Aromatic ring formamide compound as well as pharmaceutical composition and application thereof

Abstract

The invention provides an aromatic ring formyl compound with a structure as shown in a formula I, or pharmaceutically acceptable salt, stereoisomer or prodrug molecule thereof, and a pharmaceutical composition and application thereof. The novel compound has a strong anti-influenza virus effect, and can be used for preventing and treating respiratory diseases caused by influenza virus infection. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a class of aromatic ring formamide compounds, their pharmaceutical compositions and uses. Background Art

[0002] Influenza (hereinafter referred to as flu) is a serious acute respiratory infectious disease that endangers human health. It is caused by influenza virus and is characterized by high prevalence, wide spread and rapid transmission. There have been many influenza pandemics around the world in history, among which the Spanish flu pandemic in 1918 was the most serious, and more than 20 million people lost their lives due to influenza. In 2009, the "swine flu" outbreak in Mexico is currently seriously threatening the lives of people around the world, bringing great losses to human life and social economy.

[0003] Currently, the main means of treating influenza are antiviral chemical small molecule drugs that target key proteins in virus replication, such as M2 ion channel protein inhibitors, hemagglutinin (HA) inhibitors, neuraminidase (NA) inhibitors, and inhibitors of subunits (PA, PB1, PB2 and their interactions) of RNA-dependent RNA polymerase (RdRP). Antiviral means under research include antisense oligonucleotides, ribozymes and deoxyribozymes to inhibit influenza virus replication or RNA expression, etc. (Christopher F. Basler. Infectious Disorders - Drug Targets. 2007, 7, 282 - 293). Currently, the first-line antiviral drugs for influenza in clinical practice are the neuraminidase inhibitor oseltamivir and the PA inhibitor baloxavir marboxil approved for use in China at the end of 2021. Other drugs are only selected when these two types of drugs are ineffective against specific virus strains in specific populations or against general non-severe viruses. Among them, the therapeutic window of oseltamivir is relatively narrow, and it needs to be used within 48 hours of infection for the efficacy to be obvious. After years of use, various drug-resistant strains have emerged, making it difficult to meet clinical use. Baloxavir marboxil is a new anti-influenza drug with a completely new mechanism in nearly 20 years. It was obtained by Shionogi & Co., Ltd. in Japan through structural modification of the parent nucleus of dolutegravir and was approved for marketing in China in 2021. As the only single-dose oral drug approved for the treatment of influenza currently, baloxavir marboxil only needs to be taken once throughout the course of the disease to control the condition. It can stop virus excretion within 24 hours after taking baloxavir marboxil, effectively relieving influenza symptoms such as high fever and general fatigue. However, through clinical use, baloxavir marboxil has also been found to have side effects such as allergic reactions, rashes, urticaria, vomiting, etc., especially a relatively high incidence of drug-resistant strains has been found in the use of pediatric patients. Therefore, it is very necessary to develop new anti-influenza virus drugs. Summary of the Invention

[0004] Based on this, the object of the present invention is to provide anti-influenza virus drugs with novel molecular structures.

[0005] In order to achieve the above object of the invention, the present invention includes the following technical solutions.

[0006] On the one hand, the present invention provides an aromatic ring formyl compound having the structure shown in Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof:

[0007]

[0008] Wherein,

[0009] R 1 is selected from: -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 ;

[0010] L is selected from: -NH-, -NHCO-, -N=CH-, -NHCH2-, -O-,

[0011] Ring A is selected from: one or more 5-10 membered heteroaryl groups substituted or unsubstituted by R, one or more C6-C 10 aryl groups;

[0012] Ring B is selected from: one or more 5-6 membered heteroaryl groups substituted or unsubstituted by R, one or more phenyl groups substituted or unsubstituted by R;

[0013] Ring C is selected from: one or more 5-10 membered heteroaryl groups substituted or unsubstituted by R, one or more C6-C 10 aryl groups;

[0014] Each R is independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 , -NHSO2R 2 , -SO2R 2 , -COOH, -COOR 2 , -CONHR 2 , -CONR 2 R 3, halogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heteroalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or two adjacent Rs and the atoms to which they are attached together form a C3-C8 cycloalkyl or 3- to 8-membered heteroalkyl;

[0015] Each R 2 , R 3 is independently selected from: C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heteroalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or R 2 , R 3 and the nitrogen atom to which it is attached together form a 3- to 8-membered heteroalkyl;

[0016] R 4 is a natural or unnatural amino acid residue;

[0017] m is selected from: 1, 2, 3, 4, 5.

[0018] In some embodiments, R 1 is selected from: -NH2, -OH, C1-C3 alkoxy.

[0019] In some embodiments, R 1 is selected from: -NH2, -OH, methoxy, ethoxy.

[0020] In some embodiments, L is selected from: -NHCO-, -N=CH-.

[0021] In some embodiments, ring A is selected from:

[0022] Each X1 is independently selected from O, S, NR 7 ;

[0023] Each X2 is independently selected from: CR 5 , CR 6 , N;

[0024] Y is selected from: CR 5 R 6 , O, S, NR 7 ;

[0025] n is selected from: 0, 1, 2, 3;

[0026] R 5 、R 6 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 、-NHR 2 、-NR 2 R 3 、-NHSO2R 2 、-SO2R 2 、-COOH, -COOR 2 、-CONHR 2 、-CONR 2 R 3 、halogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl;

[0027] R 7 is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0028] In some embodiments, ring A is selected from:

[0029]

[0030] R 5 、R 6 、R 7 are each independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0031] Y is selected from: O, S.

