Polycyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a polycyclic compound as well as a pharmaceutical composition and application thereof. The substituted polycyclic compound is shown as a formula (I). The compound has low toxicity to normal cells, can play a significant anti-influenza virus role in vivo, has high drug safety, and can be developed into anti-influenza virus drugs. # imgabs0 #

Description

[0001] This application is a divisional application of the application with the application date of August 9, 2021, application number 202110909120.3, and invention title "Polycyclic Compounds and Their Pharmaceutical Compositions and Uses". Technical Field

[0002] The present invention relates to, but is not limited to, the technical field of medicinal chemistry, and particularly relates to a polycyclic compound and its pharmaceutical composition and uses. Background Art

[0003] 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. The result of this Drift is the cause of influenza outbreaks. Human influenza outbreaks are mainly caused by infections with Influenza A Virus and Influenza B Virus. Influenza C Virus mainly infects humans and other mammals such as pigs and cows, and usually only causes epidemics in a small area.

[0004] Baloxavir marboxil is translated as baloxavir marboxil, usually called baloxavir ester, and the trade name is Xofluza TM , which is the first single-dose oral antiviral drug developed by Shionogi & Co., Ltd., and was approved for marketing in Japan and the United States in 2018 respectively.

[0005] Chinese Patent CN107709321A discloses baloxavir ester compounds, and its chemical structure is:

[0006]

[0007] This 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, and finally inhibits virus proliferation. It is mainly used for the treatment of IAV and IBV infections. According to literature reports, in clinical trials, the median time for improvement of influenza symptoms of baloxavir ester is shorter than that of oseltamivir and placebo, which are 73.2 h (hours), 81.0 h, and 102.3 h respectively. However, the total incidence of adverse reactions is comparable to that of oseltamivir and placebo, which are 25% and 30% respectively, and is generally high. And there is about 10% drug resistance. Therefore, there is still an urgent need in the art to develop anti-influenza virus drugs with novel structures while reducing the incidence of drug adverse reactions and drug resistance. SUMMARY OF THE INVENTION

[0008] The present inventors have developed a polycyclic compound with a novel structure, which has an anti-influenza virus effect.

[0009] On the one hand, the present invention provides a polycyclic compound shown in (I), a tautomer, a stereoisomer, and a pharmaceutically acceptable salt thereof:

[0010]

[0011] In formula (I), R0 is hydrogen or Here, n is 0, 1, 2, 3, or 4; R6 is halogen, hydroxyl, amino, or carboxyl;

[0012] R1 is selected from: hydrogen, R7-C(O)-, R7-O-C(O)-, R7-O-(CH2) n1 -, R7-O-C(O)-O-(CH2) n1 -, -P(O)(OR8)(YR9), or -S(O)2-R 10 , wherein, R7 is selected from the following groups which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C3-C8 cycloalkyl, C1-C18 alkyl, or, R7 is C1-C18 alkyl substituted by C3-C6 cycloalkyl which is optionally substituted or unsubstituted by one or more groups A; n1 is 1, 2, 3, or 4; both R8 and R9 are hydrogen, R8 is hydrogen, and R9 or both R8 and R9 are selected from the following groups which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, amino acid residues esterified or amidated with carboxyl; 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;

[0013] Y1 and Y2 are each independently selected from oxygen, sulfur, or -NR 12 -; here, R 12 - is hydrogen, or C1-C6 alkyl;

[0014] m is 1, or 2, or 3;

[0015] R2, R3, R4, and R5 are each independently selected from: hydrogen, C1-C8 alkyl, C1-C8 alkyl substituted by group A, R 11 -O-C(O)-, R 11-O-C(O)-O-(CH2) n2 -; R 11 Selected from the following groups which are unsubstituted or substituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; n2 is 1, 2, 3 or 4;

[0016] Alternatively, R2, R3 together with the carbon to which they are attached form a carbonyl group; R4 and R5 are as defined above;

[0017] Here, the group A is: hydroxyl, carboxyl, amino, halogen, trifluoromethyl, mercapto, C1-C18 alkoxycarbonyloxy, C1-C18 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy, C6-C12 aryloxy, C5-C12 heteroaryloxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C12 aryl, C5-C12 heteroaryl.

[0018] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (II):

[0019]

[0020] The definitions of the substituents in formula (II) are as described above.

[0021] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (III):

[0022]

[0023] The definitions of the substituents in formula (III) are as described above.

[0024] In some embodiments, the present invention provides a polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (IV):

[0025]

[0026] The definitions of the substituents in formula (IV) are as described above.

