New use of a class of compounds in the inhibition of alpha-1,6-fucosyltransferase

Abstract

The present invention provides a new use of a class of compounds in the inhibition of alpha-1,6-fucosyltransferase. Specifically, the present invention provides the use of an active ingredient comprising one or more compounds containing the structure of - (M) n or not containing the structure of - (M) n such as NH125, chlorhexidine, sulfo-N-succinimidyl oleate, etc., or a pharmaceutically acceptable salt, isomer or mixture of isomers, solvate or crystal form thereof, as an alpha-1,6-fucosyltransferase targeted inhibitor in the treatment or prevention of related diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel use of compounds in the inhibition of α-1,6-fucosyltransferase. Background Technology

[0002] Core-fucosylation is an important post-translational modification of proteins, catalyzed by α-1,6-fucosyltransferase (FUT8). It involves the transfer of L-fucose from GDP-β-L-fucose to the innermost N-acetylglucosamine residue (N-GlcNAc) of the N-glycan, forming an α-1,6-fucosidic bond. FUT8 is the only enzyme in mammals responsible for core-fucosylation, and its aberrant expression is closely related to the development and progression of various diseases. Studies have shown that FUT8 overexpression promotes disease progression through multiple mechanisms, including: 1. Tumors: FUT8 overexpression promotes the proliferation, invasion, and metastasis of tumor cells such as metastatic melanoma, triple-negative breast cancer, and liver cancer, and reduces the immune system's recognition and attack on tumors; 2. Inflammatory diseases: FUT8 exacerbates inflammatory responses in psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease by promoting the production of inflammatory mediators; 3. Autoimmune diseases: FUT8 regulates immune responses and promotes the production of autologous core fucosylated antibodies, leading to diseases such as systemic lupus erythematosus and multiple sclerosis; 4. Viral infections: FUT8 promotes the recognition and binding of pathogens to host cells, driving viral infections such as hepatitis C virus, vesicular stomatitis virus, SARS-CoV-2, and human immunodeficiency virus; 5. Fibrotic diseases: FUT8 increases the core fucosylation level of fibrosis-related proteins, promoting the progression of diseases such as pulmonary fibrosis and peritoneal fibrosis; 6. Neurodegenerative diseases: FUT8 promotes neuroinflammation and neuronal damage, leading to neurodegenerative diseases such as Alzheimer's disease.

[0003] Although the importance of FUT8 as a therapeutic target for disease is widely recognized, there is still a lack of specific and selective FUT8 inhibitors.

[0004] In summary, there is an urgent need in this field to develop new specific and selective FUT8 inhibitors. Summary of the Invention

[0005] The purpose of this invention is to provide a new use of the compound in inhibiting FUT8 enzyme activity, thus providing a new solution for treating the aforementioned diseases.

[0006] In a first aspect of the invention, a use of a class of active ingredients is provided, characterized in that,

[0007] The active ingredient includes one or more ingredients containing -(M) nThe structure shown may not contain elements such as -(M). n - A compound with the structure shown or a pharmaceutically acceptable salt, isomer, mixture of isomers, solvates, or crystal form thereof;

[0008] in,

[0009] Each M is independently a divalent group selected from the following group: -CH2-, -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=S)O-, -NH-C(=O)-, -NH-C(=S)-, -NH-C(=NH)-, -NH-C(=NH)-NH-, -NH-C(=O)-NH-, and -NH-C(=S)-NH-;

[0010] n is an integer from 3 to 30 (preferably, an integer from 5 to 20, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 18, 19 or 20);

[0011] Furthermore, the stated use is selected from one or more uses in the group below;

[0012] (a) Preparation of α-1,6-fucosyltransferase targeting inhibitor;

[0013] (b) To prepare a medicine or pharmaceutical composition for the treatment or prevention of diseases or conditions related to the activity or expression level of α-1,6-fucosyltransferase; and

[0014] (c) Preparing a medicament or pharmaceutical composition for the treatment or prevention of tumor metastasis; and

[0015] (d) Prepare pharmaceutical compositions for the production of low-core or coreless fucosylated antibodies.

[0016] In another preferred embodiment, the disease or condition related to the activity or expression level of α-1,6-fucosyltransferase refers to a disease or condition related to excessive activity or overexpression of α-1,6-fucosyltransferase.

[0017] In another preferred embodiment, the tumor is selected from the group consisting of cervical cancer, metastatic melanoma, liver cancer, glioblastoma, non-small cell lung cancer, breast cancer, or combinations thereof.

[0018] In another preferred embodiment, the disease or condition is selected from the group consisting of: tumors, inflammatory diseases, autoimmune diseases, viral infections, fibrotic diseases, and neurodegenerative diseases.

[0019] In another preferred embodiment, the tumor includes: metastatic melanoma, breast cancer (such as triple-negative breast cancer), liver cancer, cervical cancer, glioblastoma, and non-small cell lung cancer.

[0020] In another preferred embodiment, the inflammatory disease includes: psoriatic arthritis, rheumatoid arthritis.

[0021] In another preferred embodiment, the autoimmune disease includes systemic lupus erythematosus and multiple sclerosis.

[0022] In another preferred embodiment, the viral infection includes: hepatitis C virus infection, vesicular stomatitis virus infection, SARS-CoV-2 infection, and human immunodeficiency virus infection.

[0023] In another preferred embodiment, the fibrotic disease includes pulmonary fibrosis and peritoneal fibrosis.

[0024] In another preferred embodiment, the neurodegenerative disease includes Alzheimer's disease.

[0025] In another preferred embodiment, the active ingredient comprises one or more ingredients containing -(M) n - A compound with the structure shown, or a pharmaceutically acceptable salt, isomer, mixture of isomers, solvates, or crystal form thereof.

[0026] In another preferred embodiment, the isomer includes an optical isomer.

[0027] In another preferred embodiment, the mixture of isomers comprises a racemic mixture.

[0028] In another preferred embodiment, the substance containing -(M) n - The compounds with the structure shown are shown in Formula I;

[0029] R 1 -(M) n -R 2 (I)

[0030] in,

[0031] M and n are as defined in the first aspect;

[0032] R 1 and R 2 Each is independently selected from the following groups: H, -COOH, -COOC 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-10 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, glycosyl;

[0033] And R 1 and R 2 At least one of them is not H;

[0034] The optional substitution refers to unsubstituted or substituted substances, or substances substituted by one or more Rs. S replace;

[0035] Each R S Independently selected from the following groups: D, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, Nitro, Cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, oxo (=O), -C(=O)H, -C(=O)-C 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)H, -S(=O)C 1-6 Alkyl, -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O - M + -S(=O)2H, -S(=O)2C 1-6 Alkyl group, -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + amino, C 1-6 Alkylamino, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Carbocyclic group, -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5 to 10-membered heteroaryl; or, two Rs located on the same or adjacent ring atoms. S Together with the ring atoms they are attached to, they form: C 3-10 Carbocyclic groups, -4 to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl, of which M +It is a monovalent cation; and the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted by substituents selected from the group consisting of: D, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, Nitro, Cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 Ester group, oxy group, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Carbocyclic group, -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, -C 1-4 Alkylene-C 6-10 Aryl and -C 1-4 Alkylene-5 to 10-membered heteroaryl groups.

