Naphthalene sulfonamide derivatives and their medical use

Abstract

The present application relates to the formula I shown with the promotion of mitochondrial fusion naphthalene sulfonamide derivatives and its use in the preparation of treating mitochondrial dynamic disorder caused by disease drugs and pharmaceutical compositions containing them. Wherein, X is C or N or O atom; Y is N or O or S atom; represents a single bond or double bond; represents a single bond or double bond; R1, R2 are each independently hydrogen or benzene ring, wherein the benzene ring is optionally substituted with 1, 2, 3, 4 or 5 R3 which are the same or different, R3 are each independently selected from the following groups: halogen, alkyl, alkoxy, phenyl.

Description

Technical Field

[0001] This invention relates to naphthalenesulfonamide derivatives that promote mitochondrial fusion and their use in the preparation of medicaments for treating diseases caused by mitochondrial dynamic disorders and pharmaceutical compositions containing them. Background Technology

[0002] Mitochondria are central to regulating cellular energy homeostasis and fate determination. They maintain normal function through continuous fusion and division, and excessive fragmentation due to an imbalance between fusion and division is a significant marker of many human diseases. The molecular machines mediating mitochondrial fusion and division are all members of the dynamin superfamily, with mitochondrial outer membrane fusion being executed by mitochondrial fusionins (MFN1 and MFN2). Abnormal mitochondrial dynamics are closely associated with the development of various diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases. In these diseases, mitochondria often exhibit morphological abnormalities, functional decline, and impaired interactions with other organelles. Mutations in MFN2 lead to various inherited neurodegenerative diseases such as Charcot-Marie-Tooth disease (CMT2A). Given the prevalence of mitochondrial fragmentation in various pathological conditions, the controllable enhancement of mitochondrial fusion capacity holds broad application prospects. Therefore, the development of small molecule compounds that promote mitochondrial fusion is crucial for the treatment of mitochondrial-related diseases and is a highly anticipated and urgently needed frontier direction in life science and biomedical research. Summary of the Invention

[0003] This invention relates to compounds having mitochondrial fusion-promoting effects as shown in Formula I, Ia, Ib, Ic or Id, their racemic or optical isomers, their solvates, or pharmaceutically acceptable salts thereof, and their use in the preparation of medicaments for treating metabolic syndromes and pharmaceutical compositions containing them.

[0004] 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.

[0005]

[0006] in,

[0007] X is a C, N, or O atom;

[0008] Y represents N, O, or S atoms;

[0009] Represents a single or double bond;

[0010] Represents a single or double bond;

[0011] 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.

[0012] 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.

[0013] 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.

[0014]

[0015] in,

[0016] X is a C, N, or O atom;

[0017] Y represents N, O, or S atoms;

[0018] Represents a single or double bond;

[0019] Represents a single or double bond;

[0020] R1 is hydrogen or a benzene ring, wherein the benzene ring is optionally substituted by 1, 2, 3 or 4 identical or different R3 groups, each of which is independently selected from the following groups: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0021] 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.

[0022]

[0023] in,

[0024] 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 of which is independently selected from the following groups: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0025] 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.

[0026]

[0027] in,

[0028] R3 is one, two, three or four identical or different substituents that may be present on the benzene ring, each of which is independently selected from the following groups: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0029] 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.

[0030]

[0031] in,

[0032] 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 of which is independently selected from the following groups: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0033] 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.

[0034]

[0035] in,

[0036] R3 is one, two, three or four identical or different substituents that may be present on the benzene ring, each of which is independently selected from the following groups: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0037] 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.

[0038] 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.

[0039] 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: halogen, C1-8 alkyl, C1-8 alkoxy, phenyl.

[0040] 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: halogen, C1-6 alkyl, C1-6 alkoxy, phenyl.

[0041] 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: halogen, C1-4 alkyl, C1-4 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 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.

[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 each independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, methoxy, phenyl.

[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 above applicable embodiments, 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, C1-8 alkyl, C1-8 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 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: halogen, C1-4 alkyl, C1-4 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 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.

[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 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.

[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 a halogen.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a C1-8 alkyl group.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a C1-8 alkoxy group.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is 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 a C1-6 alkyl group.