[0027] In some embodiments, in the above formula (I), both Y1 and Y2 are oxygen; in some embodiments, in the above formula (I), both Y1 and Y2 are -NR 12 -, where R 12 - is hydrogen, or C1-C6 alkyl; in some embodiments, in the above formula (I), Y1 is -NR12 -, where R 12 - is hydrogen or a C1-C6 alkyl group; Y2 is oxygen; in some embodiments, in the above formula (I), Y1 is -NR 12 -, where R 12 - is hydrogen or a C1-C6 alkyl group; Y2 is sulfur; in some embodiments, in the above formula (I), Y1 is oxygen and Y2 is -NR 12 -, where R 12 - is hydrogen or a C1-C6 alkyl group; in some embodiments, in the above formula (I), Y1 is sulfur and Y2 is -NR 12 -, where R 12 - is hydrogen or a C1-C6 alkyl group.

[0028] 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 a halogen; in some preferred embodiments, R6 is fluorine, chlorine or bromine; more preferably fluorine; in some embodiments, in formula (I), (II), (III) or (IV), R0 is

[0029] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is hydrogen.

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

[0031] In some embodiments, in the above formulas (I), (II), (III), or (IV), R1 is R7-O-C(O)-, and R7 is selected from the following groups which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C3-C8 cycloalkyl, C1-C18 alkyl; in some embodiments, R7 is C1-C18 alkyl substituted by C3-C6 cycloalkyl which is optionally substituted or unsubstituted by one or more groups A; preferably, R7 is selected from C1-C18 alkyl which is substituted or unsubstituted by one or more groups A; more preferably, R7 is methyl or ethyl;

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

[0033] In some embodiments, in the above formulas (I), (II), (III), or (IV), R1 is R7-O-C(O)-O-(CH2) n1 -, R7 is selected from the following groups which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C3-C8 cycloalkyl, C1-C18 alkyl, or R7 is C1-C18 alkyl substituted by C3-C6 cycloalkyl which is optionally substituted or unsubstituted by one or more groups A; n1 is 1, 2, 3, or 4; preferably, R7 is selected from C1-C 18 alkyl, and n1 is 1, 2; more preferably, R7 is methyl or ethyl, and n1 is 1;

[0034] In some embodiments, in the above formulas (I), (II), (III), or (IV), R1 is -P(O)(OR8)(YR9), and both R8 and R9 are hydrogen;

[0035] 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 which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, carboxyl-esterified or amidated amino acid residues; Y is nitrogen (-NH-) or an oxygen atom; preferably, R9 is selected from C6-C20 aryl, C1-C18 alkyl, C3-C8 cycloalkyl, carboxyl-esterified or amidated amino acid residues which are optionally 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 -P(O)(OR8)(YR9), and both R8 and R9 are selected from the following groups which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, carboxyl-esterified or amidated amino acid residues; Y is nitrogen (-NH-) or an oxygen atom; preferably, both R8 and R9 are selected from C1-C18 alkyl, C3-C8 cycloalkyl, carboxyl-esterified amino acid residues which are optionally 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-);

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

[0038] In some embodiments, in the above formula (I), (II), (III) or (IV), R1 is -S(O)2-R 10 , R 10 is an amino group;

[0039] 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 which are optionally substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino; preferably, R 10The following unsubstituted 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;

[0040] In some embodiments, in the above formulas (I), (II), (III) or (IV), m is 1; in some embodiments, m is 2.

[0041] In some embodiments, in the above formulas (I), (II), (III) or (IV), R2, R3, R4 and R5 are all hydrogen.

[0042] In some embodiments, in the above formulas (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.

[0043] In some embodiments, in the above formulas (I), (II), (III) or (IV), R2, R3, R4 and R5 are each independently C1-C8 alkyl substituted by group A; preferably, R2, R3, R4 and R5 are each independently C1-C3 alkyl substituted by group A; more preferably, R2, R3, R4 and R5 are each independently methyl substituted by hydroxyl, carboxyl, amino, or halogen.

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

[0045] In some embodiments, in the above formulas (I), (II), (III) or (IV), R3, R4 and R5 are all hydrogen, and R2 is R 11 -O-C(O)-O-(CH2) n2 -; R 11Selected from the following groups which are unsubstituted or substituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; n2 is 1, 2, 3 or 4; preferably, R 11 Selected from: C1-C18 alkyl, C3-C8 cycloalkyl, n2 is 1 or 2; more preferably, R 11 Selected from C1-C18 alkyl, n2 is 1.

