WO2017025031A1

WO2017025031A1 - Diazaoxa heterocyclic spiro-dione piperazine alkaloid derivative having antiviral activity and preparation method thereof

Info

Publication number: WO2017025031A1
Application number: PCT/CN2016/094330
Authority: WO
Inventors: 于跃
Original assignee: 于跃
Priority date: 2015-08-10
Filing date: 2016-08-10
Publication date: 2017-02-16
Also published as: CN106795174B; CN106795174A

Abstract

Disclosed is a diazaoxa heterocyclic spiro-dione piperazine alkaloid derivative having an antiviral activity and a preparation method thereof. The compound is a compound of formula (I), has anti-RSV, HSV-1 and EV71 activities and has the following structure: wherein R₁, R₂, R₃, R₄ are each independently selected from 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; and a chemical bond (A) represents a bond (B) that points into the page or a bond (C) that points out of the page. "-----" indicates a single bond or does not exist, and when "-----" represents a single bond, R₁ and R₂ do not exist.

Description

Antiviral activity bis-oxaoxacyclohexanedione piperazine alkaloid derivative and preparation method thereof

Technical field

The present invention relates to a bis-oxaoxacyclohexanedione piperazine alkaloid derivative and a preparation method thereof, and to the above-mentioned bis-oxaoxacyclohexanedione piperazine alkaloid derivative in the preparation of an antiviral drug application. The diazoxide heterodone piperazine alkaloid derivative of the present invention has broad-spectrum antiviral activity and exhibits strong antiviral activity against both RNA virus and DNA virus, especially to respiratory syncytial virus (RSV). Herpes simplex virus (HSV-1) and enterovirus 71 (EV71) have strong inhibitory activities.

Background technique

Respiratory syncytial virus (RSV, also known as Paramyxoviridae) is an RNA virus belonging to the family Paramyxoviridae. RSV infection can cause pneumonia and a variety of lower respiratory tract diseases. At least 3 million infants and young children worldwide are admitted to the hospital each year because of RSV infection. At least 160,000 of them die, so RSV is also known as child killer (Science, 2013, 342, 546). -547). There are currently no clinically applicable vaccines, and ribavirin (ribavirin) is the only chemotherapeutic drug used in clinical practice (J. Med. Chem. 2008, 51, 875–896).

Herpes simplex virus (HSV-1) is a wrapped DNA virus belonging to the herpes family virus, which can cause various diseases in humans, such as gingivostomatitis and keratoconjunctivitis. Encephalitis and infections of the reproductive system and neonates.

Enterovirus 71 (EV71) is the main pathogen of hand, foot and mouth disease. It was first isolated from sputum specimens of infants with central nervous system diseases in California in 1969. It is a new enteric virus discovered by humans. Mainly infected with infants and young children, it can cause acute infections with fever, rash, herpes and herpes angina in the hands, feet, mouth and other parts. The infection is often accompanied by neurological complications, which can lead to children. death. At present, although there are some reports on EV71 replication cycle antiviral drugs, EV71 vaccine development, RNA, etc., no clinically effective prevention and treatment measures have been found.

In summary, the development of drug-leading compounds, drug candidates, and clinically effective drugs for preventing and/or treating diseases caused by RSV, HSV-1, and EV71 infections has become a top priority.

Summary of the invention

The present invention provides a bis-oxaoxacyclohexanedione piperazine alkaloid compound of the formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula I has the structure:

Wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkyl acyl, alkoxy acyl, cycloalkyl acyl, alkenyl, alkenyl acyl, alkynyl, Alkynyl, aryl, arylalkyl, aryl acyl, heteroaryl, heteroarylalkyl, heteroaryl acyl, saturated or unsaturated heterocyclic, saturated or unsaturated heterocyclic alkyl, saturated Or an unsaturated heterocyclic acyl group; the above R ₁ , R ₂ , R ₃ , R ₄ groups are optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl) , trifluoromethyl, trifluoroacetyl, decyl, halogen, nitro, amino, azido (-N ₃ ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C =O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), one or more of phenyl Substitution; n is 0 or 1; chemical bond

Indicates the key pointing to the paper

Or point to a key outside the paper

"-----" means that a single bond or non-existent, and when "-----" represents a single bond, R ₁ and R ₂ do not exist; the precondition is that when R ₃ and R _{4 are} simultaneously H, When R ₁ and R _{2 are} not the same

symbol

A linkage site representing the R ₁ , R ₂ group to N in the structure of Formula I.

The compounds of formula I according to the invention do not include compounds 239 and 539 and their racemates, but may include stereoisomers thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, A solvate of a pharmaceutically acceptable salt or a salt thereof.

In another embodiment of the invention, R ₁ , R ₂ , R ₃ , R ₄ are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxy acyl, C3- C10 cycloalkyl, C3-C10 cycloalkyl acyl, C2-C8 alkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaryl acyl, 4 to 12-membered saturated or unsaturated a heterocyclic group, a 4- to 12-membered saturated or unsaturated heterocyclic group C1-C4 alkyl group, a 4- to 12-membered saturated or unsaturated heterocyclic acyl group; and the above R ₁ , R ₂ , R ₃ , R ₄ The group is optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl), fluorenyl, halogen, nitro, amino, azido (-N ₃ ) , mercapto, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy (such as A One or more substitutions of oxy, ethoxy, t-butoxy), phenyl; other definitions are the same as above.

In another embodiment of the invention, R ₁ , R ₂ , R ₃ , R ₄ are each independently selected from H, C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkane. Alkyl, C1-C8 haloalkyl, C3-C10 cycloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C10 heteroaryl, C5-C10 heteroaryl C1-C4 alkyl, C5-C10 heteroaryl acyl, C5-C12 saturated or An unsaturated heterocyclic group, a C5-C12 saturated or unsaturated heterocyclic group C1-C4 alkyl group, a C5-C12 saturated or unsaturated heterocyclic acyl group; the above R ₁ , R ₂ , R ₃ , R ₄ groups are optional By hydroxyl, hydroxymethyl, carboxyl, acetylamino, methyl, decyl, halogen, nitro, amino, azido (-N ₃ ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl ( -C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy, one or more substitutions in the phenyl group; heterocyclic groups involved in the above groups, The heteroatoms in the heteroaryl group are independently selected from the group consisting of 1-5 heteroatoms in N, O, S or Se; the other definitions are the same as above.

In another embodiment of the invention, R ₃ and R ₄ are each independently H, methyl, ethyl, isopropyl, C ₅ H ₁₁ , C ₆ H ₁₃ , C ₈ H ₁₇ , 3-hydroxy-propyl base

2-carboxy-ethyl

P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinoline-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH ₂ CO), Propionyl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, tri Fluoroacetyl, allyl, ethynyl, propargyl, tert-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, diphenylmethyl

R ₁ and R ₂ are each independently H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxy acyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl acyl, C2-C8. Alkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C12 Heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaryl acyl, 4- to 12-membered saturated or unsaturated heterocyclic group, 4 to 12-membered saturated or unsaturated heterocyclic ring a C1-C4 alkyl group, a 4- to 12-membered saturated or unsaturated heterocyclic acyl group; the above R ₁ , R ₂ , R ₃ , R ₄ groups may be optionally a hydroxyl group, a hydroxymethyl group, a carboxyl group, an acetylamino group, C1-C4 alkyl (such as methyl, ethyl, propyl), fluorenyl, halogen, nitro, amino, azido (-N ₃ ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), Carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), phenyl One or more substitutions; the other definitions are the same as above.

2-carboxy-ethyl

R ₁ and R ₂ are each independently n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl , 3-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl-pentyl, 1-fluoro-2-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-methyl-hexyl, 1-fluoro-3-ethyl-hexyl, 1-chloro-3-methyl-pentyl, 1-chloro-2-methyl-pentyl, 1-chloro- 2-methyl-hexyl, 1-chloro-3-methyl-hexyl, 1-chloro-3-ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl- Pentyl, 1-bromo-2-methyl-hexyl, 1-bromo-3-methyl-hexyl, 1-bromo-3-ethyl-hexyl, acetyl, propionyl, n-butyryl, isobutyryl, Isovaleryl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-pentanoyl, 2-methyl-hexanoyl, 3-methyl -hexanoyl, 3-ethyl-hexanoyl, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-pentanoyl, 2-methyl-hexanoyl, 3-methyl -hexanoyl, 3-ethyl-hexanoyl, trifluoroacetyl, difluoroacetyl, chloroacetyl, bromoacetyl, pentafluoropropionyl, perfluorobutyryl, 1-fluoro-3-methyl-pentyl Acyl, 1-fluoro-2-methyl-pentanoyl, 1-fluoro-2-methyl-hexanoyl, 1-fluoro-3-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-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-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, heptadienyl, n-octenyl, octadienyl, octatrienyl, 3 -methyl-pent-2-enyl, 2-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-methyl-hex-2-enyl, 3-ethyl -hex-2-enyl, propionyl, but-2-enoyl, methacryloyl, pent-3-enoyl, isopentenyl, pentadiene Acyl, hex-4-enoyl, hept-5-enoyl, heptadienoyl, heptylenoyl, oct-6-enoyl, octadienoyl, octylenoyl, 3-methyl-pentane- 2-enoyl, 2-methyl-pent-2-enoyl, 2-methyl-hex-2-enoyl, 3-methyl-hex-2-enoyl, 3-ethyl-hex-2- Alkenoyl, ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, heptadienyl, n-octynyl , octadiynyl, octantylene, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-ynyl, 3-B -hex-2-ynyl, propargyl, n-butynyl, but-2-ynyl, n-pentynyl, isopenynyl, n-hexynyl, n-heptynyl, Heptadiynyl, n-alkynyl, octadiynyl, octantynyl, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-ynyl acyl, 3-ethyl-hex-2-ynyl acyl, phenyl, naphthyl, benzyl, phenethyl imidazolyl, pyridyl, oxazolyl, isomer Azolyl, triazolyl, tetrazolyl Furanyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, fluorenyl, oxazolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzoselenadiazole Base, coumarin, isocoumarin, azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline , thiazolinyl, tetrahydropyranyl, dihydrocoumarin, dihydroisocoumarin, tetrahydroquinolyl, tetrahydroisoquinolinyl, tetrahydrocarbazolyl, pyrimidine base, purine base The above R ₁ , R ₂ , R ₃ , R ₄ groups are optionally hydroxy, hydroxymethyl, carboxyl, acetylamino, sulfhydryl, halogen, nitro, amino, azide (-N ₃ ), fluorenyl One of cyano, t-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, methoxy, ethoxy, or Multiple substitutions; other definitions are the same as above.

