gel, 60-120 mesh) 10% ethyl acetate, as flowing phase purifying crude compound, obtains the expectation compound (26g, 90%) of white solid.¹H NMR (400MHz, CDCl₃): δ ppm 7.73-7.69 (d, J=16Hz, 1H), 7.55-7.51 (m, 2H), 7.11-7.07 (m, 2H), 6.36-6.32 (d, J=16Hz, 1H).

The preparation of step 2:7-fluorine isoquinolin-1 (2H)-one

Thermotropism (125 DEG C) diphenyl ether (25ml) adds (E)-3-(4-fluorophenyl) acryloyl group azide portionwise (5g, 26.2mmol).At 250 DEG C, 4h is heated in reaction.Reacting substance is cooled to room temperature and dilutes with petroleum ether.Will precipitation Solid filter, by petroleum ether, obtain crude compound (2.45g, 57%).Crude compound without be further purified i.e. for Next step.

¹H NMR (400MHz, CD₃OD): δ ppm 7.96-7.93 (m, 1H), 7.76-7.72 (m, 1H), 7.56-7.51 (m, 1H), 7.18-7.16 (m, 1H), 6.72-6.70 (m, 1H)；MS:MS m/z 164.1 (M⁺+1)。

The preparation of step 3:7-fluoro-4-methoxyisoquinoliae-1 (2H)-one

In the methanol solution of 7-fluorine isoquinolin-1 (2H)-one (11g, 67.4mmol), at room temperature add oxalic acid idous Acyl benzene (21.7g, 67.4mmol), adds methanesulfonic acid (7.78g, 81mmol) subsequently.Under reflux reacting substance is heated 3h.Steam Send out solvent and dilute residue with cold water.The solid of precipitation is filtered and washes with water, obtains the roughening in pale red solid and close Thing (11g, 84%).¹H NMR (400MHz, CD₃OD): δ ppm 8.06-8.04 (m, 1H), 7.96-7.93 (m, 1H), 7.62- 7.54 (m, 2H), 6.74 (s, 1H), 3.89 (s, 3H)；MS:MS m/z 194.1 (M⁺+1)。

The preparation of the chloro-7-of step 4:1-fluoro-4-methoxyisoquinoliae

POCl by fluoro-for 7-4-methoxyisoquinoliae-1 (2H)-one (11g, 56.9mmol)₃(100ml) solution backflow 18h.Under reduced pressure evaporate solvent and dilute residue with cold water.Make aqueous solution alkalize by solid sodium carbonate, and use acetic acid second Ester extracts.The organic layer of merging is dried through anhydrous sodium sulfate, filters and under reduced pressure evaporate, obtaining crude compound.Pass through silicon Glue chromatography (20% ethyl acetate in petroleum ether) purifying crude compound, obtains the expectation compound in pale solid (2.9g, 24%).

¹H NMR (400MHz, CDCl₃): δ ppm 8.36-8.32 (m, 1H), 7.93-7.90 (m, 1H), 7.88 (s, 1H), 7.70-7.65 (m, 1H), 4.11 (s, 3H)；MS:MS m/z 212.1 (M⁺+1)。

The preparation of 1,7-bis-fluoro-4-methoxyisoquinoliae

In the DMSO solution of the chloro-7-of 1-fluoro-4-methoxyisoquinoliae (3.7g, 17.48mmo1), at room temperature add fluorine Change caesium (10.26g, 69.9mmol).Reaction vessel (manometer tube) is sealed and at 145 DEG C, heats 18h.By reacting substance water Dilute and be extracted with ethyl acetate.By the organic layer of merging through anhydrous Na₂SO₄It is dried and under reduced pressure evaporates, obtaining roughening and close Thing.By silica gel chromatography purifying crude compound, obtain the expectation compound (1.7g, 49%) of white solid.¹H NMR (400MHz, CD₃OD): δ ppm 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.47 (m, 1H), 7.46 (s, 1H), 4.04 (s, 3H)；¹⁹F NMR: δ ppm 109.65 (1F) ,-78.53 (1F)；MS:MS m/z 196.1 (M⁺+1)。

2-chloro-6-methoxyl group quinoxaline and the preparation of 3-chloro-6-methoxyl group ketone

Step 1:6-methoxyl group quinoxaline-2 (1H)-one and the preparation of 7-methoxyl group quinoxaline-2 (1H)-one

To 4-methoxybenzene-1, ethanol (50ml) solution of 2-diamidogen (5g, 36.2mmol) adds 2-Oxoacetic Acid second Ester (4.06g, 39.8mmol).Under reflux by reacting substance heated overnight.Under reduced pressure evaporate solvent, and by residue second Acetoacetic ester dilutes, and is then evaporated to be dried, obtains crude compound.Use petroleum ether crude compound, obtain in regional isomer The crude compound (5.1g, 80% productivity) of mixture (black solid).The most separated isomer of this crude compound is i.e. for next Step.¹H NMR (400MHz, DMSO-d₆): δ ppm 8.17 (s, 1H), 7.98 (s, 1H), 7.70-7.68 (d, J=8Hz, 1H), 7.31-7.30 (d, J=4Hz, 1H), 7.27-7.20 (m, 2H), 6.93-6.90 (m, 1H), 6.77-6.76 (d, J= 4Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H)；MS:MS m/z 177.0 (M⁺+1)。

Step 2 and 3:2-chloro-6-methoxyl group quinoxaline and the preparation of 3-chloro-6-methoxyl group quinoxaline

By 6-methoxyl group quinoxaline-2 (1H)-one and 7-methoxyl group quinoxaline-2 (1H)-one (3g, 18.28mmol) POCl₃(20ml) solution backflow 3h.Under reduced pressure evaporate solvent and dilute residue with cold water.Made water-soluble by solid sodium carbonate Basified, and be extracted with ethyl acetate.The organic layer of merging is dried through anhydrous sodium sulfate, filters and under reduced pressure evaporate, To crude compound.By silica gel chromatography (20% ethyl acetate in petroleum ether) purifying crude compound, it is provided that regional isomerism The mixture (3.7g) of body.Mixture above by S F C purifies and separates 2g, it is provided that the 2-chloro-7-first in pale solid Epoxide quinoxaline (0.7g, 34.7%) and 2-chloro-7-methoxyl group quinoxaline (0.9g, 44.6%).

2-chloro-6-methoxyl group quinoxaline:

¹H NMR (400MHz, DMSO-d6): δ ppm¹H NMR (400MHz, CDCl3): δ ppm 8.71 (s, 1H), 7.91-7.89 (d, J=8Hz, 1H), 7.46-7.38 (m, 2H), 3.97 (s, 3H)；MS:MS m/z 194.9 (M⁺+1)。

2-chloro-7-methoxyl group quinoxaline:

¹H NMR (400MHz, CDCl₃): δ ppm 8.63 (s, 1H), 7.99-7.96 (d, J=12Hz, 1H), 7.43- 7.40 (d, J=12Hz, 1H), 7.30 (s, 1H), 3.96 (s, 3H)；MS:MS m/z 194.9 (M⁺+1)。

The preparation of 1-chloro-4-ethyoxyl isoquinolin

The preparation of step 1:1-chloro-4-ethyoxyl isoquinolin

In acetonitrile (10mL) solution of 1-chlorine isoquinolin-4-alcohol (1.0g, 5.5mmol), at room temperature add K₂CO₃ (2.3g, 16.7mmol), adds iodoethane (0.87ml, 11.0mmol) subsequently.At room temperature reactant mixture is stirred overnight. Under reduced pressure evaporate solvent, and by residue diluted with water and be extracted with ethyl acetate.By the organic layer of merging through anhydrous Na₂S O₄It is dried and under reduced pressure evaporates, obtaining crude compound.By silica gel chromatography purifying crude compound, obtain in pale solid 1-chloro-4-ethyoxyl isoquinolin (0.7g, 62%).¹H NMR (400MHz, CD₃OD): δ ppm 8.26-8.24 (m, 2H), 7.79 (s, 1H), 7.76-7.26 (m, 2H), 4.29-4.24 (q, J=6.8Hz, 2H), 1.58-1.54 (t, J=6.8Hz, 3H)； MS:MS m/z207.7 (M⁺+1)。

