Polycyclic compounds and pharmaceutical compositions and uses thereof

Abstract

The present invention discloses a polycyclic compound and a pharmaceutical composition and use thereof. The substituted polycyclic compound is as shown in formula (I). The compound has low toxicity to normal cells, can exert significant anti-influenza virus effect in vivo, has high drug safety, and can be developed into an anti-influenza virus drug.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, but is not limited thereto, and in particular to a polycyclic compound and a pharmaceutical composition and use thereof. Background Art

[0002] Influenza viruses are divided into three types: influenza A virus (IAV), influenza B virus (IBV), and influenza C virus (ICV). Among them, the surface antigen of influenza A virus is prone to mutation, which is called drift, to avoid recognition by the human immune system. This drift is the cause of influenza outbreaks. Human influenza outbreaks are mainly caused by influenza A and influenza B virus infections. Influenza C virus mainly infects humans and other mammals such as pigs and cattle, and usually only causes small-scale epidemics.

[0003] Baloxavir marboxil, commonly known as baloxavir dipyroxil, trade name Xofluza TM , the first single-dose oral antiviral drug developed by Shionogi Pharmaceutical Co., Ltd., was approved for marketing in Japan and the United States in 2018.

[0004] Chinese patent CN107709321A discloses a baloxavir ester compound, the chemical structure of which is:

[0005]

[0006] The drug has an inhibitory effect on viral cap-dependent endonuclease, and inhibits the synthesis of viral proteins by inhibiting the synthesis of influenza virus mRNA, ultimately inhibiting viral proliferation, and is mainly used to treat IAV and IBV infections. According to literature reports, in clinical trials, the median improvement time of influenza symptoms with baloxavir dipyramide was shorter than that of oseltamivir and placebo, which were 73.2h (hours), 81.0h, and 102.3h, respectively. However, the incidence of total adverse reactions was comparable to that of oseltamivir and placebo, at 25% and 30%, respectively, which was generally higher. In addition, about 10% of drug resistance has emerged. Therefore, this field still urgently needs to develop anti-influenza virus drugs with new structures, while reducing the incidence of adverse drug reactions and drug resistance. Summary of the invention

[0007] The inventors have developed a polycyclic compound with a novel structure, which has an anti-influenza virus effect.

[0008] In one aspect, the present invention provides a polycyclic compound, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as shown in (I):

[0009]

[0010] In formula (I), R0 is hydrogen or Here, n is 0, 1, 2, 3 or 4; R6 is halogen, hydroxyl, amino or carboxyl;

[0011] R1 is selected from: hydrogen, R7-C(O)-, R7-OC(O)-, R7-O-(CH2) n1 -、R7-OC(O)-O-(CH2) n1 -, -P(O)(OR8)(YR9), or -S(O)2-R 10 , wherein R7 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C3-C8 cycloalkyl groups, C1-C18 alkyl groups, or R7 is C1-C18 alkyl groups optionally substituted or unsubstituted by C3-C6 cycloalkyl groups; n1 is 1, 2, 3 or 4; R8 and R9 are both hydrogen, R8 is hydrogen, and R9 or R8 and R9 are selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups, carboxyl esterified or amidated amino acid residues; Y is nitrogen (-NH-) or an oxygen atom; R 10 is hydroxyl, amino, or selected from the following groups which are substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino;

[0012] Y1 and Y2 are each independently selected from oxygen, sulfur, or -NR 12 -; Here, R 12 - is hydrogen or C1-C6 alkyl;

[0013] m is 1, 2, or 3;

[0014] R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkyl substituted by group A, R 11 -OC(O)-、R 11 -OC(O)-O-(CH2) n2 -; R 11Selected from the following groups which are substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups; n2 is 1, 2, 3 or 4;

[0015] Alternatively, R2, R3 and the carbon to which they are attached together form a carbonyl group; R4 and R5 are as defined above;

[0016] Here, the group A is: hydroxyl, carboxyl, amino, halogen, trifluoromethyl, mercapto, C1-C18 alkoxycarbonyloxy, C1-C18 alkoxy, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C6-C12 aryloxy, C5-C12 heteroaryloxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C12 aryl, C5-C12 heteroaryl.

[0017] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (II):

[0018]

[0019] The substituents in formula (II) are as defined above.

[0020] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (III):

[0021]

[0022] The substituents in formula (III) are as defined above.