In another embodiment of the invention, R ₃ and R ₄ are each independently 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 of Tables 1-5 or tautomers thereof, stereoisomers thereof, racemates thereof, non-equivalence of enantiomers thereof A mixture of the mixture, its geometric isomer, its solvate, its pharmaceutically acceptable salt or a salt thereof.

In another preferred embodiment, in the compound of formula I, R ₁ , R ₂ , R ₃ , R ₄ are specific to the corresponding positions in the specific compounds 1-239, 301-539, 601-893, and 900-953 in Tables 1-5. Group.

It will be understood that the above preferred groups may be combined with one another to form the various preferred compounds of the invention, which are limited in scope and are not described herein.

The present invention provides a bisoxazinidine spirobiperazine alkaloid compound of the formula I-1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula I-1 has the structure:

_{_{_{R 1, R 2, R 3}}} , R ₄ is defined above with various embodiments of the compound of formula I is R _{_{_{1, R 2, R 3,}}} R 4 is defined.

For the convenience of the present invention, the parent core structure of the compound of formula I-1 is labeled as follows:

The compound of the formula I-1 of the present invention does not include

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

The present invention provides a diisoxazole spirodione piperazine alkaloid compound of the formula I-2, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomeric thereof A non-equal mixture of a body, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula 1-2 has the following structure:

For the convenience of the present invention, the parent core structure of the compound of formula I-2 is labeled as follows:

The present invention provides a bisoxazinidine spirobone piperazine alkaloid compound of the formula I-3, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula 1-3 has the following structure:

The definition of R _3, R ₄ is _3, R ₄ defined for the compound of formula I each of R in the above embodiments.

For the convenience of the present invention, the parent core structure of the compound of formula I-3 is labeled as follows:

The present invention provides a bisisoxazoline spidinone piperazine alkaloid compound of the formula I-4, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and an enantiomer thereof A non-equal mixture of a body, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula I-4 has the following structure:

For the convenience of the present invention, the parent core structure of the compound of the formula I-4 is labeled as follows:

In the present invention: the alkenyl group involved in the group contains one or more double bonds unless otherwise specified; the alkynyl group involved in the group contains one or more triple bonds, and any of the alkynyl groups involved Containing one or more double bonds; the alkyl group referred to in the group, for example, the alkyl group in the "alkyl group, alkyl acyl group, arylalkyl group, haloalkyl group, haloalkyl group" is a linear or branched alkyl group. Preferred is a C1-C8 linear or branched alkyl group, further preferably a methyl group, an ethyl group, a propyl group, a n-butyl group, an isobutyl group, a t-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group or a n-heptyl group. , n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl, 3-methyl-hexyl, 3-ethyl-hexyl; alkenyl groups involved in the group, for example The alkenyl group in the "alkenyl group, alkenyl group" is a linear or branched alkenyl group, and has one or more double bonds, preferably a C2-C8 straight or branched alkenyl group, and further preferably a vinyl group or a propylene group. Base, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, n-pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, Heptadienyl, heptadienyl, n-octenyl, octadienyl, octatrienyl, 3-methyl-pent-2-enyl, 2-methyl-pent-2-enyl, 2 -Methyl-hex-2-enyl, 3-methyl-hex-2-enyl, 3-ethyl-hex-2-enyl; a cycloalkyl group as referred to in the group, for example, said "cycloalkyl" The cycloalkyl group in the cycloalkyl acyl group is a C3-C10 cycloalkyl group, preferably a cyclopropyl group, a cyclobutane group, a cyclopentyl group, a cyclohexane group, a cycloheptyl group or a cyclooctyl group; The alkynyl group referred to in the group, for example, the alkynyl group in the "alkynyl, alkynyl" is a straight or branched alkynyl group, containing one or more triple bonds, optionally containing one or more double bonds, preferably a C2-C8 linear or branched alkynyl group, further preferably an ethynyl group, a propynyl group, a n-butynyl group, a but-2-ynyl group, an n-pentynyl group, an isopentynyl group, a n-hexynyl group, a n-heptynyl group. , heptadienyl, n-octynyl, octadiynyl, octantylene, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl- Hex-2-ynyl, 3-ethyl-hex-2-ynyl; aryl group referred to in the group, for example, "aryl" in the "aryl, arylalkyl, aryl acyl" is an aromatic hydrocarbon Base a monocyclic, bicyclic, fused ring aryl group, further preferably a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, further preferably a phenyl group or a naphthyl group; a heteroaryl group referred to in the group such as the "heteroaryl group" The heteroaryl group in the "heteroarylalkyl group, heteroaryl acyl group" is an aryl group having 1 to 5 independently selected from N, O, S or Se hetero atoms, preferably containing 1 to 5 independently selected from a 5- to 12-membered heteroaryl group of a hetero atom of N, O, S or Se, further preferably an imidazolyl group, a pyridyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a quinine group Lolinyl, oxazinyl, thienyl, phenothiazine, benzothienyl, thiazolyl, thiadiazolyl, fluorenyl, oxazolyl, isoquinolyl, benzofuranyl, benzothiazolyl a benzoselenadiazole group, a coumarin group, a isocoumarin group; a heterocyclic group to be referred to in the group, for example, said "saturated or unsaturated heterocyclic group, saturated or unsaturated heterocyclic alkyl group, saturated or The heterocyclic group in the unsaturated heterocyclic acyl group is a monocyclic or polycyclic heterocyclic group having 1 to 5 independently selected from N, O, S or Se hetero atoms, preferably containing 1 to 5 independently selected From N, O a 4- to 12-membered monocyclic or polycyclic heterocyclic group of the S or Se hetero atom, more preferably azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuran Base, dioxane, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrocoumarin, dihydroisocoumarin, tetrahydroquinolyl, tetrahydroisoquinolinyl, tetra Hydroxycarbazolyl, pyrimidinyl, purine base; "arylalkyl" is preferably benzyl or phenylethyl; the "alkoxy" is preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, uncle Butoxycarbonyl, etc.; the cycloalkyl, aryl, heteroaryl, heterocyclic group involved in the group is a monocyclic, polycyclic or fused ring; the acyl groups involved in the group are all carbonyl (C=O); The halogens referred to in the group are monohalogenated or polyhalogenated, ie monofluoro, monochloro, monobromo, monoiodo, or polyfluoro, polychlorinated, polybrominated, polyiodo, optionally Two or more of fluorine, chlorine, bromine, and iodine are substituted; the "halogen" is preferably fluorine, chlorine, bromine, or iodine.

Chemical bond in the compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 of the present invention

Means pointing to the key in the paper at the same time

Or point to the key outside the paper

The term "pharmaceutically acceptable salt" in the present invention means a non-toxic addition salt of an inorganic or organic acid and/or a base, see "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 by subjecting the base or acid functional groups to the appropriate organic or inorganic Prepared separately by acid or base reaction. Representative salts include, but are not limited to, the following: acetate, adipic acid Salt, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, camphorate, digluconate, cyclopentane propionate , dodecane sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydrogen iodine Acid salt, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, over Sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate . Further, the basic nitrogen-containing group may be quaternized by a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfate, For example, dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl, octadecyl chloride, bromide and iodide An aralkyl halide such as benzyl and phenethyl bromide. Water or oil soluble or dispersible products are thus obtained.

Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid. The basic addition salt 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 by reacting a carboxylic acid group with a suitable The base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) is prepared separately or reacted with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations 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 the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

The term "solvate" in the present invention means a solvate of the compound of the formula I, the formula I-1, the formula I-2, the formula I-3, the compound of the formula I-4 or a salt thereof and the organic solvent and/or water. The organic solvent is preferably acetone, acetonitrile, methanol or ethanol, and the solvate formed is preferably a monohydrate of the compound of the formula I, the formula I-1, the formula I-2, the formula I-3, the compound of the formula I-4 or a salt thereof, Hydrate, trihydrate, monomethanolate, dimethanolate, monoacetonitrile, diacetonitrile, monoacetone, diacetone, hemi-fumarate monohydrate, fumarate Dihydrate, fumarate monoethanolate, and the like. Further preferred are monohydrate, fumarate dihydrate, fumarate monoethanolate. Further preferred are compounds 1100-1105.

The term "geometric isomer" as used in the present invention means both Z and E geometric configurations when a compound having a double bond is contained in the compound of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4. compound of.

The compounds of the formula I, the formula I-1, the formula I-2, the formula I-3 and the formula I-4 of the present invention exist in various tautomeric forms (in which the proton of one atom of the molecule is transferred to another atom, the molecular The chemical bonds between the atoms are then rearranged). See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992). The term "tautomer" as used herein. Refers to compounds produced by proton transfer, it being understood that all tautomeric forms (as long as they may be present) are included within the scope of the invention. For example, when a compound having a amide bond, an enol bond, or an imidazole is contained in a compound of the formula I, the formula I-1, the formula I-2, the formula I-3, or the formula I-4, a pair of interconversions which can be converted each other isomer.

As used herein, "non-equal mixture of enantiomers" refers to a mixture of two pairs of enantiomers in non-equimolar amounts, i.e., having an ee value greater than zero and less than 100%.

Compounds of the 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 thereof and The drug may contain asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms may allow the compounds of the invention to exist in enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as, for example, (R)- or (based on absolute stereochemistry). S) - configuration. Thus, all such possible isomers, optically pure forms of single stereoisomers, mixtures thereof, racemic mixtures (or "racemates"), diastereomeric mixtures of the compounds of the invention A single diastereomer is included in the present invention. The terms "S" and "R" configurations as used herein are defined according to the following definition: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. 45: 13-30 (1976). The terms α and β are used for the ring position of the cyclic compound. The α-side of the reference plane is the preferred substituent on one side of the lower numbered position. Those substituents on the opposite side of the reference plane employ a beta descriptor. It should be noted that this usage differs from the usage for the annular stereonuclear, in which "α" means "below the plane" and represents the absolute configuration. The terms alpha and beta configurations as used herein are defined in accordance with paragraph 203 of the Chemical Abstracts Index Guide-Appendix IV (1987).

The compound of formula I, formula I-1, formula I-2, formula I-3, formula I-4 is selected from the compounds of Tables 1-5 or tautomers thereof, stereoisomers thereof, and racemization thereof. A non-equal mixture of the enantiomers, geometric isomers thereof, solvates thereof, pharmaceutically acceptable salts thereof or solvates thereof.