The preparation of step 2:1-fluoro-4-ethyoxyl isoquinolin

In the DMSO solution of 1-chloro-4-ethyoxyl isoquinolin (4.8g, 23.12mmol), at room temperature add cesium fluoride (6.9g, 46.24mmol).Reaction vessel (manometer tube) is sealed and at 145 DEG C, heats 18h.By reacting substance dilute with water And be extracted with ethyl acetate.By organic layer through anhydrous Na₂SO₄It is dried and under reduced pressure evaporates, obtaining crude compound.Pass through silica gel Purification by chromatography crude compound, obtains the expectation compound (2.6g, 58.8%) of white solid.MS:MS m/z 192.3 (M⁺ +1)。

The preparation of 1-methyl cyclopropane-1-sulfonamide

Step 1: the preparation of cyclopropyl sulfonyl ylcarbamate

0 DEG C, under nitrogen, in DCM (800ml) solution of cyclopropanesulfonamide (100g, 82.6mmol), add three second Amine (234ml, 165mmol), adds DMAP (10.28g, 82.6mmol) subsequently.It is slowly added DCM in this reactant mixture (400ml) the Boc anhydride (247ml, 107mmol) in.At room temperature gained mixture is stirred 4h.By reactant mixture water Dilute and be extracted with ethyl acetate.Organic layer 1.5NHCl solution and the 10%NaHCO that will merge₃Washing, and through anhydrous slufuric acid Sodium is dried, and filters and under reduced pressure evaporates, obtaining the crude compound (143g, 65.0%) in solid.This crude product is directly used in Next step.¹H NMR (400MHz, DMSO-d6): δ ppm 11.08 (s, 1H), 2.90 (m, 1H), 1.48 (s, 9H), 1.06 (m, 4H).

Step 2:(1-methylcyclopropyl groups) preparation of sulfonylcarbamic acid tertiary butyl ester

Cyclopropyl sulfonyl ylcarbamate (4.3g, 20mmol) solution is dissolved in anhydrous THF (100ml) And it is cooled to-78 DEG C.Positive BuLi (17.6ml, 44mmol, 2.5M are in hexane) it is slowly added in this solution.Reaction is made to mix Thing is warming up to the time of room temperature experience 1.5h.Then this mixture is cooled to-78 DEG C, and add positive BuLi (20mmol, 8ml, 2.5M is in hexane) solution, stirs 1h, and adds the pure solution of iodomethane (5.68g, 40mmol).Reactant mixture is made to heat up To ambient temperature overnight, at room temperature use saturated NH₄Cl (100ml) aqueous solution quencher.EtOAc (100ml) is used to extract.To merge Organic layer with saline wash, at Na₂SO₄Upper dry, filter and also under reduced pressure evaporate, obtain yellow oil, by their own alkane Middle crystallization, it is provided that in flaxen solid product (3.1g, 81%).¹H NMR (400MHz, DMSO-d₆): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).

The preparation of step 3:1-methyl cyclopropane-1-sulfonamide

The N-tert-butyl group-(1-methyl) cyclopropyl-sulfonamide (1.91g, 10mmol) solution is dissolved in dioxane (30ml) in the 4M HCl in, and at room temperature reactant mixture is stirred 16h.Remove solvent in a vacuum, obtain yellow oil Shape thing, crystallizes it from EtOAc/ hexane (1: 4,40ml), it is thus achieved that the 1-methyl-cyclopropyl sulfonamide of white solid (1.25g, 96%).¹H NMR (400MHz, CDCl₃): δ ppm 6.73 (s, 2H), 1.43 (s, 3H), 1.14-1.12 (m, 2H), 0.75-0.73 (m, 2H).

The preparation of 1-(methyl fluoride) cyclopropane-1-sulfonamide

The preparation of step 1:1-(hydroxymethyl) cyclopropyl sulfonyl ylcarbamate

Through 30min to the 750mL's of cyclopropyl sulfonyl ylcarbamate (30g, 136mmol) at-78 DEG C THF solution is added dropwise over butyl lithium (1.6M is stored in hexane, 212mL, 339mmol), and at-78 DEG C, gained is mixed Thing stirring 1h.Produce formaldehyde gas from paraformaldehyde (by heating at 180 DEG C), and purged to the most anti-at-30 DEG C Answer 30min in material.At the same temperature 1h is stirred in reaction, be then allowed to warm to room temperature.By reaction ammonium chloride solution Liquid quencher dilute with water.Wash gained material by ethyl acetate, and make water layer be acidified to pH～2 and be extracted with ethyl acetate. The Organic substance that merges is dried over sodium sulfate, filter and also under reduced pressure evaporate, obtain white solid expectation compound (27g, 79%).¹H NMR (400MHz, DMSO-d₆): δ ppm 10.90 (sb, 1H), 4.95 (sb, 1H), 3.75 (s, 2H), 1.42 (s, 9H), 1.27 (m, 2H), 1.08 (m, 2H).

Step 2:(1-(methyl fluoride) cyclopropyl) preparation of sulfonylcarbamic acid tertiary butyl ester

To (1-hydroxymethyl) cyclopropyl at-78 DEG C) sulfonylcarbamic acid tertiary butyl ester (10g, 39.98mmol) DCM (150ml) solution is added dropwise over DAST (25.7g, 159mmol).Reacting substance is stirred 2hr.By reacting substance 1N NaOH solution (200ml) quencher, separates DCM layer.

Wash DCM layer by NaOH solution (400ml), make with 1.5N HCl solution (600ml) water layer of merging be acidified, and use DCM extracts.The organic layer of merging is dried through anhydrous sodium sulfate, filters and under reduced pressure evaporates, obtains in brown solid Expect compound (9.8g, 97%).¹H NMR (400MHz, CDCl₃): δ ppm 6.97 (br, s, 1H), 4.74-4.62 (d, J= 48Hz, 2H), 1.83-1.80 (m, 2H), 1.56-1.44 (m, 9H), 1.20-1.11 (m, 2H).

The preparation of step 3:1-(methyl fluoride) cyclopropane-1-sulfonamide

At room temperature to (1-(methyl fluoride) cyclopropyl) sulfonylcarbamic acid tertiary butyl ester (19.8g, 38.7mmol) DCM (100ml) solution is added dropwise over TFA (30ml, 387mmol).Reacting substance is stirred 2hr.Under reduced pressure evaporate reaction Material, obtains the expectation compound (6g, 100%) in pale solid.¹H NMR (400MHz, CDCl₃): δ ppm 4.78- 4.66 (d, J=48Hz, 2H), 2.61 (br, s, 1H), 1.59-1.56 (m, 2H), 1.13-1.10 (m, 2H).

The preparation of compound 11

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 5 Thing 11.

Compound 11:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(4,6-dimethoxy-isoquinoline-1-base oxygen Base)-14a-(1-(methyl fluoride) Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6, 7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo ten Pentaene-6-ylcarbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.06 (d, J=9.03Hz, 1H) 7.51 (s, 1H) 7.42 (d, J= 2.51Hz, 1H) 7.14 (dd, J=9.16,2.64Hz, 1H) 5.79 (br.s., 1H) 5.29 (br.s., 1H) 4.54-4.65 (m, 2H) 4.02 (s, 3H) 3.95 (s, 3H) 3.03-3.09 (m, 3H) 2.67 (d, J=17.57Hz, 2H) 1.77 (d, J=4.77Hz, 1H) 1.62 (d, J=11.80Hz, 2H) 1.43 (s, 1H) 1.29-1.35 (m, 9H) 1.24 (br.s., 2H) 1.12 (s, 9H) 0.99 (dd, J=13.05,6.53Hz, 6H) 0.89-0.94 (m, 3H)；MS:MS m/z 816.4 (M⁺+1)。

Compound 12 and the preparation of compound 13

Use intermediate described herein and follow the general program system illustrated for synthesis compound 7 and compound 8 Standby compound 12 and compound 13.

