CN106795174A

CN106795174A - A kind of antiviral activity dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives and preparation method thereof

Info

Publication number: CN106795174A
Application number: CN201680002296.8A
Authority: CN
Inventors: 于跃
Original assignee: 于跃
Current assignee: Yangzhou blue biomedicine technology Co., Ltd.
Priority date: 2015-08-10
Filing date: 2016-08-10
Publication date: 2017-05-31
Anticipated expiration: 2036-08-10
Also published as: WO2017025031A1; CN106795174B

Abstract

The present invention relates to a kind of antiviral activity dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives and preparation method thereof, and in particular to anti-RSV, HSV 1, EV71 activity of compound of formula I, compound of formula I have following structure：Wherein R₁、R₂、R₃、R₄It is each independently selected from optionally substituted H, alkyl, cycloalkyl, alkyl acyl, alkoxyacyl, cycloalkanoyl, alkenyl, alkenylacyl, alkynyl, alkynylacyl, aryl, aryl alkyl, aryl-acyl, heteroaryl, heteroaryl alkyl, heteroaroyl, saturation or unsaturated heterocycle base, saturation or unsaturated heterocycle base alkyl, saturation or unsaturated heterocycle base acyl group；N is 0 or 1；Chemical bondRepresent the key pointed in paperOr the key outside sensing paper" " represents singly-bound or does not exist, and when " " represents singly-bound, R₁、R₂Do not exist.

Description

A kind of antiviral activity dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives and preparation method thereof

Technical field

The present invention relates to a kind of dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives and preparation method thereof, the invention further relates to application of the above-mentioned dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives in antiviral drugs is prepared.The dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives of the present invention have broad anti-viral activity, stronger antiviral activity is shown to RNA virus and DNA virus, extremely strong inhibitory activity especially is respectively provided with to Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), Enterovirus 71 (EV71) etc..

Background technology

Respiratory Syncytial Virus(RSV) (respiratory syncytial virus, abbreviation syncytial virus, RSV also belong to Paramyxoviridae), is a kind of RNA virus, belongs to Paramyxoviridae.Rsv infection can trigger pneumonia and a variety of lower respiratory illnesses, the annual whole world at least 3,000,000 infants and is admitted to hospital because of the infection of RSV viruses, and wherein at least has 160,000 people dead, therefore RSV is also referred to as children killer (Science, 2013,342,546-547).Currently without the vaccine that can be applied to clinic, Ribavirin (ribavirin) is unique chemotherapeutic agent (J.Med.Chem.2008,51,875-896) for being applied to clinic.

Herpes simplex virus type 1 (Herpes simplex virus, HSV-1) it is a kind of DNA virus being wrapped in, belong to bleb coe virus, the a variety of diseases of the mankind, such as gingivostomatitis (gingivostomatitis), keratoconjunctivitis (keratoconjunctivitis), encephalitis (encephalitis) and genital system infection and neonatal infection can be caused.

Enterovirus 71 (Enterovirus 71, EV71) be hand-foot-and-mouth disease main pathogens, separated first from infant faeces sample of the California with central nervous system disease within 1969, it is a kind of new enterovirus that the mankind have found, based on main infection infant, the acute infectious disease using fash, bleb and the herpangina at the position such as heating and hand, foot, oral cavity as principal character can be caused, it is infected often with neurological complication, can seriously cause death of child.At present, though the report for having some to be directed in terms of EV71 replicative cycles antiviral drugs, EV71 vaccine development, RNA, does not find clinical effective prevention and treatment measure yet.

In summary, the lead compound of exploitation prevention and/or the caused disease for the treatment of RSV, HSV-1, EV71 infection, drug candidate and clinical effective medicine turn into the task of top priority.

The content of the invention

The present invention provides the solvate of a kind of dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt, it is characterised in that compound of formula I has following structure：

Wherein R₁、R₂、R₃、R₄It is each independently selected from H, alkyl, cycloalkyl, alkyl acyl, alkoxyacyl, cycloalkanoyl, alkenyl, alkenylacyl, alkynyl, alkynylacyl, aryl, aryl alkyl, aryl-acyl, heteroaryl, heteroaryl alkyl, heteroaroyl, saturation or unsaturated heterocycle base, saturation or unsaturated heterocycle base alkyl, saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl；N is 0 or 1；Chemical bondRepresent to point to the key in paperOr the key outside sensing paper" --- -- " represents singly-bound or is not present, and when " --- -- " represents singly-bound, R₁、R₂It is not present；Precondition is to work as R₃、R₄When simultaneously for H, R₁、R₂It is asynchronouslySymbolRepresent R₁、R₂The bonded site of group and N in Formulas I structure.

Formula I does not include compound 239 and 539 and its racemic modification, but may include the solvate of its stereoisomer, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt.

In another embodiment of the present invention, R₁、R₂、R₃、R₄It is each independently selected from H, C1-C8 alkyl, C1-C8 alkyl acyls, C1-C8 alkoxyl acyl group, C3-C10 cycloalkyl, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C12 heteroaryls, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaroyls, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base C1-C4 alkyl, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl；It is other to be defined as above.

In another embodiment of the present invention, R₁、R₂、R₃、R₄It is each independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyls, C1-C8 alkyl acyls, C1-C8 haloalkyls acyl group, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C10 heteroaryls, C5-C10 heteroaryl C1-C4 alkyl, C5-C10 heteroaroyls, C5-C12 Saturation or unsaturated heterocycle base, C5-C12 saturations or unsaturated heterocycle base C1-C4 alkyl, C5-C12 saturations or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, methyl, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies, the substitution of one or more of phenyl；Hetero atom in the heterocyclic radical that is related in above-mentioned group, heteroaryl is the 1-5 hetero atom in N, O, S or Se；It is other to be defined as above.

In another embodiment of the present invention, R₃、R₄It is each independently H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇, 3- hydroxyl-propyls2- CARBOXY-ETHYLsP-chlorobenzyl, a nitrobenzyl, phenyl, furans -3- bases, naphthalene -1- bases, quinoline-8-yl, trifluoromethyl, acetyl group, chloracetyl (ClCH₂CO), propiono, valeryl, caproyl, heptanoyl group, caprylyl, ring propiono, cyclohexanoyl, benzoyl, a fluoro benzoyl, meta-methoxy benzoyl, an azidobenzoyl, trifluoroacetyl group, pi-allyl, acetenyl, propargyl, tertbutyloxycarbonyl, cyclopropyl, cyclopenta, cyclohexyl, azetidine, THP trtrahydropyranyl, benzhydrylR₁、R₂It is each independently H, C1-C8 alkyl, C1-C8 alkyl acyls, C1-C8 alkoxyl acyl group, C3-C10 cycloalkyl, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C12 heteroaryls, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaroyls, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base C1-C4 alkyl, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl；It is other to be defined as above.

In another embodiment of the present invention, R₃、R₄It is each independently H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇, 3- hydroxyl-propyls2- CARBOXY-ETHYLsP-chlorobenzyl, a nitrobenzyl, phenyl, furans -3- bases, naphthalene -1- bases, quinoline-8-yl, trifluoromethyl, acetyl group, chloracetyl (ClCH₂CO), propiono, valeryl, caproyl, heptanoyl group, caprylyl, ring propiono, cyclohexanoyl, benzoyl, a fluoro benzoyl, meta-methoxy benzoyl, an azidobenzoyl, trifluoroacetyl group, pi-allyl, acetenyl, propargyl, tertbutyloxycarbonyl, cyclopropyl, cyclopenta, cyclohexyl, azetidine, THP trtrahydropyranyl, benzhydrylR₁、R₂It is each independently the fluoro- 3- Methyl pentyls of n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3- Methyl pentyls, 2- Methyl pentyls, 2- Methyl-hexyls, 3- Methyl-hexyls, 3- ethyl hexyls, 1-, the fluoro- 2- Methyl pentyls of 1-, the fluoro- 2- Methyl-hexyls of 1-, the fluoro- 3- Methyl-hexyls of 1-, the fluoro- 3- ethyl hexyls of 1-, the chloro- 3- Methyl pentyls of 1-, 1- chloro-2-methyls-amyl group, 1- chloro-2-methyls-hexyl, 1- chlorine - 3- Methyl-hexyls,The chloro- 3- ethyl hexyls of 1-,The bromo- 3- Methyl pentyls of 1-,The bromo- 2- Methyl pentyls of 1-,The bromo- 2- Methyl-hexyls of 1-,The bromo- 3- Methyl-hexyls of 1-,The bromo- 3- ethyl hexyls of 1-,Acetyl group,Propiono,Positive bytyry,Isobutyryl,Positive valeryl,Isovaleryl,Pivaloyl group,Positive caproyl,Positive heptanoyl group,Positive caprylyl,3- methyl-pentanoyls,2- methyl-pentanoyls,2- Methyl-hexanoyls,3- Methyl-hexanoyls,3- ethyls-caproyl,Acetyl group,Propiono,Positive bytyry,Isobutyryl,Positive valeryl,Isovaleryl,Pivaloyl group,Positive caproyl,Positive heptanoyl group,Positive caprylyl,3- methyl-pentanoyls,2- methyl-pentanoyls,2- Methyl-hexanoyls,3- Methyl-hexanoyls,3- ethyls-caproyl,Trifluoroacetyl group,Two acetyl fluorides,Chloracetyl,Acetyl bromide,Five fluorine propionos,Perfluorobutyrl,The fluoro- 3- methyl-pentanoyls of 1-,The fluoro- 2- methyl-pentanoyls of 1-,The fluoro- 2- Methyl-hexanoyls of 1-,The fluoro- 3- Methyl-hexanoyls of 1-,The fluoro- 3- ethyls-caproyls of 1-,The chloro- 3- methyl-pentanoyls of 1-,1- chloro-2-methyls-valeryl,1- chloro-2-methyls-caproyl,The chloro- 3- Methyl-hexanoyls of 1-,The chloro- 3- ethyls-caproyls of 1-,The bromo- 3- methyl-pentanoyls of 1-,The bromo- 2- methyl-pentanoyls of 1-,The bromo- 2- Methyl-hexanoyls of 1-,The bromo- 3- Methyl-hexanoyls of 1-,The bromo- 3- ethyls-caproyls of 1-,Vinyl,Acrylic,Pi-allyl,N-butene base,Isobutenyl,But-2-ene base,Butadienyl,N-pentene base,Isopentene group,Pentadienyl,N-hexylene base,Nhepene base,Heptadiene base,Heptantriene base,Positive octenyl,Octadienyl,Sarohornene base,3- methyl-amyl- 2- alkenyls,2- methyl-amyl- 2- alkenyls,2- methyl-hex- 2- alkenyls,3- methyl-hex- 2- alkenyls,3- ethyls-hex- 2- alkenyls,Propiono,But-2-ene acyl group,Methacrylyl,Amyl- 3- enoyl-s,Iso-amylene acyl group,Pentadiene acyl group,Hex- 4- enoyl-s,Hept- 5- enoyl-s,Heptadiene acyl group,Heptantriene acyl group,Oct-6-ene acyl group,Octadiene acyl group,Sarohornene acyl group,3- methyl-amyl- 2- enoyl-s,2- methyl-amyl- 2- enoyl-s,2- methyl-hex- 2- enoyl-s,3- methyl-hex- 2- enoyl-s,3- ethyls-hex- 2- enoyl-s,Acetenyl,Propinyl,Positive butynyl,Butyl- 2- alkynyls,Positive pentynyl,Isoamyl alkynyl,Positive hexin base,Positive heptynyl,Heptadiyne base,Positive octynyl,Pungent diynyl,Pungent three alkynyl,2- methyl-amyl- 2- alkynyls,2- methyl-hex- 2- alkynyls,3- methyl-hex- 2- alkynyls,3- ethyls-hex- 2- alkynyls,Alkynes propiono,Positive butynyl acyl group,Butyl- 2- alkynylacyls,Positive pentynyl acyl group,Isoamyl alkynylacyl,Positive hexin base acyl group,Positive heptynyl acyl group,Heptadiyne base acyl group,Positive octynyl acyl group,Pungent diynyl acyl group,Pungent three alkynylacyl,2- methyl-amyl- 2- alkynylacyls,2- methyl-hex- 2- alkynylacyls,3- methyl-hex- 2- alkynylacyls,3- ethyls-hex- 2- alkynylacyls,Phenyl,Naphthyl,Benzyl,Phenethyl imidazole radicals,Pyridine radicals,Oxazolyl,Isoxazolyl,Triazol radical,Tetrazole base,Furyl,Quinolyl,Oxazinyl,Thienyl,Thiazolyl,Thiadiazolyl group,Indyl,Carbazyl,Isoquinolyl,Benzofuranyl,Benzothiazolyl,Selenole base,Cumarin base,Isocoumarin base,Azetidinyl,Oxetanyl,Morpholinyl,Piperidyl,Piperazinyl,Tetrahydrofuran base,Dioxane base,Oxazoline,Thiazolinyl,THP trtrahydropyranyl,Dihydrocoumarin base,Dihydroiso-coumarin base,Tetrahydric quinoline group,Tetrahydro isoquinolyl,Tetrahydro carbazole base,Pyrimidine bases,Purine bases；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, methoxyl group, ethyoxyl, one or more of substitution；It is other to be defined as above.