The solvate of the solvate or salt of the formula I and the formula I-1 is preferably a monohydrate, a fumarate dihydrate or a fumarate monoethanolate; further preferably a compound 1100-1105.

In another preferred embodiment, R ₁ , R ₂ , R ₃ , and R ₄ in the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are the specific compounds in Tables 1-5. Specific groups at corresponding positions in 1-239, 301-539, 601-893, and 900-953.

Another embodiment of the present invention provides an antiviral agent, which comprises one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4. Compounds or tautomers thereof, stereoisomers thereof, racemates thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable thereof Any one or more of a salt of a salt or a salt thereof is used as an active ingredient.

Another embodiment of the present invention provides a pharmaceutical composition comprising any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4. Compounds or tautomers thereof, stereoisomers thereof, racemates thereof, non-isomeric mixtures of enantiomers thereof, geometric isomers thereof, solvates thereof, pharmaceutically acceptable thereof Any one or more of a salt or a solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment of the present invention provides a pharmaceutical composition comprising any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or a compound thereof a tautomer, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a salt thereof Any one or more of the solvates, and at least one other antiviral drug. The pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like.

Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a solvate of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a salt thereof, in the preparation of an antiviral drug use.

Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a treatment, and/or prevention of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof Application in medicines for respiratory diseases, hand, foot and mouth disease, immune diseases, and inflammatory diseases.

Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof a treatment, and/or prevention of a body, a racemate thereof, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof Application in medicines for diseases caused by RSV, HSV-1, EV71. The disease is selected from the group consisting of: respiratory diseases, pneumonia, gingivitis, keratoconjunctivitis, encephalitis, reproductive system infections, rashes of the hands, feet, mouth, etc., herpes and herpetic angina.

Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof Use of a body, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a medicament. The medicament is for the treatment of diseases caused by respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), and enterovirus 71 (EV71).

Another embodiment of the invention provides any one or more of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or tautomers thereof, and stereoisomers thereof Preparation of anti-RSV, HSV-, a racemate, a non-equal mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof 1. Application of EV71 drug lead compound.

Another embodiment of the invention provides any one or more of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or each other An isomer, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a salt thereof The use of solvates in the preparation of anti-RSV, HSV-1, EV71 drug candidates.

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

method one:

Step (1): 2,4-diaminobutyric acid (when n=0, it may be L-form, D-form, or DL racemate) or ornithine (when n=1, it may be L-form, D Type, or DL racemate) as raw materials, in KHSO ₄ , NaHSO ₄ , HCl, H ₂ SO ₄ , HClO ₄ , TfOH, KHSO ₄ -SiO ₂ , NaHSO ₄ -SiO ₂ , H ₂ SO ₄ -SiO ₂ , Under the action of HClO ₄ -SiO ₂ or TfOH-SiO ₂ , the reaction temperature is 30 to 120 ° C (preferably 80 to 120 ° C) in water or an alcohol solution, and the reaction is carried out for 4 to 120 hours (preferably 12 to 96 hours) to obtain a compound of formula II. This step of the reaction can be carried out in accordance with the method disclosed in JP-A-2013-53115A or a similarly improved method.

Step (2): The compound of the formula II is refluxed in an organic solvent under the action of an oxidizing agent to give a compound of the formula III. The oxidizing agent is preferably mCPBA or hydrogen peroxide; the oxidizing agent is preferably used in an amount of from 2.0 to 4.0 times, more preferably from 2.5 to 3.5 times, the molar amount of the compound of the formula II; and the organic solvent is preferably acetone, dichloromethane, chloroform or THF.

Step (3): The compound of the formula III is reacted in an organic solvent under the action of an initiator or a base to obtain a compound of the formula IV (that is, a compound of the formula I-3, I-4 when R ₃ and R ₄ are H). The initiator is selected from the group consisting of Ag ⁺ containing compounds or TEMPO, preferably Ag ₂ CO ₃ , AgNO ₃ , AgOAc, AgOTf, Ag ₂ O; bases preferably alkali metal carbonates or alkali metal hydrogencarbonates such as Na ₂ CO ₃ , K ₂ CO ₃ , Rb ₂ CO ₃ , Cs ₂ CO ₃ ; The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, toluene; and the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.

Step (4): the compound of the formula IV is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula V (that is, a compound of the formula I-3, I-4 when R ₃ and R _{4 are} different at the same time), and the alkylation reaction conditions are General conditions in the field: in an organic solvent, reacted under the action of a base or an alkylating agent, wherein the alkylating agent is preferably R ₃ X or R ₄ X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R ₃ The definition of R _{4 is} the same as the definition of R ₃ and R ₄ in any of the above aspects of the invention; the base is preferably an alkali metal carbonate (preferably Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ ), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH ₃ ONa, EtONa, t-BuOK); acylation reaction conditions are also routine in the art In an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R ₃ X or R ₄ X (acid halide), R ₃ OR ₃ or R ₄ OR ₄ (anhydride), wherein X is a halogen, Preferably, chlorine, bromine, iodine, R ₃ , R ₄ are as defined above for R ₃ and R ₄ in any of the above, and the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, Sodium acetate, Morpholine, imidazole, dimethylaniline, DMAP, 2,6- lutidine. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.

Step (5): The compound of the formula V is reacted in an organic solvent under a reducing agent to give a compound of the formula VI (i.e., a compound of the formula I-1, I-2 when R ₁ and R ₂ are H). The reducing agent is preferably H ₂ and Pd/C, H ₂ and PtO ₂ , H ₂ and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH ₃ , B ₂ H ₆ ). The reaction temperature is preferably -20 ° C to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.

Step (6): the compound VI is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula VII (ie, a compound of the formula I-1, I-2 when R ₁ and R _{2 are} different at the same time), and the alkylation reaction conditions are in the art. Conventional conditions: in an organic solvent, reacted under the action of a base or an alkylating agent, wherein the alkylating agent is preferably R ₁ X or R ₂ X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R ₁ , The definition of R _{2 is} the same as the definition of R ₁ and R ₁ in any of the above aspects of the invention; the base is preferably an alkali metal carbonate (preferably Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ ), an alkali metal hydroxide (preferably LiOH, NaOH, KOH), an alkali metal hydride (preferably NaH, LiH or KH) or an alkali metal alkoxide (preferably CH ₃ ONa, EtONa, t-BuOK); the acylation reaction conditions are also conventional in the art: In an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R ₁ X or R ₂ X (acid halide), R ₁ OR ₁ or R ₂ OR ₂ (anhydride), wherein X is a halogen, preferably Chlorine, bromine, iodine, R ₁ , R ₂ are as defined above for any of the above-mentioned R ₃ and R ₄ , and the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine or acetic acid. sodium, Morpholine, imidazole, dimethylaniline, DMAP, 2,6- lutidine. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.

Method Two:

Step (1): The compound of the formula III is reacted in an organic solvent under a reducing agent to give a compound of the formula VIII. The reducing agent is preferably H ₂ and Pd/C, H ₂ and PtO ₂ , H ₂ and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH ₃ , B ₂ H ₆ ). The reaction temperature is preferably -20 ° C to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.

Step (2): The compound of the formula VIII is reacted in an organic solvent under the action of a base or a Mitsunobu reagent to obtain a compound of the formula IX (that is, the formula I-1, I when R ₁ , R ₂ , R ₃ and R ₄ are both H) -2 compound). The base is preferably an alkali metal carbonate or an alkali metal hydrogencarbonate such as Na ₂ CO ₃ , K ₂ CO ₃ , Rb ₂ CO ₃ , Cs ₂ CO ₃ , an alkali metal hydroxide (preferably LiOH, NaOH, KOH), a base. Metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH ₃ ONa, EtONa, t-BuOK); Mitsunobu reagents preferably DEAD and PPh ₃ , DIAD and PPh ₃ , DEAD and PEt ₃ , DIAD and PEt ₃ ; The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, dichloromethane, chloroform; the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.

Step (3): a compound of the formula IX is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula VII (ie, a compound of the formula I-1, I-2), and the alkylation reaction conditions are conventional conditions in the art: in an organic solvent, in a base, Reaction under the action of an alkylating agent, wherein the alkylating agent is preferably R ₁ X, R ₂ X, R ₃ X or R ₄ X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R ₁ , R ₂ And R ₃ , R ₄ are as defined above for R ₁ , R ₂ , R ₃ , R ₄ ; the base is preferably an alkali metal carbonate (preferably Na ₂ CO ₃ , K ₂ CO ₃ , Cs) ₂ CO ₃ ), an alkali metal hydroxide (preferably LiOH, NaOH, KOH), an alkali metal hydride (preferably NaH, LiH or KH) or an alkali metal alkoxide (preferably CH ₃ ONa, EtONa, t-BuOK); The reaction conditions are also conventional in the art: in an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R ₁ X, R ₂ X, R ₃ X or R ₄ X (acyl halide), R. ₁ OR ₁ , R ₂ OR ₂ , R ₃ OR ₃ or R ₄ OR ₄ (anhydride), wherein X is a halogen, preferably chlorine, bromine, iodine, the definitions of R ₁ , R ₂ , R ₃ , R ₄ are the same as the invention at any preceding for _{_{_{R 1, R 2, R 3}}} , R ₄ is defined The base is preferably an alkali metal hydroxide (e.g., NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2,6- lutidine. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.

Method 3: Compounds 239 and 539 were obtained according to the method described in Chinese Patent (Application No.: 201510201548.7):

Compounds 239 and 539 are then structurally modified by similar hydrocarbylation or acylation modification methods in methods one and two to provide a series of compounds falling within the scope of formula I and formula I-1.

In the above synthesis method, a synthesis method of Formula IV, Formula V, Formula VI, Formula VII, and Formula IX is provided, which comprises Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4. A method of synthesizing a compound.

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

a chemical bond in the diketopiperazine ring

Means pointing to the key in the paper at the same time

Or point to the key outside the paper

Chemical bond in sulfhydryl

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

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

Chemical bond

Means pointing to the key in the paper at the same time

Or point to the key outside the paper

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 in the following (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

Detailed ways

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

Example 1 Synthesis of 2,5-diketopiperazine derivative (Formula II)

The synthesis can be carried out according to the synthesis method described in JP-A-2013-53115A, WO2012109256A2, WO2010078373A1, WO2008003626A1; or according to the literature: Journal of Asian Natural Products Research, 2010, 12(1): 51-55 and Chinese Journal of Natural The method described in Medicines, 2011, 9(1): 0078-0080 gives eleutherazine B or cyclo-di-N ^δ- acetyl-L-ornithyl, followed by hydrazine hydrate according to the literature Fitoterapia, 2014, Vol. 98, 91-97. The hydrolyzed acyl method described herein hydrolyzes the corresponding acyl group to give the corresponding L-ornithine condensed 2,5-diketopiperazine derivative (compound 1001).