[0032] In some embodiments, ring A is selected from:

[0033] Each X1 is independently selected from O, S, NR 7 ;

[0034] Each X2 is independently selected from: CR 5 、N;

[0035] Y is selected from: CR 5 R 6 、O, S, NR7 ;

[0036] R 5 、R 6 、R 7 are each independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0037] In some embodiments, ring A is selected from:

[0038] each X1 is independently selected from O, S;

[0039] X2 is CH;

[0040] Y is CH2;

[0041] R 5 、R 6 、R 7 are each independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0042] In some embodiments, ring A is selected from:

[0043] R 5 is selected from: -H, methyl, ethyl.

[0044] In some embodiments, ring B is selected from:

[0045] each X1 is independently selected from O, S, NR 7 ;

[0046] R 7 is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0047] In some embodiments, ring B is selected from:

[0048]

[0049] In some embodiments, ring B is selected from:

[0050] X1 is O or S.

[0051] In some of these embodiments, ring C is selected from:

[0052]

[0053] Each X1 is independently selected from O, S, NR 7 ;

[0054] R 7 is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl;

[0055] R 8 and R 9 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 -NHR 2 -NR 2 R 3 -NHSO2R 2 -SO2R 2 -COOH, -COOR 2 -CONHR 2 -CONR 2 R 3 halogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0056] In some of these embodiments, ring C is selected from:

[0057]

[0058] In some of these embodiments, ring C is selected from:

[0059] R 8 and R 9 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -COOH, -COOR 2, halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0060] R 2 Selected from: C1-C3 alkyl.

[0061] In some embodiments, R 8 and R 9 At least one of them is a carboxyl group.

[0062] In some embodiments, ring C Selected from:

[0063]

[0064] R 8 Selected from: -H, -NO2, -COOH, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy.

[0065] In some embodiments, the aromatic ring formyl compound has the structure shown in Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X:

[0066]

[0067] wherein, R 1 Selected from: -NH2, -OH, C1-C3 alkoxy;

[0068] Each X1 is independently selected from: O, S;

[0069] Each X2 is independently selected from: CH, N;

[0070] Y is selected from: CH2, O, S;

[0071] n is selected from: 0, 1, 2, 3;

[0072] R 5 , R 6 Are independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0073] R 8 , R 9 Are independently selected from: -H, -CN, -NO2, -NH2, -OH, -COOH, -COOR 2 , halogen, C1-C3 alkyl, C1-C3 alkoxy; R 2 Selected from: C1-C3 alkyl.

[0074] In some embodiments, the aromatic ring formyl compound is selected from the following compounds:

[0075]

[0076]

[0077] In a second aspect, the present invention also provides the use of the aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of a drug for anti-influenza virus.

[0078] The present invention also provides the use of the aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of a drug for preventing or treating influenza virus infection.

[0079] In some embodiments, the influenza virus is an influenza A virus.

[0080] The present invention also provides the use of the aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of a drug for preventing or treating influenza.

[0081] In a third aspect, the present invention also provides a drug for preventing or treating influenza virus infection, which is prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, and the active ingredient includes the aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as described in the present invention.

[0082] The present invention provides a new class of aromatic ring formyl compounds. This class of compounds has a compositional structure in which three aromatic rings or heteroaromatic rings are connected. Through antiviral activity experiments, it is found that this class of compounds has strong in vitro anti-influenza virus activity and low cytotoxicity, and can be used to prepare anti-influenza virus drugs with high antiviral activity and high anti-drug resistance, and can be used to prevent and treat respiratory diseases caused by influenza virus infection, providing the possibility for the development of new anti-influenza, avian influenza and other respiratory virus drugs. Detailed Embodiments

[0083] The technical solutions of the present invention will be further described below through specific examples. Those skilled in the art should understand that the examples are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0084] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not used to limit the present invention.

[0085] As used in this invention, the terms "comprising" and "having" and any variations thereof are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product or device that includes a series of steps is not limited to the listed steps or modules, but may optionally further include steps not listed, or may optionally further include other steps inherent to these processes, methods, products or devices.

[0086] As used in this invention, "a plurality of" means two or more. "And / or" describes the relationship between related objects and indicates that three relationships may exist. For example, A and / or B may represent: A exists alone, A and B exist simultaneously, and B exists alone. The character " / " generally indicates that the related objects before and after are in an "or" relationship.

[0087] In the compounds described in this invention, when any variable (such as R, R 2 , R 3 etc.) appears more than once in any component, its definition for each appearance is independent of the definition for each other appearance. Similarly, combinations of substituents and variables are allowed as long as such combinations render the compound stable. The line extending from a substituent into the ring system indicates that the bond referred to can be attached to any ring atom capable of being substituted. If the ring system is polycyclic, it means that this bond is only attached to any appropriate carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of this invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by the techniques of the art and the methods set forth below. If a substituent itself is substituted by more than one group, it is to be understood that these groups can be on the same carbon atom or different carbon atoms as long as the structure is stable.

[0088] As used in this invention, the term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" for "C1-C6" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or a branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.

[0089] As used in this invention, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and bicyclic or polycyclic includes spiro rings, fused rings and bridged rings. For example: "cycloalkyl" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0090] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0091] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring substituent, wherein one or more ring atoms are heteroatoms selected from N, O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Bicyclic or polycyclic includes spiro, fused and bridged rings. For example: morpholinyl, piperidinyl, pyrrolidinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, and the like, and their N-oxides. The attachment of the heterocyclic substituent can be through a carbon atom or through a heteroatom.