In another embodiment of the present invention, R₃、R₄It is each independently H, methyl, acetyl group, trifluoroacetyl group, fluoroform Base, tertbutyloxycarbonyl；It is other to be defined as above.

In another embodiment of the present invention, compound or its dynamic isomer of the compound of formula I in table 1-5, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt.

In another preference, R in compound of formula I₁、R₂、R₃、R₄It is the specific group of relevant position in particular compound 1-239,301-539,601-893,900-953 in table 1-5.

It should be understood that above-mentioned preferred group can be mutually combined to form the various preferred compounds of the present invention, as space is limited, tire out one by one state herein.

The present invention provides the solvate of a kind of structure of Formulas I -1 bisoxazines alkane spiral shell diketopiperazine alkaloid compound, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -1 has following structure：

R₁、R₂、R₃、R₄Each embodiment compounds of formula I as defined above in R₁、R₂、R₃、R₄Definition.

For convenience of stating, the present invention is as follows to the compound mother nucleus structure label of Formulas I -1：

Formula I-1 compounds do not includeAnd the racemic modification of the two, but may include the solvate of its stereoisomer, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt.

The present invention provides the solvate of a kind of Shuan isoxazole alkyl spiral shell diketopiperazines alkaloid compound of the structure of Formulas I -2, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -2 has following structure：

For convenience of stating, the present invention is as follows to the compound mother nucleus structure label of Formulas I -2：

The present invention provides the solvate of a kind of structure of Formulas I -3 bisoxazines quinoline spiral shell diketopiperazine alkaloid compound, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -3 has following structure：

R₃、R₄Each embodiment compounds of formula I as defined above in R₃、R₄Definition.

For convenience of stating, the present invention is as follows to the compound mother nucleus structure label of Formulas I -3：

The present invention provides the solvate of a kind of Shuan isoxazoline spiral shell diketopiperazines alkaloid compound of the structure of Formulas I -4, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -4 has following structure：

For convenience of stating, the present invention is as follows to the compound mother nucleus structure label of Formulas I -4：

In the present invention：During without specified otherwise, one or more double bonds are contained in the alkenyl being related in group；Contain one or more three keys in the alkynyl being related in group, and optionally contain one or more double bonds in the alkynyl being related to；Alkyl in the alkyl for example described " alkyl, alkyl acyl, aryl alkyl, haloalkyl, haloalkyl acyl group " being related in group is straight or branched alkyl; it is preferred that C1-C8 straight or branched alkyls, further preferred methyl, ethyl, propyl group, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3- Methyl pentyls, 2- Methyl pentyls, 2- Methyl-hexyls, 3- Methyl-hexyls, 3- ethyl hexyls；Alkenyl in the alkenyl for example described " alkenyl, alkenylacyl " being related in group is straight or branched alkenyl; contain one or more double bonds; it is preferred that C2-C8 straight or branched alkenyls, further preferred vinyl, acrylic, pi-allyl, n-butene base, isobutenyl, but-2-ene base, butadienyl, n-pentene base, isopentene group, pentadienyl, n-hexylene base, nhepene base, Heptadiene base, heptantriene base, positive octenyl, octadienyl, sarohornene base, 3- methyl-amyl- 2- alkenyls, 2- methyl-amyl- 2- alkenyls, 2- methyl-hex- 2- alkenyls, 3- methyl-hex- 2- alkenyls, 3- ethyls-hex- 2- alkenyls；Cycloalkyl in the cycloalkyl for example described " cycloalkyl, cycloalkanoyl " being related in group is C3-C10 cycloalkyl, preferably cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base；Alkynyl in the alkynyl for example described " alkynyl, alkynylacyl " being related in group is straight or branched alkynyl; contain one or more three keys; optionally contain one or more double bonds; it is preferred that C2-C8 straight or branched alkynyls, further preferred acetenyl, propinyl, positive butynyl, butyl- 2- alkynyls, positive pentynyl, isoamyl alkynyl, positive hexin base, positive heptynyl, heptadiyne base, positive octynyl, pungent diynyl, pungent three alkynyl, 2- methyl-amyl- 2- alkynyls, 2- methyl-hex- 2- alkynyls, 3- methyl-hex- 2- alkynyls, 3- ethyls-hex- 2- alkynyls；" aryl " in the aryl for example described " aryl, aryl alkyl, aryl-acyl " being related in group is aryl; it is preferred that monocyclic, bicyclic, fused ring aryl; the monocyclic or bicyclic aryl of further preferably 6-10 carbon atom, further preferred phenyl, naphthyl；For example described " the heteroaryl of heteroaryl being related in group, heteroaryl alkyl, heteroaryl in heteroaroyl " is independently selected from N containing 1-5, O, the heteroatomic aryl of S or Se, 1-5 are preferably comprised independently selected from N, O, heteroatomic 5 yuan of S or Se is to 12 unit's heteroaryls, further preferred imidazole radicals, pyridine radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, quinolyl, oxazinyl, thienyl, phenothiazinyl, benzothienyl, thiazolyl, thiadiazolyl group, indyl, carbazyl, isoquinolyl, benzofuranyl, benzothiazolyl, selenole base, cumarin base, isocoumarin base；Heterocyclic radical for example described " saturation or the unsaturated heterocycle base being related in group, saturation or unsaturated heterocycle base alkyl, heterocyclic radical in saturation or unsaturated heterocycle base acyl group " is independently selected from N containing 1-5, O, S or Se is heteroatomic monocyclic or multiring heterocyclic, 1-5 are preferably comprised independently selected from N, O, heteroatomic 4 yuan to 12 yuan of S or Se monocyclic or multiring heterocyclic, further preferred azetidinyl, oxetanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrofuran base, dioxane base, oxazoline, thiazolinyl, THP trtrahydropyranyl, dihydrocoumarin base, Dihydroiso-coumarin base, tetrahydric quinoline group, tetrahydro isoquinolyl, tetrahydro carbazole base, pyrimidine bases, purine bases；" aryl alkyl " preferably benzyl, phenylethyl；" alkoxyacyl " preferably methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, tertbutyloxycarbonyl etc.；The cycloalkyl that is related in group, aryl, heteroaryl, heterocyclic radical are monocyclic, polycyclic or condensed ring；The acyl group being related in group is carbonyl (C=O)；The halo being related in group is monohaloalkyl or polyhalo, i.e., single fluoro, monochloro generation, single bromo, single iodo, or many fluoro, many chloros, many bromos, many iodos, two or more optional fluorine, chlorine, bromine, iodine substitution；" halogen " preferably fluorine, chlorine, bromine, iodine.

Chemical bond in the present invention in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4Represent to point to the key in paper simultaneouslyOr simultaneously point to paper outside key

Term " pharmaceutically acceptable salt " refers to the addition salts of atoxic inorganic or organic acid and/or alkali in the present invention, reference can be made to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.These salt can be finally separating in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4 to be prepared with purge process situ, or is prepared respectively by making alkali or acid functional group be reacted respectively with appropriate organic or inorganic acid or alkali.Representative salt is including but not limited to following：Acetate, adipic acid Salt, alginates, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, digluconate, cyclopentane propionate, dodecyl sulphate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionates, lactate, maleate, mesylate, nicotinate, 2- naphthalene sulfonates, oxalates, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, p- toluene fulfonate and undecylate.In addition, Basic nitrogen-containing groups can be by following reagent quaternization：Elementary alkyl halide, such as methyl, ethyl, propyl group and butyl chloride compound, bromide and iodide；Dialkylsulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates；Long chain halide, such as decyl, dodecyl, myristyl, stearyl chlorides, bromide and iodide；Aralkyl halide, such as benzyl and phenylethyl bromide.Water or oil-soluble or dispersible product can so be obtained.