[0046] In some embodiments, in the above formulas (I), (II), (III) or (IV), R3, R4 and R5 are all hydrogen, and R4 is R 11 -O-C(O)-; R 11 Selected from the following groups which are unsubstituted or substituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; preferably, R 11 Selected from: C1-C18 alkyl, C3-C8 cycloalkyl; more preferably, R 11 Selected from C1-C18 alkyl; in some embodiments, R 11 Selected from C1-C3 alkyl.

[0047] In some embodiments, in the above formulas (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 C1-C18 alkyl; 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 C1-C3 alkyl; 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, methyl or ethyl.

[0048] In some embodiments, in the above formulas (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.

[0049] In some embodiments, in the above formulas (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 hydroxy, carboxy, amino, or halogen.

[0050] In some embodiments, the above polycyclic compounds provided by the present invention are selected from the following compounds:

[0051]

[0052]

[0053] On the other hand, the present invention provides a pharmaceutical composition comprising the above polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salts thereof.

[0054] The present invention discloses a pharmaceutical composition, which uses the polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salts thereof described in the present invention as one of the active ingredients or the main active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0055] In a third aspect, the present invention also provides a preparation route for the polycyclic compound represented by formula (I), which route comprises the following steps:

[0056]

[0057] The compound of formula (V) is deprotected from Pr1 and Pr2 protecting groups to obtain the compound of formula (I) where both R1 and R0 are hydrogen;

[0058] Or after the deprotection of Pr2 protecting group from formula (V), it reacts with R0-O-S(O)2-R 13 or R0-O-H to obtain the compound of formula (VI); then after the deprotection of Pr1 protecting group from the compound of formula (VI), the compound of formula (I) where R1 is hydrogen is obtained; optionally, it further reacts with R1-X to obtain the compound of formula (I);

[0059] Or, after the deprotection of Pr1 and Pr2 protecting groups from the compound of formula (V), it reacts with R0-O-S(O)2-R 13 or R0-O-H, and R1-X respectively to obtain the compound of formula (I);

[0060] Here, X is a leaving group such as halogen, Pr1 is a hydroxyl protecting group, Pr2 is an amino protecting group, and R 13 is a C1-C6 alkyl group, or a phenyl group substituted with a C1-C6 alkyl group; the definitions of other substituents in formula (V), formula (VI), R0-O-S(O)2-R 13 and R0-O-H are the same as the definitions of the corresponding groups in formula (I).

[0061] In a fourth aspect, the present invention provides that the above polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salts thereof can be used against influenza virus and for the treatment and / or prevention of diseases caused by influenza virus.

[0062] The polycyclic compound described in the present invention can be formulated into a pharmaceutical composition and administered to patients in a variety of suitably selected administration routes, including systemic routes such as oral or parenteral, by intravenous, intramuscular, transdermal, or subcutaneous, etc.

[0063] Definition:

[0064] Part of the present invention is a pharmaceutically acceptable solvate, which may be a hydrate or a crystal with other solvents, such as ethanol, etc.

[0065] Part of the present invention is a pharmaceutically acceptable salt:

[0066] If the compound of the present invention is basic, the appropriate "pharmaceutically acceptable salt" includes the conventional non-toxic salts of the compound of the present invention formed by reacting with inorganic acids or organic acids. For example, it includes salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and also includes 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, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0067] If the compound of the present invention is acidic, the appropriate "pharmaceutically acceptable salt" refers to the salt prepared from the compound of the present invention by a pharmaceutically acceptable non-toxic base including inorganic bases and organic bases. The salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc.

[0068] The term "alkyl" means a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups. The alkyl group may be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably 1-3, and most preferably 1 or 2 substituents.

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

[0070] The term "alkynyl" means an aliphatic hydrocarbon group containing an unsaturated carbon-carbon triple bond, including straight-chain and branched-chain groups. The alkyl group may be substituted or unsubstituted. The carbon-carbon triple bond may be one or more.

[0071] The term "alkylamino" means a group in which an alkyl group is linked to a nitrogen atom, and the nitrogen atom has at least one hydrogen atom, and the nitrogen atom may be linked to one alkyl group or two alkyl groups.

[0072] The term "cycloalkyl" refers to a monocyclic or fused ring (where "fused" rings mean that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group consisting entirely of carbon atoms, where one or more of the rings do not have a fully conjugated π-electron system. Examples of cycloalkyl (but not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl can be substituted or unsubstituted.