[0092] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S, and the aromatic ring can be monocyclic, bicyclic or polycyclic. For example, but not limited to: quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, etc.; "heteroaryl" is also understood to include any N-oxide derivative of a heteroaryl containing nitrogen. The attachment of the heteroaryl can be through a carbon atom or through a heteroatom.

[0093] As will be understood by those skilled in the art, "halo" or "halogen" as used in the present invention means chlorine, fluorine, bromine and iodine.

[0094] In one embodiment of the present invention, the present invention provides an aromatic ring formyl compound having the structure shown in Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof:

[0095]

[0096] wherein,

[0097] R 1 is selected from: -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 ;

[0098] L is selected from: -NH-, -NHCO-, -N=CH-, -NHCH2-, -O-,

[0099] Ring A is selected from: one or more 5- to 10-membered heteroaryl groups which are substituted or unsubstituted by R, one or more C6-C 10 aryl groups;

[0100] Ring B is selected from: one or more 5- to 6-membered heteroaryl groups which are substituted or unsubstituted by R, one or more phenyl groups which are substituted or unsubstituted by R;

[0101] Ring C is selected from: one or more 5- to 10-membered heteroaryl groups which are substituted or unsubstituted by R, one or more C6-C 10 aryl groups;

[0102] Each R is independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 , -NHSO2R 2 , -SO2R 2 , -COOH, -COOR 2 , -CONHR 2 , -CONR 2 R 3 , halogen, C1-C6 alkyl, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by C1-C6 alkylthio, C1-C6 alkyl substituted by C1-C6 alkylamino, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or two adjacent Rs and the atoms to which they are attached together form a C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl;

[0103] Each R 2 , R 3 are independently selected from: C1-C6 alkyl, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by C1-C6 alkylthio, C1-C6 alkyl substituted by C1-C6 alkylamino, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or R 2 , R 3 and the nitrogen atom to which it is attached together form a 3- to 8-membered heterocycloalkyl;

[0104] R4 is a natural or unnatural amino acid residue;

[0105] m is selected from: 1, 2, 3, 4, 5.

[0106] The present invention includes the free form of the compound of formula I, as well as its pharmaceutically acceptable salts and stereoisomers. The pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, the salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0107] Accordingly, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting the basic compounds of the present invention with inorganic or organic acids. For example, the conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts prepared 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0108] If the compound of the present invention is acidic, the appropriate "pharmaceutically acceptable salts" refer to salts prepared by reacting with pharmaceutically acceptable non-toxic bases 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. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. The salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0109] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977:66:1 - 19 describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0110] Metabolites of the compounds and their pharmaceutically acceptable salts involved in the present invention, as well as prodrugs that can be converted in vivo into the structures of the compounds and their pharmaceutically acceptable salts involved in the present application, are also included in the claims of the present invention.

[0111] In another embodiment, the present invention provides a method for treating diseases caused by influenza virus infection in humans or other mammals using a compound having the structure of formula I and its pharmaceutically acceptable salts.

[0112] In another embodiment, the present invention also provides a pharmaceutical composition, which contains an active ingredient within a safe and effective amount range, as well as a pharmaceutically acceptable carrier or excipient.

[0113] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule.

[0114] The "active ingredient" and the pharmaceutical composition described in the present invention can be used to prepare drugs for preventing and / or treating diseases caused by influenza virus infection.

[0115] "Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the active ingredient per dose, more preferably, 10 - 200 mg of the active ingredient per dose. Preferably, the "per dose" is one tablet.

[0116] "Pharmaceutically acceptable carrier or excipient" means one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0117] "Compatibility" herein means that the components in the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0118] Some examples of pharmaceutically acceptable carriers or excipients are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0119] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interactions. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0120] There is no particular limitation on the administration mode of the active ingredient or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0121] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0122] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or mixed with the following components:

[0123] (a) Fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0124] (b) Binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0125] (c) Humectants, such as glycerol;

[0126] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0127] (e) Sustained-release agents, such as paraffin wax;

[0128] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0129] (g) Wetting agents, such as cetyl alcohol and glycerol monostearate;

[0130] (h) Adsorbents, such as kaolin; and

[0131] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form can also contain buffering agents.

[0132] The solid dosage forms described above can also be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax-like substances.

[0133] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.

[0134] In addition to the active ingredient, the suspension may contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0135] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0136] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs.

[0137] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health condition of the patient, which are all within the scope of the skills of a skilled physician.

[0138] The compound of Formula I can be used in combination with other drugs known for treating or ameliorating similar conditions. When administered in combination, the mode of administration and dosage of the original drug remain unchanged, while the compound of Formula I is taken simultaneously or subsequently. When the compound of Formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula I is preferably used. The combination of drugs also includes taking the compound of Formula I and one or more other known drugs over overlapping time periods. When the compound of Formula I is used in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than the dosage when they are used alone.

[0139] The present invention will be further illustrated below with specific examples. It should be understood that these examples are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0140] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0141] The raw materials in the following examples can be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0142] Example 1: Synthesis of Compound 1

[0143]

[0144] Synthesis of Intermediate 3-(5-Formylthiophen-2-yl)benzoic Acid (b1c1):

[0145] In a mixed solvent of toluene, ethanol and water (3:3:1, 70 mL), 5-bromothiophene-2-carbaldehyde (b1) (1.04 g, 6.28 mmol), 3-boronic acid benzoic acid (c1) (1.00 g, 5.24 mmol), potassium carbonate (2.17 g, 15.71 mmol) and tetrakis(triphenylphosphine)palladium (0.30 g, 0.26 mmol) were added. After replacing with nitrogen for protection, the temperature was raised to 90 °C and stirred for 7 hours. After the reaction was completed by TLC detection, the temperature was lowered, and it was clarified and layered. 6N hydrochloric acid was added to adjust the pH to 1-2, and a pale yellow solid was precipitated. It was filtered and dried to obtain a yellow solid cake. The filtrate was extracted once with dichloromethane (60 mL), and the solvent was evaporated to obtain a yellow solid. The two solids were combined, and each was slurried with water and petroleum ether / ethyl acetate (v / v) = 2 / 1 in turn, and finally dried to obtain 0.86 g of the crude product of intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1), with a yield of 71%.