[0023] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (IV):

[0024]

[0025] The substituents in formula (IV) are as defined above.

[0026] In some embodiments, in the above formula (I), Y1 and Y2 are both oxygen; in some embodiments, in the above formula (I), Y1 and Y2 are both -NR 12 -, here, R 12 - is hydrogen, or C1-C6 alkyl; in some embodiments, in the above formula (I), Y1 is -NR 12 -, here, R 12- is hydrogen, or C1-C6 alkyl; Y2 is oxygen; in some embodiments, in the above formula (I)), Y1 is -NR 12 -, here, R 12 - is hydrogen, or C1-C6 alkyl; Y2 is sulfur; in some embodiments, in the above formula (I), Y1 is oxygen, Y2 is -NR 12 -, here, R 12 - is hydrogen, or C1-C6 alkyl; in some embodiments, in the above formula (I), Y1 is sulfur, Y2 is -NR 12 -, here, R 12 - is hydrogen or C1-C6 alkyl.

[0027] In some embodiments, in the above formula (I), (II), (III) or (IV), R0 is H; in some embodiments, in the above formula (I), (II), (III) or (IV), R0 is wherein n is 1, 2, 3 or 4; in some embodiments, in the above formula (I), (II), (III) or (IV), R6 is halogen; in some preferred embodiments, R6 is fluorine, chlorine or bromine; more preferably fluorine; in some embodiments, in the above formula (I), (II), (III) or (IV), R0 is

[0028] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is hydrogen.

[0029] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is R7-C(O)-, R7 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon group, C5-C20 heteroaryl group, C3-C8 cycloalkyl group, C1-C18 alkyl group; in some embodiments, R7 is C1-C18 alkyl group substituted by C3-C6 cycloalkyl group optionally substituted or unsubstituted by one or more groups A; preferably, R7 is selected from C1-C18 alkyl group substituted or unsubstituted by one or more groups A; more preferably, R7 is methyl or ethyl;

[0030] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is R7-OC(O)-, R7 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon group, C5-C20 heteroaryl group, C3-C8 cycloalkyl group, C1-C18 alkyl group; in some embodiments, R7 is C1-C18 alkyl group substituted by C3-C6 cycloalkyl group optionally substituted or unsubstituted by one or more groups A; preferably, R7 is selected from C1-C18 alkyl group substituted or unsubstituted by one or more groups A; more preferably, R7 is methyl or ethyl;

[0031] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is R7-O-(CH2) n1 -, R7 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon group, C5-C20 heteroaryl group, C3-C8 cycloalkyl group, C1-C18 alkyl group, n1 is 1, 2, 3 or 4; In some embodiments, R7 is a C1-C18 alkyl group substituted or unsubstituted by a C3-C6 cycloalkyl group substituted or unsubstituted by one or more groups A, and n1 is 1, 2, 3 or 4; Preferably, R7 is selected from a C1-C18 alkyl group substituted or unsubstituted by one or more groups A, and n1 is 1 or 2; More preferably, R7 is a methyl group or an ethyl group, and n1 is 1;

[0032] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is R7-OC(O)-O-(CH2) n1 -, R7 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C3-C8 cycloalkyl groups, C1-C18 alkyl groups, or, R7 is a C1-C18 alkyl group substituted by a C3-C6 cycloalkyl group optionally substituted or unsubstituted by one or more groups A; n1 is 1, 2, 3 or 4; preferably ...1-C 18 alkyl, n1 is 1 or 2; more preferably, R7 is methyl or ethyl, and n1 is 1;

[0033] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -P(O)(OR8)(YR9), R8 and R9 are both hydrogen;

[0034] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -P(O)(OR8)(YR9), R8 is hydrogen, and R9 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups, carboxyl esterified or amidated amino acid residues; Y is nitrogen (-NH-) or an oxygen atom; preferably, R9 is selected from C6-C20 aromatic hydrocarbon groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, carboxyl esterified or amidated amino acid residues substituted or unsubstituted by one or more groups A, and Y is nitrogen (-NH-) or an oxygen atom; more preferably, Y is a nitrogen atom (-NH-);