[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 C1-6 alkoxy group.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a C1-4 alkyl group.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is a C1-4 alkoxy 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 fluorine.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is chlorine.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is bromine.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is iodine.

[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 above applicable embodiments, wherein R1 is independently hydrogen or a benzene ring, and R3 is methyl.

[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 trifluoromethyl.

[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 a methoxy group.

[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 phenyl.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0069] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0070] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0071] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0072] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0073] 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.

[0074] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0075] 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, C1-4 alkyl, C1-4 alkoxy, phenyl.

[0076] 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.

[0077] In this invention, the substitution position of R3 on the ring is as follows:

[0078]

[0079] 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:

[0080] N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 1)

[0081] N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 2)

[0082] N-{5-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 3)

[0083] N-{5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 4)

[0084] N-(5-{[3,5-di(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 5)

[0085] N-{5-[(4-methoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 6)

[0086] N-{5-[(3,5-dimethoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 7)

[0087] N-{5-[(4-biphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 8)

[0088] N-{5-[(4-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 9)

[0089] N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 10)

[0090] N-{5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 11)

[0091] N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 12)

[0092] N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 13)

[0093] N-{5-[(4-iodophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 14)

[0094] N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 15)

[0095] N-[(5-diphenylmethyl)-1,3,4-oxadiazol-2-yl]naphthalene-1-sulfonamide (compound 16)

[0096] N-{5-[(4-bromophenyl)methyl]-1,3-triazol-2-yl}naphthyl-1-sulfonamide (compound 17)

[0097] N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 18)

[0098] N-[5-(4-trifluoromethyl)benzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 19)

[0099] N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 20)

[0100] N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 21)

[0101] N-[5-(2,4-dichlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 22)

[0102] N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 23)

[0103] N-{[5-(4-biphenyl)methyl]thiazolyl-2-yl}naphthalene-1-sulfonamide (compound 24)

[0104] The compound of Formula 1 described in the first aspect of the present invention can be prepared using conventional synthetic routes as needed.

[0105] 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:

[0106]

[0107] 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:

[0108]

[0109] 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:

[0110]

[0111] 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.

[0112] The third aspect of this invention relates to the use of compounds of formula I, Ia, Ib, Ic, or Id, stereoisomers thereof, prodrugs and pharmaceutically active metabolites thereof, pharmaceutically acceptable salts, solvates, hydrates thereof, or pharmaceutical compositions of the third aspect of this invention in the preparation of medicaments for the treatment and / or prevention of diseases caused by mitochondrial dynamic disorders. The diseases caused by mitochondrial dynamic disorders include, but are not limited to, neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases.

[0113] The fourth aspect of this invention relates to the use of compounds of formula I, Ia, Ib, Ic, or Id, their stereoisomers, their prodrugs and pharmaceutically active metabolites, their pharmaceutically acceptable salts, solvates, hydrates, or pharmaceutical compositions of the third aspect of this invention, in medicaments for the treatment and / or prevention of diseases caused by mitochondrial dynamic disorders. The diseases caused by mitochondrial dynamic disorders include, but are not limited to, neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases.

[0114] The fifth aspect of this invention relates to a method for treating and / or preventing diseases or conditions caused by mitochondrial dynamic disorders. 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 acceptable salt, solvate, or hydrate of any of the compounds of formula I, Ia, Ib, Ic, or Id as described in any of the first aspects of this invention. The diseases caused by mitochondrial dynamic disorders include, but are not limited to, neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases.

[0115] 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.

[0116] The various aspects and features of the present invention will be further described below.

[0117] 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.

[0118] 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.

[0119] 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 "C1-8 alkyl" refers to an alkyl group having a specified number of carbon atoms, which is straight-chain or branched, and may include its daughter groups, such as C1-6 alkyl, C1-4 alkyl, C1-3, C1-2 alkyl, C2-5 alkyl, C2-4 alkyl, 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.

[0120] As described herein, the terms “halogen,” “primary atom,” “halogenated,” etc., refer to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine.

[0121] 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.

[0122] 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.

[0123] The groups defined by the terms used in this document may also be optionally substituted with -CN, -OH, -NH2, C1-4 alkyl, C1-4 alkoxy or halogen mono- or poly-substituted.

