CN106795174B

CN106795174B - Antiviral active diazacyclospirodiketopiperazine alkaloid derivative and preparation method thereof

Info

Publication number: CN106795174B
Application number: CN201680002296.8A
Authority: CN
Inventors: 于跃
Original assignee: Yangzhou Blue Biomedical Technology Co ltd
Current assignee: Yangzhou blue biomedicine technology Co., Ltd.
Priority date: 2015-08-10
Filing date: 2016-08-10
Publication date: 2020-04-28
Anticipated expiration: 2036-08-10
Also published as: WO2017025031A1; CN106795174A

Abstract

The invention relates to an antiviral active diazacyclospirodione piperazine alkaloid derivative and a preparation method thereof, in particular to anti-RSV, HSV-1 and EV71 activities of a compound shown in a formula I, wherein the compound shown in the formula I has the following structure:

wherein R is₁、R₂、R₃、R₄Each independently selected from the group consisting of optionally substituted H, alkyl, cycloalkyl, alkylacyl, alkoxyacyl, cycloalkylacyl, alkenyl, alkenylacyl, alkynyl, alkynylacyl, aryl, arylalkyl, arylacyl, heteroaryl, heteroarylalkyl, heteroarylacyl, saturated or unsaturated heterocyclyl, saturated or unsaturated heterocyclylalkyl, saturated or unsaturated heterocyclylacyl; n is 0 or 1; chemical bond(s)

Indicating keys pointing into the surface of the paper

Or keys pointing out of the plane of the paper

"- - - - -" represents a single bond or is absent, and when "- - - -" represents a single bond,R₁、R₂is absent.

Description

Antiviral active diazacyclospirodiketopiperazine alkaloid derivative and preparation method thereof

Technical Field

The invention relates to a diaza-oxacyclo-spirodiketopiperazine alkaloid derivative and a preparation method thereof, and also relates to an application of the diaza-oxacyclo-spirodiketopiperazine alkaloid derivative in preparation of antiviral drugs. The diaza-oxacyclo spirodiketopiperazine alkaloid derivative has broad-spectrum antiviral activity, has stronger antiviral activity on RNA viruses and DNA viruses, and particularly has strong inhibitory activity on Respiratory Syncytial Virus (RSV), herpes simplex virus (HSV-1), enterovirus 71(EV71) and the like.

Background

Respiratory syncytial virus (RSV, also belonging to the family paramyxoviridae), an RNA virus, belongs to the family paramyxoviridae. RSV infection causes pneumonia and a variety of lower respiratory tract diseases, with at least 300 million infants admitted to the hospital every year by RSV viral infection, with at least 16 million deaths, and thus RSV is also known as a child killer (Science,2013,342, 546-547). There is no vaccine available in clinic, and ribavirin (ribavirin) is the only chemotherapeutic drug in clinic (j.med.chem.2008,51, 875-.

Herpes simplex virus type 1 (HSV-1) is an enveloped DNA virus belonging to the family of herpesviridae and can cause a number of diseases in humans, such as gingivitis, keratoconjunctivitis, encephalitis, reproductive infections and neonatal infections.

Enterovirus 71(Enterovirus 71, EV71) is a main pathogen of hand-foot-and-mouth disease, is firstly separated from an infant fecal specimen with central nervous system diseases in California in 1969, is a new Enterovirus discovered by human beings, mainly infects infants, can cause acute infectious diseases mainly characterized by fever and rash, herpes and herpangina of hands, feet, oral cavity and other parts, and the infection is often accompanied with nervous system complications and can seriously cause the death of children. At present, although there are some reports on EV71 replication cycle antiviral drugs, EV71 vaccine development, RNA and the like, no clinically effective prevention and treatment measures are found.

In view of the above, it is urgent to develop lead compounds, candidate drugs and clinically effective drugs for preventing and/or treating diseases caused by RSV, HSV-1 and EV71 infections.

Disclosure of Invention

The invention provides a dinitrogen oxacyclo spirodione piperazine alkaloid compound with a structure shown in a formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the salt thereof, which is characterized in that the compound shown in the formula I has the following structure:

wherein R is₁、R₂、R₃、R₄Each independently selected from the group consisting of H, alkyl, cycloalkyl, alkanoyl, alkoxyacyl, cycloalkylacyl, alkenyl, alkenylacyl, alkynyl, alkynylacyl, aryl, arylalkyl, arylacyl, heteroaryl, heteroarylalkyl, heteroarylacyl, saturated or unsaturated heterocyclyl, saturated or unsaturated heterocyclylalkyl, saturated or unsaturated heterocyclylacyl; r is as defined above₁、R₂、R₃、R₄The groups are optionally substituted by hydroxy, hydroxymethyl, carboxy, acetamido, C1-C4 alkyl (e.g., methyl, ethyl, propyl), trifluoromethyl, trifluoroacetyl, mercapto, halogen, nitro, amino, azido (-N-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy (e.g. methyl)Oxy, ethoxy, t-butoxy), phenyl; n is 0 or 1; chemical bond(s)

Indicating keys pointing into the surface of the paper

Or keys pointing out of the plane of the paper

"- - - - -" represents a single bond or is absent, and when "- - - -" represents a single bond, R is₁、R₂Is absent; provided that when R is₃、R₄While being H, R₁、R₂Is not simultaneously

Symbol

Represents R₁、R₂The group is bonded to the site of N in the structure of formula I.

The compounds of formula I according to the present invention do not include compounds 239 and 539 and their racemates, but may include stereoisomers thereof, unequal mixtures of its enantiomers, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of their salts.

In another embodiment of the present invention, R₁、R₂、R₃、R₄Each independently selected from H, C1-C8 alkyl, C1-C8 alkanoyl, C1-C8 alkoxyacyl, C3-C10 cycloalkyl, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkenylacyl, C2-C8 alkynyl, C2-C8 alkynylacyl, C6-C10 aryl, C6-C10 arylC 1-C4 alkyl, C6-C10 arylacyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroarylacyl, 4-to 12-membered saturated or unsaturated heterocyclyl C1-C4 alkyl, 4-to 12-membered saturated or unsaturated heterocyclyl acyl; r is as defined above₁、R₂、R₃、R₄The groups are optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (e.g. methyl, ethyl, propyl), mercapto, halogen, nitro, amino, azido (-N-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy (e.g. methoxy, ethoxy, tert-butoxy), phenyl; the other definitions are the same as above.

In another embodiment of the present invention, R₁、R₂、R₃、R₄Each is independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkylacyl, C1-C8 haloalkylacyl, C3-C10 cycloalkylacyl, C10-C10 alkenyl, C10-C10 alkenylacyl, C10-C10 alkynyl, C10-C10 alkynylacyl, C10-C10 aryl, C10-C10 arylC 10 alkyl, C10-C10 arylacyl, C10-C10 heteroaryl, C10-C10 heteroarylC 10-C10 alkyl, C10-C10 heteroarylacyl, C10-C10 saturated or unsaturated heterocyclyl C10 alkyl, C10-C10 saturated or unsaturated heterocyclyl; r is as defined above₁、R₂、R₃、R₄The radicals being optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, methyl, mercapto, halogen, nitro, amino, azido (-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy, phenyl; the hetero atoms in the heterocyclic group and the heteroaryl group related in the groups are 1-5 hetero atoms independently selected from N, O, S or Se; the other definitions are the same as above.

In another embodiment of the present invention, R₃、R₄Each independently of the other is H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇3-hydroxy-propyl

2-carboxy-ethyl

P-chlorobenzyl, m-nitrobenzyl,Phenyl, furan-3-yl, naphthalen-1-yl, quinolin-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH)₂CO), propionyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, trifluoroacetyl, allyl, ethynyl, propargyl, t-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, benzhydryl

R₁、R₂Each independently is H, C1-C8 alkyl, C1-C8 alkanoyl, C1-C8 alkoxyacyl, C3-C10 cycloalkyl, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkenylacyl, C2-C8 alkynyl, C2-C8 alkynoyl, C6-C10 aryl, C6-C10 arylC 1-C4 alkyl, C6-C10 arylacyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroarylacyl, 4-to 12-membered saturated or unsaturated heterocyclyl C1-C4 alkyl, 4-to 12-membered saturated or unsaturated heterocyclyl acyl; r is as defined above₁、R₂、R₃、R₄The groups are optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (e.g. methyl, ethyl, propyl), mercapto, halogen, nitro, amino, azido (-N-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy (e.g. methoxy, ethoxy, tert-butoxy), phenyl; the other definitions are the same as above.