[0036] In another preferred embodiment, M + It is an ammonium ion or a monovalent metal cation (such as an alkali metal or alkaline earth metal cation).

[0037] In another preferred embodiment, M + Selected from the following group Na + K + .

[0038] In another preferred embodiment, the glycosyl group includes monosaccharides and disaccharides.

[0039] In another preferred embodiment, the C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups include onium ions or onium salts formed therefrom.

[0040] In another preferred embodiment, R 1 Selected from the following group: C with optional substitution 3-10 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, wherein the optional substitution is as defined above. In another preferred embodiment, R 1 Selected from the following group: optionally substituted 4- to 10-membered heterocyclic groups, optionally substituted C 6-10 Aryl, or optionally substituted 5 to 10 heteroaryl groups.

[0041] In another preferred embodiment, R 1 In, the C3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups include onium ions or onium salts formed therefrom.

[0042] In another preferred embodiment, R 1 In this context, the 5- to 10-membered heteroaryl group is a nitrogen-containing heteroaryl group.

[0043] In another preferred embodiment, R 1 In this context, the 5- to 10-membered heteroaryl group is a 5-membered nitrogen-containing heteroaryl group.

[0044] In another preferred embodiment, R 1 In this context, the 5-membered nitrogen-containing heteroaryl group contains 1, 2, or 3 nitrogen atoms as ring atoms and does not contain any other heterocyclic atoms.

[0045] In another preferred embodiment, R 1 In this context, the 5-membered nitrogen-containing heteroaryl group is as follows:

[0046]

[0047] in,

[0048] R 41 and R 42 Each is independently selected from the following groups: H, and optionally substituted C. 1-6 Alkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-10 Carbocyclic group, optionally substituted -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, optionally substituted -C 1-4 Alkylene-C 6-10 aryl and optionally substituted -C 1-4 alkylene-5 to 10-membered heteroaryl groups;

[0049] X - It is a monovalent anion.

[0050] In another preferred embodiment, R 1 for Where R 41 R 42 and X - As defined above.

[0051] In another preferred embodiment, R 41 and R 42 Each is independently selected from the following groups: H, and optionally substituted C. 1-6 Alkyl, optionally substituted -C1-4 Alkylene-C 3-10 Carbocyclic group, optionally substituted -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, optionally substituted -C 1-4 Alkylene-C 6-10 aryl and optionally substituted -C 1-4 Alkylene-5 to 10-membered heteroaryl groups.

[0052] In another preferred embodiment, R 41 and R 42 Each is independently selected from the following groups: H, and optionally substituted C. 1-6 Alkyl groups, and optionally substituted -C 1-4 Alkylene-C 6-10 Aryl. In another preferred embodiment, R 41 and R 42 Each is independently selected from the following groups: H, C 1-6 Alkyl and -C 1-4 Alkylene-C 6-10 Aryl. In another preferred embodiment, R 41 and R 42 Each is independently selected from the following groups: H, C 1-6 Alkyl and benzyl.

[0053] In another preferred embodiment, R 41 Selected from the following group: C with optional substitution 1-6 Alkyl, optionally substituted -C 1-4 Alkylene-C 3-10 Carbocyclic group, optionally substituted -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, optionally substituted -C 1-4 Alkylene-C 6-10 aryl and optionally substituted -C 1-4 Alkylene-5 to 10-membered heteroaryl groups.

[0054] In another preferred embodiment, R 41 Selected from the following group: C with optional substitution 1-6 Alkyl groups, and optionally substituted -C 1-4 Alkylene-C 6-10 Aryl. In another preferred embodiment, R 41 Selected from the following group: C 1-6 Alkyl and -C 1-4 Alkylene-C 6-10 Aryl. In another preferred embodiment, R 41 Selected from the following group: C 1-6 Alkyl and benzyl.

[0055] In another preferred embodiment, R 42 Selected from the following group: H, optional substituted C 1-6 alkyl.

[0056] In another preferred embodiment, R 42 Each is independently selected from the following groups: H, C 1-6 Alkyl group. In another preferred embodiment, R 42 Selected from the following group: H, methyl.

[0057] In another preferred embodiment, R 1 In, the optional substitution of C 6-10 The aryl group is an optionally substituted phenyl group.

[0058] In another preferred embodiment, R 1 In, the optional substitution of C 6-10 In aryl groups, the optional substitution refers to unsubstituted or substituted aryl groups or groups containing one or more (e.g., 1, 2, or 3, preferably 2) R groups. S Replace; and each R S Selected independently from the following group: halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, each R S Select independently from the following groups: F, Cl, Br.

[0059] In another preferred example, X - It is a halide anion. In another preferred embodiment, X - Selected from the following group: Cl - ,Br - I - .

[0060] In another preferred embodiment, R 1 In, the optional substitution of C 6-10 Aryl is

[0061]

[0062] Among them, each R S1 Independently for H or R S R S As defined above.

[0063] In another preferred embodiment, R 1 for Where R S1 As defined above.

[0064] In another preferred embodiment, each R S1 Independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, each R S Select independently from the following groups: H, F, Cl, Br.

[0065] In another preferred embodiment, each RS1 Selected independently from the following group: halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, each R S Select independently from the following groups: F, Cl, Br.

[0066] In another preferred embodiment, R 1 In this context, the optionally substituted 4- to 10-membered heterocyclic group is...

[0067]

[0068] Among them, each R S2 Independently for H or R S R S As defined above.

[0069] In another preferred embodiment, R 1 for Where R S2 As defined above.

[0070] In another preferred embodiment, each R S2 Independently selected from the following groups: H, C 1-6 Alkyl, -C(=O)H, -C(=O)-C 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)H, -S(=O)C 1-6 Alkyl, -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O - M + -S(=O)2H, -S(=O)2C 1-6 Alkyl group, -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + .

[0071] In another preferred example, an R S2 For H or C 1-6 Alkyl group, another selected from the group consisting of: -C(=O)H, -C(=O)-C 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)H, -S(=O)C 1-6 Alkyl, -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O- M + -S(=O)2H, -S(=O)2C 1-6 Alkyl group, -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + .

[0072] In another preferred example, an R S2 For H, the other is selected from the following groups: -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O - M + -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + .

[0073] In another preferred example, an R S2 For H, the other is selected from the following group: -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + .

[0074] In another preferred embodiment, R 2 For H.

[0075] In another preferred embodiment, n is an integer from 6 to 20 (preferably, an integer from 9 to 20, such as 9, 10, 11, 12, 13, 14, 15, 16, 18, 18, 19 or 20).

[0076] In another preferred example, -(M) n - At least 5 (preferably at least 7, more preferably at least 9) of them are -(CH2)-.

[0077] In another preferred example, -(M) n - There are at least 4 (preferably 6, more preferably 8) consecutive -(CH2)- in it.

[0078] In another preferred example, -(M) n -Selected from the following group:

[0079] -(CH2) n -、

[0080] -(CH2) n1 -(M1 ) n3 -(CH2) n2 -(M 2 ) n4 -;

[0081] in,

[0082] n1 and n2 are each independent integers from 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15), n3 is 1, 2 or 3, n4 is 0 or 1, and n1+n2≥5 (preferably n1+n2≥7, more preferably n1+n2≥9) and n1+n2+n3+n4≤20;

[0083] Each M 1 Selected from the following groups: -CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH3)=C(CH3)-, -NH-C(=O)-, -NH-C(=NH)-, -NH-C(=NH)-NH- and -NH-C(=O)-NH-;

[0084] M 2 It is -C(=O)O-.

[0085] In another preferred example, -(M) n -Selected from the following group:-(CH2) n -、-(CH2) n1 -CH = CH-(CH2) n2 -C(=O)-、-(CH2) n1 -NH-C(=NH)-NH-C(=NH)-NH-(CH2) n2 -C(=O)O-.

[0086] In another preferred embodiment, the compound is selected from Table A below:

[0087] Table A

[0088] .

[0090] In another preferred embodiment, the compound is compound A-1 (i.e., NH125), compound A-2 (sulfonyl-N-succinimide oleate), or a combination thereof.

[0091] In another preferred embodiment, R 1 and R 2 None of them are H.

[0092] In another preferred embodiment, R 1 and R 2Each is independently selected from the following group: -COOH, optionally substituted -COOC 1-6 Alkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5 to 10 heteroaryl groups, glycosyl.

[0093] In another preferred embodiment, R 1 and R 2 They are the same or different.

[0094] In another preferred embodiment, R 1 and R 2 Each of the Cs can be substituted independently. 6-10 Aryl (preferably, optionally substituted phenyl).

[0095] In another preferred embodiment, R 1 and R 2 Each of the Cs can be substituted independently. 6-10 aryl (preferably, optionally substituted phenyl), wherein the optional substitution refers to unsubstituted or substituted phenyl groups (e.g., 1 or 2, preferably 1) R groups. S Replace; and each R S Selected independently from the following group: halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, each R S Independently selected from the following groups: F, Cl, Br; more preferably, R S It is Cl.

[0096] In another preferred embodiment, R 1 and R 2 Each independently is:

[0097]

[0098] Among them, each R S3 Independently for H or R S R S As defined above.

[0099] In another preferred embodiment, R S3 Selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, R S3 Selected from the following group: H, F, Cl, Br.

[0100] In another preferred embodiment, R S3 Selected from the following group: halogens, C 1-6 Alkyl, C 1-6 Haloalkyl; preferably, R S3Selected from the following groups: F, Cl, Br.

[0101] In another preferred embodiment, R 1 and R 2 Each is independently -COOH, or optionally substituted -COOC. 1-6 alkyl.

[0102] In another preferred embodiment, R 1 and R 2 Each is independently -COOH, -COOC 1-6 Alkyl group; preferably -COOH.

[0103] In another preferred embodiment, R 1 and R 2 Each is an independent glycosyl group.

[0104] In another preferred embodiment, R 1 and R 2 Each person independently selects from the following groups:

[0105]

[0106] In another preferred embodiment, R 1 and R 2 Each of the Cs can be substituted independently. 3-10 Carbon cyclic group.

[0107] In another preferred embodiment, R 1 and R 2 In, the C 3-10 The carbon cyclic group contains a double bond.

[0108] In another preferred embodiment, R 1 and R 2 Each of the Cs can be substituted independently. 3-10 Carbocyclic group (preferably, optionally substituted C) 3-10 Cycloalkenyl), wherein the optional substitution refers to unsubstituted or substituted compounds with one or more (e.g., 1, 2, 3, 4, 5, or 6) R S Replace; and each R S Independently selected from the following group: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl alkyl group and oxo group (=O), preferably each R S Independently selected from the following group: hydroxyl, C 1-6 Alkyl and oxo groups (=O).

[0109] In another preferred embodiment, R 1 and R 2 Each independently

[0110]

[0111] Among them, each R S4 Independently for H or R S R S As defined above.

[0112] In another preferred embodiment, each R S4 Independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, each R S4 Independently selected from the following groups: H, C 1-6 alkyl.

[0113] In another preferred embodiment, n is an integer from 6 to 15 (preferably, an integer from 7 to 12, such as 8, 9, 10, 11 or 12).

[0114] In another preferred example, -(M) n -for:

[0115] -(M 4 ) n5 -(M 3 ) n4 -(M 4 ) n5 -

[0116] in,

[0117] n4 is an integer from 6 to 15 (preferably, an integer from 7 to 12, such as 8, 9, 10, 11 or 12), each n5 is independently 0, 1, 2 or 3, and n4 + n5 ≤ 15 (preferably ≤ 12);

[0118] Each M 3 Independently selected from the following groups: -CH2-, -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-;

[0119] Each M 4 Independently selected from the following groups: -C(=O)-, -C(=S)-, -NH-C(=O)-, -NH-C(=S)-, -NH-C(=NH)-, -NH-C(=NH)-NH-, -NH-C(=O)-NH-, and -NH-C(=S)-NH-.

[0120] In another preferred embodiment, n4 is an integer from 6 to 15 (preferably, an integer from 7 to 12, such as 8, 9, 10, 11 or 12), each n5 is independently 0 or 1, and n4 + n5 ≤ 15 (preferably ≤ 12).

[0121] In another preferred embodiment, each M 3 Independently selected from the following groups: -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-; and each M 4 Select independently from the following groups: -C(=O)-, -C(=S)-.

[0122] In another preferred embodiment, n4 is an integer from 6 to 15 (preferably, an integer from 7 to 12, such as 8, 9, 10, 11 or 12), each n5 is independently 1, 2 or 3, and n4 + n5 ≤ 15 (preferably ≤ 12).