[0035] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -P(O)(OR8)(YR9), R8 and R9 are both selected from the following groups optionally substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups, carboxyl-esterified or amidated amino acid residues; Y is nitrogen (-NH-) or an oxygen atom; preferably, R8 and R9 are both selected from C1-C18 alkyl groups, C3-C8 cycloalkyl groups, carboxyl-esterified amino acid residues substituted or unsubstituted by one or more groups A, and Y is nitrogen (-NH-) or an oxygen atom; more preferably, Y is a nitrogen atom (-NH-);

[0036] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -S(O)2-R 10 , R 10 is hydroxyl group;

[0037] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -S(O)2-R 10 , R 10 It is amino group;

[0038] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -S(O)2-R 10 , R 10 is selected from the following groups substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino; preferably, R 10Unsubstituted following groups: C1-C8 alkyl, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino; more preferably, R 10 unsubstituted methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, or dimethylamino;

[0039] In some embodiments, in the above formula (I), (II), (III) or (IV), m is 1; in some embodiments, m is 2.

[0040] In some embodiments, in the above formula (I), (II), (III) or (IV), R2, R3, R4 and R5 are all hydrogen.

[0041] In some embodiments, in the above formula (I), (II), (III) or (IV), R2, R3, R4 and R5 are each independently hydrogen or C1-C8 alkyl; preferably, R2, R3, R4 and R5 are each independently hydrogen or C1-C3 alkyl; more preferably, R2, R3, R4 and R5 are each independently hydrogen or methyl.

[0042] In some embodiments, in the above formula (I), (II), (III) or (IV), R2, R3, R4 and R5 are each independently a C1-C8 alkyl group substituted by group A; preferably, R2, R3, R4 and R5 are each independently a C1-C3 alkyl group substituted by group A; more preferably, R2, R3, R4 and R5 are each independently a hydroxyl group, a carboxyl group, an amino group, or a methyl group substituted by a halogen.

[0043] In some embodiments, in the above formula (I), (II), (III) or (IV), R3, R4 and R5 are all hydrogen, R2 is R 11 -OC(O)-;R 11 is selected from the following groups which are substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups; preferably, R 11 Selected from: C1-C18 alkyl, C3-C8 cycloalkyl; More preferably, R 11 An alkyl group selected from C1-C18.

[0044] In some embodiments, in the above formula (I), (II), (III) or (IV), R3, R4 and R5 are all hydrogen, R2 is R 11 -OC(O)-O-(CH2) n2 -; R 11is selected from the following groups which are substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups; n2 is 1, 2, 3 or 4; preferably, R 11 is selected from: C1-C18 alkyl, C3-C8 cycloalkyl, n2 is 1 or 2; more preferably, R 11 An alkyl group selected from C1-C18, and n2 is 1.

[0045] In some embodiments, in the above formula (I), (II), (III) or (IV), R3, R4 and R5 are all hydrogen, R4 is R 11 -OC(O)-;R 11 is selected from the following groups which are substituted or unsubstituted by one or more groups A: C6-C20 aromatic hydrocarbon groups, C5-C20 heteroaryl groups, C2-C18 alkenyl groups, C2-C18 alkynyl groups, C1-C18 alkyl groups, C3-C8 cycloalkyl groups, C3-C8 heterocycloalkyl groups; preferably, R 11 Selected from: C1-C18 alkyl, C3-C8 cycloalkyl; More preferably, R 11 is selected from C1-C18 alkyl; in some embodiments, R 11 An alkyl group selected from C1-C3.

[0046] In some embodiments, in the above formula (I), (II), (III) or (IV), R2, R3 and the carbon to which they are attached together form a carbonyl group; R4 and R5 are independently selected from hydrogen or a C1-C18 alkyl group; in some embodiments, R2, R3 and the carbon to which they are attached together form a carbonyl group, and R4 and R5 are independently selected from hydrogen or a C1-C3 alkyl group; in some embodiments, R2, R3 and the carbon to which they are attached together form a carbonyl group, and R4 and R5 are independently selected from hydrogen, a methyl group or an ethyl group.

[0047] In some embodiments, in the above formula (I), (II), (III) or (IV), R4 and R5 are both hydrogen, and R2, R3 and the carbon to which they are attached together form a carbonyl group.

[0048] In some embodiments, in the above formula (I), (II), (III) or (IV), R2, R3 and R4 are all hydrogen, and R5 is a C1-C3 alkyl substituted by group A; group A is selected from hydroxyl, carboxyl, amino, or halogen.