2.64 g of L-ornithine was dissolved in 250 mL of water, an equal volume of 0.16% KHSO ₄ solution was added, and the reaction was refluxed for 2 days. After concentration under reduced pressure, a silica gel column chromatography gave 1.36 g of compound 1001. 60%, HPLC purity was 98.5%.

Replace with an appropriate amount of NaHSO ₄ , HCl, H ₂ SO ₄ , HClO ₄ , TfOH, KHSO ₄ -SiO ₂ , NaHSO ₄ -SiO ₂ , H ₂ SO ₄ -SiO ₂ , HClO ₄ -SiO ₂ or TfOH-SiO ₂ The above 0.16% KHSO _{4 is} reacted in a water or alcohol solution at a temperature of 30 to 120 ° C for 4 to 120 hours to obtain a compound 1001 in a yield of 40% to 60%.

Replace the above L-bird with DL-ornithine, D-ornithine, DL-2,4-diaminobutyric acid, L-2,4-diaminobutyric acid or D-2,4-diaminobutyric acid For the amino acid starting material, the compound 1002 is obtained in a yield of about 60%.

Compound 1003

Compound 1004

Compound 1005

Or compound 1006

Example 2 Oxidation of a compound of formula II to its fluorenyl derivative (formula III)

According to the literature: Liu Jia, 2014, Ph.D thesis of East China University of Science and Technology, “Study on oxidation reaction of primary amines and exploration of synthesis of key fragments of (+)-Pederin natural products”, page 9 shows oxidation of benzylamine to benzene The method of formaldehyde oxime is modified to obtain a compound of the formula II (compound 1001-1006) which is refluxed in an organic solvent under the action of an oxidizing agent to obtain a compound of the formula III; the oxidizing agent is preferably m-CPBA or hydrogen peroxide; the amount of the oxidizing agent is preferably a compound of the formula II The molar amount is 2.0-4.0 times, further preferably 2.5-3.5 times; and the organic solvent is preferably acetone, dichloromethane, chloroform or THF.

2.28 g of compound 1001 (10 mmol) was weighed and dissolved in 100 mL of acetone, 2.5 equiv.m-CPBA (25 mmol) was added, and the reaction was carried out at reflux temperature for 4 hours. After usual workup and silica gel column chromatography, 1.79 g of compound 1007 was obtained. The rate is about 70%, The HPLC purity was 98.7%.

The oxidizing agent in the above reaction may be replaced by hydrogen peroxide in a molar amount of 2.0 to 4.0 times that of the compound 1001, and the solvent may be replaced by dichloromethane, chloroform or THF; and the compound 1007 may be obtained in a yield of 45% to 75%.

The reaction starting compound 1001 was replaced by the compound 1002-1006, and the compound 1008-1012 was obtained in a yield of 68%, 72%, 59%, 62%, 57%, respectively.

Example 3 Preparation of a compound of formula IV by cyclization of a compound of formula III

According to the literature: Chem. Commun., 2014, 50, 6906-6908; Angew. Chem. Int. Ed. 2012, 51, 8816-8820; Chem. Sci., 2013, 4, 4030–4034; Tetrahedron Vol 41, The method of No. 22, pp. 5241-5260, 1985, etc., or a suitable optimization thereof, is carried out, and a compound of the formula IV is prepared by cyclization of a compound of the formula III.

Weigh 2.56g Compound 1007 (10mmol) dissolved in 150mL DMA (N, N- dimethylacetamide), was added _{_{1.0equiv.Ag 2 CO 3 (10mmol),}} 0.5equiv.K 2 CO 3 (5mmol), in After reacting for 24 hours at room temperature, a conventional post-treatment and silica gel column chromatography gave 2.02 g of Compound 1013 with a yield of about 80% and HPLC purity of 98.2%.

In the above reaction, Ag ₂ CO ₃ may be replaced by Ag ₂ CO ₃ , AgNO ₃ , AgOAc, AgOTf, Ag ₂ O or TEMPO in a molar amount of 1.0-2.0 times that of the compound 1001, and K ₂ CO ₃ may be replaced by Na ₂ CO. ₃ , Rb ₂ CO ₃ , Cs ₂ CO ₃ ; solvent DMA can be replaced by DMF, THF, acetonitrile, acetone, toluene; reaction temperature can be between 0 and 60 ° C, yielding compound 1013 in 65% to 85% yield .

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

Example 4 Hydrocarbylation and acylation of a compound of formula IV to give a compound of formula I-3, I-4

According to the literature: CN 103396372A; Organic Letters, 2011, Vol. 13, No. 18, 4838-4841; Journal of Agricultural and Food Chemistry, 2015, Vol. 63, 3734-4741; Macromolecular Chemistry and Physics, 2014, Vol. 215, 2268-2273; Fitoterapia, 2014, Vol. 98, 91-97; Journal of Organic Chemistry, 2011, Vol. .76,1155-1158;WO 2014189343A1;Canadian Journal of Chemistry (2014),92(12),1145-1149;European Journal of Medicinal Chemistry (2014),83,236-244;WO 2014060767A1;Journal of Applied Polymer Science(2012) , 124(2), 1707-1715 and other similar methods of hydrocarbylation and acylation of NH in the 2,5-piperazinedione structure reported in the prior art. Hydrocarbylation and acylation of the compound of formula IV Modification gives compounds of formula I-3, I-4.

(1) 252 mg of compound 840 (1 mmol) was weighed and dissolved in 20 mL of DMF, and 2.4 equiv. NaH (2.4 mmol) was added in three portions. After stirring at room temperature for half an hour, 3.0 equiv.MeI was added, and the reaction was carried out at 30 ° C for 4 h. The reaction material was almost completely disappeared by TLC, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then evaporated to silica gel column to afford compound 841 (93.1 mg, yield: about 35%) (120.4 mg, yield about 43%).

Replace MeI in the above reaction with EtBr, i-PrBr, bromocyclopropane, CF ₃ I, allyl bromide, propargyl bromide, diphenyl bromide, BnBr, bromocyclohexane, nC ₆ H ₁₃ Br , p-chlorobenzyl bromide, reacting at room temperature to reflux temperature for 4-12 hours, obtaining compounds 843-846, 848, 850-853, 855, 862, 863, 873, 874, 887 in a yield of 30% to 81% 888.

(2) 252 mg of compound 840 (1 mmol) was weighed, dissolved in 20 mL of CH ₂ Cl ₂ , 2.5 equiv.Ac ₂ O (2.5 mmol), 0.6 mL of Et ₃ N and a catalytic amount of DMAP were stirred at room temperature for 2 hours. The reaction material was almost completely disappeared by TLC. The CH ₂ Cl _{2 was} extracted twice, and the organic layer was dried over anhydrous sodium sulfate. After concentrated and then purified by silica gel column chromatography to afford compound 865 (111.8 mg, yield: 38%) Compound 867 (151.3 mg, yield about 45%).

Replace Ac ₂ O in the above reaction with Boc ₂ O, BzCl, trifluoroacetic anhydride, chloroacetyl chloride, cyclopropionyl chloride, cyclohexanoyl chloride, octanoyl chloride, hexanoyl chloride, m-azidobenzoyl chloride, m. The oxybenzoyl chloride is reacted at room temperature for 0.5 to 6 hours to give compounds 868-870, 873-886 in a yield of 38% to 88%.

(3) Weigh 252 mg of compound 840 (1 mmol), dissolved in 20 mL of DMF, add 2.5 equiv. bromobenzene (2.5 mmol), 2.0 equiv. K ₂ CO ₃ (2.0 mmol), catalytic amount of CuI and N, N- Dimethylethylenediamine (CAS RN: 110-70-3), after stirring at 110-115 ° C for 12 hours, the reaction material was almost completely disappeared by TLC, and extracted with ethyl acetate twice. The layer was concentrated and purified by silica gel column chromatography eluting

The bromobenzene in the above reaction is replaced with 1-bromonaphthalene, 8-bromoquinoline and 3-bromofuran, and reacted at 100-120 ° C for 12 to 24 hours to obtain compound 856-858 in a yield of 75% to 86%. .

(4) using compound 848 as a raw material, according to the method of methylation or acetylation in the above (1) or (2), respectively, obtaining compounds 847 and 849 in a yield of 89% and 95%; respectively, using compounds 862 and 865 as According to the acylation method described in (2), Boc ₂ O is used as an acylating agent to obtain compounds 861 and 866 (yield 90% or more); 863, 865 and 870 are used as raw materials, respectively, according to (2) In the alkylation method described above, hexane, nC ₆ H ₁₃ Br, and nC ₅ H ₁₁ Br are used as alkylating agents to obtain compounds 864, 872, and 871 (yield is about 75%).

(5) Weigh 290 mg of compound 852 (1 mmol), dissolved in 100 mL of dichloromethane, add 1.1 equiv. 1-azido-2-methoxyethane (1.1 mmol), 5 mL of water, and add a catalytic amount of ascorbic acid. Sodium and copper sulfate pentahydrate were reacted at 40 ° C for 5 h. The reaction was completed by TLC. The mixture was extracted with dichloromethane (200 mL) and washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. After concentration, by silica gel column chromatography, 332 mg of Compound 859 was obtained in a yield of about 85% with a HPLC purity of 97.9%.

Using compound 853 as a starting material, 1-fold amount of 1-azido-2-methoxyethane (2.2 mmol) was added in the same manner as above to give compound 860 in a yield of about 78%.

Among them, 1-azido-2-methoxyethane was prepared as follows:

2-methoxyethanol (1.0 mmol) was dissolved in anhydrous THF (50 mL), then triethylamine (4.0 mmol) was added, and methanesulfonyl chloride (4.0 mmol) was added dropwise to the mixture. After completion, the solvent was evaporated to dryness, and then evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,, The mixture was reacted for 4 h at rt.