Compound 12:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(4,6-dimethoxy-isoquinoline-1-base oxygen Base)-14a-(1-(methyl fluoride) Cyclopropylsulfonyl carbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6, 7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo ten Pentaene-6-aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.89 (s, 1H) 8.09 (d, J=9.29Hz, 1H) 7.52 (s, 1H) 7.45 (d, J=2.51Hz, 1H) 7.17 (dd, J=9.03,2.51Hz, 1H) 5.81 (br.s., 1H) 5.37 (t, J=9.66Hz, 1H) 4.96-5.03 (m, 2H) 4.67-4.75 (m, 2H) 4.43-4.61 (m, 1H) 4.00-4.05 (m, 3H) 3.96 (s, 3H) 3.85 (d, J=10.79Hz, 1H) 3.23 (d, J=7.03Hz, 2H) 2.59-2.71 (m, 2H) 2.29-2.36 (m, 1H) 1.70-1.82 (m, 2H) 1.63 (td, J=8.47,5.40Hz, 4H) 1.36 (s, 3H) 1.31 (s, 3H) 1.25-1.28 (m, 3H) 1.15-1.21 (m, 2H) 0.97 (d, J=4.52Hz, 6H) 0.87-0.93 (m, 2H)；MS:MS m/z 870.4 (M⁺+1)。

Compound 13:((2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-((4,6-dimethoxy-isoquinoline-1- Base) epoxide)-14a-(((1-(methyl fluoride) cyclopropyl) sulfonyl) carbamoyl)-7,11-dimethyl-5,16-dioxo- 1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] Diaza cyclopentadecylene-6-base) carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.07 (d, J=9.29Hz, 1H) 7.52 (s, 1H) 7.42 (d, J= 2.26Hz, 1H) 7.09-7.16 (m, 1H) 6.71 (d, J=8.53Hz, 1H) 5.80 (s, 1H) 5.34 (br.s., 1H) 4.81- 4.81 (m, 1H) 4.62-4.71 (m, 3H) 4.02 (s, 4H) 3.95 (s, 4H) 2.67-2.75 (m, 3H) 2.42 (br.s., 1H) 1.83 (br.s., 1H) 1.66 (d, J=7.53Hz, 6H) 1.48 (br.s., 1H) 1.17 (s, 11H) 1.00 (d, J=6.53Hz, 3H) 0.95 (d, J=6.27Hz, 4H)；MS:MS m/z 870.6 (M⁺+1)。

The preparation of compound 14

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 14.

Compound 14:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(4,6-dimethoxy-isoquinoline-1-base oxygen Base)-7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5,6,7,8, 9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene- 6-aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.07 (d, J=9.03Hz, 1H) 7.53 (s, 1H) 7.44 (d, J= 2.51Hz, 1H) 7.28 (d, J=8.28Hz, 1H) 7.15 (dd, J=9.03,2.51Hz, 1H) 5.81 (br.s., 1H) 5.34- 5.40 (m, 1H) 5.02 (dd, J=10.42,7.40Hz, 1H) 4.67-4.74 (m, 2H) 3.98-4.04 (m, 4H) 3.95 (s, 3H) 3.84-3.90 (m, 1H) 3.20 (br.s., 1H) 2.58-2.72 (m, 2H) 2.35 (q, J=8.11Hz, 1H) 1.79 (d, J= 7.03Hz, 1H) 1.57-1.69 (m, 5H) 1.54 (s, 3H) 1.42-1.51 (m, 2H) 1.37 (s, 3H) 1.27-1.33 (m, 1H) 1.17 (dd, J=14.18,8.91Hz, 1H) 0.96-1.00 (m, 8H) 0.89-0.93 (m, 3H)；MS:MS m/z 852.5 (M⁺+ 1)。

Compound 15 and the preparation of compound 16

Use intermediate described herein and follow the general program system illustrated for synthesis compound 7 and compound 8 Standby compound 15 and compound 16.

Compound 15:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(7-fluoro-4,6-dimethoxy-isoquinoline- 1-base epoxide)-7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5, 6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo Ten pentaene-6-aminocarbamic acids 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 7.75 (d, J=11.54Hz, 1H) 7.58 (d, J=8.28Hz, 1H) 7.54 (s, 1H) 5.82 (br.s., 1H) 5.33-5.40 (m, 1H) 5.04 (d, J=10.54Hz, 1H) 4.64-4.73 (m, 2H) 3.97-4.05 (m, 7H) 3.86 (d, J=10.79Hz, 1H) 2.57-2.72 (m, 2H) 2.34 (d, J=6.53Hz, 1H) 1.79 (d, J=6.78Hz, 1H) 1.57-1.70 (m, 5H) 1.53 (s, 3H) 1.48 (d, J=11.04Hz, 1H) 1.39 (s, 3H) 1.32 (br.s., 1H) 1.12-1.29 (m, 3H) 1.08 (s, 3H) 0.98 (d, J=6.53Hz, 6H) 0.87-0.93 (m, 3H)；MS:MS m/z 870.4(M⁺+1)。

Compound 16:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-(7-fluoro-4,6-dimethoxy-isoquinoline- 1-base epoxide)-7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5, 6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo Ten pentaene-6-aminocarbamic acids 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 7.75 (d, J=11.54Hz, 1H) 7.58 (d, J=8.28Hz, 1H) 7.54 (s, 1H) 5.81 (br.s., 1H) 5.36 (t, J=10.29Hz, 1H) 4.95 (t, J=10.42Hz, 1H) 4.65-4.72 (m, 2H) 4.03 (d, J=2.01Hz, 7H) 3.83 (d, J=10.29Hz, 1H) 2.73 (dt, J=13.93,6.84Hz, 3H) 2.36-2.44 (m, 1H) 1.85 (br.s., 1H) 1.57-1.74 (m, 5H) 1.54 (s, 3H) 1.45 (d, J=11.80Hz, 2H) 1.41 (s, 3H) 1.30 (d, J=14.05Hz, 3H) 1.14 (s, 4H) 1.01 (d, J=6.27Hz, 3H) 0.95 (d, J= 6.53Hz, 3H) 0.91 (br.s., 2H)；MS:MS m/z 868.9 (M⁺-1)。

Compound 17 and the preparation of compound 18

Use intermediate described herein and follow the general program system illustrated for synthesis compound 7 and compound 8 Standby compound 17 and compound 18.Compound 17:((2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-((7-methoxyl group quinoline Quinoline-2-base) epoxide)-7,11-dimethyl-14a-(((1-methylcyclopropyl groups) sulfonyl) carbamoyl)-5,16-dioxy Generation-1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [1, 4] diaza cyclopentadecylene-6-base) carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

NMR (400MHz, CD₃OD): δ ppm 8.26 (s, 1H) 7.87 (d, J=9.03Hz, 1H) 7.32 (d, J= 2.76Hz, 1H) 7.26-7.30 (m, 1H) 5.88 (br.s., 1H) 5.34 (br.s., 1H) 4.75 (s, 1H) 4.68 (br.s., 1H) 4.07 (d, J=8.78Hz, 1H) 3.99 (s, 3H) 3.84 (s, 1H) 2.66 (d, J=7.03Hz, 2H) 2.27 (br.s., 1H) 1.74-1.83 (m, 1H) 1.69 (br.s., 1H) 1.60 (d, J=8.03Hz, 3H) 1.54 (s, 4H) 1.40 (d, J=6.27Hz, 3H) 1.31 (s, 2H) 1.26 (s, 4H) 1.20 (s, 3H) 0.97 (dd, J=13.68,6.40Hz, 7H) 0.88 (br.s., 2H)； MS:MS m/z 823.5 (M⁺+1)。