[0049] In some embodiments, the polycyclic compound provided by the present invention is selected from the following compounds:

[0050]

[0051]

[0052] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned polycyclic compound, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof.

[0053] The present invention discloses a pharmaceutical composition, which uses the polycyclic compound, tautomer, stereoisomer and pharmaceutically acceptable salt thereof as an active ingredient or one of the main active ingredients, and is supplemented with a pharmaceutically acceptable carrier.

[0054] In a third aspect, the present invention also provides a preparation route of the polycyclic compound represented by formula (I), which comprises the following steps:

[0055]

[0056] The compound of formula (V) is subjected to removal of the Pr1 and Pr2 protecting groups to obtain a compound of formula (I) wherein both R1 and R0 are hydrogen;

[0057] Or formula (V) after removing the Pr2 protecting group and then reacting with R0-OS(O)2-R 13 or R0-OH to obtain a compound of formula (VI); then the compound of formula (VI) is deprotected by removing the Pr1 protecting group to obtain a compound of formula (I) wherein R1 is hydrogen; optionally, further reacted with R1-X to obtain a compound of formula (I);

[0058] Alternatively, the compound of formula (V) is reacted with R0-OS(O)2-R 13 Or R0-OH, and R1-X to obtain a compound of formula (I);

[0059] Here, X is a leaving group such as a halogen, Pr1 is a hydroxyl protecting group, Pr2 is an amino protecting group, and R 13 is a C1-C6 alkyl group or a C1-C6 alkyl-substituted phenyl group; Formula (V), Formula (VI), R0-OS(O)2-R 13 , and the definitions of other substituents in R0-OH are the same as those of the corresponding groups in formula (I).

[0060] In a fourth aspect, the present invention provides the above-mentioned polycyclic compounds, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof, which can be used to resist influenza viruses, and to treat and / or prevent diseases caused by influenza viruses.

[0061] The polycyclic compounds of the present invention can be formulated into pharmaceutical compositions and administered to patients according to a variety of suitable administration routes, including systemic administration such as oral or parenteral, intravenous, intramuscular, transdermal or subcutaneous.

[0062] definition:

[0063] Part of the present invention is a pharmaceutically acceptable solvate, which can be a crystalline hydrate or a crystallized product with other solvents, such as ethanol.

[0064] Forming part of the present invention are the pharmaceutically acceptable salts of:

[0065] If the compound of the present invention is basic, then suitable "pharmaceutically acceptable salts" include conventional non-toxic salts of the compound of the present invention formed by reacting the compound of the present invention with an inorganic acid or an organic acid. For example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. are included, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. are also included.

[0066] If the compound of the present invention is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared from the compound of the present invention by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like.

[0067] The term "alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched groups. Alkyl groups may be substituted or unsubstituted. When substituted alkyl groups, the substituents are preferably one or more, more preferably 1 to 3, and most preferably 1 or 2 substituents.

[0068] The term "alkenyl" refers to an aliphatic hydrocarbon group containing an unsaturated carbon-carbon double bond, including straight-chain and branched groups. The alkyl group may be substituted or unsubstituted. The carbon-carbon triple bond may be one or more.

[0069] The term "alkynyl" refers to an aliphatic hydrocarbon group containing an unsaturated carbon-carbon triple bond, including straight-chain and branched groups. The alkyl group may be substituted or unsubstituted. The carbon-carbon triple bond may be one or more.

[0070] The term "alkylamino" refers to a group in which an alkyl group is connected to a nitrogen atom, wherein the nitrogen atom has at least one hydrogen atom, and the nitrogen atom may be connected to one or two alkyl groups.

[0071] The term "cycloalkyl" refers to a monocyclic or fused ring ("fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with other rings in the system) group that is all carbon, wherein one or more rings do not have a completely connected π electron system, examples of cycloalkyl (not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted.

[0072] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms with a completely conjugated π electron system. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two.

[0073] The term "arylalkyl" refers to an alkyl group substituted with an aryl group.

[0074] The term "heteroaryl" refers to a monocyclic or fused ring group of multiple atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and having a completely conjugated π electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole.

[0075] The term "alkoxy" refers to a group in which an alkyl group is linked to an oxygen group, where the alkyl group may be a straight chain, branched chain or cyclic alkyl group.