[0073] The term "aryl" refers to a monocyclic or fused polycyclic group of 1 to 12 carbon atoms having a fully conjugated π-electron system. Non-limiting examples of aryl are phenyl, naphthyl, and anthracenyl. Aryl can 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.

[0074] The term "arylhydrocarbyl" refers to a hydrocarbyl group substituted by an aryl group.

[0075] 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, with the remaining ring atoms being C, and further having a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryl are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.

[0076] The term "alkoxy" refers to a group in which an alkyl group is linked to an oxygen atom, where the alkyl group can be straight-chain, branched-chain, or cycloalkyl.

[0077] The term "aryloxy" refers to a group in which an aryl group is linked to an oxygen atom

[0078] The term "hydroxy" refers to the -OH group.

[0079] The term "amino" refers to the -NH2 group.

[0080] The term "carboxyl" refers to the -COOH group.

[0081] The term "mercapto" refers to the -SH group.

[0082] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0083] The numerical ranges mentioned in this application, such as "C1 - C18", mean that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 18 carbon atoms.

[0084] The polycyclic compounds described in the present invention have an inhibitory effect on influenza viruses.

[0085] The polycyclic compounds described in the present invention have low toxicity to normal cells, can play a significant anti-influenza virus effect in vivo, and have high drug safety, and can be developed into anti-influenza virus drugs. Detailed implementation mode

[0086] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. The structures of all compounds are determined by MS.

[0087] Example 1:

[0088]

[0089] Synthesis of Compound 1b:

[0090] 5 g of Compound 1a, 65 mg of p-toluenesulfonic acid, 2.7 g of ethylene glycol, and 50 ml of benzene were added to a reaction flask. The system was equipped with a water separator and heated under reflux to separate water for 24 hours. The system was concentrated to dryness, dichloromethane and water were added for liquid separation, the organic phase was separated out, concentrated to dryness and separated by silica gel column to obtain 3.94 g of Compound 1b, with a yield of 72%, ESI-MS(+): m / z 506.19 [M+H]; 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 a 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 under reduced pressure to dryness 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] Example 2:

[0093]

[0094] Synthesis of Compound 2b:

[0095] 5 g of Compound 1a, 65 mg of p-toluenesulfonic acid, 4.5 g of 2-hydroxy-2-methylpropanoic acid, and 50 ml of benzene were added to a reaction flask. The system was equipped with a water separator and heated under reflux to separate water for 24 hours. The system was concentrated to dryness, dichloromethane and water were added for liquid separation, the organic phase was separated out, concentrated to dryness and separated by silica gel column to obtain 4.03 g 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 a reaction flask, and hydrogenation was carried out at room temperature and atmospheric pressure for 24 hours. After the reaction was completed, the system was filtered through diatomaceous earth; the system was concentrated under reduced pressure to dryness, and purified by silica gel column chromatography to obtain 2.04 g of compound 2c, with a yield of 91%, ESI-MS(+): m / z 324.10 [M+H];

[0098] Example 3:

[0099]

[0100] Synthesis of compound 3b:

[0101] 5 g of compound 1a, 65 mg of p-toluenesulfonic acid, 3.86 g of 2-amino-2-methylpropanol, and 50 ml of benzene were added to a reaction flask, and the system was equipped with a water separator and heated under reflux to separate water for 24 hours. The system was concentrated to dryness, dichloromethane and water were added for liquid separation, the organic phase was separated out, concentrated to dryness and separated by silica gel column chromatography to obtain 4.33 g 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 a reaction flask, and hydrogenation was carried out at room temperature and atmospheric pressure for 24 hours. After the reaction was completed, the system was filtered through diatomaceous earth; the system was concentrated under reduced pressure to dryness, and purified by silica gel column chromatography to obtain 1.94 g of compound 3c, with a yield of 88%, ESI-MS(+): m / z 309.13 [M+H];

[0104] Example 4:

[0105]

[0106] Synthesis of compound 4b:

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

[0108] Synthesis of compound 4c:

[0109] Add 2 g of compound 4b, 20 ml of methanol and 0.2 g of 10% palladium on carbon to the reaction flask, and hydrogenate at room temperature and atmospheric pressure for 24 hours. After the reaction is completed, filter the system through diatomaceous earth; concentrate the system under reduced pressure to dryness, and purify it by silica gel column chromatography to obtain 1 g of compound 4c, with a yield of 82%, ESI-MS(+): m / z 355.11 [M+H];

[0110] Example 5:

[0111]

[0112] Synthesis of compound 5b:

[0113] Add 3 g of compound 1a, 40 mg of p-toluenesulfonic acid, 4.06 g of N-Cbz-glycinamide, and 50 ml of benzene to the reaction flask. Equip the system with a water separator and heat under reflux to separate water for 24 hours. Concentrate the system to dryness, add dichloromethane and water for liquid separation, separate the organic phase, concentrate to dryness and separate by silica gel column chromatography to obtain 1.44 g of compound 5b, with a yield of 34%, ESI-MS(+): m / z 652.22 [M+H];

[0114] Synthesis of compound 5c:

[0115] Add 1.2 g of compound 5b, 20 ml of methanol and 0.2 g of 10% palladium on carbon to the reaction flask, and hydrogenate at room temperature and atmospheric pressure for 24 hours. After the reaction is completed, filter the system through diatomaceous earth; concentrate the system under reduced pressure to dryness, and purify it by silica gel column chromatography to obtain 0.43 g of compound 4c, with a yield of 81%, ESI-MS(+): m / z 294.09 [M+H];

[0116] Example 6:

[0117]

[0118] Synthesis of compound DSC2501:

[0119] Add 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 to the reaction flask, and heat the system at 60 °C for 6 hours. After the reaction is completed, concentrate the system to dryness, extract with dichloromethane and water, concentrate the organic phase to dryness, and purify it by silica gel column chromatography 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] 0.13 g of compound DSC2501, 41 mg of potassium carbonate, 16 mg of potassium iodide, 1.2 ml of tetrahydrofuran, 0.2 ml of N,N-dimethylformamide and 3 ml of water were added to a reaction flask. The system was stirred and heated to 60 °C, and 55 mg of chloromethyl methyl carbonate was added. The system was reacted at 60 °C for 8 hours, cooled to room temperature, concentrated under reduced pressure until no solvent came out. The system was extracted with water and dichloromethane, concentrated to dryness, and purified by silica gel column chromatography to obtain 0.13 g of compound DSC2502 with a yield of 89%. ESI-MS(+): m / z 616.14 [M+H].

[0122] Following the same method as in the above example, commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds were used to synthesize the following example compounds.

[0123]

[0124]

[0125]

[0126] Example 7: Toxicity study of the compound on normal cells

[0127] The MDCK (Madin-Darby Canine Kidney) cell suspension was inoculated into a 96-well plate at a concentration of 5×10 4 cells / mL and incubated in an incubator for 24 h. The culture medium was removed, washed three times with PBS solution, and DMEM medium was added. The compound and baloxavir marboxil were prepared into a 0.1 M stock solution (containing 0.02% DMSO as a solubilizer), then diluted with DMEM medium and added to the corresponding wells, controlling the final concentration of the drug solution in the wells to be 20.0 μM. Three replicates were set for each compound. After adding the drug, incubation was continued for 72 h. The OD (Optical Density) value at 490 nm was measured using the standard MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method under dark conditions, and the cell survival rate was calculated as = (OD of the drug-treated group / OD of the normal group) × 100%. The final results were calculated using SPSS20 software as shown in Table 1 below:

[0128]

[0129]

[0130] The data showed that the synthesized compound had a weaker killing effect on normal cells and lower cytotoxicity compared to baloxavir marboxil, and had higher drug safety.

[0131] Example 8: In Vivo Antiviral Test of Compounds DSC2504, DSC2509, and DSC2515

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

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

[0134] Group Dose Day 1 (°C) Day 2 (°C) Day 3 (°C) 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 30.0 mg / kg 36.9±0.1 36.8±0.2 36.7±0.1 DSC2509 group 30.0 mg / kg 36.8±0.1 36.7±0.1 36.8±0.1 DSC2515 group 30.0 mg / kg 36.7±0.2 36.7±0.2 36.6±0.2 Baloxavir marboxil group 30.0 mg / kg 37.4±0.2 37.0±0.2 36.7±0.1

[0135] The body temperature of the mice in the normal group fluctuated within the normal range. The body temperature of the mice in the control group increased significantly, indicating successful modeling. After administration, the body temperature of the mice in the administration groups decreased significantly and returned to the normal range. Moreover, the body temperature of the mice after 6 - hour administration of compounds DSC2504, DSC2509, and DSC2515 decreased more significantly and took effect faster than that of the baloxavir marboxil group.

[0136] On the 3rd day, the mice were sacrificed by taking whole blood from the carotid artery. The lung tissues of the mice were selected, 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) × 100%.