2-carboxy-ethyl

P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinolin-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH)₂CO), propionyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, trifluoroacetyl, allyl, ethynyl, propargyl, t-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, benzhydryl

R₁、R₂Each independently is n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-ethyl-hexyl, 1-chloro-3-methyl-pentyl, 1-chloro-2-methyl-hexyl, 1-chloro-3-methyl-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-hexyl, 3-fluoro-hexyl, 1-chloro-, 1-chloro-3-ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl-hexyl, 1-bromo-3-ethyl-hexyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-valeryl, 2-methyl-hexanoyl, 3-ethyl-hexanoyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, propionyl, and the like, Pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-hexanoyl, 3-ethyl-hexanoyl, trifluoroacetyl, difluoroacetyl, chloroacetyl, bromoacetyl, pentafluoropropionyl, perfluorobutanoyl, 1-fluoro-3-methyl-pentanoyl, 1-fluoro-2-methyl-hexanoyl, 1-fluoro-3-ethyl-hexanoyl, 1-chloro-3-methyl-pentanoyl, 1-chloro-2-methyl-pentanoyl, 1-chloro-2-methyl-hexanoyl, 1-chloro-3-ethyl-hexanoyl, 1-bromo-3-methyl-pentanoyl, 1-bromo-2-methyl-hexanoyl, 1-bromo-3-ethyl-hexanoyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, n-pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, heptadienyl, heptatrienyl, n-octenyl, octadienyl, octrienyl, 3-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, allyl, n-butenyl, n-2-methyl-hexanoyl, n-hexenyl, 3-methyl-hex-2-enyl, 3-ethyl-hex-2-enyl, propionyl, but-2-enoyl, methacryloyl, pent-3-enoyl, isopentenoyl, pentadienoyl, hex-4-enoyl, hept-5-enoyl, heptadienoyl, heptatrienoyl, oct-6-enoyl, octadienoyl, octatrienoyl, 3-methyl-pent-2-enoyl, 2-methyl-hex-2-enoyl, 3-ethyl-hex-2-enoyl, ethynyl, propynyl, propargyl, and mixtures thereof, N-butynyl, but-2-alkynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, n-octynyl, octadiynyl, octynyl, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-ethyl-hex-2-ynyl, propargyl, n-butynyl, but-2-ynylacyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, n-octynyl, octynyloxy, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-ynoyl, 3-ethyl-hex-2-ynoyl, phenyl, naphthyl, benzyl, phenethylimidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, isoquinolyl, benzofuryl, benzothiazolyl, benzoselenadiazolyl, coumarinyl, isocoumarinyl, azetidinyl, oxetanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrofuranyl, dioxanyl, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrocoumarinyl, dihydroisocoumarinyl, tetrahydroquinolyl, tetrahydroisoquinolylA base, a tetrahydrocarbazolyl group, a pyrimidine base, a purine base; r is as defined above₁、R₂、R₃、R₄The radicals being optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, mercapto, halogen, nitro, amino, azido (-N₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, methoxy, ethoxy, substituted with one or more of; the other definitions are the same as above.

In another embodiment of the present invention, R₃、R₄Each independently is H, methyl, acetyl, trifluoroacetyl, trifluoromethyl, tert-butoxycarbonyl; the other definitions are the same as above.

In another embodiment of the invention, the compound of formula I is selected from the group consisting of the compounds in tables 1-5 or a tautomer thereof, stereoisomer thereof, racemate thereof, unequal mixture of enantiomers thereof, geometric isomer thereof, solvate thereof, pharmaceutically acceptable salt thereof, or solvate of a salt thereof.

In another preferred embodiment, R in the compounds of the formula I₁、R₂、R₃、R₄Are specific groups at corresponding positions in specific compounds 1-239, 301-539, 601-893, 900-953 in tables 1-5.

It is to be understood that the above preferred groups may be combined with each other to form various preferred compounds of the present invention, not to be limited to space, but not to be described in detail herein.

The invention provides a bis-oxazinane spirodione piperazine alkaloid compound with a structure shown in formula I-1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of the enantiomer thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the salt thereof, which is characterized in that the compound shown in formula I-1 has the following structure:

R₁、R₂、R₃、R₄is as defined for R in the compounds of formula I in the various embodiments above₁、R₂、R₃、R₄And (4) defining.

For convenience of description, the parent nucleus structure of the compound of formula I-1 is numbered as follows:

the compounds of the formula I-1 according to the invention do not include

And racemates of the two, but may include stereoisomers thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof, or solvates of the salts thereof.

The invention provides a bisisoxazolidine spirodione piperazine alkaloid compound with a structure shown in formula I-2, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of the enantiomer thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the salt thereof, which is characterized in that the compound shown in formula I-2 has the following structure:

For convenience of description, the parent nucleus structure of the compound of formula I-2 is numbered as follows:

the invention provides a bisoxazine spirodione piperazine alkaloid compound with a structure shown in a formula I-3, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of the enantiomer thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the salt thereof, which is characterized in that the compound shown in the formula I-3 has the following structure:

R₃、R₄is as defined for R in the compounds of formula I in the various embodiments above₃、R₄And (4) defining.

For convenience of description, the parent nucleus structure of the compound of formula I-3 is numbered as follows:

the invention provides a bisisoxazoline spirodione piperazine alkaloid compound with a structure shown in formula I-4, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the salt thereof, which is characterized in that the compound shown in formula I-4 has the following structure:

For convenience of description, the parent nucleus structure of the compound of formula I-4 is numbered as follows:

in the present invention: when not specifically stated, the alkenyl groups involved in the group contain one or more double bonds; alkynyl groups referred to in groups contain one or more triple bonds and alkynyl groups referred to optionally contain one or more double bonds; alkyl groups referred to in the groups such as the alkyl groups in said "alkyl, alkanoyl, arylalkyl, haloalkyl, haloalkanoyl" are straight-chain or branched alkyl groups, preferably C1-C8 straight-chain or branched alkyl groups, further preferably methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-hexyl, 3-ethyl-hexyl; alkenyl groups referred to in the groups such as alkenyl groups in said "alkenyl, alkenylacyl" are straight-chain or branched alkenyl groups containing 1 or more double bonds, preferably C2-C8 straight-chain or branched alkenyl groups, further preferably vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, n-pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, heptatrienyl, n-octenyl, octadienyl, octrienyl, 3-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-ethyl-hex-2-enyl; cycloalkyl groups referred to in the groups, for example cycloalkyl groups in said "cycloalkyl, cycloalkylacyl" are C3-C10 cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; alkynyl groups referred to in the groups, for example alkynyl in said "alkynyl, alkynoyl" are straight-chain or branched alkynyl groups containing 1 or more triple bonds, optionally containing one or more double bonds, preferably C2-C8 straight-chain or branched alkynyl groups, further preferably ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, n-octynyl, suberylynyl, octynyl, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-ethyl-hex-2-ynyl; aryl groups referred to in the groups such as "aryl" in said "aryl, arylalkyl, arylacyl" are aromatic hydrocarbon groups, preferably monocyclic, bicyclic, fused ring aryl groups, further preferably monocyclic or bicyclic aryl groups having 6 to 10 carbon atoms, further preferably phenyl, naphthyl; heteroaryl groups referred to in groups such as heteroaryl groups in said "heteroaryl, heteroarylalkyl, heteroarylacyl" are aryl groups containing 1 to 5 heteroatoms independently selected from N, O, S or Se, preferably 5-to 12-membered heteroaryl groups containing 1 to 5 heteroatoms independently selected from N, O, S or Se, further preferably imidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, quinolyl, oxazinyl, thienyl, phenothiazinyl, benzothienyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzoselenadiazolyl, coumarinyl, isocoumarin; the heterocyclic group referred to in the group such as the heterocyclic group in said "saturated or unsaturated heterocyclic group, saturated or unsaturated heterocyclylalkyl group, saturated or unsaturated heterocyclylacyl group" is a monocyclic or polycyclic heterocyclic group containing 1 to 5 heteroatoms independently selected from N, O, S or Se, preferably a 4-to 12-membered monocyclic or polycyclic heterocyclic group containing 1 to 5 heteroatoms independently selected from N, O, S or Se, further preferably azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxanyl, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrocoumarinyl, dihydroisocoumarinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrocarbazolyl, pyrimidinyl, purine base; "arylalkyl" is preferably benzyl, phenylethyl; the "alkoxyacyl group" is preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.; the cycloalkyl, aryl, heteroaryl and heterocyclic radical involved in the group are monocyclic, polycyclic or fused rings; the acyl groups referred to in the groups are all carbonyl (C ═ O); the halogen substitution involved in the group is monohalo or polyhalo, i.e., monofluoro, monochloro, monobromo, monoiodo, or polyfluoro, polychlorinated, polybromo, polyiodo, optionally substituted with two or more fluoro, chloro, bromo, iodo; the "halogen" is preferably fluorine, chlorine, bromine, iodine.

Chemical bonds in the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 of the invention

Indicating simultaneous pointing of keys in the paper

Or keys pointing out of the paper at the same time

The term "pharmaceutically acceptable salts" as used herein refers to non-toxic inorganic or organic acid and/or base addition salts, as described in "Salt selection for basic drugs", int.J.pharm. (1986),33, 201-217. These salts can be prepared in situ during the final isolation and purification of the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, or separately by reacting the base or acid functions with the appropriate organic or inorganic acid or base, respectively. Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecanoate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. In addition, basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, dodecyl, tetradecyl, octadecyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like. Water or oil-soluble or dispersible products are thus obtained.

Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include the following: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, or separately by reacting the carboxylic acid group with an appropriate base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to: cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The term "solvate" in the present invention refers to a solvate formed by the compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a salt thereof of the present invention with an organic solvent and/or water, the organic solvent is preferably acetone, acetonitrile, methanol, ethanol, and the formed solvate is preferably a monohydrate, dihydrate, trihydrate, monomethanolate, dimethanol compound, monoacetonitrile compound, diacetonitrile compound, monoacetonide compound, diacetone compound, diproprione compound, hemifumarate monohydrate, fumarate dihydrate, fumarate monoethanol compound, and the like of the compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a salt thereof. Further preferred are monohydrate, fumarate dihydrate and fumarate monoethanol complex. Further preferred are compounds 1100-1105.

The term "geometrical isomers" in the present invention refers to Z, E two geometrical configurations of the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, when they contain a double bond.

The compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 of the present invention exist in various tautomeric forms (wherein a proton of one atom of a molecule is transferred to another atom, and the chemical bond between the atoms of the molecule is subsequently rearranged). See, e.g., March, advanced organic chemistry: reactions, Mechanisms and Structures (Advanced Organic Chemistry: Reactions, mechanics and Structures), fourth edition, John Wiley & Sons, pages 69-74 (1992). The term "tautomer" as used herein refers to compounds produced by proton transfer, and it is to be understood that all tautomeric forms, insofar as they may exist, are included within the scope of the invention. For example, a pair of tautomers which are present when the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 contain a functional group such as an amide bond, an enol bond, an imidazole, etc.

The term "a mixture of diastereomers" as used herein means a mixture of two enantiomers in a non-equimolar amount, i.e., having an ee of greater than 0 and less than 100%.