Can be used for being formed the sour example of pharmaceutically acceptable acid-addition salts includes following acid：Inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid；Organic acid, such as oxalic acid, maleic acid, Loprazolam, butanedioic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid.Base addition salts can be prepared in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, being finally separating for the compound of Formulas I -4 with purge process situ, or prepared by making hydroxy-acid group be prepared respectively with appropriate alkali (such as hydroxide, carbonate or the bicarbonate of pharmaceutically acceptable metal cation) reaction, or with ammonia or organic primary, secondary or tertiary amine reaction.Pharmaceutically acceptable salt includes but is not limited to：Cation based on alkali and alkaline earth metal ions, such as sodium, lithium, potassium, calcium, magnesium, aluminium salt, and non-toxic ammonium, quaternary ammonium and amine cation, including but not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methyl amine, dimethyl amine, Trimethylamine, triethylamine, ethamine etc..Other representational organic amines for forming base addition salts include diethylamine, ethylenediamine, monoethanolamine, diethanol amine, piperazine etc..

Term " solvate " refers to formula I in the present invention, Formulas I -1, Formulas I -2, Formulas I -3, the compound or its salt of Formulas I -4 and organic solvent and/or the solvate of water formation, the preferred acetone of organic solvent, acetonitrile, methanol, ethanol, the solvate preferred formula Formulas I of formation, Formulas I -1, Formulas I -2, Formulas I -3, the monohydrate of the compound or its salt of Formulas I -4, dihydrate, trihydrate, one methanol solvate, diformazan alcohol adduct, one acetonitrile compound, diacetonitrile compound, one acetone compound, two acetone compounds, hemifumarate monohydrate, fumarate dihydrate, ethanolates of fumarate one etc..Further preferred monohydrate, fumarate dihydrate, the ethanolates of fumarate one.Still more preferably compound 1100-1105.

Term " geometric isomer " refers to the compound of two kinds of geometric configurations of Z, E when in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4 containing double bond in the present invention.

There are various tautomeric forms (wherein the proton translocation of an atom of molecule is on another atom, and the chemical bond between the atom of molecule then enters rearrangement) in formula I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4.See, e.g., March, Advanced Organic Chemistry：Reaction, mechanism and structure (Advanced Organic Chemistry：Reactions, Mechanisms and Structures), fourth edition, john wiley ＆ sons, the 69-74 pages (1992).Term " dynamic isomer " used herein Refer to the compound produced by proton translocation, it should be appreciated that all tautomeric forms (as long as there may be at them) are included in the scope of the invention.Such as when in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4 containing amido link, enol key, imidazoles functional group when exist a pair can mutual phase transformation a pair of dynamic isomers.

" the non-equal amount of mixture of enantiomter " of the present invention refers to that the mixture of two pairs of non-equimolar amounts of enantiomter, i.e. its ee value are more than 0 and less than 100%.

The compounds of this invention, including Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4 or its stereoisomer and its any pharmaceutically acceptable salt, ester, metabolin and prodrug, can include the carbon atom of Asymmetrical substitute.The carbon atom of such Asymmetrical substitute can cause the compounds of this invention to exist with enantiomter, diastereoisomer and other stereoisomeric forms in any ratio, and they can be defined according to absolute stereochemical as such as (R)-or (S)-configuration.Therefore, all such possible isomers of the compounds of this invention, the single stereoisomers of optical voidness form, their mixture, racemic mixture (or " racemate "), non-enantiomer mixture, single diastereoisomer are included in the present invention.Term " S " used herein and " R " configuration are according to defined below：IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl.Chem.45：13-30(1976).Term α and β are used for the ring position of cyclic compound.α-side of reference plane is the side that preferred substituent is located at relatively low numbered positions.Those substituents positioned at reference plane opposite side use β descriptors.It should be noted that the usage and the usage for being used for ring-type stereoparent are otherwise varied, " α " refers to " below plane " and represents absolute configuration in ring-type parent nucleus.Term α and beta comfiguration used herein are according to the 203rd section of definition of Chemical Abstracts Index Guide-Appendix IV (1987).

Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4 compound or its dynamic isomer in table 1-5, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt.

The solvate of Formulas I, the solvate of Formulas I -1 or salt preferably its monohydrate, fumarate dihydrate, the ethanolates of fumarate one；Further preferred compound 1100-1105.

In another preference, R in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the compound of Formulas I -4₁、R₂、R₃、R₄It is the specific group of relevant position in particular compound 1-239,301-539,601-893,900-953 in table 1-5.

Another embodiment of the present invention provides a kind of antivirotic, it is characterised in that the antivirotic contains any of solvate of any one or several compounds in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, Formulas I -4 or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt or several as active ingredient.

Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterized in that the pharmaceutical composition includes any of solvate of any one or several compounds or its dynamic isomer in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt or several, and at least one pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterized in that any of solvate comprising any one or several compounds in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, Formulas I -4 or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt or several, and other at least one antiviral drugs.Pharmaceutical composition optimizing injection, oral formulations, freeze drying powder injection, the suspending agent etc..

Another embodiment of the present invention provides purposes of the solvate of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its dynamic isomer in Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in antiviral drugs is prepared.

Another embodiment of the present invention provides application of the solvate of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its dynamic isomer in Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in treatment and/or prevention breathing problem, hand-foot-and-mouth disease, immunity disease, the medicine of inflammatory disease is prepared.

Another embodiment of the present invention provides application of the solvate of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its dynamic isomer in Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in the medicine for preparing treatment and/or the prevention disease as caused by RSV, HSV-1, EV71.The disease is selected from：Fash, bleb and the herpangina at the positions such as breathing problem, pneumonia, gingivostomatitis, keratoconjunctivitis, encephalitis, genital system infection, hand, foot, oral cavity.

Another embodiment of the present invention provides purposes of the solvate of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its dynamic isomer in Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in medicine is prepared.The medicine is used to treat Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), disease caused by Enterovirus 71 (EV71).

Another embodiment of the present invention provides application of the solvate of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its dynamic isomer in Formulas I -4, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in anti-RSV, HSV-1, EV71 lead compound is prepared.

Another embodiment of the present invention provides Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, any one or several compounds or its is mutual in Formulas I -4 Tautomeric, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, application of the solvate in anti-RSV, HSV-1, EV71 drug candidate is prepared of its pharmaceutically acceptable salt or its salt.

Another embodiment of the present invention provides Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the preparation method of the compound of Formulas I -4, comprises the following steps：

Method one：

Step (1)：With 2,4-diamino-butanoic (can be L-type, D types or DL racemies during n=0) or ornithine (can be L-type, D types or DL racemies during n=1) for raw material, in KHSO₄、NaHSO₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂In the presence of, in water or alcoholic solution, reaction temperature is 30 to 120 DEG C (preferably 80 to 120 DEG C), reacts 4 to 120 hours (preferably 12 to 96 hours), obtains Formula II compound.Step reaction can be according to the method disclosed in patent TOHKEMY 2013-53115A or the method being similarly modified on this basis.

Step (2)：Formula II compound is under oxidant effect, and back flow reaction obtains formula III compound in organic solvent.The preferred mCPBA of oxidant or hydrogen peroxide；2.0-4.0 times, further preferred 2.5-3.5 times of the mole of the consumption preferred formula II compounds of oxidant；The preferred acetone of organic solvent, dichloromethane, chloroform, THF.

Step (3)：Formula III compound is in the presence of initiator, alkali, and reaction obtains formula IV compound (i.e. R in organic solvent₃、R₄Formulas I -3, I-4 compounds during for H).Initiator, which is selected from, contains Ag⁺Compound or TEMPO, preferably Ag₂CO₃、AgNO₃、AgOAc、AgOTf、Ag₂O；Alkali preferred alkali metal carbonate or alkali metal hydrogencarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃；The preferred DMF of organic solvent, DMA, THF, acetonitrile, acetone, toluene；Reaction temperature is 0 to 60 DEG C, preferably 20 to 40 DEG C.

Step (4)：Formula IV compound obtains Formula V compound (i.e. R through alkylation reaction or acylation reaction₃、R₄Formulas I -3, I-4 compounds when when different for H), alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₃X or R₄X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₃、R₄Definition with any of the above-described place of the invention to R₃、R₄Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₃X or R₄X (carboxylic acid halides), R₃OR₃Or R₄OR₄(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₃、R₄Definition with any of the above-described place of the invention to R₃、R₄Definition, alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc..The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..

Step (5)：In organic solvent, reaction obtains Formula IV compound (i.e. R to Formula V compound under reducing agent effect₁、R₂Formulas I -1, I-2 compounds during for H).The preferred H of reducing agent₂With Pd/C, H₂And PtO₂、H₂With Raney's nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borine (BH₃、B₂H₆).Preferably -20 DEG C of reaction temperature is to reflux temperature.The preferred dichloromethane of organic solvent, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

Step (6)：VI compounds obtain Formula VII compound (i.e. R through alkylation reaction or acylation reaction₁、R₂Formulas I -1, I-2 compounds when when different for H), alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₁X or R₂X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂Definition with any of the above-described place of the invention to R₁、R₁Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₁X or R₂X (carboxylic acid halides), R₁OR₁Or R₂OR₂(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂Definition with any of the above-described place of the invention to R₃、R₄Definition, alkali is excellent Select alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines.The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..

Method two：

Step (1)：In organic solvent, reaction obtains Formula VIII compound to formula III compound under reducing agent effect.The preferred H of reducing agent₂With Pd/C, H₂And PtO₂、H₂With Raney's nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borine (BH₃、B₂H₆).Preferably -20 DEG C of reaction temperature is to reflux temperature.The preferred dichloromethane of organic solvent, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

Step (2)：Formula VIII compound is in the presence of alkali or Mitsunobu reagents, and reaction obtains Formula IX compound (i.e. R in organic solvent₁、R₂、R₃、R₄Formulas I -1, I-2 compounds when being H).Alkali preferred alkali metal carbonate or alkali metal hydrogencarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃, alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Mitsunobu reagents preferred DEAD and PPh₃, DIAD and PPh₃, DEAD and PEt₃, DIAD and PEt₃；The preferred DMF of organic solvent, DMA, THF, acetonitrile, acetone, dichloromethane, chloroform；Reaction temperature is 0 to 60 DEG C, preferably 20 to 40 DEG C.

Step (3)：Formula IX compound obtains Formula VII compound (i.e. Formulas I -1, I-2 compounds) through alkylation reaction or acylation reaction, and alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₁X、R₂X、R₃X or R₄X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Definition with any of the above-described place of the invention to R₁、R₂、R₃、R₄Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₁X、R₂X、R₃X or R₄X (carboxylic acid halides), R₁OR₁、R₂OR₂、R₃OR₃Or R₄OR₄(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Definition with any of the above-described place of the invention to R₁、R₂、R₃、R₄Definition, alkali preferred alkali metal hydroxide (such as NaOH, KOH), Triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc..The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..