[0146] Synthesis of Compound 1:

[0147] Intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) (0.15 g, 0.65 mmol) and 2-aminothiophene-3-carboxamide (0.09 g, 0.65 mmol) were added to ethanol (40 mL). 5 drops of concentrated hydrochloric acid were added under stirring at room temperature, and the reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated to obtain a purple-red solid, and then recrystallized with methanol / ethyl acetate to obtain 0.14 g of the target compound 1 as a purple-red solid, with a yield of 58%. 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 5.0 Hz, 2H), 7.97 (s, 2H), 7.66 (d, J = 10.0 Hz, 1H).

[0148] Example 2: Synthesis of Compound 2

[0149]

[0150] Using intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide as raw materials, and using the synthesis method of Example 1, compound 2 was obtained as an orange-red solid, 0.18 g, with a yield of 51%. 1HNMR(500MHz, DMSO-d6) δ 8.68(s, 1H), 8.22(s, 1H), 8.05(d, J = 5.0Hz, 1H), 8.00(s, 1H), 7.95(d, J = 5.0Hz, 1H), 7.80(dd, J = 10.0, 5.0Hz, 2H), 7.62(t, J = 5.0Hz, 1H), 7.46(s, 1H), 2.73(t, J = 5.0Hz, 2H), 2.70(t, J = 5.0Hz, 2H), 1.78(m, 2H), 1.71(m, 2H).

[0151] Example 3: Synthesis of Compound 3

[0152]

[0153] Using intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) and 3-aminothiophene-2-carboxamide as raw materials, and using the synthesis method of Example 1, Compound 3 was obtained as an orange-red solid, 0.09 g, with a yield of 39%. 1 H NMR(300MHz, DMSO-d6) δ 13.11(s, 1H), 9.07(s, 1H), 8.29(d, J = 3.0Hz, 1H), 8.24(s, 1H), 8.07(d, J = 9.0Hz, 1H), 7.97(d, J = 6.0Hz, 1H), 7.86(d, J = 3.0Hz, 1H), 7.82(s, 1H), 7.80(s, 2H), 7.63(m, 1H), 7.54(d, J = 6.0Hz, 1H).

[0154] Example 4: Synthesis of Compound 4

[0155]

[0156] Using intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) and 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxamide as raw materials, and using the synthesis method of Example 1, Compound 4 was obtained as an orange-red solid, 0.20 g, with a yield of 75%. 11H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.74 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.62 (m, 1H), 7.55 (s, 1H), 4.69 (s, 2H), 3.85 (t, J = 6.0 Hz, 1H), 2.86 (t, J = 6.0 Hz, 1H).

[0157] Example 5: Synthesis of Compound 5

[0158]

[0159] Using intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) and 2-aminobenzamide as starting materials, and adopting the synthesis method of Example 1, Compound 5 was obtained as a white solid, 0.17 g, with a yield of 75%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.55 (s, 1H), 8.08 (d, J = 3.0 Hz, 1H), 7.86 (dd, J = 9.0, 3.0 Hz, 2H), 7.64 (dd, J = 9.0, 3.0 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 7.15 (d, J = 3.0 Hz, 1H), 6.80 (d, J = 6.0 Hz, 1H), 6.73 (m, 1H), 6.03 (m, 1H).

[0160] Example 6: Synthesis of Compound 6

[0161]

[0162] Using intermediate 3-(5-formylthiophen-2-yl)benzoic acid (b1c1) and 3-aminoisonicotinamide as starting materials, and adopting the synthesis method of Example 1, Compound 6 was obtained as a white solid, 0.07 g, with a yield of 30%. 11H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 6.0 Hz, 1H), 8.10 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.90 (m, 2H), 7.57 (m, 1H), 7.53 (d, J = 3.0 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 6.38 (s, 1H), 3.88 (s, 3H).

[0163] Example 7: Synthesis of Compound 7

[0164]

[0165] Synthesis of Intermediate Ethyl 2-(5-bromofuran-2-carboxamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (a2b2):

[0166] Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (a2) (1.18 g, 5.24 mmol) and N,N-diisopropylethylamine (0.68 g, 5.24 mmol) were added to dry dichloromethane (50 mL). 5-Bromofuran-2-carbonyl chloride (1.10 g, 5.24 mmol) was slowly added dropwise under ice bath conditions, and then the mixture was stirred overnight at room temperature. The next day, TLC showed that the reaction was complete. Dichloromethane (50 mL) and water (50 mL) were added, and the organic layer was separated. Then it was washed with water (50 mL) again, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. Then it was slurried with petroleum ether / ethyl acetate (v / v) = 4 / 1 (10 mL), filtered and dried to obtain 1.53 g of yellow filter cake as intermediate ethyl 2-(5-bromofuran-2-carboxamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (a2b2), with a yield of 73%. 1 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.39 (d, J = 3.0 Hz, 1H), 6.92 (d, J = 3.0 Hz, 1H), 4.33 (q, J = 6.0 Hz, 2H), 2.72 (s, 2H), 2.62 (s, 2H), 1.73 (s, 3H), 1.36 (t, J = 6.0 Hz, 3H).