The compounds of the present invention, including compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, or stereoisomers thereof, and any pharmaceutically acceptable salts, esters, metabolites, and prodrugs thereof, may contain asymmetrically substituted carbon atoms such asymmetrically substituted carbon atoms may allow the compounds of the present invention to exist in enantiomeric, diastereomeric, and other stereoisomeric forms, which may be defined, for example, as (R) -or (S) -configurations according to absolute stereochemistry, thus, all such possible isomers, optically Pure forms of a single stereoisomer, mixtures thereof, racemic mixtures (or "racemates"), diastereomeric mixtures, single diastereomers of the compounds of the present invention are encompassed by the following definitions as used herein, the terms "S" and "R" configurations are used herein according to the following definitions: the IU1974 intermediates for Section E, the terms of the biochemical chemistry, Pure. chem.45: 13-30.). α and the compounds used in the Absolute procedures for the cyclic substitution of the parent nucleus, which is described with reference to the absolute stereogenic nucleus 3957, the absolute position of the loop substituent as used in the present application, and which is described with reference to the absolute stereogenic nucleus for the absolute position of the Absolute 3982, the parent nucleus, which is referred to the absolute stereogenic description of the present application.

The compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 is selected from the group consisting of the compounds in tables 1-5 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof.

The solvate of the solvate or salt of formula I or formula I-1 is preferably a monohydrate, a fumarate dihydrate, a fumarate monoethanol complex; further preferred are compounds 1100-1105.

In another preferred embodiment, R in the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4₁、R₂、R₃、R₄Are specific groups at corresponding positions in specific compounds 1-239, 301-539, 601-893, 900-953 in tables 1-5.

Another embodiment of the present invention provides an antiviral agent characterized in that it comprises any one or more compounds of any one or more of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of the salt thereof, as an active ingredient.

Another embodiment of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises any one or more of the compounds of any one or more of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment of the present invention provides a pharmaceutical composition characterized by comprising any one or more compounds of any one or more of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof, and at least one other antiviral drug. The pharmaceutical composition is preferably selected from injection, oral preparation, lyophilized powder for injection, suspending agent, etc.

Another embodiment of the invention provides the use of any one or more of the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a salt thereof, in the preparation of an antiviral medicament.

In another embodiment of the invention, the invention provides an application of any one or more compounds of formula I, formula I-1, formula I-2, formula I-3 and formula I-4 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof in preparing medicines for treating and/or preventing respiratory diseases, hand-foot-and-mouth diseases, immune diseases and inflammatory diseases.

Another embodiment of the invention provides the use of any one or more compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof for the manufacture of a medicament for the treatment and/or prevention of diseases caused by RSV, HSV-1, EV 71. The disease is selected from: respiratory diseases, pneumonia, gingivitis, conjunctivitis, encephalitis, infections of the reproductive system, rashes, herpes and herpangina in the hands, feet, oral cavity, etc.

Another embodiment of the invention provides the use of any one or more of the compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a salt thereof, in the manufacture of a medicament. The medicine is used for treating diseases caused by Respiratory Syncytial Virus (RSV), herpes simplex virus (HSV-1) and enterovirus 71(EV 71).

In another embodiment of the invention, the invention provides the application of any one or more compounds of formula I, formula I-1, formula I-2, formula I-3 and formula I-4 or tautomers thereof, stereoisomers thereof, racemates thereof, unequal mixtures of enantiomers thereof, geometrical isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates of salts thereof in preparing anti-RSV, HSV-1 and EV71 medicament lead compounds.

In another embodiment, the invention provides the use of any one or more compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a salt thereof, in the preparation of a drug candidate against RSV, HSV-1, EV 71.

Another embodiment of the present invention provides a process for the preparation of compounds of formula I, formula I-1, formula I-2, formula I-3, formula I-4, comprising the steps of:

the method comprises the following steps:

step (1): 2, 4-diaminobutyric acid (L, D, or DL racemate when n is 0) or ornithine (L, D, or DL racemate when n is 1) is used as a raw material, and KHSO is added₄、NaHSO₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂At a reaction temperature of 30 to 120 ℃ (preferably 80 to 120 ℃) in water or an alcohol solution for 4 to 120 hours (preferably 12 to 96 hours) to obtain the compound of the formula II. The reaction of this step can be carried out according to the method disclosed in the patent JP patent publication 2013-53115A or a similar improved method based thereon.

Step (2): and carrying out reflux reaction on the compound of the formula II in an organic solvent under the action of an oxidant to obtain the compound of the formula III. The oxidizing agent is preferably mCPBA or hydrogen peroxide; the amount of the oxidizing agent to be used is preferably 2.0 to 4.0 times, more preferably 2.5 to 3.5 times, the molar amount of the compound of formula II; the organic solvent is preferably acetone, dichloromethane, chloroform, THF.

And (3): reacting the compound of the formula III in an organic solvent under the action of an initiator and alkali to obtain a compound of a formula IV (namely R)₃、R₄Compounds of formula I-3, I-4 in the case of H). The initiator is selected from Ag-containing initiators⁺Compounds or TEMPO, preferably Ag₂CO₃、AgNO₃、AgOAc、AgOTf、Ag₂O; the base is preferably an alkali metal carbonate or bicarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃(ii) a The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, toluene; the reaction temperature is from 0 to 60 ℃ and preferably from 20 to 40 ℃.

And (4): the compound of the formula IV is subjected to alkylation reaction or acylation reaction to obtain a compound of the formula V (namely R)₃、R₄Compounds of formula I-3, I-4 when not both H) are conventional in the art: in organic solvent, under the action of alkali and hydrocarbonizing reagent, in which the hydrocarbonizing reagent is preferably R₃X or R₄X (halogenated hydrocarbon) wherein X is halogen, preferably chlorine, bromine, iodine, R₃、R₄Is as defined for R in any of the above-mentioned places of the invention₃、R₄The definition of (1); the base is preferably an alkali metal carbonate (preferably Na)₂CO₃、K₂CO₃、Cs₂CO₃) Alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH)₃ONa, EtONa, t-BuOK); the acylation reaction conditions are also conventional in the art: in organic solvent, under the action of alkali and acylating agent, wherein the acylating agent is preferably R₃X or R₄X (acyl halide), R₃OR₃Or R₄OR₄(anhydrides) in which X is halogen, preferably chlorine, bromine, iodine, R₃、R₄Is as defined for R in any of the above-mentioned places of the invention₃、R₄As defined above, the base is preferably an alkali metal hydroxide (e.g., NaOH, KOH), triethylamine, pyridine, or vinegarSodium, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-lutidine, and the like. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane, etc.

And (5): the compound of formula V reacts in an organic solvent under the action of a reducing agent to obtain a compound of formula VI (namely R)₁、R₂Compounds of formula I-1, I-2 when H). The reducing agent is preferably H₂And Pd/C, H₂And PtO₂、H₂And Raney Nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, Borane (BH)₃、B₂H₆). The reaction temperature is preferably from-20 ℃ to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

And (6): the VI compound is subjected to alkylation reaction or acylation reaction to obtain a compound (namely R) in the formula VII₁、R₂Compounds of formula I-1, I-2, when not both H), the alkylation reaction conditions are conventional in the art: in organic solvent, under the action of alkali and hydrocarbonizing reagent, in which the hydrocarbonizing reagent is preferably R₁X or R₂X (halogenated hydrocarbon) wherein X is halogen, preferably chlorine, bromine, iodine, R₁、R₂Is as defined for R in any of the above-mentioned places of the invention₁、R₁The definition of (1); the base is preferably an alkali metal carbonate (preferably Na)₂CO₃、K₂CO₃、Cs₂CO₃) Alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH)₃ONa, EtONa, t-BuOK); the acylation reaction conditions are also conventional in the art: in organic solvent, under the action of alkali and acylating agent, wherein the acylating agent is preferably R₁X or R₂X (acyl halide), R₁OR₁Or R₂OR₂(anhydrides) in which X is halogen, preferably chlorine, bromine, iodine, R₁、R₂Is as defined for R in any of the above-mentioned places of the invention₃、R₄As the base, alkali metal hydroxides (e.g., NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-lutidine and the like are preferable. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane, etc.

The second method comprises the following steps:

step (1): and reacting the compound shown in the formula III in an organic solvent under the action of a reducing agent to obtain the compound shown in the formula VIII. The reducing agent is preferably H₂And Pd/C, H₂And PtO₂、H₂And Raney Nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, Borane (BH)₃、B₂H₆). The reaction temperature is preferably from-20 ℃ to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform.

Step (2): reacting the compound of formula VIII in an organic solvent under the action of a base or a Mitsunobu reagent to obtain a compound of formula IX (namely R)₁、R₂、R₃、R₄Compounds of formula I-1, I-2, both H). The base is preferably an alkali metal carbonate or bicarbonate, such as Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃Alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH)₃ONa, EtONa, t-BuOK); preferred Mitsunobu reagents are DEAD and PPh₃DIAD and PPh₃DEAD and PEt₃DIAD and PEt₃(ii) a The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, dichloromethane, chloroform; the reaction temperature is from 0 to 60 ℃ and preferably from 20 to 40 ℃.

And (3): formula (II)The compound IX is subjected to alkylation reaction or acylation reaction to obtain a compound of a formula VII (namely a compound of a formula I-1 and a compound of a formula I-2), wherein the alkylation reaction condition is a condition conventional in the field: in organic solvent, under the action of alkali and hydrocarbonizing reagent, in which the hydrocarbonizing reagent is preferably R₁X、R₂X、R₃X or R₄X (halogenated hydrocarbon) wherein X is halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Is as defined for R in any of the above-mentioned places of the invention₁、R₂、R₃、R₄The definition of (1); the base is preferably an alkali metal carbonate (preferably Na)₂CO₃、K₂CO₃、Cs₂CO₃) Alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH)₃ONa, EtONa, t-BuOK); the acylation reaction conditions are also conventional in the art: in organic solvent, under the action of alkali and acylating agent, wherein the acylating agent is preferably R₁X、R₂X、R₃X or R₄X (acyl halide), R₁OR₁、R₂OR₂、R₃OR₃Or R₄OR₄(anhydrides) in which X is halogen, preferably chlorine, bromine, iodine, R₁、R₂、R₃、R₄Is as defined for R in any of the above-mentioned places of the invention₁、R₂、R₃、R₄As the base, alkali metal hydroxides (e.g., NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-lutidine and the like are preferable. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane, etc.