Method three：According to Chinese patent (application number：201510201548.7) record method obtain compound 239 and 539：Then using similar hydrocarbylation in method one, two or it is acylated method of modifying structural modification is carried out to compound 239 and 539, can obtain series and fall into Formulas I, the compound in the range of Formulas I -1.

The synthetic method of formula IV, Formula V, Formula IV, Formula VII, Formula IX is given in above-mentioned synthetic method, it comprises Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, the synthetic method of the compound of Formulas I -4.

Another embodiment of the present invention provides a kind of formula III midbody compound, it is characterised in that formula III has following structure：Chemical bond wherein in diketopiperazine ringRepresent to point to the key in paper simultaneouslyOr simultaneously point to paper outside keyChemical bond in oximidoRepresent with double bond in imines into " Z " or " E " configuration；N is 0 or 1.

Another embodiment of the present invention provides a kind of Formula VIII midbody compound, it is characterised in that Formula VIII has following structure：Chemical bondRepresent to point to the key in paper simultaneouslyOr simultaneously point to paper outside keyN is 0 or 1.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and each technical characteristic specifically described in below (eg embodiment) can be combined with each other, so as to constitute new or preferred technical scheme.As space is limited, no longer tire out one by one herein and state.

Embodiment

For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But these embodiments only are not used for limiting the scope of the present invention or implementation principle for being better understood from invention, embodiments of the present invention are not limited to herein below.

The synthesis of the 2,5- Diketopiperazine derivatives (Formula II) of embodiment 1

Can be according to patent：Synthetic method described in TOHKEMY 2013-53115A, WO2012109256A2, WO2010078373A1, WO2008003626A1 is synthesized；Or according to document：Journal of Asian Natural Products Research,2010,12(1):51-55 and Chinese Journal of Natural Medicines, 2011,9 (1):In 0078-0080 The method of record obtains eleutherazine B or cyclo-di-N^δ- acetyl-L-ornithyl, then using hydrazine hydrate according to document Fitoterapia, 2014; hydrolysis acyl group method described in Vol.98,91-97, hydrolyzes corresponding acyl group; obtain 2, the 5- Diketopiperazine derivatives (compound 1001) of corresponding L-Orn condensation.

Weigh 2.64g L-Orns to be dissolved in 250mL water, add isometric 0.16%KHSO₄Solution, back flow reaction 2 days after being concentrated under reduced pressure, through silica gel column chromatography, obtains 1.36g compounds 1001, yield is about that 60%, HPLC purity is 98.5%.

Using the NaHSO of appropriate amount₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂Replace above-mentioned 0.16%KHSO₄, in water or alcoholic solution, at a temperature of 30 to 120 DEG C, react 4 to 120 hours, compound 1001 obtained with 40% to 60% yield.

Using DL- ornithines, D-Orn, DL-2,4- diaminobutyric acids, 2,4-diaminobutyric acid or D-2,4- diaminobutyric acid replace above-mentioned L-Orn raw material, compound 1002 are obtained with 60% or so yieldCompound 1003Compound 1004Compound 1005Or compound 1006

The Formula II compound oxidation of embodiment 2 is its oximido derivant (formula III)

According to document：Liu Jia, 2014《East China University of Science Ph.D. Dissertation》The method that " the oxidation reaction research of primary amine compound and the synthesis of (+)-Pederin natural products critical segments are explored " benzylamine recorded of page 9 is oxidized to benzaldoxime is improved, Formula II compound (compound 1001-1006) is obtained under oxidant effect, back flow reaction obtains formula III compound in organic solvent；The preferred m-CPBA of oxidant or hydrogen peroxide；2.0-4.0 times, further preferred 2.5-3.5 times of the mole of the consumption preferred formula II compounds of oxidant；The preferred acetone of organic solvent, dichloromethane, chloroform, THF.

Weigh 2.28g compounds 1001 (10mmol) to be dissolved in 100mL acetone, add under 2.5equiv.m-CPBA (25mmol), reflux temperature and react 4 hours, through conventional post processing, silica gel column chromatography, 1.79g compounds 1007 are obtained, yield is about 70% HPLC purity is 98.7%.

Oxidant can be replaced hydrogen peroxide in above-mentioned reaction, and its mole dosage is 2.0-4.0 times of compound 1001, and solvent can be replaced dichloromethane, chloroform, THF；Compound 1007 is obtained with 45% to 75% yield.

Reaction raw materials compound 1001 replaces with compound 1002-1006, obtains compound 1008-1012 respectively with 68%, 72%, 59%, 62%, 57% yield

The formula III compound cyclization formula IV compounds of embodiment 3

Can be according to document：Chem.Commun.,2014,50,6906–6908；Angew.Chem.Int.Ed.2012,51,8816–8820；Chem.Sci.,2013,4,4030–4034；The method of Tetrahedron Vol 41, No.22, pp.5241-5260,1985 grade record carries out appropriate Optimal improvements on this basis, by formula III compound cyclization formula IV compounds.

Weigh 2.56g compounds 1007 (10mmol) to be dissolved in 150mL DMA (DMA), add 1.0equiv.Ag₂CO₃(10mmol)、0.5equiv.K₂CO₃(5mmol), after reacting 24 hours at room temperature, through conventional post processing, silica gel column chromatography, obtains 2.02g compounds 1013, yield is about that 80%, HPLC purity is 98.2%.

Ag in above-mentioned reaction₂CO₃It can be replaced Ag₂CO₃、AgNO₃、AgOAc、AgOTf、Ag₂O or TEMPO, its mole dosage is 1.0-2.0 times of compound 1001, K₂CO₃It can be replaced Na₂CO₃、Rb₂CO₃、Cs₂CO₃；Solvent DMA can be replaced DMF, THF, acetonitrile, acetone, toluene；Reaction temperature can be 0 to 60 DEG C between, compound 1013 is obtained with 65% to 85% yield.

Reaction raw materials compound 1007 replaces with compound 1008-1012, obtains compound 840,1014,900,1015,1016 respectively with 78%, 82%, 65%, 67%, 65% yield

Hydrocarbylation, the acylation modification of the formula IV compound of embodiment 4 obtain Formulas I -3, I-4 compounds

Can be according to document：CN 103396372A；Organic Letters,2011,Vol.13,No.18,4838-4841；Journal of Agricultural and Food Chemistry,2015,Vol.63,3734-3741；Macromolecular Chemistry and Physics,2014,Vol.215,2268-2273；Fitoterapia,2014,Vol.98,91-97；Journal of Organic Chemistry,2011,Vol.76,1155-1158；WO 2014189343A1；Canadian Journal of Chemistry(2014),92(12),1145-1149；European Journal of Medicinal Chemistry(2014),83,236-244；WO 2014060767A1；Journal of Applied Polymer Science (2012); 124 (2); N-H hydrocarbylation in 1707-1715 and other similar 2,5- piperazinedione structures reported in the prior art, the method for being acylated modification, which carry out hydrocarbylation to formula IV compound, is acylated modification obtains Formulas I -3, I-4 compounds.

(1) 252mg compounds 840 (1mmol) are weighed, it is dissolved in 20mL DMF, 2.4equiv.NaH (2.4mmol) is added in three times, at room temperature after stirring half an hour, add 3.0equiv.MeI, reacted at 30 DEG C after 4h, TLC detection reaction raw materials are almost wholly absent, and ethyl acetate is extracted twice, anhydrous sodium sulfate drying organic layer, after concentration, through silica gel column chromatography, obtaining compound 841, (35%) 93.1mg, yield is about, obtaining compound 842, (43%) 120.4mg, yield is about.

MeI in above-mentioned reaction is replaced with into EtBr, i-PrBr, cyclopropane bromide, CF₃I, allyl bromide, bromoallylene, propargyl bromide, diphenyl bromomethane, BnBr, bromocyclohexane, n-C₆H₁₃Br, to bromine chloride, in being reacted 4-12 hours under room temperature to reflux temperature, compound 843-846,848,850-853,855,862,863,873,874,887,888 are obtained with 30% to 81% yield.

(2) 252mg compounds 840 (1mmol) are weighed, 20mL CH are dissolved in₂Cl₂In, add 2.5equiv.Ac₂O (2.5mmol), 0.6mL Et₃N and catalytic amount DMAP, after stirring 2 hours at room temperature, TLC detection reaction raw materials are almost wholly absent, CH₂Cl₂It is extracted twice, anhydrous sodium sulfate drying organic layer, after concentration, through silica gel column chromatography, obtaining compound 865, (111.8mg, yield is about that 38%), obtaining compound 867, (45%) 151.3mg, yield is about.

By Ac in above-mentioned reaction₂O replaces with Boc₂O, BzCl, TFAA, chloracetyl chloride, the formyl chloride of ring third, cyclohexanecarbonyl chloride, caprylyl chloride, caproyl chloride, an azidobenzoyl chlorine, meta-methoxy chlorobenzoyl chloride, react 0.5 to 6 hour at room temperature, compound 868-870,873-886 is obtained with 38% to 88% yield.

(3) 252mg compounds 840 (1mmol) are weighed, are dissolved in 20mL DMF, 2.5equiv. bromobenzenes (2.5mmol), 2.0equiv.K is added₂CO₃(2.0mmol), the CuI of catalytic amount and N, N- dimethyl-ethylenediamine (CAS RN：110-70-3), in after stirring reaction at 110-115 DEG C 12 hours, TLC detection reaction raw materials are almost wholly absent, ethyl acetate is extracted twice, anhydrous sodium sulfate drying organic layer, after concentration, through silica gel column chromatography, obtaining compound 854, (78%) 256mg, yield is about.

Bromobenzene in above-mentioned reaction is replaced with into 1- bromonaphthalenes, 8- bromoquinolines, 3- bromine furans, in being reacted 12 to 24 hours at 100-120 DEG C, compound 856-858 is obtained with 75% to 86% yield.

(4) with compound 848 be raw material according to methylated in above-mentioned (1) or (2) or acetylation method, compound 847,849 is obtained with 89%, 95% yield respectively；It is respectively raw material with compound 862,865, according to the process for acylating described in (2), with Boc₂O is acylating agent, can obtain compound 861,866 (yield more than 90%)；It is respectively raw material with 863,865,870, according to the alkylation described in (2), respectively with bromohexane, n-C₆H₁₃Br、n-C₅H₁₁Br is alkylating agent, can obtain compound 864,872,871 (yield is 75% or so).

(5) 290mg compounds 852 (1mmol) are weighed, it is dissolved in 100mL dichloromethane, add 1.1equiv.1- azido -2- Ethyl Methyl Ethers (1.1mmol), 5mL water, after the sodium ascorbate and cupric sulfate pentahydrate that add catalytic amount, 5h is reacted in 40 DEG C, TLC detection display reactions are completed, the extraction of 200mL dichloromethane is added into reaction solution, and uses water, saturated sodium-chloride washing successively, anhydrous sodium sulfate drying, filtering, after filtrate concentration, through silica gel column chromatography, 332mg compounds 859 are obtained with about 85% yield, HPLC purity is 97.9%.