[0167] Synthesis of Compound 7

[0168] In a mixed solvent of toluene, ethanol and water (3:3:1, 70 mL), ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (a2b2) (0.20 g, 0.50 mmol), 3-boronic acid benzoic acid (c1) (0.09 g, 0.53 mmol), potassium carbonate (0.21 g, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (0.029 g, 0.025 mmol) were added. After replacing with nitrogen for protection, the temperature was raised to 90 °C and stirred for 7 hours. After the reaction was completed by TLC detection, the temperature was lowered, and it was clarified and layered. 6N hydrochloric acid was added to adjust the pH to 1-2, and then extracted with DCM (60 mL×2). The organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain a dark green solid. It was slurried with petroleum ether / ethyl acetate (v / v) = 2 / 1 (10 mL), filtered and dried to obtain the target compound 7, which was a dark green solid of 0.15 g, with a yield of 68%. 1 H NMR(300MHz,DMSO-d6)δ12.18(s,1H),8.46(s,1H),8.10(d,J=9.0Hz,1H),7.97(d,J=9.0Hz,1H),

[0169] 7.67-7.61(m,1H),7.45(d,J=3.0Hz,1H),7.37(d,J=3.0Hz,1H),4.39(q,J=6.0Hz,2H),2.73(s,2H),2.62(s,2H),1.73(s,4H),1.34(t,J=6.0Hz,3H).

[0170] Example 8: Synthesis of Compound 8

[0171]

[0172] In a mixed solvent of tetrahydrofuran / water (1:1, 40 mL), compound 7 (0.10 g, 0.23 mmol) and lithium hydroxide monohydrate (0.039 g, 0.91 mmol) were added, and then the temperature was raised to 50 °C and stirred for 24 hours. After the reaction was completed by TLC detection, heating was stopped, and it was cooled to room temperature. Tetrahydrofuran was removed by rotary evaporation under reduced pressure. The remaining solution was adjusted to pH = 1-2 with 6N hydrochloric acid, and a solid was precipitated. It was filtered, washed with water and dried. The obtained filter cake was slurried with petroleum ether / ethyl acetate (v / v) = 2 / 1 (10 mL), filtered and dried to obtain the target compound 8, which was a yellow-green solid of 0.08 g, with a yield of 85%. 11H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.10 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 3.0 Hz, 1H), 2.74 (s, 2H), 2.62 (s, 2H), 1.74 (s, 4H).

[0173] Example 9: Synthesis of Compound 9

[0174]

[0175] Synthesis of Intermediate 5-Bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2):

[0176] In dry dichloromethane (50 mL), 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (a3) (1.27 g, 6.45 mmol) and N,N-diisopropylethylamine (0.84 g, 6.45 mmol) were added. 5-Bromofuran-2-carbonyl chloride (1.26 g, 6.45 mmol) was slowly added dropwise under an ice bath condition, and then the mixture was stirred overnight at room temperature. The next day, after the reaction was completed as detected by TLC, dichloromethane (50 mL) and water (50 mL) were added. The organic layer was separated, then washed once with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. Then it was slurried with petroleum ether / ethyl acetate (v / v) = 4 / 1 (10 mL), filtered and dried to obtain 1.05 g of yellow filter cake as Intermediate 5-Bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2), with a yield of 44%. 1 1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.31 (d, J = 6.0 Hz, 1H), 6.89 (d, J = 6.0 Hz, 1H), 2.74 (s, 2H), 2.65 (s, 2H), 1.74 (s, 4H).

[0177] Synthesis of Compound 9:

[0178] In a mixed solvent of toluene, ethanol and water (3:3:1, 70 mL), 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) (0.20 g, 0.54 mmol), 3-boronic acid benzoic acid (0.095 g, 0.57 mmol), potassium carbonate (0.23 g, 1.63 mmol) and tetrakis(triphenylphosphine)palladium (0.032 g, 0.027 mmol) were added. After replacing with nitrogen protection, the temperature was raised to 90 °C and stirred for 9 hours. When the reaction was completed by TLC detection, the temperature was lowered, and it was clarified and layered. 6N hydrochloric acid was added to adjust the pH to 1-2, and then extracted with DCM (100 mL × 2). The organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a yellow solid. It was slurried with petroleum ether / ethyl acetate (v / v) = 2 / 1 (10 mL), filtered and dried to obtain the target compound 9, which was 0.11 g of yellow solid with a yield of 48%. 1 H NMR (300 MHz, DMSO-d6) δ 13.03 (br s, 1H), 8.38 (s, 1H), 8.09 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.41 - 7.37 (m, 2H), 2.76 (s, 2H), 2.66 (s, 2H), 1.75 (s, 4H).

[0179] Example 10: Synthesis of Compound 10

[0180]

[0181] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 5-boronic acid-2-chlorobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 10 was obtained, which was 0.16 g of white solid with a yield of 67%. 1 H NMR (300 MHz, DMSO-d6) δ 13.69 (br s, 1H), 13.01 (s, 1H), 8.22 (d, J = 3.0 Hz, 1H), 7.95 (dd, J = 9.0, 3.0 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.42 (s, 2H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0182] Example 11: Synthesis of Compound 11

[0183]

[0184] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 3-borono-4-chlorobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 11 was obtained as a light blue solid, 0.13 g, with a yield of 54%. 1 H NMR (300 MHz, DMSO-d6) δ 13.43 (br s, 1H), 12.91 (s, 1H), 8.42 (d, J = 3.0 Hz, 1H), 7.96 (dd, J = 9.0, 3.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 3.0 Hz, 1H), 2.75 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0185] Example 12: Synthesis of Compound 12