The third method comprises the following steps: compounds 239 and 539 were obtained according to the method described in Chinese patent (application No. 201510201548.7):

then, the compounds 239 and 539 are structurally modified by adopting a similar alkylation or acylation modification method in the first method and the second method, and a series of compounds falling into the scope of formula I and formula I-1 can be obtainedA compound (I) is provided.

The synthesis methods of the formula IV, the formula V, the formula VI, the formula VII and the formula IX are given in the synthesis methods, and comprise the synthesis methods of the compounds of the formula I, the formula I-1, the formula I-2, the formula I-3 and the formula I-4.

Another embodiment of the present invention provides an intermediate compound of formula III, characterized in that formula III has the following structure:

wherein the chemical bond in the diketopiperazine ring

Indicating simultaneous pointing of keys in the paper

Or keys pointing out of the paper at the same time

Chemical bond in oxime group

Represents a "Z" or "E" configuration with respect to the double bond in the imine; n is 0 or 1.

Another embodiment of the present invention provides an intermediate compound of formula VIII, characterized in that formula VIII has the following structure:

chemical bond(s)

Indicating simultaneous pointing of keys in the paper

Or keys pointing out of the paper at the same time

n is 0 or 1.

It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (e.g., examples) may be combined with each other to constitute a new or preferred technical solution. Not to be reiterated herein, but to the extent of space.

Detailed Description

In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.

Example Synthesis of 12, 5-Diketopiperazine derivative (formula II)

According to the patent: synthesizing by the synthesis methods described in JP patent laid-open Nos. 2013-53115A, WO2012109256A2, WO2010078373A1 and WO2008003626A 1; or according to the literature: the elutherazine B or cyclo-di-N obtained by the methods described in Journal of Asian Natural products Research,2010,12(1): 51-55 and Chinese Journal of Natural Medicines,2011,9(1):0078-^δ-acetyl-L-ornithyl, followed by hydrolysis of the corresponding acyl group using hydrazine hydrate according to the acyl group hydrolysis method described in the literature, fitotenapia, 2014, vol.98,91-97, to give the corresponding L-ornithine condensed 2, 5-diketopiperazine derivative (compound 1001).

Weighing 2.64g L-ornithine in 250mL water, adding an equal volume of 0.16% KHSO₄The solution was refluxed for 2 days, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain 1.36g of compound 1001 with a yield of about 60% and an HPLC purity of 98.5%.

Using an appropriate amount of NaHSO₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂Replacing said 0.16% KHSO₄In water or alcohol solution at 30-120 deg.c for 4-120 hr to react in 40-120%Compound 1001 was obtained in 60% yield.

The compound 1002 was obtained in a yield of about 60% by replacing the L-ornithine with DL-ornithine, D-ornithine, DL-2, 4-diaminobutyric acid, L-2, 4-diaminobutyric acid or D-2, 4-diaminobutyric acid

Compound 1003

Compound 1004

Compound 1005

Or compound 1006

EXAMPLE 2 Oxidation of a Compound of formula II to its oximino derivative (formula III)

According to the literature: liujia, 2014, "research on oxidation reaction of primary amine compounds and synthesis of key fragments of (+) -Pederin natural products" explore a method for oxidizing benzylamine into benzaldoxime recorded on page 9 "to improve, and obtain a compound (a compound 1001-1006) in a formula II, which is subjected to reflux reaction in an organic solvent under the action of an oxidant to obtain a compound in a formula III; the oxidant is preferably m-CPBA or hydrogen peroxide; the amount of the oxidizing agent to be used is preferably 2.0 to 4.0 times, more preferably 2.5 to 3.5 times, the molar amount of the compound of formula II; the organic solvent is preferably acetone, dichloromethane, chloroform, THF.

2.28g of compound 1001(10mmol) was dissolved in 100mL of acetone, and 2.5equiv.m-CPBA (25mmol) was added thereto, followed by reaction at reflux temperature for 4 hours, and conventional workup and silica gel column chromatography gave 1.79g of compound 1007, with a yield of about 70% and an HPLC purity of 98.7%.

In the reaction, the oxidant can be replaced by hydrogen peroxide, the molar dosage of the oxidant is 2.0-4.0 times of that of the compound 1001, and the solvent can be replaced by dichloromethane, chloroform or THF; compound 1007 was obtained in 45% to 75% yield.

The reaction raw material compound 1001 is replaced by the compound 1002-1012 to obtain the compound 1008-1012 in the yields of 68%, 72%, 59%, 62% and 57%, respectively

EXAMPLE 3 cyclization of Compounds of formula III to Compounds of formula IV

Can be prepared according to the literature: chem. commun.,2014,50, 6906-6908; angew.chem.int.ed.2012,51, 8816-; chem.sci.,2013,4, 4030-4034; the compound of formula IV is prepared by cyclization of a compound of formula III by a method described in Tetrahedron Vol 41, No.22, pp.5241-5260,1985, etc., or by appropriate optimization and improvement based thereon.

2.56g of compound 1007(10mmol) are weighed out and dissolved in 150mL of DMA (N, N-dimethylacetamide) and 1.0equiv.Ag is added₂CO₃(10mmol)、0.5equiv.K₂CO₃(5mmol) was reacted at room temperature for 24 hours, followed by conventional workup and silica gel column chromatography to give 2.02g of compound 1013 in a yield of about 80% and a HPLC purity of 98.2%.

In the above reaction, Ag₂CO₃Can be replaced by Ag₂CO₃、AgNO₃、AgOAc、AgOTf、Ag₂O or TEMPO in a molar amount of 1.0 to 2.0 times that of the compound 1001, K₂CO₃Can be replaced by Na₂CO₃、Rb₂CO₃、Cs₂CO₃(ii) a The solvent DMA can be replaced by DMF, THF, acetonitrile, acetone and toluene; reaction temperatureCompound 1013 can be obtained in a yield of 65% to 85% between 0 and 60 ℃.

The reaction starting material compound 1007 was replaced with the compound 1008-1012 to obtain the compounds 840, 1014, 900, 1015, 1016 in the yields of 78%, 82%, 65%, 67%, 65%, respectively

EXAMPLE 4 modification of the Compounds of formula IV by alkylation and acylation to give Compounds of formula I-3, I-4

Can be prepared according to the literature: 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; WO2014189343a 1; canadian Journal of Chemistry (2014),92(12),1145 and 1149; european journal of Medicinal Chemistry (2014),83, 236-244; WO 2014060767a 1; the compound of formula IV is alkylated and acylated to obtain the compounds of formula I-3 and I-4 by the similar alkylation and acylation modification method of N-H in 2, 5-piperazinedione structure reported in Journal of applied Polymer Science (2012),124(2),1707-1715 and other prior arts.

(1) 252mg of compound 840(1mmol) was weighed, dissolved in 20mL of DMF, and 2.4equiv. nah (2.4mmol) was added in three portions, stirred at room temperature for half an hour, then 3.0equiv. mei was added, after reaction at 30 ℃ for 4h, TLC detected that the reaction material had almost completely disappeared, extracted twice with ethyl acetate, dried organic layer over anhydrous sodium sulfate, concentrated, and chromatographed on silica gel column to give compound 841(93.1mg, yield about 35%) which gave compound 842(120.4mg, yield about 43%).

The MeI in the reaction is replaced by EtBr,i-PrBr, bromocyclopropane, CF₃I. Allyl bromide, propargyl bromide, diphenyl methyl bromide, BnBr, bromocyclohexane, n-C₆H₁₃Br and p-chlorobenzyl bromide are reacted at room temperature to reflux temperature for 4-12 hr to obtain 843-846, 848, 850-853, 855, 862, 863, 873, 874, 887 and 888 compounds in 30-81% yield.

(2) 252mg of compound 840(1mmol) were weighed out and dissolved in 20mL CH₂Cl₂To the mixture, 2.5equiv.Ac was added₂O(2.5mmol)，0.6mL Et₃N and a catalytic amount of DMAP, stirred at room temperature for 2 hours, the TLC detection shows that the reaction raw material almost completely disappears and CH₂Cl₂Extraction was performed twice, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography to give compound 865(111.8mg, yield about 38%) and compound 867(151.3mg, yield about 45%).

Reacting Ac in the above reaction₂Replacement of O with Boc₂O, BzCl, trifluoroacetic anhydride, chloroacetyl chloride, cyclopropane carbonyl chloride, cyclohexanecarbonyl chloride, octanoyl chloride, hexanoyl chloride, m-azidobenzoyl chloride, m-methoxybenzoyl chloride, at room temperature for 0.5 to 6 hours to obtain the compounds 868-870 and 873-886 with a yield of 38 to 88%.

(3) 252mg of compound 840(1mmol) were weighed out, dissolved in 20mL of DMF, and 2.5equiv. bromobenzene (2.5mmol) and 2.0equiv.K were added₂CO₃(2.0mmol) and catalytic amounts of CuI and N, N-dimethylethylenediamine (CAS RN: 110-70-3), after stirring at 110 ℃ and 115 ℃ for 12 hours, the TLC detection of the almost complete disappearance of the starting materials, extraction with ethyl acetate twice, drying of the organic layer with anhydrous sodium sulfate, concentration and silica gel column chromatography gave compound 854(256mg, yield about 78%).

The bromobenzene in the reaction is replaced by 1-bromonaphthalene, 8-bromoquinoline and 3-bromofuran, and the reaction is carried out at the temperature of 100 ℃ to 120 ℃ for 12 to 24 hours to obtain the compound 856-858 in the yield of 75 to 86 percent.

