N-substituted-(1, 2, 4-oxadiazole-3-yl) naphthalene-1-sulfonamide derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a compound as shown in a formula I, a stereoisomer, a prodrug and a pharmaceutically active metabolite thereof, pharmaceutically acceptable salt, a solvate and a hydrate thereof, a pharmaceutical composition containing the compound, and application of the compound in preparation of medicines for preventing and / or treating diseases or symptoms related to virus infection.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an N-substituted-(1,2,4-oxadiazol-3-yl)naphthyl-1-sulfonamide derivative and its use in the preparation of drugs for the prevention and / or treatment of viral diseases caused by various viruses. Background Technology

[0002] Viral infection and transmission pose a serious threat to human health and public health security. In the World Health Organization's 2019 list of the "Top Ten Global Health Threats," viruses occupied almost half of the spots, including influenza virus, Ebola virus, dengue virus, and human immunodeficiency virus (HIV). In January 2020, the novel coronavirus disease 2019 (COVID-19) broke out in China, and on March 11, the World Health Organization officially declared it a global pandemic. Furthermore, recent outbreaks of influenza and monkeypox viruses have also posed significant challenges to human life. Looking back over the past two decades, every viral infectious disease that has spread widely worldwide has dealt a fatal blow to humanity.

[0003] Faced with the fierce onslaught of viruses against humanity, we must take effective prevention and control measures. Currently, prevention and control measures against viruses can be mainly divided into two categories: pharmaceutical interventions (PHIs) and non-pharmaceutical interventions (NPIs). NPIs are primarily obtained by constructing epidemiological models of viruses and are typically used to develop quarantine measures and isolation protocols that align with disease trends. Their aim is to effectively control the spread of the virus and are suitable for the early stages of a pandemic. PHIs mainly include immunization, represented by vaccines, and drug therapy related to antiviral drugs. Vaccine development is characterized by its long development time, high difficulty, and high risk, making it more suitable for long-term prevention against known pathogens. Clinical drugs, due to their ease of storage and production, have become the main means of preventing and controlling viral infections, especially suitable for emergency control during sudden outbreaks. Therefore, the research and development of antiviral drugs has become a key area of ​​focus for medicinal chemists.

[0004] Antiviral therapies can be broadly categorized into virus-targeting drugs and host-targeting drugs. Currently, most first-line antiviral therapies target the virus's own structure, working by interfering with its replication cycle. However, in actual clinical use, these drugs have gradually revealed various drawbacks (lack of broad-spectrum activity, susceptibility to drug resistance, etc.). Therefore, developing highly effective, drug-resistant, and broad-spectrum antiviral drugs has become a major challenge in antiviral drug development.

[0005] Clathrin plays a crucial role not only in the transport of substances in the human body, but also in the entry of many viruses into the body via clathrin-mediated endocytosis (CME). These viruses include dengue virus and hepatitis C virus from the Flaviviridae family, rhinovirus type 2 and enteroviruses from the Picornaviridae family, as well as well-known viruses such as human immunodeficiency virus, Ebola virus, and hantavirus, covering almost all viral types. Because host-targeted antiviral strategies are not affected by the virus's own structure, clathrin is considered a highly promising target for broad-spectrum antiviral drugs.

[0006] In CME, clathrin, adaptor protein (AP-2), and dynamin are all essential key molecules. Currently, the mechanism of viral clathrin-mediated endocytosis is relatively well understood. The entire endocytosis process can be roughly divided into four stages: 1) nucleation of clathrin-coated pits; 2) capture in coated pits by transporters; 3) bending and invagination of the cell membrane; and 4) vesicle scission and uncoating.

[0007] Therefore, inhibiting clathrin can block viral clathrin-mediated endocytosis into cells. The purpose of this invention is to synthesize novel clathrin formulations for use in the preparation of broad-spectrum antiviral drugs for the prevention and / or treatment of viral diseases caused by various viruses. Summary of the Invention

[0008] The technical problem solved by this invention is to provide a compound as shown in Formula I, Ia, Ib, Ic or Id, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, and to provide its use in the preparation of medicaments for treating virus-related diseases.

[0009] The first aspect of this invention relates to compounds of Formula I, their stereoisomers, their prodrugs and pharmaceutically active metabolites, their pharmaceutically acceptable salts, solvates, and hydrates.

[0010]

[0011] in,

[0012] X is a C, N, or O atom;

[0013] Y represents N, O, or S atoms;

[0014] Represents a single or double bond;

[0015] Represents a single or double bond;

[0016] R1 and R2 are each independently hydrogen or benzene rings, wherein the benzene rings are optionally substituted by 1, 2, 3, 4 or 5 identical or different R3 groups, each of which is independently selected from the following groups: halogen, alkyl, alkoxy, phenyl.

[0017] In a preferred embodiment of the present invention, the compound of formula I, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, wherein R1 and R2 are not simultaneously hydrogen.

[0018] In a preferred embodiment of the present invention, the compound of formula I, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above may be a compound of formula Ia.

[0019]

[0020] in,

[0021] X is a C, N, or O atom;

[0022] Y represents N, O, or S atoms;

[0023] Represents a single or double bond;

[0024] Represents a single or double bond;

[0025] R1 is a hydrogen atom or a benzene ring, wherein the benzene ring is optionally substituted by 1, 2, 3, or 4 identical or different R3 groups, each R3 being independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0026] In a preferred embodiment of the present invention, the compound of formula I can be a compound of formula Ib, Ic, or Id, its stereoisomers, its prodrugs and active metabolites, its pharmaceutically acceptable salts, solvates, or hydrates.

[0027]

[0028] in,

[0029] R1 is independently hydrogen or a benzene ring, and R3 is 1, 2, 3, or 4 identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0030] In another preferred embodiment of the present invention, the compound of formula I can be a compound of formula Ib, or a stereoisomer thereof, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, or hydrate.

[0031]

[0032] in,

[0033] R3 is one, two, three, or four identical or different substituents optionally present on the benzene ring, each R3 independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0034] In another preferred embodiment of the present invention, the compound of formula I can be the compound shown in formula Ic, or its stereoisomers, its prodrugs and active metabolites, its pharmaceutically acceptable salts, solvates, or hydrates.

[0035]

[0036] in,

[0037] R1 is independently hydrogen or a benzene ring, and R3 is 1, 2, 3, or 4 identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0038] In another preferred embodiment of the present invention, the compound of formula I can be the compound shown in formula Id, or its stereoisomers, its prodrugs and active metabolites, its pharmaceutically acceptable salts, solvates, or hydrates.

[0039]

[0040] in,

[0041] R3 is one, two, three, or four identical or different substituents optionally present on the benzene ring, each R3 independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0042] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a substituent optionally present on the ring.

[0043] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is two identical or different substituents optionally present on the ring.

[0044] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is each independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0045] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is each independently selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl.

[0046] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is each independently selected from the following groups: halogen, C 1-4 Alkyl, C1-4 Alkoxy, phenyl.

[0047] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is each independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, phenyl.

[0048] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is each independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, methoxy, phenyl.

[0049] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is one, two or three identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

[0050] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is one or two identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0051] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is one or two identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, phenyl.

[0052] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is one or two identical or different substituents optionally present on the benzene ring, each R3 being independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, methoxy, phenyl.

[0053] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a halogen.

[0054] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-8 alkyl.

[0055] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-8 Alkyl group.

[0056] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is phenyl.

[0057] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-6 alkyl.

[0058] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-6 Alkyl group.

[0059] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-4 alkyl.

[0060] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the applicable embodiments described above, wherein R1 is independently hydrogen or a benzene ring, and R3 is C 1-4 Alkyl group.

[0061] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is fluorine.

[0062] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is chlorine.

[0063] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is bromine.

[0064] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is iodine.

[0065] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is methyl.

[0066] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is trifluoromethyl.

[0067] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a methoxy group.

[0068] In another preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is phenyl.

[0069] In a preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 is optionally monosubstituted at the 4-position of the benzene ring.