Compound 18:((2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-((7-methoxyl group quinoxaline-2-base) oxygen Base)-7,11-dimethyl-14a-(((1-methylcyclopropyl groups) sulfonyl) carbamoyl)-5,16-dioxo-1,2,3,5,6, 7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo ten Pentaene-6-base) carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.27 (s, 1H) 7.87 (d, J=9.03Hz, 1H) 7.34 (d, J= 2.51Hz, 1H) 7.28 (dd, J=9.03,2.76Hz, 1H) 5.88 (br.s., 1H) 5.32 (t, J=10.29Hz, 1H) 4.73- 4.81 (m, 1H) 4.66 (t, J=8.41Hz, 1H) 4.12 (d, J=10.54Hz, 1H) 3.99 (s, 3H) 3.84 (d, J= 10.29Hz, 1H) 2.70 (dd, J=13.93,7.65Hz, 3H) 2.45-2.59 (m, 2H) 1.98 (s, 2H) 1.85 (d, J= 6.02Hz, 1H) 1.70-1.77 (m, 2H) 1.61 (br.s., 3H) 1.54 (s, 3H) 1.31-1.47 (m, 2H) 1.28 (s, 4H) 1.23 (s, 3H) 0.96 (t, J=6.90Hz, 6H) 0.87 (br.s., 2H)；MS:MS m/z 823.5 (M⁺+1)。

Compound 19 and the preparation of compound 20

Use intermediate described herein and follow the general program system illustrated for synthesis compound 7 and compound 8 Standby compound 19 and compound 20.Compound 19:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(4-ethyoxyl isoquinoline Quinoline-1-base epoxide)-7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2, 3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] phenodiazine Miscellaneous cyclopentadecylene-6-aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.16 (t, J=8.03Hz, 2H) 7.74 (t, J=7.78Hz, 1H) 7.54-7.60 (m, 2H) 5.83 (br.s., 1H) 5.37 (t, J=10.29Hz, 1H) 5.00-5.06 (m, 1H) 4.69-4.77 (m, 2H) 4.25 (q, J=7.03Hz, 2H) 4.02 (d, J=12.05Hz, 1H) 3.87 (d, J=10.79Hz, 1H) 2.58-2.75 (m, 3H) 2.35 (d, J=8.53Hz, 1H) 1.73-1.84 (m, 1H) 1.58-1.70 (m, 5H) 1.53-1.57 (m, 6H) 1.40-1.51 (m, 2H) 1.31-1.37 (m, 4H) 1.28 (s, 1H) 1.09-1.21 (m, 1H) 0.98 (dd, J=6.27,5.02Hz, 6H) 0.91 (s, 5H)；MS:MS m/z 836.5 (M⁺+1)。

Compound 20:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-2-(4-ethyoxyl isoquinolyl-1 epoxide)- 7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.16 (t, J=7.40Hz, 2H) 7.74 (t, J=7.78Hz, 1H) 7.53-7.59 (m, 2H) 5.83 (br.s., 1H) 5.36 (s, 1H) 4.93-4.99 (m, 1H) 4.69-4.79 (m, 2H) 4.24 (q, J =6.94Hz, 2H) 4.04 (d, J=10.29Hz, 1H) 3.85 (d, J=11.29Hz, 1H) 2.63-2.79 (m, 3H) 2.42 (br.s., 1H) 1.85 (d, J=9.54Hz, 1H) 1.62-1.77 (m, 3H) 1.52-1.59 (m, 6H) 1.39-1.49 (m, 3H) 1.36 (s, 3H) 1.27-1.32 (m, 3H) 1.17 (s, 1H) 0.89-1.01 (m, 11H) .MS:MS m/z 836.4 (M⁺+1)。

The preparation of compound 21

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 5 Thing 21.

Compound 21:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(4,6-dimethoxy-isoquinoline-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Ylcarbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.06 (d, J=9.04Hz, 1H) 7.51 (s, 1H) 7.42 (d, J= 2.51Hz, 1H) 7.13 (dd, J=9.03,2.51Hz, 1H) 5.81 (br.s., 1H) 5.37 (t, J=10.16Hz, 1H) 5.01 (dd, J=10.54,7.28Hz, 1H) 4.62-4.69 (m, 2H) 3.98-4.04 (m, 4H) 3.89-3.96 (m, 4H) 3.18-3.25 (m, 1H) 2.89-2.97 (m, 1H) 2.55-2.70 (m, 2H) 2.38 (q, J=7.86Hz, 1H) 1.77 (td, J=10.54, 6.27Hz, 1H) 1.70 (dd, J=8.28,5.27Hz, 1H) 1.57-1.66 (m, 3H) 1.35-1.46 (m, 1H) 1.24-1.34 (m, 3H) 1.02-1.22 (m, 12H) 0.98 (t, J=6.53Hz, 6H) 0.88-0.94 (m, 1H)；MS:MS m/z 784.2 (M⁺+ 1)。

The preparation of compound 22

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 22.

Compound 22:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(4,6-dimethoxy-isoquinoline-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.06 (d, J=9.29Hz, 1H) 7.53 (s, 1H) 7.43 (d, J= 2.51Hz, 1H) 7.15 (dd, J=9.16,2.64Hz, 1H) 5.81 (br.s., 1H) 5.37 (t, J=10.04Hz, 1H) 5.00- 5.06 (m, 1H) 4.67-4.73 (m, 2H) 3.97-4.04 (m, 4H) 3.95 (s, 3H) 3.83-3.89 (m, 1H) 3.22 (d, J= 9.54Hz, 1H) 2.94 (s, 1H) 2.56-2.71 (m, 2H) 2.36 (d, J=7.28Hz, 1H) 1.75-1.84 (m, 1H) 1.71 (dd, J=8.03,5.27Hz, 1H) 1.56-1.66 (m, 3H) 1.39-1.46 (m, 1H) 1.37 (s, 3H) 1.24-1.32 (m, 2H) 1.03-1.22 (m, 4H) 0.98 (t, J=7.53Hz, 9H) 0.88-0.93 (m, 1H)；MS:MS m/z 838.2 (M⁺+1)。

The preparation of compound 23

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 5 Thing 23.

Compound 23:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-fluoro-4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Ylcarbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 9.09 (s, 1H) 8.17 (dd, J=9.03,5.27Hz, 1H) 7.74 (dd, J=9.54,2.51Hz, 1H) 7.49-7.58 (m, 2H) 5.83 (br.s., 1H) 5.36 (t, J=10.67Hz, 1H) 5.03 (t, J=10.67Hz, 1H) 4.63-4.78 (m, 2H) 3.99-4.05 (m, 4H) 3.85 (d, J=10.54Hz, 1H) 2.97 (tt, J =7.94,4.86Hz, 1H) 2.64-2.78 (m, 3H) 2.41 (ddd, J=13.80,9.66,4.14Hz, 1H) 1.78-1.87 (m, 1H) 1.73 (dd, J=8.28,5.77Hz, 1H) 1.56-1.67 (m, 3H) 1.29-1.49 (m, 5H) 1.04-1.21 (m, 12H) 1.00 (d, J=6.53Hz, 3H) 0.95 (d, J=6.27Hz, 3H)；MS:MS m/z 772.4 (M⁺+1)。

The preparation of compound 24

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 24.

Compound 24:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-fluoro-4-methoxyisoquinoliae-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 9.10 (s, 1H) 8.19 (dd, J=9.16,5.40Hz, 1H) 7.76 (dd, J=9.54,2.51Hz, 1H) 7.51-7.61 (m, 2H) 5.80-5.85 (m, 1H) 5.36 (t, J=10.54Hz, 1H) 4.99-5.06 (m, 1H) 4.65-4.77 (m, 2H) 3.99-4.05 (m, 4H) 3.81 (d, J=10.29Hz, 1H) 2.94-3.00 (m, 1H) 2.64-2.79 (m, 3H) 2.41 (ddd, J=13.80,9.79,4.27Hz, 1H) 1.85 (d, J=6.27Hz, 1H) 1.73 (dd, J=8.28,5.77Hz, 1H) 1.57-1.68 (m, 3H) 1.44 (d, J=12.05Hz, 1H) 1.29-1.39 (m, 7H) 1.09-1.20 (m, 3H) 1.04-1.08 (m, 3H) 1.00 (d, J=6.53Hz, 3H) 0.94 (d, J=6.53Hz, 3H)；MS:MS m/z 824.2(M⁺-1)。

The preparation of compound 25

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 25.