[0076] The term "aryloxy" refers to a group in which an aryl group is attached to an oxygen

[0077] The term "hydroxy" refers to the -OH group.

[0078] The term "amino" refers to a -NH2 group.

[0079] The term "carboxy" refers to a -COOH group.

[0080] The term "mercapto" refers to a -SH group.

[0081] The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0082] The numerical ranges mentioned in this application, such as "C1-C18", mean that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 18 carbon atoms.

[0083] The polycyclic compound of the present invention has an inhibitory effect on influenza virus.

[0084] The polycyclic compound of the present invention has low toxicity to normal cells, can exert significant anti-influenza virus effect in vivo, and has high drug safety, and can be developed into an anti-influenza virus drug. DETAILED DESCRIPTION

[0085] The following examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The structures of all compounds are determined by MS.

[0086] Embodiment 1:

[0087]

[0088] Synthesis of compound 1b:

[0089] 5g of compound 1a, 65mg of p-toluenesulfonic acid, 2.7g of ethylene glycol, and 50ml of benzene were added to the reaction flask, and the system was heated to reflux and separated for 24 hours with a water separator. The system was concentrated to dryness, and dichloromethane and water were added to separate the organic phase, which was concentrated to dryness and separated by silica gel column to obtain 3.94g of compound 1b, with a yield of 72%, ESI-MS (+): m / z 506.19 [M+H];

[0090] Synthesis of compound 1c:

[0091] 3.8 g of compound 1b, 30 ml of methanol and 0.45 g of 10% palladium on carbon were added to the reaction flask and hydrogenated at room temperature and normal pressure for 24 hours. After the reaction, the system was filtered with diatomaceous earth; the system was concentrated to dryness under reduced pressure and purified by silica gel column to obtain 1.9 g of compound 1c, with a yield of 90%, ESI-MS (+): m / z 282.12 [M+H];

[0092] Embodiment 2:

[0093]

[0094] Synthesis of compound 2b:

[0095] 5g of compound 1a, 65mg of p-toluenesulfonic acid, 4.5g of 2-hydroxy-2-methylpropionic acid, and 50ml of benzene were added to the reaction flask, and the system was heated to reflux and separated for 24 hours with a water separator. The system was concentrated to dryness, dichloromethane and water were added to separate the organic phase, and the organic phase was concentrated to dryness and separated by silica gel column to obtain 4.03g of compound 2b, with a yield of 68%, ESI-MS (+): m / z 548.22 [M+H];

[0096] Synthesis of compound 2c:

[0097] 3.8 g of compound 2b, 30 ml of methanol and 0.41 g of 10% palladium on carbon were added to the reaction flask and hydrogenated at room temperature and normal pressure for 24 hours. After the reaction, the system was filtered with diatomaceous earth; the system was concentrated to dryness under reduced pressure and purified by silica gel column to obtain 2.04 g of compound 2c, with a yield of 91%, ESI-MS (+): m / z 324.10 [M+H];

[0098] Embodiment 3:

[0099]

[0100] Synthesis of compound 3b:

[0101] 5g of compound 1a, 65mg of p-toluenesulfonic acid, 3.86g of 2-amino-2-methylpropanol, and 50ml of benzene were added to the reaction flask, and the system was heated to reflux and separated for 24 hours with a water separator. The system was concentrated to dryness, dichloromethane and water were added to separate the organic phase, and the organic phase was concentrated to dryness and separated by silica gel column to obtain 4.33g of compound 3b, with a yield of 75%, ESI-MS (+): m / z 533.21 [M+H];

[0102] Synthesis of compound 3c:

[0103] 3.8 g of compound 3b, 30 ml of methanol and 0.42 g of 10% palladium on carbon were added to the reaction flask and hydrogenated at room temperature and normal pressure for 24 hours. After the reaction, the system was filtered with diatomaceous earth; the system was concentrated to dryness under reduced pressure and purified by silica gel column to obtain 1.94 g of compound 3c, with a yield of 88%, ESI-MS (+): m / z 309.13 [M+H];

[0104] Embodiment 4:

[0105]

[0106] Synthesis of compound 4b:

[0107] 3g of compound 1a, 1ml of triethylamine, 1.05g of methyl 2-amino-3-mercaptopropionate, 5 drops of trifluoroacetic acid and 30ml of cyclohexane were added to the reaction flask, and the system was heated to reflux and separated for 24 hours with a water separator. The system was concentrated to dryness, dichloromethane and water were added to separate the organic phase, and the organic phase was concentrated to dryness and separated by silica gel column to obtain 2.07g of compound 4b, with a yield of 55%, ESI-MS (+): m / z 579.19 [M+H];

[0108] Synthesis of compound 4c:

[0109] 2g of compound 4b, 20ml of methanol and 0.2g of 10% palladium on carbon were added to the reaction flask and hydrogenated at room temperature and normal pressure for 24 hours. After the reaction, the system was filtered with diatomaceous earth; the system was concentrated to dryness under reduced pressure and purified by silica gel column to obtain 1g of compound 4c, with a yield of 82%, ESI-MS (+): m / z 355.11 [M+H];

[0110] Embodiment 5:

[0111]

[0112] Synthesis of compound 5b:

[0113] 3g of compound 1a, 40mg of p-toluenesulfonic acid, 4.06g of N-Cbz-glycylamine, and 50ml of benzene were added to the reaction flask, and the system was heated to reflux and separated for 24 hours with a water separator. The system was concentrated to dryness, dichloromethane and water were added to separate the organic phase, and the organic phase was concentrated to dryness and separated by silica gel column to obtain 1.44g of compound 5b, with a yield of 34%, ESI-MS (+): m / z 652.22 [M+H];

[0114] Synthesis of compound 5c:

[0115] 1.2 g of compound 5b, 20 ml of methanol and 0.2 g of 10% palladium on carbon were added to the reaction flask and hydrogenated at room temperature and normal pressure for 24 hours. After the reaction, the system was filtered with diatomaceous earth; the system was concentrated to dryness under reduced pressure and purified by silica gel column to obtain 0.43 g of compound 4c, with a yield of 81%, ESI-MS (+): m / z 294.09 [M+H];

[0116] Embodiment 6:

[0117]

[0118] Synthesis of compound DSC2501:

[0119] 0.2 g of compound 1c, 0.242 g of compound INT-1, 0.11 g of pyridine and 20 ml of 1,4-dioxane were added to the reaction flask, and the system was heated at 60°C for 6 hours. After the reaction, the system was concentrated to dryness, extracted with dichloromethane and water, and the organic phase was concentrated to dryness and purified by silica gel column to obtain 0.25 g of compound DSC2501, with a yield of 68%, ESI-MS (+): m / z 528.15 [M+H].

[0120] Synthesis of compound DSC2502:

[0121] 0.13g of compound DSC2501, 41mg of potassium carbonate, 16mg of potassium iodide, 1.2ml of tetrahydrofuran, 0.2ml of N,N-dimethylformamide and 3ml of water were added to the reaction flask, the system was stirred and heated to 60°C, and 55mg of chloromethyl methyl carbonate was added. The system was reacted at 60°C for 8 hours, cooled to room temperature, and concentrated under reduced pressure until no solvent was obtained. The system was extracted with water and dichloromethane, concentrated to dryness, and the system was purified by silica gel column to obtain 0.13g of compound DSC2502, with a yield of 89%, ESI-MS (+): m / z 616.14 [M+H].

[0122] The following example compounds were synthesized by the same method as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0123]

[0124]

[0125]

[0126] Example 7: Study on the toxicity of compounds to normal cells

[0127] 5×10 4 The MDCK (Madin-Darby Canine Kidney, canine kidney epithelial cells) cell suspension was inoculated into a 96-well plate at a concentration of 100 μg / mL, incubated in an incubator for 24 h, the culture medium was removed, washed three times with PBS solution, DMEM culture medium was added, the compound and baloxavir ester were configured into a 0.1M mother solution (containing 0.02% DMSO for solubilization), then diluted with DMEM culture medium, added to the corresponding wells, and the final concentration of the drug solution in the well was controlled to be 20.0 μM. Three replicate wells were set for each compound. After the addition of the drug, the incubation was continued for 72 h. The OD (Optical Density) value at 490 nm was tested using the standard MTT (tetramethylthiazolium microenzyme reaction colorimetric method) method under light-proof conditions, and the cell survival rate was calculated as (OD of the drug group / OD of the normal group) × 100%. The final results were calculated using SPSS 20 software, as shown in Table 1 below:

[0128]

[0129]

[0130] The data show that compared with baloxavir dipyramide, the synthetic compound has a weaker killing effect on normal cells, has lower cytotoxicity, and is safer as a drug.