It is the 1- azido -2- Ethyl Methyl Ethers (2.2mmol) that raw material is measured according to above-mentioned reaction condition, 1 times of increase with compound 853, compound 860 is obtained with about 78% yield.

Wherein, 1- azidos -2- Ethyl Methyl Ethers are prepared as follows：

2-methyl cellosolve (1.0mmol) is dissolved in anhydrous THF (50mL), it is subsequently added triethylamine (4.0mmol), mesyl chloride (4.0mmol) is added dropwise under ice bath, it is stirred overnight at room temperature, TLC detection display reactions are completed, dichloromethane is extracted after solvent evaporated, water is used successively, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, it is dissolved in after concentration in 50mL DMF, it is slowly added into sodium azide (4.0mmol), 105 DEG C of reaction 4h after charging is finished, TLC detection display reactions are completed, it is slowly added into reaction solution after 20mL water, extracted with dichloromethane, water is used successively, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, it is standby after concentration.

(6) weigh 332mg compounds 851 (1.0mmol) to be dissolved in 50mL THF, in BH is added dropwise at 0 DEG C₃·Me₂S (7.0mL, 2.0M in THF, 14.0mmol), clear-cutting forestland is stayed overnight to reaction is stirred at room temperature, and absolute ethyl alcohol (5mL), 3M NaOH (9.0mL) and 30%H are added under ice bath₂O₂Solution (2.0mL), back flow reaction uses CH after 1 hour₂Cl₂Extraction, saturated sodium-chloride washing, anhydrous sodium sulfate drying, filtering after filtrate concentration, through silica gel column chromatography, 269mg compounds 890 is obtained with about 73% yield, HPLC purity is 98.9%.

With compound 850 be raw material according to above-mentioned reaction condition, BH₃·Me₂S, 3 M NaOH and 30%H₂O₂Consumption halve, compound 889 is obtained with about 75% yield.

(7) compound 890 (1.0mmol) is taken to be dissolved in 60mL acetone, in the Jones reagent (Jones reagents) that appropriate new configuration is added at 0 DEG C, clear-cutting forestland is stayed overnight to reaction is stirred at room temperature, through conventional post processing, silica gel column chromatography, compound 892 and compound 893 are obtained with about 46% and 25% yield respectively, HPLC purity is more than 98%.

With compound 889 be raw material according to above-mentioned reaction condition, compound 891 is obtained with about 65% yield, HPLC purity is 98.3%.

Embodiment 5

According to the hydrocarbylation of N-H in 2, the 5- piperazinedione structures described in embodiment 4 or prior art, the method for being acylated modification or the like, the specific R described in table 1-5 can obtain₃、R₄Formulas I -3, the I-4 compounds of modification.

The reduction of the Formula V of embodiment 6 (Formulas I -3, I-4) compound

According to document：CN104529814A；Org.Lett.,2001,3,1637-1639；J.Org.Chem.,1996,61,3849-3862；Tetrahedron,2005,61,5725-5734；J.Org.Chem.,2006,71,7083-7086；Angew.Chem.Int.Ed., 2005,117,5807-5809 or in the prior art other reduction imines methods, by Formula V (Formulas I -3, I-4) reduction obtain Formula IV compound (i.e. R₁、R₂Formulas I -1, I-2 compounds during for H).

Weigh 252mg compounds 1014 (1mmol) to be dissolved in EtOH (50ml), thunder niobium nickel (Raney-Nickel, 1.0g) is added, in 1atm H₂Under effect, in after stirring reaction 12h at 25 DEG C, filtering out thunder niobium nickel, after being concentrated under reduced pressure, compound 1 (220mg, 86%) is obtained.

Above-mentioned reaction raw materials compound 1014 is replaced with into compound 840,1013,900,1015,1016, corresponding reduzate is obtained with similar yield.

The hydrocarbylation or acylation modification of the Formula V of embodiment 7 (Formulas I -3, I-4) compound obtain Formula VII (Formulas I -1, I-2) compound

(1) 256mg compounds 1 (1mmol) are weighed, 30mL CH are dissolved in₂Cl₂In, add 5.5equiv.Ac₂O (5.5mmol), 1.5mL Et₃N and catalytic amount DMAP, after stirring 1.5 hours at room temperature, TLC detection reaction raw materials are almost wholly absent, CH₂Cl₂It is extracted twice, anhydrous sodium sulfate drying organic layer, after concentration, through silica gel column chromatography, compound 2,3,7,8, HPLC purity is obtained more than 98% with 28%, 20%, 18%, 15% yield respectively.

By Ac in above-mentioned reaction₂O replaces with BzCl, TFAA, chloracetyl chloride, the formyl chloride of ring third, propionyl chloride, cyclohexanecarbonyl chloride, valeric chloride, oenanthyl chloro, caprylyl chloride, caproyl chloride, an azidobenzoyl chlorine, meta-methoxy chlorobenzoyl chloride, a fluorobenzoyl chloride, Boc₂O, reacts 0.5 to 8 hour, corresponding monoacylated, double acylations, triacylate and four acylates in table 1 is obtained with 30% to 90% yield at room temperature.

(2) according to the similar hydrocarbylation process described in embodiment 4, using following hydrocarbylating agent：MeI, EtBr, i-PrBr, cyclopropane bromide, CF₃I, allyl bromide, bromoallylene, propargyl bromide, diphenyl bromomethane, BnBr, bromocyclohexane, n-C₆H₁₃Br, 1- bromonaphthalenes, 8- bromoquinolines, 3- bromine furans are replaced with to bromine chloride, a nitrobenzyl bromine, bromobenzene, in being reacted 4-12 hours under room temperature to reflux temperature, corresponding list hydrocarbylation, double hydrocarbylations, trialkyl and tetraalkyl product in table 1 are obtained with 30% to 81% yield.

(3) according to the different hydrocarbylations described in embodiment 4 or different acyl or hydrocarbylation and the synthetic method (relating generally to embodiment 4 (4)) or synthetic method similar on this basis for being acylated the compound modified jointly; using corresponding hydrocarbylation or acylting agent, the product that different hydrocarbylations or different acyl or hydrocarbylation and acylation are modified jointly in table 1 can be prepared.

(4) carboxylic acid condensation method：Weigh 1-Boc- acridine -2- carboxylic acids (201mg, 1.0mmol) it is dissolved in dry toluene (30mL), add DCC (1.0mmol), DMAP (0.17mmol), at room temperature stir 10 minutes, add compound 1 (0.01mmol), be heated to 65 DEG C reaction 48 hours after, after filtering, being concentrated under reduced pressure, through silica gel column chromatography, it is respectively 97.8%, 98.3% to obtain compound 49 and 50, HPLC purity respectively with 43%, 45% yield.(the 1-Boc- acridine -2- carboxylic acids used in the reaction are racemic modification, also can prepare corresponding isomers using the 1-Boc- acridine -2- carboxylic acids of single D or L-configuration)

1-Boc- acridines -2- carboxylic acids in above-mentioned reaction are replaced with In reaction 24 to 48 hours at 60 to 80 DEG C, double condensation product in table 1 (such as 55,56,176,181,188,193,205,214,231,236) and 40% or so single condensation product (such as 177,182) are obtained with 30% to 50% yield, above-mentioned double condensation product can be under conditions of this area routinely de- Ac or Boc, and partial removal or whole removing Ac or Boc obtain compound 54,239 in table 1.Wherein, single condensation product with above-mentioned carboxylic acid can be condensed again and formed after asymmetric double condensation product, and the reaction such as method progress hydrocarbylation, acylation, reduction, oxidation, click recorded according still further to the present invention obtains having in table 1 compound accordingly replaced.Above-mentioned Boc, Ac, Me, the carboxylic acid of propargyl protection, can be by corresponding carboxylic acid and Boc₂O、Ac₂It is prepared by the reaction such as O, MeI, propargyl bromide.

For example, compound 1 DCC, DMAP effect under, first withReaction 10 hours, the main single condensation product of production, then again withAfter reaction 20 hours, under MeONa-MeOH effects, the Ac on removing side chain can obtain compound 206, three step total recoverys are up to 42%.Note：Obtaining compoundAfterwards, it can carry out methylating after modification, then the Ac under MeONa-MeOH effects on removing side chain, can obtain compound 208, total recovery is up to 33%.

Using the condensation condition in the reducing condition and the present embodiment in embodiment 6, compound 228 can be obtained with 63% total recovery, HPLC purity is 96.5%.

(5) partial reduction of pendant double bonds and Restore All after being condensed：Weigh Compound 239 (0.1mmol) is dissolved in 10mLCH₃OH-CH₂Cl₂In (volume ratio 1:1) Pd-C of catalytic amount, is added, at room temperature in 1atm H₂After the lower reaction 2h of effect, Pd-C is filtered to remove, compound 52,53 is obtained with 45%, 48% yield respectively through silica gel column chromatography after concentration, HPLC purity is respectively 98.5%, 99.0%.In table 1 other side chains contain the compound of double bond can be by above-mentioned reaction condition, by double bond part Or Restore All.

The addition of pendant double bonds after condensation：Using reagent (such as BH similar in embodiment 4 (6)₃·Me₂S, 3 M NaOH and 30%H₂O₂) reacted.For example compound 236 can use above-mentioned reaction condition to prepare compound 237 with 80% yield；While obtaining 8% or so Markovnikov addition product 238.

The oxidation of pendant hydroxyl group after condensation：Using Jones reagent oxidations in embodiment 4 (7), the product for containing single or double carboxyl in side chain can obtain.Such as compound 239 obtains compound 59,60, HPLC purity more than 98% with 32%, 48% yield respectively under the effect of Jones reagents.

The glycosylation modification of embodiment 8

(1) Weigh Compound 1 (0.1mmol) and the glucose tri- chloroacetimidate (0.22mmol) of the full benzoyl protections of 2.2equiv. are dissolved in the CH of 20mL dryings₂Cl₂In, addMolecular sieve, is stirred after half an hour at room temperature under argon gas protection, and at 0 DEG C, 0.1equiv.TMSOTf (0.01mmol) is added dropwise, keeps after 0 DEG C of stirring reaction half an hour, TLC detections raw material almost hour, is filtered to removeMolecular sieve, after being concentrated under reduced pressure, it is dissolved in methanol, add proper amount of methanol sodium and adjust pH 9.0~10.0, stirring reaction is after 2 hours, plus in cationic ion-exchange resin and pH to 7.0 or so, it is concentrated under reduced pressure, after silica gel column chromatography, it is respectively 96.5%, 97.2% to obtain compound 41,42, HPLC purity respectively with 38%, 42% yield.