Compound 25:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(5-chloro-4-methoxy isoquinolyl-1 Epoxide)-7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5,6,7, 8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo 15 Alkene-6-aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.18 (dd, J=8.41,1.13Hz, 1H) 7.78 (dd, J=7.53, 1.00Hz, 1H) 7.72 (s, 1H) 7.48 (t, J=8.03Hz, 1H) 5.83 (br.s., 1H) 5.36 (t, J=9.91Hz, 1H) 5.01-5.07 (m, 1H) 4.69-4.79 (m, 2H) 3.96-4.03 (m, 4H) 3.83 (d, J=10.79Hz, 1H) 3.19 (br.s., 1H) 2.60-2.74 (m, 3H) 2.32 (br.s., 1H) 1.73-1.81 (m, 1H) 1.56-1.71 (m, 5H) 1.54 (s, 3H) 1.46- 1.51 (m, 1H) 1.39 (br.s., 1H) 1.31-1.35 (m, 3H) 1.24 (d, J=7.28Hz, 2H) 0.97 (t, J=6.02Hz, 6H) 0.90 (s, 6H)；MS:MS m/z 856.2 (M⁺+1)。

Compound 26 and the preparation of compound 27

Use intermediate described herein and follow the general program system illustrated for synthesis compound 5 and compound 6 Standby compound 26 and compound 27.

Compound 26:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(6-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.86 (s, 1H) 8.37 (s, 1H) 7.82 (d, J=9.03Hz, 1H) 7.36-7.44 (m, 2H) 5.87 (br.s., 1H) 5.37 (t, J=10.42Hz, 1H) 5.02 (dd, J=10.54,7.28Hz, 1H) 4.64-4.73 (m, 2H) 4.04 (dd, J=11.80,3.51Hz, 1H) 3.95 (s, 3H) 3.84 (d, J=10.79Hz, 1H) 3.18-3.23 (m, 1H) 2.90-2.98 (m, 1H) 2.64 (d, J=8.53Hz, 2H) 2.31-2.38 (m, 1H) 1.68-1.80 (m, 2H) 1.55-1.67 (m, 3H) 1.36-1.45 (m, 1H) 1.22-1.34 (m, 2H) 1.15-1.22 (m, 2H) 1.02-1.13 (m, 11H) 0.98 (d, J=6.27Hz, 3H) 0.94 (d, J=6.53Hz, 3H) 0.86 (br.s., 1H)；MS:MS m/z 755.4 (M⁺ +1)。

Compound 27:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(6-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.38 (s, 1H) 7.82 (d, J=9.03Hz, 1H) 7.34-7.46 (m, 2H) 5.86 (br.s., 1H) 5.26-5.38 (m, 1H) 4.53-4.76 (m, 2H) 4.12 (q, J=7.28Hz, 1H) 3.95 (s, 3H) 3.85 (d, J=10.29Hz, 1H) 2.94 (br.s., 1H) 2.62-2.77 (m, 2H) 2.46 (br.s., 1H) 1.55-1.87 (m, 5H) 1.23-1.42 (m, 6H) 1.14 (s, 11H) 1.05 (dd, J=6.53,4.02Hz, 2H) 0.89-0.98 (m, 6H)；MS:MS m/z 755.4(M⁺+1)。

Compound 28 and the preparation of compound 29

Use intermediate described herein and follow the general program system illustrated for synthesis compound 5 and compound 6 Standby compound 28 and compound 29.

Compound 28:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.24 (s, 1H) 7.86 (s, 1H) 7.23-7.33 (m, 2H) 5.89 (d, J =2.76Hz, 1H) 5.36 (t, J=9.54Hz, 1H) 5.05 (br.s., 1H) 4.62-4.75 (m, 2H) 4.07 (d, J= 8.28Hz, 1H) 3.98 (s, 3H) 3.85 (d, J=10.79Hz, 1H) 2.93 (br.s., 1H) 2.60-2.72 (m, 2H) 2.31 (br.s., 1H) 1.68-1.82 (m, 2H) 1.54-1.67 (m, 3H) 1.36-1.48 (m, 1H) 1.16-1.32 (m, 5H) 1.11 (s, 11H) 0.96 (dd, J=18.82,6.53Hz, 6H) 0.81-0.91 (m, 1H)；MS:MS m/z 755.4 (M⁺+1)。

Compound 29:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamate.

¹H NMR (400MHz, CD₃OD): δ ppm 8.25 (s, 1H) 7.84 (d, J=9.03Hz, 1H) 7.33 (d, J= 2.51Hz, 1H) 7.26 (dd, J=9.03,2.76Hz, 1H) 5.88 (br.s., 1H) 5.29 (br.s., 1H) 4.71 (d, J= 11.54Hz, 1H) 4.56-4.64 (m, 1H) 4.16 (br.s., 1H) 3.98 (s, 3H) 3.88 (d, J=10.29Hz, 1H) 2.94 (br.s., 1H) 2.68 (dd, J=13.43,7.91Hz, 2H) 2.50 (br.s., 1H) 1.95-2.00 (m, 1H) 1.73-1.89 (m, 3H) 1.62 (br.s., 2H) 1.32 (d, J=12.05Hz, 4H) 1.20-1.27 (m, 1H) 1.13 (s, 12H) 0.93-0.97 (m, 7H)；MS:MS m/z 755.4 (M⁺+1)。

Compound 30 and the preparation of compound 31

Use intermediate described herein and follow the general program system illustrated for synthesis compound 7 and compound 8 Standby compound 30 and compound 31.

Compound 30:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.89 (s, 1H) 8.26 (s, 1H) 7.87 (d, J=9.03Hz, 1H) 7.25-7.35 (m, 2H) 5.88 (d, J=2.76Hz, 1H) 5.33-5.41 (m, 1H) 5.03 (dd, J=10.67,7.15Hz, 1H) 4.76-4.81 (m, 1H) 4.69 (t, J=8.41Hz, 1H) 3.96-4.07 (m, 4H) 3.81 (d, J=10.79Hz, 1H) 3.23 (br.s., 2H) 2.90-3.00 (m, 1H) 2.66 (d, J=6.02Hz, 2H) 2.29-2.38 (m, 1H) 1.54-1.82 (m, 5H) 1.40 (d, J=6.27Hz, 1H) 1.28-1.35 (m, 3H) 1.25 (s, 3H) 1.03-1.22 (m, 5H) 0.84-1.02 (m, 7H)； MS:MS m/z 809.2 (M⁺+1)。

Compound 31:(2R, 6S, 7R, 11S, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.27 (s, 1H) 7.86 (d, J=9.03Hz, 1H) 7.33 (d, J= 2.76Hz, 1H) 7.27 (dd, J=9.29,2.76Hz, 1H) 5.86 (br.s., 1H) 5.30 (br.s., 1H) 4.57-4.77 (m, 2H) 4.15 (br.s., 1H) 3.93-4.04 (m, 4H) 3.84 (d, J=10.79Hz, 1H) 2.94 (br.s., 1H) 2.63-2.74 (m, 2H) 2.51 (d, J=14.31Hz, 2H) 1.98 (s, 1H) 1.72-1.91 (m, 3H) 1.62 (br.s., 2H) 1.32 (d, J= 12.30Hz, 4H) 1.28 (s, 3H) 1.22 (s, 3H) 1.10 (d, J=4.52Hz, 3H) 0.95 (t, J=6.02Hz, 6H)；MS:MS m/z 807.2(M⁺-1)。

The preparation of compound 32

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 32.

