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WO2017114509A1 - 醛基类化合物及其制法和用途 - Google Patents

醛基类化合物及其制法和用途 Download PDF

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WO2017114509A1
WO2017114509A1 PCT/CN2016/113835 CN2016113835W WO2017114509A1 WO 2017114509 A1 WO2017114509 A1 WO 2017114509A1 CN 2016113835 W CN2016113835 W CN 2016113835W WO 2017114509 A1 WO2017114509 A1 WO 2017114509A1
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group
compound
synthesis
straight
substituted
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PCT/CN2016/113835
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English (en)
French (fr)
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柳红
年永
李建
希尔根菲尔德饶福
林岱宗
刘海龙
周宇
蒋华良
陈凯先
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中国科学院上海药物研究所
吕贝克大学生物化学学院
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Publication of WO2017114509A1 publication Critical patent/WO2017114509A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to aldehyde-based compounds as enterovirus proteases or coronavirus main protease inhibitors, processes for their preparation, pharmaceutical compositions containing such compounds, and uses.
  • Infectious diseases caused by enteroviruses are common in children. Its clinical features are mild patient burnout, fatigue, low fever, etc. Severe patients can be infected with the whole body, and the vital organs such as brain, heart, liver and spinal cord are damaged, and the sequelae are worse and severe. These diseases are spread all over the world and have a high incidence in humid, warm, poorly populated areas and densely populated areas. Some viruses are often prevalent, and the prevalence in different years can be caused by different types of viruses, and some viruses have a periodicity.
  • EV71 and CVA16 are highly homologous in evolution. Both viruses belong to the family Picaraviridae, Enterovirus, and Human enterovirus A in their taxonomic status. Generally, the clinical symptoms caused by CVA16 infection are milder and less associated with neurological diseases. In addition to causing hand, foot and mouth disease, EV71 often causes serious central nervous system diseases such as encephalitis, meningitis, aseptic meningitis, and acute Delayed paralysis, etc., more serious can lead to pulmonary edema and heart failure, and the mortality rate is extremely high.
  • Enterovirus is a naked virion with a icosahedral structure. Because it is coated with a lipid-free outer membrane, conventional disinfectants are not effective in inactivating the virus. Although the two pathogens are sensitive to temperature, they are completely inactivated at 56 ° C for 30 min, but the virus can survive for several weeks at 4 ° C, and can survive for several years at -20 ° C, and can survive for a long time in the natural environment. Therefore, it is difficult to effectively prevent and control enterovirus infection.
  • the enterovirus is a single strand of sense strand RNA, which has 5'- and 3'-untranslated regions at both ends, and a viral protein coding region in the middle.
  • the coding region contains only one open reading frame, so the original translation product of the virus is a polyprotein precursor with a molecular weight of about 243 kDa.
  • the polyprotein needs to be further cleaved by the virus's own encoded 2A and 3C proteases and processed into 11 mature functional protein subunits (Vp1-Vp4, 2A-2C, 3A-3D) to complete viral replication and assembly.
  • the 2A protease is responsible for the cleavage of the Vp1/2A junction sequence; the 3C protease is responsible for the cleavage of the other 8 sites in the polyprotein (including Vp2/Vp3, Vp3/Vp1, 2A/2B, 2B/2C, 2C/3A, 3A).
  • /3B, 3B/3C, 3C/3D junction sequence because it can recognize multiple different sites, plays a major role in the processing of viral polyprotein precursors, so 3C protease is also called primary protease.
  • the 3C protease also has RNA binding activity. Shin-Ru13 et al.
  • EV71 3C can directly participate in viral replication by binding to the 5'-UTR of the viral genome through two functional motifs, "KFRDI” and "VGK".
  • 3C protease promotes virus proliferation by interacting with various host factors.
  • the host's own protein translation system is shut down by cleavage of the CstF-64 host factor, providing more raw material for viral protein synthesis.
  • the production of the host antiviral factor interferon beta (IFN-[beta]) is inhibited by binding to retinoic acid-inducible gene I (RIG-I).
  • 3C protease inhibitors have the potential to be used in clinical and treatment of diseases associated with enterovirus infections such as hand, foot and mouth disease.
  • the chiral carbon atoms C*, C* 2 , C* 3 are each independently S-type, R-type, or a combination thereof;
  • n 0 or 1;
  • X is CH 2 or NR 5 ;
  • R 1 is selected from the group consisting of unsubstituted or substituted with 1 to 3 substituents: C 3 -C 7 cycloalkyl, trifluoromethyl, C 2 -C 6 alkynyl, 4 to 7-membered heterocyclic, C 5 -C 7 An aryl group, a 5- to 7-membered heteroaryl group; the heteroaryl group having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituents are each independently selected from the group consisting of halogen, C1 to C4 Linear or branched alkyl, C1-C4 straight or branched alkenyl, C2-C4 straight or branched alkynyl, C1-C4 straight or branched alkoxy, C1-C4 straight or branched Alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, decyl, C1-C4 acyl
  • R 2 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: a C 3 -C 7 cycloalkyl group, a 5 to 12 membered heterocyclic group (preferably a 5 to 7 membered heterocyclic group or a 6-membered aryl group) And a 5- to 7-membered heterocyclic group), a C6-C12 aryl group, a 5- to 12-membered heteroaryl group, or a -Cbz; wherein each of the heterocyclic or heteroaryl groups has 1 to 3 selected from the group consisting of oxygen and sulfur.
  • the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl , C1-C6 linear or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxyl, fluorenyl, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two adjacent substituents together with a carbon atom to which they are attached constitute a 5-7 membered ring;
  • R 3 is a C1-C6 alkylene group which is unsubstituted or substituted by 1 to 3 substituents; the substituents are each independently selected from a C1 to C6 straight or branched alkyl group, a C1 to C6 straight chain or a branched alkoxy group, a substituted or unsubstituted C3 to C7 cycloalkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, said heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; wherein the cycloalkyl, aryl and heteroaryl groups are one or more selected from halogen, C1-C6 straight or branched alkyl, cyano Substituting a group of a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoro
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, a C3-C7 cycloalkyl group, a C1-C6 acyl group, a C5-C7 aryl group, a benzyl group or a 5- to 7-membered heteroaryl group; the heteroaryl group having 1-3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the aryl, benzyl or 5- to 7-membered heteroaryl is optionally selected from one or more selected from the group consisting of halogen, C1-C6 straight or branched hydrocarbon, cyano, nitro, amino, hydroxy, hydroxy
  • R 1 is a substituted or unsubstituted phenyl group, preferably an unsubstituted phenyl group.
  • R 2 is a 5-6 membered heterocyclic group containing benzene, N, O or S, preferably a 5-6 membered heterocyclic group having a benzo N group.
  • Y is -CON(R 4 )R 3 -;
  • R 1 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: trifluoromethyl, alkynyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, phenyl , thienyl, pyrazolyl, thiazolyl, pyridyl, furyl.
  • the chiral carbon atoms C* and C* 2 are S-type, and the chiral carbon atom C* 3 is S-type, R-type, or a combination thereof;
  • R 3 is unsubstituted or substituted with 1-3 substituents of C1 ⁇ C6 alkylene; and the substituents are each independently selected from C1 ⁇ C6 straight or branched chain alkyl, C1 ⁇ C6 straight or Branched alkoxy, substituted or unsubstituted C3 to C7 cycloalkyl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, a C1-C4 straight or branched alkyl group, a C2-C4 straight or branched alkenyl group, and a C2-C4 straight or branched alkynyl group.
  • n 1;
  • R 3 is a C1-C3 alkylene group which is unsubstituted or substituted with 1-3 substituents; the substituents are each independently selected from the group consisting of C1-C6 straight or branched alkyl groups, substituted or not Substituted C3-C6 cycloalkyl; said alkyl or cycloalkyl optionally being selected from one or more selected from the group consisting of halogen, C1-C4 straight or branched alkyl, cyano, nitro, amino, hydroxy
  • the group consisting of a methylol group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a C1-C4 alkoxy group, a fluorenyl group, and a C1-C4 acyl group is substituted.
  • n 0;
  • X is NR 5 ;
  • R 1 is a group selected from the group consisting of unsubstituted or substituted with 1 to 3 substituents: cyclopentyl, cyclohexane, phenyl, thienyl;
  • R 2 is a group selected from the group consisting of phenyl, benzoheterocyclyl, 5- to 12-membered heteroaryl which is unsubstituted or substituted by 1 to 3 substituents; preferably, the benzoheterocycle And a 5- to 12-membered heteroaryl ring is selected from the group consisting of benzodioxole, hydrazine, isoxazole, 2-hydropropran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzo Thiophene, dihydrobenzodioxane, quinoxaline, benzofuran, carbazole, benzimidazole, quinoline;
  • R 5 is selected from the group consisting of hydrogen, a C1 to C4 linear or branched alkyl group, a C2 to C4 linear or branched alkenyl group, and a C2 to C4 linear or branched alkynyl group.
  • the aldehyde group compound is selected from the compounds shown in Table A.
  • the condensing agent is EDCI (1-ethyl-(3-dimethyl) Aminopropyl)carbodiimide hydrochloride);
  • each group is as defined in the first aspect of the invention.
  • the step (3) is carried out in the presence of a base, and the base is selected from the group consisting of sodium hydrogencarbonate or triethylamine.
  • a pharmaceutical composition comprising: a therapeutically effective amount of one or more compounds of the formula (I) according to the first aspect of the invention, or A pharmaceutically acceptable salt.
  • a pharmaceutical composition for the preparation of a disease associated with the treatment or prevention of an enterovirus infection in a third aspect of the invention, there is provided a pharmaceutical composition for the preparation of a disease associated with the treatment or prevention of an enterovirus infection.
  • the pharmaceutical composition is for inhibiting enterovirus and coronavirus replication; preferably, the pharmaceutical composition is for inhibiting enterovirus 3C protease.
  • the related diseases caused by the enterovirus infection include: respiratory tract infection, herpetic angina, epidemic rash, hand, foot and mouth disease or meningitis.
  • a compound of formula (I) according to the first aspect of the invention for the manufacture of a medicament for inhibiting replication of enteroviruses and coronaviruses.
  • the present inventors After long-term and intensive research, the present inventors have prepared a class of compounds of formula I which are capable of inhibiting the replication of enteroviruses and coronaviruses. And the compound has higher inhibitory activity than the enterovirus and coronavirus replication inhibiting compounds of the prior art. Based on the above findings, the inventors completed the present invention.
  • An object of the present invention is to provide an aldehyde group compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer or a racemate.
  • Another object of the present invention is to provide a process for producing a compound of the above formula (I).