[0123] In another preferred embodiment, M 3 All are -CH2-; and each M 4 It is independently selected from the following groups: -NH-C(=O)-, -NH-C(=S)-, -NH-C(=NH)-, -NH-C(=NH)-NH-, -NH-C(=O)-NH-, and -NH-C(=S)-NH-.

[0124] In another preferred example, -(M) n -Selected from the following group:

[0125] -NH-C(=NH)-NH-C(=NH)-NH-(CH2) n4 -NH-C(=NH)-NH-C(=NH)-NH-;

[0126] -NH-C(=O)-NH-C(=NH)-NH-(CH2) n4 -NH-C(=NH)-NH-C(=O)-NH-;

[0127] -(M 3 ) n4 -;

[0128] -C(=O)-(M 3 ) n4 -C(=O)-;

[0129] in,

[0130] Each M 3 Independently selected from the following groups: -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-;

[0131] n4 is an integer between 7 and 12.

[0132] In another preferred embodiment, the compound is selected from Table B below:

[0133] Table B

[0134]

[0135] In another preferred embodiment, the compound is compound B-1 (i.e., chlorhexidine).

[0136] In another preferred embodiment, the compound is free of compounds such as -(M). n - Compounds with the structure shown; and said compounds are selected from Table C below:

[0137] Table C

[0138]

[0139] In another preferred embodiment, R 1 R 2 M and n are each independently the corresponding functional groups of the specific compounds shown in Tables A, B and C.

[0140] In another preferred embodiment, the active ingredient comprises one or more compounds selected from the table below, or pharmaceutically acceptable salts, isomers, mixtures of isomers, solvates, or crystal forms thereof:

[0141]

[0142] In a second aspect of the invention, a pharmaceutical composition is provided, comprising:

[0143] (a) an active ingredient, said active ingredient as defined in the first aspect; and

[0144] (b) Pharmaceutically acceptable carriers.

[0145] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition used as a targeted inhibitor of α-1,6-fucosyltransferase.

[0146] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for treating or preventing diseases or conditions related to the activity or expression level of α-1,6-fucosyltransferase.

[0147] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for treating or preventing tumor metastasis.

[0148] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for producing low-core fucosylated or coreless fucosylated antibodies.

[0149] In a third aspect of the invention, a method for targeted inhibition of α-1,6-fucosyltransferase is provided, comprising the steps of: contacting a subject with an active ingredient as defined in the first aspect, thereby inhibiting the activity of α-1,6-fucosyltransferase.

[0150] In another preferred embodiment, the method is non-therapeutic in vitro.

[0151] In another preferred embodiment, the object is an enzyme or a cell.

[0152] In another preferred embodiment, the cell is a human cell.

[0153] In another preferred embodiment, the cells are tumor cells.

[0154] In another preferred embodiment, the cells are selected from the group consisting of HeLa cells, A375 cells, GAK cells, HEK293 cells, or combinations thereof.

[0155] In a fifth aspect of the invention, a method for inhibiting transpore invasion of tumor cells is provided, comprising the steps of: contacting tumor cells with an active ingredient as defined in the first aspect, thereby inhibiting transpore invasion of tumor cells.

[0156] In another preferred embodiment, the method is non-therapeutic in vitro.

[0157] In another preferred embodiment, the cells are selected from the group consisting of HeLa cells, A375 cells, GAK cells, HEK293 cells, or combinations thereof.

[0158] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0159] Figure 1 The purification curves and SDS-PAGE results of the recombinant α-1,6-fucosyltransferase are shown.

[0160] Figure 2 The results of the in vitro enzyme activity assay for α-1,6-fucosyltransferase are shown.

[0161] Figure 3 The graphs showing the inhibition of α-1,6-fucosylation by a series of small molecule compounds are presented.

[0162] Figure 4 The cell-killing curves of compounds NH125 and chlorhexidine (CHX) on A375 cells are shown.

[0163] Figure 5 The cellular-level inhibition curves of core fucosylation of compounds NH125 and chlorhexidine (CHX) are shown.

[0164] Figure 6The results of laser confocal microscopy (Scalebar 25 μm) show the inhibition of core fucosylation by NH125 and chlorhexidine at the cellular level.

[0165] Figure 7 The results of NH125 and chlorhexidine inhibiting the transpore invasion of the melanoma cell line A375 are shown (Scalebar 100 μm). Figure A shows the in vitro invasion assay used to assess cell migration and invasion capabilities. A375 cells were treated with DMSO, CHX (LC: 1 μM; HC: 10 μM), or NH125 (LC: 0.2 μM; HC: 5 μM), respectively. The scale bar for the experimental results is 100 μm. Figure B shows the statistical significance of the data from the in vitro invasion assay (Student's t-test: ****, P < 0.0001). Detailed Implementation

[0166] After long-term and in-depth research, the inventors unexpectedly discovered that a series of compounds with specific structures possess excellent inhibitory activity against α-1,6-fucosyltransferase. Based on this, the inventors completed this invention.

[0167] the term

[0168] Unless otherwise specified, the terms or abbreviations herein have the conventional meanings as understood by those skilled in the art.

[0169] Unless otherwise stated, the term "alkyl," either on its own or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64 ... 1-6 It represents 1-6 carbons, C 1-4 (Indicates 1-4 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl.

[0170] The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Generally, alkenyl groups have 1-6 carbon atoms, i.e., C64-C64. 1-6 Alkenyl and ynyl groups have 1-6 carbon atoms, i.e., C64. 1-6 Alkynyl. Examples of this type of unsaturated alkyl group include: vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologues and isomers.

[0171] As used herein, the term "carbocyclic group" refers to a group having a specified number of ring atoms (e.g., C12, C23 ...23, C23, C2 3-10A carbocyclic group is a non-aromatic hydrocarbon ring that is fully saturated or contains one or more double bonds. A "carbocyclic group" can be a monocyclic ring (such as cyclopropyl, cyclobutyl, cyclohexyl, etc.) or a bicyclic or polycyclic hydrocarbon ring, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. The term "heterocyclic group" refers to a carbocyclic group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heterocyclic groups can be monocyclic, bicyclic, or polycyclic systems. Generally, heterocyclic groups typically comprise 4 to 10 ring atoms (i.e., 4 to 10 membered heterocyclic alkyl groups) and contain 1, 2, 3, or 4 heterocyclic atoms. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valeron, imidazolidinone, hydantoin, dioxolane, benzodiimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinine ring, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or heteroatom.

[0172] As used herein, the term "alkylene", either on its own or as part of another substituent, refers to a divalent group derived from an alkane, such as -CH2-.