Compound 32:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(6-methoxyl group quinoxaline-2-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10, 11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-base Carbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.88 (s, 1H) 8.39 (s, 1H) 7.92 (s, 1H) 7.83 (d, J= 9.03Hz, 1H) 7.39-7.45 (m, 2H) 5.86 (br.s., 1H) 5.34-5.40 (m, 1H) 5.03 (dd, J=10.79, 7.78Hz, 2H) 4.66-4.77 (m, 2H) 4.02 (dd, J=11.92,3.39Hz, 1H) 3.78-3.84 (m, 1H) 3.20 (br.s., 1H) 2.91-2.98 (m, 1H) 2.63-2.68 (m, 2H) 2.29-2.35 (m, 1H) 1.55-1.80 (m, 5H) 1.39 (br.s., 1H) 1.28-1.35 (m, 2H) 1.24-1.28 (m, 4H) 1.22 (s, 3H) 1.04-1.20 (m, 4H) 0.99 (d, J= 6.53Hz, 3H) 0.94 (d, J=6.53Hz, 3H) 0.87 (br.s., 1H)；MS:MS m/z 809.4 (M⁺+1)。

The preparation of compound 33

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 33.

Compound 33:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(7-fluoro-4,6-dimethoxy-isoquinoline-1-base epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7, 8,9,10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diazacyclo 15 Alkene-6-aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 7.74 (d, J=11.54Hz, 1H) 7.57 (d, J=8.28Hz, 1H) 7.54 (s, 1H) 5.81 (br.s., 1H) 5.37 (t, J=10.42Hz, 1H) 5.02 (dd, J=10.42,7.40Hz, 1H) 4.64- 4.71 (m, 2H) 4.03 (d, J=1.25Hz, 6H) 3.95-4.00 (m, 1H) 3.82-3.87 (m, 1H) 3.22 (d, J=6.53Hz, 1H) 2.90-2.97 (m, 1H) 2.57 (d, J=4.27Hz, 2H) 2.31-2.38 (m, 1H) 1.74-1.82 (m, 1H) 1.70 (dd, J =8.03,5.27Hz, 1H) 1.57-1.66 (m, 3H) 1.38 (s, 3H) 1.23-1.33 (m, 3H) 1.10-1.22 (m, 3H) 1.02- 1.09 (m, 4H) 0.98 (dd, J=6.53,3.76Hz, 6H) 0.93 (d, J=6.53Hz, 1H)；MS:MS m/z 856.2 (M⁺+ 1)。

The preparation of compound 34

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 34.

Compound 34:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-14a-(Cyclopropylsulfonyl carbamyl Base)-2-(isoquinolyl-1 epoxide)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14, 14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6-aminocarbamic acid 1, 1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.22 (d, J=8.78Hz, 1H) 8.00 (d, J=6.02Hz, 1H) 7.92 (s, 2H) 7.83 (d, J=8.03Hz, 1H) 7.72 (td, J=7.53,1.25Hz, 1H) 7.54 (t, J=7.15Hz, 1H) 7.34 (d, J=5.77Hz, 1H) 5.90 (br.s., 1H) 5.36 (t, J=10.04Hz, 1H) 5.04 (br.s., 2H) 4.72- 4.81 (m, 3H) 4.62 (s, 1H) 4.01 (br.s., 1H) 3.85 (d, J=10.79Hz, 1H) 2.94 (br.s., 1H) 2.61- 2.76 (m, 2H) 1.74-1.82 (m, 1H) 1.68-1.73 (m, 1H) 1.64 (dd, J=9.54,5.27Hz, 3H) 1.41 (br.s., 1H) 1.30 (s, 3H) 1.23-1.28 (m, 1H) 1.19 (d, J=8.28Hz, 4H) 0.98 (dd, J=9.03,6.53Hz, 6H) 0.90-0.94 (m, 1H) 0.87 (s, 3H)；MS:MS m/z 776.2 (M⁺-1)。

The preparation of compound 35

Use intermediate described herein and prepare chemical combination by following the general program illustrated for synthesis compound 7 Thing 35.

Compound 35:(2R, 6S, 7R, 11R, 13aS, 14aR, 16aS, Z)-2-(4-methoxyisoquinoliae-1-base epoxide)- 7,11-dimethyl-14a-(1-methylcyclopropyl groups sulfuryl amino formoxyl)-5,16-dioxo-1,2,3,5,6,7,8,9, 10,11,13a, 14,14a, 15,16,16a-ten hexahydro rings third also [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] diaza cyclopentadecylene-6- Aminocarbamic acid 1,1,1-tri-fluoro-2-methyl-prop-2-base ester.

¹H NMR (400MHz, CD₃OD): δ ppm 8.14 (dd, J=17.69,8.16Hz, 2H) 7.74 (ddd, J= 8.28,7.03,1.25Hz, 1H) 7.55-7.59 (m, 2H) 5.83 (br.s., 1H) 5.36 (t, J=10.29Hz, 1H) 5.03 (br.s., 1H) 4.74 (d, J=10.29Hz, 2H) 4.03 (s, 3H) 3.86 (d, J=10.54Hz, 1H) 3.21 (d, J= 18.07Hz, 1H) 2.58-2.74 (m, 2H) 2.34 (br.s., 1H) 1.74-1.83 (m, 1H) 1.56-1.70 (m, 5H) 1.53 (s, 3H) 1.38-1.50 (m, 3H) 1.31-1.35 (m, 3H) 1.13-1.29 (m, 3H) 0.97 (t, J=6.02Hz, 6H) 0.90 (s, 5H)；MS:MS m/z 823.4 (M⁺+1)。

Biological study

HCV NS3/4A proteinase complex enzyme test and HCV replicon based on the cell test of the disclosure can be used, And proceed as described below preparation, implement and verify: the generation of recombinant HCV NS3/4A proteinase complex

Generation described below comes from the HCV NS3 proteinase complex of BMS strain, H77 strain or J4L6S strain.Produce these pure The recombinant protein changed, for homogeneous test method(s) (homogeneous assay) (seeing below), to provide the compound of the disclosure To the most effectively suppress the instruction of HCV NS3 proteolytic activity.

From Dr.T.Wright, San Francisco hospital (San Francisco Hospital) obtains to be felt from HCV- The serum of dye patient.From by the DNA fragmentation obtained by the reverse transcription-pcr (RT-PCR) of serum RNA (ribonucleic acid), and make With the primer selected based on homology between other genotype 1a strain, structure HCV genome (BMS strain) engineered entirely Long cDNA (complementary DNA (cDNA)) template.Classification method according to Simmonds et al. (sees PSimmonds, KA Rose, S Graham, SW Chan, F McOmish, BC Dow, EA Follett, PL Yap and H Marsden, J. Clin.Microbiol., 31 (6), 1493-1503 (1993)), from measuring whole genome sequence, genotype 1a is belonged to HCV separator.Have according to aminoacid sequence and HCV genotype 1a (H77) of display non-structural region NS2-5B that ＞'s 97% is same Property and have the homogeneity of 87% with genotype 1b (J4L6S).Obtaining infection clone from R.Purcell (NIH) is H77 (1a gene Type) and J4L6S (1b genotype), and sequence announce in Genbank (AAB67036, sees Yanagi, M., Purcell, R.H., Emerson, S.U. and Bukh, J.Proc.Natl.Acad.Sci.U.S.A.94 (16), 8738-8743 (1997)； AF054247, sees Yanagi, M., St Claire, M., Shapiro, M., Emerson, S.U., Purcell, R.H. and Bukh, J., Virology 244 (1), 161-172. (1998)).