[0070] In a preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is optionally disubstituted at positions 2 and 3 on the benzene ring.

[0071] In a preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is optionally disubstituted at positions 2 and 4 on the benzene ring.

[0072] In a preferred embodiment of the invention, the compound represented by formula I, Ia, Ib, Ic or Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is optionally disubstituted at the 3 and 5 positions on the benzene ring.

[0073] In a preferred embodiment of the present invention, the compound of formula Ib, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, and R3 optionally contains one or two identical or different substituents, each R3 being independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0074] In a preferred embodiment of the present invention, the compound of formula Ib, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, R3 is a substituent optionally present on the benzene ring, monosubstituted at the 4-position on the benzene ring, and R3 is selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0075] In a preferred embodiment of the present invention, the compound of formula Ib, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, R3 is two identical or different substituents optionally present on the benzene ring, with disubstituted at positions 3 and 5 on the benzene ring, and each R3 is independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0076] In a preferred embodiment of the present invention, the compound represented by formula Ic, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, and R3 optionally contains one or two identical or different substituents, each R3 being independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0077] In a preferred embodiment of the present invention, the compound represented by formula Ic, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen or a benzene ring, R3 is a substituent optionally present on the benzene ring, monosubstituted at the 4-position on the benzene ring, and R3 is selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0078] In a preferred embodiment of the present invention, the compound represented by formula Ic, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the above-applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, R3 is two identical or different substituents optionally present on the benzene ring, with double substitution at positions 2 and 3 on the benzene ring, and each R3 is independently selected from the following groups: halogens.

[0079] In a preferred embodiment of the present invention, the compound represented by formula Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, and R3 optionally contains one or two identical or different substituents, each R3 being independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0080] In a preferred embodiment of the present invention, the compound represented by formula Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, R3 is a substituent optionally present on the benzene ring, monosubstituted at the 4-position on the benzene ring, and R3 is selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl.

[0081] In a preferred embodiment of the present invention, the compound represented by formula Id, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or any of the embodiments applicable above, wherein R1 is independently hydrogen, R3 is two identical or different substituents optionally present on the benzene ring, with disubstituted at positions 2 and 4 on the benzene ring, and each R3 is independently selected from the following groups: halogens.

[0082] In this invention, the substitution position of R3 on the ring is as follows:

[0083]

[0084] In a preferred embodiment of the present invention, the compound represented by Formula I, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, are selected from the following compounds:

[0085] N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (Compound 1)

[0086] N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 2)

[0087] N-{5-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 3)

[0088] N-{5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 4)

[0089] N-(5-{[3,5-di(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 5)

[0090] N-{5-[(4-methoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 6)

[0091] N-{5-[(3,5-dimethoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 7)

[0092] N-{5-[(4-biphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 8)

[0093] N-{5-[(4-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 9)

[0094] N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 10)

[0095] N-{5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 11)

[0096] N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 12)

[0097] N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 13)

[0098] N-{5-[(4-iodophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 14)

[0099] N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 15)

[0100] N-[(5-diphenylmethyl)-1,3,4-oxadiazol-2-yl]naphthalene-1-sulfonamide (compound 16)

[0101] N-{5-[(4-bromophenyl)methyl]-1,3-triazol-2-yl}naphthyl-1-sulfonamide (compound 17)

[0102] N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 18)

[0103] N-[5-(4-trifluoromethyl)benzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 19)

[0104] N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 20)

[0105] N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 21)

[0106] N-[5-(2,4-dichlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 22)

[0107] N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 23)

[0108] N-{[5-(4-biphenyl)methyl]thiazolyl-2-yl}naphthalene-1-sulfonamide (compound 24)

[0109] The compound of Formula 1 described in the first aspect of the present invention can be prepared using conventional synthetic routes as needed.

[0110] In a preferred embodiment of the invention, compounds of formula Ib, their racemic or optical isomers, their pharmaceutically acceptable salts, solvates, and hydrates can be prepared, exemplarily, via the following reaction route:

[0111]

[0112] In a preferred embodiment of the invention, the compound of formula Ic, its racemic or optical isomer, its pharmaceutically acceptable salt, solvate, or hydrate can be prepared, exemplarily, via the following reaction route:

[0113]

[0114] In a preferred embodiment of the invention, the compound of formula Id, its racemic or optical isomer, its pharmaceutically acceptable salt, solvate, or hydrate can be prepared, exemplarily, via the following reaction route:

[0115]

[0116] The second aspect of the invention relates to pharmaceutical compositions comprising at least a compound of formula I, Ia, Ib, Ic or Id as described in any of the first aspects of the invention, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, and one or more pharmaceutically acceptable carriers or excipients.

[0117] The third aspect of this invention relates to the use of compounds, stereoisomers, prodrugs and pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, hydrates, or pharmaceutical compositions of any of the formulas I, Ia, Ib, Ic, or Id described in any of the first aspects of this invention in the preparation of medicaments for treating and / or preventing diseases or conditions associated with viral infections. The viral infections described include, but are not limited to, infections caused by viruses such as rhinovirus, enterovirus (e.g., EV71), cardiac viruses, hepatitis viruses, influenza viruses, SARS viruses, Ebola viruses, hemorrhagic fever viruses, and human immunodeficiency viruses. The diseases or conditions associated with viral infections described are selected from respiratory diseases (including, but not limited to, the common cold (summer cold), pharyngitis, tonsillitis, and membranous laryngitis), digestive diseases, hemorrhagic fever, meningitis / encephalitis, immunodeficiency diseases, hepatitis, hand-foot-mouth disease, neurological diseases (including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis), neurogenic pulmonary edema, etc.

[0118] The fourth aspect of this invention relates to compounds of formula I, Ia, Ib, Ic, or Id as described in any of the first aspects of this invention, their stereoisomers, their prodrugs and pharmaceutically active metabolites, their pharmaceutically acceptable salts, solvates, hydrates, or pharmaceutical compositions as described in the third aspect of this invention, wherein said compounds, their racemic or optical isomers, their pharmaceutically acceptable salts, solvates, hydrates, or pharmaceutical compositions are used to treat and / or prevent diseases or conditions associated with viral infections. The viral infections described include, but are not limited to: rhinoviruses, enteroviruses (e.g., EV71), cardiac viruses, hepatitis viruses, influenza viruses, SARS viruses, Ebola viruses, hemorrhagic fever viruses, and human immunodeficiency viruses.

[0119] The fifth aspect of this invention relates to a method for treating and / or preventing diseases or conditions associated with viral infection. The method comprises administering to a subject in need a therapeutic and / or preventative effective amount of at least one compound body, stereoisomer, prodrug, or pharmaceutically active metabolite of formula I, Ia, Ib, Ic, or Id as described in any of the first aspects of this invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The viral infections described include, but are not limited to, infections caused by viruses such as rhinovirus, enterovirus (e.g., EV71), cardiac virus, hepatitis virus, influenza virus, SARS virus, Ebola virus, hemorrhagic fever virus, and human immunodeficiency virus. The diseases or conditions associated with viral infection described are selected from respiratory diseases (including, but not limited to, the common cold (summer cold), pharyngitis, tonsillitis, and membranous laryngitis), digestive diseases, hemorrhagic fever, meningitis / encephalitis, immunodeficiency diseases, hepatitis, hand-foot-and-mouth disease, neurological diseases (including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis), and neurogenic pulmonary edema.

[0120] Features of any aspect or sub-aspect of the present invention are equally applicable to any other aspect or sub-aspect of the other aspect. In the present invention, for example, when referring to "first aspect of the present invention," "any sub-aspect" means any sub-aspect of the first aspect of the present invention, and has the same meaning when referred to in other aspects in a similar manner.

[0121] The various aspects and features of the present invention will be further described below.

[0122] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still intends to provide a more detailed description and explanation of these terms and phrases. In the event of any inconsistency between the terms and phrases mentioned and their known meanings, the meanings expressed in this invention shall prevail.