[0173] The term "alkoxy" is used in its conventional sense to refer to alkyl groups that are attached to the rest of the molecule via an oxygen atom. Unless otherwise stated, the term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which can be monocyclic or fused together or covalently linked polycyclic (up to three-cyclic) groups. Generally, aryl groups have 6-10 ring atoms. The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Generally, heteroaryl groups have 5-10 ring atoms, i.e., 5- to 10-membered heteroaryl groups, preferably 5- to 6-membered heteroaryl groups, and contain 1, 2, 3, or 4 heteroatoms (preferably N). Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, and isobenzofuranyl. (furyl), isoindolyl, indene, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc. The substituents in the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents listed below.

[0174] In some embodiments, the terms above (such as “alkyl,” “carbocyclic,” “heterocyclic,” “aryl,” and “heteroaryl”) will include substituted and unsubstituted forms of the specified group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted forms provided below, while the term “alkyl” and the associated aliphatic group refer to the unsubstituted form unless specified otherwise.

[0175] Unless otherwise defined, substituents in alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be a variety of groups selected from the group consisting of: -halogen, -OR a -NR a R b -SR a -SiR a R b R c -OC(O)R a -C(O)R a -CO2R a-CONR a R b -OC(O)NR a R b -NR b C(O)R a -NR a -C(O)NR b R c -NR b C(O)2R a -NH-C(NH2)=NH, -NR a C(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -CN and -NO2, in quantities ranging from zero to (2M+1), where M is the total number of carbon atoms in this group. R a R b and R c Each independently represents hydrogen and unsubstituted C. 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted -C 1-4 Alkylene-aryl. When R a and R b When attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR a R b It refers to the combination of 1-pyrrolidinyl and 4-morpholinyl.

[0176] Similarly, unless otherwise defined, the substituents of aryl and heteroaryl groups are diverse and are generally selected from: -halogen, -OR a -OC(O)R a -NR a R b -SR a -R a -CN, -NO2,

[0177] -CO2R a -CONR a R b -C(O)R a -OC(O)NR a R b -NRb C(O)R a -NR b C(O)2R a -NR a -C(O)NR b R c -NH-C(NH2)=NH, -NR a C(NH2)=NH、-NH-C(NH2)=NR a -S(O)R a -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in quantities ranging from zero to the total number of open valences on the aromatic ring system; where R a R b and R c Independently selected from hydrogen, C 1-8 Alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, unsubstituted -C 1-4 alkylene-aryl or heteroaryl and unsubstituted -C 1-4 Alkylene-aryloxy group.

[0178] The two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CH2). q The substituents of -U- are used, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -A-(CH2). r -B-, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or single bonds, and r is an integer from 1 to 3. One single bond in the resulting new ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CH2). s -X-(CH2) t The substituents are substituted, where s and t are independent integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0179] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0180] As used in this article, the term "nitro" refers to -NO2.

[0181] As used herein, the term "cyano" refers to -CN

[0182] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more (e.g., all) H atoms are substituted with a halogen (e.g., F, Cl, Br, or I). Examples of haloalkyl groups include, but are not limited to, -CF3.

[0183] As used in this article, "hydroxyalkyl" means that one or more H atoms in an alkyl group as defined above are replaced by hydroxyl groups.

[0184] As used in this article, “deuterated alkyl” means that one or more H atoms in an alkyl group as defined above are replaced by D atoms.

[0185] As used herein, the term "ester group" refers to a group having a specified number of carbon atoms and being such as -C(O)-OR or -OC(O)-, where R is an alkyl group, such as -C(O)OCH3 or -OC(O)CH3.

[0186] As used herein, the term "alkanoyl" refers to a group having a specified number of carbon atoms and is indicated as -C(O)-R, where R is an alkyl group, such as -C(O)CH3.

[0187] As used in this article, the term "aldehyde group" refers to -C(O)H.

[0188] As used herein, the term "amino" refers to -NH2.

[0189] As used herein, the term "alkylamino" refers to an amino group in which one or two H atoms are replaced by an alkyl group, such as -NH(CH3) or -N(CH3). 2。 For dialkylamino groups, the alkyl moiety can be the same or different, and can also combine with the nitrogen atom attached to each alkyl group to form a 3-7 membered ring. Therefore, alkylamino groups include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, etc.

[0190] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0191] As used herein, the terms “containing,” “comprising,” or “including” indicate that various ingredients may be used together in mixtures or compositions of the present invention. Therefore, the terms “consistent with…” and “composed of…” are included in the term “containing.”

[0192] As used herein, the term "pharmaceuticalally acceptable" means a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0193] As used herein, the term "therapeutic effective dose" refers to any amount of a drug as described below, which, when used alone or in combination with another therapeutic agent, promotes disease regression, manifested as a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of impairment or disability caused by the disease. The "therapeutic effective dose" of the drug of this invention also includes a "preventive effective dose," which is any amount of a drug as described below, which, when administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or suffering from a relapse of the disease, inhibits the occurrence or recurrence of the disease.

[0194] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0195] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0196] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0197] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0198] The term "pharmaceutically acceptable salt" is intended to include salts prepared from active compounds with relatively non-toxic acids or bases, depending on the specific substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (solvent-free or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid (solvent-free or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, etc.; and salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galactunoric acid, etc. (see, for example, Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Some specific compounds of the present invention contain both basic and acidic functional groups, thereby enabling the compounds to be converted into basic addition salts or acid addition salts.

[0199] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this invention, those salts are equivalent to the parent form of the compound.

[0200] In addition to the salt form, the present invention also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.

[0201] Some compounds of the present invention may exist in both solvated and hydrated forms, including hydrated forms. The hydrated forms are generally equivalent to the hydrated forms and should be included within the scope of the present invention. Some compounds of the present invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent for the applications contemplated by the present invention and should be included within the scope of the present invention.

[0202] Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention. When the compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), it will be understood by those skilled in the art that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).

[0203] The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds. A non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C). 2 H) or carbon-13 ( 13C). In addition to the uses described in this application, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of this invention.

[0204] α-1,6-fucosyltransferase targeted inhibitor and its preparation method

[0205] Unless otherwise specified, the term “α-1,6-fucosyltransferase” in this article also includes its mutants, truncated forms, etc.

[0206] This invention relates to the novel use of a class of compounds, including some known compounds, in inhibiting the activity of α-1,6-fucosyltransferase (FUT8). These compounds include, for example, NH125, chlorhexidine, and sulfonyl-N-succinimide oleate, which can effectively inhibit FUT8 enzyme activity, thereby intervening in diseases related to abnormal expression of core fucosylation, such as cancer, neurodegenerative diseases, and autoimmune diseases. Experimental data show that these compounds can significantly inhibit FUT8 enzyme activity and exhibit good effects in cell models.