[0131] Example 8: In vivo antiviral testing of compounds DSC2504, DSC2509, and DSC2515

[0132] 120 SPF BALB / c mice were randomly divided into six groups, 20 mice in each group, namely DSC2504 group, DSC2509 group, DSC2515 group, baloxavir group, control group, and blank group. After one week of adaptive feeding, the mice were anesthetized, and 50uL of H1N1 virus venom was slowly dripped into the nasal cavity of the mice using a pipette, while the blank group was only dripped with an equal volume of normal saline.

[0133] 24 hours after virus infection, the corresponding compound was dissolved in sodium carboxymethyl cellulose aqueous solution and administered by gavage. The dose was controlled at 30.0 mg / kg. The blank group and the control group were administered with an equal volume of sodium carboxymethyl cellulose aqueous solution. The administration was continued for 3 days. The body temperature of the mice was tested 6 hours after administration. The test was performed once a day. The weighted average of the body temperature data of each group of mice was used as the body temperature data of the mice in this group. The results are shown in Table 2:

[0134] Group dose Day 1(℃) Day 2 (℃) Day 3(℃) Blank group --- 36.5±0.2 36.8±0.1 36.4±0.2 Control group --- 37.9±0.1 38.4±0.1 38.5±0.2 DSC2504 Group 30.0mg / kg 36.9±0.1 36.8±0.2 36.7±0.1 DSC2509 Group 30.0mg / kg 36.8±0.1 36.7±0.1 36.8±0.1 DSC2515 Group 30.0mg / kg 36.7±0.2 36.7±0.2 36.6±0.2 Baloxavir Dipivoxil Group 30.0mg / kg 37.4±0.2 37.0±0.2 36.7±0.1

[0135] The body temperature of mice in the normal group fluctuated within the normal range, while the body temperature of mice in the control group increased significantly, indicating that the model was successfully established. After administration, the body temperature of mice in the drug administration group decreased significantly and returned to normal. Moreover, the body temperature of mice treated with compounds DSC2504, DSC2509, and DSC2515 decreased more significantly than that of the baloxavir group 6 hours after administration, and the effect was faster.

[0136] On the third day, whole blood was collected from the carotid artery of the mice and the mice were killed. The lung tissues of the mice were selected and weighed, and the lung index of each group of mice was calculated according to the following formula:

[0137] Lung index = (mouse lung weight / mouse body weight) x 100%.

[0138] Then the formaldehyde average value is used for calculation, and the calculation results are shown in Table 3:

[0139]

[0140]

[0141] After mice are infected with the virus, the virus will cause the edema and enlargement of the mouse lung tissue. Therefore, the lung index of the control group is significantly increased compared with the blank group. The drug-treated group can obviously kill the virus, resulting in a significant decrease in the mouse lung index. Moreover, compared with the baloxavir dieppi group, the lung index of the DSC2504 group, the DSC2509 group, and the DSC2515 group decreased more significantly, indicating that the compounds DSC2504, DSC2509, and DSC2515 have a more obvious killing effect in vivo than baloxavir dieppi, that is, they have a significant inhibitory effect on the increase of the mouse lung index caused by virus infection.

Claims

1. A polycyclic compound as shown in (I) and a pharmaceutically acceptable salt thereof: In formula (I), R0 is R1 is selected from hydrogen, R7-OC(O)-, R7-O-(CH2) n1 -、R7-OC(O)-O-(CH2) n1 -;in, R7 is selected from the following unsubstituted groups: methyl; n1 is 1; Y1 and Y2 are each independently selected from oxygen, sulfur, or -NR 12 -; where R 12 is hydrogen or methyl; m is 1; R2, R3, R4 and R5 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkyl substituted by group A, R 11 -OC(O)-;R 11 Selected from methyl; or, R2, R3 and the carbon to which they are connected together form a carbonyl group; the group A is: hydroxyl.

2. A polycyclic compound as shown in (II) and a pharmaceutically acceptable salt thereof: The substituents in formula (II) are as defined in formula (I) of claim 1.

3. The polycyclic compound and pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds:

4. A pharmaceutical composition comprising the polycyclic compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof.

5. Use of the polycyclic compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4 in the preparation of an anti-influenza virus drug.

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