[0123] As described herein, the term "pharmaceutically acceptable" means, for example, when describing "pharmaceutically acceptable salt," that the salt is not only physiologically acceptable to the subject, but can also refer to a synthetic substance that has pharmaceutical value.

[0124] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group, preferably having 1-12 carbon atoms, more preferably having 1-10, 1-8, 1-6, 1-4, or 1-3 carbon atoms. The term "C" refers to a saturated straight-chain or branched monovalent hydrocarbon group. 1-8 "Alkyl" refers to an alkyl group having a specified number of carbon atoms, which is either straight-chain or branched, and may include its daughter groups, such as C16, C26, C36, C46, ​​C56, C66, C66, C7 ... 1-6 Alkyl, C 1-4 Alkyl, C 1-3 C 1-2 Alkyl, C2-5 Alkyl, C 2-4 Alkyl groups, etc. Typical examples of "alkyl" include, but are not limited to, methyl, ethyl-n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl-neopentyl, hexyl, heptyl, octyl, etc.

[0125] As described herein, the terms “halogen,” “primary atom,” “halogenated,” etc., refer to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine.

[0126] As used herein, the term "haloalkyl" refers to an alkyl group that is mono- or poly-substituted with a halogen such as fluorine, chlorine, bromine, or iodine. Preferred haloalkyl groups are chloromethyl, chloroethyl, dichloroethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, etc.

[0127] As used herein, the term "alkoxy" refers to the group -OR, where R is an alkyl group as defined herein. Typical examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc.

[0128] The groups defined by the terms mentioned above may also optionally be replaced by -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkyl or halogen mono or polysubstituted.

[0129] In cases where the compound name used in this article differs from the chemical structural formula, the chemical structural formula shall prevail.

[0130] As described herein, the term "effective dose" refers to a dose that can achieve treatment and / or prevention of the disease or condition described in this invention in a subject.

[0131] As described herein, the term "pharmaceutical composition" can also refer to a "composition" that can be used to treat and / or prevent the diseases or conditions described herein in subjects, particularly mammals.

[0132] As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, larynx, cattle, horse, etc., that receives a compound of Formula I of the present invention or a pharmaceutical composition thereof to treat and / or prevent the disease or condition described herein.

[0133] As stated herein, unless otherwise specified, "%" refers to weight / weight percentage, especially in the case of describing solid substances. Of course, in the case of describing liquid substances, the "%" may refer to weight / volume percentage (for solids dissolved in liquids) or volume / volume percentage (for liquids dissolved in liquids).

[0134] In this invention, the viral infections include, but are not limited to, infections caused by viruses such as rhinovirus, enterovirus (e.g., EV71), cardiac virus, hepatitis virus, influenza virus, SARS virus, Ebola virus, hemorrhagic fever virus, and human immunodeficiency virus, with infections caused by influenza virus being preferred.

[0135] In this invention, the diseases or symptoms related to viral infection are selected from respiratory diseases (including but not limited to: the common cold (summer cold), pharyngitis, tonsillitis, and membranous laryngitis), digestive diseases, hemorrhagic fever, meningitis / encephalitis, immunodeficiency diseases, hepatitis, hand-foot-mouth disease, nervous system diseases (including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis), neurogenic pulmonary edema, etc.

[0136] In one embodiment of the present invention, a method for preventing and / or treating diseases related to viral infections, including rhinovirus, enterovirus (e.g., EV71), cardiac virus, hepatitis virus, influenza virus, SARS virus, Ebola virus, hemorrhagic fever virus, and human immunodeficiency virus, is provided, comprising administering a preventive and / or therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof or its hydrate to a patient requiring prevention and / or treatment of diseases related to viral infections, including rhinovirus, enterovirus (e.g., EV71), cardiac virus, hepatitis virus, influenza virus, SARS virus, Ebola virus, hemorrhagic fever virus, and human immunodeficiency virus.

[0137] The compounds of this invention are a novel class of broad-spectrum antiviral inhibitors. A key feature of this class of compounds is their ability to treat diseases caused by viruses such as rhinovirus, enterovirus (e.g., EV71), cardiac viruses, hepatitis viruses, influenza viruses, SARS viruses, Ebola viruses, hemorrhagic fever viruses, and human immunodeficiency viruses. These viral diseases include, but are not limited to: respiratory diseases, digestive diseases, hemorrhagic fever, meningitis / encephalitis, immunodeficiency diseases, hepatitis, hand-foot-and-mouth disease, neurological diseases (including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis), and neurogenic pulmonary edema.

[0138] The respiratory conditions mentioned include, but are not limited to: the common cold (summer cold), pharyngitis, tonsillitis, and membranous laryngitis.

[0139] According to the present invention, the pharmaceutical composition of the compounds of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, cavity, buccal, vaginal, or topical administration. Extra-enteric administration includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or administration via an external implantation device. Oral, intraperitoneal, or intravenous administration is preferred. Furthermore, to ensure the effective treatment of central nervous system disorders by the compounds of the present invention, intraventricular administration is preferred to overcome the potentially low blood-brain barrier permeability of the compounds.

[0140] When taken orally, the compounds of this invention can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Tablets typically use lactose and corn starch as carriers, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use lactose and dried corn starch as diluents. Aqueous suspension formulations usually involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral dosage forms.

[0141] When used rectally, the compounds of this invention are generally formulated as suppositories, which are prepared by mixing the drug with a suitable non-irritating excipient. This excipient is solid at room temperature but melts and releases the drug at rectal temperatures. Such excipients include cocoa butter, beeswax, and polyethylene glycol. When used topically, particularly for treating affected areas or organs easily accessible by topical application, such as ocular skin or lower bowel neurological disorders, the compounds of this invention can be formulated into different topical formulations depending on the affected area or organ, as detailed below:

[0142] When applied topically to the eyes, the compounds of this invention can be formulated as a micronized suspension or solution, using an isotonic sterile saline solution of a specific pH as the carrier, with or without preservatives. Furthermore, for ophthalmic use, the compounds can also be formulated as an ointment, such as petrolatum.

[0143] When applied topically to the skin, the compounds of this invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers suitable for ointments include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified waxes, and water; carriers suitable for lotions or creams include, but are not limited to, mineral oil-dehydrated sorbitol monostearate, Tween 60, hexadecane wax, hexadecene aromatic alcohol, 2-octyldecane alcohol, alcohols, and water.

[0144] When applied topically to the intestines, the compounds of the present invention can be formulated as rectal suppositories or suitable enema formulations as described above, or they can also be used as topical transdermal patches.

[0145] The compounds of this invention can also be administered in sterile injectable formulations, including sterile water or oil suspensions or sterile injectable solutions. Suitable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils, such as monoglycerides or diglycerides, can also be used as solvents or suspension media.

[0146] As described herein, a “therapeutic effective amount” means, within reasonable medical judgment, an amount sufficient to treat or prevent a patient’s disease while avoiding serious side effects at a sufficiently low level (within a reasonable benefit / risk ratio). The therapeutic effective amount of a compound will vary depending on the specific compound chosen (e.g., considering the compound’s potency, effectiveness, and half-life), the chosen route of administration, the disease being treated, the severity of the disease being treated, the patient’s age, size, weight, and physical condition, the patient’s medical history, the duration of treatment, the nature of concurrent therapies, the desired therapeutic effect, and other factors, but can still be routinely determined by those skilled in the art.

[0147] It should also be noted that the specific dosage and method of administration of the compounds of this invention for different patients depend on many factors, including the patient's age, weight, sex, natural health condition, nutritional status, the activity intensity of the compound, the time of administration, the metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 1-100 mg / kg body weight / day. Detailed Implementation

[0148] The present invention can be further described through the following embodiments and test examples. However, the scope of the present invention is not limited to the following embodiments or test examples. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from the spirit and scope thereof. The present invention provides a general and / or specific description of the materials and test methods used in the tests. Although many materials and operating methods used to achieve the objectives of the present invention are known in the art, the present invention is still described in as much detail as possible herein.