It is used for H77 and J4L6S strain producing recombinant NS3/4A proteinase complex.As (seen by P.Gallinari etc. Gallinari P, Paolini C, Brennan D, Nardi C, Steinkuhler C, De Francesco R.Biochemistry.38 (17): 5620-32, (1999)) describe, manipulation encodes the recombinant HCV NS3/4A of these strains The DNA of proteinase complex (amino acid/11 027-1711).Increase in short, 3 '-end in NS4A coding region adds three lysines Molten tail (solubilizing tail).Cysteine in the P1 position of NS4A-NS4B cracking site (amino acid/11 711) is changed Become glycine, to avoid the Proteolytic enzyme of lysine tails (tag).Additionally, introduce half by PCR at amino acid position 1454 Cystine is to mutant serine, to prevent autolytic cleavage in NS3 unwindase territory.At pET21b bacterial expression vector (Novagen) clonal vaviation DNA fragmentation in, and describe according to P.Gallinari et al., modified code (sees Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, Steinkuhler C, De Francesco R., J Virol.72 (8): 6758-69 (1998)), at escherichia coli (Escherichia.coli) strain BL21 (DE3) (Invitrogen) NS3/4A complex is expressed in.In short, with 0.5 mM of (mM) isopropyl ss-D-1-sulfur generation at 20 DEG C Noside (thiogalactopyranoside, IPTG) induction NS3/4A proteinase complex is expressed 22 hours.Allusion quotation The fermentation (1 liter (L)) of type produces about 10 grams of (g) wet cells and sticks with paste (wet cell paste).Described cell is resuspended in molten In born of the same parents' buffer (10mL/g), described lysis buffer is by 25mMN-(2-hydroxyethyl) piperazine-N '-(2-ethanesulfonic acid) (HEPES), pH7.5,20% glycerol, 500mM sodium chloride (NaCl), 0.5%Triton X-100,1 mcg/ml (" μ g/ ML ") lysozyme, 5mM magnesium chloride (MgCl₂), 1 μ g/ml Dnasel, 5mM beta-mercaptoethanol (β ME) composition, press down without protease Preparation-ethylenediaminetetraacetic acid (EDTA) (Roche), is homogenized at 4 DEG C and cultivates 20 minutes (min).This homogenate is through at 4 DEG C Under, the 235000g ultracentrifugation supersound process of 1 hour and clarification.Adding imidazoles to ultimate density in supernatant is 15mM, and PH value is regulated to 8.0.This crude protein extract is carried in buffer B (25mMHEPES, pH8.0,20% the third three Alcohol, 500mM NaCl, 0.5%Triton X-100,15mM imidazoles, 5mM β ME) nickel-nitrilotriacetic acid(NTA) (Ni-of pre-equilibration NTA) on post.Flow velocity load sample with 1mL/min.(identical with buffer B, but contain with the buffer C of 15 times of column volumes 0.2%Triton X-100) wash this post.With the buffer D of 5 times of column volumes (identical with buffer C, but the imidazoles Han 200mM) This protein of eluting.

Collect the part containing NS3/4A proteinase complex, and load it with buffer D (25mM HEPES, PH7.5,20% glycerol, 300mM NaCl, 0.2%Triton X-100,10mM β ME) desalting column of pre-equilibration On Superdex-S200.Flow velocity load sample with 1mL/min.Collect the part containing NS3/4A proteinase complex and concentrate To about 0.5mg/ml.Judged, derived from the NS3/4A albumen of BMS, H77 and J4L6S strain by SDS-PAGE and mass spectral analysis The purity of multienzyme complex is more than 90%.At this enzyme is stored in-80 DEG C, in defrosting on ice and before the use at test buffer Middle dilution.

FRET peptide method of inspection is to monitor HCV NS3/4A proteolytic activity

The purpose of this tested in vitro method be the compound of the detection disclosure to as above derived from BMS strain, H77 strain Or the suppression of the HCV NS3 proteinase complex of J4L6S strain.This method of inspection provides the compound of the disclosure the most effectively to press down The instruction of HCV NS3 proteolytic activity processed.

In order to monitor HCV NS3/4A proteinase activity, use NS3/4A peptide substrates.This substrate is that Taliani et al. exists RET S1 (Resonance energy transfer depsipeptides substrate described in Anal.Biochem.240 (2): 60-67 (1996) (Resonance Energy Transfer Depsipeptide Substrate)；AnaSpec, Inc.cat#22991) (FRET peptide).The sequence of this peptide is generally based on the NS4A/NS4B nature cracking site of HCV NS3 protease, simply in this cracking There is ester bond rather than amido link in site.This peptide also contains fluorogenic donor EDANS near an end of peptide, and at another end Containing receptor DABCYL near end.The fluorescence of (RET) quencher peptide is shifted by the intermolecular resonant energy between donor and receptor, But along with this peptide of NS3 protease cracking, the fluorescence discharging product and donor from RET quencher becomes obvious.

In the case of the compound of the presence or absence disclosure, with three kinds of recombinant NS3/4A proteinase complex it One cultivates peptide substrates.By using Cytofluor Series 4000 to monitor the formation of fluorescence reaction product in real time, measure chemical combination The depression effect of thing.

Reagent is as follows: HEPES and glycerol (Ultrapure) obtain from GIBCO-BRL.Dimethyl sulfoxide (DMSO) is certainly Sigma obtains.Beta-mercaptoethanol obtains from Bio Rad.

Test buffer: 50mM HEPES, pH7.5；0.15M NaCl；0.1%Triton；15% glycerol；10mM β ME.Substrate: 2 μMs of ultimate densities (the 2mM stock solution in DMSO from being stored in-20 DEG C).HCV NS3/4A albumen Enzyme 1a (1b) type, 2-3nM ultimate density (5 μMs of stock solutions in next comfortable 25mM HEPES, pH7.5,20% glycerol, 300mM NaCl, 0.2%Triton-X100,10mM β ME).Potency is limited to the change of (assay limit) close to inspection Compound, by adding 50 μ g/ml fetal bovine serum albumin (Sigma) and being down to by final protease concentration in test buffer 300pM makes this inspection more sensitive.

Testing in the 96 hole polystyrene blackboards of Falcon.25 μ l in test buffer are contained in each hole Compound and the 25 μ l of NS3/4A proteinase complex, the 50 μ l disclosure in 10%DMSO/ test buffer are slow in test Rush the substrate in liquid.Also on identical inspection panel, prepare tester (without compound).By this multienzyme complex and compound or right According to solution mixing 1min, then cause enzymatic reaction by interpolation substrate.Use CytofluorSeries 4000 immediately (Perspective Biosystems) reads inspection panel.It is set as this instrument launching wavelength 340nm and excitation wavelength 490nm, reads data at 25 DEG C.Reaction generally carries out about 15min.

Calculate by following equation and suppress percentage ratio:

100-[(δF_inh/δF_con)x100]

Change in fluorescence in wherein δ F is the range of linearity of this curve.Suppression-concentration data application nonlinear curve is intended Close, and use formula y=A+ ((B-A)/(1+ ((C/x) ^D))), by Excel XLfit computed in software 50% valid density (IC₅₀)。

It has been found that disclosure compound, the suppression of its tested NS3/4A complex to more than one type, there is class Like inhibition activity, although described compound shows without exception to the 1b strain comparison higher potency of 1a strain.

The generation of HCV replicon

As by Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R., Science 285 (5424): 110-3 (1999) describes, and sets up the full cell system of HCV replicon, and modified glimmering to introduce Light element enzyme reporter gene, as Krieger etc. illustrate first (Krieger N, Lohmann V and Bartenschlager R, J.Virol.75 (10): 4614-4624 (2001)).Directly use in the upstream of neomycin marker gene and be positioned in core Ascl restriction site, by the CDNA of the Renilla luciferase gene of encoding human source form and be directly fused to fluorescein Connexon (linker) sequence of 3 '-end of enzyme gene introduces in replicon construct (construct).It is also introduced into 1179 Adaptive mutation (serine is to isoleucine) (Blight KJ, KolykhaloV, AA, Rice, CM, Science 290 (5498): 1972-1974).By first making plasmid DNA and ScaI linearisation produce this HC V replicon structure of constructive expression Build the stable cell lines of body.According to preparation business description use T7MegaScript transcript reagent box (Ambion, Austin, TX) RNA transcript is in vitro synthesized.The in vitro transcription thing of cDNA is transfected in human liver cell oncocyte system HUH-7.Optional In the presence of the label neomycin (G418) selected, it is achieved the selection of the cell of constructive expression's HCV replicon.Pushing away in time Move and produce for normal chain and strand RNA and protein generation, the cell line obtained by sign.