[0207] As used herein, the terms “compound of the invention,” “small molecule compound of the invention,” “α-1,6-fucosyltransferase targeting inhibitor,” and “inhibitor of the invention” are used interchangeably and refer to compounds as described in the first aspect. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compound.

[0208] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0209] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0210] Furthermore, the compounds of this invention also include prodrugs of compounds represented by formula (I). The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of formula (I), or salts or solutions of compounds of formula (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0211] Preferably, the tumor includes, but is not limited to, metastatic melanoma and cervical cancer. The tumor can be any tumor regulated by α-1,6-fucosyltransferase expression.

[0212] In some implementations, a new use is provided for a class of compounds in inhibiting the activity of α-1,6-fucosyltransferase (FUT8) enzyme.

[0213] In some implementations, a series of small molecule compounds are provided as α-1,6-fucosyltransferase targeting inhibitors for the preparation of antitumor drugs.

[0214] In some implementations, these compounds directly inhibit the enzymatic activity of α-1,6-fucosyltransferase at the biochemical level, thereby inhibiting the formation of core fucose.

[0215] In some embodiments, the compound is selected from NH125, chlorhexidine, sulfonyl-N-succinimide oleate, crocin, crocin II, olancetin, astaxanthin, chlorhexidine acetate impurity C, rumacato, 1-decyl-3-methylimidazolium bromide, resveratrol, SH-4-54, or any combination thereof.

[0216]

[0217] In some implementations, NH125 and chlorhexidine hydrochloride inhibit the enzymatic activity of α-1,6-fucosyltransferase in tumor cells, thereby inhibiting the production of core fucose and thus blocking the invasion of tumor cells.

[0218] In some embodiments, the use of the compound in the preparation of a medicament that inhibits FUT8 enzyme activity for the treatment of diseases associated with abnormal expression of core fucosylation is also provided.

[0219] In some embodiments, the small molecule compound includes, but is not limited to, a single small molecule, which may be its optical isomer or racemate, its solvate, or its pharmaceutically acceptable salt.

[0220] In some embodiments, the small molecule inhibitor is used as a monomer of a compound, an optical isomer thereof, a racemic mixture thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the small molecule compound can be used alone to inhibit the enzymatic activity of α-1,6-fucosyltransferase, or it can be one of a combination of multiple compounds to inhibit the enzymatic activity of α-1,6-fucosyltransferase.

[0222] In some embodiments, the α-1,6-fucosyltransferase is of mammalian origin.

[0223] In some embodiments, the α-1,6-fucosyltransferase is a protein recombinantly expressed in vitro, or in cells, or in mammals.

[0224] In some implementations, the tumor diseases include, but are not limited to, metastatic melanoma, glioblastoma, non-small cell lung cancer, cervical cancer, and other diseases caused by abnormal expression of core fucosylation.

[0225] Pharmaceutical Compositions and Administration

[0226] Because the compounds of this invention possess excellent inhibitory activity against α-1,6-fucosyltransferase and low cytotoxicity, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat, prevent, and alleviate diseases or conditions related to the activity or expression level of α-1,6-fucosyltransferase. According to the prior art, the compounds of this invention can be used to treat the following diseases: metastasis of tumors such as cancers (e.g., cervical cancer, metastatic melanoma, liver cancer, glioblastoma, non-small cell lung cancer, breast cancer, etc.).

[0227] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-500 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0228] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0229] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0230] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0231] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0232] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0233] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0234] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0235] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0236] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0237] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0238] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0239] The main advantages of this invention include

[0240] This invention provides a series of inhibitors that can directly target and inhibit α-1,6-fucosyltransferase and their application in the preparation of antitumor drugs. Experiments have demonstrated that this series of compounds can directly inhibit the catalytic activity of α-1,6-fucosyltransferase, directly blocking core fucosylation. Therefore, this series of compounds can be used as active ingredients to treat diseases associated with α-1,6-fucosyltransferase overexpression. Specifically, it intervenes in the following diseases by inhibiting α-1,6-fucosyltransferase: by inhibiting tumor cell proliferation, invasion, and metastasis, it enhances the immune system's recognition and attack on various tumors such as melanoma, breast cancer, and liver cancer; it alleviates inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease; it regulates immune responses and inhibits autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis; it inhibits the binding of pathogens to host cells, reducing viral infections such as hepatitis C virus, vesicular stomatitis virus, SARS-CoV-2, and human immunodeficiency virus; it slows down the progression of pulmonary fibrosis and peritoneal fibrosis by inhibiting the expression of fibrosis-related proteins; and it reduces neuroinflammation and protects neurons, thereby alleviating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0241] In addition, these compounds can also be used to inhibit α-1,6-fucosyltransferase activity during antibody production to produce low-core or coreless fucosylated therapeutic antibodies, thus broadening their application scope.

[0242] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0243] Example 1: The effect of a series of compounds on the targeted inhibition of α-1,6-fucosyltransferase

[0244] The experimental method is as follows:

[0245] (1) Expression and purification of α-1,6-fucosyltransferase:

[0246] In this experiment, the mammalian Expi293 cell line was used to express the recombinant protein of the constructed α-1,6-fucosyltransferase. The plasmid vector and expression structure were pSectag2A_3×Flag_FUT8(68-575). The expression conditions were: shaker environment: 5% CO2 / 37℃ / 110rpm; Expi293 cell viability: above 95%; cell density at transfection: 2.5×10⁻⁶. 6 Cells / mL; Transfection ratio: Cell volume (L): FUT8 plasmid: PEI40000 (transfection reagent) = 1:3:9; GlutaMAX-I (Thermo, 100× to 1×) was added 24 h after transfection; The supernatant was collected by centrifugation 120 h after transfection and recombinant protein purification experiment was performed. The purification procedure was as follows: After the transient transfection expression of α-1,6-fucosyltransferase recombinant protein, the supernatant was collected by centrifugation. First, Flag-Beads were used for affinity column loading, impurity washing, and competitive elution purification with Flag small peptides. Then, the eluent was concentrated and purified using S200 molecular sieve. After purification, SDS-PAGE experiment was performed to confirm protein purity and target band (see attached). Figure 1 Finally, based on the S200 purification curve and SDS-PAGE experimental results, the sample was collected, concentrated, and its concentration was measured. After being flash-frozen in liquid nitrogen, it was stored in a -80℃ freezer for later use.