(4) By the methylation or acetylation method in (1) or (2) above using the compound 848 as a starting material, compounds 847 and 849 were obtained in yields of 89% and 95%, respectively; starting with 862 and 865 compounds, respectively, Boc was prepared according to the acylation method described in (2)₂O is an acylating agent, so that compounds 861 and 866 can be obtained (the yield is more than 90 percent); using 863, 865 and 870 as raw materials, respectively, and bromohexane and n-C as raw materials according to the alkylation method described in (2)₆H₁₃Br、n-C₅H₁₁Br was used as an alkylating agent, and compounds 864, 872 and 871 (yield about 75%) were obtained.

(5) 290mg of compound 852(1mmol) was weighed, dissolved in 100mL of dichloromethane, 1.1 equiv.1-azido-2-methoxyethane (1.1mmol) and 5mL of water were added, and after a catalytic amount of sodium ascorbate and copper sulfate pentahydrate were added, the reaction was carried out at 40 ℃ for 5 hours, TLC detection showed completion of the reaction, 200m L of dichloromethane was added to the reaction solution for extraction, and the reaction solution was washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, filtered, and after the filtrate was concentrated, the mixture was subjected to silica gel column chromatography to give 332mg of compound 859 in about 85% yield, with an HPLC purity of 97.9%.

Compound 860 was obtained in about 78% yield from compound 853 as a starting material by increasing 1 fold amount of 1-azido-2-methoxyethane (2.2mmol) under the above reaction conditions.

Wherein, the 1-azido-2-methoxyethane is prepared by the following method:

dissolving 2-methoxyethanol (1.0mmol) in anhydrous THF (50m L), adding triethylamine (4.0mmol), dropwise adding methanesulfonyl chloride (4.0mmol) under ice bath, stirring overnight at room temperature, detecting by TLC to show that the reaction is finished, evaporating the solvent, extracting by dichloromethane, washing by water and saturated sodium chloride in turn, drying by anhydrous sodium sulfate, dissolving in 50mL DMF after concentration, slowly adding sodium azide (4.0mmol), reacting for 4h at 105 ℃ after the addition is finished, detecting by TLC to show that the reaction is finished, slowly adding 20m L water into the reaction solution, extracting by dichloromethane, washing by water and saturated sodium chloride in turn, drying by anhydrous sodium sulfate, and concentrating for later use.

(6) 332mg of compound 851(1.0mmol) were weighed out and dissolved in 50mL of THF, and BH was added dropwise at 0 ℃₃·Me₂S (7.0mL,2.0M in THF,14.0mmol), naturally returned to room temperature, stirred overnight, and added absolute ethanol (5mL), 3M NaOH (9.0mL) and 30% H under ice bath₂O₂The solution (2.0mL) was refluxed for 1 hour, and then reacted with CH₂Cl₂Extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate and chromatography on a silica gel column gave 269mg of compound 890 in about 73% yield with an HPLC purity of 98.9%.

BH is prepared from compound 850 under the above reaction conditions₃·Me₂S, 3M NaOH and 30% H₂O₂All in half, gave compound 889 in about 75% yield.

(7) Dissolving compound 890(1.0mmol) in 60mL of acetone, adding a proper amount of newly configured Jones reagent (Jones reagent) at 0 ℃, naturally returning to room temperature, stirring for reaction overnight, and performing conventional aftertreatment and silica gel column chromatography to obtain compound 892 and compound 893 with yields of about 46% and 25%, respectively, wherein the HPLC purity is above 98%.

Compound 891 was obtained in about 65% yield and HPLC purity 98.3% under the above reaction conditions starting from compound 889.

Example 5

Hydrocarbons of N-H in the 2, 5-piperazinedione structure as described in example 4 or in the prior artBy a method of modifying the acyl group or the like, the specific R groups shown in tables 1 to 5 can be obtained₃、R₄Modified compounds of formula I-3, I-4.

EXAMPLE 6 reduction of Compounds of formula V (formulae I-3, I-4)

According to the literature: CN 104529814A; org, lett, 2001,3, 1637-; chem.,1996,61, 3849-; tetrahedron,2005,61,5725 and 5734; chem, 2006,71, 7083-; reduction of formula V (formulas I-3, I-4) to provide compounds of formula VI (i.e., R-3, I-4) by Angew. chem. int. Ed.,2005,117,5807-₁、R₂Compounds of formula I-1, I-2 when H).

252mg of 1014(1mmol) of the compound were weighed out and dissolved in EtOH (50ml), and Raney-Nickel (1.0 g) was added under 1atm H₂After stirring at 25 ℃ for 12 hours, the reaction mixture was filtered to remove Ranbium nickel, and the filtrate was concentrated under reduced pressure to give Compound 1(220mg, 86%).

The above reaction starting material compound 1014 was replaced with compounds 840, 1013, 900, 1015, 1016 to give the corresponding reduction products in similar yields.

EXAMPLE 7 modification of the hydrocarbylation or acylation of Compounds of formula V (formulas I-3, I-4) to Compounds of formula VII (formulas I-1, I-2)

(1) 256mg of Compound 1(1mmol) are weighed out and dissolved in 30mL CH₂Cl₂To the mixture, 5.5equiv.Ac was added₂O(5.5mmol)，1.5mL Et₃N and a catalytic amount of DMAP, stirred at room temperature for 1.5 hours, the TLC detection shows that the reaction raw material almost completely disappears and CH₂Cl₂Extracting twice, drying the organic layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography to obtain compounds 2, 3, 7, and 8 with yields of 28%, 20%, 18%, and 15%, respectively, and with HPLC purity of above 98%.

Reacting Ac in the above reaction₂Replacing O with BzCl, trifluoroacetic anhydride, chloroacetyl chloride, cyclopropane carbonyl chloride, propionyl chloride, cyclohexanoyl chloride, valeroyl chloride, heptanoyl chloride, octanoyl chloride, hexanolAcyl chloride, m-azidobenzoyl chloride, m-methoxybenzoyl chloride, m-fluorobenzoyl chloride, Boc₂O, at room temperature for 0.5 to 8 hours, to give the corresponding mono-, di-, tri-and tetraacylated products in table 1 in yields of 30% to 90%.

(2) Following a similar hydrocarbylation procedure as described in example 4, the following hydrocarbylating reagents were employed: MeI, EtBr, i-PrBr, bromocyclopropane, CF₃I. Allyl bromide, propargyl bromide, diphenyl methyl bromide, BnBr, bromocyclohexane, n-C₆H₁₃Br, p-chlorobenzyl bromide, m-nitrobenzyl bromide and bromobenzene are replaced by 1-bromonaphthalene, 8-bromoquinoline and 3-bromofuran, and the reaction is carried out for 4 to 12 hours at the temperature from room temperature to the reflux temperature, and the corresponding mono-alkylation, di-alkylation, tri-alkylation and tetra-alkylation products in the table 1 are obtained with the yield of 30 to 81 percent.

(3) Products of the different hydrocarbylations or different acylations or co-modifications of hydrocarbylations and acylations in table 1 can be prepared according to the synthesis of the differently hydrocarbylated or differently acylated or co-modified hydrocarbylations and acylations described in example 4 (mainly referring to example 4(4)) or a similar synthesis based thereon, using the corresponding hydrocarbylating or acylating agents.

(4) Carboxylic acid condensation process: 1-Boc-acridine-2-carboxylic acid (201mg,1.0mmol) was weighed, dissolved in dry toluene (30mL), DCC (1.0mmol) and DMAP (0.17mmol) were added, stirred at room temperature for 10 minutes, compound 1(0.01mmol) was added, heated to 65 ℃ for reaction for 48 hours, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to give compounds 49 and 50 in yields of 43% and 45%, respectively, with HPLC purities of 97.8% and 98.3%. (the 1-Boc-acridine-2-carboxylic acid used in the reaction is racemic or a corresponding isomer can be prepared from a single D or L configuration of 1-Boc-acridine-2-carboxylic acid)

Replacement of 1-Boc-acridine-2-carboxylic acid in the above reaction by

Reaction at 60 to 80 ℃ for 24 to 48 hours gives the bis-condensation products of Table 1 (e.g., 55, 56, 176, 181, 188, 193, 205, 214, 231, 236) and about 40% mono-condensation products (e.g., 177, 182) in yields of 30% to 50%, which can be partially or completely removed under conditions conventional in the art for Ac or Boc removal to give compounds 54, 239 of Table 1. Wherein the mono-condensation product may be condensed with the above carboxylic acid to form an asymmetric di-condensation product, followed by alkylation, acylation, reduction, oxidation, click, etc. according to the method of the present invention to obtain the compounds having the corresponding substitution in Table 1. The Boc, Ac, Me and propargyl protected carboxylic acid can be prepared from the corresponding carboxylic acid and Boc₂O、Ac₂O, MeI, propargyl bromide and the like.

For example, compound 1 is first reacted with DCC or DMAP

Reacting for 10 hours, mainly producing a mono-condensation product, then reacting with

After 20 hours of reaction, Ac on the side chain is removed under the action of MeONa-MeOH, and the compound 206 can be obtained, and the total yield of the three steps can reach 42%. Note that: in the presence of a compound

Then, after methylation modification, Ac on the side chain is removed under the action of MeONa-MeOH, and the compound 208 can be obtained with the total yield of 33 percent.

Using the reduction conditions of example 6 and the condensation conditions of this example, compound 228 was obtained in 63% overall yield with an HPLC purity of 96.5%.