[0124] In cases where the compound name used in this article differs from the chemical structural formula, the chemical structural formula shall prevail.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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).

[0129] In this invention, the diseases caused by mitochondrial dynamic disorder include, but are not limited to: neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases.

[0130] 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.

[0131] 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.

[0132] 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:

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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

[0139] 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.

[0140] 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.

[0141] 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.

[0142] Example 1: Preparation of N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 1)

[0143] Step A: Preparation of N-(naphthalene-1-sulfonyl)(methylthioalkyl)methylaniline

[0144] 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]+). 1H 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), 7.737.61 (m, 3H), 2.24 (s, 3H).

[0145] Step B: Preparation of N-hydroxy-N′-(naphthalene-1-sulfonyl)guanidine

[0146] 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]+). 1H 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).

[0147] Step C: Preparation of N-{5-[(4-bromophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide

[0148] 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), and 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 organic phases were combined and separated by column chromatography in 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]+). 1H 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). 13C 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.

[0149] Example 2: Preparation of N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 2)

[0150] 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 (600 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.66 (d, J = 9.3 Hz, 1H), 8.39 8.31 (m, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.10 (dd, J = 8.4, 1.6 Hz, 1H), 7.76 7.72 (m, 1H), 7.71 7.63 (m, 4H), 7.46 (d, J = 7.9 Hz, 2H), 4.29 (s, 2H). 13C 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.

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

[0152] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-chlorophenylacetic acid. After concentration under reduced pressure and drying, a white solid product was obtained with a yield of 32.9%. ESI-MS (m / z): 400.05 ([M+H]+). ¹H NMR (600MHz, DMSO-d6) δ 12.63 (s, 1H), 8.65 (d, J = 8.6Hz, 1H), 8.37 8.26 (m, 2H), 8.11 (d, J = 6.9Hz, 1H), 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). 13C 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.

[0153] Example 4: Preparation of N-{5-[(4-fluorophenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 4)

[0154] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-fluorophenylacetic acid. After concentration under reduced pressure and drying, a white solid product was obtained with a yield of 35.9%. ESI-MS (m / z): 384.08 ([M+H]+). ¹H NMR (400MHz, DMSO-d6) δ 8.65 (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).

[0155] Example 5: Preparation of N-(5-{[3,5-di(trifluoromethyl)phenyl]methyl}-1,2,4-oxadiazol-3-yl)naphthalene-1-sulfonamide (compound 5)

[0156] Following the method described above for synthesizing target compound 1, 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]+). 1H NMR (600MHz, DMSO-d6) δ 12.63 (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). 13CNMR (151MHz, DMSO-d6) δ178.13, 162.55, 137.54, 135.52, 134.13, 133.78, 131.72, 13 1.18, 130.84, 130.62, 129.66, 128.83, 127.74, 127.47, 124.72, 124.42, 121.73, 31.67.

[0157] Example 6: Preparation of N-{5-[(4-methoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 6)

[0158] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-methoxyphenylacetic acid. After concentration under reduced pressure and drying, a white solid was obtained with a yield of 30.8%. ESI-MS (m / z): 396.08 ([M+H]+). 1H NMR (600MHz, DMSO-d6) δ 12.62 (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). 13C 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.

[0159] Example 7: Preparation of N-{5-[(3,5-dimethoxyphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 7)

[0160] Following the method described above for synthesizing target compound 1, 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 with a yield of 30.1%. ESI-MS (m / z): 426.12 ([M+H]+). ¹H NMR (600MHz, DMSO-d6) δ 12.62 (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). 13C 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.

[0161] Example 8: Preparation of N-{5-[(4-biphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 8)

[0162] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with 4-biphenylacetic acid. After concentration under reduced pressure and drying, a white solid product was obtained with a yield of 51.0%. ESI-MS (m / z): 442.12 ([M+H]+). 1H NMR (600MHz, DMSO-d6) δ 12.66 (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). 13C NMR (151MHz, DMS0-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.