Produce represent the H77 strain of genotype 1a stable HCV replicon luciferase reporter gene cell line (Yanagi M, Purcell RH, Emerson SU etc., the transcript from the strand full length cDNA clone of hepatitis C virus is directly being transcribed Entering in chimpanzee liver is infectious (Transcripts from a single full-length cDNA clone of hepatitis C Virus are infectious when directly transfected into the liVer of a chimpanzee).Proc Natl Acad Sci USA 1997；94 (16): 8738-8743), as previously for gene Type 1b (Con1) replicon luciferase cell line is illustrated.Replicon construct is modified, by described by introducing sudden change Sudden change introduces coding NS3 helicase domain (being substituted at 1496 proline) and NS5A by leucine (at 2204 serines To isoleucine) gene in, with improve cell cultivate in duplication.

HCV replicon luciferase reporter gene is analyzed

Exploitation HCV replicon luciferase assay is sick to HCV genotype 1a and 1b with compound described in the monitoring disclosure The depression effect that poison replicates.Make the HUH-7 cell of constructive expression's HCV replicon containing 10% hyclone (FCS) (Sigma) and 1mg/mL G418 (Gibco-BRL) Dulbecco ' s improve Eagle culture medium (Dulbecco ' s Modified Eagle Media, DMEM) (Gibco-BRL) middle growth.In DMSO, compound serial dilution 3 is used for 20 again Point titration, is subsequently transferred to aseptic 384 hole tissue culture treated plates (Corning catalog number 3571).Then thin with 50 μ L Born of the same parents are with 3.0 × 10³DMEM in described plate is inoculated by the density of individual cells/well, and it is (final that described DMEM contains 4%FCS DMSO concentration is 0.5%).After cultivating 3 days at 37 DEG C, use EnduRen as substrate (Promega catalog number E6485) Analyze the Renilla uciferase activity of cell.EnduRen substrate is diluted in DMEM, is then added in described plate extremely The ultimate density of 7.5 μMs.At 37 DEG C, described plate is cultivated 2hr, uses light-emitting procedure to utilize Viewlux immediately after Imager (Perkin Elmer) reading 30 seconds.For evaluating the cytotoxicity of compound, utilize Cell Titer-Blue The plate that (Promega, catalog number G8082) contains EnduRen by multiplexing produces CC₅₀Value.By Cell-Titer Blue (3 μ L) adds cultivation 8hr to each hole and at 37 DEG C.Viewlux Imager is used to read swashing from each hole Sending out wavelength is 525/10nm and the fluorescence signal of a length of 598/10nm of transmitted wave.

By using the EC of four parameter logistic equation computerized compounds₅₀Value:

Y=A+ ((B-A)/(1+ ((C/x) ^D))),

Wherein A and B represents that minimum and maximum % suppresses respectively, and C is EC₅₀, D is hill slope (hill slope) and x generation Table compound concentration.

Table 2 shows the EC of the representative compound of the disclosure₅₀Value.Scope is as described below: A=0.20nM-1.0nM；B= 1.01nM-2.0nM；C=2.01nM-5.0nM；D=5.01nM-68nM.

Table 2

Compound number	Genotype 1a EC₅₀(nM)	Genotype 1b EC₅₀(nM)
			3	A	A
4	4.9	2.8
			5	0.41	1.2
6	B	C
			7	B	A
8	C	B
			9	1.0	0.36
11	C	A
			12	C	B
13	D	C
			14	C	B
15	B	B
			17	D	D
18	D	D
			19	C	B
21	B	A
			22	B	A
23	D	D
			24	D	D
25	B	A
			26	214.8	86.5
27	D	D
			28	D	B
29	D	D
			30	C	A
31	D	D
			32	D	D
33	C	B

34	C	A
			35	1.96	0.51

It will be apparent to one skilled in the art that the disclosure is not limited to foregoing illustrative embodiment, Er Qieke To be embodied in other concrete form without departing from its essential characteristics.It is therefore contemplated that each embodiment is the most all regarded Explaining property and nonrestrictive, should refer to appended claims rather than previous embodiment, therefore, in appended right All changes in the implication of claim equivalents and scope are intended to be included herein.

Claims

1. formula (I) compound,

Or its pharmaceutically acceptable salt, wherein

Q is 1；

-----It it is double bond；

R^pIt is selected from

Wherein R^pIt is connected to parent molecular moiety by the arbitrary commutable carbon atom in this group；

N is 0,1,2,3,4,5 or 6；

X⁰Selected from CH and N；

X¹Selected from CH and N；

X²Selected from CH and C (R^a)；

X³Selected from CH, C (R^a) and N；Condition is X¹And X³In at least one be not N；

Each R^aIndependently selected from alkoxyl and halogen；

R^xSelected from methyl and ethyl；

R^yAnd R^zIt is respectively hydrogen；

R²Selected from hydrogen, alkyl and haloalkyl；And

R³Selected from alkoxy carbonyl and halo alkoxy carbonyl；

Wherein " alkyl " refers to the group derived from the straight or branched saturated hydrocarbons containing 1 to 10 carbon atom, and " alkoxyl " is Refer to be connected to the alkyl of parent molecular moiety by oxygen atom.

2. the compound of claim 1, or its pharmaceutically acceptable salt, wherein R^xIt it is methyl.

3. the compound of claim 2, or its pharmaceutically acceptable salt, wherein

N is 0,1,2 or 3.

4. formula (II) compound,

Or its pharmaceutically acceptable salt, wherein

N is 0,1,2,3,4,5 or 6；

Each R¹Independently selected from alkoxyl and halogen；

R²Selected from hydrogen, alkyl and haloalkyl；And

R³Selected from alkoxy carbonyl and halo alkoxy carbonyl.

5. a compound, it is selected from

Or its pharmaceutically acceptable salt.

6. a compositions, it comprises the compound according to any one of claim 1-5 or its pharmaceutically acceptable salt and medicine Acceptable carrier on.

7. the compositions of claim 6, it comprises at least one other compound with anti-HCV activity further.

8. the compositions of claim 7, at least one in other compound wherein said is interferon or ribavirin.

9. the compositions of claim 8, wherein this interferon is selected from interferon-ALPHA 2B, glycol interferon alpha, composite interference Element, interferon-ALPHA 2A and lymphoblastoid interferon-tau.

10. the compositions of claim 7, at least one in other compound wherein said is selected from interleukin-22, interleukin 6, white Interleukin 12, imiquimod, ribavirin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.

The compositions of 11. claim 7, the effectively suppression of at least one in other compound wherein said is selected from following target Function to treat HCV infection: HCV metalloproteases, HCV serine protease, HCV polymerase, HCV unwindase, HCV NS4B albumen, HCV entrance, HCV assembling, HCV abjection, HCV NS5A albumen and IMPDH.

12. compound or its pharmaceutically acceptable salt according to any one of claim 1-5 are used for treating HCV infection in preparation Purposes in the medicine of patient.

The purposes of 13. claim 12, wherein this medicine further contained in give any one of claim 1-5 compound or At least one given before its pharmaceutically acceptable salt, afterwards or simultaneously has other compound of anti-HCV activity.

The purposes of 14. claim 13, at least one in other compound wherein said is interferon or ribavirin.

15. the purposes of claim 14, wherein said interferon is selected from interferon-ALPHA 2B, glycol interferon alpha, composite dry Disturb element, interferon-ALPHA 2A and lymphoblastoid interferon-tau.

The purposes of 16. claim 13, at least one in other compound wherein said is selected from interleukin-22, interleukin 6, white Interleukin 12, imiquimod, ribavirin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.

The purposes of 17. claim 13, the effectively suppression of at least one in other compound wherein said is selected from following target Function to treat HCV infection: HCV metalloproteases, HCV serine protease, HCV polymerase, HCV unwindase, HCV NS4B albumen, HCV entrance, HCV assembling, HCV abjection, HCV NS5A albumen and IMPDH.