(6) 332 mg of compound 851 (1.0 mmol) was dissolved in 50 mL of THF, and BH ₃ ·Me ₂ S (7.0 mL, 2.0 M in THF, 14.0 mmol) was added dropwise at 0° C. Anhydrous ethanol (5 mL), 3M NaOH (9.0 mL), and a 30% H ₂ O ₂ solution (2.0 mL) were added, and the mixture was refluxed for 1 hour, then extracted with CH ₂ Cl ₂ and washed with saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by silica gel column chromatography to yield 269 mg of Compound 890.

Using compound 850 as a starting material, the amounts of BH ₃ ·Me ₂ S, 3 M NaOH and 30% H ₂ O ₂ were all halved according to the above reaction conditions, and compound 889 was obtained in a yield of about 75%.

(7) Compound 890 (1.0 mmol) was dissolved in 60 mL of acetone, and an appropriate amount of freshly prepared Jones reagent (Jones reagent) was added at 0 ° C, and the reaction was naturally returned to room temperature, stirred overnight, and subjected to conventional post-treatment, silica gel column chromatography. Compound 892 and Compound 893 were obtained in yields of about 46% and 25%, respectively, and the HPLC purity was 98% or more.

Using Compound 889 as a starting material, Compound 891 was obtained in a yield of about 65% according to the above reaction conditions, and HPLC purity was 98.3%.

Example 5

According to the method of alkylation, acylation modification of NH in the structure of 2,5-piperazinedione described in Example 4 or the prior art, or the like, the specific R ₃ and R ₄ described in Table 1-5 can be obtained. Modified compounds of formula I-3, I-4.

Example 6 Reduction of a compound of formula V (Formula I-3, I-4)

According to the literature: CN104529814A; Org. Lett., 2001, 3, 1637-1639; J. Org. Chem., 1996, 61, 3849-3862; Tetrahedron, 2005, 61, 5725-5734; J. Org. 2006, 71, 7783-7086; Angew. Chem. Int. Ed., 2005, 117, 5807-5809 or other methods of reducing imines in the prior art, reducing the formula V (formulas I-3, I-4) The compound of formula VI (i.e., the compound of formula I-1, I-2 when R ₁ and R ₂ are H) are obtained.

252 mg of compound 1014 (1 mmol) was weighed and dissolved in EtOH (50 ml), and Raney-Nickel (1.0 g) was added, and the reaction was stirred at 25 ° C for 12 h under the action of 1 atm H ₂ . After concentration under reduced pressure, Compound 1 (220 mg, 86%) was obtained.

The above reaction starting material compound 1014 was replaced with the compound 840, 1013, 900, 1015, 1016 to give the corresponding reduced product in a similar yield.

EXAMPLE 7 Alkylation or acylation of a compound of formula V (Formula I-3, I-4) affords a compound of formula VII (Formula I-1, I-2)

(1) Weigh 256 mg of Compound 1 (1 mmol), dissolved in 30 mL of CH ₂ Cl ₂ , and added 5.5 equiv.Ac ₂ O (5.5 mmol), 1.5 mL of Et ₃ N and a catalytic amount of DMAP, and stirred at room temperature for 1.5 hours. The reaction material was almost completely disappeared by TLC, and the CH ₂ Cl _{2 was} extracted twice. The organic layer was dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography with yields of 28%, 20%, 18%, and 15% respectively. Compounds 2, 3, 7, and 8 were obtained, and the HPLC purity was 98% or more.

Replace Ac ₂ O in the above reaction with BzCl, trifluoroacetic anhydride, chloroacetyl chloride, cyclopropylcarbonyl chloride, propionyl chloride, cyclohexanoyl chloride, valeryl chloride, heptanoyl chloride, octanoyl chloride, hexanoyl chloride, m-azidobenzene Formyl chloride, m-methoxybenzoyl chloride, m-fluorobenzoyl chloride, Boc ₂ O, react at room temperature for 0.5 to 8 hours, and obtain the corresponding monoacylated, double in Table 1 in a yield of 30% to 90%. Acylation, triacylation and tetraacylation products.

(2) According to a similar hydrocarbylation process as described in Example 4, the following hydrocarbylating agents were employed: MeI, EtBr, i-PrBr, bromocyclopropane, CF ₃ I, allyl bromide, propargyl bromide, Phenyl bromide, BnBr, bromocyclohexane, nC ₆ H ₁₃ Br, p-chlorobenzyl bromide, m-nitrobenzyl bromide, bromobenzene are replaced by 1-bromonaphthalene, 8-bromoquinoline, 3-bromofuran, The reaction is carried out at room temperature to reflux temperature for 4-12 hours to give the corresponding monoalkylation, dialkylation, trihydrocarbylation and tetrahydrocarbylation products of Table 1 in a yield of from 30% to 81%.

(3) a method for synthesizing a compound which is modified in accordance with the different hydrocarbylation or different acylation or hydrocarbylation and acylation described in Example 4 (mainly related to Example 4 (4)) or a synthetic method similar thereto, The products of the different hydrocarbylation or different acylation or hydrocarbylation and acylation in Table 1 can be prepared using the corresponding hydrocarbylation or acylating agents.

(4) Carboxylic acid condensation method: 1-Boc-acridine-2-carboxylic acid (201 mg, 1.0 mmol) was weighed and dissolved in dry toluene (30 mL), and DCC (1.0 mmol) and DMAP (0.17 mmol) were added. After stirring at room temperature for 10 minutes, the compound 1 (0.01 mmol) was added, and the mixture was heated to 65 ° C for 48 hours, filtered, concentrated under reduced pressure, and then subjected to silica gel column chromatography to afford compound 49 in yield of 43% and 45%, respectively. 50, HPLC purity was 97.8%, 98.3%, respectively. (The 1-Boc-acridine-2-carboxylic acid used in the reaction is a racemate, and the corresponding isomer can also be prepared using 1-Boc-acridin-2-carboxylic acid in a single D or L configuration)

Replace 1-Boc-acridin-2-carboxylic acid in the above reaction with

The reaction is carried out at 60 to 80 ° C for 24 to 48 hours, and the double condensation products (for example, 55, 56, 176, 181, 188, 193, 205, 214, 231, 236) in Table 1 are obtained in a yield of 30% to 50%. And about 40% of a single condensation product (for example, 177, 182), the above double condensation product can be partially or completely removed by Ac or Boc under the conditions of conventional de-Ac or Boc in the art to obtain the compound 54 and 239 in Table 1. . Wherein, the single condensation product can be recondensed with the above carboxylic acid to form an asymmetric double condensation product, and then subjected to a hydrocarbylation, acylation, reduction, oxidation, click reaction, etc. according to the method of the present invention to obtain a corresponding substitution in Table 1. compound of. The above Boc, Ac, Me, propargyl protected carboxylic acid can be prepared by reacting the corresponding carboxylic acid with Boc ₂ O, Ac ₂ O, MeI, propargyl bromide or the like.

For example, compound 1 under the action of DCC and DMAP,

The reaction is carried out for 10 hours, mainly producing a single condensation product, and then

After reacting for 20 hours, the Ac on the side chain was removed under the action of MeONa-MeOH to obtain Compound 206, and the total yield in three steps was up to 42%. Note: in getting the compound

After the methylation modification, the Ac on the side chain was removed by the action of MeONa-MeOH to obtain the compound 208, and the total yield was 33%.

Using the reducing conditions in Example 6 and the condensation conditions in this example, Compound 228 was obtained in a total yield of 63% with a HPLC purity of 96.5%.

(5) Partial reduction and total reduction of side chain double bonds after condensation: Compound 239 (0.1 mmol) was weighed and dissolved in 10 mL of CH ₃ OH-CH ₂ Cl ₂ (volume ratio 1:1), and a catalytic amount of Pd-C was added. After reacting for 2 h at room temperature under the action of 1 atm H ₂ , the Pd-C was removed by filtration, and after concentration, the compound 52 and 53 were obtained by silica gel column chromatography at a yield of 45% and 48%, respectively, and the HPLC purity was 98.5%, 99.0, respectively. %. The compounds having a double bond in the other side chains in Table 1 can partially or completely reduce the double bond by the above reaction conditions.

Addition of side chain double bonds after condensation: The reaction was carried out using a similar reagent as in Example 4 (6) (e.g., BH ₃ ·Me ₂ S, 3 M NaOH, and 30% H ₂ O ₂ ). For example, compound 236 can be prepared in a yield of 80% using the above reaction conditions; and about 8% of the Martensitic addition product 238 is obtained.

Oxidation of side chain hydroxyl groups after condensation: The product of the mono- or dicarboxyl group in the side chain can be obtained by oxidation with the Jones reagent in Example 4 (7). For example, compound 239 was obtained in the yield of 32% and 48%, respectively, under the action of Jones reagent, and the HPLC purity was 98% or more.

Example 8 Glycosylation modification

(1) Weighed Compound 1 (0.1 mmol) and 2.2 equiv. Perbenzoyl-protected glucose trichloroacetimidate (0.22 mmol) was dissolved in 20 mL of dry CH ₂ Cl ₂ and added.

After molecular sieves were stirred at room temperature for half an hour under argon atmosphere, 0.1 equiv.TMSOTf (0.01 mmol) was added dropwise at 0 ° C, and the reaction was stirred at 0 ° C for half an hour.

Molecular sieve, concentrated under reduced pressure, dissolved in methanol, added with appropriate amount of sodium methoxide to adjust the pH 9.0 ~ 10.0, stirred for 2 hours, then neutralized the pH to 7.0 with cation exchange resin, concentrated under reduced pressure, after silica gel column chromatography, Compounds 41 and 42 were obtained in a yield of 38% and 42%, respectively, and the HPLC purity was 96.5% and 97.2%, respectively.

Replacing the perbenzoyl-protected glucose trichloroacetimidate with perbenzoyl-protected galactose trichloroacetimide ester gives compounds 43 and 44 in similar yields.

After the above glycosidation reaction, the methylation reaction was carried out by the methylation method described in Example 4, and then the benzoyl group was removed under MeONa-MeOH to obtain a compound 45-48 in a yield of 60%. about.

(2) Weighed compound 239 (0.1 mmol) and 2.2 equiv. Perbenzoyl-protected glucose trichloroacetimidate (0.22 mmol) was dissolved in 20 mL of dry CH ₂ Cl ₂ and added.

After the molecular sieve was stirred at room temperature for half an hour under argon atmosphere, 0.1 equiv.TMSOTf (0.01 mmol) was added dropwise at 0 ° C, and the reaction was stirred at 0 ° C for 1.5 hours, and the raw material was detected by TLC for almost hour, and filtered.