[0163] Example 9: Preparation of N-{5-[(4-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl}naphthalene-1-sulfonamide (compound 9)

[0164] Following the method described above for synthesizing target compound 1, p-bromophenylacetic acid in the reaction system was replaced with p-methylphenylacetic acid. After concentration under reduced pressure and drying, a white solid product was obtained with a yield of 62.6%. ESI-MS (m / z): 380.11 ([M+H]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.1 Hz, 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.

[0165] Example 10: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 10)

[0166] Step D: Preparation of 5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-amine

[0167] 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, the precipitate was dried to give a white solid product in 75.0% yield. ESI-MS (m / z): 253.99 ([M+H]+). ¹H NMR (400 MHz, DMSO-d6) δ: 7.54 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.93 (s, 2H), 4.03 (s, 2H).

[0168] Step E: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonyl

[0169] 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) δ 11.25 (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). 13CNMR (101MHz, DMSO-d6) δ164.49, 157.69, 141.47, 135.59, 134.07, 132.20, 131.7 9, 131.47, 131.40, 129.01, 128.53, 127.77, 127.21, 126.70, 126.30, 124.73, 31.08.

[0170] Example 11: Preparation of N-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide (compound 11)

[0171] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 13.77 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.71 7.68 (m, 3H), 7.65 7.61 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.18 (s, 2H). 13C 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.

[0172] Example 12: Preparation of N-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 12)

[0173] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.83 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.55 7.49 (m, 3H), 7.20 7.15 (m, 2H), 7.10

[0174] 7.04 (m, 2H), 3.82 (s, 2H). 13C 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.

[0175] Example 13: Preparation of N-{5-[(2,3-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 13)

[0176] 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-M: (m / z): 434.01 ([M+H]+). ¹H NMR (600 MHz, DMSO-d6) δ 8.82 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 7.3 Hz, 1H), 7.95 (dd, J = 24.7, 7.9 Hz, 2H), 7.56 7.47 (m, 4H), 7.30 7.27 (m, 1H), 7.23 (dd, J = 7.7, 1.6 Hz, 1H), 4.02 (s, 2H). 13C 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.

[0177] Example 14: Preparation of N-{5-[(4-iodophenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 14)

[0178] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 13.67 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 7.3, 1.3 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 8.1, 1.4 Hz, 1H), 7.67 7.56 (m, 5H), 7.04 6.99 (m, 2H), 3.91 (s, 2H). 13C 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.

[0179] Example 15: Preparation of N-{5-[(3-trifluoromethylphenyl)methyl]-1,3,4-oxadiazol-2-yl}naphthalene-1-sulfonamide (compound 15)

[0180] 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]+). 1H NMR (600MHz, DMSO-d6) δ 13.63 (s, 1H), 8.75 (d, J = 8.5Hz, 1H), 8.16 (d, J = 7.2Hz, 1H), 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.

[0181] Example 16: Preparation of N-[(5-phenylmethyl)-1,3,4-oxadiazol-2-yl)naphthalene-1-sulfonamide (compound 16)

[0182] 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. E:I-MS (m / z): 442.12 ([M+H]+). ¹H NMR (600 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.13 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.55-7.51 (m, 3H), 7.37 (d, J = 7.5 Hz, 1H), 7.26-7.19 (m, 6H), 7.14-7.10 (m, 4H), 5.44 (s, 1H).

[0183] Example 17: Preparation of N-{5-[(4-bromophenyl)methyl]-1,3-triazol-2-yl}naphthalene-1-sulfonamide (compound 17)

[0184] Step F: Preparation of N-{5-[(4-bromophenyl)(hydroxy)methyl]-1,3-thiazolyl-2-yl} tert-butyl carbamate

[0185] 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. Subsequently, 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).

[0186] Step G: Preparation of 5-[(4-bromophenyl)methyl]-1,3-triazol-2-amine

[0187] 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]+). 1H 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).

[0188] Step H: Preparation of N-[5-(4-bromobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide

[0189] 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, separated by column chromatography with petroleum ether:ethyl acetate = 1:20, concentrated under reduced pressure and dried to give a white solid product in 51.1% yield. ESI-MS (m / z): 460.98 ([M+H]+). 1H NMR (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 (d d, J=8.3, 1.1Hz, 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). 13C 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.