[0247] (2) In vitro enzyme activity assay of α-1,6-fucosyltransferase:

[0248] The activity of recombinantly expressed α-1,6-fucosyltransferase was tested using the GDP-Glo ​​kit provided by Promega. The detailed procedure was performed in two steps. The first step was the enzyme activity assay of α-1,6-fucosyltransferase: a gradient titration experiment was conducted on 0-1000 nM purified recombinant α-1,6-fucosyltransferase protein containing a 3×Flag tag. The reaction system included 10 μM GDP-L-fucose, 5 μM core heptaose, and a buffer system (HEPES 50 mM, NaCl 100 mM, Triton X-100 0.01%, BSA 0.1%, pH...).

[0249] 7.50); ​​The reaction conditions were 37℃ for 1 hour. The second step was product detection: 10 μL of GDP assay reagent was added to the first step reaction system in a 1:1 ratio to stop the reaction in a white opaque 384-well plate, and incubated in the dark at room temperature for 30 minutes (four parallel tests were performed in the same group). Finally, the data were read using a multi-functional microplate reader and the average value of the parallel readings was calculated. The detection data were processed and plotted using GraphPad Prism 8 software. Figure 2 .

[0250] The data processing results clearly show that as the concentration of α-1,6-fucosyltransferase increases, the amount of product GDP gradually increases. When the concentration of α-1,6-fucosyltransferase reaches 125 nM, the reaction tends to saturate. This confirms that the purified α-1,6-fucosyltransferase with the 3×Flag tag has enzymatic activity and can be used for subsequent batch small molecule activity testing experiments.

[0251] (3) Test the in vitro enzyme activity inhibitory effects of a series of small molecule compounds on α-1,6-fucosyltransferase.

[0252] The inhibitory activity of a series of small molecule compounds was titrated using the GDP-Glo ​​kit (Promega). The reaction system consisted of: 10 nM α-1,6-fucosyltransferase; 10 μM GDP-L-fucose; and 5 μM core heptaose. The buffer system, reaction time, and temperature were the same as those used in the α-1,6-fucosyltransferase activity assay. The positive control group consisted of a reaction system without α-1,6-fucosyltransferase plus an equal volume of DMSO, and the negative control group consisted of an equal volume of DMSO. Other conditions were the same as those used in the experimental group. Each gradient was tested four times. After the titration experiments, the data were processed using GraphPad Prism 7 software.

[0253] The obtained titration curve is attached. Figure 3As shown in Table 1, the measured IC50 values ​​indicate that this series of small molecule compounds have varying degrees of inhibitory effects on the enzyme activity of α-1,6-fucosyltransferase at the in vitro biochemical level.

[0254] Table 1

[0255]

[0256]

[0257] Example 2: Inhibitory effects of compounds NH125 and chlorhexidine on the enzyme activity of intracellular α-1,6-fucosyltransferase

[0258] The experimental method is as follows:

[0259] (1) The cytotoxic effects of compounds NH125 and chlorhexidine on the metastatic melanoma cell line A375.

[0260] The cytotoxicity of CHX and NH125 against the metastatic melanoma cell line A375 was tested using the CCK8-Kit. Specifically, A375 cells were treated with a gradient of CHX and NH125 (starting from the highest concentration of 100 μM) diluted in culture medium (90% DMEM, 10% FBS) for 72 hours. Then, 10 μL of CCK8 cell viability assay reagent was added to each well, and the cells were incubated at 37°C for 4 hours. Readings were then performed using a microplate reader. The results were calculated using Prism, and a killing curve was plotted. The results are shown in the attached figure. Figure 4 The results are shown in the attached figure. Based on the results, NH125 and CHX are compatible with the A375 IC. 50 The values ​​are 6.8 μM and 13.2 μM, respectively.

[0261] (2) Flow cytometry analysis of the inhibitory effect of compounds NH125 and chlorhexidine on the core fucosylation level of metastatic melanoma cell line A375.

[0262] Based on the principle that lentil lectin LCA specifically recognizes N-octagana glycoproteins containing core fucose, A375 cells were first treated with 5 μM NH125 or 10 μM CHX for 72 h, followed by FITC-tagged LCA staining, and then flow cytometry analysis. The final results of the flow cytometry data processing using Flowjo are shown in the attached figure. Figure 5 As shown, compared with the negative control and positive control samples, 5 μM NH125 and 10 μM CHX both had different degrees of inhibitory effect on the core fucosylation of A375 cells at the cell level, with 5 μM NH125 showing the most significant inhibitory effect.

[0263] (3) Laser confocal imaging of the inhibitory effect of NH125 and chlorhexidine on the core fucosylation level of metastatic melanoma cell line A375.

[0264] Based on the principle that lentil lectin LCA specifically recognizes N-octaglycoproteins containing core fucosylation, A375 cells (72h) treated with different concentrations of NH125 / CHX were stained with FITC-tagged LCA. Cell nuclei were stained with DAPI, and then the core fucosylation changes on the cell surface of A375 cells before and after compound treatment were imaged using a laser confocal microscope. The experimental results are attached. Figure 6 As shown.

[0265] According to the appendix Figure 6 The study directly demonstrated the inhibitory effect of 5 μM NH125 and 10 μM CHX on core fucosylation in A375 cells.

[0266] Example 3: Inhibitory effect of compounds NH125 and chlorhexidine on transpore invasion of metastatic melanoma cell line A375

[0267] The experimental method is as follows:

[0268] Previous studies in the field have shown that overexpression of α-1,6-fucosyltransferase is a driving factor for the metastatic invasion of metastatic melanoma, and that inhibiting or knocking out α-1,6-fucosyltransferase can significantly inhibit the metastatic invasion of melanoma. Based on the successful targeting of α-1,6-fucosyltransferase and significant inhibition of core fucosylation by NH125 and CHX at the cellular level in Example 3, we used a transwell invasion assay to test the inhibitory effects of NH125 and CHX on the metastatic melanoma cell line A375. The experimental method is as follows: A375 cells were treated with DMSO, 5 μM NH125, and 10 μM CHX for 72 h, respectively. Then, the original culture medium was discarded, and A375 cells were washed with PBS, digested with trypsin, centrifuged, and resuspended in culture medium for later use. Cells in each group were counted using a cell counting chamber, and then 5000 cells / well were added to transwell invasion cell culture plates (Sigma-Aldrich, catalog) pre-coated with matrix gel (Corning 356234). In cell culture chamber number: CLS3421, after culturing for 24 hours, the culture chamber was removed, washed, and stained with crystal violet. Then, bright-field microscopy was used to photograph the transpore invasion of A375 cells, as shown in the attached image. Figure 7 .

[0269] Analysis of the figure shows that, compared with the DMSO group, 5 μM NH125 and 10 μM CHX can completely inhibit the transpore invasion of metastatic melanoma cell line A375.