The glucose tri- chloroacetimidate that the galactolipin tri- chloroacetimidate protected with full benzoyl replaces the full benzoyl protection in above-mentioned reaction can obtain compound 43,44 with similar yield

After above-mentioned glycosylation reaction, carried out using the methylation method described in embodiment 4 after methylation reaction, then benzoyl is removed under the conditions of MeONa-MeOH, can obtain compound 45-48, yield is 60% or so.

(2) Weigh Compound 239 (0.1mmol) and the glucose tri- chloroacetimidate (0.22mmol) of the full benzoyl protections of 2.2equiv. are dissolved in the CH of 20mL dryings₂Cl₂In, addMolecular sieve, is stirred after half an hour at room temperature under argon gas protection, and at 0 DEG C, 0.1equiv.TMSOTf (0.01mmol) is added dropwise, and keeps 0 DEG C of stirring reaction after 1.5 hours, TLC detections raw material almost hour, is filtered to removeMolecular sieve, after being concentrated under reduced pressure, is dissolved in methanol, adds proper amount of methanol sodium and adjusts pH 9.0~10.0, and stirring reaction is after 2 hours, plus in cationic ion-exchange resin and pH is to 7.0 or so, is concentrated under reduced pressure, after silica gel column chromatography, respectively It is respectively 97.5%, 97.3% to obtain compound 57,58, HPLC purity with 45%, 33% yield.

The side chain Click of embodiment 9 reacts

Weigh Compound 231 (1mmol), it is dissolved in 100mL dichloromethane, add 2.2equiv. triazonmethane (2.2mmol), 8mL water, after the sodium ascorbate and cupric sulfate pentahydrate that add catalytic amount, 4.5h is reacted in 40 DEG C, TLC detection display reactions are completed, the extraction of 200mL dichloromethane is added into reaction solution, and uses water, saturated sodium-chloride washing successively, anhydrous sodium sulfate drying, filtering, after filtrate concentration, through silica gel column chromatography, compound 232 is obtained with about 80% yield, HPLC purity is 97.3%.

Embodiment 10

According to the method described in embodiment 1-9 or in the prior art similar reaction or this area is carried out on its basis routinely replace, 840,1014,1013,900,1015,1016 are used for raw material, any compound in table 1-5 can be prepared, all of above compound is passed through¹H NMR, ESI-MS carry out structural identification and HPLC purity testings, part of compounds through CD,¹H-¹H COSY, HMQC, HMBC, NOESY carry out structural identification.As space is limited, the present invention, which is all in table 1-5, lists ESI-MS data.Acyl chlorides used in synthetic method of the present invention, can be prepared by respective acids according to the conventional acyl chlorides preparation method in this area, i.e., respective acids are prepared with thionyl chloride or oxalyl chloride reaction.

Compound and its active testing result prepared by the present invention of embodiment 11

Antiviral activity method of testing：The compounds of this invention is according to patent to the inhibitory activity of Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), Enterovirus 71 (EV71)：CN104800212A；What the method described in CN104774159A was tested.Antiviral activity test can also be according to document：Zhang,Y.J.；Stein,D.A.；Fan,S.M.；Wang,K.Y.；Kroeker,A.D.；Meng,X.J.；Iversen,P.L.；Matson,D.O.Vet.Microbiol.2006,117(2-4),117-129；Method described in CN104004042A is tested, or is tested using other similar method of testings in the prior art.

The present invention tests all compounds to Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), the inhibitory activity of Enterovirus 71 (EV71), in order to the convenience write of the present invention and be easy to it is more concise intuitively understand the present invention, the ESI-MS of the compounds of this invention is only listed below and its to Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), the inhibitory activity data (being shown in Table 1-5) of Enterovirus 71 (EV71).

As space is limited, the typical compound of the invention only listed in Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, Formulas I -4 is in table 1-5.

Table 12 (R), the compound of Formulas I -1, ESI-MS and antiviral (RSV, HSV-1, EV71) activity data of 2 ' (R) configurations

Table 22 (S), the compound of Formulas I -1, ESI-MS and antiviral (RSV, HSV-1, EV71) activity data of 2 ' (S) configurations

Table 32 (R), 2 ' (R) configurations and 2 (S), the compound of racemic modification Formulas I -2, ESI-MS and antiviral (RSV, HSV-1, EV71) activity data of 2 ' (S) configuration mixed in equal amounts

2 (R) respectively obtained after the chiral fractionations of compound 601-839 in table 3, the isomers of 2 ' (R) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 601-839 in table 3 definition it is identical) and 2 (S), the isomers of 2 ' (S) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 601-839 in table 3 definition it is identical).

2 (R) that above-mentioned chiral resolution is obtained, the isomers, 2 (S) of 2 ' (R) configurations, the isomers of 2 ' (S) configurations shows equal antiviral activity in anti-RSV, HSV-1, EV71 active testing, the antiviral activity no significant difference with its racemate compound 601-839.The above results show that enantiomter compound and racemate compound show equal antiviral activity in terms of antiviral (RSV, HSV-1, EV71) activity.The spatial configuration of 2,2 ' positions has no significant effect to antiviral activity.

Table 42 (R), 2 ' (R) configurations and 2 (S), the compound of racemic modification Formulas I -3, ESI-MS and antiviral (RSV, HSV-1, EV71) activity data of 2 ' (S) configuration mixed in equal amounts

2 (R) respectively obtained after the chiral fractionations of compound 840-893 in table 4, the isomers of 2 ' (R) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 840-893 in table 4 definition it is identical) and 2 (S), the isomers of 2 ' (S) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 840-893 in table 4 definition it is identical).

2 (R) that above-mentioned chiral resolution is obtained, the isomers, 2 (S) of 2 ' (R) configurations, the isomers of 2 ' (S) configurations shows equal antiviral activity in anti-RSV, HSV-1, EV71 active testing, the antiviral activity no significant difference with its racemate compound 840-893.The above results show that enantiomter compound and racemate compound show equal antiviral activity in terms of antiviral (RSV, HSV-1, EV71) activity.The spatial configuration of 2,2 ' positions has no significant effect to antiviral activity.

Table 52 (R), 2 ' (R) configurations and 2 (S), the compound of racemic modification Formulas I -4 of 2 ' (S) configuration mixed in equal amounts, ESI-MS and it is antiviral (RSV, HSV-1, EV71) activity data

2 (R) respectively obtained after the chiral fractionations of compound 900-953 in table 5, the isomers of 2 ' (R) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 900-953 in table 5 definition it is identical) and 2 (S), the isomers of 2 ' (S) configurations：(R₁、R₂、R₃、R₄Definition group corresponding with compound 900-953 in table 5 definition it is identical).

2 (R) that above-mentioned chiral resolution is obtained, the isomers, 2 (S) of 2 ' (R) configurations, the isomers of 2 ' (S) configurations shows equal antiviral activity in anti-RSV, HSV-1, EV71 active testing, the antiviral activity no significant difference with its racemate compound 900-953.The above results show that enantiomter compound and racemate compound are at antiviral (RSV, HSV-1, EV71) Active aspect shows equal antiviral activity.The spatial configuration of 2,2 ' positions has no significant effect to antiviral activity.

" A " represents the half-inhibition concentration (IC of compound in table 1-5₅₀) it is 1-500ng/mL, " B " represents the half-inhibition concentration (IC of compound₅₀) it is 1.0-20 μ g/mL, " C " represents the half-inhibition concentration (IC of compound₅₀) be more than for 50 μ g/mL.

ClCH in table 1-5₂C (O) represents chloracetyl；CF₃C (O) represents trifluoroacetyl group；C_nH_2n+1Represent alkyl (n is 4,5,6,7,8)；SymbolRepresent R₁、R₂、R₃、R₃The bonded site of group and N in Formulas I, Formulas I -2, Formulas I -3, the structure of Formulas I -4；.

The preparation of the solvate of compound and its salt in the table 1-5 of embodiment 12

(1) preparation of the ethanolates of fumarate one and fumarate dihydrate

By taking the fumarate solvate of compound 239,539 as an example：

Weigh Compound 239,539 each 100mg are dissolved in 8mL absolute ethyl alcohols respectively, at room temperature, 1.0equiv. fumaric acid and 7mL absolute ethyl alcohols is added thereto, be heated to 60 DEG C stirring 1 minute after (fumaric acid is completely dissolved), it is cooled at room temperature, continues to stir two hours, precipitation is collected by filtration, dry, respectively obtain the ethanolates 1100 (98mg) of fumarate one and 1101 (105mg)；Above-mentioned solvate 1100,1101 each 50mg are weighed respectively in being dissolved at 60 DEG C in 5mL ethanol and 1mL water, it is filtered to remove insoluble matter, and be stirred at room temperature 12 hours, precipitation is collected by filtration, after drying, obtained solid is placed in 25 DEG C, under conditions of 60% relative humidity, two days is stood, obtains fumarate dihydrate 1102 (43mg) and 1103 (40mg).Through¹H NMR, solid-state¹³C NMR or specific rotatory power test do not find that racemization phenomenon occurs for the solvate containing chiral amino acid in above-mentioned solvate.

(2) preparation of monohydrate

By taking the solvate of compound 239,539 and its salt as an example：

Weigh Compound 239,539 each 10mg are suspended in 10mL water respectively, in being stirred two hours at 28-30 DEG C, precipitation is collected by filtration, solid will be obtained and be placed in 35 DEG C, under conditions of 75% relative humidity, 3 days are stood, monohydrate 1104 (7.2mg) and 1105 (7.8mg) is obtained.

The structure of compound 239, the solvate of 539 salt or solvate 1100-1105 is as follows：

The solvate or solvate 1100-1105 of above-mentioned salt have carried out differential thermal analysis/thermogravimetric analysis, elementary analysis, infrared absorption spectroscopy, solid-state respectively¹³C-NMR is analyzed, and differential thermogravimetric analysis data are only listed below：Using Thermo plus TG8120 differential thermogravimetric analysis instrument, (sample size for being used to measure is respectively 3-5mg, the rate of heat addition：10 DEG C/min, primary standard substance：Aluminum oxide) carry out differential thermogravimetric analysis, endothermic peak：72.1-85.3 DEG C nearby has an endothermic peak, and 177.2-180.3 DEG C nearby has an endothermic peak.

The storage stability test of embodiment 13

(the results are shown in Table 6) under conditions of 40 DEG C, 75% relative humidity and 50 DEG C of open-top receptacles in, compound 1100-1105 is stored respectively, and detect 2 months after storage stability.On storage stability, by HPLC to it is initial when and storage 2 months after the purity of each test compound measure, and (specific method can be found in the method described in WO2009128421A1) is compared to result.