[0149] For all the following examples, standard operating and purification methods known to those skilled in the art were used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). All solvents used in the reactions, unless otherwise specified, were standardized and pretreated.

[0150] The technical solution of the present invention will be described in detail below with reference to the specific embodiments. However, it should be understood that the present invention is not limited to the specific examples described below.

[0151] Example 1: Preparation of N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 1)

[0152] Step A: Preparation of N-(naphthalene-1-sulfonyl)(methylthioalkyl)methylaniline

[0153] A mixed solution of S-methylisothiourea hydrochloride (0.39 g, 2.77 mmol) and sodium hydroxide (2.00 mL, 2 mol / L) was stirred uniformly at 0 °C. 1-Naphthalenesulfonyl chloride (0.31 g, 1.39 mmol) dissolved in dichloromethane (15.00 mL) was slowly added to the reaction system, resulting in a milky white precipitate. After the addition was complete, the low-temperature reaction apparatus was removed, and stirring continued for 30 minutes at room temperature. After the reaction was complete, the reaction solution was concentrated, and the residue was extracted with dichloromethane, separated by column chromatography with petroleum ether:ethyl acetate (5:1), concentrated under reduced pressure, and dried to obtain a white solid with a yield of 90.3%. ESI-MS (m / z): 281.04 ([M+H)). + ). 1 H NMR (400MHz, DMSO-d6) δ 8.68 (d, J=8.6Hz, 1H), 8.23 ​​(dd, J=7.3, 1.2Hz, 1H), 8.19 (d, J=8.3Hz, 1H), 8.06 (d, J=8.0Hz, 1H), 7.73-7.61 (m, 3H), 2.24 (s, 3H).

[0154] Step B: Preparation of N-hydroxy-N′-(naphthalene-1-sulfonyl)guanidine

[0155] The reaction intermediate N-(naphthalene-1-sulfonyl)(methylthioalkyl)methylaniline (0.33 g, 1.18 mmol) was added to a solution of anhydrous methanol (10.00 mL) containing hydroxylamine hydrochloride (0.82 g, 11.78 mmol) and triethylamine (1.97 mL, 14.14 mmol). The mixture was heated to reflux and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was extracted with ethyl acetate, followed by separation by dichloromethane:methanol (10:1) column chromatography. The residue was concentrated under reduced pressure and dried to give a white solid in 87.1% yield. ESI-MS (m / z): 266.06 ([M+H)). + ). 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 9.35 (s, 1H), 8.74 (d, J=8.1Hz, 1H), 8.14 (dd, J=7.3, 1.2Hz, 1H), 8.11 (d, J=8.3Hz, 1H), 8.02 (d, J=7.7Hz, 1H), 7.66-7.55 (m, 3H).

[0156] Step C: Preparation of N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide

[0157] N-hydroxy-N′-(naphthalene-1-sulfonyl)guanidine (0.15 g, 0.55 mmol), HOBt (0.11 g, 0.82 mmol), EDCI (0.16 g, 0.85 mmol), Et3N (0.24 mL, 1.65 mmol), and p-bromophenylacetic acid (0.18 g, 0.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (5.00 mL). The mixture was heated to reflux at 90 °C and stirred for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and water and ethyl acetate were added to separate the two phases. The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were separated by column chromatography with acetone:petroleum ether (3:1). The solution was concentrated under reduced pressure and dried to give a white solid in 66.7% yield. ESI-MS (m / z): 446.00 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 8.65 (d, J = 7.8Hz, 1H), 8.41-8.23 (m, 2H), 8.11 (d, J = 8.1Hz, 1H), 7.76-7.73 (m, 1H), 7.71-7.66 (m, 2H), 7.50 (d, J=8.2Hz, 2H), 7.21-7.15 (m, 2H), 4.15 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ178.61, 162.64, 135.53, 134.15, 133.80, 133.55, 131 .93, 131.82, 129.68, 128.86, 127.74, 127.48, 124.88, 124.42, 121.04, 31.69.

[0158] Example 2: Preparation of N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 2) Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-trifluoromethylphenylacetic acid. After concentration under reduced pressure and drying, a white solid was obtained, with a yield of 31.9%. ESI-MS (m / z): 434.08 ([M+H) + ). 1H NMR (600MHz, DMSO-d6) δ12.65 (s, 1H), 8.66 (d, J = 9.3Hz, 1H), 8.39-8.31 (m, 1H), 8.29 (d, J = 8.2Hz, 1H), 8.10 (dd, J=8.4, 1.6Hz, 1H), 7.76-7.72 (m, 1H), 7.71-7.63 (m, 4H), 7.46 (d, J=7.9Hz, 2H), 4.29 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ178.41, 162.64, 138.93, 135.53, 134.15, 133.78, 131.83, 130.63, 129.67, 128.85, 127.74, 127.47, 125.90, 125.87, 124.86, 124.41, 32.07.

[0159] Example 3: Preparation of N-{5-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 3)

[0160] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-chlorophenylacetic acid. The mixture was concentrated under reduced pressure and dried to obtain a white solid product with a yield of 32.9%. ESI-MS (m / z): 400.05 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 8.65 (d, J = 8.6Hz, 1H), 8.37-8.26 (m, 2H), 8.11 (d, J = 6.9Hz, 1 H), 7.76-7.74 (m, 1H), 7.72-7.65 (m, 2H), 7.37 (d, J=8.4Hz, 2H), 7.24 (d, J=8.5Hz, 2H), 4.17 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ178.68, 162.64, 135.53, 134.15, 133.81, 131.81, 131.57, 129.68, 129.00, 128.85, 127.74, 127.48, 124.88, 124.42, 31.62.

[0161] Example 4: Preparation of N-{5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 4)

[0162] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-fluorophenylacetic acid. The mixture was concentrated under reduced pressure and dried to obtain a white solid product in 35.9% yield. ESI-MS (m / z): 384.08 ([M+H)). + ). 1 H NMR (400MHz, DMSO-d6) δ8.65 (d, J=7.8Hz, 1H), 8.35-8.26 (m, 2H), 8.10 (d, J=8. 0Hz, 1H), 7.77-7.64(m, 3H), 7.29-7.20(m, 2H), 7.16-7.09(m, 2H), 4.15(s, 2H).

[0163] Example 5: Preparation of N-(5-{[3,5-di(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 5)

[0164] Following the method described above for synthesizing target compound 1, the p-bromophenylacetic acid in the reaction system was replaced with 3,5-bis(trifluoromethyl)phenylacetic acid. After drying, a white solid product was obtained, with a yield of 33.3%. ESI-MS (m / z): 502.07 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 8.64 (d, J=8.6Hz, 1H), 8.36-8.24 (m, 2H), 8.10 (d, J=8.1Hz, 1H), 8.06 (d, J=10.8Hz, 3H), 7.75-7.72 (m, 1H), 7.70-7.58 (m, 2H), 4.42 (s, 2H). 13 CNMR (151MHz, DMSO-d6) δ178.13, 162.55, 137.54, 135.52, 134.13, 133.78, 131.72, 131 .18, 130.84, 130.62, 129.66, 128.83, 127.74, 127.47, 124.72, 124.42, 121.73, 31.67.

[0165] Example 6: Preparation of N-{5-[(4-methoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 6)

[0166] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-methoxyphenylacetic acid. The mixture was concentrated under reduced pressure and dried to obtain a white solid in 30.8% yield. ESI-MS (m / z): 396.08 ([M+H)). + ).1 H NMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 8.67 (d, J = 8.8Hz, 1H), 8.35 (d, J = 7.5Hz, 1H), 8.29 (d, J = 8.3Hz, 1H), 8.10 (d, J = 8. 3Hz, 1H), 7.76-7.73 (m, 1H), 7.72-7.65 (m, 2H), 7.11 (d, J=8.7Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 4.06 (s, 2H), 3.71 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ179.31, 162.63, 158.93, 135.53, 134.15, 133.82, 131.81 , 130.66, 129.68, 128.85, 127.48, 125.88, 124.90, 124.42, 114.48, 55.54, 31.53.

[0167] Example 7: Preparation of N-{5-[(3,5-dimethoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 7) Following the method described above for the synthesis of target compound 1, the p-bromophenylacetic acid in the reaction system was replaced with 3,5-bis(methoxy)phenylacetic acid. The mixture was concentrated under reduced pressure and dried to give a white solid, yield 30.1%. ESI-MS (m / z): 426.12 ([M+H) + ). 1 HNMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 8.66 (d, J = 8.6Hz, 1H), 8.32 (d, J = 7.4Hz, 1H), 8.28 (d, J = 8.2Hz, 1H) , 8.10 (d, J=7.6Hz, 1H), 7.76-7.73 (m, 1H), 7.70-7.66 (m, 2H), 6.39-6.37 (m, 3H), 4.06 (s, 2H), 3.67 (s, 6H). 13 C NMR (151MHz, DMSO-d6) δ178.74, 162.69, 160.99, 136.08, 135.51, 134.15, 133.88, 131.7 0, 129.67, 128.83, 127.74, 127.47, 124.87, 124.44, 107.71, 99.44, 55.62, 40.54, 32.49.

[0168] Example 8: Preparation of N-{5-[(4-biphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 8)

[0169] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with 4-biphenylacetic acid. The mixture was concentrated under reduced pressure and dried to obtain a white solid product in 51.0% yield. ESI-MS (m / z): 442.12 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.66 (s, 1H), 8.68 (d, J = 9.2Hz, 1H), 8.35 (d, J = 7.3Hz, 1H), 8.30 (d, J = 8.1Hz, 1H), 8.11 (d, J = 8.3Hz, 1H), 7.77-7.70 (m, 2H), 7.69-7.66 (m, 1H), 7.63 (d, J=8.1Hz, 2H), 7.59 (d, J=8.1Hz, 2H), 7. 47-7.45 (m, 2H), 7.38-7.35 (m, 1H), 7.30 (d, J=8.2Hz, 2H), 4.20 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ178.98, 162.67, 140.16, 135.55, 134.16, 133.81, 133.29, 131.83, 130.18, 129.69, 129.41, 128.87, 127.96, 127.49, 127.39, 127.11, 124.91, 124.42, 31.99.

[0170] Example 9: Preparation of N-{5-[(4-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 9)

[0171] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid was replaced with p-methylphenylacetic acid in the reaction system. The mixture was concentrated under reduced pressure and dried to obtain a white solid product in 62.6% yield. ESI-MS (m / z): 380.11 ([M+H)). + ). 1 HNMR (600MHz, DMSO-d6) δ12.60 (s, 1H), 8.65 (d, J = 8.6Hz, 1H), 8.33 (d, J = 7.4Hz, 1H), 8.30 (d, J = 8.2Hz, 1H) , 8.11 (d, J = 8.1Hz, 1H), 7.78-7.72 (m, 1H), 7.72-7.65 (m, 2H), 7.10-7.06 (m, 4H), 4.08 (s, 2H), 2.25 (s, 3H). 13C NMR (151MHz, DMSO-d6) δ179.12, 162.64, 136.93, 135.53, 133.82, 131.78, 131.01 , 129.68, 129.63, 129.39, 128.85, 127.74, 127.48, 124.89, 124.41, 31.97, 21.09.

[0172] Example 10: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 10)

[0173] Step D: Preparation of 5-[(4-bromophenyl)methyl]-1,3,4-oxadiazole-2-amine

[0174] Aminourea hydrochloride (2.07 g, 18.60 mmol) and p-bromophenylacetic acid (2.00 g, 9.30 mmol) were dissolved in phosphorus oxychloride (25.00 mL), and the mixture was heated to reflux at 80 °C with stirring for 30 minutes. After heating, stirring was continued for 5 hours. The reaction flask was placed in an ice bath, and a 50% sodium hydroxide solution was slowly added to alkalinize the reaction solution to pH 7-8. The mixture was filtered under reduced pressure, and the resulting precipitate was recrystallized from anhydrous ethanol. After concentration under reduced pressure and drying, a white solid product was obtained, with a yield of 75.0%. ESI-MS (m / z): 253.99 ([M+H)). + ). 1 H NMR (400MHz, DMSO-d6) δ: 7.54 (d, J=8.4Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 6.93 (s, 2H), 4.03 (s, 2H).

[0175] Step E: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonyl

[0176] 5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-amine (0.67 g, 2.64 mmol) and 1-naphthalenesulfonyl chloride (0.60 g, 2.64 mmol) were dissolved in chloroform (5.00 mL), and pyridine (1.32 mL) was added. The mixture was stirred at room temperature for 48 hours. After the reaction was stopped, the reaction solution was concentrated, and the residue was extracted with dichloromethane and washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The combined organic phases were separated by column chromatography in a dichloromethane:methanol ratio of 10:1. The solution was concentrated under reduced pressure and dried to give a white solid in 30.2% yield, with a melting point of 208-210 °C. ESI-MS (m / z): 444.00 ([M+H)). + ). 1H NMR (600MHz, DMSO-d6) δ11.25 (s, 1H), 8.81 (s, 1H), 8.09 (d, J=7.2Hz, 1H), 7.99-7.92 (m, 1H), 7.84 ( d, J=8.1Hz, 1H), 7.60-7.40 (m, 5H), 7.23 (dd, J=8.2, 5.0Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 3.16 (s, 2H). 13 CNMR (101MHz, DMSO-d6) δ164.49, 157.69, 141.47, 135.59, 134.07, 132.20, 131.79 , 131.47, 131.40, 129.01, 128.53, 127.77, 127.21, 126.70, 126.30, 124.73, 31.08.

[0177] Example 11: Preparation of N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide (compound 11)

[0178] Following the method described above for synthesizing compound 10, a white solid product, N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide, was obtained in 29.8% yield. ESI-MS (m / z): 434.09 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ13.77 (s, 1H), 8.66 (d, J = 8.6Hz, 1H), 8.26 (d, J = 7.2Hz, 1H), 8.18 (d, J = 8.2Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.71-7.68 (m, 3H), 7.65-7.61 (m, 2H), 7.50 (d, J=8.0Hz, 2H), 4.18 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ158.27, 156.64, 138.30, 137.63, 134.23, 133.92, 130.55, 129.16, 128.18, 128.12, 127.70, 127.19, 125.95, 125.93, 125.89, 124.83, 31.01.

[0179] Example 12: Preparation of N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 12)

[0180] Following the method described above for synthesizing compound 10, a white solid product, N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide, was obtained in 52.1% yield. ESI-MS (m / z): 384.0816 ([M+H]). + ). 1 H NMR (600MHz, DMSO-d6) δ11.21 (s, 1H), 8.83 (d, J = 9.2Hz, 1H), 8.11 (d, J = 7.2Hz, 1H), 7.98 (d, J = 8.2H z, 1H), 7.93 (d, J=7.7Hz, 1H), 7.55-7.49 (m, 3H), 7.20-7.15 (m, 2H), 7.10-7.04 (m, 2H), 3.82 (s, 2H). 13 C NMR (101MHz, DMSO-d6) δ164.50, 158.05, 141.46, 134.08, 131.40, 131.08, 131 .00, 129.01, 128.54, 127.79, 127.22, 126.71, 126.31, 124.75, 115.77, 30.88.

[0181] Example 13: Preparation of N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 13)

[0182] Following the method described above for synthesizing compound 10, a white solid product, N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide, was obtained in 28.4% yield. ESI-MS (m / z): 434.01 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ8.82 (d, J=8.3Hz, 1H), 8.08 (d, J=7.3Hz, 1H), 7.95 (dd, J=24.7, 7. 9Hz, 2H), 7.56-7.47 (m, 4H), 7.30-7.27 (m, 1H), 7.23 (dd, J=7.7, 1.6Hz, 1H), 4.02 (s, 2H). 13 C NMR (101MHz, DMSO-d6) δ164.48, 156.48, 141.38, 136.42, 134.06, 131.40, 130.43, 129.85, 129.00, 128.65, 128.54, 127.81, 127.21, 126.71, 126.29, 124.70, 30.67.

[0183] Example 14: Preparation of N-{5-[(4-iodophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 14)

[0184] Following the method described above for synthesizing compound 10, a white solid product, N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide, was obtained in 28.5% yield. ESI-MS (m / z): 491.99 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ13.67 (s, 1H), 8.71 (d, J=8.4Hz, 1H), 8.17 (dd, J=7.3, 1.3Hz, 1H), 8.09 ( d, J=8.2Hz, 1H), 8.00 (dd, J=8.1, 1.4Hz, 1H), 7.67-7.56 (m, 5H), 7.04-6.99 (m, 2H), 3.91 (s, 2H). 13 C NMR (101MHz, DMSO-d6) δ158.17, 139.32, 137.82, 134.44, 134.19, 132.83, 131 .80, 128.92, 128.56, 127.77, 127.53, 126.83, 126.47, 124.84, 93.66, 30.99.

[0185] Example 15: Preparation of N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 15)

[0186] Following the method described above for synthesizing compound 10, a white solid product, N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide, was obtained in 26.4% yield. ESI-MS (m / z): 434.08 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ13.63 (s, 1H), 8.75 (d, J = 8.5Hz, 1H), 8.16 (d, J = 7.2Hz, 1 H), 8.06 (d, J=8.2Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 7.67-7.47 (m, 7H), 4.07 (s, 2H). 13C NMR (101MHz, DMSO-d6) δ160.91, 158.00, 139.74, 136.36, 134.17, 133.70, 132.57, 130 .08, 128.84, 128.66, 127.77, 127.35, 126.71, 126.63, 126.13, 124.76, 124.38, 31.12.

[0187] Example 16: Preparation of N-[(5-phenylmethyl)-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide (compound 16)

[0188] Following the method described above for synthesizing compound 10, a white solid product, N-[(5-phenylmethyl)-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide, was obtained in 29.6% yield. ESI-MS (m / z): 442.12 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ8.82 (s, 1H), 8.13 (d, J = 7.1Hz, 1H), 8.00 (d, J = 8.1Hz, 1H), 7.95 (d, J = 8.6Hz , 1H), 7.55-7.51 (m, 3H), 7.37 (d, J=7.5Hz, 1H), 7.26-7.19 (m, 6H), 7.14-7.10 (m, 4H), 5.44 (s, 1H).

[0189] Example 17: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3-triazol-2-yl}naphthalene-1-sulfonamide (compound 17)

[0190] Step F: Preparation of N-{5-[(4-bromophenyl)(hydroxy)methyl]-1,3-thiazolyl-2-yl} tert-butyl carbamate

[0191] 2-(N-tert-butyl carboxylate)aminothiazole (0.20 g, 1.00 mmol) was dissolved in anhydrous tetrahydrofuran (5.00 mL). Under nitrogen protection at -78 °C, 2.5 mol / L n-butyllithium (0.88 mL, 2.20 mmol) was slowly added. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. Then, a solution of p-bromobenzaldehyde (0.22 g, 1.20 mmol) dissolved in anhydrous tetrahydrofuran (5.00 mL) was added. After the addition was complete, the mixture was stirred for another 16 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, separated by dichloromethane:methanol (100:1) column chromatography, concentrated under reduced pressure, and dried to give a white solid in 41.1% yield. ESI-MS (m / z): 387.01 ([M+H)). + ). 1H NMR (600MHz, DMSO-d6) δ11.30 (s, 1H), 7.54 (d, J=8.4Hz, 2H), 7.35 (d, J=8.5Hz , 2H), 7.14 (s, 1H), 6.24 (d, J=4.3Hz, 1H), 5.89 (d, J=4.3Hz, 1H), 1.45 (s, 9H).

[0192] Step G: Preparation of 5-[(4-bromophenyl)methyl]-1,3-triazol-2-amine

[0193] N-{5-[(4-bromophenyl)(hydroxy)methyl]-1,3-thiazolyl-2-yl} tert-butyl carbamate (0.19 g, 0.50 mmol), trifluoroacetic acid (0.52 mL, 6.94 mmol), and triethylsilane (0.63 mL, 3.97 mmol) were dissolved in dichloromethane (20.00 mL) and stirred at room temperature for 16 hours. The reaction was stopped, the reaction solution was concentrated, and the residue was extracted with dichloromethane, washed with saturated NaHCO3 solution, and then separated by dichloromethane:methanol = 100:1 column chromatography. The product was concentrated under reduced pressure and dried to give a pale yellow solid product in 82.1% yield. ESI-MS (m / z): 270.96 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ7.48 (d, J=8.3Hz, 2H), 7.17 (d, J=8.3Hz, 2H), 6.74 (s, 2H), 6.70 (s, 1H), 3.87 (s, 2H).

[0194] Step H: Preparation of N-[5-(4-bromobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide

[0195] 5-[(4-bromophenyl)methyl]-1,3-triazol-2-amine (0.53 g, 1.96 mmol) and 1-naphthalenesulfonyl chloride (0.45 g, 1.96 mmol) were dissolved in chloroform (12.00 mL), and pyridine (1.00 mL) was added. The mixture was stirred at room temperature for 48 hours. The residue was extracted with dichloromethane, washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride solution, and separated by column chromatography with petroleum ether:ethyl acetate (1:20). The product was concentrated under reduced pressure and dried to give a white solid product in 51.1% yield. ESI-MS (m / z): 460.98 ([M+H) + ). 1HNMR (400MHz, DMSO-d6) δ8.67 (dd, J=8-7, 1.1Hz, 1H), 8.15 (d, J=8.3Hz, 1H), 8.12 (dd, J=7.3, 1.2Hz, 1H), 8.04 ( dd, J=8.3, 1.1H, 1H), 7.69-7.57 (m, 3H), 7.50 (d, J=8.5Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 7.07 (s, 1H), 3.87 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.35, 138.67, 137.34, 134.30, 133.64, 131.98, 131.16, 129.13, 128.21, 127.91, 127.67, 127.15, 126.24, 124.77, 124.68, 121.51, 32.15.

[0196] Example 18: Preparation of N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 18)

[0197] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 35.2% yield. ESI-MS (m / z): 415.03 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.56 (s, 1H), 8.69 (d, J = 8.1Hz, 1H), 8.17-8.11 (m, 2H), 8.04 (d, J = 6.8Hz, 1H), 7.6 8-7.67 (m, 1H), 7.64-7.57 (m, 2H), 7.37 (d, J=8.4Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 7.06 (s, 1H), 3.89 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.35, 138.24, 137.34, 134.30, 133.63, 131.93, 130.77, 129.13, 129.06, 128.22, 127.91, 127.67, 127.15, 126.24, 124.77, 121.48, 32.10.

[0198] Example 19: Preparation of N-[5-(4-trifluoromethyl)benzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 19)

[0199] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(4-trifluoromethylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 36.8% yield. ESI-MS (m / z): 449.06 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.59 (s, 1H), 8.68 (d, J=8.2Hz, 1H), 8.14 (dd, J=16.5, 8.4Hz, 2H), 8.04 (dd, J= 8.1, 1.3Hz, 1H), 7.71-7.66 (m, 3H), 7.64-7.58 (m, 2H), 7.47 (d, J=8.0Hz, 2H), 7.11 (s, 1H), 4.01 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.37, 144.11, 137.31, 134.30, 133.64, 129.73, 129.13, 128.21, 128 .08, 127.92, 127.67, 127.15, 126.23, 126.00, 125.97, 125.66, 124.76, 124.11, 121.85, 32.49.

[0200] Example 20: Preparation of N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 20)

[0201] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 21.4% yield. ESI-MS (m / z): 395.09 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.52 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 8.13 (dd, J=21.9, 8.3Hz, 2H), 8.03 (d, J=8.3 Hz, 1H), 7.68-7.67 (m, 1H), 7.64-7.56 (m, 2H), 7.16-7.08 (m, 4H), 7.03 (s, 1H), 3.83 (s, 2H), 2.27 (s, 3H). 13C NMR (151MHz, DMSO-d6) δ168.32, 136.35, 136.09, 134.30, 133.60, 129.68, 129.12, 128 .76, 128.22, 127.90, 127.64, 127.14, 126.25, 125.71, 124.77, 120.98, 32.52, 21.11.

[0202] Example 21: Preparation of N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 21)

[0203] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 29.5% yield. ESI-MS (m / z): 411.08 ([M+H)). + ). 1 H NMR (600MHz, DMSO-d6) δ12.51 (s, 1H), 8.69 (d, J=8.5Hz, 1H), 8.18-8.12 (m, 2H), 8.06-8.02 (m, 1H), 7.67-7.54 (m, 3H), 7.30-7.23 (m, 1H), 7.17-7.12 (m, 2H), 7.04-7.00 (m, 1H), 6.89-6.84 (m, 2H), 3.81 (s, 2H), 3.73 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ168.31, 158.58, 134.30, 133.60, 131.02, 129.95, 129.12 , 127.90, 127.64, 127.14, 126.26, 126.09, 124.77, 120.82, 114.50, 55.50, 32.08.

[0204] Example 22: Preparation of N-[5-(2,4-dichlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 22)

[0205] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(2,4-dichlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 23.3% yield. ESI-MS (m / z): 448.99 ([M+H)). + ). 1H NMR (600MHz, DMSO-d6) δ12.61 (s, 1H), 8.69 (d, J=8.5Hz, 1H), 8.25-8.12 (m, 2H), 8.04 (d, J =7.0Hz, 1H), 7.68-7.67(m, 1H), 7.65-7.59(m, 3H), 7.42(s, 2H), 7.03(s, 1H), 3.99(s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.20, 137.34, 135.70, 134.29, 133.66, 133.05, 132.64, 129.43, 129.13, 128.28, 128.21, 127.92, 127.64, 127.15, 126.22, 124.77, 122.77, 122.05, 30.25.

[0206] Example 23: Preparation of N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 23)

[0207] Following the method described above for synthesizing compound 17, a white solid product, N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide, was obtained in 22.8% yield. ESI-MS (m / z): 433.02 ([M+H]). + ). 1 H NMR (600MHz, DMSO-d6) δ12.59 (s, 1H), 8.69 (s, 1H), 8.19-8.10 (m, 2H), 8.08-8.02 (m, 1H), 7.68- 7.66 (m, 1H), 7.65-7.58 (m, 2H), 7.50-7.42 (m, 2H), 7.23-7.21 (m, 1H), 7.02 (s, 1H), 3.98 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.19, 137.34, 134.30, 133.66, 132.73, 129.14, 128.20, 127.92, 127.64, 127.16, 126.21, 124.77, 123.21, 121.85, 117.15, 115.23, 30.09.

[0208] Example 24: Preparation of N-{[5-(4-biphenyl)methyl]thiazolyl-2-yl}naphthalene-1-sulfonamide (compound 24)

[0209] Following the method described above for synthesizing compound 17, a white solid product, N-{[5-(4-biphenyl)methyl]thiazol-2-yl}naphthalene-1-sulfonamide, was obtained in 26.9% yield. ESI-MS (m / z): 457.10 ([M+H) + ). 1 H NMR (600MHz, DMSO-d6) δ12.56 (s, 1H), 8.69 (d, J=8.5Hz, 1H), 8.14 (dd, J=11.8, 7.7Hz, 2H), 8.03 (d, J=8. 0Hz, 1H), 7.69-7.57 (m, 7H), 7.47-7.45 (m, 2H), 7.34 (dd, J=24.5, 7.6Hz, 3H), 7.10 (s, 1H), 3.94 (s, 2H). 13 C NMR (151MHz, DMSO-d6) δ168.34, 140.28, 138.46, 137.36, 133.62, 129.47, 129.39, 129.13, 127.91, 127.86, 127.67, 127.44, 127.15, 127.08, 126.25, 125.25, 124.78, 121.30, 32.49.

[0210] The chemical names and structural formulas of compounds 1-24 prepared in Examples 1-24 are shown in the table below.

[0211]

[0212]

[0213]

[0214] Example 25: Cytotoxicity test of the test compound

[0215] The cytotoxicity of the compounds was investigated at the cellular level using the MTT assay based on MDCK cells. MDCK cells were seeded in growth medium in 96-well microtiter plates and cultured under the following conditions: 5% CO2, 37°C. After 24 h of culture, the culture medium was removed, and different concentrations of the compound (100 μM, 50 μM, 25 μM, and 12.5 μM, with three replicates for each concentration) were added. A blank control group (containing only an equal volume of culture medium, without the compound) was also included. The plates were cultured for another 24 h. Finally, 20 μL of a 5 mg / mL solution was added. -1Incubate the cells in MTT phosphate-buffered saline solution for 3 hours. Remove the culture medium, add 100 μL of DMSO to each well, shake, and read the absorbance (OD) value using an enzyme-linked immunosorbent assay (ELISA) analyzer to calculate the inhibitory rate of the compound on the cells. Inhibition rate of the compound on cells = (Absorbance of the control group - Absorbance of the experimental group) / Absorbance of the control group.

[0216] The inhibition rate-concentration curve was fitted using Origin 8.0 plotting software, and its CC was calculated. 50 value.

[0217] Table 1. Cytotoxicity tests of the target compounds

[0218] Compound numbering CC 50 (μM) 1 134.58 2 139.26 3 134.08 4 NT 5 31.30 6 ＞200 7 ＞200 8 125.61 9 ＞200 10 NT 11 145.17 12 ＞200 13 152.18 14 139.05 15 146.01 16 NT 17 22.62 18 25.10 19 30.22 20 25.46 21 183.32 22 19.67 23 21.99 24 146.53

[0219] NT = not test

[0220] Example 26: Inhibitory activity of the test compound against influenza virus

[0221] The anti-influenza virus activity of some target compounds was tested using the standard plaque method. Influenza virus PR / 8 (H1N1) was used as the test virus strain. The test compounds were dissolved in DMSO and diluted with culture medium to a concentration of 100 μM. Dimethyl sulfoxide was used as a blank control.

[0222] MDCK cells were seeded at a specific concentration into 96-well cell culture plates and cultured for 24 hours at 37°C with 5% CO2. After removing the culture medium, PR / 8 (H1N1) influenza virus was inoculated into MDCK cells and allowed to adsorb at 37°C for 2 hours. The virus solution was then discarded. Different concentrations of the test compound were added, with each concentration tested in triplicate. A virus control group (infected with the virus but without the compound) was set up and cultured for another 24 hours at 37°C. The number of virus strains in the cells was determined using the standard plaque assay for MDCK cells, and the virus survival rate was calculated. Virus survival rate = (number of virus strains in the experimental group / number of virus strains in the control group) × 100%.

[0223] Using Origin 8.0 plotting software, an S-shaped curve was fitted to the "inhibition rate-concentration" relationship to calculate the half-maximal inhibitory concentration (IC50) of the compound against the virus. 50 ).

[0224] The inhibitory activity of the compounds of the present invention against influenza virus was determined according to the above method, and the results are shown in the table below.

[0225] Table 2 Results of the assay of the target compound's activity against influenza virus

[0226]

[0227]

[0228] NT = not test

[0229] The results of the test results on the inhibitory activity of the target compounds against influenza virus PR / 8 (H1N1) show that the compounds of the present invention can significantly reduce the survival rate of influenza virus and effectively inhibit the activity of influenza virus. Among them, compounds 17 and 22 have very strong inhibitory activity against influenza virus.

[0230] Example 27: Inhibitory activity of the compounds of the present invention on transferrin receptor internalization

[0231] The test compound was serially diluted from 400 μM in cell maintenance medium, resulting in four concentration gradients (2-fold increments). Alexa 568-transferrin was diluted to 80 μg / mL using PBS buffer. HeLa cells were seeded into 96-well plates, 100 μL per well. Experimental, positive, and blank control groups were established, with 50 μL of different concentrations of the test compound, Pitstop2, and DMSO added to each group, respectively. Cells were cultured overnight after serum removal before administration. After administration, cells were incubated at 37°C with 5% CO2 for 15 minutes. Then, 50 μL of diluted Alexa 568-transferrin was added, and incubation continued for another 15 minutes. The final volume of each test well was 200 μL, and the administered concentration was 0.25 times the pretreatment concentration. After incubation, the cells were first washed twice with live-cell imaging solution, then fixed with pre-cooled anhydrous methanol for 30 minutes. Hoechst 33342 nucleic acid dye was then added, and cell state and transferrin internalization levels were observed under a fluorescence microscope. Nine images were then taken from each well, fluorescence values ​​were recorded, and inhibition rates were calculated.

[0232] Table 2. Inhibitory effects of different concentrations of compounds on clathrin-regulated transferrin endocytosis.

[0233]

[0234]

[0235] In this context, "++" represents an inhibition rate of 50%-100%, and "+" represents an inhibition rate of 30%-50%.

[0236] The inhibition experiment of transferrin endocytosis by the test target compounds showed that all the test target compounds could inhibit transferrin from entering cells.

[0237] Example 28: Binding ability test of the compound of the present invention with clathrin

[0238] Power on the Reichert 2SPR instrument according to standard operating procedures, and prepare PBST buffer and PBST solution containing 1% DMSO. Begin chip installation, installing the carboxymethyl dextran hydrogel chip according to standard procedures. Prepare to begin the formal experiment; the buffer will flush the entire internal flow path system at a high flow rate. Then, activate the chip using EDC / NHS, preparing a sufficient volume of clathrin and blocking buffer (PBST solution containing 1% DMSO). Start the coupling program: coupling time 7 minutes, flow rate 10 μL / min, final clathrin coupling amount approximately 6000 RU (Ch1 channel). After immobilizing the protein with ethanolamine (pH = 8.5), begin sample detection. Set the analyte binding time to 80 s, flow rate 30 μL / min; dissociation time to 120 s, flow rate 30 μL / min; allow for natural dissociation without analyte regeneration. Prepare the corresponding samples to be detected as required, and start the automatic detection program. Analyze the results; perform data fitting analysis based on the results to obtain the final affinity fitting KD value.

[0239] Table 3. Binding effects of different concentrations of compounds on clathrin.

[0240] Compound numbering KD(M) 1 3.21 x 10 -4 ]] 2 6.94 x 10 -5 ]] 3 1.32 x 10 -4 ]]> 4 2.66 x 10 -4 ]] 5 4.06 x 10 -4 ]] 6 5.37 x 10 -4 ]]> 7 1.73 x 10 -3 ]]> 8 2.41 x 10 -3 ]]> 9 3.12 x 10 -4 ]]> 10 9.05 x 10 -5 ]]> 11 6.89 x 10 -5 ]]> 12 5.88 x 10 -4 ]]> 13 <![CDATA[6.64×10 -5 ]]> 14 <![CDATA[2.00×10 -3 ]]> 15 <![CDATA[3.44×10 -3 ]]> 17 <![CDATA[1.37×10 -5 ]]> 18 <![CDATA[1.47×10 -5 ]]> 19 <![CDATA[2.61×10 -6 ]]> 20 <![CDATA[2.28×10 -6 ]]> 21 <![CDATA[1.48×10 -5 ]]> 22 <![CDATA[1.55×10 -4 ]]> 23 <![CDATA[4.54×10 -5 ]]> 24 <![CDATA[3.14×10 -5 ]]>

[0241] NT: not test

[0242] The binding results of the test target compounds to clathrin show that compounds 2, 10, 11, 13, 17, 18, 19, 20, 21, 23 and 24 mentioned in this invention have a strong binding ability to clathrin.

Claims

1. The compound shown in Formula 1, its stereoisomers, its prodrugs and active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates. in, X is a C, N, or O atom; Y represents N, O, or S atoms; Represents a single or double bond; Represents a single or double bond; R1 and R2 are each independently hydrogen or benzene rings, wherein the benzene rings are optionally substituted by 1, 2, 3, 4 or 5 identical or different R3 groups, each of which is independently selected from the following groups: halogen, alkyl, alkoxy, phenyl.

2. The compound of claim 1, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, wherein the compound is a compound of formula Ia. in, X is a C, N, or O atom; Y represents N, O, or S atoms; Represents a single or double bond; Represents a single or double bond; R1 is a hydrogen atom or a benzene ring, wherein the benzene ring is optionally substituted by 1, 2, 3, 4, or 5 identical or different R3 groups, each of which is independently selected from the following groups: halogen, carbon, hydrogen, carbon ... 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

3. The compound of claim 1, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, wherein the compound is a compound represented by formula Ib, Ic, or Id. in, R1 is independently hydrogen or a benzene ring, and R3 is independently selected from the following groups: halogen, C 1-8 Alkyl, C 1-8 Alkoxy, phenyl.

4. The compound of any one of claims 1-3, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, wherein, R1 is independently hydrogen or a benzene ring, and R3 is one, two, or three identical or different substituents optionally present on the benzene ring, wherein R3 is independently selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl. Preferably, R3 is one or two identical or different substituents optionally present on the benzene ring, and R3 is independently selected from the following groups: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl. Furthermore, R3 is one or two identical or different substituents optionally present on the benzene ring, and R3 is independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, phenyl. More preferably, R3 is one or two identical or different substituents optionally present on the benzene ring, and R3 is independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, methoxy, phenyl.

5. The compound of any one of claims 1-4, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, selected from: N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (Compound 1) N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 2) N-{5-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 3) N-{5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 4) N-(5-{[3,5-di(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 5) N-{5-[(4-methoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 6) N-{5-[(3,5-dimethoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 7) N-{5-[(4-biphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 8) N-{5-[(4-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 9) N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 10) N-{5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 11) N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 12) N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 13) N-{5-[(4-iodophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 14) N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 15) N-[(5-diphenylmethyl)-1,3,4-oxadiazol-2-yl]naphthalene-1-sulfonamide (compound 16) N-{5-[(4-bromophenyl)methyl]-1,3-triazol-2-yl}naphthyl-1-sulfonamide (compound 17) N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 18) N-[5-(4-trifluoromethyl)benzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 19) N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 20) N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 21) N-[5-(2,4-dichlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 22) N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 23) N-{[5-(4-biphenyl)methyl]thiazolyl-2-yl}naphthyl-1-sulfonamide (compound 24).

6. A pharmaceutical composition comprising at least one compound according to any one of claims 1-5, its stereoisomer, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, hydrate, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of the compound of any one of claims 1-5, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating and / or preventing diseases or conditions associated with viral infection.

8. The compound of any one of claims 1-5, its stereoisomer, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, hydrate, or the pharmaceutical composition of claim 6, for the treatment and / or prevention of diseases or conditions related to viral infection.

9. A method for treating and / or preventing a disease or condition associated with a viral infection, the method comprising administering to a subject in need a therapeutically or preventively effective amount of at least one compound of any one of claims 1-5, its stereoisomer, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, or hydrate.

10. The use of claim 7, the compound of claim 8, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or the method of claim 9, wherein the viral infection includes, but is not limited to, infections caused by viruses such as rhinovirus, enterovirus (e.g., EV71), cardiac virus, hepatitis virus, hemorrhagic fever virus, influenza virus, SARS virus, Ebola virus, and human immunodeficiency virus.

11. The use of claim 7, the compound of claim 8, its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, hydrates, or the method of claim 9, wherein the disease or condition related to viral infection is selected from respiratory diseases (including but not limited to: common cold pharyngitis, tonsillitis and membranous laryngitis), digestive diseases, hemorrhagic fever, meningitis / encephalitis, immunodeficiency diseases, hepatitis, hand-foot-mouth disease, nervous system diseases (including aseptic meningitis, encephalitis and poliomyelitis-like paralysis), neurogenic pulmonary edema, etc.

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