Molecular sieve, concentrated under reduced pressure, dissolved in methanol, added with appropriate amount of sodium methoxide to adjust the pH 9.0 ~ 10.0, stirred for 2 hours, then neutralized the pH to 7.0 with cation exchange resin, concentrated under reduced pressure, after silica gel column chromatography, Compounds 57 and 58 were obtained in a yield of 45% and 33%, respectively, and the HPLC purity was 97.5% and 97.3%, respectively.

Example 9 Side Chain Click Reaction

The compound 231 (1 mmol) was weighed, dissolved in 100 mL of dichloromethane, 2.2 equiv. azide methane (2.2 mmol), 8 mL of water, and a catalytic amount of sodium ascorbate and copper sulfate pentahydrate were added and reacted at 40 ° C for 4.5 h. , TLC detection showed that the reaction was completed, and the reaction mixture was extracted with 200 mL of dichloromethane, and washed successively with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The yield gave Compound 232 with a HPLC purity of 97.3%.

Example 10

According to the method described in Examples 1-9 or the similar reaction in the prior art or the conventional replacement in the art, using 840, 1014, 1013, 900, 1015, 1016 as raw materials, Table 1-5 can be prepared. For any of the compounds, all of the above compounds were structurally confirmed by ¹ H NMR, ESI-MS, and HPLC purity. Some of the compounds were confirmed by CD, ¹ H- ¹ H COSY, HMQC, HMBC, and NOESY. Due to space limitations, the present invention lists the ESI-MS data in Tables 1-5. The acid chloride used in the synthesis process of the present invention can be prepared by the corresponding acid according to the conventional acid chloride preparation method in the art, that is, the corresponding acid is reacted with thionyl chloride or oxalyl chloride.

Example 11 Compounds Prepared by the Invention and Activity Test Results

Antiviral activity test method: The inhibitory activity of the compound of the present invention against respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), enterovirus 71 (EV71) is tested according to the method described in the patent: CN104800212A; CN104774159A. of. Antiviral activity tests can also be performed according to the literature: Zhang, YJ; Stein, DA; Fan, SM; Wang, KY; Kroeker, AD; Meng, XJ; Iversen, PL; Matson, DOVet. Microbiol. 2006, 117 (2- 4), 117-129; the method described in CN104004042A is tested, or tested by other similar test methods in the prior art.

The present invention tests the inhibitory activity of all compounds against respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), enterovirus 71 (EV71), for the convenience of the present invention and for a more concise and intuitive understanding of the present invention. In the following, only ESI-MS of the compound of the present invention and its inhibitory activity against respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), and enterovirus 71 (EV71) are listed (see Table 1-5). .

Due to space limitations, the present invention only lists typical compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 in Tables 1-5.

Table 1 Activity data of compounds of formula I-1, ESI-MS and antiviral (RSV, HSV-1, EV71) in 2(R), 2'(R) configuration

Table 2 2(S), 2'(S) configuration of compound of formula I-1, ESI-MS and antiviral (RSV, HSV-1, EV71) activity data

Table 3 2 (R), 2' (R) configuration and 2 (S), 2 ' (S) configuration of the same amount of racemic compound of formula I-2, ESI-MS and anti-virus (RSV, HSV -1, EV71) activity data

Isomers of the 2(R), 2'(R) configuration obtained by chiral resolution of compounds 601-839 in Table 3:

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in compounds 601 to 839 in Table 3) and 2 (S), 2' (S) configuration isomers:

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in the compounds of 601 to 839 in Table 3).

The chiral separation of the isomers of the 2(R), 2'(R) configuration, the 2(S), 2'(S) configuration of the isomers in the anti-RSV, HSV-1, EV71 activities The test showed equivalent antiviral activity, and there was no significant difference in the antiviral activity of the racemic compound 601-839. The above results indicate that the enantiomer compound and the racemic compound exhibit equivalent antiviral activity in antiviral (RSV, HSV-1, EV71) activities. The stereo configuration at position 2, 2' had no significant effect on viral activity.

Table 4 2(R), 2' (R) configuration and 2 (S), 2' (S) configuration of the same amount of racemic compound of formula I-3, ESI-MS and anti-virus (RSV, HSV -1, EV71) activity data

The isomers of the 2(R), 2'(R) configuration obtained by chiral resolution of the compound 840-893 in Table 4:

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in the compounds 840-893 in Table 4) and 2 (S), 2' (S) configuration isomers:

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in the compounds 840-893 in Table 4).

The chiral separation of the isomers of the 2(R), 2'(R) configuration, the 2(S), 2'(S) configuration of the isomers in the anti-RSV, HSV-1, EV71 activities The test showed equivalent antiviral activity, and there was no significant difference in the antiviral activity of the racemic compound 840-893. The above results indicate that the enantiomer compound and the racemic compound exhibit equivalent antiviral activity in antiviral (RSV, HSV-1, EV71) activities. The stereo configuration at position 2, 2' had no significant effect on viral activity.

Table 5 2 (R), 2' (R) configuration and 2 (S), 2 ' (S) configuration of the same amount of racemic compound of formula I-4, ESI-MS and anti-virus (RSV, HSV-1, EV71) activity data

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

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in the compounds 900-953 in Table 5) and 2 (S), 2' (S) configuration isomers:

(R ₁ , R ₂ , R ₃ , R _{4 have} the same definitions as the corresponding groups in the compounds 900-953 in Table 5).

The chiral separation of the isomers of the 2(R), 2'(R) configuration, the 2(S), 2'(S) configuration of the isomers in the anti-RSV, HSV-1, EV71 activities The test showed equivalent antiviral activity, and there was no significant difference in the antiviral activity of the racemic compound 900-953. The above results indicate that the enantiomer compound and the racemic compound are antiviral (RSV, HSV-1, EV71). It exhibits the same antiviral activity in terms of activity. The stereo configuration at position 2, 2' had no significant effect on viral activity.

In Table 1-5, "A" indicates that the compound has a half-inhibitory concentration (IC ₅₀ ) of 1-500 ng/mL, and "B" indicates that the compound has a half-inhibitory concentration (IC ₅₀ ) of 1.0-20 μg/mL, and "C" indicates a compound. The half-inhibitory concentration (IC ₅₀ ) was greater than 50 μg/mL.

In Table 1-5, ClCH ₂ C(O) represents a chloroacetyl group; CF ₃ C(O) represents a trifluoroacetyl group; and C _n H _2n+1 represents an n-alkyl group (n is 4, 5, 6, 7, 8) );symbol

And a bonding site of N in the structure of R ₁ , R ₂ , R ₃ , and R ₃ and a structure of Formula I, Formula I-2, Formula I-3, and Formula I-4;

Example 12 Preparation of Solvates of Compounds and Salts thereof in Tables 1-5

(1) Preparation of fumarate monoethanolate and fumarate dihydrate

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

100 mg of each of the compounds 239 and 539 were dissolved in 8 mL of absolute ethanol, and 1.0 equiv. of fumaric acid and 7 mL of absolute ethanol were added thereto at room temperature, and the mixture was heated to 60 ° C and stirred for 1 minute (fumaric acid was completely dissolved). After cooling to room temperature, stirring was continued for two hours, and the precipitate was collected by filtration and dried to obtain a fumarate monoethanolate 1100 (98 mg) and 1101 (105 mg), respectively; 50 mg of each of the above solvates 1100 and 1101 were weighed. Dissolve in 5 mL of ethanol and 1 mL of water at 60 ° C, remove insoluble matter by filtration, and stir at room temperature for 12 hours. The precipitate is collected by filtration. After drying, the obtained solid is placed at 25 ° C and 60% relative humidity. After two days, fumarate dihydrate 1102 (43 mg) and 1103 (40 mg) were obtained. No racemization of the solvate containing a chiral amino acid in the above solvate was observed by ¹ H NMR, solid-state ¹³ C NMR or specific optical rotation.

(2) Preparation of monohydrate

Take the solvates of compounds 239, 539 and their salts as examples:

10 mg of each of the compounds 239 and 539 were weighed and suspended in 10 mL of water, and stirred at 28-30 ° C for two hours. The precipitate was collected by filtration, and the solid was placed under the conditions of 35 ° C and 75% relative humidity, and allowed to stand for 3 days. Monohydrate 1104 (7.2 mg) and 1105 (7.8 mg) were obtained.

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

The solvates or solvates 1100-1105 of the above salts were subjected to differential thermal analysis/thermogravimetric analysis, elemental analysis, infrared absorption spectroscopy, solid state ¹³ C-NMR analysis, respectively. Only the differential thermogravimetric analysis data is listed below: using Thermo plus TG8120 differential thermogravimetric analyzer (measured sample volume of 3-5mg, heating rate: 10 °C / min, reference material: alumina) for differential thermogravimetric analysis, endothermic peak: 72.1- There is an endothermic peak near 85.3 °C, and an endothermic peak near 177.2-180.3 °C.

Example 13 Storage Stability Test

Compounds 1100-1105 were stored at 40 ° C, 75% relative humidity (see Table 6 for results) and 50 ° C open containers, respectively, and storage stability after 2 months was measured. Regarding the storage stability, the purity of each test compound was measured by HPLC at the initial time and after storage for 2 months, and the results were compared (for the specific method, see the method described in WO2009128421A1).

Table 6 Storage stability test at 40 ° C, 75% relative humidity

It can be seen from the test results in Table 6 that the solvate of the solvate or salt has extremely excellent storage stability, and further, the test in the open container at 50 ° C also shows that the purity of the solvate is almost no two months later. Change while compound The purity of 239, 539 is reduced by more than 3%, and it can also be seen that the solvate of the solvate or salt has the advantage of ultra high stability and is convenient for long-term storage.

The compounds of the formula I, I-1, I-2, I-3, and I-4 in addition to the compounds described in Tables 1-5 of the present invention may also be synthesized according to the methods described in Examples 1-10. . All of the diazoxide heterodoxadione piperazine alkaloid derivatives (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4) of the present invention are for RSV, HSV-1, and EV71. Has a significant inhibitory effect, the half-inhibitory concentration (IC ₅₀ ) is from 1 to 500 ng / mL, and the half-toxic concentration (TC ₅₀ ) is in the range of 10-300 μg / mL, the compound of the present invention or its stereoisomer, its elimination A non-equal mixture of a polar body, an enantiomer thereof, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, can be used for the preparation of a therapeutic and/or prophylactic respiratory disease, hand and foot. Drug lead compounds, drug candidates, drugs for oral diseases, immune diseases, and inflammatory diseases.