The storage stability test under conditions of 40 DEG C, 75% relative humidity of table 6

The solvate of solvate or salt has extremely excellent storage stability it can be seen from the test result in table 6, in addition, testing experiment displays that the purity of solvate after two months has almost no change in 50 DEG C of open-top receptacles, and compound 239th, 539 purity is reduced more than 3%, thus can also find out that the solvate of solvate or salt has the advantages that ultrastability, is easy to long term storage.

Except the compound in other Formulas I of the chemical combination beyond the region of objective existence described in table 1-5 of the present invention, I-1, I-2, I-3, I-4 range of structures can also be synthesized according to the embodiment 1-10 methods recorded.All dinitrogen oxa- ring spiral shell diketopiperazine alcaloid-derivatives (Formulas I, Formulas I -1, Formulas I -2, Formulas I -3, Formulas I -4) of the present invention are respectively provided with significant inhibitory action to RSV, HSV-1, EV71, its half-inhibition concentration (IC₅₀) 1 to 500ng/mL, and median toxic concentration (TC₅₀) in 10-300 μ g/mL, it is seen that the compounds of this invention or its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt can be used for preparing treatment and/or prevention breathing problem, hand-foot-and-mouth disease, immunity disease, the lead compound of inflammatory disease, drug candidate, medicine.

All documents referred in the present invention are all incorporated as bibliography in this application, are individually recited just as each document as with reference to such.In addition, it is to be understood that after the above of the present invention has been read, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims limited range.

Claims

The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure a kind of, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt, it is characterised in that compound of formula I has following structure：

Wherein R₁、R₂、R₃、R₄It is each independently selected from H, alkyl, cycloalkyl, alkyl acyl, alkoxyacyl, cycloalkanoyl, alkenyl, alkenylacyl, alkynyl, alkynylacyl, aryl, aryl alkyl, aryl-acyl, heteroaryl, heteroaryl alkyl, heteroaroyl, saturation or unsaturated heterocycle base, saturation or unsaturated heterocycle base alkyl, saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl；N is 0 or 1；Chemical bondRepresent to point to the key in paperOr the key outside sensing paper" --- -- " represents singly-bound or is not present, and when " --- -- " represents singly-bound, R₁、R₂It is not present；Precondition is to work as R₃、R₄When simultaneously for H, R₁、R₂It is asynchronouslySymbolRepresent R₁、R₂The bonded site of group and N in Formulas I structure.
The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure described in claim 1, it is characterised in that R₁、R₂、R₃、R₄It is each independently selected from H, C1-C8 alkyl, C1-C8 alkyl acyls, C1-C8 alkoxyl acyl group, C3-C10 cycloalkyl, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C12 heteroaryls, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaroyls, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base C1-C4 alkyl, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl.
The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure described in claim any one of 1-2, it is characterised in that R₁、R₂、R₃、R₄It is each independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyls, C1-C8 alkyl acyls, C1-C8 haloalkyl acyl groups, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C10 heteroaryls, C5-C10 heteroaryl C1-C4 alkyl, C5-C10 heteroaroyls, C5-C12 saturations or unsaturated heterocycle base, C5-C12 saturations or unsaturated heterocycle base C1-C4 alkyl, C5-C12 saturations or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, methyl, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies, the substitution of one or more of phenyl；Hetero atom in the heterocyclic radical that is related in above-mentioned group, heteroaryl is only The on the spot 1-5 hetero atom in N, O, S or Se.
The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure described in claim any one of 1-3, it is characterised in that R₃、R₄It is each independently H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇, 3- hydroxyl-propyls2- CARBOXY-ETHYLsP-chlorobenzyl, a nitrobenzyl, phenyl, furans -3- bases, naphthalene -1- bases, quinoline-8-yl, trifluoromethyl, acetyl group, chloracetyl (ClCH₂CO), propiono, valeryl, caproyl, heptanoyl group, caprylyl, ring propiono, cyclohexanoyl, benzoyl, a fluoro benzoyl, meta-methoxy benzoyl, an azidobenzoyl, trifluoroacetyl group, pi-allyl, acetenyl, propargyl, tertbutyloxycarbonyl, cyclopropyl, cyclopenta, cyclohexyl, azetidine, THP trtrahydropyranyl, benzhydrylR₁、R₂It is each independently H, C1-C8 alkyl, C1-C8 alkyl acyls, C1-C8 alkoxyl acyl group, C3-C10 cycloalkyl, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenylacyls, C2-C8 alkynyls, C2-C8 alkynylacyls, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl-acyls, C5-C12 heteroaryls, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaroyls, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base C1-C4 alkyl, 4 yuan to 12 yuan of saturation or unsaturated heterocycle base acyl group；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl group), sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxies (such as methoxyl group, ethyoxyl, tert-butoxy), the substitution of one or more of phenyl.
The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure described in claim any one of 1-4, it is characterised in that R₃、R₄It is each independently H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇, 3- hydroxyl-propyls2- CARBOXY-ETHYLsP-chlorobenzyl, a nitrobenzyl, phenyl, furans -3- bases, naphthalene -1- bases, quinoline-8-yl, trifluoromethyl, acetyl group, chloracetyl (ClCH₂CO), propiono, valeryl, caproyl, heptanoyl group, caprylyl, ring propiono, cyclohexanoyl, benzoyl, a fluoro benzoyl, meta-methoxy benzoyl, an azidobenzoyl, trifluoroacetyl group, pi-allyl, acetenyl, propargyl, tertbutyloxycarbonyl, cyclopropyl, cyclopenta, cyclohexyl, azetidine, THP trtrahydropyranyl, benzhydrylR₁、R₂It is each independently n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3- Methyl pentyls, 2- Methyl pentyls, 2- Methyl-hexyls, 3- Methyl-hexyls, 3- ethyl hexyls, the fluoro- 3- Methyl pentyls of 1-, the fluoro- 2- Methyl pentyls of 1-, the fluoro- 2- Methyl-hexyls of 1-, the fluoro- 3- Methyl-hexyls of 1-, the fluoro- 3- ethyl hexyls of 1-, the chloro- 3- Methyl pentyls of 1-, 1- chloro-2-methyls-amyl group, 1- chloro-2-methyls-hexyl, the chloro- 3- Methyl-hexyls of 1-, the chloro- 3- ethyl hexyls of 1-, the bromo- 3- Methyl pentyls of 1-, the bromo- 2- Methyl pentyls of 1-, the bromo- 2- Methyl-hexyls of 1-, the bromo- 3- Methyl-hexyls of 1-, the bromo- 3- ethyl hexyls of 1-, acetyl group, propiono, positive bytyry, isobutyryl, positive valeryl, isovaleryl, pivaloyl group, positive caproyl, positive heptanoyl group, positive caprylyl, 3- methyl-pentanoyls, 2- methyl-pentanoyls, 2- Methyl-hexanoyls, 3- Methyl-hexanoyls, 3- ethyls-caproyl, acetyl group, propiono, positive bytyry, isobutyryl, positive valeryl, isovaleryl, pivaloyl group, positive caproyl, positive heptanoyl group, positive caprylyl, 3- methyl-pentanoyls, 2- methyl-pentanoyls, 2- Methyl-hexanoyls, 3- Methyl-hexanoyls, 3- ethyls-caproyl, trifluoroacetyl group, two acetyl fluorides, chloracetyl, acetyl bromide, five fluorine propionos, perfluorobutyrl, the fluoro- 3- methyl-pentanoyls of 1-, the fluoro- 2- methyl-pentanoyls of 1-, the fluoro- 2- methyl of 1- - caproyl,The fluoro- 3- Methyl-hexanoyls of 1-,The fluoro- 3- ethyls-caproyls of 1-,The chloro- 3- methyl-pentanoyls of 1-,1- chloro-2-methyls-valeryl,1- chloro-2-methyls-caproyl,The chloro- 3- Methyl-hexanoyls of 1-,The chloro- 3- ethyls-caproyls of 1-,The bromo- 3- methyl-pentanoyls of 1-,The bromo- 2- methyl-pentanoyls of 1-,The bromo- 2- Methyl-hexanoyls of 1-,The bromo- 3- Methyl-hexanoyls of 1-,The bromo- 3- ethyls-caproyls of 1-,Vinyl,Acrylic,Pi-allyl,N-butene base,Isobutenyl,But-2-ene base,Butadienyl,N-pentene base,Isopentene group,Pentadienyl,N-hexylene base,Nhepene base,Heptadiene base,Heptantriene base,Positive octenyl,Octadienyl,Sarohornene base,3- methyl-amyl- 2- alkenyls,2- methyl-amyl- 2- alkenyls,2- methyl-hex- 2- alkenyls,3- methyl-hex- 2- alkenyls,3- ethyls-hex- 2- alkenyls,Propiono,But-2-ene acyl group,Methacrylyl,Amyl- 3- enoyl-s,Iso-amylene acyl group,Pentadiene acyl group,Hex- 4- enoyl-s,Hept- 5- enoyl-s,Heptadiene acyl group,Heptantriene acyl group,Oct-6-ene acyl group,Octadiene acyl group,Sarohornene acyl group,3- methyl-amyl- 2- enoyl-s,2- methyl-amyl- 2- enoyl-s,2- methyl-hex- 2- enoyl-s,3- methyl-hex- 2- enoyl-s,3- ethyls-hex- 2- enoyl-s,Acetenyl,Propinyl,Positive butynyl,Butyl- 2- alkynyls,Positive pentynyl,Isoamyl alkynyl,Positive hexin base,Positive heptynyl,Heptadiyne base,Positive octynyl,Pungent diynyl,Pungent three alkynyl,2- methyl-amyl- 2- alkynyls,2- methyl-hex- 2- alkynyls,3- methyl-hex- 2- alkynyls,3- ethyls-hex- 2- alkynyls,Alkynes propiono,Positive butynyl acyl group,Butyl- 2- alkynylacyls,Positive pentynyl acyl group,Isoamyl alkynylacyl,Positive hexin base acyl group,Positive heptynyl acyl group,Heptadiyne base acyl group,Positive octynyl acyl group,Pungent diynyl acyl group,Pungent three alkynylacyl,2- methyl-amyl- 2- alkynylacyls,2- methyl-hex- 2- alkynylacyls,3- methyl-hex- 2- alkynylacyls,3- ethyls-hex- 2- alkynylacyls,Phenyl,Naphthyl,Benzyl,Phenethyl imidazole radicals,Pyridine radicals,Oxazolyl,Isoxazolyl,Triazol radical,Tetrazole base,Furyl,Quinolyl,Oxazinyl,Thienyl,Thiazolyl,Thiadiazolyl group,Indyl,Carbazyl,Isoquinolyl,Benzofuranyl,Benzothiazolyl,Selenole base,Cumarin base,Isocoumarin base,Azetidinyl,Oxetanyl,Morpholinyl,Piperidyl,Piperazinyl,Tetrahydrofuran base,Dioxane base,Oxazoline,Thiazolinyl,THP trtrahydropyranyl,Dihydrocoumarin base,Dihydroiso-coumarin base,Tetrahydric quinoline group,Tetrahydro isoquinolyl,Tetrahydro carbazole base,Pyrimidine bases,Purine bases；Above-mentioned R₁、R₂、R₃、R₄Group is optionally by hydroxyl, methylol, carboxyl, acetylamino, sulfydryl, halogen, nitro, amino, azido (- N₃), guanidine radicals, cyano group, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O), thio (=S), sulfonyl, methoxyl group, ethyoxyl, one or more of substitution.
The dinitrogen oxa- ring spiral shell diketopiperazine alkaloid compound of Formulas I structure described in claim any one of 1-5, it is characterised in that the solvate of compound 1-238,301-538,601-893,900-953 or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in table 1-5.
A kind of structure of Formulas I -1 bisoxazines alkane spiral shell diketopiperazine alkaloid compound, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -1 has following structure：