(5) Partial and total reduction of the side chain double bonds after condensation: weighing compound 239(0.1mmol) and dissolving in 10mLCH₃OH-CH₂Cl₂Adding catalytic amount of Pd-C into the solution (the volume ratio is 1:1), and adding H at room temperature under 1atm₂After reacting for 2h under the action, Pd-C is removed by filtration, and after concentration, the compounds 52 and 53 are obtained by silica gel column chromatography with the yield of 45 percent and the yield of 48 percent respectively, and the HPLC purities are 98.5 percent and 99.0 percent respectively. The other compounds in Table 1 having double bonds in their side chains can partially or completely reduce the double bonds by the above reaction conditions.

Addition of side chain double bonds after condensation: using reagents similar to those described in example 4(6) (e.g. BH)₃·Me₂S, 3M NaOH and 30% H₂O₂) The reaction is carried out. For example, compound 236 can be prepared using the reaction conditions described above in 80% yield to give compound 237; meanwhile, about 8 percent of Ma-shi addition product 238 is obtained.

Oxidation of side chain hydroxyl groups after condensation: by oxidation using the Jones reagent in example 4(7), a product containing a mono-or di-carboxyl group in the side chain can be obtained. For example, compound 239 provides compounds 59 and 60 in 32% and 48% yields, respectively, with an HPLC purity of 98% or more, using Jones' reagent.

Example 8 glycosylation modification

(1) Compound 1(0.1mmol) and 2.2equiv. total benzoyl protected glucose trichloroacetimidate (0.22mmol) were weighed out and dissolved in 20mL dry CH₂Cl₂In (1), adding

Molecular sieve, stirring half small under argon protection at room temperatureAfter that, 0.1equiv.TMSOTf (0.01mmol) was added dropwise at 0 ℃ and the reaction was stirred at 0 ℃ for half an hour, and then the starting material was detected by TLC for almost an hour and filtered off

Concentrating the molecular sieve under reduced pressure, dissolving the molecular sieve in methanol, adding a proper amount of sodium methoxide to adjust the pH to be 9.0-10.0, stirring the mixture to react for 2 hours, adding cation exchange resin to neutralize the pH to be about 7.0, concentrating the mixture under reduced pressure, and performing silica gel column chromatography to obtain compounds 41 and 42 with the yields of 38% and 42% respectively, wherein the HPLC purities are 96.5% and 97.2% respectively.

Replacing the all benzoyl protected glucose trichloroacetimidate in the above reaction with the all benzoyl protected galactose trichloroacetimidate gives compounds 43, 44 in similar yields

After the glycosylation reaction, the methylation reaction was carried out by the methylation method described in example 4, and then the benzoyl group was removed under the MeONa-MeOH condition, whereby compounds 45 to 48 were obtained with a yield of about 60%.

(2) Compound 239(0.1mmol) and 2.2equiv. total benzoyl protected glucose trichloroacetimidate (0.22mmol) were weighed out and dissolved in 20mL dry CH₂Cl₂In (1), adding

Stirring with molecular sieve at room temperature under argon atmosphere for half an hour, adding 0.1equiv.TMSOTf (0.01mmol) dropwise at 0 deg.C, reacting at 0 deg.C under stirring for 1.5 hr, detecting by TLC for almost hr, filtering to remove

Concentrating molecular sieve under reduced pressure, dissolving in methanol, adding appropriate amount of sodium methoxide to adjust pH to 9.0-10.0, stirring for 2 hr, neutralizing pH to about 7.0 with cation exchange resin, concentrating under reduced pressure, and performing silica gel column chromatography to obtain the final product with yield of 45% and 33% respectivelyCompounds 57 and 58 were obtained with HPLC purities of 97.5% and 97.3%, respectively.

Example 9 side chain Click reaction

Weighing compound 231(1mmol), dissolving in 100mL dichloromethane, adding 2.2equiv azidomethane (2.2mmol) and 8mL water, adding catalytic amount of sodium ascorbate and copper sulfate pentahydrate, reacting at 40 ℃ for 4.5h, detecting by TLC to show that the reaction is completed, adding 200m L dichloromethane into the reaction solution for extraction, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing silica gel column chromatography to obtain compound 232 with about 80% yield and HPLC purity of 97.3%.

Example 10

Any of the compounds of tables 1-5 can be prepared by following the procedures described in examples 1-9 or analogous reactions of the prior art or by performing art-recognized substitutions based thereon using 840, 1014, 1013, 900, 1015, 1016 as starting materials, all of which are processed¹H NMR and ESI-MS for structure confirmation and HPLC purity determination, and part of the compound is subjected to CD,¹H-¹And (3) carrying out structure confirmation on HCOSY, HMQC, HMBC and NOESY. For purposes of disclosure, the ESI-MS data is set forth in tables 1-5. The acid chlorides used in the synthesis of the present invention may be prepared from the corresponding acids according to conventional acid chloride preparation methods in the art, i.e., by reacting the corresponding acids with thionyl chloride or oxalyl chloride.

Example 11 Compounds prepared according to the invention and the results of their Activity tests

Antiviral activity test method: the inhibitory activity of the compounds of the invention against Respiratory Syncytial Virus (RSV), herpes simplex virus (HSV-1), enterovirus 71(EV71) is as per the patent: CN 104800212A; tested by the method described in CN 104774159A. Antiviral activity assays can also be performed according to the literature: 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; the test was performed according to the method described in CN104004042A, or according to other similar test methods known in the art.

The inhibitory activity of all compounds on Respiratory Syncytial Virus (RSV), herpes simplex virus (HSV-1) and enterovirus 71(EV71) is tested, and for the convenience of writing and the convenience of more concise and intuitive understanding of the invention, only ESI-MS of the compounds and the inhibitory activity data on Respiratory Syncytial Virus (RSV), herpes simplex virus (HSV-1) and enterovirus 71(EV71) are listed below (see tables 1-5).

For the sake of brevity, the present invention lists only typical compounds of formula I, formula I-1, formula I-2, formula I-3, and formula I-4 in tables 1-5.

TABLE 12 data for compound of formula I-1 in (R), 2' (R) configuration, ESI-MS and antiviral (RSV, HSV-1, EV71) activity

TABLE 22 (S), 2' (S) configuration of the compounds of formula I-1, ESI-MS and antiviral (RSV, HSV-1, EV71) Activity data

TABLE 32 data for equal mixtures of the (R),2 '(R) configuration and the 2(S), 2' (S) configuration for the external racer compound of formula I-2, ESI-MS and antiviral (RSV, HSV-1, EV71) activity

Isomers of 2(R), 2' (R) configuration obtained after chiral resolution of compound 601-839 in Table 3:

(R₁R₂、R₃、R₄the same as those defined for the corresponding groups in the compound 601-839 in Table 3) and isomers of 2(S), 2' (S) configuration:

(R₁、R₂、R₃、R₄the same as the corresponding groups in compound 601-839 of Table 3).

The isomers with 2(R), 2' (R) configuration and the isomers with 2(S),2(S) configuration obtained by the chiral resolution show equivalent antiviral activity in the activity tests of anti-RSV, HSV-1 and EV71, and have no obvious difference with the antiviral activity of the racemate compound 601-839. The above results indicate that the enantiomer compounds and the racemate compounds exhibited equivalent antiviral activity in terms of antiviral (RSV, HSV-1, EV71) activity. The spatial configuration of 2, 2' position has no obvious influence on antiviral activity.

TABLE 42 data for equal mixtures of the (R),2 '(R) configuration and the 2(S), 2' (S) configuration for the external racer compound of formula I-3, ESI-MS and antiviral (RSV, HSV-1, EV71) activity

Isomers of 2(R), 2' (R) configuration obtained after chiral resolution of the compound 840-893 in Table 4 respectively:

(R₁、R₂、R₃、R₄the same as those of the corresponding groups in compound 840-893 in Table 4) and isomers of the 2(S), 2' (S) configuration:

(R₁、R₂、R₃、R₄the same as the corresponding groups in compound 840-893 in Table 4).

The isomers with 2(R),2 '(R) configuration and the isomers with 2(S), 2' (S) configuration obtained by the chiral resolution show equivalent antiviral activity in the activity tests of anti-RSV, HSV-1 and EV71, and have no obvious difference from the antiviral activity of the racemate compound 840-893. The above results indicate that the enantiomer compounds and the racemate compounds exhibited equivalent antiviral activity in terms of antiviral (RSV, HSV-1, EV71) activity. The spatial configuration of 2, 2' position has no obvious influence on antiviral activity.

TABLE 52 data for equal combinations of the (R),2(R) and 2(S),2(S) configurations for the external racer compound of formula I-4, ESI-MS and antiviral (RSV, HSV-1, EV71) activity

Isomers of 2(R), 2' (R) configuration obtained after chiral resolution of compound 900-953 in Table 5, respectively:

(R₁、R₂、R₃、R₄the same as the corresponding groups in compound 900-953 in table 5) and isomers of the 2(S), 2' (S) configuration:

(R₁、R₂、R₃、R₄the definition of (a) is the same as that of the corresponding group in compound 900-953 in table 5).

The isomers with 2(R),2 '(R) configuration and the isomers with 2(S), 2' (S) configuration obtained by the chiral resolution show equivalent antiviral activity in the activity tests of anti-RSV, HSV-1 and EV71, and have no obvious difference from the antiviral activity of the racemate compound 900-953. The above results indicate that the enantiomer compounds and the racemate compounds exhibited equivalent antiviral activity in terms of antiviral (RSV, HSV-1, EV71) activity. The spatial configuration of 2, 2' position has no obvious influence on antiviral activity.

"A" in tables 1 to 5 represents the half Inhibitory Concentration (IC) of the compound₅₀) Is 1-500ng/mL, and "B" represents the half Inhibitory Concentration (IC) of the compound₅₀) 1.0-20. mu.g/mL, "C" represents the half Inhibitory Concentration (IC) of the compound₅₀) Greater than 50. mu.g/mL.

ClCH in tables 1-5₂C (O) represents a chloroacetyl group; CF (compact flash)₃C (O) represents a trifluoroacetyl group; c_nH_2n+1Represents a normal alkyl group (n is 4,5, 6,7 or 8); symbol

Represents R₁、R₂、R₃、R₃The group is bonded with the N in the structures of formula I, formula I-2, formula I-3 and formula I-4; .