[0138] Then, calculated based on the average value of formaldehyde, the calculation results are shown in Table 3 below:

[0139]

[0140]

[0141] After mice are infected with the virus, the virus will cause the pulmonary tissue of the mice to edematously enlarge. Therefore, the lung index of the control group is significantly higher than that of the blank group. Since the administration group can significantly kill the virus, the lung index of the mice is significantly decreased. Moreover, compared with the baloxavir marboxil group, the decrease in the lung index of the DSC2504 group, DSC2509 group, and DSC2515 group is more obvious, indicating that the compounds DSC2504, DSC2509, and DSC2515 have a more obvious killing effect in vivo than baloxavir marboxil, that is, they have an obvious inhibitory effect on the increase in the lung index of mice caused by virus infection.

Claims

1. A polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (I): In formula (I), R0 is hydrogen or Here, n is 0, 1, 2, 3 or 4; R6 is halogen, hydroxyl, amino or carboxyl; R1 is selected from: hydrogen, R7-C(O)-, R7-O-C(O)-, R7-O-(CH2) n1 -, R7-O-C(O)-O-(CH2) n1 -, -P(O)(OR8)(YR9), or -S(O)2-R 10 , wherein, R7 is selected from the following groups, which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C3-C8 cycloalkyl, C1-C18 alkyl, or, R7 is C1-C18 alkyl substituted by C3-C6 cycloalkyl which is optionally substituted or unsubstituted by one or more groups A; n1 is 1, 2, 3 or 4; both R8 and R9 are hydrogen, R8 is hydrogen and R9 or both R8 and R9 are selected from the following groups, which are optionally substituted or unsubstituted by one or more groups A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, carboxyl esterified or amidated amino acid residues; Y is a nitrogen or oxygen atom; R 10 is hydroxy, amino, or is 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; Y1 and Y2 are each independently selected from oxygen, sulfur, or -NR 12 -; where R 12 - is hydrogen, or C1-C6 alkyl; m is 1, 2, or 3; R2, R3, R4 and R5 are each independently selected from: hydrogen, C1-C8 alkyl, C1-C8 alkyl substituted with group A, R 11 -O-C(O)-, R 11 -O-C(O)-O-(CH2) n2 -; R 11 selected from the following groups which are unsubstituted or substituted with one or more group A: C6-C20 aryl, C5-C20 heteroaryl, C2-C18 alkenyl, C2-C18 alkynyl, C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; n2 is 1, 2, 3 or 4; Alternatively, R2, R3, and the carbon to which they are attached together form a carbonyl group; Here, the group A is: hydroxyl, carboxyl, amino, halogen, trifluoromethyl, mercapto, C1-C18 alkoxycarbonyloxy, C1-C18 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy, C6-C12 aryloxy, C5-C12 heteroaryloxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C12 aryl, C5-C12 heteroaryl.

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

3. A polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (III): The definitions of the substituents in formula (III) are as defined in formula (I) of claim 1.

4. A polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (IV): The definitions of the substituents in formula (IV) are as defined in formula (I) of claim 1.

5. The polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R0 is wherein n is 1, 2, 3 or 4; and R6 is a halogen; preferably, R6 is fluorine or bromine; more preferably fluorine, and particularly preferably, R0 is 6. The polycyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds:

7. A method for preparing the polycyclic compound tautomer, stereoisomer, and pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps: The compound of formula (V) is deprotected from Pr1 and Pr2 to obtain the compound of formula (I) where both R1 and R0 are hydrogen; Alternatively, after removing the Pr2 protecting group in formula (V), it reacts with R0-O-S(O)2-R 13 or R0-O-H to obtain the compound of formula (VI); then, after removing the Pr1 protecting group from the compound of formula (VI), the compound of formula (I) where R1 is hydrogen is obtained; optionally, it further reacts with R1-X to obtain the compound of formula (I); Alternatively, after the removal of the Pr1 and Pr2 protecting groups from the compound of formula (V), it is reacted with R0-O-S(O)2-R 13 or R0-O-H, and R1-X respectively to obtain the compound of formula (I); 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 phenyl group substituted with a C1-C6 alkyl group; the definitions of the other substituents in formula (V), formula (VI), R0-O-S(O)2-R 13 and R0-O-H are the same as the definitions of the corresponding groups in formula (I).

8. A pharmaceutical composition comprising the polycyclic compound tautomer, stereoisomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

9. The polycyclic compound tautomer, stereoisomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 8 can be used for anti-influenza virus and its application in the preparation of anti-influenza virus drugs.

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