[0186]

[0187] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 5-borono-2-methoxybenzoic acid as raw materials, and using the synthesis method of Example 9, compound 12 was obtained as a light blue solid, 0.11 g, with a yield of 46%. 1 H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 12.95 (br s, 1H), 8.08 (d, J = 3.0 Hz, 1H), 7.98 (dd, J = 9.0, 3.0 Hz, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 3.90 (s, 3H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0188] Example 13: Synthesis of Compound 13

[0189]

[0190] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 4-borono-2-fluorobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 13 was obtained as a light blue solid, 0.13 g, with a yield of 56%. 11H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 7.96 (d, J = 3.0 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 2.77 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0191] Example 14: Synthesis of Compound 14

[0192]

[0193] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 5-borom-phthalic acid as raw materials, and using the synthesis method of Example 9, Compound 14 was obtained as a yellow solid, 0.13 g, with a yield of 55%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.51 (br s, 2H), 12.89 (s, 1H), 8.71 (s, 1H), 8.57 (s, 2H), 8.46 (s, 1H), 8.44 (s, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0194] Example 15: Synthesis of Compound 15

[0195]

[0196] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 5-boro-2-fluorobenzoic acid as raw materials, and using the synthesis method of Example 9, Compound 15 was obtained as a yellow solid, 0.17 g, with a yield of 73%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.56 (br s, 1H), 13.01 (s, 1H), 8.30 (dd, J = 6.0, 3.0 Hz, 1H), 8.09, 8.09 - 8.04 (m, 1H), 7.54 - 7.47 (m, 1H), 7.41 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 3.0 Hz, 1H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0197] Example 16: Synthesis of Compound 16

[0198]

[0199] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 3-boron-5-nitrobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 16 was obtained as a yellow solid, 0.12 g, with a yield of 49%. 1 H NMR (300 MHz, DMSO-d6) δ 13.93 (br s, 1H), 12.96 (s, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0200] Example 17: Synthesis of Compound 17

[0201]

[0202] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 3-boron-4-fluorobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 17 was obtained as a yellow solid, 0.13 g, with a yield of 56%. 1 H NMR (300 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.47 (dd, J = 6.0, 3.0 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.57 - 7.50 (m, 1H), 7.43 (d, J = 6.0 Hz, 1H), 7.19 (d, J = 6.0 Hz, 1H), 2.75 (s, 2H), 2.66 (s, 2H), 1.75 (s, 4H).

[0203] Example 18: Synthesis of Compound 18

[0204]

[0205] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 3-boron-5-fluorobenzoic acid as raw materials, and using the synthesis method of Example 9, compound 18 was obtained as a yellow solid, 0.14 g, with a yield of 61%. 11H NMR (300 MHz, DMSO-d6) δ 13.56 (br s, 1H), 13.05 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 9.0, 3.0 Hz, 1H), 7.69 (d, J = 9.0, 3.0 Hz, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 2.76 (s, 2H), 2.67 (s, 2H), 1.76 (s, 4H).

[0206] Example 19: Synthesis of Compound 19

[0207]

[0208] Using 2-amino-4-methylthiophene-3-carboxamide, 5-bromofuran-2-carbonyl chloride and 3-borobenzoic acid as raw materials, and using the synthesis method of Example 9, Compound 19 was obtained as a dark green solid, 0.11 g, with a yield of 49%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 12.86 (s, 1H), 8.40 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 3.0 Hz, 1H), 6.75 (s, 1H), 2.42 (s, 3H).

[0209] Example 20: Synthesis of Compound 20

[0210]

[0211] Using 2-aminothiophene-3-carboxamide, 5-bromofuran-2-carbonyl chloride and 3-borobenzoic acid as raw materials, and using the synthesis method of Example 9, Compound 20 was obtained as a gray solid, 0.22 g, with a yield of 96%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.44 (s, 1H), 8.40 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.07 (br s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.79 (br s, 1H), 7.70 - 7.65 (m, 1H), 7.51 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.07 (d, J = 6.0 Hz, 1H).

[0212] Example 21: Synthesis of Compound 21

[0213]

[0214] Using 2-aminobenzamide, 5-bromofuran-2-carbonyl chloride, and 3-borobenzoic acid as raw materials and the synthesis method of Example 9, compound 21 was obtained as a green solid (0.20 g) with a yield of 88%. 1 H NMR (300 MHz, DMSO-d6) δ 13.15 (brs, 1H), 8.55 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.16 (dd, J = 9.0, 3.0 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.76 - 7.74 (m, 1H), 7.68 - 7.62 (m, 2H), 7.55 - 7.49 (m, 1H), 7.39 (d, J = 6.0 Hz, 1H).

[0215] Example 22: Synthesis of Compound 22

[0216]

[0217] Using 2-aminobenzamide, 5-bromofuran-2-carbonyl chloride, and 3-boro-4-chlorobenzoic acid as raw materials and the synthesis method of Example 9, compound 22 was obtained as a yellowish-green solid (0.02 g) with a yield of 8%. 1 HNMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.77 (d, J = 3.0 Hz, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.94 (dd, J = 6.0, 3.0 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.77 - 7.73 (m, 3H), 7.56 - 7.50 (m, 1H), 7.49 (d, J = 6.0 Hz, 1H).

[0218] Example 23: Synthesis of Compound 23

[0219]

[0220] Using 2-aminobenzamide, 5-bromofuran-2-carbonyl chloride, and 5-boro-2-methoxybenzoic acid as raw materials and the synthesis method of Example 9, compound 23 was obtained as a dark yellow solid (0.12 g) with a yield of 49%. 11H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 3.0 Hz, 1H), 8.18 - 8.13 (m, 2H), 7.86 - 7.80 (m, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 3.90 (s, 3H).