R₁、R₂、R₃、R₄Definition with any one of claim 1-6 definition.
The Shuan isoxazole alkyl spiral shell diketopiperazines alkaloid compound of structure of Formulas I -2 a kind of, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -2 has following structure：

R₁、R₂、R₃、R₄Definition with any one of claim 1-6 definition.
A kind of structure of Formulas I -3 bisoxazines quinoline spiral shell diketopiperazine alkaloid compound, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -3 has following structure：

R₃、R₄Definition with any one of claim 1-6 definition.
The Shuan isoxazoline spiral shell diketopiperazines alkaloid compound of structure of Formulas I -4 a kind of, its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, the solvate of its pharmaceutically acceptable salt or its salt, it is characterised in that the compound of Formulas I -4 has following structure：

R₃、R₄Definition with any one of claim 1-6 definition.
The solvate of solvate or salt described in claim any one of 1-10 is selected from：Monohydrate, dihydrate, trihydrate, a methanol solvate, diformazan alcohol adduct, an acetonitrile compound, diacetonitrile compound, an acetone compound, two acetone compounds, hemifumarate monohydrate, fumarate dihydrate, the ethanolates of fumarate one；It is preferred that monohydrate, fumarate dihydrate, the ethanolates of fumarate one.
The solvate of solvate or salt described in claim 11 is selected from following compound：
Pharmaceutically acceptable salt described in claim any one of 1-10 is selected from：Hydrochloride, sulfate, phosphate, oxalates, maleate, methane sulfonates, succinate, citrate, fumarate, glucuronate salt, formates, acetate, succinate.
A kind of pharmaceutical composition, it is characterised in that any of solvate containing any one or several compounds or its dynamic isomer described in claim any one of 1-13, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt in the pharmaceutical composition several is used as active ingredient.
Pharmaceutical composition described in claim 14, it is characterised in that the pharmaceutical composition is also comprising at least one pharmaceutically acceptable carrier, diluent or excipient.
Pharmaceutical composition described in claim 15, it is characterised in that the pharmaceutical composition is also comprising other at least one antiviral drugs.Pharmaceutical composition optimizing injection, oral formulations, freeze drying powder injection, the suspending agent etc..
The purposes of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt any one of claim 1-13 or the pharmaceutical composition any one of the solvate or claim 14-16 of its salt in antiviral drugs is prepared.
The application of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt any one of claim 1-13 or the pharmaceutical composition any one of the solvate or claim 14-16 of its salt in treatment and/or prevention breathing problem, hand-foot-and-mouth disease, immunity disease, the medicine of inflammatory disease is prepared.
The application of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt any one of claim 1-13 or the pharmaceutical composition any one of the solvate or claim 14-16 of its salt in the medicine for preparing treatment and/or the prevention disease as caused by RSV, HSV-1, EV71.The disease is selected from：Fash, bleb and the herpangina at the positions such as breathing problem, pneumonia, gingivostomatitis, keratoconjunctivitis, encephalitis, genital system infection, hand, foot, oral cavity.
The purposes of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt any one of claim 1-13 or the pharmaceutical composition any one of the solvate or claim 14-16 of its salt in medicine is prepared.The medicine is used to treat Respiratory Syncytial Virus(RSV) (RSV), herpes simplex virus (HSV-1), disease caused by Enterovirus 71 (EV71).
Application of the solvate of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt any one of claim 1-13 in anti-RSV, HSV-1, EV71 lead compound is prepared.
Application of the solvate of compound or its dynamic isomer, its stereoisomer, its racemic modification, the non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt any one of claim 1-13 in anti-RSV, HSV-1, EV71 drug candidate is prepared.
The preparation method of Formulas I, Formulas I -1, Formulas I -2, Formulas I -3 or the compound of Formulas I -4 described in claim any one of 1-10, comprises the following steps：

Method one：

Step (1)：With 2,4-diamino-butanoic (can be L-type, D types or DL racemies during n=0) or ornithine (can be L-type, D types or DL racemies during n=1) for raw material, in KHSO₄、NaHSO₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂In the presence of, in water or alcoholic solution, reaction temperature is 30 to 120 DEG C (preferably 80 to 120 DEG C), reacts 4 to 120 hours (preferably 12 to 96 hours), obtains Formula II compound.Step reaction can be according to the method disclosed in patent TOHKEMY 2013-53115A or the method being similarly modified on this basis.

Step (2)：Formula II compound is under oxidant effect, and back flow reaction obtains formula III compound in organic solvent.The preferred mCPBA of oxidant or hydrogen peroxide；2.0-4.0 times, further preferred 2.5-3.5 times of the mole of the consumption preferred formula II compounds of oxidant；The preferred acetone of organic solvent, dichloromethane, chloroform, THF.

Step (3)：Formula III compound is in the presence of initiator, alkali, and reaction obtains formula IV compound (i.e. R in organic solvent₃、R₄Formulas I -3, I-4 compounds during for H).Initiator, which is selected from, contains Ag⁺Compound or TEMPO, preferably Ag₂CO₃、AgNO₃、AgOAc、AgOTf、Ag₂O；Alkali preferred alkali metal carbonate or alkali metal hydrogencarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃；The preferred DMF of organic solvent, DMA, THF, acetonitrile, acetone, toluene；Reaction temperature is 0 to 60 DEG C, preferably 20 to 40 DEG C.

Step (4)：Formula IV compound obtains Formula V compound (i.e. R through alkylation reaction or acylation reaction₃、R₄Formulas I -3, I-4 compounds when when different for H), alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₃X or R₄X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₃、R₄Definition with any of the above-described place of the invention to R₃、R₄Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₃X or R₄X (carboxylic acid halides), R₃OR₃Or R₄OR₄(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₃、R₄Definition with any of the above-described place of the invention to R₃、R₄Definition, alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc..The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..

Step (5)：In organic solvent, reaction obtains Formula IV compound (i.e. R to Formula V compound under reducing agent effect₁、R₂Formulas I -1, I-2 compounds during for H).The preferred H of reducing agent₂With Pd/C, H₂And PtO₂、H₂With Raney's nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borine (BH₃、B₂H₆).Preferably -20 DEG C of reaction temperature is to reflux temperature.The preferred dichloromethane of organic solvent, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

Step (6)：VI compounds obtain Formula VII compound (i.e. R through alkylation reaction or acylation reaction₁、R₂Formulas I -1, I-2 compounds when when different for H), alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₁X or R₂X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂Definition with any of the above-described place of the invention to R₁、R₁Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₁X or R₂X (carboxylic acid halides), R₁OR₁Or R₂OR₂(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂Definition with any of the above-described place of the invention to R₃、R₄Definition, alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc..The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..

Method two：

Step (1)：In organic solvent, reaction obtains Formula VIII compound to formula III compound under reducing agent effect.The preferred H of reducing agent₂With Pd/C, H₂And PtO₂、H₂With Raney's nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borine (BH₃、B₂H₆).Preferably -20 DEG C of reaction temperature is to reflux temperature.The preferred dichloromethane of organic solvent, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

Step (2)：Formula VIII compound is in the presence of alkali or Mitsunobu reagents, and reaction obtains Formula IX compound (i.e. R in organic solvent₁、R₂、R₃、R₄Formulas I -1, I-2 compounds when being H).Alkali preferred alkali metal carbonate or alkali metal hydrogencarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃, alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Mitsunobu reagents preferred DEAD and PPh₃, DIAD and PPh₃, DEAD and PEt₃, DIAD and PEt₃；The preferred DMF of organic solvent, DMA, THF, acetonitrile, acetone, dichloromethane Alkane, chloroform；Reaction temperature is 0 to 60 DEG C, preferably 20 to 40 DEG C.

Step (3)：Formula IX compound obtains Formula VII compound (i.e. Formulas I -1, I-2 compounds) through alkylation reaction or acylation reaction, and alkylation reaction condition is this area normal condition：In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, the wherein preferred R of hydrocarbonylation reagent₁X、R₂X、R₃X or R₄X (halogenated hydrocarbons), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Definition with any of the above-described place of the invention to R₁、R₂、R₃、R₄Definition；Alkali preferred alkali metal carbonate (preferably Na₂CO₃、K₂CO₃、Cs₂CO₃), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali alcoholate (preferably CH₃ONa、EtONa、t-BuOK)；Acylation reaction condition is also this area normal condition：In organic solvent, reacted under alkali, acylating reagent effect, the wherein preferred R of acylating reagent₁X、R₂X、R₃X or R₄X (carboxylic acid halides), R₁OR₁、R₂OR₂、R₃OR₃Or R₄OR₄(acid anhydrides), wherein X are halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Definition with any of the above-described place of the invention to R₁、R₂、R₃、R₄Definition, alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc..The above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, THF, ether, glycol dimethyl ether, DMF, dioxane etc..
A kind of formula III midbody compound, it is characterised in that formula III has following structure：Chemical bond wherein in diketopiperazine ringRepresent to point to the key in paper simultaneouslyOr simultaneously point to paper outside keyChemical bond in oximidoRepresent with double bond in imines into " Z " or " E " configuration；N is 0 or 1.
A kind of Formula VIII midbody compound, it is characterised in that Formula VIII has following structure：Chemical bondRepresent to point to the key in paper simultaneouslyOr simultaneously point to paper outside keyN is 0 or 1.