All documents mentioned in the present application are hereby incorporated by reference in their entirety as if they are individually incorporated by reference. In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the present invention.

Claims

A bis-oxaoxacyclohexanedione piperazine alkaloid of the formula I, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and a non-equal amount of its enantiomer A mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula I has the structure:

Wherein R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkyl acyl, alkoxy acyl, cycloalkyl acyl, alkenyl, alkenyl acyl, alkynyl, Alkynyl, aryl, arylalkyl, aryl acyl, heteroaryl, heteroarylalkyl, heteroaryl acyl, saturated or unsaturated heterocyclic, saturated or unsaturated heterocyclic alkyl, saturated Or an unsaturated heterocyclic acyl group; the above R 1 , R 2 , R 3 , R 4 groups are optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl) , trifluoromethyl, trifluoroacetyl, decyl, halogen, nitro, amino, azido (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C =O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), one or more of phenyl Substitution; n is 0 or 1; chemical bond
Indicates the key pointing to the paper
Or point to a key outside the paper
"-----" means that a single bond or non-existent, and when "-----" represents a single bond, R 1 and R 2 do not exist; the precondition is that when R 3 and R 4 are simultaneously H, When R 1 and R 2 are not the same
symbol
A linkage site representing the R 1 , R 2 group to N in the structure of Formula I.
The bisoxacyclohexanedione piperazine alkaloid compound of the formula I according to claim 1, wherein R 1 , R 2 , R 3 and R 4 are each independently selected from H, C1-C8 alkane. , C1-C8 alkyl acyl, C1-C8 alkoxy acyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl acyl, C2-C8 alkenyl, C2-C8 alkenyl, C2-C8 alkynyl , C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C12 heteroaryl, C5-C12 heteroaryl C1-C4 alkyl a C5-C12 heteroaryl acyl group, a 4 to 12-membered saturated or unsaturated heterocyclic group, a 4 to 12-membered saturated or unsaturated heterocyclic group C1-C4 alkyl group, a 4 to 12-membered saturated or An unsaturated heterocyclic acyl group; the above R 1 , R 2 , R 3 , R 4 groups are optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl) ), fluorenyl, halogen, nitro, amino, azido (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), One or more substitutions of thio (=S), sulfonyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), phenyl.
The bisoxacyclohexanedione piperazine alkaloid compound of the formula I according to any one of claims 1 to 2 , wherein R 1 , R 2 , R 3 and R 4 are each independently selected from H. , C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkyl acyl, C1-C8 haloalkyl acyl, C3-C10 cycloalkyl acyl, C2-C8 alkenyl, C2- C8 alkenyl group, C2-C8 alkynyl group, C2-C8 alkynyl group, C6-C10 aryl group, C6-C10 aryl C1-C4 alkyl group, C6-C10 aryl acyl group, C5-C10 heteroaryl group, C5 -C10 heteroaryl C1-C4 alkyl, C5-C10 heteroaryl acyl, C5-C12 saturated or unsaturated heterocyclic group, C5-C12 saturated or unsaturated heterocyclic group C1-C4 alkyl, C5-C12 saturated Or an unsaturated heterocyclic acyl group; the above R 1 , R 2 , R 3 , R 4 groups are optionally hydroxy, hydroxymethyl, carboxy, acetylamino, methyl, decyl, halogen, nitro, amino, azide (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 One or more substitutions in the alkoxy group or the phenyl group; the heterocyclic group in the above group, the hetero atom in the heteroaryl group is independently selected from N 1-5 heteroatoms in O, S or Se.
The bis(oxacyclohexadione) piperazine alkaloid compound of the formula I according to any one of claims 1 to 3 , wherein R 3 and R 4 are each independently H, methyl, ethyl, Isopropyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , 3-hydroxy-propyl
2-carboxy-ethyl
P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinoline-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH 2 CO), Propionyl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, tri Fluoroacetyl, allyl, ethynyl, propargyl, tert-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, diphenylmethyl
R 1 and R 2 are each independently H, C1-C8 alkyl, C1-C8 alkyl acyl, C1-C8 alkoxy acyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl acyl, C2-C8. Alkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl acyl, C5-C12 Heteroaryl, C5-C12 heteroaryl C1-C4 alkyl, C5-C12 heteroaryl acyl, 4- to 12-membered saturated or unsaturated heterocyclic group, 4 to 12-membered saturated or unsaturated heterocyclic ring a C1-C4 alkyl group, a 4- to 12-membered saturated or unsaturated heterocyclic acyl group; the above R 1 , R 2 , R 3 , R 4 groups may be optionally a hydroxyl group, a hydroxymethyl group, a carboxyl group, an acetylamino group, C1-C4 alkyl (such as methyl, ethyl, propyl), fluorenyl, halogen, nitro, amino, azido (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), Carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), phenyl One or more substitutions.
The bis(oxacyclohexadione) piperazine alkaloid compound of the formula I according to any one of claims 1 to 4, wherein R 3 and R 4 are each independently H, methyl, ethyl, Isopropyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , 3-hydroxy-propyl
2-carboxy-ethyl
P-chlorobenzyl, m-nitrobenzyl, phenyl, furan-3-yl, naphthalen-1-yl, quinoline-8-yl, trifluoromethyl, acetyl, chloroacetyl (ClCH 2 CO), Propionyl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopropanoyl, cyclohexanoyl, benzoyl, m-fluorobenzoyl, m-methoxybenzoyl, m-azidobenzoyl, tri Fluoroacetyl, allyl, ethynyl, propargyl, tert-butoxycarbonyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyranyl, diphenylmethyl
R 1 and R 2 are each independently n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl , 3-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl-pentyl, 1-fluoro-2-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-methyl-hexyl, 1-fluoro-3-ethyl-hexyl, 1-chloro-3-methyl-pentyl, 1-chloro-2-methyl-pentyl, 1-chloro- 2-methyl-hexyl, 1-chloro-3-methyl-hexyl, 1-chloro-3-ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl- Pentyl, 1-bromo-2-methyl-hexyl, 1-bromo-3-methyl-hexyl, 1-bromo-3-ethyl-hexyl, acetyl, propionyl, n-butyryl, isobutyryl, Isovaleryl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-pentanoyl, 2-methyl-hexanoyl, 3-methyl -hexanoyl, 3-ethyl-hexanoyl, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 3-methyl-pentanoyl, 2-methyl-pentanoyl, 2-methyl-hexanoyl, 3-methyl -hexanoyl, 3-ethyl-hexanoyl, trifluoroacetyl, difluoroacetyl, chloroacetyl, bromoacetyl, pentafluoropropionyl, perfluorobutyryl, 1-fluoro-3-methyl-pentanoyl , 1-fluoro-2-methyl-pentanoyl, 1-fluoro-2-methyl-hexanoyl, 1-fluoro-3-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-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 -methyl-hexanoyl, 1-bromo-3-ethyl-hexanoyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, positive Pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, heptadienyl, heptadienyl, n-octenyl, octadienyl, octatrienyl, 3- Methyl-pent-2-enyl, 2-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-methyl-hex-2-enyl, 3-ethyl -hex-2-enyl, propionyl, but-2-enoyl, methacryloyl, pent-3-enoyl, isopentenyl, pentadiene Acyl, hex-4-enoyl, hept-5-enoyl, heptadienoyl, heptylenoyl, oct-6-enoyl, octadienoyl, octylenoyl, 3-methyl-pentane- 2-enoyl, 2-methyl-pent-2-enoyl, 2-methyl-hex-2-enoyl, 3-methyl-hex-2-enoyl, 3-ethyl-hex-2- Alkenoyl, ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, heptadienyl, n-octynyl , octadiynyl, octantylene, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-ynyl, 3-B -hex-2-ynyl, propargyl, n-butynyl, but-2-ynyl, n-pentynyl, isopenynyl, n-hexynyl, n-heptynyl, Heptadiynyl, n-alkynyl, octadiynyl, octantynyl, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-ynyl acyl, 3-ethyl-hex-2-ynyl acyl, phenyl, naphthyl, benzyl, phenethyl imidazolyl, pyridyl, oxazolyl, isomer Azolyl, triazolyl, tetrazolyl Furanyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, fluorenyl, oxazolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzoselenadiazole Base, coumarin, isocoumarin, azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline , thiazolinyl, tetrahydropyranyl, dihydrocoumarin, dihydroisocoumarin, tetrahydroquinolyl, tetrahydroisoquinolinyl, tetrahydrocarbazolyl, pyrimidine base, purine base The above R 1 , R 2 , R 3 , R 4 groups are optionally hydroxy, hydroxymethyl, carboxyl, acetylamino, sulfhydryl, halogen, nitro, amino, azide (-N 3 ), fluorenyl One of cyano, t-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, methoxy, ethoxy, or Multiple substitutions.
The bisoxacyclohexadione piperazine alkaloid compound of the formula I according to any one of claims 1 to 5, which is characterized in that it is selected from the group consisting of compounds 1-238, 301-538, 601 in Tables 1-5. -893, 900-953 or its tautomers, stereoisomers thereof, racemates thereof, non-equal mixtures of their enantiomers, geometric isomers thereof, solvates thereof, pharmaceutics thereof A solvate of an acceptable salt or a salt thereof.
A bisoxazinidinedione piperazine alkaloid compound of the formula I-1, a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-equivalent enantiomer thereof A mixture of the mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula I-1 has the following structure:

R 1 , R 2 , R 3 , R 4 are as defined in any one of claims 1-6.
A diisoxazole spirodione piperazine alkaloid compound of the formula I-2, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and a non-enantiomer thereof An equivalent mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of formula 1-2 has the following structure:

R 1 , R 2 , R 3 , R 4 are as defined in any one of claims 1-6.
A bisoxazinyl spirobiperazine alkaloid compound of the formula I-3, a tautomer thereof, a stereoisomer thereof, a racemate thereof, an unequal enantiomer thereof A mixture of the mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula 1-3 has the following structure:

R 3 , R 4 are as defined in any one of claims 1-6.
A bis-oxazoline spirobone piperazine alkaloid compound of the formula I-4, a tautomer thereof, a stereoisomer thereof, a racemate thereof, and a non-enantiomer thereof An equivalent mixture, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, characterized in that the compound of the formula I-4 has the following structure:

R 3 , R 4 are as defined in any one of claims 1-6.
The solvate of the solvate or salt according to any one of claims 1 to 10, which is selected from the group consisting of monohydrate, dihydrate, trihydrate, monomethanol, dimethanolate, monoacetonitrile, diacetonitrile a compound, a monoacetate, a diacetate, a hemi-fumarate monohydrate, a fumarate dihydrate, a fumarate monoethanolate; preferably a monohydrate, a fumarate dihydrate , fumarate monoethanolate.
The solvate of the solvate or salt of claim 11 is selected from the group consisting of:
The pharmaceutically acceptable salt according to any one of claims 1 to 10, which is selected from the group consisting of hydrochloride, sulfate, phosphate, oxalate, maleate, methanesulfonate, succinate, citric acid Salt, fumarate, glucuronide, formate, acetate, succinate.
A pharmaceutical composition comprising any one or more of the compounds according to any one of claims 1 to 13 or a tautomer thereof, a stereoisomer thereof, and a foreign product thereof. Any one or more of a rotomer, a non-isomeric mixture of its enantiomers, a geometric isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, as an active ingredient.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent or excipient.
The pharmaceutical composition according to claim 15, characterized in that the pharmaceutical composition further comprises at least one other antiviral drug. The pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like.
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof And the use of a solvate thereof, a solvate thereof, or a solvate thereof, or a pharmaceutical composition according to any one of claims 14-16, for the preparation of an antiviral drug.
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof A solvate thereof, a solvate thereof, or a solvate thereof, or a pharmaceutical composition according to any one of claims 14 to 16 for the preparation of a medicament for the treatment and/or prevention of respiratory diseases, hand, foot and mouth disease, immunity The application of drugs for diseases and inflammatory diseases.
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof a solvate thereof, a solvate thereof, or a solvate thereof, or a pharmaceutical composition according to any one of claims 14 to 16 for the treatment and/or prevention caused by RSV, HSV-1, EV71 The application of the disease in medicine. The disease is selected from the group consisting of: respiratory diseases, pneumonia, gingivitis, keratoconjunctivitis, encephalitis, reproductive system infections, rashes of the hands, feet, mouth, etc., herpes and herpetic angina.
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof And the use of a solvate thereof, a solvate thereof, or a solvate thereof, or a pharmaceutical composition according to any one of claims 14-16, for the preparation of a medicament. The medicament is for the treatment of diseases caused by respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), and enterovirus 71 (EV71).
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof And the use of a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a lead compound for anti-RSV, HSV-1, EV71 drugs.
A compound according to any one of claims 1 to 13, or a tautomer thereof, a stereoisomer thereof, a racemate thereof, a non-isomeric mixture of its enantiomers, or a geometric isomer thereof The use of a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a drug candidate against RSV, HSV-1, EV71.
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 10, comprising the steps of:

method one:

Step (1): 2,4-diaminobutyric acid (when n=0, it may be L-form, D-form, or DL racemate) or ornithine (when n=1, it may be L-form, D Type, or DL racemate) as raw materials, in KHSO 4 , NaHSO 4 , HCl, H 2 SO 4 , HClO 4 , TfOH, KHSO 4 -SiO 2 , NaHSO 4 -SiO 2 , H 2 SO 4 -SiO 2 , Under the action of HClO 4 -SiO 2 or TfOH-SiO 2 , the reaction temperature is 30 to 120 ° C (preferably 80 to 120 ° C) in water or an alcohol solution, and the reaction is carried out for 4 to 120 hours (preferably 12 to 96 hours) to obtain a compound of formula II. This step of the reaction can be carried out in accordance with the method disclosed in JP-A-2013-53115A or a similarly improved method.

Step (2): The compound of the formula II is refluxed in an organic solvent under the action of an oxidizing agent to give a compound of the formula III. The oxidizing agent is preferably mCPBA or hydrogen peroxide; the oxidizing agent is preferably used in an amount of from 2.0 to 4.0 times, more preferably from 2.5 to 3.5 times, the molar amount of the compound of the formula II; and the organic solvent is preferably acetone, dichloromethane, chloroform or THF.

Step (3): The compound of the formula III is reacted in an organic solvent under the action of an initiator or a base to obtain a compound of the formula IV (that is, a compound of the formula I-3, I-4 when R 3 and R 4 are H). The initiator is selected from the group consisting of Ag + containing compounds or TEMPO, preferably Ag 2 CO 3 , AgNO 3 , AgOAc, AgOTf, Ag 2 O; bases preferably alkali metal carbonates or alkali metal hydrogencarbonates such as Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , Cs 2 CO 3 ; The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, toluene; and the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.

Step (4): the compound of the formula IV is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula V (that is, a compound of the formula I-3, I-4 when R 3 and R 4 are different at the same time), and the alkylation reaction conditions are General conditions in the field: in an organic solvent, reacted under the action of a base or an alkylating agent, wherein the alkylating agent is preferably R 3 X or R 4 X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R 3 The definition of R 4 is the same as the definition of R 3 and R 4 in any of the above aspects of the invention; the base is preferably an alkali metal carbonate (preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), alkali metal hydroxide (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH 3 ONa, EtONa, t-BuOK); acylation reaction conditions are also routine in the art In an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R 3 X or R 4 X (acid halide), R 3 OR 3 or R 4 OR 4 (anhydride), wherein X is a halogen, Preferably, chlorine, bromine, iodine, R 3 , R 4 are as defined above for R 3 and R 4 in any of the above, and the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, Sodium acetate, Morpholine, imidazole, dimethylaniline, DMAP, 2,6- lutidine. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.

Step (5): The compound of the formula V is reacted in an organic solvent under a reducing agent to give a compound of the formula VI (i.e., a compound of the formula I-1, I-2 when R 1 and R 2 are H). The reducing agent is preferably H 2 and Pd/C, H 2 and PtO 2 , H 2 and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH 3 , B 2 H 6 ). The reaction temperature is preferably -20 ° C to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.

Step (6): the compound VI is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula VII (ie, a compound of the formula I-1, I-2 when R 1 and R 2 are different at the same time), and the alkylation reaction conditions are in the art. Conventional conditions: in an organic solvent, reacted under the action of a base or an alkylating agent, wherein the alkylating agent is preferably R 1 X or R 2 X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R 1 , The definition of R 2 is the same as the definition of R 1 and R 1 in any of the above aspects of the invention; the base is preferably an alkali metal carbonate (preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), an alkali metal hydroxide (preferably LiOH, NaOH, KOH), an alkali metal hydride (preferably NaH, LiH or KH) or an alkali metal alkoxide (preferably CH 3 ONa, EtONa, t-BuOK); the acylation reaction conditions are also conventional in the art: In an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R 1 X or R 2 X (acid halide), R 1 OR 1 or R 2 OR 2 (anhydride), wherein X is a halogen, preferably Chlorine, bromine, iodine, R 1 , R 2 are as defined above for any of the above-mentioned R 3 and R 4 , and the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine or acetic acid. Sodium, quin Porphyrin, 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 or the like.

Method Two:

Step (1): The compound of the formula III is reacted in an organic solvent under a reducing agent to give a compound of the formula VIII. The reducing agent is preferably H 2 and Pd/C, H 2 and PtO 2 , H 2 and Raney Nickel, sodium borohydride, sodium cyanoborohydride, borane (BH 3 , B 2 H 6 ). The reaction temperature is preferably -20 ° C to reflux temperature. The organic solvent is preferably dichloromethane, methanol, ethyl acetate, acetone, THF, acetonitrile or chloroform.

Step (2): The compound of the formula VIII is reacted in an organic solvent under the action of a base or a Mitsunobu reagent to obtain a compound of the formula IX (that is, the formula I-1, I when R 1 , R 2 , R 3 and R 4 are both H) -2 compound). The base is preferably an alkali metal carbonate or an alkali metal hydrogencarbonate such as Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , Cs 2 CO 3 , an alkali metal hydroxide (preferably LiOH, NaOH, KOH), a base. Metal hydride (preferably NaH, LiH or KH) or alkali metal alkoxide (preferably CH 3 ONa, EtONa, t-BuOK); Mitsunobu reagents preferably DEAD and PPh 3 , DIAD and PPh 3 , DEAD and PEt 3 , DIAD and PEt 3 ; The organic solvent is preferably DMF, DMA, THF, acetonitrile, acetone, methylene chloride or chloroform; the reaction temperature is 0 to 60 ° C, preferably 20 to 40 ° C.

Step (3): a compound of the formula IX is subjected to an alkylation reaction or an acylation reaction to obtain a compound of the formula VII (ie, a compound of the formula I-1, I-2), and the alkylation reaction conditions are conventional conditions in the art: in an organic solvent, in a base, Reaction under the action of an alkylating agent, wherein the alkylating agent is preferably R 1 X, R 2 X, R 3 X or R 4 X (halogenated hydrocarbon), wherein X is a halogen, preferably chlorine, bromine, iodine, R 1 , R 2 And R 3 , R 4 are as defined above for R 1 , R 2 , R 3 , R 4 ; the base is preferably an alkali metal carbonate (preferably Na 2 CO 3 , K 2 CO 3 , Cs) 2 CO 3 ), an alkali metal hydroxide (preferably LiOH, NaOH, KOH), an alkali metal hydride (preferably NaH, LiH or KH) or an alkali metal alkoxide (preferably CH 3 ONa, EtONa, t-BuOK); The reaction conditions are also conventional in the art: in an organic solvent, the reaction is carried out under the action of a base and an acylating agent, wherein the acylating agent is preferably R 1 X, R 2 X, R 3 X or R 4 X (acyl halide), R. 1 OR 1 , R 2 OR 2 , R 3 OR 3 or R 4 OR 4 (anhydride), wherein X is a halogen, preferably chlorine, bromine, iodine, the definitions of R 1 , R 2 , R 3 , R 4 are the same as the invention at any preceding for R 1, R 2, R 3 , R 4 is defined The base is preferably an alkali metal hydroxide (e.g., NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2,6- lutidine. The organic solvent is preferably dichloromethane, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane or the like.
An intermediate compound of formula III characterized in that formula III has the structure:
a chemical bond in the diketopiperazine ring
Means pointing to the key in the paper at the same time
Or point to the key outside the paper
Chemical bond in sulfhydryl
Indicates a "Z" or "E" configuration with a double bond in the imine; n is 0 or 1.
An intermediate compound of formula VIII, characterized in that formula VIII has the structure:
Chemical bond
Means pointing to the key in the paper at the same time
Or point to the key outside the paper
n is 0 or 1.