[0221] Example 24: Synthesis of Compound 24

[0222]

[0223] Using 2-aminobenzamide, 5-bromofuran-2-carbonyl chloride and 5-boro-2-chlorobenzoic acid as raw materials, and adopting the synthesis method of Example 9, Compound 24 was obtained as a cyan solid, 0.30 g, with a yield of 92%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 3.0 Hz, 1H), 8.19 (dd, J = 6.0, 3.0 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.73 - 7.62 (m, 3H), 7.54 - 7.49 (m, 1H), 7.41 (d, J = 6.0 Hz, 1H).

[0224] Example 25: Synthesis of Compound 25

[0225]

[0226] Using intermediate 5-bromo-N-(3-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)furan-2-carboxamide (a3b2) and 4-quinolineboronic acid as raw materials, and adopting the synthesis method of Example 9, Compound 25 was obtained as an orange solid, 0.11 g, with a yield of 49%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 9.19 (d, J = 6.0 Hz, 1H), 9.05 - 9.01 (m, 1H), 8.30 - 8.23 (m, 2H), 8.07 - 8.04 (m, 2H), 7.89 (d, J = 3.0 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H), 2.78 (m, 2H), 2.69 (m, 2H), 1.77 (m, 4H).

[0227] Example 26: Synthesis of Compound 26

[0228]

[0229] Using 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide, 4-bromobenzoyl chloride and 4-quinolineboronic acid as raw materials, and using the synthesis method of Example 9, compound 26 was obtained as an orange solid, 0.12 g, with a yield of 53%. 1 H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 9.33 (d, J = 6.0 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 8.16 - 8.07 (m, 4H), 8.01 (d, J = 3.0 Hz, 1H), 7.93 - 7.89 (m, 3H), 2.78 (s, 2H), 2.69 (s, 2H), 1.78 (s, 4H).

[0230] Example 27: Synthesis of Compound 27

[0231]

[0232] Using 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide, 3-bromobenzoyl chloride and 4-quinolineboronic acid as raw materials, and using the synthesis method of Example 9, compound 27 was obtained as an orange solid, 0.11 g, with a yield of 52%. 1 H NMR (300 MHz, DMSO-d6) δ 12.74 (br s, 1H), 9.38 (d, J = 6.0 Hz, 1H), 8.49 - 8.37 (m, 3H), 8.18 - 8.10 (m, 3H), 7.96 - 7.82 (m, 3H), 2.92 (s, 2H), 2.77 (s, 2H), 1.80 (s, 4H).

[0233] Example 28: Influenza Virus Inhibition Experiment

[0234] The basic principle for testing the inhibitory activity of the compounds of the present invention against influenza virus in this example is as follows: The infection of MDCK cells by influenza virus can cause cytopathic effects and lead to cell death. The compounds inhibit the replication of the virus by inhibiting the protease function required for virus replication, thereby inhibiting the occurrence and death of cytopathic effects. The viability of cells measured by the MTT method can reflect the anti-influenza virus activity of the compounds.

[0235] Experimental Materials:

[0236] Influenza virus: A / PR / 8 / 34 (H1N1), cells: MDCK passage cells, cultured in an incubator at 35°C with 5% CO2. Standard compound: oseltamic acid, Sigma Aldrich. Cell culture: DMEM (Gibco) containing 10% FBS, 100 U / mL penicillin and streptomycin. Other reagents: TPCK trypsin (Sigma Aldrich), PBS buffer, MTT (Sigma Aldrich).

[0237] Experimental methods:

[0238] 1. Toxicity experiment of drugs on cells

[0239] The experiment was carried out in a BSL-2 laboratory. A cell control group, a blank control (DMSO solvent control) group, and groups of test drugs at different concentrations were set up. The MDCK cell suspension with a cell density of 1.5×10 5 cells / mL was seeded into a sterile 96-well culture plate, 100 μL was added to each well, and cultured in an environment of 37°C and 5% CO2 for 24 h; the culture supernatant was discarded, the monolayer cells were washed once with PBS, gradient-diluted drugs were added to each well in the test drug groups, and equal volumes of culture medium were added to each well in the cell control group and the blank control group, and cultured routinely; the supernatant was discarded, MTT solution was added to each well, and incubated for another 4 h; the supernatant was discarded, DMSO was added, and incubated at 37°C for 10 minutes to fully dissolve the crystals, and the absorbance value (OD) was measured at a wavelength of 490 nm using an enzyme-linked immunosorbent assay (ELISA) reader, and the damage rate was calculated.

[0240] Damage rate = (average OD value of the normal cell group - average OD value of the test drug group) / (average OD value of the normal cell group - average OD value of the blank control group) × 100%.

[0241] The median toxic concentration (TC50) of the drug was calculated by the Reed-Meunch method.

[0242] 2. Antiviral effect against virus-induced cytopathic effect in vitro

[0243] The experiment was carried out in a BSL-2 laboratory. A cell control group, a virus control group, and groups of test drugs at different concentrations were set up. The MDCK cell suspension with a cell density of 1.5×10 5 cells / mL was seeded into a sterile 96-well culture plate, 100 μL was added to each well, and cultured in an environment of 37°C and 5% CO2 for 24 h; the culture supernatant was discarded, 100 μL of 100 TCID50 virus solution was added to each well in the test drug groups and the virus control group, and cultured routinely for adsorption for 2 h; the culture supernatant was discarded, 100 μL of serially diluted drugs at different concentrations was added to each well, with 4 replicates for each concentration, and cultured routinely for incubation for 2 days.