[0270] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The use of the active ingredient, characterized in that, The active ingredient includes one or more ingredients containing -(M) n The structure shown may not contain elements such as -(M). n - A compound with the structure shown or a pharmaceutically acceptable salt, isomer, mixture of isomers, solvates, or crystal form thereof; in, Each M is independently a divalent group selected from the following group: -CH2-, -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=S)O-, -NH-C(=O)-, -NH-C(=S)-, -NH-C(=NH)-, -NH-C(=NH)-NH-, -NH-C(=O)-NH-, and -NH-C(=S)-NH-; n is an integer from 3 to 30 (preferably, an integer from 5 to 20, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 18, 19 or 20); Furthermore, the stated use is selected from one or more uses in the group below; (a) Preparation of α-1,6-fucosyltransferase targeting inhibitor; (b) To prepare a medicine or pharmaceutical composition for the treatment or prevention of diseases or conditions related to the activity or expression level of α-1,6-fucosyltransferase; and (c) Preparing a medicament or pharmaceutical composition for the treatment or prevention of tumor metastasis; and (d) Prepare pharmaceutical compositions for the production of low-core or coreless fucosylated antibodies.

2. The use as described in claim 1, characterized in that, The diseases or conditions mentioned are selected from the following group: tumors, inflammatory diseases, autoimmune diseases, viral infections, fibrotic diseases, and neurodegenerative diseases.

3. The use as described in claim 2, characterized in that, The tumors include: metastatic melanoma, breast cancer, liver cancer, cervical cancer, glioblastoma, non-small cell lung cancer; and / or The inflammatory diseases mentioned include: psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease; and / or The autoimmune diseases mentioned include systemic lupus erythematosus, multiple sclerosis; and / or The viral infections include: hepatitis C virus infection, vesicular stomatitis virus infection, SARS-CoV-2 infection, human immunodeficiency virus infection; and / or The fibrotic diseases include: pulmonary fibrosis, peritoneal fibrosis; and / or The neurodegenerative diseases mentioned include Alzheimer's disease.

4. The use as described in claim 1, characterized in that, The active ingredient includes one or more ingredients containing -(M) n -A compound with the structure shown, or a pharmaceutically acceptable salt, isomer, mixture of isomers, solvates, or crystal form thereof, and the compound containing -(M) n - The compounds with the structure shown are shown in Formula I; R 1 -(M) n -R 2 (I) in, M and n are as defined in claim 1; R 1 and R 2 Each is independently selected from the following groups: H, -COOH, -COOC 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 3-10 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, glycosyl; And R 1 and R 2 At least one of them is not H; The optional substitution refers to unsubstituted or substituted substances, or substances substituted by one or more Rs. S replace; Each R S Independently selected from the following groups: D, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, Nitro, Cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, oxo (=O), -C(=O)H, -C(=O)-C 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)H, -S(=O)C 1-6 Alkyl, -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O - M + -S(=O)2H, -S(=O)2C 1-6 Alkyl group, -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + amino, C 1-6 Alkylamino, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Carbocyclic group, -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5 to 10-membered heteroaryl; or, two Rs located on the same or adjacent ring atoms. S Together with the ring atoms they are attached to, they form: C 3-10 Carbocyclic groups, -4 to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl, of which M + It is a monovalent cation; and the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted by substituents selected from the group consisting of: D, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, Nitro, Cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 Ester group, oxy group, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C 1-4 Alkylene-C 3-10 Carbocyclic group, -C 1-4 Alkyl-4 to 10-membered heterocyclic groups, -C 1-4 Alkylene-C 6-10 Aryl and -C 1-4 Alkylene-5 to 10-membered heteroaryl groups.

5. The use as described in claim 4, characterized in that, I： R 1 for: in, R 41 and R 42 Each is independently selected from the following groups: H, C 1-6 Alkyl and -C 1-4 Alkylene-C 6-10 Aryl; X - It is a monovalent anion; or, R 1 for: in, Each R S1 Independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; or, R 1 for Among them, each R S2 Independently selected from the following groups: H, C 1-6 Alkyl, -C(=O)H, -C(=O)-C 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -C(=O)O - M + -S(=O)H, -S(=O)C 1-6 Alkyl, -S(=O)OH, -S(=O)OC 1-6 Alkyl group, -S(=O)O - M + -S(=O)2H, -S(=O)2C 1-6 Alkyl group, -S(=O)2OH, -S(=O)2O-C 1-6 Alkyl group, -S(=O)2O - M + ; II: R 2 For H; as well as III: -(M) n -Selected from the following group: -(CH2) n -、 -(CH2) n1 -(M 1 ) n3 -(CH2) n2 -(M 2 ) n4 -; in, n1 and n2 are each independent integers from 1 to 15, n3 is 1, 2 or 3, n4 is 0 or 1, and n1+n2≥5 and n1+n2+n3+n4≤20; Each M 1 Selected from the following groups: -CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, -C(CH3)=C(CH3)-, -NH-C(=O)-, -NH-C(=NH)-, -NH-C(=NH)-NH- and -NH-C(=O)-NH-; M 2 It is -C(=O)O-.

6. The use as described in claim 5, characterized in that, The compounds are selected from Table A below: Table A 7. The use as described in claim 4, characterized in that, I： R 1 and R 2 Each independently is: Among them, R S3 Selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; or, R 1 and R 2 Each is independently -COOH, -COOC 1-6 Alkyl; or, R 1 and R 2 Each person independently selects from the following groups: or, R 1 and R 2 Each independently Among them, each R S4 Independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; as well as, II: -(M) n -for: -(M 4 ) n5 -(M 3 ) n4 -(M 4 ) n5 - in, n4 is an integer from 6 to 15, and each n5 is independently 0, 1, 2 or 3, and n4 + n5 ≤ 15; Each M 3 Independently selected from the following groups: -CH2-, -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-; Each M 4 Independently selected from the following groups: -C(=O)-, -C(=S)-, -NH-C(=O)-, -NH-C(=S)-, -NH-C(=NH)-, -NH-C(=NH)-NH-, -NH-C(=O)-NH-, and -NH-C(=S)-NH-.

8. The use as described in claim 7, characterized in that, The compounds are selected from Table B below: Table B 9. The use as described in claim 1, characterized in that, The compound in question does not contain substances such as -(M). n - Compounds with the structure shown; and said compounds are selected from Table C below: Table C 10. The use as described in claim 1, characterized in that, The active ingredient comprises one or more compounds selected from the table below, or their pharmaceutically acceptable salts, isomers, mixtures of isomers, solvates, or crystal forms:

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