[0190] Example 18: Preparation of N-[5-(4-chlorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 18)

[0191] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.69 (d, J = 8.1 Hz, 1H), 8.17 8.11 (m, 2H), 8.04 (d, J = 6.8 Hz, 1H), 7.68 7.67 (m, 1H), 7.64 7.57 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 3.89 (s, 2H). 13C 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.

[0192] Example 19: Preparation of N-[5-(4-trifluoromethyl)benzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 19)

[0193] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.14 (dd, J = 16.5, 8.4 Hz, 2H), 8.04 (dd, J = 8.1, 1.3 Hz, 1H), 7.71 7.66 (m, 3H), 7.64 7.58 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (s, 1H), 4.01 (s, 2H). 13C 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.

[0194] Example 20: Preparation of N-[5-(4-methylbenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 20)

[0195] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 21.9, 8.3 Hz, 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.

[0196] Example 21: Preparation of N-[5-(4-methoxybenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 21)

[0197] 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]+). 1H 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). 13C 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.

[0198] Example 22: Preparation of N-[5-(2,4-dichlorobenzyl)thiazolyl]naphthalene-1-sulfonamide (compound 22)

[0199] 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 (600 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.25 8.12 (m, 2H), 8.04 (d, J = 7.0 Hz, 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). 13C 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.

[0200] Example 23: Preparation of N-[5-(2-chloro-4-fluorobenzyl)thiazolyl-2-yl]naphthalene-1-sulfonamide (compound 23)

[0201] 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]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.59 (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). 13C NMR (151MHz, DMSO-d6) 6168.19, 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.

[0202] Example 24: Preparation of N-{[5-(4-biphenyl)methyl]thiazol-2-yl}naphthalene-1-sulfonamide (compound 24)

[0203] Following the method described above for synthesizing compound 17, a white solid product N-{[5-(4-biphenyl)methyl]thiazolyl-2-yl}naphthalene-1-sulfonamide was obtained in 26.9% yield. ESI-MS (m / z): 457.10 ([M+H]+). ¹H NMR (600 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.14 (dd, J = 11.8, 7.7 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.69 7.57 (m, 7H), 7.47 7.45 (m, 2H), 7.34 (dd, J = 24.5, 7.6 Hz, 3H), 7.10 (s, 1H), 3.94 (s, 2H). 13C NMR (151MHz, DMS0-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.

[0204] Example 25: Evaluation of the binding interaction between the compound and MNF1 using the MST method

[0205] MFN1 / 2-MGD or MFN1 was labeled using a monomeric protein labeling kit. Combination experiments were performed at constant concentrations of labeled MFN1 / 2-MGD or MFN1. Serial dilutions of the small molecule (0.01 nM, 0.10 nM, 1 nM, 10 nM, 100 nM, 1000 nM, 10000 nM, 10000 nM, 100000 nM) were prepared in PBS (containing 2% DMSO) and mixed with the labeled protein. The mixture was loaded onto a vector, and the fluorescence signal induced by thermophoresis was recorded. The dissociation constant (KD) was calculated using software.

[0206] Table 1. Activity evaluation results of the compounds

[0207] Example KD(nM) Example KD(nM) 1 - 13 34.23 2 - 14 - 3 - 15 16.54 4 210.34 16 - 5 5.33 17 350.62 6 13.56 18 210.15 7 - 19 - 8 - 20 3.85 9 100.32 21 23.66 10 1.21 22 - 11 - 23 18.03 12 - 24 -

[0208] - Not detected.

Claims

1. The use of the compound of Formula I, its racemic or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments for treating pneumonia caused by viral infections and pharmaceutical compositions containing them. 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 formula I according to claim 1, its racemate or optical isomer, its solvate, or a pharmaceutically or physiologically acceptable salt thereof, wherein the compound is 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}naphthalene-1-sulfonamide (compound 24) 3. The use of the compound according to claims 1 and 2, its racemate or optical isomer, its solvate, or its pharmaceutically or physiologically acceptable salt for the preparation of a medicament for the treatment of diseases caused by mitochondrial disorders and a medicament containing such ingredients.

4. The diseases caused by mitochondrial disorders are selected from neurodegenerative diseases, cancer, cardiovascular diseases, age-related diseases, and metabolic diseases.

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