[0244] The cytopathic effect (CPE) was observed under an optical microscope, and the degree of cell lesion was recorded according to the following 6-level standard: "-" indicates no cell lesion; "±" indicates less than 10% cell lesion; "+" indicates approximately 25% cell lesion; "++" indicates approximately 50% cell lesion; "+++" indicates approximately 75% cell lesion; "++++" indicates more than 75% cell lesion. The half-maximal inhibitory concentration (IC50) was calculated using GraphPad Prism 5.0.

[0245] The results are shown in Table 1 below.

[0246] Table 1: Inhibitory effects of compounds on mutant influenza viruses

[0247]

[0248] As can be seen from the above table, the compounds of the present invention all have a relatively high level of inhibitory activity against the A / PR / 8 / 34 (H1N1) virus strain. The inhibitory activities of some compounds (such as Compounds 1, 8, and 21) against the A / PR / 8 / 34 (H1N1) virus strain are higher than or equivalent to that of oseltamivir, the first-line drug for influenza (in this experiment, its in vivo metabolite oseltamic acid was used for control testing). At the same time, through cytotoxicity evaluation and comparison, the compounds of the present invention all have low cytotoxicity (MCC is 100 μM or above), and some compounds have a lower pharmacodynamic-to-toxicity ratio compared to oseltamivir (such as Compounds 1, 8, and 21), indicating that the compounds of the present invention have better drug-likeness.

[0249] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0250] The above-described embodiments merely represent several implementation manners of the present invention, and the description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims

1. An aromatic ring formyl compound having the structure shown in Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof: Wherein, R 1 Selected from: -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 ; L is selected from: -NH-, -NHCO-, -N=CH-, -NHCH2-, -O-, Ring A Selected from: one or more R-substituted or unsubstituted 5- to 10-membered heteroaryl groups, one or more R-substituted or unsubstituted C6-C 10 aryl groups; Ring B Selected from: one or more R-substituted or unsubstituted 5- to 6-membered heteroaryl groups, one or more R-substituted or unsubstituted phenyl groups; Ring C Selected from: one or more R-substituted or unsubstituted 5- to 10-membered heteroaryl groups, one or more R-substituted or unsubstituted C6-C 10 aryl groups; Each R is independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 , -NHSO2R 2 , -SO2R 2 , -COOH, -COOR 2 , -CONHR 2 , -CONR 2 R 3 , halogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, or two adjacent Rs and the atoms attached to them together form a C3-C8 cycloalkyl or 3-8 membered heteroalkyl; Each R 2 and R 3 are each independently selected from: C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycloalkyl; R 4 is a natural or non-natural amino acid residue; m is selected from: 1, 2, 3, 4, 5.

2. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 1, characterized in that, Ring A Selected from: Each X1 is independently selected from O, S, NR 7 ; Each X2 is independently selected from: CR 5 、CR 6 、N; Y is selected from: CR 5 R 6 , O, S, NR 7 ; n is selected from: 0, 1, 2, 3; R 5 and R 6 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 , -NHSO2R 2 , -SO2R 2 , -COOH, -COOR 2 , -CONHR 2 , -CONR 2 R 3 , halogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heteroalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl; R 7 Selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

3. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 2, characterized in that, Ring A Selected from: R 5 、R 6 、R 7 are each independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy; Y is selected from: O, S.

4. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 1, characterized in that, Ring B Selected from: Each X1 is independently selected from O, S, NR 7 ; R 7 Selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

5. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 4, characterized in that, Ring B Selected from:

6. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to any one of claims 1-5, characterized in that, Ring C Selected from: Each X1 is independently selected from O, S, NR 7 ; R 7 Selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkylthio-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; R 8 and R 9 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -OR 2 , -NHR 2 , -NR 2 R 3 , -NHSO2R 2 , -SO2R 2 , -COOH, -COOR 2 , -CONHR 2 , -CONR 2 R 3 , a halogen, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group, a C1-C6 alkyl group substituted with a C1-C6 alkylthio group, a C1-C6 alkyl group substituted with a C1-C6 alkylamino group, a C3-C8 cycloalkyl group, a 3-8 membered heteroalkyl group, a C6-C 10 aryl group, a 5-10 membered heteroaryl group; Preferably, R 8 and R 9 at least one of them is a carboxyl group.

7. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 1, characterized in that, The aromatic ring formyl compound has the structure shown in Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X: wherein, R 1 is selected from: -NH2, -OH, C1-C3 alkoxy groups; Each X1 is independently selected from: O, S; Each X2 is independently selected from: CH, N; Y is selected from: CH2, O, S; n is selected from: 0, 1, 2, 3; R 5 、R 6 are each independently selected from: -H, halogen, C1-C3 alkyl, C1-C3 alkoxy; R 8 and R 9 are each independently selected from: -H, -CN, -NO2, -NH2, -OH, -COOH, -COOR 2 , halogen, C1-C3 alkyl, C1-C3 alkoxy; R 2 is selected from: C1-C3 alkyl.

8. The aromatic ring formyl compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule according to claim 1, characterized in that, The aromatic ring formyl compound is selected from the following compounds:

9. Use of the aromatic ring formyl compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof in the preparation of a drug for preventing or treating influenza virus infection; preferably, the influenza virus is an influenza A virus.

10. A pharmaceutical composition for preventing or treating influenza virus infection, characterized in that, Prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, and the active ingredient comprises the aromatic ring formyl compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

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