Example 12 preparation of solvates of the Compounds of tables 1-5 and salts thereof

(1) Fumarate monoethanol compound and fumarate dihydrate preparation

Fumarate solvates of compounds 239, 539 are exemplified:

weighing compounds 239 and 539, 100mg respectively, dissolving in 8mL of absolute ethanol, adding 1.0equiv. fumaric acid and 7mL of absolute ethanol at room temperature, heating to 60 ℃, stirring for 1 minute (fumaric acid is completely dissolved), cooling to room temperature, continuing stirring for two hours, filtering, collecting precipitate, and drying to obtain fumarate monoethanol complex 1100(98mg) and 1101(105mg), respectively; the above solvates 1100 and 1101 were each 50mg weighed out and dissolved in 5mL of ethanol and 1mL of water at 60 ℃ and filtered to remove insoluble matter, and stirred at room temperature for 12 hours, and after collecting precipitates by filtration and drying, the obtained solid was left to stand at 25 ℃ and 60% relative humidity for two days to obtain fumarate dihydrate 1102(43mg) and 1103(40 mg). Warp beam¹HNMR, solid state¹³The C NMR or specific optical rotation tests do not find that the solvate containing the chiral amino acid in the solvate generates racemization.

(2) Preparation of monohydrate

Solvates of compounds 239, 539 and their salts are exemplified:

compounds 239 and 539 were weighed and suspended in 10mL of water at 10mg each, stirred at 28-30 ℃ for two hours, and the precipitate was collected by filtration, and the resulting solid was left to stand at 35 ℃ under 75% relative humidity for 3 days to obtain monohydrate 1104(7.2mg) and 1105(7.8 mg).

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

the solvate of the salt or the solvate 1100-1105 are subjected to differential thermal analysis/thermogravimetric analysis, elemental analysis, infrared absorption spectrum, and solid state analysis, respectively¹³C-NMR analysis, thermogravimetric analysis data are shown as the following differences: differential thermogravimetric analysis was carried out using a Thermo plusTG8120 differential thermogravimetric analyzer (the amounts of samples for measurement were varied from 3 to 5mg, respectively, heating rate: 10 ℃/min, reference substance: alumina), endothermic peak: an endothermic peak is observed at a temperature of about 72.1 to 85.3 ℃ and an endothermic peak is observed at a temperature of about 177.2 to 180.3 ℃.

Example 13 storage stability test

The compound 1100-1105 was stored in an open container at 40 deg.C, 75% relative humidity (see Table 6) and 50 deg.C, respectively, and tested for storage stability after 2 months. With respect to storage stability, the purity of each test compound was measured initially and after 2 months of storage by HPLC and the results were compared (see methods described in WO2009128421a1 for specific methods).

TABLE 6 storage stability test at 40 ℃ and 75% relative humidity

As can be seen from the test results in table 6, the solvate of solvate or salt has extremely excellent storage stability, and the test in an open container at 50 ℃ also shows that the purity of solvate hardly changes after two months, while the purity of compounds 239 and 539 decreases by more than 3%, so that the solvate of solvate or salt has the advantage of ultra-high stability and is convenient for long-term storage.

Compounds other than the compounds shown in tables 1-5 of the present invention which fall within the structural ranges of I, I-1, I-2, I-3 and I-4 may also be used in accordance with the present inventionThe synthesis was carried out by the method described in examples 1 to 10. All the diazacyclospirodiketopiperazine alkaloid derivatives (formula I, formula I-1, formula I-2, formula I-3 and formula I-4) have obvious inhibition effects on RSV, HSV-1 and EV71, and half Inhibition Concentration (IC)₅₀) At 1 to 500ng/mL, and half Toxic Concentration (TC)₅₀) In the concentration of 10-300 mu g/mL, the compound or the stereoisomer, the racemate, the unequal mixture of the enantiomer, the geometric isomer, the solvate, the pharmaceutically acceptable salt or the solvate of the salt can be used for preparing a medicinal lead compound, a candidate medicament and a medicament for treating and/or preventing respiratory diseases, hand-foot-and-mouth diseases, immune diseases and inflammatory diseases.

All documents mentioned in this application are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the above disclosure, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims

1. A diaza-oxacyclospirodiketopiperazine alkaloid compound of the structure of formula I, its tautomers, its stereoisomers, its racemates, unequal mixtures of its enantiomers, its geometric isomers, its pharmaceutically acceptable salts, characterized in that the compound of formula I has the following structure:

wherein R is₁、R₂、R₃、R₄Each independently selected from H, C1-C8 alkyl, C1-C8 alkylacyl, C1-C8 alkoxyacyl, C3-C10 cycloalkyl, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkenylacyl, C2-C8 alkynyl, C2-C8 alkynoyl, C6-C10 aryl, C6-C10 arylC 1-C4 alkyl, C6-C10 arylacyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroarylacyl, 4-to 12-membered saturated or unsaturatedAnd heterocyclyl, 4-to 12-membered saturated or unsaturated heterocyclyl C1-C4 alkyl, 4-to 12-membered saturated or unsaturated heterocyclylcarbonyl; r is as defined above₁、R₂、R₃、R₄The radicals being optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl, trifluoromethyl, trifluoroacetyl, mercapto, halogen, nitro, amino, azido (-N-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy, phenyl; n is 0 or 1; chemical bond(s)

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2. The diaza-oxacyclospirodiketopiperazine alkaloid compound of formula I according to claim 1, wherein R is₁、R₂、R₃、R₄Each independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkylacyl, C1-C8 haloalkylacyl, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkenylacyl, C2-C8 alkyneC2-C8 alkynoyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryloyl, C5-C10 heteroaryl, C5-C10 heteroaryl C1-C4 alkyl, C5-C10 heteroarylacyl, C5-C12 saturated or unsaturated heterocyclyl, C5-C12 saturated or unsaturated heterocyclyl C1-C4 alkyl, C5-C12 saturated or unsaturated heterocyclylacyl; r is as defined above₁、R₂、R₃、R₄The radicals being optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, methyl, mercapto, halogen, nitro, amino, azido (-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy, phenyl; the hetero atoms in the heterocyclic group and the heteroaryl group referred to in the above groups are 1 to 5 hetero atoms independently selected from N, O, S or Se.

3. A diaza-oxacyclospirodiketopiperazine alkaloid compound of the structure of formula I, its tautomers, its stereoisomers, its racemates, unequal mixtures of its enantiomers, its geometric isomers, its pharmaceutically acceptable salts, characterized in that the compound of formula I has the following structure:

wherein R is₃、R₄Each independently of the other is H, methyl, ethyl, isopropyl, C₅H₁₁、C₆H₁₃、C₈H₁₇3-hydroxy-propyl

2-carboxy-ethyl

P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinolin-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH)₂CO), propionyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexaneAcyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, trifluoroacetyl, allyl, ethynyl, propargyl, tert-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, benzhydryl

R₁、R₂Each independently is H, C1-C8 alkyl, C1-C8 alkanoyl, C1-C8 alkoxyacyl, C3-C10 cycloalkyl, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkenylacyl, C2-C8 alkynyl, C2-C8 alkynoyl, C6-C10 aryl, C6-C10 arylC 1-C4 alkyl, C6-C10 arylacyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroarylacyl, 4-to 12-membered saturated or unsaturated heterocyclyl C1-C4 alkyl, 4-to 12-membered saturated or unsaturated heterocyclyl acyl; r is as defined above₁、R₂、R₃、R₄The groups are optionally substituted by hydroxyl, hydroxymethyl, carboxyl, acetamido, C1-C4 alkyl, mercapto, halogen, nitro, amino, azido (-N)₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, C1-C4 alkoxy, phenyl; n is 0 or 1; chemical bond(s)

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4. The diaza-oxacyclospirodiketopiperazine alkaloid compound of formula I according to claim 3, wherein R is₁、R₂Each independently is n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-ethyl-hexyl, 1-chloro-3-methyl-pentyl, 1-chloro-2-methyl-hexyl, 1-chloro-3-methyl-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-hexyl, 3-fluoro-hexyl, 1-chloro-, 1-chloro-3-ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl-hexyl, 1-bromo-3-ethyl-hexyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-hexanoyl, 3-ethyl-hexanoyl, trifluoroacetyl, difluoroacetyl, chloroacetyl, bromoacetyl, pentafluoropropionyl, pentanoyl, hexanoyl, 3-methyl-hexanoyl, 3-ethyl-hexanoyl, trifluoroacetyl, perfluorobutanoyl, 1-fluoro-3-methyl-pentanoyl, 1-fluoro-2-methyl-hexanoyl, 1-fluoro-3-ethyl-hexanoyl, 1-chloro-3-methyl-pentanoyl, 1-chloro-2-methyl-hexanoyl, 1-chloro-3-ethyl-hexanoyl, 1-bromo-3-methyl-pentanoyl, 1-bromo-2-methyl-pentanoyl, 1-bromo-2-methyl-hexanoyl, 1-bromo-3-ethyl-hexanoyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, n-pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, heptadienyl, heptatrienyl, n-octenyl, octadienyl, octatrienylA radical, 3-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-ethyl-hex-2-enyl, propionyl, but-2-enoyl, methacryloyl, pent-3-enoyl, isopentenoyl, pentadienoyl, hex-4-enoyl, hept-5-enoyl, heptadienoyl, heptatrienoyl, oct-6-enoyl, octadienoyl, octenoyl, 3-methyl-pent-2-enoyl, 2-methyl-hex-2-enoyl, methyl-2-penten-2-enoyl, methyl-2-butenoyl, 3-methyl-hex-2-enoyl, 3-ethyl-hex-2-enoyl, ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, n-octynyl, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-ethyl-hex-2-ynyl, propargyl propionyl, n-butynyl, but-2-ynoyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, n-octynyl, octynyl, Octynoyl, 2-methyl-pent-2-ynoyl, 2-methyl-hex-2-ynoyl, 3-ethyl-hex-2-ynoyl, phenyl, naphthyl, benzyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, isoquinolyl, benzofuryl, benzothiazolyl, benzoselenadiazolyl, coumarinyl, isocoumarinyl, azetidinyl, oxetanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrofuranyl, dioxanyl, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrocoumarinyl, dihydroisocoumarinyl, Tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydrocarbazolyl, pyrimidyl, purine base; r is as defined above₁、R₂、R₃、R₄The radicals being optionally substituted by hydroxy, hydroxymethyl, carboxy, acetylamino, mercapto, halogen, nitro, amino, azido (-N₃) Guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C ═ O), oxo (═ O), thio (═ S), sulfonyl, methoxy, ethoxy.