  • a further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the above formula (I) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a compound of the above formula (I) for the preparation of a disease associated with infection caused by an enterovirus, such as respiratory infection, herpetic angina, epidemic rash, hand, foot and mouth disease, Use in drugs such as meningitis.
  • an enterovirus such as respiratory infection, herpetic angina, epidemic rash, hand, foot and mouth disease
  • the compounds of the invention are useful for inhibiting enterovirus and coronavirus replication, particularly against enterovirus 3C protease.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 naphthenic a group, a C 1 -C 10 alkoxy group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C 1 -C 10 aldehyde group, a C 2 -C 10 acyl group, a C 2 -C 10 ester group, an amino group, a phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 ⁇ C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • 3-8 membered heterocyclic group refers to a group formed by a 3 to 8 membered saturated ring having from 1 to 3 hetero atoms selected from the group consisting of N, S, O; for example, pyrrolidinyl group, Piperidinyl, piperazinyl, morpholinyl, or the like.
  • 6-10 membered aryl refers to a group formed by the loss of one hydrogen atom of a 6 to 10 membered aryl group; for example, a phenyl group, a naphthyl group, or the like.
  • 5-10 membered heteroaryl refers to a group of 5 to 8 membered aryl groups having from 1 to 3 heteroatoms selected from the group consisting of N, S, and O, each of which is heteroaryl.
  • the cyclic system of the group may be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, fluorenyl, imidazopyridyl, quinolyl Or a similar group.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • isomeric forms such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • a single stereochemical isomer of the compound of the invention or its enantiomer Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • the valence tautomers include interconversion through some bonding electron recombination.
  • C1 to C6 means that the group may have 1 to 6 carbon atoms, for example, 1, 2, 3, 4 or 5.
  • the present invention provides an aldehyde group compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate, a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • each group is as described above.
  • n, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 are each independently the corresponding group corresponding to each specific compound in the examples.
  • aldehyde group compounds of the present invention are preferably selected from the compounds shown in Table A below:
  • the invention also provides a process for the synthesis of a compound of formula I, in particular, wherein the compound of formula I is prepared by the following scheme:
  • Step a dissolving dimethyl tert-butoxycarbonyl glutamate in a solvent, adding -78 ° C to the base to stir, then adding bromoacetonitrile, and stirring to obtain the compound I a ,
  • the solvent is tetrahydrofuran or dioxane;
  • the base is lithium hexamethyldisilazide or lithium diisopropylamide;
  • Step b dissolving I a in a solvent, adding a catalytic amount of platinum dioxide, stirring until the reaction of the starting material is complete, filtering, adding a base, and stirring under reflux to obtain a compound I b ;
  • the base is sodium carbonate or sodium acetate;
  • the solvent It is a mixed solvent of methanol and chloroform;
  • Step c dissolving I b in a solvent, stirring until the reaction is completed, and spinning the solvent to obtain a compound I c ;
  • the solvent is a mixed solvent of dichloromethane and trifluoroacetic acid;
  • Step d the substituted carboxylic acid and I c are dissolved in a solvent, and a condensation reaction is carried out with the aid of a condensing agent to obtain a compound I d ;
  • the solvent is dichloromethane or DMF;
  • Step e dissolving the compound I d in a solvent, adding sodium borohydride, and stirring to obtain a compound I e , the solvent is methanol, tetrahydrofuran, ethanol;
  • Step f dissolving compound I e in a solvent, adding an oxidizing agent, adding a base, and stirring to obtain a final product I f
  • the solvent is dichloromethane or tetrahydrofuran
  • the oxidizing agent is Dess-Martin oxidizing agent or dimethyl sulfoxide And oxalyl chloride
  • the base is sodium hydrogencarbonate or triethylamine
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount selected from the group consisting of aldehyde-based compounds represented by formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates and solvates thereof
  • a pharmaceutically acceptable carrier useful for treating diseases associated with enterovirus and coronavirus replication.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the pharmaceutical composition of the aldehyde group compound represented by (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and one or more of the hydrates and solvates thereof can be used as an enterovirus 3C protease inhibitor for treatment Enterovirus infection or a disease associated with coronavirus infection.
  • the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by direct salt formation reaction of the free base of the compound with an inorganic or organic acid.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against enterovirus and coronavirus replication, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the present invention
  • the pharmaceutical composition of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with enterovirus and coronavirus replication, such as prevention and/or treatment of diseases associated with intestinal virus and coronavirus replication abnormalities.
  • the compounds of the present invention are useful for the treatment of respiratory tract infections, herpetic angina, epidemic rash, hand, foot and mouth disease, meningitis and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) a slow solvent such as paraffin; (f) absorption Accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the compounds according to the invention as described above can be used clinically in mammals, including humans and animals, by route of administration to the mouth, nose, skin, lungs, or gastrointestinal tract, and more preferably orally.
  • the daily dose is preferably 0.01 to 200 mg/kg body weight, taken at once, or 0.01 to 100 mg/kg body weight in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc. They are all within the skill of a skilled physician.
  • the analytical data of the samples were determined by the following instruments: NMR was determined by GEMINI-300, Bruker AMX-400 and INVOA-600 NMR, TMS (tetramethylsilane) was used as internal standard, and the chemical shift was in ppm. The constant unit is Hz; the mass spectra were determined by Finnigan Model MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
  • N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester (1-1) (6 g, 21.8 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and LiHMDS was slowly dropped at -78 °C.
  • the compound 1-5 (2.6 g) was dissolved in a solution of trifluoroacetic acid in dichloromethane (1/1, v/v), stirred at room temperature for 1 hour, concentrated, and then added with 100 ml of dichloromethane and washed with saturated sodium carbonate. The layer was dried over anhydrous sodium sulfate and evaporated.
  • the oily intermediate obtained in the above step was dissolved in a mixed solution of methanol/water (1:2, v/v), and 3 equivalents of a 1 M aqueous sodium hydroxide solution was added thereto, and stirred at room temperature. After the TLC monitoring (ultraviolet) reaction was completed, the pH was adjusted to -2, ethyl acetate was extracted, washed with saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and evaporated.
  • D-phenylalanine (5g, 30.3mmol) was dissolved in 60mL of 48% hydrobromic acid, cooled to 0 ° C, sodium nitrite (2.6g, 37.5mmol) was added in portions, stirred at temperature for 1 hour, raised to The reaction was continued for 10 hours at room temperature. After completion of the reaction, the mixture was extracted with EtOAc EtOAc.
  • the compound 12-3 (4 g) was dissolved in 30 mL of methanol, and 1 mL of concentrated sulfuric acid was added thereto, and the mixture was heated and heated to 70 ° C for 2 hours. The methanol was evaporated to dryness, and then evaporated, evaporated, evaporated, evaporated, evaporated.
  • the diisopropylaminolithium solution (2 equivalents of LDA tetrahydrofuran solution, 19 mL) was diluted with 10 mL of tetrahydrofuran, then argon-protected, cooled to -78 ° C, tert-butyl acetate (4.87 g, 42 mmol) was added and stirred for 1 hour.
  • Add L-benzyl The reaction solution of oxycarbonylproline and CDI was controlled at -78 ° C for 2 hours. After quenching with 2 mL of water, the mixture was evaporated to EtOAc.
  • the inhibitory activity of the compound on EV71-3C protease was determined: purified 3C protease and chemically synthesized fluorescent substrate polypeptide were used.
  • the coding sequence of EV71 virus 3C protease was cloned into pET-21a vector, and the hexahistidine tag was introduced into the C-terminus of the vector by E.coli.
  • the purification of the protease was carried out by Ni-NTA affinity chromatography and Superdex. 200 molecular exclusion chromatography was completed.
  • the substrate polypeptide will use a Dabcyl-KIGNTIEALFQGPPKFRE-Edans fluorescent polypeptide corresponding to the junction sequence between EV71 2C/3A, and the detection of polypeptide cleavage is excited by 340 nm excitation light, monitored by 490 nm emission light. Synthesis of compound at each concentration after mixing with a gradient of 3C protease inhibition was determined situation polypeptide cleavage efficiency; by three independent experiments for each compound is calculated 3C protease half maximal inhibitory concentration IC 50. The experimental results are shown in Table 1.
  • the inhibitory activity of the compound on SARS (Severe Acute Respiratory Syndrom) coronavirus main protease (SARS-CoV M pro ) was determined: the enzyme level inhibitory activity against the inhibitor of 3C protease was determined by fluorescence resonance energy transfer (FRET) technique. .
  • FRET fluorescence resonance energy transfer
  • the inhibitory activity of the compound against CVB3 (Coxsachievirus B3) 3C protease was determined: 20.0 ⁇ L of buffer (20 mM Tris, 100 mM NaCl, 1 mM EDTA, 10 mM DTT, pH 7.4) was added to each well in a 96-well plate while 2.5 ⁇ L of the compound was added. (final concentrations were 100 ⁇ M, 33 ⁇ M, 11 ⁇ M, 3.7 ⁇ M, 1.2 ⁇ M, 0.4 ⁇ M, 0.13 ⁇ M, 0.004 ⁇ M, respectively) and 2.5 ⁇ L CVB3 3Cpro (final concentration 3 ⁇ M). Incubate for 10 min at 37 °C.
  • Fluorescent substrate diluted in 25 ⁇ L of buffer was then added. Fluorescence parameters were measured using a Ge n5 fluorescence spectrometer with excitation and emission wavelengths of 340 nm and 490 nm, respectively, and maintained at 37 ° C for 15 min. A negative control was used in which no compound was added to the control and the rest were identical. The data obtained were processed using the software GraphPad Prism 6.0, and the experimental results are shown in Table 3.
  • the compound was assayed for replication inhibition activity of each virus: a 96 ⁇ l/well gradient concentration of the compound was added to the 96 well, followed by the addition of 50 ⁇ l/well of virus buffer, followed by the immediate addition of 50 ⁇ l/well of the cultured RD cells (rhabdomyosarcoma cells), 37 ° C. Incubate for 3-4 days until the maximum cytopathic effect is observed.
  • the medium was aspirated, 75 ⁇ l of 5% MTS phenol red medium was added, and cultured at 37 ° C, 5% CO 2 for 1.5 hours.
  • the fluorescence value of each well at a wavelength of 498 nM was measured, and a graph of the concentration of the compound and the cell reaction was plotted. Accelrys custom software calculates the EC 50 value of the compound.
  • Some compounds were selected to test the inhibition of EV68-WT virus replication. From the above experimental results, it can be seen that the compound has a good inhibitory effect on EV68-WT virus replication, and the activity reaches the nanomolar level.
  • the compound of the present invention also has a certain inhibitory effect on the replication of MNV-CW1 virus, and the activity of some compounds is better than that of the positive compound AG7088, and the EC 50 of compounds 56 and 48 is less than 1 ⁇ mol, and the therapeutic index TI>20.
  • Compound 18 of the present invention was administered by intragastric administration and intravenous injection respectively at a dose of 10 mg/kg, a dose of 10 mL/kg, and a drug of DMSO/Tween 80/normal saline (5:5:90, v/v/v). ) formulated. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • Subcutaneous administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • 0.3 mL of blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of Compound 18 in rat plasma was determined by LC/MS/MS.
  • the plasma concentration peak time Tmax was 1 h
  • the peak concentration Cmax was 1919.4 ng/ml
  • the area under the curve was AUC0-t was 6876.0 ng ⁇ h/ml
  • the half-life t1/2 is 1.35 h.
  • AUC0-t was 23361.2 ng ⁇ h/ml
  • the absolute bioavailability of the rats after subcutaneous injection of 10 mg/kg of Compound 18 was 29.4%.

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Abstract

本发明涉及药物化学和药物治疗学领域，具体涉及作为肠道病毒蛋白酶抑制剂的通式I的化合物，同时对冠状病毒（SARS）主蛋白酶也具有显著抑制活性，可用于治疗相关疾病。本发明还涉及该类化合物的制备方法、这些化合物的药用组合物、它们的药用盐、对映体形式、非对映异构体及外消旋化合物。

Description

醛基类化合物及其制法和用途 技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及作为肠道病毒蛋白酶或冠状病毒主蛋白酶抑制剂的醛基类化合物、其制备方法、含此类化合物的药物组合物及用途。
背景技术
肠道病毒属病毒引起的传染病多发于儿童。其临床特征为轻度患者倦怠、乏力、低热等，重症患者可全身感染，脑、心、肝、脊髓等重要器官损伤，愈后较差，并有后遗症，严重者会导致死亡。此类疾病分布于全球各地，在潮湿温暖﹑卫生条件差﹑人口密集地区发病率高。有些病毒的感染常发生流行，不同年份的流行可由不同种型的病毒引起，有些病毒感染的流行有周期性。
其中近些年在亚太地区大规模爆发的手足口病便是由多种的肠病毒引致，其中以柯萨奇病毒A组16型(CVA16)和肠道病毒71型(EV71)最为常见。目前尚无针对手足口病的预防及治疗方法，临床上仅仅采用广谱抗病毒药物进行治疗。所以现在开发一种用于手足口病治疗的EV71和CVA16抑制剂是一件非常有意义且富有挑战性的工作。
EV71和CVA16在进化上高度同源，两种病毒在分类地位上均属于微小RNA病毒科(Picronaviridae)，肠病毒属(Enterovirus)，人类肠病毒A种(Human enterovirus A)。通常CVA16感染引起的临床症状较温和，较少伴发神经系统病变；而EV71除引起手足口病外，还常常引起严重的中枢神经系统疾病，如脑炎、脑膜炎、无菌性脑膜炎、急性迟缓性麻痹等，更严重的可导致肺水肿和心脏衰竭，死亡率极高。
肠道病毒为正二十面体结构的裸露的病毒粒子，因其无脂质外膜包被，常规的消毒液均不能有效将病毒灭活。两种致病原虽对温度敏感，56℃下30min即彻底失活，但病毒在4℃下可存活数周，-20℃下可存活数年，在自然环境中可长期存活。因此，有效防控肠道病毒感染存在较大难度。
肠道病毒为单股正义链RNA，其两端分别为5’-和3’-非翻译区；中间为病毒蛋白编码区。该编码区只包含一个开放阅读框，故病毒的原初翻译产物为一个分子量约243KDa的多聚蛋白前体。该多聚蛋白需要进一步被病毒自身编码的2A和3C蛋白酶切割，加工成11个成熟的功能性蛋白亚基(Vp1-Vp4，2A-2C，3A-3D)以完成病毒的复制和装配。其中2A蛋白酶负责Vp1/2A接合序列的切割；而3C蛋白酶负责多聚蛋白中另外8个位点的切割(包括Vp2/Vp3，Vp3/Vp1，2A/2B，2B/2C，2C/3A，3A/3B，3B/3C，3C/3D接合序列)，因其可以识别多个不同的位点，在病毒多聚蛋白前体的加工中发挥主要作用，因此3C蛋白酶又被称为主蛋白酶。此外，3C蛋白酶还具有RNA结合活性。Shin-Ru13等证明EV71 3C可以通过“KFRDI”和“VGK”两个功能基序结合病毒基因组的5’-UTR，从而直接参与病毒的复制。另一方面，3C蛋白酶又通过与多种宿主因子相互作用而促进病毒的增殖。如通过切割CstF-64宿主因子而关闭宿主自身的蛋白质翻译系统，从而为病毒蛋白合成提供更多的原料。通过结合视黄酸诱导基因I(RIG-I)而抑制宿主抗病毒因子干扰素β(IFN-β)的产生。3C在肠道病毒病毒生活周期中的关键作用，使得该蛋白酶可以作为有效的抗病毒靶点；而在人类中缺少3C蛋白酶的同源蛋白，因此，有效的 3C蛋白酶抑制剂有应用于临床、治疗手足口病等肠道病毒感染引起的相关疾病的可能。
综上所述，本领域迫切需要开发3C蛋白酶抑制剂。
发明内容
本发明的目的是提供一种3C蛋白酶抑制剂。
本发明的第一方面，提供了一种通式(I)所示的醛基类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体：
Figure PCTCN2016113835-appb-000001
其中，
手性碳原子C*、C*2、C*3各自独立地为S型、R型，或其组合；
n＝0或1；
X为CH2或者NR5；
Y为选自下组的连接基团：-CON(R4)R3-、-CH2＝CH2-；
R1选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、三氟甲基、C2～C6炔基、4～7元杂环基、C5～C7芳基、5～7元杂芳基；所述杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C1～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1-C4酰基、酰胺基、磺酰基、氨基磺酰基、C1-C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5-7元环；
R2选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、5～12元杂环基(优选为5～7元杂环基或6元芳基并5～7元杂环基)、C6～C12芳基、5～12元杂芳基、或-Cbz；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1-C4酰基、酰胺基、磺酰基、氨基磺酰基、C1-C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5-7元环；
R3为未被取代或者被1-3个取代基取代的C1～C6的亚烷基；所述取代基各自独立地选自C1～C6直链或支链烷基、C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷基、取代或未取代的C6～C12芳基、取代或未取代的5～12元杂芳基，所述杂芳基含有1～3个选自氧、硫和氮的杂原子；其中，所述的环烷基、芳基、杂芳基被一个或多个选自卤素、C1～C6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基的基团所取代；
R4、R5各自独立地选自下组：氢、卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C3-C7环烃基、C1-C6酰基、C5-C7芳基、苄基或者5～7元杂芳基；所述杂芳基含有1-3个选自氧、硫和氮的杂原子；其中，所述的芳基、苄基或者5～7元杂芳基任选地被一个或多个选自卤素、C1～C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基的基团所取代。
在另一优选例中，R1为取代或未取代的苯基，优选为未取代的苯基。
在另一优选例中，R2为苯并含N、O或S的5-6元杂环基，优选为苯并含N的5-6元杂环基。
在另一优选例中，通式(I)中：
Y为-CON(R4)R3-；
R1选自未被取代或者被1-3个取代基取代的以下基团：三氟甲基、炔基、环丙烷基、环丁烷基、环戊烷基、环己烷基、苯基、噻吩基、吡唑基、噻唑基、吡啶基、呋喃基。
在另一优选例中，通式(I)中：
手性碳原子C*、C*2为S型，手性碳原子C*3为S型、R型，或其组合；
R3为未被取代或者被1-3个取代基取代的C1～C6的亚烷基；所述取代基各自独立地选自C1～C6直链或支链烷基、C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷基；
R4、R5各自独立地选自氢、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基。
在另一优选例中，通式(I)中：
n＝1；
R3为未被取代或者被1-3个取代基取代的C1～C3的亚烷基；所述取代基各自独立地选自下组：C1～C6直链或支链烷基、取代或未取代的C3～C6环烷基；所述的烷基或环烷基任选地被一个或多个选自卤素、C1～C4直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基中的基团所取代。
在另一优选例中，通式(I)中：
n＝0；
X为NR5；
R1为未被取代或者被1-3个取代基取代的选自下组的基团：环戊烷基、环己烷基、苯基、噻吩基；
R2为未被取代或者被1-3个取代基取代的选自下组的基团：苯基、苯并杂环基、5～12元杂芳基；优选地，所述苯并杂环和5～12元杂芳环选自苯并二氧杂环戊烯、吲哚、异噁唑、2-氢丙吡喃、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、苯并呋喃、吲唑、苯并咪唑、喹啉；
R5选自氢、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基。
在另一优选例中，所述醛基类化合物选自表A中所示的化合物。
本发明的第二方面，提供了一种如本发明第一方面所述通式(I)所示的化合物的制备方法，包括步骤：
Figure PCTCN2016113835-appb-000002
(1)在惰性溶剂中，在缩合剂存在下，用式II化合物和式Ic化合物反应，得到式Id化合物；优选地，所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)；
Figure PCTCN2016113835-appb-000003
(2)在惰性溶剂中，用式Id化合物进行还原反应，得到式Ie化合物；优选地，所述的还原反应用硼氢化物作为还原剂；
Figure PCTCN2016113835-appb-000004
(3)在惰性溶剂中，用式Ie化合物进行氧化反应，得到式If化合物，即式(I)化合物；优选地，所述的氧化反应用Dess-Martin氧化剂或二甲基亚砜和草酰氯作为氧化剂；
上述各式中，各基团的定义如本发明第一方面所述。
在另一优选例中，所述的步骤(3)在碱存在下进行，且所述的碱选自下组：碳酸氢钠，或三乙基胺。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物，或其药学上可接受的盐。
本发明的第三方面，提供了一种用于制备治疗或预防肠道病毒感染引起的相关疾病的药物组合物。
在另一优选例中，所述的药物组合物用于抑制肠道病毒和冠状病毒复制；优选地，所述的药物组合物用于抑制肠道病毒3C蛋白酶。
在另一优选例中，所述肠道病毒感染引起的相关疾病包括：呼吸道感染、疱疹性咽峡炎、流行性皮疹病、手足口病或脑膜炎。
本发明的第四方面，提供了一种如本发明第一方面所述的通式(I)化合物用于制备抑制肠道病毒和冠状病毒复制的药物的用途。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅， 在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，制备得到了一类能够抑制肠道病毒和冠状病毒复制的式I化合物。且与现有技术中的肠道病毒和冠状病毒复制抑制化合物相比，所述的化合物具有更高的抑制活性。基于上述发现，发明人完成了本发明。
本发明的一个目的在于提供一种通式(I)所示的醛基类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
本发明的另一个目的在于提供一种上述通式(I)所示化合物的制备方法。
本发明的再一个目的在于提供一种包含治疗有效量的一种或多种上述通式(I)所示化合物或其药学上可接受的盐的药物组合物。
本发明的又一个目的在于提供上述通式(I)所示化合物在制备用于肠道病毒感染引起的相关的疾病，例如呼吸道感染、疱疹性咽峡炎、流行性皮疹病、手足口病、脑膜炎等的药物中的用途。
本发明的化合物可用于抑制肠道病毒和冠状病毒复制，特别是抑制肠道病毒3C蛋白酶。
术语
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C1～C10烷基、C3～C10环烷基、C1～C10烷氧基、卤素、羟基、羧基(-COOH)、C1～C10醛基、C2～C10酰基、C2～C10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C1-C10烷基、氰基、OH、硝基、C3～C10环烷基、C1～C10烷氧基、氨基。
除特别说明之处，本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
术语“C1～C6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3～8元饱和环失去一个氢原子形成的基团：N、S、O；例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6～10元芳基失去一个氢原子形成的基团；例如苯基、萘基，或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5～8元芳基失去一个氢原子形成的基团：N、S、O，其中每个杂芳基的环状体系可以是单环或多环的；例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1～C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(＝O)-基团，如-COOCH3、-COOC2H5、 -COOC3H7、-COOC4H9，或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团，所述的烯烃可以是单烯烃、二烯烃或三烯烃，例如-CH＝CH2、-C2H4＝CH2、-CH＝C2H4，或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中，形如“C1～C6”，表示该基团可以具有1个至6个碳原子，例如1个、2个、3个、4个或5个。
式(I)所示的醛基类化合物
本发明提供一种通式(Ⅰ)表示的醛基类化合物，其对映异构体、非对映异构体、外消旋体及其混合物或其药学上可接受的盐，
Figure PCTCN2016113835-appb-000005
其中，各基团的定义如上所述。
在另一优选例中，n、X、Y、R1、R2、R3、R4、R5各自独立地为实施例中各个具体化合物所对应的相应基团。
特别地，本发明所述的醛基类化合物优选自下表A中所示的化合物：
表A
Figure PCTCN2016113835-appb-000006
Figure PCTCN2016113835-appb-000007
Figure PCTCN2016113835-appb-000008
Figure PCTCN2016113835-appb-000009
Figure PCTCN2016113835-appb-000010
Figure PCTCN2016113835-appb-000011
Figure PCTCN2016113835-appb-000012
Figure PCTCN2016113835-appb-000013
Figure PCTCN2016113835-appb-000014
式(I)化合物的制备
本发明还提供了一种具有通式I的化合物的合成方法，具体地，所述的式I化合物通过下列所示流程进行制备：
Figure PCTCN2016113835-appb-000015
步骤a:将叔丁氧羰基谷氨酸二甲酯溶解在溶剂中，-78℃加入碱搅拌，然后加入溴乙腈，继续搅拌，得化合物Ia，所述溶剂为四氢呋喃或二氧六环；所述碱为六甲基二硅基氨基锂或二异丙基氨基锂；
步骤b:将Ia溶解在溶剂中，加入催化量二氧化铂，搅拌至原料反应完全，过滤，加入碱，回流搅拌，得化合物Ib；所述碱为碳酸钠或醋酸钠；所述溶剂为甲醇、氯仿的混合溶剂；
步骤c:将Ib溶解在溶剂中，搅拌至反应完全，旋干溶剂得化合物Ic；所述溶剂为二 氯甲烷和三氟乙酸混合溶剂；
步骤d:将取代羧酸与Ic溶于溶剂中，在缩合剂辅助下进行缩合反应得到化合物Id；所述溶剂为二氯甲烷或DMF；
步骤e:将化合物Id溶于溶剂中，加入硼氢化钠，搅拌，得化合物Ie，所述溶剂为甲醇、四氢呋喃、乙醇；
步骤f:将化合物Ie溶解在溶剂中，加入氧化剂，加入碱，搅拌，得终产物If，所述溶剂为二氯甲烷或四氢呋喃；所述氧化剂为Dess-Martin氧化剂或二甲基亚砜和草酰氯；所述碱为碳酸氢钠或三乙基胺；
X、Y、R1、R2与前述要求中的定义相同。
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物，所述药物组合物包含治疗有效量的选自式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地，药学上可接受的载体，其可用于治疗肠道病毒和冠状病毒复制等相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明所述的式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种，或者上述包含治疗有效量的选自式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物可以作为肠道病毒3C蛋白酶抑制剂，用于治疗肠道病毒感染或冠状病毒感染相关疾病。
本发明化合物的药用盐的制备，可以采用化合物的游离碱与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
由于本发明化合物具有优异的对肠道病毒和冠状病毒复制的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肠道病毒和冠状病毒复制相关的疾病，例如预防和/或治疗与肠道病毒和冠状病毒复制异常相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：呼吸道感染、疱疹性咽峡炎、流行性皮疹病、手足口病、脑膜炎等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、 山梨醇等)、乳化剂(如
Figure PCTCN2016113835-appb-000016
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
如上所述的根据本发明的化合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径，更优选为口服。日剂量优选为0.01～200mg/kg体重，一次性服用，或0.01～100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些 都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。实施例中的所有参数以及其余的说明，除另有说明外，都是以质量为说明依据的。
样品的分析数据由以下仪器测定：核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定，TMS(四甲基硅烷)为内标，化学位移单位为ppm，耦合常数单位为Hz；质谱由Finnigan MAT-711型，MAT-95和LCQ-DECA型质谱仪以及IonSpec 4.7 Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产)；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板；石油醚沸程为60-90℃；采用紫外灯，碘缸显色。除另有说明外，以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例1:化合物1的合成
Figure PCTCN2016113835-appb-000017
合成路线：
Figure PCTCN2016113835-appb-000018
化合物1-3的合成：
氩气保护下，将N-叔丁氧羰基-L-谷氨酸二甲酯(1-1)(6g，21.8mmol)溶于60mL无水四氢呋喃中，于-78℃条件下缓慢滴LiHMDS(1M in THF)的四氢呋喃溶液(47mL,47mmol)，滴加过程保持温度稳定在-78℃，约持续1小时。滴毕后在-78℃条件搅拌1小时。将溴乙腈(2.79g，23.3mmol)溶于20ml四氢呋喃中，随后将该溶液缓慢滴入到反应体系中，滴加过程持续1～2小时。控温-78℃，继续反应20小时。THL监测(碱性高锰酸钾显色)反应完毕后，向反应液中加入3mL甲醇及冰醋酸与四氢呋喃的混合溶液22.7mL(v/v＝1/7.5)淬灭反应，搅拌10min后升至室温。倾入40mL饱和氯化钠溶液充分搅拌，可见反应体系分层。分离有机层，并用乙酸乙酯(EA)萃取水相，合并有机层后用无水硫酸钠干燥，浓缩，柱层析(Flash,PE:EA＝4:20)得到淡黄色油状物1-3 3.9g，收率为58％。
1H NMR(CDCl3,400MHz)δ5.23(d,J＝9.0Hz,1H),4.43-4.36(m,1H),3.77(s,1H),3.76(s,1H),2.89-2.69(m,3H),2.20-2.14(m,2H),1.45(s,9H)ppm.
ESI-MS m/z 215[M+H-boc]+.
化合物1-5的合成：
将化合物1-3(5g，15.9mmol)溶于3mL氯仿和50mL甲醇的混合溶液中，加入二氧化铂(0.3g)，在氢气条件下，室温搅拌。TLC监测(碱性高锰酸钾)反应完全后减压抽滤，滤液蒸干，补加入甲醇50mL，乙酸钠(8.46g，31.8mmol)，加热回流，约12小时反应完全。反应液减压浓缩，残留物用乙酸乙酯/饱和氯化钠萃取，无水硫酸钠干燥，柱层析(Flash,PE:EA＝8:20)得无色油状物1-5(2.6g)，收率为57％。
1H NMR(CDCl3,400MHz)δ6.02(br,1H),5.49(d,J＝7.8Hz,1H),4.33-4.27(m,1H),3.72(s,3H),3.36-3.31(m,2H),2.49-2.40(m,2H),2.16-2.06(m,1H),1.89-1.77(m,2H),1.41(s,9H)ppm.
ESI-MS m/z 309[M+Na]+.
化合物1-6的合成：
将化合物1-5(2.6g)溶于三氟乙酸的二氯甲烷溶液(1/1,v/v)中，室温搅拌1小时，浓缩后加入二氯甲烷100ml，饱和碳酸钠溶液洗，有机层用无水硫酸钠干燥，浓缩得油状物1-6(2.7g)，收率99％。
化合物1-9的合成：
将Cbz-缬氨酸(1.26g,5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到80ml二氯甲烷溶液中，室温搅拌30min。随后加入苯丙氨酸甲酯(0.896g,5mmol)，滴入1.2当量的三乙胺，室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取，经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后，合并有机层无水硫酸钠干燥，浓缩后得白色粘稠状固体1.8g，产率90％。
化合物1-10的合成：
将1-9(1.8g,4.36mmol)溶于80ml甲醇中，加入0.2g的Pd/C，氢气环境下室温搅拌。约24小时后反应完全。利用硅藻土抽滤反应液，浓缩得到化合物1-101.15g,产率94.7％。
化合物1-13的合成：
将酸1-11(5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到30ml二氯甲烷溶液中，室温搅拌30min。随后加入1-10(5mmol)，滴入1.2当量的三乙胺，室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取，经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后，合并有机层无水硫酸钠干燥，浓缩得白色油状物质，可直接用于下步反应。
将上步制得油状中间体溶解于甲醇/水(1:2,v/v)的混合溶液中，加入3当量的1M氢氧化钠水溶液，室温下搅拌。TLC监测(紫外)反应完全后，调节pH至-2，乙酸乙酯萃取，饱和氯化钠溶液洗，有机层用无水硫酸钠干燥，浓缩得白色固体1.4g，收率61.5％。
化合物1-14的合成：
将1-13(592mg,1.3mmol)和中间体1-6(242mg,1.3mmol)溶于20mlDMF溶液中，随后加入缩合剂HATU(592mg,1.6mmol)和1.2当量的三乙胺，室温下搅拌。TLC监测(紫外)反应完全后，使用乙酸乙酯/饱和氯化铵溶液萃取，经饱和食盐水洗涤、无水硫酸钠干燥后，浓缩有机层。通过快速柱色谱(CH2Cl2:MeOH＝30:1)分离后，得到淡黄色油状产物1-14 320mg，收率39.5％。
化合物1-15的合成：
将1-14(320mg,0.51mmol)溶于20ml甲醇中，分批缓慢加入硼氢化钠(107mg,2.9mmol)，室温下搅拌约2小时反应完全。待反应完毕后，加入约20ml饱和食盐水淬灭反应，浓缩掉反应体系甲醇后，加入二氯甲烷萃取。有机相经饱和食盐水洗涤、无水硫酸钠干燥后，浓缩得到淡黄色油状物质1-15，可直接用于下步反应。
化合物1的合成：
将中间体1-15(173mg,0.29mmol)溶于20ml二氯甲烷溶于中，加入戴斯-马汀氧化剂(147mg,0.35mmol)和碳酸氢钠固体(29mg,0.35mmol)，在室温下搅拌。TLC监测(紫外)反应完全后，抽滤反应体系，所得滤液用饱和碳酸氢钠溶于萃取，有机层经饱和食盐水洗涤，无水硫酸钠干燥后浓缩。经快速柱色谱(CH2Cl2:MeOH＝20:1)分离纯化，得到白色固体粉末化合物1共62mg，产率35.9％。
1H NMR(400MHz,CDCl3):δ9.45-9.36(m,1H),7.76(d,J＝7.6Hz,1H),7.54-7.18(m,8H),7.03-6.98(m,1H),6.54-6.18(m,1H),5.18-4.90(m,1H),4.61(m,2H),4.49-4.14(m,2H),3.48-3.13(m,4H),2.65(m,1H),2.44-2.28(m,1H),2.26-2.17(m,1H),2.02-1.64(m,3H),0.92(m,6H).ESI-MS m/z 595.22[M+H]+.
实施例2:化合物2的合成
Figure PCTCN2016113835-appb-000019
用化合物1-11替换实施例1中的酸1-13，合成方法参考化合物1的合成，得到化合物2。1H NMR(400MHz,CDCl3):δ9.32-9.26(m,1H),7.81(m,1H),7.54-7.18(m,8H),7.13-6.91(m,1H),6.44-6.08(m,1H),5.15-4.90(m,1H),4.65(m,2H),4.47-4.04(m,2H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 496.15[M+H]+.
实施例3:化合物3的合成
Figure PCTCN2016113835-appb-000020
用化合物3-1替换实施例1中的1-11，合成方法参考化合物1的合成，得到化合物3。1H NMR(400MHz,CDCl3):δ9.52-9.43(m,1H),7.54-7.25(m,5H),6.47-6.18(m,2H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.45-3.03(m,4H),2.65(m,1H),2.54-2.30(m,4H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.92(m,6H).ESI-MS m/z 512.24[M+H]+.
实施例4:化合物4的合成
Figure PCTCN2016113835-appb-000021
用化合物4-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物4。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,9H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 447.20[M+H]+.
实施例5:化合物5的合成
Figure PCTCN2016113835-appb-000022
用化合物5-1替换实施例1中的1-11，合成方法参考化合物1的合成，得到化合物5。1H NMR(400MHz,CDCl3):δ9.52-9.39(m,1H),7.64-7.17(m,8H),6.47-6.18(m,1H),6.070(s,2H),5.14-4.96(m,1H),4.45-4.04(m,2H),3.45-3.03(m,4H),2.65(m,1H),2.54-2.30(m,1H),2.25-2.08(m,1H),2.12-1.44(m,3H),0.96(m,6H).ESI-MS m/z 551.24[M+H]+.
实施例6:化合物6的合成
Figure PCTCN2016113835-appb-000023
用化合物4-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物6。1H NMR(400MHz,CDCl3):δ9.46-9.34(m,1H),7.54-7.25(m,9H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.45-3.03(m,4H),2.65(m,1H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.92(m,6H).ESI-MS m/z 546.26[M+H]+.
实施例7:化合物7的合成
Figure PCTCN2016113835-appb-000024
用化合物5-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物7。1H NMR(400MHz,CDCl3):δ9.52-9.41(m,1H),7.64-7.17(m,8H),6.47-6.18(m,1H),6.07(s,2H),5.14-4.96(m,1H),4.45-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.25-2.08(m,1H),2.12-1.44(m,3H).ESI-MS m/z 452.17[M+H]+.
实施例8:化合物8的合成
Figure PCTCN2016113835-appb-000025
用化合物8-1替换实施例1中的1-11，合成方法参考化合物1的合成，得到化合物8。1H NMR(400MHz,CDCl3):δ9.58-9.42(m,1H),8.78(s,1H),7.92(s,1H),7.54-7.25(m,5H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.91(s,3H),3.45-3.03(m,4H),2.65(m,1H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.94(m,6H).ESI-MS m/z 511.26[M+H]+.
实施例9:化合物9的合成
Figure PCTCN2016113835-appb-000026
用化合物9-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物9。1H NMR(400MHz,CDCl3):δ9.48-9.36(m,1H),8.78(s,1H),8.68(s,1H),7.92(s,1H),7.54-7.15(m,5H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.45-3.03(m,4H),2.65(m,1H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.94(m,6H).ESI-MS m/z 526.24[M+H]+.
实施例10:化合物10的合成
Figure PCTCN2016113835-appb-000027
用化合物9-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物10。1H NMR(400MHz,CDCl3):δ9.50-9.45(m,1H),8.80(s,1H),8.65(s,1H),7.89(s,1H), 7.54-7.15(m,5H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 427.17[M+H]+.
实施例11:化合物11的合成
Figure PCTCN2016113835-appb-000028
用化合物8-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物11。1H NMR(400MHz,CDCl3):δ9.58-9.42(m,1H),8.78(s,1H),7.92(s,1H),7.54-7.25(m,5H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.87(s,3H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 427.17[M+H]+.
实施例12:化合物12的合成
Figure PCTCN2016113835-appb-000029
化合物12-3的合成：
将D-苯丙氨酸(5g，30.3mmol)溶于60mL 48％的氢溴酸中，降温至0℃分批加入亚硝酸钠(2.6g，37.5mmol)，控温搅拌1小时，升至室温，继续反应10小时。反应完毕，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析得无色油状化合物12-3 5.75g，收率为83％。
化合物12-4的合成：
将化合物12-3(4g)溶于30mL甲醇中，加入1mL浓硫酸，加热，升温至70℃，反应2小时。浓缩蒸除甲醇，加入10mL水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析得无色油状物12-4，3.95g，收率为93％。
化合物12-5的合成：
将L-苄氧羰基缬氨酸(3g，11.9mmol)溶于15mL无水四氢呋喃中，氩气保护，加入1，1’-二羰基咪唑(CDI，2.13g，13.1mmol)，室温搅拌1小时，降温至-78℃，待用。用10mL四氢呋喃将二异丙基胺基锂溶液(2当量LDA四氢呋喃溶液，19mL)稀释后，氩气保护，降温至-78℃，加入乙酸叔丁酯(4.87g，42mmol)，搅拌1小时。加入L-苄 氧羰基缬氨酸与CDI的反应液，控温-78℃，继续反应2小时。加入2mL水淬灭，升至室温，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析得黄色油状物12-5 2.1g，收率为60％。
化合物12-6的合成：
将化合物12-4(2g，8.23mmol)溶于30mL THF中，加入化合物12-5(5.75g，16.5mmol)，碳酸钾(2.56g，18.54mmol)，四丁基碘化铵(200mg)，室温反应36小时。将反应液倾入60mL水中，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析得化合物12-6 1.26g，收率为30％。
化合物12-7的合成：
将化合物12-6(1.26g，2.47mmol)溶于15mL三氟乙酸与二氯甲烷的混合溶液(v/v＝3/1)中，控温30℃，反应4小时。浓缩，加入10mL水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析得化合物12-7 760mg，收率为75％。
化合物12-8的合成：
将化合物12-7(0.76g，1.85mmol)溶于20mL甲醇中，加入10％Pd-C(80mg)，
排出空气，通入氢气，室温搅拌10小时。抽滤，浓缩得化合物12-8 0.44g，收率为85％。
化合物12的合成：
用化合物8-1替换实施例1中的酸1-11，化合物12-8替换实施例1中的1-10，合成方法参考化合物1的合成，得到化合物12。1H NMR(400MHz,CDCl3):δ9.56-9.41(m,1H),8.79(s,1H),7.90(s,1H),7.54-7.18(m,5H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.91(s,3H),3.45-3.03(m,5H),2.65-2.57(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.94(m,6H).ESI-MS m/z 510.26[M+H]+.
实施例13:化合物13的合成
Figure PCTCN2016113835-appb-000030
用化合物5-1替换实施例12中的8-1，合成方法参考化合物12的合成，得到化合物13。1H NMR(400MHz,CDCl3):δ9.52-9.41(m,1H),7.64-7.17(m,8H),6.47-6.18(m,1H),6.08(s,2H),5.15-4.96(m,1H),4.47-4.04(m,2H),3.45-3.03(m,5H),2.65-2.57(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H),0.94(m,6H).ESI-MS m/z 550.25[M+H]+.
实施例14:化合物14的合成
Figure PCTCN2016113835-appb-000031
用化合物14-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合 物14。1H NMR(400MHz,CDCl3)δ9.72–9.08(m,1H),8.34–8.21(m,2H),8.16–8.10(m,1H),8.06–7.94(m,2H),7.42(ddd,J＝15.1,6.6,4.7Hz,2H),7.29(dd,J＝13.9,2.0Hz,2H),7.18–7.12(m,2H),6.51(dd,J＝36.8,13.4Hz,1H),5.04(tt,J＝15.2,7.6Hz,1H),4.47–4.18(m,1H),3.24(dd,J＝14.3,7.5Hz,4H),2.24–2.16(m,1H),2.01–1.83(m,3H),1.76–1.60(m,2H).ESI-MS m/z 526.10[M+H]+.
实施例15:化合物15的合成
Figure PCTCN2016113835-appb-000032
用化合物15-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物15。
1H NMR(400MHz,CDCl3)δ9.40(dd,J＝53.9,44.1Hz,1H),8.34–8.18(m,1H),7.40–7.28(m,3H),7.26–7.19(m,4H),6.87(dd,J＝8.4,2.5Hz,1H),6.80–6.61(m,1H),5.69(dd,J＝9.7,6.1Hz,1H),5.05–4.92(m,1H),4.36(dt,J＝8.5,5.1Hz,5H),3.49(s,1H),3.34–3.24(m,3H),3.20–3.09(m,1H),2.35–2.25(m,1H),1.86(dddd,J＝20.6,17.0,13.2,4.2Hz,3H).ESI-MS m/z 466.19[M+H]+.
实施例16:化合物16的合成
Figure PCTCN2016113835-appb-000033
用化合物16-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物16。
1H NMR(400MHz,CDCl3)δ9.68–9.22(m,1H),8.61–8.18(m,1H),7.92–7.67(m,4H),7.44–7.35(m,2H),7.31–7.27(m,2H),7.25–7.15(m,2H),7.13–6.99(m,1H),6.08–5.81(m,1H),5.12–4.97(m,1H),4.48–4.21(m,1H),3.50–3.13(m,5H),2.38–2.16(m,2H),2.02–1.84(m,2H).ESI-MS m/z 464.16[M+H]+.
实施例17:化合物17的合成
Figure PCTCN2016113835-appb-000034
用化合物17-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物17。
1H NMR(400MHz,CDCl3)δ9.56–9.25(m,1H),8.23–7.99(m,2H),7.68–7.61(m,1H),7.28(dd,J＝7.4,6.1Hz,3H),7.26–7.20(m,2H),7.01–6.94(m,1H),6.89(dd,J＝15.2,7.3Hz,1H),6.04(dd,J＝78.3,34.4Hz,1H),5.03(dq,J＝10.5,7.3Hz,1H),4.34– 4.23(m,5H),3.50–3.34(m,1H),3.32–3.23(m,3H),3.18–3.08(m,1H),2.37–2.21(m,1H),2.00–1.85(m,2H),1.77–1.69(m,1H).ESI-MS m/z 466.19[M+H]+.
实施例18:化合物18的合成
Figure PCTCN2016113835-appb-000035
用化合物18-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物18。1H NMR(400MHz,CDCl3)δ9.61-9.48(m,1H),9.46-9.20(m,1H),8.63-8.42(m,2H),8.24-7.93(m,2H),7.89-7.78(m,2H),7.34-7.27(m,3H),7.24-7.17(m,1H),6.54-6.18(m,1H),5.18-4.90(m,1H),4.49–4.14(m,1H),3.48-3.13(m,4H),2.44-2.28(m,1H),2.26-2.17(m,1H),2.02-1.64(m,3H).ESI-MS m/z 460.19[M+H]+.
实施例19:化合物19的合成
Figure PCTCN2016113835-appb-000036
用化合物19-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物19。
1H NMR(400MHz,CDCl3)δ9.53–9.19(m,1H),8.45(ddd,J＝17.0,10.0,5.9Hz,1H),7.94–7.68(m,1H),7.65(dd,J＝7.8,0.8Hz,1H),7.51–7.37(m,4H),7.31–7.27(m,4H),7.22(dd,J＝9.3,4.8Hz,1H),6.32–5.97(m,1H),5.10–5.01(m,1H),4.47–4.07(m,2H),3.51–3.34(m,1H),3.32–3.18(m,4H),2.37–2.21(m,1H),1.92–1.83(m,2H).ESI-MS m/z 448.18[M+H]+.
实施例20:化合物20的合成
Figure PCTCN2016113835-appb-000037
用化合物20-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物20。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.32-7.52(m,4H),7.48-7.25(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 448.19[M+H]+.
实施例21:化合物21的合成
Figure PCTCN2016113835-appb-000038
用化合物21-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物21。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.72-7.82(m,5H),7.42-7.25(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 460.19[M+H]+.
实施例22:化合物22的合成
Figure PCTCN2016113835-appb-000039
用化合物22-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物22。
1H NMR(400MHz,CDCl3)δ12.79–12.45(m,1H),9.53–9.29(m,1H),9.11–8.80(m,1H),8.54–8.17(m,2H),8.01–7.68(m,2H),7.55–7.42(m,1H),7.35–7.27(m,3H),7.22–7.15(m,2H),6.57(dd,J＝27.5,23.5Hz,1H),5.24–4.99(m,1H),4.35–4.22(m,1H),3.48–3.23(m,3H),2.98–2.60(m,2H),2.25(ddd,J＝13.0,12.4,5.9Hz,1H),2.14–2.06(m,1H),1.94–1.81(m,2H).ESI-MS m/z 448.19[M+H]+.
实施例23:化合物23的合成
Figure PCTCN2016113835-appb-000040
用化合物23-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物23。
1H NMR(400MHz,CDCl3)δ9.54–9.26(m,1H),8.43(ddd,J＝11.5,10.8,4.1Hz,1H),8.04(dddd,J＝36.5,9.5,5.8,1.9Hz,2H),7.74–7.60(m,1H),7.45–7.27(m,5H),7.25–7.14(m,2H),7.03–6.82(m,1H),6.61(s,1H),6.00(d,J＝53.6Hz,1H),5.15–5.00(m,1H),4.49–4.22(m,1H),3.36–3.19(m,3H),2.35–2.20(m,2H),2.05–1.95(m,2H),1.84–1.72(m,2H).ESI-MS m/z 447.19[M+H]+.
实施例24:化合物24的合成
Figure PCTCN2016113835-appb-000041
用化合物24-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物24。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,10H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.99(s,3H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 461.21[M+H]+.
实施例25:化合物25的合成
Figure PCTCN2016113835-appb-000042
用化合物25-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物25。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,9H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 465.19[M+H]+.
实施例26:化合物26的合成
Figure PCTCN2016113835-appb-000043
用化合物26-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物26。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,9H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.28(s,3H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 461.21[M+H]+.
实施例27:化合物27的合成
Figure PCTCN2016113835-appb-000044
用化合物27-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物27。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,9H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.83(s,3H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 477.21[M+H]+.
实施例28:化合物28的合成
Figure PCTCN2016113835-appb-000045
用化合物28-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物28。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,8H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16 (m,1H),2.12-1.54(m,6H).ESI-MS m/z 462.20[M+H]+.
实施例29:化合物29的合成
Figure PCTCN2016113835-appb-000046
用化合物29-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物29。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.72(s,1H),7.52-7.18(m,8H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 481.16[M+H]+.
实施例30:化合物30的合成
Figure PCTCN2016113835-appb-000047
用化合物30-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物30。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.85-7.87(m,6H),7.52-7.18(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 459.20[M+H]+.
实施例31:化合物31的合成
Figure PCTCN2016113835-appb-000048
用化合物31-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物31。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.98-7.96(m,5H),7.52-7.18(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 527.18[M+H]+.
实施例32:化合物32的合成
Figure PCTCN2016113835-appb-000049
用化合物32-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物32。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.31-7.86(m,5H),7.52-7.18(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 537.11[M+H]+.
实施例33:化合物33的合成
Figure PCTCN2016113835-appb-000050
用化合物33-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物33。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.82-7.64(m,4H),7.52-7.18(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.63(s,3H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 474.21[M+H]+.
实施例34:化合物34的合成
Figure PCTCN2016113835-appb-000051
用化合物18-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物34。1H NMR(400MHz,CDCl3)δ9.61-9.48(m,1H),9.46-9.20(m,1H),8.63-8.42(m,2H),8.24-7.93(m,2H),7.24-7.17(m,1H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 466.24[M+H]+.
实施例35:化合物35的合成
Figure PCTCN2016113835-appb-000052
用化合物18-1替换实施例2中的1-11，化合物35-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物35。1H NMR(400MHz,CDCl3)δ9.61-9.48(m,1H),9.46-9.20(m,1H),8.63-8.42(m,2H),8.24-7.93(m,2H),7.24-7.17(m,1H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.57(m,5H),1.55-1.35(m,9H).ESI-MS m/z 452.22[M+H]+.
实施例36:化合物36的合成
Figure PCTCN2016113835-appb-000053
用化合物5-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物36。1H NMR(400MHz,CDCl3):δ9.54-9.47(m,1H),7.64-7.17(m,3H),6.37-6.18(m,1H),6.07(s,2H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 458.22[M+H]+.
实施例37:化合物37的合成
Figure PCTCN2016113835-appb-000054
用化合物15-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物37。1H NMR(400MHz,CDCl3):δ9.51-9.43(m,1H),7.68-7.13(m,3H),6.37-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,5H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 471.24[M+H]+.
实施例38:化合物38的合成
Figure PCTCN2016113835-appb-000055
用化合物17-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物38。1H NMR(400MHz,CDCl3):δ9.55-9.47(m,1H),7.68-7.13(m,3H),6.32-6.11(m,1H),5.15-4.96(m,1H),4.47-4.04(m,5H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 471.24[M+H]+.
实施例39:化合物39的合成
Figure PCTCN2016113835-appb-000056
用化合物39-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物39。δ9.51-9.46(m,1H),7.56-8.12(m,4H),7.25-7.43(m,5H),6.35-6.13(m,1H),5.14-4.95(m,1H),4.46-4.04(m,1H),3.44-3.02(m,4H),2.51-2.31(m,1H),2.27-2.18(m,1H),2.12-1.89(m,3H)，1.79(s,3H).ESI-MS m/z 462.21[M+H]+.
实施例40:化合物40的合成
Figure PCTCN2016113835-appb-000057
用化合物40-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物40。1H NMR(400MHz,CDCl3):δ9.51-9.46(m,1H),7.59-8.17(m,4H),7.25-7.51(m,5H),6.37-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.75-3.03(m,4H),2.54-2.30 (m,1H),2.24-2.16(m,1H),2.27-1.52(m,3H).ESI-MS m/z 466.18[M+H]+.
实施例41:化合物41的合成
Figure PCTCN2016113835-appb-000058
用化合物41-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物41。1H NMR(400MHz,CDCl3):δ9.49-9.43(m,1H),7.59-8.18(m,4H),7.21-7.49(m,5H),6.37-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.75-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.27-1.52(m,3H).ESI-MS m/z 482.15[M+H]+.
实施例42:化合物42的合成
Figure PCTCN2016113835-appb-000059
用化合物42-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物42。δ9.50-9.44(m,1H),7.52-8.13(m,4H),7.18-7.47(m,5H),6.37-6.13(m,1H),5.15-4.95(m,1H),4.48-4.04(m,1H),3.51(s,3H),3.44-3.02(m,4H),2.51-2.31(m,1H),2.27-2.18(m,1H),2.12-1.89(m,3H).ESI-MS m/z 478.20[M+H]+.
实施例43:化合物43的合成
Figure PCTCN2016113835-appb-000060
用化合物39-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物43。δ9.51-9.46(m,1H),7.45-8.07(m,4H),6.35-6.13(m,1H),5.14-4.95(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.79(s,3H),1.62-1.41(m,11H).ESI-MS m/z 468.25[M+H]+.
实施例44:化合物44的合成
Figure PCTCN2016113835-appb-000061
用化合物42-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物44。δ9.50-9.44(m,1H),7.45-8.07(m,4H),6.37-6.13(m,1H),5.15-4.95(m,1H),4.47-4.04(m,1H),3.51(s,3H),3.45-3.03(m,2H),2.54-2.30(m, 1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 484.25[M+H]+.
实施例45:化合物45的合成
Figure PCTCN2016113835-appb-000062
用化合物14-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物45。1H NMR(400MHz,CDCl3):δ9.56-9.42(m,1H),7.42-8.13(m,4H),6.37-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 532.15[M+H]+.
实施例46:化合物46的合成
Figure PCTCN2016113835-appb-000063
用化合物46-1替换实施例2中的1-11，合成方法参考化合物2的合成，得到化合物46。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.55-7.13(m,8H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 515.12[M+H]+.
实施例47:化合物47的合成
Figure PCTCN2016113835-appb-000064
用化合物24-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物47。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,5H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.99(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 467.26[M+H]+.
实施例48:化合物48的合成
Figure PCTCN2016113835-appb-000065
用化合物48-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物48。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H), 7.52-7.18(m,4H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.99(s,3H),3.81(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 497.26[M+H]+.
实施例49:化合物49的合成
Figure PCTCN2016113835-appb-000066
用化合物24-1替换实施例2中的1-11，化合物49-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物49。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.55-7.13(m,9H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.99(s,3H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,4H),2.12-1.54(m,3H).ESI-MS m/z475.23[M+H]+.
实施例50:化合物50的合成
Figure PCTCN2016113835-appb-000067
用化合物26-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物50。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.52-7.18(m,4H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.28(s,3H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 467.26[M+H]+.
实施例51:化合物51的合成
Figure PCTCN2016113835-appb-000068
用化合物46-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物51。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),7.55-7.13(m,3H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 521.44[M+H]+.
实施例52:化合物52的合成
Figure PCTCN2016113835-appb-000069
用化合物4-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物52。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 453.24[M+H]+.
实施例53:化合物53的合成
Figure PCTCN2016113835-appb-000070
用化合物3-1替换实施例2中的1-11，化合物35-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物53。1H NMR(400MHz,CDCl3):δ9.58-9.42(m,1H),6.23(m,1H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.87(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.57(m,5H),1.55-1.35(m,9H).ESI-MS m/z 405.21[M+H]+.
实施例54:化合物54的合成
Figure PCTCN2016113835-appb-000071
用化合物3-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物54。1H NMR(400MHz,CDCl3):δ9.58-9.42(m,1H),6.23(m,1H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.87(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 419.23[M+H]+.
实施例55:化合物55的合成
Figure PCTCN2016113835-appb-000072
用化合物1-1替换实施例2中的1-11，化合物35-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物55。1H NMR(400MHz,CDCl3):δ9.32-9.26(m,1H), 7.81(m,1H),7.54-7.18(m,2H),7.13-6.91(m,1H),6.44-6.08(m,1H),5.15-4.90(m,1H),4.65(m,2H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.57(m,5H),1.55-1.35(m,9H).ESI-MS m/z 488.19[M+H]+.
实施例56:化合物56的合成
Figure PCTCN2016113835-appb-000073
用化合物30-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物56。1H NMR(400MHz,CDCl3):δ9.50-9.42(m,1H),8.85-7.87(m,6H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 465.24[M+H]+.
实施例57:化合物57的合成
Figure PCTCN2016113835-appb-000074
用化合物57-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物57。1H NMR(400MHz,CDCl3):δ9.52-9.45(m,1H),8.80-7.65(m,6H),6.35-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,11H).ESI-MS m/z 465.24[M+H]+.
实施例58:化合物58的合成
Figure PCTCN2016113835-appb-000075
用化合物18-1替换实施例2中的1-11，化合物58-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物58。1H NMR(400MHz,CDCl3)δ9.61-9.48(m,1H),9.46-9.20(m,1H),8.63-8.42(m,2H),8.24-7.93(m,3H),7.89-7.78(m,2H),7.34-7.27(m,4H),7.24-7.17(m,2H),6.54-6.18(m,1H),5.18-4.90(m,1H),4.49–4.14(m,1H),3.48-3.13(m,4H),2.44-2.28(m,1H),2.26-2.17(m,1H),2.02-1.64(m,3H).ESI-MS m/z 466.15[M+H]+.
实施例59:化合物59的合成
Figure PCTCN2016113835-appb-000076
用化合物4-1替换实施例2中的1-11，化合物59-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物59。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,12H).ESI-MS m/z 425.21[M+H]+.
实施例60:化合物60的合成
Figure PCTCN2016113835-appb-000077
用化合物4-1替换实施例2中的1-11，化合物60-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物60。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),0.5-0.7(m,5H).ESI-MS m/z 411.20[M+H]+.
实施例61:化合物61的合成
Figure PCTCN2016113835-appb-000078
用化合物4-1替换实施例2中的1-11，化合物61-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物61。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.62-1.41(m,10H).ESI-MS m/z 471.23[M+H]+.
实施例62:化合物62的合成
Figure PCTCN2016113835-appb-000079
用化合物4-1替换实施例2中的1-11，化合物62-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物62。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.32-1.49(m,9H).ESI-MS m/z 489.22[M+H]+.
实施例63:化合物63的合成
Figure PCTCN2016113835-appb-000080
用化合物4-1替换实施例2中的1-11，化合物63-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物63。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,9H).ESI-MS m/z 489.22[M+H]+.
实施例64:化合物64的合成
Figure PCTCN2016113835-appb-000081
用化合物4-1替换实施例2中的1-11，化合物64-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物64。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),7.03-7.18(m,3H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,4H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 483.18[M+H]+.
实施例65:化合物65的合成
Figure PCTCN2016113835-appb-000082
用化合物65-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物65。1H NMR(400MHz,CDCl3):δ9.31-9.46(m,1H),7.36-7.89(m,3H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.93(s,3H),3.87(s,3H),3.83(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 543.27[M+H]+.
实施例66:化合物66的合成
Figure PCTCN2016113835-appb-000083
用化合物4-1替换实施例2中的1-11，化合物66-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物66。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.54-7.25(m,4H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m, 1H),3.45-3.03(m,2H),2.54-2.30(m,3H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 438.15[M+H]+.
实施例67:化合物67的合成
Figure PCTCN2016113835-appb-000084
用化合物67-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物67。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.56-7.25(m,3H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,4H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 467.26[M+H]+.
实施例68:化合物68的合成
Figure PCTCN2016113835-appb-000085
用化合物68-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物68。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.56-7.25(m,3H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.83(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 483.25[M+H]+.
实施例69:化合物69的合成
Figure PCTCN2016113835-appb-000086
用化合物69-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物69。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.46-7.25(m,2H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.93(s,3H),3.83(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 513.26[M+H]+.
实施例70:化合物70的合成
Figure PCTCN2016113835-appb-000087
用化合物70-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物70。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H), 7.46-7.25(m,2H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.96(s,3H),3.81(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 513.26[M+H]+.
实施例71:化合物71的合成
Figure PCTCN2016113835-appb-000088
用化合物71-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物71。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.46-7.25(m,2H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.92(s,3H),3.85(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 513.26[M+H]+.
实施例72:化合物72的合成
Figure PCTCN2016113835-appb-000089
用化合物72-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物72。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.46-7.25(m,2H),6.99-6.85(m,2H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.94(s,3H),3.81(s,3H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 513.26[M+H]+.
实施例73:化合物73的合成
Figure PCTCN2016113835-appb-000090
用化合物73-1替换实施例2中的1-11，化合物34-1替换实施例2中的1-8，合成方法参考化合物2的合成，得到化合物73。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.46-7.25(m,3H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,2H),2.54-2.30(m,1H),2.24-2.16(m,1H),2.12-1.54(m,5H),1.34-1.53(m,11H).ESI-MS m/z 494.20[M+H]+.
实施例74:化合物74的合成
Figure PCTCN2016113835-appb-000091
用化合物18-1替换实施例2中的1-11，化合物74-1替换实施例2中的1-8，合成方 法参考化合物2的合成，得到化合物74。1H NMR(400MHz,CDCl3):δ9.46-9.31(m,1H),7.46-7.25(m,4H),6.47-6.18(m,1H),5.15-4.96(m,1H),4.47-4.04(m,1H),3.45-3.03(m,3H),2.54-2.30(m,3H),2.24-2.16(m,1H),2.12-1.54(m,3H).ESI-MS m/z 408.16[M+H]+.
活性测试实验
实施例1：EV71-3C蛋白酶抑制实验
测定化合物对EV71-3C蛋白酶的抑制活性：使用纯化的3C蛋白酶和化学合成的荧光底物多肽。将EV71病毒3C蛋白酶的编码序列克隆入pET-21a载体中，通过载体在蛋白的C-端引入六组氨酸标签，利用E.coli表达；蛋白酶的纯化通过Ni-NTA亲和层析和Superdex 200分子排阻层析完成。底物多肽将使用Dabcyl-KIGNTIEALFQGPPKFRE-Edans荧光多肽，该多肽序列对应于EV71 2C/3A之间的接合序列，多肽切割的检测以340nm激发光激发，通过490nm发射光监测。各合成化合物以梯度浓度与3C蛋白酶混合后，测定多肽切割效率的抑制情形；通过三次独立的实验，计算各化合物对3C蛋白酶的半数抑制浓度IC50。实验结果如表1所示。
表1:EV71 3C蛋白酶抑制活性
编号 IC50(μM) 化合物 IC50(μM)
1 6.67 13 0.67
3 0.97 16 1.92
4 0.57 17 5.21
5 1.78 18 5.79
6 1.48 19 6.48
7 0.72 20 6.82
8 1.45 21 2.72
9 0.78 22 6.48±2.27
10 1.34 23 8.67
11 2.60 25 1.47
12 1.60 26 3.82
实验结论：从以上实验结果可以看出，化合物对EV71 3C蛋白酶有较好的抑制作用，尤其是化合物3，4，7，9，13抑制活性小于1μM
实施例2：SARS冠状病毒主蛋白酶抑制活性评价
测定化合物对SARS(Severe Acute Respiratory Syndrom)冠状病毒主蛋白酶(SARS-CoV Mpro)的抑制活性：利用荧光共振能量转移(fluorescence resonance energy transfer FRET)技术测定针对3C蛋白酶的抑制剂的酶水平抑制活性。在96孔板上，每孔中加入27.5μL缓冲液(20mM Tris，100mM NaCl，1mM EDTA，pH 7.4)，同时加入2.5μL化合物(最终浓度分别为2μM、4μM、6μM、8μM、10μM、12μM、14μM、16μM、18μM、20μM)和5μL EV713Cpro(最终浓度3μM)。在37℃下共孵育15min。之后加入15μL缓冲液稀释的荧光底物(最终浓度20μM)。利用Ge n5荧光分度计测定荧光参数，激发波长和发射波长分别为340nm和490nm，保持37℃，10min后读取数据。采用阴性对照，其中对照不加入化合物，其余相同。所得数据利用软件GraphPad Prism  5处理，实验结果如表2所示。
表2:SARS冠状病毒主蛋白酶抑制活性
编号 IC50(μM) 化合物 IC50(μM)
1 5.15 16 0.32
2 7.4 17 0.78
3 0.75 18 0.56
4 0.03 19 1.69
5 0.7 20 4.64
6 0.05 21 1.13
7 0.1 22 5.4
8 0.6 23 2.62
9 0.035 24 4.21
10 0.2 25 0.111
11 0.45 26 0.79
12 1.05 AG7088 6.7
13 1.10    
实验结论：从以上实验结果可以看出，化合物对SARS冠状病毒主蛋白酶有较好的抑制作用，其中，大部分化合物抑制活性要远远优于AG7088，说明本发明的化合物可能能够用于SARS冠状病毒主蛋白酶活性或表达量相关疾病的治疗。
实施例3：CVB3 3C蛋白酶抑制活性评价
测定化合物对CVB3(Coxsachievirus B3)3C蛋白酶的抑制活性：在96孔板上，每孔中加入20.0μL缓冲液(20mM Tris，100mM NaCl，1mM EDTA，10mM DTT，pH 7.4)，同时加入2.5μL化合物(最终浓度分别为100μM、33μM、11μM、3.7μM、1.2μM、0.4μM、0.13μM、0.004μM)和2.5μL CVB3 3Cpro(最终浓度3μM)。在37℃下共孵育10min。之后加入25μL缓冲液稀释的荧光底物。利用Ge n5荧光分度计测定荧光参数，激发波长和发射波长分别为340nm和490nm，保持37℃，15min后读取数据。采用阴性对照，其中对照不加入化合物，其余相同。所得数据利用软件GraphPad Prism 6.0处理，实验结果如表3所示。
表3:CVB3 3C蛋白酶蛋白酶抑制活性
编号 IC50(μM) 化合物 IC50(μM)
3 4.11 13 6.39
4 5.94 17 1.13
5 4.76 18 1.36
6 2.32 19 1.28
7 2.61 20 0.95
8 2.64 21 2.67
9 2.50 22 1.12
10 3.66 23 1.87
11 6.10 25 1.69
12 4.43 26 0.92
实验结论：从以上实验结果可以看出，化合物对CVB3 3C蛋白酶蛋白酶有较好的抑制作用,IC50可达到1μM左右。
实施例4：化合物对各病毒复制抑制活性评价
测定化合物对各病毒复制抑制活性：在96孔中加入100μl/孔梯度浓度的化合物，随后加入50μl/孔病毒缓冲液，随后立即加入50μl/孔培养好后的RD细胞(rhabdomyosarcoma cells)，37℃培养3-4天，直到观察到最大细胞病变效果。吸去培养基，加入75μl 5％MTS的酚红培养基，37℃，5％CO2培养1.5小时，测定各孔在498nM波长的荧光值，画出化合物浓度与细胞反应的曲线图，用在Accelrys公司定制的软件计算化合物的EC50值。
表4：化合物对EV71-BRCR病毒复制抑制活性评价
Figure PCTCN2016113835-appb-000092
实验结论：从以上实验结果可以看出，化合物对EV71-BRCR病毒复制有较好的抑制作用,部分化合物活性EC50小于1μmol.。
表5：化合物对EV68-WT病毒复制抑制活性评价
Figure PCTCN2016113835-appb-000093
挑选了部分化合物测试对EV68-WT病毒复制的抑制作用,从以上实验结果可以看出，化合物对EV68-WT病毒复制有良好的抑制作用，活性达到了纳摩尔级别。
表6：化合物对MNV(Murine norovirus)-CW1病毒复制抑制活性评价
Figure PCTCN2016113835-appb-000094
实验结论：从以上实验结果可以看出，本发明的化合物对MNV-CW1病毒复制也有一定的抑制作用，部分化合物的活性优于阳性化合物AG7088,化合物56和48的EC50小于1μmol，且治疗指数TI＞20。
实施例5：化合物18大鼠体内药代动力学研究
1.实验步骤：
健康大鼠6只，体重150-200g，随机分成2组，每组3只。分别灌胃和静脉注射给予本发明化合物18，给药剂量为10mg/kg,给药体积为10mL/kg，药物以DMSO/吐温80/生理盐水(5:5:90，v/v/v)配制。试验前禁食12h，自由饮水。给药后2h统一进食。
2.采血时间点及样品处理：
皮下给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
静脉给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
按以上设定时间点经大鼠眼球后静脉丛取血0.3mL，置肝素化试管中，11000rpm离心5min，分离血浆，于-20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物18的浓度。
采用WinNonlin 5.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
4.实验结果
表7:化合物18在大鼠体内药代动力学实验结果
Figure PCTCN2016113835-appb-000095
大鼠静脉注射10mg/kg本发明化合物18后，血浆浓度达峰时间Tmax为1h，达峰浓度Cmax为1919.4ng/ml；药时曲线下面积AUC0-t为6876.0ng·h/ml；末端消除半衰期t1/2为1.35h。静脉注射给予10mg/kg本发明化合物18后，AUC0-t为23361.2ng·h/ml；经剂量标准化后，大鼠皮下注射10mg/kg化合物18后的绝对生物利用度为29.4％。
实验结论：从以上实验结果可以看出，在大鼠体内药代动力学实验中，化合物18表现出较好的药代性质。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种通式(I)所示的醛基类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体：
    Figure PCTCN2016113835-appb-100001
    其中，
    手性碳原子C*、C*2、C*3各自独立地为S型、R型，或其组合；
    n＝0或1；
    X为CH2或者NR5；
    Y为选自下组的连接基团：-CON(R4)R3-、-CH2＝CH2-；
    R1选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、三氟甲基、C2～C6炔基、4～7元杂环基、C5～C7芳基、5～7元杂芳基；所述杂环基和杂芳基各自含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C1～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1-C4酰基、酰胺基、磺酰基、氨基磺酰基、C1-C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5-7元环；
    R2选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、5～12元杂环基(优选为5～7元杂环基或6元芳基并5～7元杂环基)、C6～C12芳基、5～12元杂芳基、或-Cbz；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1-C4酰基、酰胺基、磺酰基、氨基磺酰基、C1-C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5-7元环；
    R3为未被取代或者被1-3个取代基取代的C1～C6的亚烷基；所述取代基各自独立地选自C1～C6直链或支链烷基、C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷基、取代或未取代的C6～C12芳基、取代或未取代的5～12元杂芳基，所述杂芳基含有1～3个选自氧、硫和氮的杂原子；其中，所述的环烷基、芳基、杂芳基被一个或多个选自卤素、C1～C6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基的基团所取代；
    R4、R5各自独立地选自下组：氢、卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C3-C7环烃基、C1-C6酰基、C5-C7芳基、苄基或者5～7元杂芳基；所述杂芳基含有1-3个选自氧、硫和氮的杂原子；其中，所述的芳基、苄基或者5～7元杂芳基任选地被一个或多个选自卤素、C1～C6直链或支链烃基、氰基、 硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基的基团所取代。
  2. 如权利要求1所述的醛基类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    Y为-CON(R4)R3-；
    R1选自未被取代或者被1-3个取代基取代的以下基团：三氟甲基、炔基、环丙烷基、环丁烷基、环戊烷基、环己烷基、苯基、噻吩基、吡唑基、噻唑基、吡啶基、呋喃基。
  3. 如权利要求2所述的醛基类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    手性碳原子C*、C*2为S型，手性碳原子C*3为S型、R型，或其组合；
    R3为未被取代或者被1-3个取代基取代的C1～C6的亚烷基；所述取代基各自独立地选自C1～C6直链或支链烷基、C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷基；
    R4、R5各自独立地选自氢、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基。
  4. 根据权利要求3所述的醛基类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    n＝1；
    R3为未被取代或者被1-3个取代基取代的C1～C3的亚烷基；所述取代基各自独立地选自下组：C1～C6直链或支链烷基、取代或未取代的C3～C6环烷基；所述的烷基或环烷基任选地被一个或多个选自卤素、C1～C4直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1～C4烷氧基、巯基、C1～C4酰基中的基团所取代。
  5. 根据权利要求3所述的醛基类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    n＝0；
    X为NR5；
    R1为未被取代或者被1-3个取代基取代的选自下组的基团：环戊烷基、环己烷基、苯基、噻吩基；
    R2为未被取代或者被1-3个取代基取代的选自下组的基团：苯基、苯并杂环基、5～12元杂芳基；优选地，所述苯并杂环和5～12元杂芳环选自苯并二氧杂环戊烯、吲哚、异噁唑、2-氢丙吡喃、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、苯并呋喃、吲唑、苯并咪唑、喹啉；
    R5选自氢、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基。
  6. 根据权利要求1所述的醛基类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其中，所述醛基类化合物选自以下化合物：
    Figure PCTCN2016113835-appb-100002
    Figure PCTCN2016113835-appb-100003
    Figure PCTCN2016113835-appb-100004
    Figure PCTCN2016113835-appb-100005
    Figure PCTCN2016113835-appb-100006
    Figure PCTCN2016113835-appb-100007
    Figure PCTCN2016113835-appb-100008
    Figure PCTCN2016113835-appb-100009
    Figure PCTCN2016113835-appb-100010
    Figure PCTCN2016113835-appb-100011
  7. 一种如权利要求1所述通式(I)所示的化合物的制备方法，包括步骤：
    Figure PCTCN2016113835-appb-100012
    (1)在惰性溶剂中，在缩合剂存在下，用式II化合物和式Ic化合物反应，得到式Id化合物；优选地，所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)；
    Figure PCTCN2016113835-appb-100013
    (2)在惰性溶剂中，用式Id化合物进行还原反应，得到式Ie化合物；优选地，所述的还原反应用硼氢化物作为还原剂；
    Figure PCTCN2016113835-appb-100014
    (3)在惰性溶剂中，用式Ie化合物进行氧化反应，得到式If化合物，即式(I)化合物；优选地，所述的氧化反应用Dess-Martin氧化剂或二甲基亚砜和草酰氯作为氧化剂；
    上述各式中，各基团的定义如权利要求1-6任一所述。
  8. 一种药物组合物，其特征在于，所述的药物组合物包括：治疗有效量的一种或多种权利要求1所述通式(I)所示化合物，或其药学上可接受的盐。
  9. 如权利要求1所述的通式(I)的用途，其特征在于，用于制备治疗或预防肠道病毒感染引起的相关疾病的药物组合物。
  10. 如权利要求1所述的通式(I)的用途，其特征在于，用于制备抑制肠道病毒和/或冠状病毒复制的药物。
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