5. A diaza-oxacyclo spirodione piperazine alkaloid compound with a structure shown as formula I-1, I-2, I-3, I-4, which is characterized by being selected from the compounds 1-238, 301-538, 601-893, 900-953 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, and a pharmaceutically acceptable salt thereof, wherein the compounds 1-238, 301-538, 601-893, 900-953 have the following structures:

6. a bis-oxazinane spirodione piperazine alkaloid compound of formula I-1, its tautomer, its stereoisomer, its racemate, a non-equivalent mixture of its enantiomers, its geometric isomer, a pharmaceutically acceptable salt thereof, characterized in that the compound of formula I-1 has the following structure:

R₁、R₂、R₃、R₄is as defined in any one of claims 1 to 4.

7. A bis-isoxazolidine spirodione piperazine alkaloid compound of formula I-2, its tautomer, its stereoisomer, its racemate, a non-equivalent mixture of its enantiomers, its geometric isomer, a pharmaceutically acceptable salt thereof, characterized in that the compound of formula I-2 has the following structure:

R₁、R₂、R₃、R₄is as defined in any one of claims 1 to 4.

8. A bisoxazine spirodiketopiperazine alkaloid compound of formula I-3, its tautomers, its stereoisomers, its racemates, unequal mixtures of its enantiomers, its geometric isomers, its pharmaceutically acceptable salts, characterized in that the compound of formula I-3 has the following structure:

R₃、R₄is as defined in any one of claims 1 to 4.

9. A bisisoxazoline spirodiketopiperazine alkaloid compound of the structure of formula I-4, its tautomers, its stereoisomers, its racemates, unequal mixtures of its enantiomers, its geometrical isomers, its pharmaceutically acceptable salts, characterized in that the compound of formula I-4 has the following structure:

R₃、R₄is as defined in any one of claims 1 to 4.

10. Solvate 1100-1105 is characterized in that the structure of solvate 1100-1105 is as follows:

11. the pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, sulfate, phosphate, oxalate, maleate, methanesulfonate, succinate, citrate, fumarate, glucuronate, formate, acetate, succinate.

12. A pharmaceutical composition characterized in that it contains as active principle any one or several of the compounds according to any one of claims 1 to 9 or tautomers, stereoisomers, racemates, unequal mixtures of enantiomers, geometric isomers and pharmaceutically acceptable salts thereof.

13. The pharmaceutical composition of claim 12, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition further comprises at least one additional antiviral agent.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of injection, oral preparation, lyophilized powder for injection, and suspension.

16. Use of a compound according to any one of claims 1 to 9 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 12 to 15 for the preparation of a medicament for the treatment and/or prophylaxis of diseases caused by RSV, HSV-1, EV 71.

17. Use of a compound according to any one of claims 1 to 9 or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 12 to 15 for the preparation of a medicament for the treatment and/or prophylaxis of respiratory diseases, hand-foot-and-mouth diseases, immunological diseases, inflammatory diseases.

18. The use according to claim 16, characterized in that said diseases are selected from: respiratory diseases, pneumonia, gingivitis, keratoconjunctivitis, encephalitis, infections of the reproductive system, rashes, herpes and herpangina in the hands, feet and oral cavity.

19. Use of a compound according to any one of claims 1 to 9, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent mixture of enantiomers thereof, a geometric isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament against RSV, HSV-1, EV71 candidates.

20. A process for the preparation of a compound of formula I, formula I-1, formula I-2, formula I-3 or formula I-4 as claimed in any one of claims 1 to 9, comprising the steps of:

the method comprises the following steps:

step (1): 2, 4-diaminobutyric acid or ornithine in KHSO₄、NaHSO₄、HCl、H₂SO₄、HClO₄、TfOH、KHSO₄-SiO₂、NaHSO₄-SiO₂、H₂SO₄-SiO₂、HClO₄-SiO₂Or TfOH-SiO₂Under the action of (1), reacting in water or alcohol solution at the temperature of 30-120 ℃ for 4-120 hours to obtain a compound shown in a formula II;

step (2): carrying out reflux reaction on the compound of the formula II in an organic solvent under the action of an oxidant to obtain a compound of a formula III; the oxidant is selected from mCPBA or hydrogen peroxide; the dosage of the oxidant is 2.0-4.0 times of the molar weight of the compound of the formula II, and the organic solvent is selected from acetone, dichloromethane, chloroform and THF;

and (3): reacting the compound of the formula III in an organic solvent under the action of an initiator and alkali to obtain a compound of a formula IV, namely R₃、R₄Compounds of formula I-3, I-4 when H; the initiator is selected from Ag-containing initiators⁺A compound or TEMPO; the base is selected from alkali metal carbonate or alkali metal bicarbonate; the organic solvent is selected from DMF, DMA, THF, acetonitrile, acetone, and toluene; the reaction temperature is 0 to 60 ℃;

and (4): the compound of formula IV is subjected to alkylation reaction or acylation reaction to obtain a compound of formula V, namely R₃、R₄Compounds of formula I-3 and I-4 which are not simultaneously H; the alkylation reaction conditions were: in organic solvent, under the action of alkali and hydrocarbonizing reagent, where the hydrocarbonizing reagent is chosen from R₃X or R₄X, wherein X is halogen; the base is selected from alkali metal carbonate, alkali metal hydroxide, alkali metal hydride or alkali metal alkoxide; the acylation reaction conditions are as follows: in organic solvent, under the action of alkali and acylating agent, in which the acylating agent is selected from R₃X or R₄X、R₃OR₃Or R₄OR₄Wherein X is halogen, and the base is selected from alkali metal hydroxide, triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-dimethylpyridine; the organic solvent is selected from dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, and dioxane;

and (5): the compound of formula V reacts in an organic solvent under the action of a reducing agent to obtain a compound of formula VI, namely R₁、R₂Compounds of formula I-1, I-2 when H; the reducing agent is selected from H₂And Pd/C, H₂And PtO₂、H₂And Raney Nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borane; the reaction temperature is between-20 ℃ and reflux temperature; the organic solvent is selected from dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform;

and (6): the VI compound is subjected to alkylation reaction or acylation reaction to obtain a compound shown as a formula VII, namely R₁、R₂Compounds of formula I-1 and I-2 when not simultaneously H; the alkylation reaction conditions were: in organic solvent, under the action of alkali and hydrocarbonizing reagent, where the hydrocarbonizing reagent is chosen from R₁X or R₂X, wherein X is halogen; the base is selected from alkali metal carbonate, alkali metal hydroxide, alkali metal hydride or alkali metal alkoxide; the acylation reaction conditions are as follows: in organic solvent, under the action of alkali and acylating agent, in which the acylating agent is selected from R₁X or R₂X、R₁OR₁Or R₂OR₂Wherein X is halogen, and the base is selected from alkali metal hydroxide, triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-dimethylpyridine; the organic solvent is selected from dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, and dioxane;

the second method comprises the following steps:

step (1): reacting the compound shown in the formula III in an organic solvent under the action of a reducing agent to obtain a compound shown in the formula VIII; the reducing agent is selected from H₂And Pd/C, H₂And PtO₂、H₂And Raney Nickel (Raney Nickel), sodium borohydride, sodium cyanoborohydride, borane; the reaction temperature is selected from-20 ℃ to reflux temperature; the organic solvent is selected from dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile, chloroform;

step (2): reacting the compound of formula VIII in an organic solvent under the action of a base or a Mitsunobu reagent to obtain a compound of formula IX, namely R₁、R₂、R₃、R₄Compounds of formula I-1, I-2, when both are H; the base is selected from alkali metal carbonate or alkali metal bicarbonate, alkali metal hydroxide, alkali metal hydride or alkali metal alkoxide; the Mitsunobu reagent is selected from DEAD and PPh₃DIAD and PPh₃DEAD and PEt₃DIAD and PEt₃(ii) a The organic solvent is selected from DMF, DMA, THF, acetonitrile, acetone, dichloromethane, chloroform; the reaction temperature is 0 to 60 ℃;

and (3): the compound of formula IX is subjected to alkylation reaction or acylation reaction to obtain a compound of formula VII, namely a compound of formula I-1 or I-2; the alkylation reaction conditions were: in organic solvent, under the action of alkali and hydrocarbonizing reagent, where the hydrocarbonizing reagent is chosen from R₁X、R₂X、R₃X or R₄X, wherein X is halogen; the base is selected from alkali metal carbonate, alkali metal hydroxide, alkali metal hydride or alkali metal alkoxide; the acylation reaction conditions are as follows: in organic solvent, under the action of alkali and acylating agent, in which the acylating agent is selected from R₁X、R₂X、R₃X or R₄X、R₁OR₁、R₂OR₂、R₃OR₃Or R₄OR₄Wherein X is halogen, and the base is selected from alkali metal hydroxide, triethylamine, pyridine, and vinegarSodium, quinoline, imidazole, dimethylaniline, DMAP, 2, 6-lutidine; the organic solvent is selected from dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, and dioxane.

21. An intermediate compound of formula III, characterized in that formula III has the following structure: