Sulfonamide compounds, their pharmaceutical compositions and applications

Abstract

This disclosure relates to sulfonyl compounds and their pharmaceutical compositions and applications, wherein the sulfonamide compounds include the compounds shown in Formula I, and the sulfonamide compounds competitively bind to the substrate and KAT6A / KAT6B in the binding pocket of the KAT6A / KAT6B substrate acetyl coenzyme, inhibiting the acetyl coenzyme from binding to KAT6A / KAT6B and catalyzing histone-related sites, thereby preventing the expression of genes that induce the growth of cancer cells, and are used to treat tumor diseases associated with amplification of the KAT6A / KAT6B gene or overexpression of the KAT6A / KAT6B protein. JPEG2026512835000213.jpg2662(I)

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to a prior patent application filed by the applicant with the China National Intellectual Property Administration on March 27, 2023, with application number 202310308970.7, titled "Sulfonamide Compounds, Pharmaceutical Compositions and Applications thereof," and a prior patent application filed by the applicant with the China National Intellectual Property Administration on November 16, 2023, with application number 202311533391.9, titled "Sulfonamide Compounds, Pharmaceutical Compositions and Applications thereof." Both of the aforementioned prior applications are incorporated herein by reference in their entirety.

[0002] This disclosure relates to the pharmaceutical technology field, and more particularly to sulfonamide compounds, their pharmaceutical compositions, and applications. [Background technology]

[0003] Histone acetyltransferases (HATs) are enzymes that use acetyl coenzyme A (Ac-CoA) as a substrate to acetylate specific sites on histones, playing a major role in a series of epigenetic pathways. Based on the structural characteristics of the lysine acetyltransferase domain, these histone acetyltransferases can be classified into three main families: (i) p300 / CBP, (ii) GNAT, and (iii) MYST. Among these, the largest HATs family is the MYST protein, which is responsible for histone acetylation and is involved in a wide range of cellular events such as DNA repair, replication, and transcriptional activation, accounting for approximately one-third of the human genome HATs. Proteins in the MYST family have a conserved "MYST" domain, including KAT6A (MOZ / MYST3), KAT6B (Morf / MYST4 / Qkf), KAT8 (Mof / MYST1), KAT5 (Tip60), and KAT7 (Hbo1 / MYST2).

[0004] KAT6A and KAT6B are homologous genes of the same species, and their protein products form protein complexes with ING5, EAF6, BRPF1, BRPF2, or BRPF3, and can acetylate the H3K23 site using the substrate acetylcoenzyme A (Ac-CoA). KAT6A is a target of relapsing chromosomal translocations and is a characteristic site that causes acute myeloid leukemia (AML). Translocations of KAT6A and KAT6B have been found in many AML patients, giving rise to other HATs such as EP300 (this gene encodes the adenovirus E1A-associated cell p300 transcription coactivator protein), NCOA2 (the protein encoded by this gene is assumed to be nuclear hormone receptor 2), and NCOA3. In 2021, the M. Andres Blanco research group found that KAT6A can epigenetically regulate the expression of major AML genes, thereby promoting the development of AML. Therefore, inhibition of KAT6A activity can be used as a potential treatment for AML. Analysis of the KAT gene from clinical breast cancer databases revealed that approximately 10% of breast cancer patients, including isoform triple-negative breast cancer, have KAT6 gene amplification or overexpression of KAT6A and KAT6B proteins, suggesting that KAT6A or KAT6B are breast cancer susceptibility genes. Furthermore, studies have shown that a certain percentage of patients with many cancer types (including cervical cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, neuromedulloblastoma, and prostate cancer) have 8p11 amplification and KAT6A overexpression, and KAT6A ranks 12th among the most common amplified genes in cancer.

[0005] In summary, the development of inhibitors targeting KAT6A and KAT6B has broad clinical value not only in meeting unmet clinical needs for ER+ breast cancer, triple-negative breast cancer, and acute myeloid leukemia (AML), but also in other cancer types. However, currently, only Pfizer's PF-07248144 (NCT04606446) is in Phase I clinical trials. Furthermore, as can be seen from the disclosed clinical data, the long half-life of these molecules, combined with very high exposure levels, leads to severe in vivo accumulation, resulting in severe toxicity and side effects. Therefore, the development and optimization of KAT6A and KAT6B inhibitors to resolve or mitigate the safety risks caused by severe accumulation still requires significant research effort. [Overview of the Initiative]

[0006] This disclosure provides sulfonamide compounds, pharmaceutical compositions and applications thereof, which may be used to treat related cancerous conditions by inhibiting histone acetylation, inhibiting the transcription of related genes, and inhibiting cell growth.

[0007] In the first aspect, the disclosure relates to the following formula (I): [ka] (I) [In the formula, Ring A is selected from a 5-membered saturated ring, a 6-membered saturated ring, a 7-membered saturated ring, a 5-membered unsaturated ring, a 6-membered unsaturated ring, a C3-C8 spiro ring, a bridging ring, an azaspiro ring, or an azabridging ring. R1 is absent and is present in the following groups: methoxy group, ethoxy group, halogen, cyano group, nitro group, hydroxy group, alkynyl group, alkynyl group containing R6 substituent, aryl group, aryl group containing R6 substituent, heteroaryl group, heteroaryl group containing R6 substituent, alkyl group, alkyl group containing R6 substituent, cycloalkyl group, cycloalkyl group containing R6 substituent, alkoxy group, alkoxyalkyl group, alkoxyalkyl group containing R6 substituent, alkylamino group, alkylamino group containing R6 substituent, alkylmercapto group, alkylmercapto group containing R6 substituent, cyclo R6 is selected from an alkoxy group, a cycloalkoxy group containing an R6 substituent, a cycloalkylmercapto group, a cycloalkylmercapto group containing an R6 substituent, a sulfonamide group, a sulfonamide group containing an R6 substituent, a phosphoryl group, or a phosphoryl group containing an R6 substituent, of which R6 is selected from a halogen, a cyano group, a nitro group, a hydroxyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkoxyalkyl group, an alkylamino group, an alkylmercapto group, a cycloalkoxy group, a cycloalkylmercapto group, a sulfonamide group, or a phosphoryl group, and unlike R1 and R6, R2 is absent and is selected from halogen, cyano group, nitro group, hydroxyl group, aryl group, heteroaryl group, alkyl group, cycloalkyl group, alkoxy group, alkoxyalkyl group, alkylamino group, alkylmercapto group, cycloalkoxy group, cycloalkylmercapto group, sulfonamide group, or phosphoryl group. R3 is selected from a methyl group, fluorine, or hydrogen. R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from alkyl groups, cycloalkyl groups, azacyclyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkylcycloalkoxy groups, oxy groups, oxy groups substituted with R7, amino groups, amino groups substituted with R7, cycloalkyl groups, cycloalkyl groups substituted with R7, azacycloalkyl groups, azacycloalkyl groups substituted with R7, aryl groups, aryl groups substituted with R7, heteroaryl groups, or heteroaryl groups substituted with R7, of which R7 is selected from methyl groups, fluoro groups, difluoro groups, cyano groups, alkyl groups, cycloalkyl groups, alkoxy groups, alkylamino groups, alkylmercapto groups, or hydrogen, and unlike R5 and R7, Y is selected from C, CH, O, NH, or N-R8, and Z is selected from C, CH, O, NH, or N-R8, of which R8 is selected from hydrogen, methyl groups, ethyl groups, cyclobutyl groups, hydroxyethyl groups, hydroxymethyl groups, or -CH2OCH3. X is chosen from either O or S. This invention provides sulfonamide compounds having the structure shown, stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, and pharmaceutically acceptable salts thereof.

[0008] In a second aspect, the present disclosure relates to the following formula (II): [ka] (II) [In the formula, Ring A is selected from a 5-membered saturated ring, a 6-membered saturated ring, a 7-membered saturated ring, a 5-membered unsaturated ring, a 6-membered unsaturated ring, a C3-C8 spiro ring, a bridging ring, an azaspiro ring, or an azabridging ring. R1 is absent, and contains methoxy, ethoxy, halogen, cyano, nitro, hydroxy, alkynyl, and alkynyl groups containing R6 substituents. R6 is selected from aryl groups, aryl groups containing an R6 substituent, heteroaryl groups, heteroaryl groups containing an R6 substituent, alkyl groups, alkyl groups containing an R6 substituent, cycloalkyl groups, cycloalkyl groups containing an R6 substituent, alkoxy groups, alkoxy groups containing an R6 substituent, alkoxyalkyl groups, alkoxyalkyl groups containing an R6 substituent, alkylamino groups, alkylamino groups containing an R6 substituent, alkyl mercapto groups, alkyl mercapto groups containing an R6 substituent, cycloalkoxy groups, cycloalkoxy groups containing an R6 substituent, cycloalkyl mercapto groups, cycloalkyl mercapto groups containing an R6 substituent, sulfonamide groups, sulfonamide groups containing an R6 substituent, phosphoryl groups, or phosphoryl groups containing an R6 substituent, of which R6 is selected from halogens, cyano groups, nitro groups, hydroxyl groups, alkynyl groups, aryl groups, heteroaryl groups, alkyl groups, cycloalkyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkyl mercapto groups, cycloalkoxy groups, cycloalkyl mercapto groups, sulfonamide groups, or phosphoryl groups, and unlike R1 and R6, R2 is absent and is selected from halogen, cyano group, nitro group, hydroxyl group, aryl group, heteroaryl group, alkyl group, cycloalkyl group, alkoxy group, alkoxyalkyl group, alkylamino group, alkylmercapto group, cycloalkoxy group, cycloalkylmercapto group, sulfonamide group, or phosphoryl group. R3 is selected from a methyl group, fluorine, or hydrogen. R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from alkyl groups, cycloalkyl groups, azacyclyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkylcycloalkoxy groups, oxy groups, oxy groups substituted with R7, amino groups, amino groups substituted with R7, cycloalkyl groups, cycloalkyl groups substituted with R7, azacycloalkyl groups, azacycloalkyl groups substituted with R7, aryl groups, aryl groups substituted with R7, heteroaryl groups, or heteroaryl groups substituted with R7, of which R7 is selected from methyl groups, fluoro groups, difluoro groups, cyano groups, alkyl groups, cycloalkyl groups, alkoxy groups, alkylamino groups, alkylmercapto groups, or hydrogen, and unlike R5 and R7, Y is selected from C, CH, O, NH, or N-R8, and Z is selected from C, CH, O, NH, or N-R8, of which R8 is selected from hydrogen, methyl groups, ethyl groups, cyclobutyl groups, hydroxyethyl groups, hydroxymethyl groups, or -CH2OCH3. X is chosen from either O or S. This invention provides sulfonamide compounds having the structure shown, stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, and pharmaceutically acceptable salts thereof.

[0009] In a third aspect, the present disclosure relates to the following formula (III): [ka] (III) [In the formula, [ka] It is selected from single bonds or double bonds. R 11 , R 13 , R 14 and R x Each of these is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C6 alkyl group, and substituted or unsubstituted C1-C6 alkoxy group, and the substituents of the above C1-C6 alkyl group and C1-C6 alkoxy group are independently selected from hydrogen, halogen, hydroxyl group, and cyano group. Preferably, R 11 , R 13, R 14 and R x are each independently selected from a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C1-C3 alkoxy group, and the substituents of the C1-C3 alkyl group and the C1-C3 alkoxy group are each independently selected from hydrogen, halogen, a hydroxy group, and a cyano group. More preferably, R 11 , R 13 , R 14 and R x are each independently selected from a substituted or unsubstituted methyl group, an ethyl group, a methoxy group, or an ethoxy group, and the substituents of the methyl group, the ethyl group, the methoxy group, or the ethoxy group are each independently selected from halogen, a hydroxy group, and a cyano group] To provide a sulfonamide compound having a structure represented by, a stereoisomer thereof, an isotope derivative, a hydrate, a solvate, a prodrug, and a pharmaceutically acceptable salt.

[0010] R 15 is selected from a substituted or unsubstituted 5- to 6-membered heteroaryl group, and preferably, R 15 is selected from a substituted or unsubstituted 5-membered heteroaryl group.

[0011] X is selected from O or S.

[0012] In a fourth aspect, the present disclosure provides a sulfonamide compound represented by any one of the above-described formulas (I) to (III), a stereoisomer thereof, an isotope derivative, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt, an enantiomer of the sulfonamide compound represented by any one of formulas (I) to (III), a diastereoisomer, a pharmaceutical salt, a solvate, and a pharmaceutical composition comprising any one of pharmaceutically acceptable carriers).

[0013] In a fifth aspect, the present disclosure further provides an application of the pharmaceutical composition in a drug for treating a disease associated with KAT6 amplification or KAT6 overexpression.

[0014] The proposed technology of this disclosure has at least the following beneficial effects. This disclosure provides a sulfonamide compound having a benzoheterocyclic structure and a pyridoisoxazole structure, wherein the sulfonamide compound competitively targets and binds to the substrate and KAT6A / KAT6B in the binding pocket of the KAT6A / KAT6B substrate acetyl coenzyme, of which the benzoheterocyclic structure can effectively increase the electron cloud density of the sulfonamide group portion, effectively enhance the ability of the two oxygen atoms in the sulfonyl group to act as hydrogen bond acceptors, and increase the affinity for binding of the compound to the pocket, while the pyridoisoxazole structure, in which the benzene ring is substituted with pyridine, can effectively reduce the electron cloud density of NO in the isoxazole, reduce the space and degrees of freedom of the lone pair of electrons of oxygen, reduce spatial collisions, and make the binding of the compound to the pocket more suitable. The binding of these two compounds significantly enhances the ability of the compound to competitively bind to acetylcoenzyme and KAT6A / KAT6B, inhibiting acetylcoenzyme from binding to KAT6A / KAT6B and catalyzing histone-related sites, thereby preventing the expression of genes that induce cancer cell growth, and is used to treat tumor diseases associated with amplification of the KAT6A / KAT6B gene or overexpression of the KAT6A / KAT6B protein.

[0015] In particular, the compounds of the examples of this disclosure exhibit relatively good target selectivity. For example, compared to other isoforms of KAT6, the compounds of this disclosure have better selectivity for KAT6A and / or KAT6B, while also having better bioavailability and higher tumor inhibitory activity. [Modes for carrying out the invention]

[0016] To better explain the contents of this disclosure and to facilitate understanding of the proposed technology, the disclosure will be described in further detail below. It will be clear that the embodiments or examples described are only some, and not all, of the embodiments or examples of this disclosure. All other embodiments or examples that a person skilled in the art could obtain based on the embodiments or examples of this disclosure without requiring inventive effort are all within the scope of protection of the claims of this disclosure.

[0017] This disclosure is based on the following formula (I): [ka] (I) [In the formula, Ring A is selected from a 5-membered saturated ring, a 6-membered saturated ring, a 7-membered saturated ring, a 5-membered unsaturated ring, a 6-membered unsaturated ring, a C3-C8 spiro ring, a bridging ring, an azaspiro ring, or an azabridging ring. R1 is absent and is present in the following groups: methoxy group, ethoxy group, halogen, cyano group, nitro group, hydroxy group, alkynyl group, alkynyl group containing R6 substituent, aryl group, aryl group containing R6 substituent, heteroaryl group, heteroaryl group containing R6 substituent, alkyl group, alkyl group containing R6 substituent, cycloalkyl group, cycloalkyl group containing R6 substituent, alkoxy group, alkoxyalkyl group, alkoxyalkyl group containing R6 substituent, alkylamino group, alkylamino group containing R6 substituent, alkylmercapto group, alkylmercapto group containing R6 substituent, cyclo R6 is selected from an alkoxy group, a cycloalkoxy group containing an R6 substituent, a cycloalkylmercapto group, a cycloalkylmercapto group containing an R6 substituent, a sulfonamide group, a sulfonamide group containing an R6 substituent, a phosphoryl group, or a phosphoryl group containing an R6 substituent, of which R6 is selected from a halogen, a cyano group, a nitro group, a hydroxyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkoxyalkyl group, an alkylamino group, an alkylmercapto group, a cycloalkoxy group, a cycloalkylmercapto group, a sulfonamide group, or a phosphoryl group, and R1 and R6 are different. The present invention provides sulfonamide compounds selected from the compounds represented by [formula], their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

[0018] R2 is absent and is selected from halogen, cyano group, nitro group, hydroxyl group, aryl group, heteroaryl group, alkyl group, cycloalkyl group, alkoxy group, alkoxyalkyl group, alkylamino group, alkylmercapto group, cycloalkoxy group, cycloalkylmercapto group, sulfonamide group, or phosphoryl group. R3 is selected from a methyl group, fluorine, or hydrogen, and R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from alkyl groups, cycloalkyl groups, azacyclyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkylcycloalkoxy groups, oxy groups, oxy groups substituted with R7, amino groups, amino groups substituted with R7, cycloalkyl groups, cycloalkyl groups substituted with R7, azacycloalkyl groups, azacycloalkyl groups substituted with R7, aryl groups, aryl groups substituted with R7, heteroaryl groups, or heteroaryl groups substituted with R7. Of these, R7 is selected from methyl groups, fluoro groups, difluoro groups, cyano groups, alkyl groups, cycloalkyl groups, alkoxy groups, alkylamino groups, alkylmercapto groups, or hydrogen. Unlike R5 and R7, Y is selected from C, CH, O, NH or N-R8, and Z is selected from C, CH, O, NH or N-R8, of which R8 is selected from hydrogen, methyl group, ethyl group, cyclobutyl group, hydroxyethyl group, hydroxymethyl group or -CH2OCH3. X is chosen from either O or S.

[0019] In some embodiments, the sulfonamide compound is given by the following formula (II): [ka] (II) [In the formula, Ring A is selected from a 5-membered saturated ring, a 6-membered saturated ring, a 7-membered saturated ring, a 5-membered unsaturated ring, a 6-membered unsaturated ring, a C3-C8 spiro ring, a bridging ring, an azaspiro ring, or an azabridging ring. R1 is absent and is present in the following groups: methoxy group, ethoxy group, halogen, cyano group, nitro group, hydroxy group, alkynyl group, alkynyl group containing R6 substituent, aryl group, aryl group containing R6 substituent, heteroaryl group, heteroaryl group containing R6 substituent, alkyl group, alkyl group containing R6 substituent, cycloalkyl group, cycloalkyl group containing R6 substituent, alkoxy group, alkoxyalkyl group, alkoxyalkyl group containing R6 substituent, alkylamino group, alkylamino group containing R6 substituent, alkylmercapto group, alkylmercapto group containing R6 substituent, cyclo R6 is selected from an alkoxy group, a cycloalkoxy group containing an R6 substituent, a cycloalkylmercapto group, a cycloalkylmercapto group containing an R6 substituent, a sulfonamide group, a sulfonamide group containing an R6 substituent, a phosphoryl group, or a phosphoryl group containing an R6 substituent, of which R6 is selected from a halogen, a cyano group, a nitro group, a hydroxyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkoxyalkyl group, an alkylamino group, an alkylmercapto group, a cycloalkoxy group, a cycloalkylmercapto group, a sulfonamide group, or a phosphoryl group, and unlike R1 and R6, R2 is absent and is selected from halogen, cyano group, nitro group, hydroxyl group, aryl group, heteroaryl group, alkyl group, cycloalkyl group, alkoxy group, alkoxyalkyl group, alkylamino group, alkylmercapto group, cycloalkoxy group, cycloalkylmercapto group, sulfonamide group, or phosphoryl group. R3 is selected from a methyl group, fluorine, or hydrogen, and R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from alkyl groups, cycloalkyl groups, azacyclyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkylcycloalkoxy groups, oxy groups, oxy groups substituted with R7, amino groups, amino groups substituted with R7, cycloalkyl groups, cycloalkyl groups substituted with R7, azacycloalkyl groups, azacycloalkyl groups substituted with R7, aryl groups, aryl groups substituted with R7, heteroaryl groups, or heteroaryl groups substituted with R7. Of these, R7 is selected from methyl groups, fluoro groups, difluoro groups, cyano groups, alkyl groups, cycloalkyl groups, alkoxy groups, alkylamino groups, alkylmercapto groups, or hydrogen. Unlike R5 and R7, Z is selected from C, CH, O, NH or N-R8, Y is selected from C, CH, O, NH or N-R8, of which R8 is selected from hydrogen, methyl group, ethyl group, cyclobutyl group, hydroxyethyl group, hydroxymethyl group or -CH2OCH3, and X is selected from O or S. The compounds are selected from those represented by [the formula], their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

[0020] In one embodiment of the present disclosure, the sulfonamide compound is a compound represented by formula (I) or formula (II), its stereoisomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt, where, Ring A is selected from a five-membered saturated ring, a six-membered saturated ring, a five-membered unsaturated ring, or a six-membered unsaturated ring. R1 is selected from hydrogen, halogen, cyano group, nitro group, hydroxyl group, C2-C6 alkynyl group containing the R6 substituent, C1-C6 alkyl group containing the R6 substituent, and C1-C6 alkoxy group containing the R6 substituent. Of these, the R6 substituent is selected from halogen, cyano group, nitro group, hydroxyl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, or C1-C6 alkoxy group, and R1 and R6 are different.

[0021] R2 is selected from hydrogen, halogen, cyano group, nitro group, hydroxyl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, or C1-C6 alkoxy group. R3 is selected from a methyl group, fluorine, or hydrogen, and R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from heteroaryl groups containing an R6 substituent and aryl groups containing an R6 substituent, of which the R6 substituent is selected from hydrogen, fluoro, cyano groups, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, or C1-C6 alkoxy groups. Y is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. Z is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. X is chosen from either O or S.

[0022] In another embodiment of the present disclosure, the sulfonamide compound is a compound represented by formula (I) or formula (II), its stereoisomer, isotopic derivative, hydrate, solvate, prodrug or pharmaceutically acceptable salt, where, Ring A is selected from a five-membered saturated ring, a six-membered saturated ring, a five-membered unsaturated ring, or a six-membered unsaturated ring. R1 is selected from hydrogen, halogen, cyano group, nitro group, hydroxyl group, C2-C4 alkynyl group containing the R6 substituent, C1-C4 alkyl group containing the R6 substituent, or C1-C4 alkoxy group containing the R6 substituent. Of these, R6 is selected from halogen, hydroxyl group, C1-C4 alkyl group, C3-C4 cycloalkyl group, or C1-C4 alkoxy group, and is different from R1 and R6.

[0023] R2 is selected from hydrogen, halogen, hydroxyl group, C1-C4 alkyl group, or C1-C4 alkoxy group. R3 is selected from a methyl group, fluorine, or hydrogen, and R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from heteroaryl groups containing an R6 substituent and aryl groups containing an R6 substituent, of which the R6 substituent is selected from hydrogen, fluoro, cyano groups, C1-C4 alkyl groups, C3-C4 cycloalkyl groups, or C1-C4 alkoxy groups. Y is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. Z is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. X is chosen from either O or S.

[0024] In further embodiments of the present disclosure, the sulfonamide compound is a compound represented by formula (I) or formula (II), its stereoisomer, isotopic derivative, hydrate, solvate, prodrug or pharmaceutically acceptable salt, where, Ring A is selected from a five-membered saturated ring, a six-membered saturated ring, a five-membered unsaturated ring, or a six-membered unsaturated ring. R1 is selected from hydrogen, halogen, methoxy group, ethoxy group, methyl group, ethyl group, or a C2-C4 alkynyl group containing an R6 substituent, of which the R6 substituent is selected from halogen, hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, or cyclobutyl group. R2 is selected from hydrogen, halogen, hydroxyl group, methyl group, ethyl group, methoxy group, or ethoxy group. R3 is selected from a methyl group, fluorine, or hydrogen, and R4 is selected from a methyl group, fluorine, or hydrogen. R5 is selected from heteroaryl groups containing an R6 substituent and aryl groups containing an R6 substituent, of which the R6 substituent is selected from hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups. Y is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. Z is selected from CH, CH2, O, S, N, or N-R8, of which R8 is selected from hydrogen, a methyl group, or an ethyl group. X is chosen from either O or S.

[0025] In some embodiments, the sulfonamide compound is a compound represented by formula (I) or formula (II), its stereoisomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt, where, [ka] The following condensed bicyclic structures are selected: [ka] Here, [ka] It is selected from single bonds or double bonds. Preferably, the aminosulfonyl fragment (-S(=O)2-NH-) and R1 are located at the phenyl group of the condensed bicyclic structure.

[0026] In some embodiments, the sulfonamide compound is of formula (III): [ka] (III) The compounds represented by, their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, Here, [ka] It is selected from single bonds or double bonds. R 11 , R 12 , R 13 , R 14 , R x Each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and substituted or unsubstituted C2-C6 alkynyl group. Preferably, R 11 , R 12 , R 13 , R14 , R x Each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted C1-C3 alkoxy group, or substituted or unsubstituted C2-C4 alkynyl group. More preferably, R 11 , R 12 , R 13 , R 14 , R x Each of these groups is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted methyl group, substituted or unsubstituted ethyl group, substituted or unsubstituted methoxy group, substituted or unsubstituted ethoxy group, or substituted or unsubstituted ethynyl group. Each of the substituents on the above groups is independently selected from halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, or C3-C6 cycloalkyl group. Preferably, each of the substituents on the above groups is independently selected from halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C1-C3 alkoxy group, or C3-C4 cycloalkyl group, and more preferably, each of the substituents on the above groups is independently selected from halogen, hydroxyl group, cyano group, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, or cyclobutyl group. R 15 R is selected from a 5-6 membered heteroaryl group containing an R6 substituent. Preferably, 15 R6 is selected from a 5-membered heteroaryl group containing an R6 substituent. The R6 substituent is selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group or C1-C6 alkoxy group. Preferably, R6 is selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C3-C4 cycloalkyl group or C1-C3 alkoxy group. More preferably, R6 is selected from hydrogen, fluoro, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group or cyclobutyl group. X is chosen from either O or S.

[0027] In some embodiments, the aminosulfonyl fragment (-S(=O)2-NH-) and R in formula (III) 11It is located at the phenyl group of the oxygen-containing condensed ring biring. Preferably, the aminosulfonyl fragment (-S(=O)2-NH-) is located at the 6th or 7th position of the oxygen-containing condensed ring biring, R 11 It is located at the 5th or 6th position of the condensed ring biring. More preferably, an aminosulfonyl fragment (-S(=O)2-NH-) and R 11 It is located in the ortho position of the benzene ring in the oxygen-containing condensed ring biring.

[0028] In one embodiment, the aminosulfonyl fragment (-S(=O)2-NH-) is located at the 6-position of the oxygen-containing condensed ring biring, and R 11 In another embodiment, the aminosulfonyl fragment (-S(=O)2-NH-) is located at the 7th position of the oxygen-containing condensed ring biring, and R 11 It is located at the 6th position of the oxygen-containing condensed ring biring.

[0029] In some other embodiments, the sulfonamide compound is a structural compound of formula (III), where, [ka] It is selected from single bonds or double bonds. R 11 This is selected from hydrogen, a C1-C6 alkoxy group, and a C2-C6 alkynyl group containing a C3-C6 cycloalkyl substituent, preferably R 11 This group is selected from hydrogen, a methoxy group, an ethoxy group, an ethynyl group, or a cyclopropyl-ethynyl group.

[0030] R 12 is selected from hydrogen or a C1-C6 alkyl group. Preferably, R 12 This is selected from hydrogen, a methyl group, or an ethyl group.

[0031] R 13 , R 14 Each is independently selected from hydrogen or halogen. Preferably, R 13 , R 14 Each of these is independently selected from hydrogen or F.

[0032] R x is selected from hydrogen or a C1-C6 alkoxy group. Preferably, R x This is selected from hydrogen, a methoxy group, or an ethoxy group.

[0033] R 15 teeth, [ka] Selected from, R6 is selected from hydrogen, halogen, or C1-C6 alkyl group. Preferably, R6 is selected from hydrogen, fluorine, a methyl group, or an ethyl group.

[0034] X is chosen from O.

[0035] In some embodiments, R5 in the compound represented by formula (I) or formula (II), or R in the compound represented by formula (III) 15 R6 may be any one independently selected from the following groups, where R6 independently has the definition of each of the above structural formulas: [ka]

[0036] Preferably, R5 or R 15 is one of the following groups, independently selected: [ka]

[0037] More preferably, R5 or R 15 Independently [ka] They are selected from among them.

[0038] In some embodiments, the sulfonamide compound is of formula (IV): [ka] (IV) [In the formula, Ring B, together with its fused phenyl group, forms a 9-10 membered fused heterocycle, and the fused heterocycle is a partially saturated or aromatic fused heterocycle, and the ring B portion contains 1-3 heteroatoms selected from N, O, or S, or the ring B portion, together with its fused phenyl group, forms a C9-C10 fused carbon ring, and the fused carbon ring is a partially saturated or aromatic fused carbon ring. R 11 , R 12 , R 13 , R 14 , R x These are homologous or different, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl group, cyano group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl group, and substituted or unsubstituted alkynyl group, preferably R 11 , R 12 , R 13 , R 14 , R x R is homologous or homologous, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl group, cyano group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C6 cycloalkyl group, and substituted or unsubstituted C2-C6 alkynyl group, more preferably R 11 , R 12 , R 13 , R 14 , R x These are homologous or different, and each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted C1-C3 alkoxy group, or substituted or unsubstituted C2-C4 alkynyl group, and more preferably R 11 , R 12 , R 13 , R 14 , R xThese groups are homologous or homologous, and each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted methyl group, substituted or unsubstituted ethyl group, substituted or unsubstituted methoxy group, substituted or unsubstituted ethoxy group, or substituted or unsubstituted ethynyl group, and preferably, if the above group is substituted, the substituent is homologous or homologous, and each is independently selected from halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, or C3-C6 cycloalkyl group, more preferably, if the above group is substituted, the substituent is homologous or homologous, and each is independently selected from halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C1-C3 alkoxy group, or C3-C4 cycloalkyl group, and even more preferably, if the above group is substituted, the substituent is homologous or homologous, and each is independently selected from halogen, hydroxyl group, cyano group, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, or cyclobutyl group. R 15 The group is optionally selected from hydroxyl groups, amino groups, alkoxy groups, heterocyclyl groups, and heteroaryl groups substituted with an R6 substituent, preferably R 15 The R6 substituent is optionally selected from a hydroxyl group, amino group, C1-C6 alkoxy group, 4-6 membered heterocyclyl group, or 5-6 membered heteroaryl group, of which the heterocyclyl group contains 1-2 heteroatoms selected from N, O, or S, and the heteroaryl group contains 1, 2, or 3 heteroatoms selected from N, O, or S. If present, the R6 substituent is selected from hydrogen, halogen, hydroxyl group, cyano group, alkyl group, cycloalkyl group, alkoxy group, or alkylcarbonyl group, and preferably the R6 substituent is selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, or C1-C6 alkylcarbonyl group. X is selected from O or S. m and n are either homologous or different, and are each independently chosen from the integers 0, 1, 2, and 3. The compound represented by , its stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

[0039] In one form of the compound shown in formula (IV), ring B forms a 9-10 membered condensed heterocycle with its condensed phenyl group, the condensed heterocycle is partially saturated or aromatic, the ring B portion contains 1-2 heteroatoms selected from N, O, or S, the heteroatoms are linked to the condensed phenyl group, or the ring B portion forms a C9-C10 condensed carbon ring with its condensed phenyl group, the condensed carbon ring is partially saturated or aromatic, preferably the condensed carbon ring is partially saturated.

[0040] In one form of the compound shown in formula (IV), [ka] The following condensed bicyclic structures are selected: [ka] Here, [ka] The bond is selected from single or double bonds, preferably an aminosulfonyl fragment (-S(=O)2-NH-) and R 11 All of them have a condensed biringular structure. [ka] Bonded to the phenyl group in R 11 If it is not hydrogen, then an aminosulfonyl fragment (-S(=O)2-NH-) and at least one R 11 It has a condensed biringular structure. [ka] It bonds to the ortho position of the phenyl group in [the compound]. For example, the sulfonyl group in the aminosulfonyl fragment (-S(=O)2-NH-) is [ka] The non-condensed covalent carbon atoms of the benzene ring in the following formula may be bonded to, for example, the carbon atoms at positions a, b, c, or d: [ka] In one form of the compound shown in formula (IV), R x This is selected from substituted or unsubstituted C1-C6 alkoxy groups, preferably a substituted or unsubstituted C1-C3 alkoxy group, and more preferably a substituted or unsubstituted methoxy group.

[0041] In one form of the compound shown in formula (IV), R 11 The group is selected from hydrogen, deuterium, halogen, cyano group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C6 cycloalkyl group, and optionally a C2-C6 alkynyl group substituted with a C3-C6 cycloalkyl group, preferably hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted C1-C3 alkoxy group, substituted or unsubstituted C3-C4 cycloalkyl group, and optionally a C2-C4 alkynyl group substituted with a C3-C4 cycloalkyl group, and more preferably H, F, Cl, cyano group, methoxy group, cyclopropyl group, ethynyl group, and cyclopropylalkynyl group.

[0042] In one form of the compound shown in formula (IV), R 12 The group is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C1-C6 alkoxy groups, preferably hydrogen, deuterium, halogen, substituted or unsubstituted C1-C3 alkyl groups, and substituted or unsubstituted C1-C3 alkoxy groups, and more preferably H, deuterium, F, Cl, methyl group, and methoxy group.

[0043] In one form of the compound shown in formula (IV), R 13 , R 14Each of these is independently selected from hydrogen, deuterium, halogen, and substituted or unsubstituted C1-C6 alkyl groups, preferably hydrogen, deuterium, F, Cl, Br, and substituted or unsubstituted C1-C3 alkyl groups, and more preferably hydrogen, deuterium, and F.

[0044] In one form of the compound shown in formula (IV), R 15 The group is selected from a 4-6 membered heterocyclyl group or a 5-6 membered heteroaryl group optionally substituted with an R6 substituent, wherein the heterocyclyl group contains 1-2 heteroatoms selected from N, and the heteroaryl group contains 1-3 heteroatoms selected from N, preferably a 4-5 membered heterocyclyl group or a 5 membered heteroaryl group, wherein the heterocyclyl group contains 1 heteroatom selected from N, and the heteroaryl group contains 1-3 heteroatoms selected from N, more preferably a 5 membered heteroaryl group, wherein the heteroaryl group contains 2 heteroatoms selected from N. In particular, R 15 The following are selected from the following bases: [ka] The above R6 substituent is selected from hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylcarbonyl group, preferably the above R6 substituent is selected from hydrogen, halogen, C1-C3 alkyl group, C1-C3 alkoxy group, and C1-C3 alkylcarbonyl group, more preferably the above R6 substituent is selected from hydrogen, fluoro, methyl group, ethyl group, methoxy group, ethoxy group, and acetyl group, and most preferably hydrogen, fluoro, and methyl group.

[0045] This disclosure further provides compounds represented by formulas (I), (II), (III), or (IV), stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically usable salts thereof.

[0046] In preferred embodiments, the compounds represented by formula (I), (II), (III), or (IV) above, their deuterides, hydrates, solvates, stereoisomers, or pharmaceutically active salts may be selected from the following compounds, their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically active salts. [ka] [ka]

[0047] The present disclosure preferably includes the following compounds, their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts. [ka]

[0048] The present disclosure more preferably relates to the following compounds, their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts. [ka]

[0049] According to embodiments of this disclosure, the isotope derivative may be a deuterated compound.

[0050] According to the above configuration, the sulfonamide compound of the Disclosure has a benzoheterocyclic structure and a pyridoisoxazole structure. By including the benzoheterocyclic structure located on one side of the sulfonamide group, the electron cloud density of the sulfonamide group portion is effectively increased, effectively enhancing the ability of the two oxygen atoms in the sulfonamide group to act as hydrogen bond acceptors, and increasing the affinity for binding to the pocket of the compound of the Disclosure. On the other hand, the pyridoisoxazole structure, in which the benzene ring is substituted with pyridine, effectively reduces the electron cloud density of NO in the isoxazole, decreasing the space and degrees of freedom of the lone pair of electrons of oxygen, reducing spatial collisions, and making the binding to the pocket of the compound of the Disclosure more suitable. The binding of both significantly improves the ability of the compound of the Disclosure to competitively bind to acetylcoenzymes KAT6A and KAT6B, and is significantly superior to similar compounds reported.

[0051] In some embodiments, the sulfonamide compounds of the present disclosure may also include compounds of formulas (I) to (IV), their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, such as enantiomers, diastereoisomers, pharmaceutically acceptable salts, prodrugs, isotopic derivatives, and solvates, and it is understood that conventional designs can be carried out based on the compounds of formulas (I) to (IV) of the present disclosure as active reactants, thereby maintaining the pharmacokinetic properties of the compounds of formulas (I) to (IV).

[0052] This disclosure further provides pharmaceutical compositions comprising a compound represented by formulas (I) to (IV) as an active ingredient, one of its stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, for example, one of the enantiomers, diastereoisomers, pharmaceutically acceptable salts, solvates, and pharmaceutically acceptable carriers of the compound. The pharmaceutical compositions of this application may be used for drugs to treat diseases associated with KAT6 (preferably KAT6A and / or KAT6B) amplification or overexpression.

[0053] This disclosure also relates to the use of any one of the compounds represented by formulas (I) to (IV), their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts, for example, the compounds of formulas (I) to (IV) or their pharmaceutically acceptable salts, in the manufacture of drugs for treating and / or preventing diseases associated with KAT6 amplification or overexpression.

[0054] This disclosure further relates to a method for diagnosing, preventing or treating a disease associated with KAT6 amplification or overexpression, comprising administering to a patient in need a therapeutically effective amount and / or a prophylactically effective amount of any one of the compounds represented by formulas (I) to (IV), their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically effective salts, for example, the compounds represented by formulas (I) to (IV) or their pharmaceutically effective salts, or a pharmaceutical composition.

[0055] According to embodiments of this disclosure, diseases associated with KAT6 amplification or overexpression include cancers comprising at least one of the following: breast cancer, triple-negative breast cancer, acute myeloid leukemia, lung cancer, lung adenocarcinoma, hematological malignancies, gastrointestinal tumors, genital tumors, prostate cancer, nervous system tumors, or head and neck cancers. Of these, breast cancer is preferably ER+ breast cancer or ER+ / HER2- breast cancer, lung cancer is preferably non-small cell lung cancer, and prostate cancer is preferably castration-resistant prostate cancer.

[0056] Beneficial effects Compared to KAT6-targeting compounds known in the prior art, the compounds of the present disclosure not only exhibit relatively good target selectivity and higher protein-level inhibitory effects, but more advantageously, the preferred compounds of the present disclosure have a suitable half-life, are clinically suited to a once-daily administration regimen, and, when combined with their relatively appropriate exposure levels, are even less likely to cause in vivo accumulation, thereby effectively reducing the safety risks associated with the accumulation of the compounds.

[0057] This disclosure also discloses a method for producing the above sulfonyl compound, comprising the following reaction pathway and manufacturing steps: [ka] Here, A, Z, Y, R1, R2, and X independently have the definitions described above. Alternatively, C10B is selected from the compounds shown in formula (IV) above.

[0058] Specifically, the manufacturing method includes the following steps: (1) Compound C01 is obtained by ammonia water reacting SM1 with ammonia water at 40-80°C. (2) Compound C01 and phosphorus oxychloride are mixed, followed by the addition of N,N-dimethylformamide, and the mixture is reacted at 50-100°C to obtain compound C02. (3) Compound C02 is dissolved in the first solvent, cesium acetate is added, and the mixture is reacted at 20°C to 100°C to obtain compound C03. (4) Compound C03 is dissolved in methanol, the first basic reagent is added, and compound C04 is obtained under high temperature and high pressure reaction conditions. (5) Compound C04, PCl5 and POCl3 are dissolved in the second solvent and reacted at 20°C to 60°C to obtain compound C05. (6) Compound C05 and N-bromosuccinimide (NBS) are dissolved in the third solvent, a radical initiator is added, and the mixture is reacted at 30°C to 100°C to obtain compound C06. (7) Compound C06 and compound SM2 are dissolved in the fourth solvent, a second basic reagent is added, and an alkylation reaction is carried out to obtain compound C07. (8) Compound C07 and compound SM3 are dissolved in the fifth solvent, the third basic reagent is added, and the mixture is reacted at 20°C to 60°C to obtain compound C08. (9) Dissolve compound SM4A or compound SM4B in solvent 6, add the fourth basic reagent and react at -80°C to -40°C, then inject SO2 gas and react, add N-chlorosuccinimide (NCS) and react at -80°C to -40°C to obtain compound C09A or compound C09B, respectively. (10) Compound C08 and compound C09A or compound C09B are dissolved in solvent number seven, a basic reagent number five is added, and the mixture is reacted at a temperature range of 20°C to 100°C to obtain compound C10A or compound C10B.

[0059] In some embodiments, in step (3), the first solvent comprises at least one of tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile.

[0060] In some embodiments, in step (4), the first basic reagent is selected from at least one of sodium hydride, sodium methoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0061] In some embodiments, in step (5), the second solvent comprises at least one of tetrahydrofuran, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF).

[0062] In some embodiments, in step (6), the third solvent comprises at least one of carbon tetrachloride and benzene.

[0063] In some embodiments, in step (6), the radical initiator comprises at least one of dibenzoyl peroxide (BPO) and azobisisobutyronitrile (AIBN).

[0064] In some embodiments, in step (7), the fourth solvent comprises at least one of tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane, chloroform, N-methylpyrrolidone (NMP), and acetonitrile.

[0065] In some embodiments, in step (7), the second basic reagent comprises at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, sodium hydride, and N,N-diisopropylethylamine.

[0066] In some embodiments, in step (8), the fifth solvent comprises at least one of methanol, ethanol, tert-butanol, isopropanol, and water.

[0067] In some embodiments, in step (8), the third basic reagent comprises at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

[0068] In some embodiments, in step (9), the sixth solvent includes at least one of tetrahydrofuran, dichloromethane, and chloroform.

[0069] In some embodiments, in step (9), the fourth basic reagent includes at least one of n-butyllithium, lithium diisopropylamide (LDA), lithium bistrimethylsilylamide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), and potassium bis(trimethylsilyl)amide (KHMDS).

[0070] In some embodiments, in step (10), the seventh solvent comprises at least one of tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile.

[0071] In some embodiments, in step (10), the fifth basic reagent includes at least one of the following: sodium hydride, lithium diisopropylamide (LDA), lithium bistrimethylsilylamide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, and pyridine.

[0072] In some embodiments, sulfonyl compound C10A is one of the compounds shown in formula I, and sulfonyl compound C10B is one of the compounds shown in formula II.

[0073] In some embodiments, compound C09A may be produced from compound SM4A, and compound C09B may be produced from compound SM4B.

[0074] In other embodiments, compound C09 may be purchased directly, and correspondingly, compound C10 may be obtained according to the following synthesis method. [ka] Here, A, Y, R1, R2, and X independently have the definitions described above. Alternatively, C10 is selected from the compounds shown in formula (IV) above.

[0075] (definition) Unless otherwise defined, terms used herein have the same meanings as those generally understood by those skilled in the art. Terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit this disclosure.

[0076] The compounds defined or disclosed herein include all their stereoisomers, optical isomers, and racemates (if such isomers exist). Unless otherwise stated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of this disclosure. The compounds of this disclosure can be isolated in optically active or racemic forms. Optically active forms can be produced by splitting the racemic form or by synthesis from optically active starting materials. All methods for producing the compounds of this disclosure, and the intermediates produced therein, are considered part of this disclosure. When producing enantiomer or diastereoisomer products, they can be isolated by conventional methods, such as chromatography or fractional crystallization.

[0077] The compounds defined or disclosed by the present disclosure may also exist in multiple geometric isomers such as C=C double bonds, C=N double bonds, and ring systems, and all such stable isomers are included in the present disclosure. The cis and trans (or E and Z) geometric isomers of the compounds of the present disclosure are described and can be isolated in the form of a mixture of isomers or an isolated isomeric form.

[0078] The compounds defined or disclosed by the present disclosure can exist in multiple tautomeric forms, among which a hydrogen atom moves to other parts of the molecule and the chemical bonds between atoms in the molecule are rearranged thereby. It should be understood that all tautomeric forms are included in the present disclosure as much as possible.

[0079] The compounds defined or disclosed by the present disclosure may exist in free form or in the form of pharmaceutically acceptable salts, and thus both the free form and the salts are within the scope of the present disclosure. One form of the compound may be converted to another form as needed. The free base or acid may be converted to a salt, and the salt may be converted to a free compound or another salt.

[0080] The isotope derivatives described herein refer to the fact that the above compounds can include compounds labeled with one or more isotope substitutions or isotopes. For example, H can be 1 H, 2 H (D or deuterium), and 3 H (T or tritium) in any isotopic form, C can be [[ID=~20]] 12 C, 13 C, and 14 C in any isotopic form, and O can be 16 O and 18 O, etc. in any isotopic form.

[0081] In this context, the term "alkyl group" should refer to a linear, branched, or cyclic fully saturated alkyl group that may be optionally substituted, preferably C1-C6, more preferably C1-C4, or C1-C3 alkyl group. Examples of alkyl groups include methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, and 2-methylpropyl groups. The term "alkyl group" in terms such as "alkoxy group," "alkylthio group," and "haloalkyl group" also has the same meaning.

[0082] The term "alkynyl group" refers to a linear or branched C2-C6 alkynyl group containing at least one C≡C bond, and is preferably a C2-C4 alkynyl group.

[0083] In this context, the term "cycloalkyl group" should refer to a C3-C10 monocyclic or polycyclic alkyl group, preferably a C3-C6 cycloalkyl group, and more preferably a C3-C4 cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0084] The terms "heterocycloalkyl group" or "heterocyclyl group" in this context should refer to a 3- to 10-membered cyclyl group containing at least one heteroatom (e.g., N, O, or S), preferably a 3- to 6-membered cyclyl group, which may be, for example, a 3, 4, 5, or 6-membered cyclyl group, and may be aromatic (heteroaryl group) or non-aromatic. This includes azetidinyl group, oxetanyl group, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, tetrahydrofuranyl group, tetrahydropyranyl group, pyranyl group, furanyl group, morpholinyl group, pyrrolyl group, piperidinyl group, imidazolyl group, pyridinyl group, and pyrimidinyl group.

[0085] In this context, the term "aryl group" should refer to a substituted or unsubstituted C6-C10 aromatic group having a monocyclic or fused ring, including phenyl and naphthyl groups.

[0086] In this context, the term "heteroaryl group" should refer to a 5- to 10-membered aromatic group containing at least one heteroatom (e.g., N, O, or S), preferably a 5- to 6-membered aromatic group, which may be a 3, 4, 5, or 6-membered aromatic group, for example, an optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted diazole (pyrazolyl group, imidazolyl group), optionally substituted triazole (1,2,3-triazolyl group, 1,2,4-triazolyl group), optionally substituted thiophene, optionally substituted isothiazole, or optionally substituted pyridine (2-pyridine, 3-pyridine, or 4-pyridine).

[0087] The term "halogen" refers to F, Cl, Br, and I.

[0088] The terms "substituted" or "optionally substituted" mean that there are one or more substituents, preferably 1 to 5 substituents, more preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, at any carbon (or nitrogen) position in the molecule, where each substituent is homologous or homologous, and each substituent may be independently selected from hydroxyl groups, thiols, carboxyl groups, cyano groups, nitro groups, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups, C1-C6 thioethers, C1-C6 acyl groups, C1-C6 alkylamines, C1-C6 dialkylamines, carboxyl groups, and the like.

[0089] The naming of each substituent site is understood according to the usual nomenclature of compounds in this art. For example, for substituent sites on heterocyclic or heteroaromatic rings, it is understood according to the commonly named aryl group of the heterocyclic or heteroaromatic ring. For example, for benzofuran or 2,3-dihydrobenzofuran, the site numbers are as follows: [ka]

[0090] Used in this specification [ka] This represents a chemical bond.

[0091] The term "pharmaceutically acceptable salt" is used to describe a salt form of one or more compounds described herein, provided to increase the solubility of the compounds in gastric juice of a patient's gastrointestinal tract in order to promote the dissolution and bioavailability of the compounds. pharmaceutically acceptable salts, where applicable, include salts derived from pharmaceutically acceptable inorganic or organic bases and acids.

[0092] The term "effective" may mean, but is not limited to, an amount / dose of an active pharmaceutical ingredient that, when used in the context of its intended use, achieves, or is sufficient to, prevent, inhibit the onset of, improve, delay or treat (to some extent, preferably completely relieve) a disease, symptom or condition, in a subject who needs or is receiving such treatment.

[0093] The term "pharmaceutically acceptable carrier" can mean any and all solvents, dispersion media, or coatings suitable for drug administration.

[0094] The embodiments of this disclosure will be further described below in the form of several examples. However, the embodiments of this disclosure are not limited to the following specific examples. They can be appropriately modified and implemented without altering the claims. [Examples]

[0095] Example 1 Sulfonyl compound 1-1: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide: [ka]

[0096] Synthesis pathway [ka]

[0097] Step 1, the production of intermediate C08, includes the following reaction pathway and production steps. [ka]

[0098] Step 1: Preparation of Intermediate C01 Compound SM1 (86.0 g, 1 eq) was added to aqueous ammonia (100 mL), and the reaction system was heated to 50°C under nitrogen gas protection and stirred for 16 hours. A solid precipitated, and liquid chromatography-mass spectrometry (LCMS) indicated completion of the reaction. The mixture was filtered, the filter cake was washed with water, and the filtrate was concentrated to one-third under reduced pressure. The precipitated solid was then filtered again, combined, and dried to obtain the crude intermediate C01 (74.1 g, 96.2% yield), which was used directly in the next step without further treatment.

[0099] Step 2: Production of Intermediate C02 Intermediate C01 (74.1 g, 1 eq) was mixed with POCl3 (800 mL). The mixture was heated to 70°C under nitrogen gas protection and stirred for 30 min. Then, when the temperature was raised to 90°C, DMF (4.0 mL, 0.12 eq) was added and the mixture was stirred for 2 hours to allow the reaction to proceed. LC-MS indicated completion of the reaction, and the mixture was quenched with crushed ice and adjusted to basicity with saturated sodium carbonate solution. At this point, a solid precipitated, which was filtered, the filter cake was collected, washed three times with a small amount of water, and the solid was dried. The mother liquor was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried. All the resulting solids were combined to obtain the crude product of intermediate C02 (64.1 g, 96.2% yield), which was used directly to the next step without further treatment.

[0100] Step 3: Production of Intermediate C03 Intermediate C02 (64.1 g, 1 eq) and CsOAc (192.8 g, 3 eq) were dissolved in DMF (800 mL), heated to 70°C under nitrogen gas protection, and stirred for 16 hours to allow the reaction to proceed. LC-MS indicated completion of the reaction. The reaction system was quenched in an ice water mixture, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotary dried. The resulting crude product was slurryed with a mixed solution of ethyl acetate and n-hexane, filtered, and the resulting filtration cake was dried to obtain the crude intermediate C03 (58.1 g, yield 80.5%), which was used directly in the next step without further processing.

[0101] Step 4: Production of Intermediate C04 58.0 g, 1 eq of CO3, sodium methoxide (149.1 g, 10 eq), and methanol (2 L) were added to a 5 L high-pressure reaction vessel. After purging with nitrogen gas, the mixture was heated to 150°C and reacted for 16 hours at a pressure of 10 standard atmospheric pressure or less. The reaction was monitored by cooling and LC-MS indicated completion of the reaction. The mixture was then cooled to room temperature, the reaction system was added to a small amount of water, and rotary distillation was performed under reduced pressure to remove most of the methanol. The aqueous phase was then acidified with hydrochloric acid to precipitate the solid, which was then filtered, the filter cake was collected, and washed with a small amount of water. The solid was dried. The mother liquor was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotary dried. The resulting solids were combined twice to obtain the crude intermediate CO4 (14.9 g, 80.5% yield), which was used directly in the next step without further processing.

[0102] Step 5: Production of Intermediate C05 At room temperature, a mixture containing intermediate C04 (14.9 g, 1 eq), POCl3 (13.8 g, 1 eq), PCl5 (18.7 g, 1 eq), and DCM (1.2 L) was gradually mixed with DMF (6.7 g, 1 eq). The mixture was heated to 40°C under nitrogen gas protection and stirred for 30 minutes to allow the reaction to proceed. LC-MS revealed approximately 50% of the product, along with some remaining starting material and some dichloro-substituted by-products. After cooling to room temperature, the reaction system was quenched in an ice water mixture, adjusted to basicity with saturated sodium carbonate solution, precipitated the solid, filtered, collected the filter cake, washed with a small amount of water, and dried the solid. The mother liquor was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting solids were combined twice and purified by normal-phase column chromatography to obtain intermediate C05 (5.21 g, 31.5% yield).

[0103] Step 6: Production of Intermediate C06 Intermediate C05 (5.21 g, 1 eq), N-bromosuccinimide (NBS, 5.12 g, 1 eq), and dibenzoyl peroxide (BPO, 1.38 g, 0.2 eq) were dissolved in carbon tetrachloride (400 mL). Under N2 protection, the mixture was heated to 90°C and stirred for 3 hours to allow the reaction to proceed. LC-MS characterized 57% of the product, 20% of the by-products, and the remaining 14% of the starting material. The reaction was stopped, the mixture was cooled to room temperature, quenched with saturated sodium bisulfite solution, and further extracted three times with a large amount of ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The mixture was purified by normal-phase column chromatography to obtain intermediate C06 (2.83 g, 37.9% yield).

[0104] Step 7: Production of Intermediate C07 Intermediate C06 (2.83 g, 1 eq), pyrazole (1.11 g, 1.5 eq), and DIEA (2.79 g, 2 eq) were dissolved in acetonitrile. Under N2 protection, the mixture was heated to 90°C and reacted overnight under reflux with stirring. Reaction completion was characterized by LC-MS, the reaction was stopped, the mixture was cooled to room temperature, and after rotational drying, it was purified by normal-phase column chromatography to obtain intermediate C07 (1.76 g, yield 65.6%).

[0105] Step 8: Production of the main intermediate C08 Intermediate C07 (1.76 g, 1 eq) was dissolved in tert-butanol (200 mL), and then acetohydroxamic acid (1.07 g, 2 eq) and potassium carbonate (1.85 g, 2 eq) were added to the solution. Under N2 protection, the temperature was gradually raised to 30°C, and the mixed solution was stirred overnight to allow the reaction to proceed. Reaction completion was characterized by LC-MS, the reaction was stopped, and the solution was cooled to room temperature. The solution was diluted with ethyl acetate, the carbonate was filtered, the filter cake was washed three times with ethyl acetate, and the filtrates were combined and rotated dry. The resulting residue was purified by normal-phase column chromatography to obtain the main intermediate C08 (1.22 g, 69.5% yield) as a pale yellow solid. MS: [M+1] + : 246.1. 1H NMR (400 MHz, DMSO- d6) δ 7.90 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 6.54 (s, 1H), 6.33(t, J = 2.0 Hz, 1H), 6.21 (s, 2H), 5.42 (s, 2H), 3.98 (s, 3H).

[0106] Step 2: Preparation of 2,3-dihydrobenzofuran-7-sulfonyl chloride (C09A) Compound SM1 (800 mg, 1 eq) was dissolved in freshly distilled tetrahydrofuran (20 mL). After the compound was completely dissolved, n-butyllithium (2.5 M in n-hexane, 1.9 mL, 1.2 eq) was gradually added dropwise at -78°C and the reaction was carried out for 10 minutes. SO2 gas was injected at -78°C for 10 minutes, and after natural warming to room temperature, N-chlorosuccinimide (NCS, 534 mg, 1 eq) was added and the reaction was carried out at room temperature for 1 hour. The reaction system was quenched in saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting solid was purified by normal-phase column chromatography to obtain intermediate C09A (397.2 mg, yield 45.6%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.68 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 8.4 Hz, 1H), 4.91-4.85 (m, 2H), 3.42-3.31 (m, 2H).

[0107] Step 3: Preparation of sulfonyl compound 1-1 Intermediate C08 (25.1 mg, 1 eq) was dissolved in freshly distilled tetrahydrofuran (3 mL). After complete dissolution of the compound, sodium hydride (7.3 mg, 3 eq) was added at 0°C, and the reaction was carried out with stirring under N2 protection at 0°C for 20 minutes. Next, 2,3-dihydrobenzofuran-7-sulfonyl chloride (C09A, 44.6 mg, 2 eq) was added to the reaction system. The mixture was stirred overnight at room temperature, and the completion of the reaction was characterized by LC-MS. The reaction system was quenched in saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined. Washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. Purification by preparative liquid chromatography at high pressure yielded sulfonyl compound 1-1 (10.6 mg, yield 24.2%) as a white solid. MS: [M+1] + : 427.95.

[0108] Sulfonyl compound 1-1 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.05 (s, 1H), 7.89(s, 1H), 7.78 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 6.96-6.86 (m, 1H), 6.62 (s, 1H), 6.33 (s, 1H), 5.43 (s, 2H), 4.61 (t, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.23-3.11 (m, 2H).

[0109] II. A method for producing sulfonyl compounds, which differs from Example 1 in that it is produced according to a production method similar to step-1 of Example 1 to obtain the following sulfonyl chloride compounds (C09) D-1 to D-13, as shown in Table 1 below.

[0110] [Table 1-1] [Table 1-2]

[0111] In Example 1, the sulfonyl chloride compound C09A was replaced with the above compounds D-1 and D-13 to obtain 13 new sulfonamide compounds.

[0112] III. A method for producing a sulfonyl compound, which is different from Example 1 in that the sulfonyl chloride compound C09A is replaced with the structures shown in D-14A and D-14B.

Chemical formula

[0113] Step 1: Production of the sulfonyl chloride compounds D-14A and D-14B, and the synthetic route was as follows.

Chemical formula

[0114] Step - 1: Production of compound D-14A-1 and compound D-14B-1 Under nitrogen gas protection, compound SM1 (19.7 g, 1 eq) was dissolved in a mixed solvent of dichloromethane (500 mL) and methanol (300 mL), and a dichloromethane solution (500 mL) of tetrabutylammonium tribromide (78.1 g, 1.5 eq) was added dropwise at 0 °C. The temperature was raised to room temperature and stirred for 1.5 h, and the completion of the reaction was characterized by GCMS. The reaction system was quenched by adding it to 1 L of water, extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotary dried. The crude product was purified by normal-phase liquid chromatography to obtain a mixture of D-14A-1 and D-14B-1 (16.7 g, yield 57.1%). GCMS (ES, m / z): 240 / 242 [M].

[0115] Step - 2: Production of compound D-14A and compound D-14B A mixture of D-14A-1 and D-14B-1 (2.0 g, 1 eq) was dissolved in freshly distilled tetrahydrofuran (20 mL). Under N2 protection, the mixture was stirred at -78 °C, and n-butyllithium (2.5 M in hexanes, 4.0 mL, 1.2 eq) was added dropwise. The temperature was maintained, and the reaction was allowed to proceed for 10 min. SO2 gas was injected at -78 °C for 10 min. After gradually warming to room temperature, NCS (1.1 g, 1 eq) was added, and the reaction was carried out at room temperature for 1 h. Water was added to the reaction system to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by a normal-phase chromatography column to obtain a mixture of D-14A and D-14B (0.85 g, yield 39.2%, 1 by 1H NMR, D-14A:D-14B = 2:1).

[0116] Sulfonyl chloride compound D-14A 1 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.66 (s, 1H), 6.80 (s, 1H), 4.02 (s, 3H), 2.85 - 2.77 (m, 4H), 1.84 - 1.81 (m, 4H). Sulfonyl chloride compound D-14B 1 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.36 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.27 - 3.25 (m, 2), 2.81 - 2.79 (m, 2H), 1.80 - 1.77 (m, 4H).

[0117] IV. A method for producing a sulfonyl compound, which is different from Example 1 in that C09A is replaced with the structure shown by D-15.

Chemical formula

[0118] Step 1: Preparation of sulfonyl chloride compound D-15, the synthetic route was as follows. [ka]

[0119] Step 1: Preparation of Compound D-15-1 Under nitrogen gas protection, SM1 (5.1 g, 1 eq) was added to a 250 mL three-necked flask, and N,N-diethylformamide (50 mL) was added to the flask to completely dissolve it. After complete dissolution, SM2 (5.7 g, 1.5 eq), potassium iodide (0.41 g, 0.1 eq), and potassium carbonate (8.5 g, 2.5 eq) were added sequentially to the system, and the reaction was carried out overnight at 120°C under nitrogen gas protection. The reaction mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phase was washed three times with saturated sodium chloride solution. The resulting residue was concentrated under reduced pressure, and the crude product was purified by normal-phase column chromatography to obtain D-15-1 (6.1 g, yield 85.1%), a white solid.

[0120] Step 2: Preparation of Compound D-15-2 D-15-1 (6.1 g, 1 eq) was dissolved in toluene (60 mL), polyphosphate (4.11 g, 2 eq) was added to the system, and the mixture was heated to 120°C under nitrogen gas protection and reacted overnight. After the reaction was complete, the reaction product was quenched with crushed ice, extracted three times with ethyl acetate, and the combined organic phase was washed three times with saturated sodium chloride solution. The resulting residue was concentrated under reduced pressure, and the crude product was purified by normal-phase column chromatography to obtain D-15-2 (4.1 g, yield 84.1%), a white solid.

[0121] Step 3: Preparation of Compound D-15 Under nitrogen gas protection, D-15-2 (800 mg, 1 eq) was dissolved in freshly distilled tetrahydrofuran (20.0 mL), and n-butyllithium (2.5 M in n-hexane, 0.34 mL, 1 eq) was slowly added dropwise at -78 °C. The mixture was reacted for 10 min, followed by injecting sulfur dioxide gas for 10 min. Then, the temperature was gradually raised to room temperature, NCS (470 mg, 1 eq) was added, and the mixture was reacted at room temperature for 1 hour. The reaction system was quenched by injecting it into a saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The crude product was purified by a normal-phase chromatography column to obtain the sulfonyl compound D-15 (300 mg, yield 34.5%) as a pale yellow solid.

[0122] Sulfonyl compound D-15 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.87 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 3.80 (s, 3H).

[0123] V. A method for producing a sulfonyl compound, which is different from Example 1 in that C09A is replaced with the structure shown by D-16.

Chemical formula

[0124] Step - 1: Production of compound D-16-1 D-15-2 (3.1 g, 1 eq) was dissolved in ethanol, rhodium carbon (100 mg) was added, and the mixture was reacted with hydrogen gas (1 atm) at room temperature for 4 hours. The completion of the reaction was characterized by GCMS, followed by pressure filtration. The filter cake was washed with ethanol and rotary evaporated to obtain the crude product D-16-1 (2.6 g). The crude product was directly used in the next step without further purification.

[0125] Step - 2: Production of compound D-16 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-16.

[0126] Sulfonyl chloride compound D-16 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.38 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.83 (t, J = 8.4 Hz, 2H), 3.99 (s, 3H), 3.22 (t, J = 8.4 Hz, 2H)

[0127] VI. A method for producing a sulfonyl compound, which differs from Example 1 in that it is produced according to a production method similar to that of D-15, to obtain the following sulfonyl chloride compound D-17 (5-methoxy-2,3-benzofuran-4-sulfonyl chloride), the structure of which is shown below. [ka] (D-17)

[0128] Sulfonyl chloride compound D-17 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 8.01 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 3.84 (s, 3H).

[0129] 7. A method for producing a sulfonyl compound, which differs from Example 1 in that it is produced according to a method similar to that of D-15 to obtain the following sulfonyl chloride compound D-18 (5-methoxy-2,3-benzofuran-6-sulfonyl chloride), the structure of which is shown below. [ka] (D-18)

[0130] Sulfonyl chloride compound D-18 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.89 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 3.80 (s, 3H).

[0131] 8. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-19. [ka]

[0132] The synthesis route for D-19 was as follows: [ka]

[0133] Step 1: Preparation of Compound D-19 Under nitrogen gas protection, a mixture of SM1 (200 mg, 1 eq) and chlorosulfonic acid (5 mL) was heated to 100°C and stirred for 1 hour to allow the reaction to proceed. The completion of the reaction was characterized by LC-MS. The reaction system was quenched in ice water, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted three times with ethyl acetate. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain sulfonyl chloride compound D-19 (67 mg, yield 22.1%), which was a yellow solid.

[0134] Sulfonyl chloride compound D-19 1H NMR (400 MHz, CDCl3-d) δ (ppm): 9.34 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.58-7.54 (m, 2H), 4.23 (s, 3H).

[0135] IX. A method for producing a sulfonyl compound, which differs from Example 1 in that it is produced according to a method similar to that of D-19 to obtain the following sulfonyl chloride compound D-20 (quinoline-8-sulfonyl chloride), the structure of which is shown below. [ka] D-20

[0136] Sulfonyl chloride compound D-20 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.42-9.36(m, 2H), 8.48-8.45(m, 2H), 8.23-8.20(m, 1H), 8.04-8.00(m, 1H).

[0137] 10. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-21. [ka] (D-21)

[0138] The synthesis route for D-21 was as follows: [ka]

[0139] Step 1: Preparation of Compound D-21-1 SM1 (10.1 g, 1 eq) was dissolved in tetrahydrofuran (800 mL), and under nitrogen gas protection, vinyl magnesium bromide (1 M in THF, 120 mL, 3 eq) was added dropwise at -78°C. The reaction was stirred at -78°C for 3 hours and characterized as complete by TLC. The reaction system was quenched in saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-21-1 (3.79 g, yield 38.9%). [M+1] + : 226.05.

[0140] Step 2: Preparation of Compound D-21-2 D-21-1 (3.7 g, 1 eq) was dissolved in tetrahydrofuran (100 mL), and under nitrogen gas protection, sodium hydride (0.98 g, 60% content, 1.5 eq) was added at 0°C. The reaction was carried out with stirring under N2 protection at 0°C for 20 min. Next, iodomethane (3.48 g, 1.5 equiv) was added to the reaction system and the reaction was carried out with stirring at 0°C for 1.5 hours. The completion of the reaction was characterized by LC-MS. The reaction system was quenched in saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound D-21-2 (3.4 g, yield 86.5%). [M+1] + : 240.05. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.48 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4..9 (s, 3H), 3.85 (s, 3H).

[0141] Step 3: Preparation of Compound D-21 Compound D-15 was prepared according to step 3 of the procedure to obtain sulfonyl chloride compound D-21. [M+1] + : 260.10.

[0142] 11. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structures shown in D-22A and D-22B. [ka]

[0143] The synthesis routes for D-22A and D-22B were as follows: [ka]

[0144] Step 1: Preparation of Compound D-22-1 SM1 (15.1 g, 1 eq) and potassium carbonate (16.5 g, 1 eq) were added to acetone (500 mL), and the mixture was stirred at 80°C for 1 hour under nitrogen gas protection. The temperature was then lowered to 0°C, iodomethane (84.8 g, 5.5 equiv) was added, and the temperature was subsequently raised to 80°C and stirred for 16 hours. The reaction was characterized as complete by GC-MS. The reaction system was quenched in water, extracted three times with ethyl acetate, and the combined organic phase was washed three times with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-22-1 (15.1 g, 90.1% yield). GC-MS (ES, m / z): [M] + :152.

[0145] Step 2: Preparation of compounds D-22A-2 and D-22B-2 D-22-1 (5 g, 1 eq) was dissolved in tetrahydrofuran (250 mL), and under nitrogen gas protection, bromine (5.25 g, 1.0 eq) was added dropwise at 0°C. The reaction was carried out with stirring under N2 protection at 0°C for 20 minutes. The reaction system was quenched in saturated sodium carbonate aqueous solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The mixture was purified by normal-phase column chromatography to obtain a mixture of compounds D-22A-2 and D-22B-2 (7.1 g, 92.2% yield). GCMS (ES, m / z): [M] + :230 / 232.

[0146] Step 3: Preparation of Compounds D-22A and D-22B Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compounds D-22A and D-22B.

[0147] Sulfonyl chloride compound D-22A 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.40 (s, 1H), 6.67 (s, 1H), 6.11 (s, 2H), 4.03 (s, 3H).

[0148] Sulfonyl chloride compound D-22B 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.11 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.34 (s, 2H), 3.98 (s, 3H).

[0149] 12. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-23. [ka] (D-23)

[0150] The synthesis route for D-23 was as follows: [ka]

[0151] Step 1: Preparation of Compound D-23-1 At 0°C, sodium hydroxide (14.2 g, 2.4 eq) was dissolved in 59 mL of water. Then, SM1 (30.1 g, 1 eq) and 1,2-dibromoethane (111.1 g, 4 eq) were added to the sodium hydroxide aqueous solution. The temperature was raised to 100°C and the mixture was stirred for 16 hours to allow the reaction to proceed. The completion of the reaction was characterized by TLC. The reaction system was diluted with water and extracted three times with dichloromethane. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-23-1 (28.3 g, yield 56.2%).

[0152] Step 2: Preparation of Compound D-23-2 D-23-1 (20.1 g, 1 eq) was dissolved in tetrahydrofuran (250 mL), and under nitrogen gas protection, n-butyllithium (26 mL, 2.5 M in hexane, 1.0 eq) was added dropwise at -78°C. The mixture was stirred and reacted at -78°C for 2 hours, and the completion of the reaction was characterized by TLC. The reaction system was quenched in saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain a mixture of compound D-23-2 (8.2 g, yield 84.2%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.79 (t, J = 1.2 Hz, 1H), 6.70-6.63 (m, 2H), 4.53 (t, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.18 (t, J = 8.4 Hz, 2H).

[0153] Step 3: Preparation of Compound D-23-3 A mixture of compound D-23-2 (8.2 g, 1 eq) was dissolved in 240 mL of dichloromethane, and dibromohydantoin (11.4 g, 0.5 eq) was added at 0°C. The reaction was stirred and maintained at 0°C for 2 hours, and the completion of the reaction was characterized by TLC. The reaction system was quenched in water, extracted three times with dichloromethane, and the combined organic phase was washed three times with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-23-3 (9.4 g, 75.4% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.06 (s, 1H), 6.98 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.14 (t, J = 8.8 Hz, 2H).

[0154] Step 4: Preparation of Compound D-23 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-23.

[0155] Sulfonyl chloride compound D-23 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.35 (s, 1H), 7.03 (s, 1H), 4.66 (t, J = 8.8 Hz, 2H), 4.02 (s, 3H), 3.33 (t, J = 8.8 Hz, 2H).

[0156] 13. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-24. [ka] (D-24)

[0157] The synthesis route for D-24 was as follows: [ka]

[0158] The sulfonyl chloride compound D-24 was synthesized using SM1 as the starting material, following a manufacturing method similar to that of D-23, and with operating steps similar to steps 1-4 of D-23.

[0159] Sulfonyl chloride compound D-24 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.78 (s, 1H), 6.52 (s, 1H), 4.75 (t, J = 8.8 Hz, 2H), 4.06 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H).

[0160] 14. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-25. [ka] (D-25)

[0161] The synthesis route for D-25 was as follows: [ka]

[0162] Step 1: Preparation of Compound D-25-1 SM1 (1.5 g, 1.0 equiv), SM2 (1.34 g, 1.5 equiv), Pd2(dba)3 (657.1 mg, 0.1 equiv), XantPhos (830.4 mg, 0.2 equiv), and triethylamine (2.18 g, 3 equiv) were dissolved in 1,4-dioxane (20 mL) and reacted overnight at 100°C with nitrogen gas protection. Reaction completion was characterized by LC-MS. The reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-25-1 (1.8 g, 99.2% yield). [M+H] + :253.15.

[0163] Step 2: Preparation of Compound D-25 Compound D-25-1 (1.5 g, 1.0 equiv) was dissolved in dichloromethane (30 mL), acetic acid (6 mL) was added, the reaction system was cooled to 0°C, and SO2Cl2 (6.1 g, 7.5 eq) was added dropwise while stirring. After the addition was complete, the temperature was maintained at 0°C and stirring continued for 10 min. 0.12 mL of water was added at 0°C, the reaction was raised to room temperature, and stirring continued for 1 hour. The completion was characterized by LC-MS. The reaction mixture was quenched with 5 mL of ice water, the organic phase was separated, extracted three times with dichloromethane, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-25 (680 mg, yield 50.2%). [M+H] + :229.05. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 9.08 (s, 2H), 8.90 (d, J = 1.6 Hz, 1H), 8.42-8.32 (m, 2H).

[0164] 15. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-26. [ka] (D-26)

[0165] The synthesis route for D-26 was as follows: [ka]

[0166] Step 1: Preparation of Compound D-26-1. SM1 (3.9 g, 1.0 equiv) was dissolved in 26 mL of trifluoroacetic acid, and triethylsilane (9.4 g, 4 eq) was added at room temperature. The mixture was stirred overnight at room temperature under nitrogen gas protection. Completion of the reaction was characterized by TLC. The reaction system was directly subjected to vacuum distillation, and the crude product was purified by normal-phase column chromatography to obtain Compound D-26-1 (3.4 g, 92.7% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.44 (d, J = 1.6 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 3.86-3.81 (m, 6H), 2.90 (t, J = 8.0 Hz, 2H), 2.82 (t, J = 8.0 Hz, 2H), 2.12-2.05 (m, 2H).

[0167] Step 2: Preparation of Compound D-26 Compound D-26-1 (0.5 g, 1.0 equiv) and tetramethylethylenediamine (358.6 mg, 1.1 eq) were dissolved in n-hexane (10 mL). The mixture was cooled to -78°C under nitrogen gas protection, and n-butyllithium (1.23 mL, 2.5 M in hexane, 1.1 eq) was added dropwise. The mixture was stirred at 0°C for 2 hours. The reaction system was then cooled to -65°C, sulfur dioxide gas was injected for 10 minutes, and the mixture was stirred and automatically heated to 10°C. The resulting precipitate was collected by filtration and then washed with ethyl ether (filtered under nitrogen gas protection). The resulting solid was redispersed in 20 mL of n-hexane to form a homogeneous slurry. Under nitrogen gas protection, the temperature was lowered to 0°C, and sulfonyl chloride (208.2 mg, 0.55 eq) was added dropwise. After addition was complete, the mixture was kept at 0°C and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (40 mL), backwashed twice with saturated sodium chloride solution, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by normal-phase column chromatography to obtain compound D-26 (270 mg, yield 34.6%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.75 (s, 1H), 3.97 (s, 6H), 3.01-2.96 (m, 4H), 2.19-2.11(m, 2H).

[0168] 16. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-27. [ka] (D-27)

[0169] The synthesis route for D-27 was as follows: [ka]

[0170] Step 1: Preparation of Compound D-27 Compound D-26-1 (0.6 g, 1.0 equiv) and tetramethylethylenediamine (430 mg, 1.1 eq) were dissolved in n-hexane (15 mL). The mixture was cooled to -78°C under nitrogen gas protection, and n-butyllithium (1.48 mL, 2.5 M in hexane, 1.1 eq) was added dropwise. The mixture was stirred at 0°C for 2 hours. The reaction system was then cooled to -65°C, sulfur dioxide gas was injected for 10 minutes, and the mixture was stirred and automatically heated to 10°C. The resulting precipitate was collected by filtration and then washed with ethyl ether (filtered under nitrogen gas protection). The resulting solid was redispersed in 20 mL of n-hexane to form a homogeneous slurry. Under nitrogen gas protection, the mixture was cooled to 0°C, and sulfonyl chloride (500.6 mg, 1.1 eq) was added dropwise. After addition, the mixture was kept at 0°C and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (40 mL), backwashed twice with saturated sodium chloride solution, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by normal-phase column chromatography to obtain compound D-27 (100 mg, 9.6% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 4.03 (s, 3H), 3.97 (s, 3H), 3.14-3.05 (m, 4H), 2.23-2.20(m, 2H).

[0171] 17. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-28. [ka] (D-28)

[0172] The synthesis route for D-28 was as follows: [ka]

[0173] The sulfonyl chloride compound D-28 was synthesized using SM1 as the starting material, following a manufacturing method similar to that of D-15, and with operating steps similar to steps 1-3 of D-15. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.59 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H).

[0174] 18. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-29. [ka] (D-29)

[0175] The synthesis route for D-29 was as follows: [ka]

[0176] Step 1: Preparation of Compound D-29-1 SM1 (4.6 g, 1.0 equiv) was dissolved in 92 mL of tetrahydrofuran, cooled to -78°C under nitrogen gas protection, and n-butyllithium (15 mL, 2.5 M in hexane, 1.2 eq) was added dropwise. After stirring for 30 minutes while maintaining the temperature, a solution of iodomethane (8.8 g, 2 eq) in tetrahydrofuran was added dropwise. The mixture was stirred for 2 hours while maintaining the temperature at 0°C, and the completion of the reaction was characterized by TLC. The reaction system was quenched in saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-29-1 (3.7 g, yield 64.2%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.37 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.83-6.80 (m, 1H), 6.47-6.46 (m, 1H), 3.78 (s, 3HHJH) JH), 2.40 (s, 3H).

[0177] Step 2: Preparation of Compound D-29 Compound D-29 was synthesized using D-29-1 as the starting material, following operating steps similar to step-2 of the manufacturing method for D-26.

[0178] Sulfonyl chloride compound D-29 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.70 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 4.07 (s, 3HHJH JH), 2.51 (s, 3H).

[0179] 19. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-30. [ka] (D-30)

[0180] The synthesis route for D-30 was as follows: [ka]

[0181] Step 1: Preparation of Compound D-30-1 SM1 (5.1 g, 1.0 eq), 3-bromopropene (4.5 g, 1.5 eq), and potassium carbonate (8.5 g, 2.5 eq) were dissolved in 100 mL of N,N-dimethylformamide, and the mixture was heated to 120°C under nitrogen gas protection and stirred for 16 hours. The reaction was characterized as complete by TLC. The reaction system was quenched in water, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound D-30-1 (5.8 g, 91.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.28 (t, J = 8.4 Hz, 1H), 6.74-6.72 (m, 2H), 6.08-6.03 (m, 1H), 5.48-5.43 (m, 1H), 5.29-5.26 (m, 1H), 4.65-4.63 (m, 2H), 3.84 (s, 3H).

[0182] Step 2: Preparation of Compound D-30-2 D-30-1 (3.0 g, 1.0 equiv) was dissolved in 30 mL of n-hexane, cooled to 0°C under nitrogen gas protection, and diethylaluminum chloride (12.4 mL, 1 M in hexane, 1 eq) was added. The resulting mixture was gradually heated to room temperature and stirred for 1 hour, and the completion of the reaction was characterized by TLC. The reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-30-2 (1.9 g, yield 51.8%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.01 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.03-5.93 (m, 1H), 5.72 (s, 1H), 5.09-5.04 (m, 2H), 3.87 (s, 3H), 3.40-3.38 (m, 2H).

[0183] Step 3: Preparation of Compound D-30-3 D-30-2 (1.6 g, 1.0 eq) was dissolved in 25 mL of chloroform, cooled to 0°C under nitrogen gas protection, copper trifluoromethanesulfonate (0.9 g, 0.38 eq) was added, and the resulting mixture was heated to 65°C and stirred for 16 hours. The completion of the reaction was characterized by TLC. The reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-30-3 (480 mg, yield 30.2%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.01 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.09-5.05 (m, 1H), 3.88 (s, 3H), 3.42-3.34 (m, 1H), 2.91-2.85 (m, 1H), 1.54-1.52 (m, 3H).

[0184] Step 4: Preparation of Compound D-30 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-30.

[0185] 20. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-31. [ka] (D-31)

[0186] The synthesis route for D-31 was as follows: [ka]

[0187] Steps 1 and 2: Preparation of Compound D-31-2 Compound D-31-2 was synthesized by steps 1 and 2 of the synthesis of compound D-23-2, using SM1 and 1,3-dibromopropane as starting materials, following a manufacturing method similar to that of D-23. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.76-6.68 (m, 2H), 6.61 (d, J = 2.0 Hz, 1H), 4.19-4.17 (m, 2H), 3.77 (s, 3H), 2.82-2.78 (m, 2H), 2.04-1.98 (m, 2H).

[0188] Step 3: Preparation of Compound D-31 D-31-2 (3.1 g, 1.0 eq) was dissolved in 50 mL of dichloromethane, cooled to 0°C under nitrogen gas protection, chlorosulfonic acid (6.4 g, 3 eq) was added dropwise, and the resulting mixture was stirred for 1 hour. The reaction was characterized as complete by TLC. The reaction system was quenched in saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound D-31 (800 mg, yield 16.2%).

[0189] Sulfonyl chloride compound D-31 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.40 (s, 1H), 6.77 (s, 1H), 4.19(t, J = 8.8 Hz, 2H), 3.97 (s, 3H), 2.88-2.85 (m, 2H), 2.06-2.00 (m, 2H).

[0190] 21. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-32. [ka] (D-32)

[0191] The synthesis route for D-32 was as follows: [ka]

[0192] Manufacturing of compound D-32 Compound D-32 was synthesized using SM1 as the starting material, following a procedure similar to steps 2 and 3 of compound D-21. [M+1] + : 260.15.

[0193] Sulfonyl chloride compound D-32 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.72 (s, 1H), 7.22 (d, J = 3.2 Hz, 1H), 7.15 (s, 1H), 3.88 (s, 3H), 3.48 (s, 3H).

[0194] 22. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-33. [ka] (D-33)

[0195] The synthesis route for D-33 was as follows: [ka]

[0196] Step 1: Preparation of Compound D-33-1 SM1 (20.1 g, 1 eq), potassium carbonate (32.9 g, 1.6 eq), and iodomethane (31.8 g, 1.5 eq) were mixed in N,N-dimethylformamide (DMF, 120 mL), stirred, heated, and the temperature was raised to 60°C and stirred for 16 hours. TLC characterized the completion of the reaction. The reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound D-33-1 (18.2 g, yield 81.2%). GCMS (ES, m / z), [M] + :184. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.16 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.75-6.72 (m, 1H), 3.85 (s, 3H), 2.95-2.87 (m, 4H), 2.16-2.08 (m, 2H).

[0197] Step 2: Preparation of Compound D-33 Compound D-33 was synthesized using D-33-1 as the starting material, following a procedure similar to step-3 of D-31.

[0198] Sulfonyl chloride compound D-33 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.79 (s, 1H), 7.01 (s, 1H), 4.04 (s, 3H), 3.03-2.99 (m, 2H), 2.95-2.89 (m, 2H), 2.21-2.12 (m, 2H).

[0199] 23. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-34. [ka] (D-34)

[0200] The synthesis route for D-34 was as follows: [ka]

[0201] Manufacturing of compound D-34 Compound D-34 was synthesized using compound D-28-2 as the starting material, following a procedure similar to that of D-16, and following steps 1 and 2 of D-16.

[0202] Sulfonyl chloride compound D-34 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.71 (d, J = 9.2 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 4.92 (t, J = 8.8 Hz, 2H), 3.96 (s, 3H), 3.27 (t, J = 8.8 Hz, 2H),

[0203] 24. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-35. [ka] (D-35)

[0204] The synthesis route for D-35 was as follows: [ka]

[0205] Manufacturing of compound D-35 Compound D-35 was synthesized using SM1 as the starting material, following operating steps similar to those in step-2 of the manufacturing method for D-26.

[0206] Sulfonyl chloride compound D-35 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.15 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 4.47-4.45 (m, 2H), 4.31-4.29 (m, 2H), 3.96 (s, 3H).

[0207] 25. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-36. [ka] (D-36)

[0208] The synthesis route for D-36 was as follows: [ka]

[0209] Step 1: Preparation of Compound D-36-1 Under nitrogen gas protection, the mixture SM1 (5.1 g, 1 eq), pyridinium p-toluenesulfonate (PPTS, 80 mg, 0.01 eq), and toluene (400 mL) were heated to 130°C. The mixture was then heated under reflux using a water splitter, and 2,2-dimethoxypropane (6.2 g, 1.5 equiv) was added in several portions every 15 minutes, while toluene (50 mL) was added simultaneously to compensate for solvent loss. After reacting for 2 hours, the completion of the reaction was characterized by TLC. The mixture was directly mixed with silica gel, the sample was stirred, and purified by normal-phase column chromatography to obtain compound D-36-1 (3.7 g, 56.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 6.14-6.11 (m, 1H), 1.58 (s, 6H).

[0210] Manufacturing of compound D-36 Compound D-36 was synthesized using D-36-1 as the starting material, following a procedure similar to steps 1 and 2 of compound D-33.

[0211] Sulfonyl chloride compound D-36 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.90 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 1.75 (s, 6H).

[0212] 26. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-37. [ka] (D-37)

[0213] The synthesis route for D-37 was as follows: [ka]

[0214] Manufacturing of compound D-37 Compound D-37 was synthesized using SM1 as the starting material, following a procedure similar to steps 1 and 2 of compound D-25.

[0215] Sulfonyl chloride compound D-37 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 9.46 (s, 1H), 9.08 (s, 1H), 8.73(d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 4.27 (s, 3H).

[0216] 27. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-38. [ka] (D-38)

[0217] The synthesis route for D-38 was as follows: [ka]

[0218] Step 1: Preparation of Compound D-38-1 At room temperature, compound SM1 (500 mg, 1 eq) was dissolved in acetic acid (3 mL). After complete dissolution, it was added to a suspension of zinc powder (10 g) containing acetic acid (30 mL), and the mixture was reacted overnight at 100°C. The reaction was characterized as complete by TLC, the reaction mixture was filtered, washed multiple times with ethyl acetate, concentrated under reduced pressure, and purified by normal-phase column chromatography to obtain compound D-36-1 (0.42 g, 90.2% yield).

[0219] Step 2: Preparation of Compound D-38-2 At room temperature, compound D-38-1 (420 mg, 1 eq) was dissolved in dichloromethane (10 mL). After complete dissolution, 1,3-dibromo-5,5-dimethylhydantoin (362 mg, 0.5 eq) was added, and the mixture was reacted at room temperature for 1 hour. Completion of the reaction was characterized by TLC. The reaction system was quenched in water, and the reaction products were extracted three times with dichloromethane. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain D-38-2 (530 mg, yield 86.21%).

[0220] Step 3: Preparation of Compound D-38 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-38.

[0221] Sulfonyl chloride compound D-38 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.70 (s, 1H), 6.45 (s, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.97 (s, 3H), 2.76 (t, J = 5.2 Hz, 2H), 2.06-1.99 (m, 2H).

[0222] 28. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-39. [ka] (D-39)

[0223] The synthesis route for D-39 was as follows: [ka]

[0224] Step 1: Preparation of Compound D-39-1 At room temperature, compound SM1 (0.5 g, 1 eq) was dissolved in acetonitrile (50 mL). After complete dissolution, N-bromosuccinimide (NBS, 547.2 mg, 1 eq) and ferric chloride (0.5 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. TLC characterized the completion of the reaction. The reaction system was quenched by adding water, and the reaction products were extracted three times with ethyl acetate. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-39-1 (650 mg, yield 87.84%).

[0225] Step 2: Preparation of Compound D-39-2 Compound D-39-1 (650 mg, 1 eq) and triethylsilane (943 mg, 3 eq) were dissolved in TFA (10 mL), and after complete dissolution, the mixture was stirred at room temperature for 1 hour. The completion of the reaction was characterized by TLC, the reaction system was quenched by adding saturated sodium carbonate aqueous solution, the reaction product was extracted three times with ethyl acetate, the combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain D-39-2 (500 mg, yield 81.20%).

[0226] Step 3: Preparation of Compound D-39 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-39.

[0227] Sulfonyl chloride compound D-39 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.49 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.45-3.44 (m, 2H), 2.91-2.85 (m, 2H), 2.18-2.08 (m, 2H).

[0228] 29. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-40. [ka] (D-40)

[0229] The synthesis route for D-40 was as follows: [ka]

[0230] Step 1: Preparation of Compound D-40 Under nitrogen gas protection, D-SM1 (450 mg, 1 eq) was dissolved in freshly distilled tetrahydrofuran (20.0 mL), and n-butyllithium (2.5 M in n-hexane, 1.0 mL, 1.25 eq) was gradually added dropwise at -78°C, reacting for 10 minutes. Subsequently, sulfur dioxide gas was injected for 15 minutes, and the temperature was gradually raised to room temperature. A solution of NCS (400 mg, 1.5 eq) in dichloromethane was added, and the mixture was reacted at room temperature for 1 hour. The reaction system was injected into saturated aqueous ammonium chloride and quenched, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotated-dried. The crude product was purified by normal-phase chromatography column to obtain the pale yellow solid sulfonyl compound D-40 (84 mg, yield 17.2%).

[0231] Sulfonyl compound D-40 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.24 (dd, J=9.2, 2.4Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H).

[0232] 30. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-41. [ka] (D-41)

[0233] The synthesis route for D-41 was as follows: [ka]

[0234] Manufacturing of compound D-41 Compound D-41 was synthesized using SM1 as the starting material, following a procedure similar to steps 1 to 3 of compound D-31.

[0235] Sulfonyl compound D-41 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.26 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 4.39 (t, J =5.2, 2H), 3.79 (s, 3H), 2.85 (t, J =6.4, 2H), 2.13-2.07 (m, 2H).

[0236] 31. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-42. [ka] (D-42)

[0237] The synthesis route for D-42 was as follows: [ka]

[0238] Manufacturing of compound D-42 Compound D-42 was synthesized using SM1 as the starting material, following a procedure similar to step-3 of compound D-15.

[0239] Sulfonyl compound D-42 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 8.49 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 4.61-4.59 (m, 2H), 4.39-4.37 (m, 2H).

[0240] 32. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-43. [ka] (D-43)

[0241] The synthesis route for D-43 was as follows: [ka]

[0242] Manufacturing of compound D-43 Compound D-43 was synthesized using SM1 as the starting material, following a manufacturing method similar to that of compound D-15, and performing operating steps similar to steps 1-3 of D-15.

[0243] Sulfonyl compound D-43 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.64 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H).

[0244] 33. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-44. [ka] (D-44)

[0245] The synthesis route for D-44 was as follows: [ka]

[0246] Step 1: Preparation of Compound D-44-1 At 0°C, a solution of liquid bromine (0.15 mL) in chloroform (5 mL) was added dropwise to a stirred mixture of SM1 (0.4 g, 1 eq), silver trifluoroacetate (0.64 g, 1 eq), and chloroform (10 mL). The mixture was stirred for 10 minutes, and the completeness of the reaction was characterized by TLC. The reaction system was quenched by adding saturated sodium carbonate aqueous solution, and the reactants were extracted three times with dichloromethane. The combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-44-1 (0.35 g, yield 56.4%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.96 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 6.00 (s, 2H).

[0247] Manufacturing of compound D-44 Compound D-44 was synthesized using D-44-1 as the starting material, following a procedure similar to steps 2 and 3 of compound D-21.

[0248] Sulfonyl compound D-44 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.06 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 4.03 (s, 3H).

[0249] 34. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-45. [ka] (D-45)

[0250] The synthesis route for D-45 was as follows: [ka]

[0251] Step 1: Preparation of Compound D-45 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-45.

[0252] Sulfonyl compound D-45 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.59-7.57 (m, 1H), 7.38-7.36 (m, 1H), 7.26-7.24 (m, 1H).

[0253] 35. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-46. [ka] (D-46)

[0254] The synthesis route for D-46 was as follows: [ka]

[0255] Steps 1-2: Preparation of Compound D-46-2 Compound D-46-2 was synthesized using SM1 as the starting material, following a manufacturing method similar to that of compound D-15, and performing operating steps similar to steps 1-2 of D-15. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.76 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H).

[0256] Step 3: Preparation of Compound D-46-3 To a mixture of D-46-2 (600 mg, 1 equiv), THF (6.00 mL), and DIEA (6.00 mL), CuI (35.4 mg, 0.1 equiv) and Pd(dppf)Cl2.CH2Cl2 (151.4 mg, 0.1 equiv) were added. Under nitrogen gas protection, cyclopropylacetylene (184.2 mg, 1.5 equiv) was added at 0°C, and the mixture was vigorously stirred overnight at room temperature. Completion of the reaction was characterized by TLC, the reaction system was quenched by adding water, the reactants were extracted three times with ethyl acetate, the combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain compound D-46-3 (380 mg, 76.8% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.71 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 1.56-1.54(m, 1H), 0.97-0.88 (m, 4H).

[0257] Manufacturing of compound D-46 Compound D-15 was prepared according to the procedure in step 3 to obtain sulfonyl chloride compound D-46.

[0258] Sulfonyl compound D-46 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.69 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 1.63-1.61(m, 1H), 0.99-0.88(m, 4H).

[0259] 36. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-47. [ka] (D-47)

[0260] The synthesis route for D-47 was as follows: [ka]

[0261] Manufacturing of compound D-47 Compound D-15 was prepared according to steps 1 to 3 to obtain sulfonyl chloride compound D-47.

[0262] Sulfonyl compound D-47 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.77 (d, J = 8.8 Hz, 1H), 6.78-6.76 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.88-5.86 (m, 1H), 5.12 (s, 2H), 3.94 (s, 3H).

[0263] 37. A method for producing a sulfonyl compound, which differs from Example 1 in that C09A is replaced with the structure shown in D-48. [ka] (D-48)

[0264] The synthesis route for D-48 was as follows: [ka]

[0265] Manufacturing of compound D-48 Compound D-16 was prepared according to steps 1 and 2 of the procedure to obtain sulfonyl chloride compound D-48.

[0266] Sulfonyl compound D-48 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.80 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.41 (t, J = 5.2 Hz, 2H), 3.94 (s, 3H), 2.71 (t, J = 7.2 Hz, 1H), 2.12-2.07(m, 2H).

[0267] 38. A method for producing a sulfonyl compound, which differs from Example 1 in that C08 is replaced with the structural formula shown in I-1. [ka]

[0268] The synthesis route for compound I-1 was as follows: [ka]

[0269] Step 1: Intermediate C06 (1.8 g, 1 eq) and 3,3-difluoroazetidine hydrochloride (1.34 g, 1.5 eq) were dissolved in dichloromethane (70 mL). A solution of N,N-diisopropylethylamine (DIEA, 2.68 g, 3 eq) in dichloromethane (10 mL) was added dropwise at 0°C. The mixture was stirred under N2 protection at 0°C for 5 hours, and LC-MS indicated the completion of the reaction. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting solid was purified by normal-phase column chromatography to obtain intermediate I'-1 (0.85 g, yield 45.5%). [M+1] + : 273.05.

[0270] Step 2: Following the steps of Step 8 of C08, intermediate I'-1 (0.85 g, 1 eq) was reacted with acetohydroxamic acid to obtain major intermediate I-1 (0.33 g, 41.6% yield). [M+1] + : 271.10.

[0271] 39. A method for producing a sulfonyl compound, which differs from Example 1 in that C08 is replaced with the structural formula shown in I-2. [ka]

[0272] The difference from compound I-1 is that intermediate I-2 is obtained by replacing "3,3-difluoroazetidine hydrochloride" in step-1 of compound I-1 with "dimethylamine". [M+1] + : 223.10.

[0273] 40. A method for producing a sulfonyl compound, which differs from Example 1 in that C08 is replaced with the structural formula shown in I-3. [ka]

[0274] The difference from compound I-1 is that intermediate I-3 was obtained by replacing "3,3-difluoroazetidine hydrochloride" in step-1 of compound I-1 with "tetrahydropyrrole". [M+1] + : 249.10.

[0275] 41. A method for producing a sulfonyl compound, wherein C08 is replaced with the structural formula shown in I-4A and 1-4B. [ka]

[0276] The difference from compound I-1 is that in step-1 of compound I-1, "3,3-difluoroazetidine hydrochloride" is replaced with "triazole" to form intermediate I-4A([M+1] + :246.10) and intermediate 1-4B([M+1] + The goal was to obtain (246.10).

[0277] 42. A method for producing a sulfonyl compound, wherein compound C08 is replaced with the structural formula shown in I-5. [ka]

[0278] The synthesis route for compound I-5 was as follows: [ka]

[0279] The difference from compound I-1 was that intermediate I-5 was obtained by replacing "3,3-difluoroazetidine hydrochloride" with "3-methoxyazetidine hydrochloride" in step-1 of compound I-1. [M+1] + : 265.10.

[0280] 43. A method for producing a sulfonyl compound, which differs from Example 1 in that compound C08 is replaced with the structural formulas shown in I-6 and I-7. [ka]

[0281] Specifically, the synthesis routes for compounds I-6 and I-7 were as follows: [ka]

[0282] Step 1: Dissolve intermediate C07 (1 g, 1 eq) in freshly distilled tetrahydrofuran (50 mL), cool to -78°C under N2 protection, stir, add dropwise a solution of n-butyllithium in n-hexane (2.5 M in hexane, 4.8 mL, 3 eq), stir at -78°C for 5 min, add tetrahydrofuran (30 mL) of N-fluorobenzenesulfonimide (3.8 g, 3 eq), stir overnight, and gradually raise from -78°C to room temperature. Reaction completion was characterized by LC-MS, the reaction system was quenched in saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotary dried. The resulting crude product was purified by preparative liquid chromatography, yielding compound I'-6 (195 mg, yield 18.1%) ([M+1] + :267.10.) and I'-7 (98 mg, yield 8.1%) ([M+1] + :285.10.) was obtained.

[0283] Step 2: Following the steps of Step 8 of C08, react intermediate I'-6 or I'-7 with acetohydroxamic acid to obtain the main intermediate I-6 ([M+1] + :264.10) and I-7([M+1] + :282.05) was obtained.

[0284] I-6: 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.03 (d, J = 2.8 Hz, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 7.45 (d, J = 46.8 Hz, 1H), 6.42 (s, 1H), 6.30 (s, 2H), 3.90 (s, 3H).

[0285] I-7: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 6.52-6.51(m, 1H), 6.39 (s, 2H), 3.91 (s, 3H).

[0286] 44. A method for producing a sulfonyl compound, which differs from Example 1 in that compound C08 is replaced with the structural formula shown in I-8. [ka]

[0287] Specifically, the synthesis route for compound I-8 was as follows: [ka]

[0288] The difference from compound I-1 was that intermediate I-8 was obtained by replacing "3,3-difluoroazetidine hydrochloride" in step-1 of compound I-1 with "4-methylpyrazole". [M+1] + : 260.10.

[0289] I-8: 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.39 (s, 1H), 7.33-7.29 (m, 1H), 6.49 (d, J = 0.8 Hz, 1H), 5.33 (s, 2H), 4.75 (s, 3H), 4.08 (s, 3H), 2.11 (s, 3H).

[0290] 45. A method for producing a sulfonyl compound, which differs from Example 1 in that compound C08 is replaced with the structural formula shown in I-9. [ka]

[0291] Specifically, the synthesis route for compound I-9 was as follows: [ka]

[0292] The difference from compound I-1 was that intermediate I-9 was obtained by replacing "3,3-difluoroazetidine hydrochloride" in step-1 of compound I-1 with "4-fluoropyrazole". [M+1] + : 264.15.

[0293] I-9: 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.45-7.41 (m, 2H), 6.63 (s, 1H), 5.28 (s, 2H), 4.67 (s, 2H), 4.07 (s, 3H).

[0294] 46. ​​A method for producing a sulfonyl compound, which differs from Example 1 in that compound C08 is replaced with the structural formula shown in I-10. [ka]

[0295] Specifically, the synthesis route for compound I-10 was as follows: [ka]

[0296] The difference from compound I-1 was that intermediate I-10 was obtained by replacing "3,3-difluoroazetidine hydrochloride" in step-1 of compound I-1 with "3-methylpyrazole". [M+1] + : 260.10.

[0297] I-10: 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.45 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 1.6 Hz, 1H), 6.11 (s, 1H), 5.32 (s, 2H), 4.67 (s, 2H), 4.07 (s, 3H), 2.31 (s, 3H).

[0298] Example 2 Compound 1-2: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide; Compound 1-3: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-1-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide; [ka]

[0299] Step 1: Preparation of Compounds 1-2 and 1-3 Following the procedure in step-1 of compound 1-1, the main intermediate C08 was condensed with a mixture of D-14A and D-14B, and purified by high-pressure preparative liquid chromatography to obtain compounds 1-2 and 1-3. Compound 1-2 [M+1] + : 470.15. Compound 1-3:[M+1] + : 470.00.

[0300] Compound 1-2 1H NMR (400 MHz, DMSO-d6) δ (ppm):10.61 (s, 1H), 7.90 (s, 1H), 7.50 (d, J = 10.8 Hz, 2H), 6.86 (s, 1H), 6.70 (s, 1H), 6.33 (s, 1H), 5.45 (s, 2H), 3.95 (s, 3H), 3.72 (s, 3H), 2.75-2.68 (m, 4H), 1.72 (s, 4H).

[0301] Compound 1-3 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.25 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 6.99 (s, 1H), 6.72 (s, 1H), 6.33 (s, 1H),5.44 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 3.11 (s, 2H), 2.72 -2.68 (m, 2H), 1.68 - 1.64 (m, 4H).

[0302] Following a manufacturing method similar to that of Examples 1-2, D-series intermediates and C08, C09, or I-series intermediates were produced to obtain the sulfonyl compounds of Examples 1-97, which are shown in Table 2.

[0303] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30] [Table 2-31] [Table 2-32]

[0304] Example 96 Compound 1-96: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-4-ethynyl-benzofuran-7-sulfonamide: [ka]

[0305] Synthesis pathway [ka]

[0306] Preparation of compound 1-96-D Compound 1-96-D was synthesized using SM1 as the starting material, following a manufacturing method similar to that of compound D-46, and performing steps similar to steps 1-4 of D-46. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.76 (d, J = 8.4 Hz, 1H), 7.55-7.54 (m, 1H), 7.51-7.33 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 1.14 (s, 9H), 0.24 (s, 6H).

[0307] Step 5: Preparation of Compound 1-96-E Following the procedure in step-1 of 1-1, the main intermediate C08 and 1-96-D were condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-96-E. [M+1] + : 564.25

[0308] Step 6: Preparation of Compound 1-96 Compound 1-96-E (18 mg, 1 eq) was dissolved in 0.5 mL of tetrahydrofuran, and tetramethylammonium fluoride (20.8 mg, 7 eq) was added at 0°C. The mixture was stirred at room temperature for 16 hours, and the completeness of the reaction was characterized by LC-MS. The reaction mixture was purified directly by preparative liquid chromatography to obtain compound 1-96 (4.8 mg, 32.3% yield). [M+1] + : 450.15

[0309] Compound 1-96 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (s, 1H), 7.87 (d, J =1.6Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.5 (d, J = 1.2Hz, 1H), 7.43 (d, J =7.6Hz, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 5.39 (s, 2H), 4.61 (s, 1H), 3.91 (s, 3H).

[0310] Example 97 Compound 1-97: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-4,6-dimethoxy-2,3-dihydrobenzofuran-5-sulfonamide; Compound 1-98: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-4,6-dimethoxy-2,3-dihydrobenzofuran-7-sulfonamide; [ka]

[0311] Synthesis pathway [ka]

[0312] Preparation of compound 1-97-B Compound 1-97-B was synthesized using SM1 as the starting material, following a manufacturing method similar to that of compound D-15-2, and performing operations similar to steps 1-2 of D-15.

[0313] Preparation of compound 1-97-C Compound 1-97-C was synthesized using 1-97-B as the starting material, following a manufacturing method similar to that of compound D-16-1, and performing a procedure similar to step-1 of D-16.

[0314] Step 4: Preparation of Compound 1-97-D At room temperature, compound 1-97-C (830 mg, 1 eq) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (NBS, 820.1 mg, 1 eq) was added. After stirring at room temperature for 16 hours, the reaction was characterized as complete by TLC. The reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-97-D (1.0 g, yield 84.1%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.17 (s, 1H), 4.67 (t, J = 8.8 Hz, 2H), 3.89-3.83 (m, 6H), 3.19 (t, J = 8.8 Hz, 2H).

[0315] Step 5: Preparation of a mixture of compound 1-97-E and compound 1-98-E Tetramethylethylenediamine (161.6 mg, 1.2 eq) was dissolved in n-hexane (5 mL), cooled to -78°C under nitrogen gas protection, and n-butyllithium (0.46 mL, 2.5 M in hexane, 1.0 eq) was added dropwise. The mixture was stirred at -50°C for 1 hour. At -78°C, a solution of compound 1-97-D (0.3 g, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise to the above solution, and the temperature was gradually raised to 0°C and stirred for 2 hours. Next, the reaction system was cooled to -65°C, sulfur dioxide gas was injected for 10 minutes, and the mixture was stirred and automatically raised to 10°C. The resulting precipitate was collected by filtration and then washed with ethyl ether (filtered under nitrogen gas protection). The resulting solid was redispersed in 10 mL of n-hexane to form a homogeneous slurry. Under nitrogen gas protection, the mixture was cooled to 0°C, and sulfonyl chloride (62.7 mg, 0.4 eq) was added dropwise. After addition, the mixture was maintained at 0°C and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (40 mL), backwashed twice with saturated sodium chloride solution, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by normal-phase column chromatography to obtain a mixture of compound 1-97-E and compound 1-98-E (200 mg, yield 63.6%). Both obtained sulfonyl chloride compounds were confirmed by NOE.

[0316] Sulfonyl chloride compound 1-97-E 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.26 (s, 1H), 4.74 (t, J = 8.8 Hz, 2H), 4.02 (s, 6H), 3.34 (t, J = 8.8 Hz, 2H).

[0317] Sulfonyl chloride compound 1-98-E 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.04 (s, 1H), 4.82 (t, J = 8.8 Hz, 2H), 3.98-3.95 (m, 6H), 3.12 (t, J = 8.8 Hz, 2H).

[0318] Step 6: Preparation of Compounds 1-97 and 1-98 Following the procedure in step-1 of 1-1, the main intermediate C08 was condensed with a mixture of 1-97-E and 1-98-E, and the mixture was purified by high-pressure preparative liquid chromatography to obtain compounds 1-97 and 1-98.

[0319] Compound 1-97 [M+1] + : 488.25. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.99 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 6.39 (s, 1H), 6.34 (s, 1H), 5.45 (s, 2H), 4.60 (t, J = 8.8 Hz, 2H), 3.99 (s, 3H), 3.81 (s, 3H), 3.71 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H).

[0320] Compound 1-98 [M+1] + : 488.25. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.15 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 6.34 (s, 1H), 6.20 (s, 1H), 5.45 (s, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 2.97 (t, J = 8.8 Hz, 2H).

[0321] Example 99 Compound 1-99: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-methoxy-2,2-dimethylbenzopyran-8-sulfonamide: [ka]

[0322] Synthesis pathway [ka]

[0323] Step 1: Preparation of Compound 1-99-A SM1 (5 g, 1 eq) was dissolved in methanol (50 mL), anhydrous palladium carbon (1 g, 10%) was added under nitrogen gas protection, and after multiple substitutions with hydrogen gas, the mixture was reacted with hydrogen gas (1 atm) at room temperature for 16 hours. The reaction was characterized as complete by GC-MS, and the mixture was filtered under pressure. The filter cake was washed with ethanol and rotated dry to obtain the crude product, which was purified by normal-phase column chromatography to obtain compound 1-99-A (1.57 g, yield 33.9%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67 (s, 1H), 6.51-6.46 (m, 3H), 2.63 (t, J = 6.8 Hz, 2H), 1.69 (t, J = 6.8 Hz, 2H), 1.22 (s, 6H).

[0324] Step 2: Preparation of Compound 1-99-B 1-99-A (1.57 g, 1 eq) was dissolved in tetrahydrofuran (30 mL), and under nitrogen gas protection, sodium hydride (0.53 g, 60% content, 1.5 eq) was added at 0°C. The reaction was stirred at 0°C for 30 min under nitrogen gas protection. Next, iodomethane (1.88 g, 1.5 equiv) was added to the reaction system, and the reaction was stirred at 0°C for 2 hours. After gradually returning to room temperature, the mixture was stirred for 16 hours. The completion of the reaction was characterized by GC-MS. The reaction system was quenched in saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-99-B (1.3 g, 76.7% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 6.65-6.62 (m, 3H), 3.67 (s, 3H), 2.70 (t, J = 6.8 Hz, 2H), 1.72 (t, J = 6.8 Hz, 2H), 1.24 (s, 6H).

[0325] Step 3: Preparation of Compound 1-99-C 1-99-B (500 mg, 1 eq) was dissolved in dichloromethane (5 mL), and under nitrogen gas protection, chlorosulfonic acid (0.52 mL, 3 equiv) was added dropwise at 0°C. The mixture was stirred and reacted under nitrogen gas protection at 0°C for 2 hours. The reaction mixture was quenched with crushed ice at 0°C, extracted three times with dichloromethane, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The mixture was purified by normal-phase column chromatography to obtain compound 1-99-C (40 mg, yield 5.3%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.30 (d, J = 2.8 Hz, 2H), 7.01 (d, J = 2.8 Hz, 2H), 3.82 (s, 3H), 2.86 (t, J = 6.8 Hz, 2H), 1.93 (t, J = 6.8 Hz, 2H), 1.46 (s, 6H).

[0326] Step 4: Preparation of Compounds 1-99 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-99-C was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-99. [M+1] + : 500.30. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.87 (d, J=2.0 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 6.78 (s, 1H), 6.46 (s, 1H), 6.33-6.32 (m, 1H), 5.39 (s, 2H), 3.94 (s, 3H), 3.68 (s, 3H), 2.67 (t, J = 6.8 Hz, 2H), 1.64 (t, J = 6.8 Hz, 2H), 1.03 (s, 6H).

[0327] Example 100 Compound 1-100: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-methoxy-2,2-dimethyl-3H-benzofuran-7-sulfonamide [ka]

[0328] Synthesis pathway [ka]

[0329] Step 1: Preparation of Compound 1-100-A SM1 (20 g, 1 equiv) and potassium carbonate (111.3 g, 5 eq) were added to N,N-dimethylformamide (250 mL), and methyl bromoacetate (37.1 g, 1.5 equiv) was gradually added dropwise under nitrogen gas protection. The temperature was raised to 65°C under nitrogen gas protection and the mixture was stirred for 16 hours to allow the reaction to proceed. The completion of the reaction was characterized by GC-MS, the reaction system was quenched in water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-100-A (30 g, 94.9% yield). 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.20 (t, J = 8.0 Hz, 1H), 6.59-6.58 (m, 1H), 6.52-6.48 (m, 2H), 4.63 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H).

[0330] Step 2: Preparation of Compound 1-100-B 1-100-A (20 g, 1 eq) was dissolved in 200 mL of tetrahydrofuran and stirred at 0°C under nitrogen gas protection, and methylmagnesium bromide (3 M in ethyl ether, 102.4 mL, 3 eq) was added dropwise. After gradually raising the temperature to room temperature under nitrogen gas protection, the mixture was stirred for 3 hours, the reaction system was quenched in saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound 1-100-B (18.2 g, 92.5% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.20 (t, J = 8.0 Hz, 1H), 6.56-6.51 (m, 3H), 3.81 (s, 3H), 3.79 (s, 2H), 2.38 (s, 1H), 1.36 (s, 6H).

[0331] Step 3: Preparation of Compound 1-100-C Under nitrogen gas protection, 21.7 g, 3 eq of phosphorus pentoxide was added to 200 mL of methanesulfonic acid and mixed homogeneously. The temperature was controlled to room temperature, and 1-100-B (10 g, 1 eq) was added in several portions. The mixture was stirred for 3 hours under nitrogen gas protection while maintaining room temperature. The completion of the reaction was characterized by GC-MS. The reaction system was quenched in ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-100-C (3.5 g, yield 38.5%). 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.04-7.01 (m, 1H), 6.42-6.37 (m, 2H), 3.78 (s, 3H), 2.96 (s, 2H), 1.49 (s, 6H).

[0332] Step 4: Preparation of Compound 1-100-D Compound 1-100-D was synthesized using 1-100-C as the starting material, following operating steps similar to step-2 of the manufacturing method for D-26. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.32 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 2.99 (s, 2H), 1.56 (s, 6H).

[0333] Step 5: Manufacturing of Compound 1-100 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-100-D was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-100. [M+1] + : 486.25. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.34 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 6.53-6.51 (m, 1H), 6.33-6.32 (m, 1H), 5.45 (s, 2H), 3.97 (s, 3H), 3.73 (s, 3H), 2.87 (s, 2H), 1.18 (s, 6H).

[0334] Example 101 Compound 1-101: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-5-methoxy-3,3-dimethyl-2H-benzofuran-6-sulfonamide [ka]

[0335] Synthesis pathway [ka]

[0336] Step 1: Preparation of Compound 1-101-A SM1 (10 g, 1 eq) was dissolved in 100 mL of acetonitrile, and 3-bromo-2-methylpropene (8.6 g, 1.1 equiv) and potassium carbonate (19.97 g, 2.5 eq) were added sequentially with stirring. The mixture was heated under nitrogen gas protection and stirred at 85°C for 16 hours to allow the reaction to proceed. The completion of the reaction was characterized by GC-MS. The reaction system was filtered under reduced pressure, the filter cake was washed three times with ethyl acetate, the mother liquors were combined and rotated dry, and the compound was purified by normal-phase column chromatography to obtain compound 1-101-A (11 g, yield 82.1%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.58-7.55 (m, 1H), 7.28-7.24 (m, 1H), 6.92-6.90 (m, 1H), 6.87-6.83 (m, 1H), 5.19 (s, 1H), 5.04 (s, 1H), 4.52 (s, 2H), 1.88 (s, 3H).

[0337] Step 2: Preparation of Compound 1-101-B 1-101-A (9 g, 1 eq) was dissolved in 100 mL of toluene, and tri-n-butyltin hydride (17.3 g, 1.5 eq) and azobisisobutyronitrile (0.65 g, 0.1 eq) were added sequentially under nitrogen gas protection. The mixture was heated to reflux under nitrogen gas protection and stirred for 16 hours. After cooling to room temperature, potassium fluoride (w / w%, 10%, 30 mL) was added and the mixture was stirred for 2 hours. After liquid-liquid extraction, the organic phase was washed three times with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-101-B (2.0 g, yield 34.1%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.20-7.15 (m, 2H), 6.93-6.91 (m, 1H), 6.88-6.86 (m, 1H), 6.87-6.83 (m, 1H), 4.27 (s, 2H), 1.39 (s, 6H).

[0338] Step 3: Preparation of Compound 1-101-C 1-101-B (2.0 g, 1 eq) was dissolved in N,N-dimethylformamide (100 mL), N-bromosuccinimide (NBS, 4.8 g, 2 eq) was added, and the mixture was stirred overnight at room temperature under nitrogen gas protection. The reaction was characterized as complete by GC-MS, and the reaction mixture was quenched with saturated sodium bisulfite aqueous solution. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The compound was purified by normal-phase column chromatography to obtain compound 1-101-C (2.0 g, 62.1% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.24-7.20 (m, 2H), 6.69 (d, J= 8.4 Hz, 1H), 4.26 (s, 2H), 1.35 (s, 6H).

[0339] Step 4: Preparation of Compound 1-101-D 1-101-C (1.0 g, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and after complete dissolution, cuprous iodide (0.17 g, 0.2 equiv) and sodium methoxide (0.95 g, 4 equiv) were added, and the mixture was stirred at 145°C for 3 hours under nitrogen gas protection. The completion of the reaction was characterized by GC-MS, the reaction system was quenched in ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound 1-101-D (0.5 g, yield 62.4%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.71-6.64 (m, 3H), 4.21 (s, 2H), 3.81 (s, 3H), 1.35 (s, 6H).

[0340] Step 5: Preparation of Compound 1-101-E Compound 1-101-E was synthesized using 1-101-D as the starting material, following a procedure similar to step-2 of the manufacturing method for D-26.

[0341] Step 6: Preparation of Compound 1-101 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-101-E was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-101. [M+1] + : 486.25. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88 (d, J =2.4Hz, 1H), 7.51 (d, J =1.6Hz, 1H), 7.08 (d, J =2.4Hz, 1H), 6.88 (s, 1H), 6.52 (s, 1H), 6.33-6.31 (m, 1H), 5.39 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 1.24 (s, 6H).

[0342] Example 102 Compound 1-102: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-methoxybenzofuran-7-sulfonamide-2-d: [ka]

[0343] Synthesis pathway [ka]

[0344] Step 1: Preparation of Compound 1-102-A SM1 (2 g, 1 eq) was dissolved in 500 mL of ultra-dry tetrahydrofuran, cooled to -78°C under nitrogen gas protection, and n-butyllithium (2.5 M in n-hexane, 6.48 mL, 1.2 eq) was added dropwise to react with stirring for 30 minutes. Then, deuterium aqueous solution (D2O, 540.7 mg, 2 eq) was gradually added dropwise at -78°C. The mixture was stirred and gradually allowed to rise naturally to room temperature. The completion of the reaction was characterized by GC-MS, and the reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried the organic phase with anhydrous sodium sulfate, filtered by suction, rotated-dried, and purified by normal-phase column chromatography to obtain compound 1-102-A (2 g, 99.3% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.49(d, J =8.4 Hz, 1H), 7.08(d, J =2.0 Hz, 1H), 6.92 (dd, J =8.4, 2.0 Hz, 1H), 6.72 (s, 1H), 3.88 (s, 3H).

[0345] Step 2: Preparation of Compound 1-102-B Compound 1-102-B was synthesized using 1-102-A as the starting material, following a procedure similar to step-2 of the manufacturing method for D-26. 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.88(d, J =8.0 Hz, 1H), 7.07(d, J =8.0 Hz, 1H), 6.82 (s, 1H), 4.12 (s, 3H).

[0346] Step 3: Preparation of Compound 1-102 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-102-B was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-102. [M+1] + : 457.15. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.02(d, J=8.4Hz, 1H), 6.88 (s, 1H), 6.49 (s, 1H), 6.32 (s, 1H), 5.38 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H).

[0347] Example 103 Compound 1-103: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-5-methoxy-2,3-dihydrobenzofuran-6-sulfonamide-2,3-d2: [ka]

[0348] Synthesis pathway [ka]

[0349] Step 1: Preparation of Compound 1-103-A SM1 (2 g, 1 eq) was dissolved in 10 mL of deuterated methanol, and anhydrous palladium carbon (130 mg, 10%, 1 eq) and deuterated formic acid (1 g, 1.71 eq) were added under nitrogen gas protection. After multiple substitutions with hydrogen gas, the mixture was reacted at room temperature for 16 hours under hydrogen gas (5 atm), filtered, and the filter cake was washed three times with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by normal-phase column chromatography to obtain compound 1-103-A (0.5 g, yield 26.4%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.81 (d, J =2.4 Hz, 1H), 6.73-6.66 (m, 2H), 4.58-4.54 (m, 1H), 3.78 (s, 3H), 3.23-3.19 (m, 1H).

[0350] Step 2: Preparation of Compound 1-103-B At room temperature, 1-103-A (500 mg, 1 eq) was dissolved in dichloromethane (5 mL). After complete dissolution, 1,3-dibromo-5,5-dimethylhydantoin (469.7 mg, 0.5 eq) was added at 0°C and the mixture was stirred at 0°C for 2 hours. Completion of the reaction was characterized by TLC, and the reaction system was quenched with saturated sodium bisulfite aqueous solution. The reaction products were extracted three times with dichloromethane, the combined organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and rotated-dried. The crude product was purified by normal-phase column chromatography to obtain 1-103-B (350 mg, 45.2% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.00 (s, 1H), 6.84 (s, 1H), 4.61-4.56(m, 1H), 3.85 (s, 3H), 3.21-3.17(m, 1H).

[0351] Step 3: Preparation of Compound 1-103-C Compound 1-103-C was synthesized using 1-103-B as the starting material, following the procedure in step-3 of compound D-15. 1H NMR (400 MHz, CDCl3-d) δ (ppm): 7.34 (s, 1H), 7.03 (s, 1H), 4.68-4.64 (m, 1H), 4.02 (s, 3H), 3.35-3.31 (m, 1H).

[0352] Step 4: Preparation of Compound 1-103 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-103-C was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-103. [M+1] + : 460.00. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.67 (s, 1H), 7.89 (d, J =2.4Hz, 1H), 7.51 (d, J =1.6Hz, 1H), 7.24-7.06 (s, 3H), 6.57-6.52 (m, 1H), 6.32 (t, J = 2.0Hz, 1H), 5.42 (s, 2H), 4.54-4.49 (m, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.21-3.18 (m, 1H).

[0353] Example 104 Compound 1-104: N-(6-((1H-pyrazole-1-yl)methyl-d2)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-5-methoxy-2,3-dihydrobenzofuran-6-sulfonamide [ka]

[0354] Synthesis pathway [ka]

[0355] Step 1: Preparation of Compound 1-104-A 250 mg of C07 (1 eq) was dissolved in 12.5 mL of tetrahydrofuran, cooled to -78°C under nitrogen gas protection, and n-butyllithium (2.5 M in n-hexane, 1.0 mL, 2.5 eq) was gradually added dropwise to react with stirring for 30 minutes. After stirring at -78°C, deuterium aqueous solution (D2O, 0.05 mL, 3 eq) was gradually added dropwise. The mixture was stirred and gradually allowed to rise naturally to room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture to quench it, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered by suction, and rotated-dried to obtain the crude product. The above experimental procedure was repeated four times using the crude product as the starting material. The final crude product was purified by normal-phase column chromatography to obtain compound 1-104-A (150 mg, yield 59.5%). [M+1] + : 251. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.65 (s, 1H), 7.53 (s, 1H), 6.61 (s, 1H), 6.43 (s, 1H), 4.08 (s, 3H).

[0356] Step 2: Preparation of Compound 1-104-B 1-104-A (100 mg, 1 eq) was added to 30 mL of tert-butanol and completely dissolved, followed by the sequential addition of potassium carbonate (110.3 mg, 2 eq) and acetohydroxamic acid (60 mg, 2 eq). The mixture was stirred at room temperature for 16 hours under nitrogen gas protection, and the reaction was characterized as complete by LC-MS. The mixture was filtered, the filtrate was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography to obtain compound 1-104-B (45 mg, 45.9% yield). [M+1] + : 248. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (d, J =2.0Hz, 1H), 7.52 (d, J =2.0Hz, 1H), 6.57 (s, 1H), 6.33-6.32 (m, 1H), 6.20 (s, 2H), 3.98 (s, 3H).

[0357] Step 3: Preparation of Compound 1-104 Following the procedure in step-1 of 1-1, the mixture of major intermediate D-23 and 1-104-B was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-104. [M+1] + : 460.20. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84 (d, J =2.0Hz, 1H), 7.49 (s, 1H), 7.09 (s, 1H), 7.01 (s, 1H), 6.58 (s, 1H), 6.32 (s, 1H), 4.49 (t, J =8.4Hz, 2H), 3.92(s, 3H), 3.66 (s, 3H), 3.17 (t, J =8.4Hz, 2H).

[0358] Example 105 Compound 1-105: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-5-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfonamide [ka]

[0359] Synthesis pathway [ka]

[0360] Step 1: Preparation of Compound 1-105-A SM1 (5 g, 1 eq) was dissolved in 50 mL of tetrahydrofuran, cooled to 0°C under nitrogen gas protection, and methylmagnesium bromide (3 M in ethyl ether, 27.7 mL, 3 eq) was gradually added dropwise to allow the reaction to proceed. The mixture was stirred at room temperature for 3 hours, then quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, combined the organic phases, washed with saturated sodium chloride aqueous solution, dried the organic phase with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting crude product was purified by normal-phase column chromatography to obtain compound 1-105-A (4 g, yield 80.1%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.27-7.23 (m, 1H), 6.84-6.79 (m, 3H), 3.82 (s, 3H), 2.76 (s, 2H), 1.25 (s, 6H).

[0361] Step 2: Preparation of Compound 1-105-B At room temperature, 1-105-A (2 g, 1 eq) and lithium carbonate (1.23 g, 1.5 eq) were added to 50 mL of hexafluorobenzene, followed by iodobenzene diacetate (5.36 g, 1.5 eq) and palladium acetate (249.1 mg, 0.1 eq). The mixture was heated to 100°C under nitrogen gas protection and stirred for 25 hours. After the reaction system cooled to room temperature, it was filtered by suction, the filter cake was washed with ethyl acetate, the organic phases were combined, and the mixture was rotated dry under reduced pressure. The resulting crude product was purified by normal-phase column chromatography to obtain compound 1-105-B (1.2 g, 68.7% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.77 (s, 1H), 6.68-6.66 (m, 2H), 3.77 (s, 3H), 3.06 (s, 2H), 1.49 (s, 6H).

[0362] Step 3: Preparation of Compound 1-105-C 1-105-B (100 mg, 1 eq) was dissolved in 5 mL of acetonitrile, and N-bromosuccinimide (71.6 mg, 1 eq) was added at 0°C. Under nitrogen gas protection, the mixture was gradually heated to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated sodium thiosulfate aqueous solution at room temperature, extracted three times with ethyl acetate, combined with the organic phase, washed with saturated sodium chloride aqueous solution, dried the organic phase with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting crude product was purified by normal-phase column chromatography to obtain compound 1-105-C (70 mg, 69.4% yield). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 6.94 (s, 1H), 6.79 (s, 1H), 3.85 (s, 3H), 2.98 (s, 2H), 1.48 (s, 6H).

[0363] Step 4: Preparation of Compound 1-105-D Compound 1-105-D was synthesized using 1-105-C as the starting material, following the procedure in step-3 for compound D-15. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.29 (s, 1H), 6.97 (s, 1H), 4.01 (s, 3H), 3.10 (s, 2H), 1.51 (s, 6H).

[0364] Step 5: Preparation of Compound 1-105 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-105-D was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-105. [M+1] + : 486.25. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86 (d, J=2.0Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.54 (s, 1H), 6.32-6.31 (m, 1H), 5.38 (s, 2H), 3.92 (s, 3H), 3.67 (s, 3H), 2.99 (s, 2H), 1.37 (s, 6H).

[0365] Example 106 Compound 1-106: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-cyclopropyl-3,4-dihydro-1H-benzopyran-8-sulfonamide [ka]

[0366] Synthesis pathway [ka]

[0367] Step 1: Preparation of Compound 1-106-A SM1 (5 g, 1 eq) was dissolved in 150 mL of acetonitrile, and N-bromosuccinimide (15 g, 2.2 eq) was added in several portions at room temperature. The mixture was stirred at room temperature for 16 hours under nitrogen gas protection. The reaction system was cooled to 0°C in an ice bath, quenched with saturated sodium bisulfite aqueous solution, extracted three times with ethyl acetate, combined the organic phases, washed with saturated sodium chloride aqueous solution, dried the organic phase with anhydrous sodium sulfate, filtered by suction, and rotated-dried. The resulting crude product was purified by normal-phase column chromatography to obtain compound 1-106-A (2.4 g, yield 22.2%). 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.19 (s, 2H), 1.85-1.79(m, 1H), 0.98-0.89 (m, 2H), 0.64-0.61(m, 2H).

[0368] Steps 2-4: Preparation of Compound 1-106-D Compound 1-106-D was synthesized using 1-106-A as the starting material, following the steps 1 to 3 of compound D-31. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 7.48 (d, J =1.6Hz, 1H), 7.12 (d, J =1.6Hz 1H), 4.44-4.41 (m, 2H), 2.87-2.84 (m, 2H), 2.14-2.11 (m, 2H), 1.89-1.87 (m, 1H), 1.01-0.97 (m, 2H), 0.69-0.65 (m, 2H).

[0369] Step 5: Preparation of Compound 1-106 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-106-D was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-106. [M+1] + : 482.30. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.51 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.52 (d, J=1.2Hz, 1H), 7.34 (d, J=2.0Hz, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.34-6.33 (m, 1H), 5.45 (s, 2H), 4.04-4.02 (m, 2H), 3.94 (s, 3H), 2.72-2.69 (m, 2H), 1.92-1.89 (m, 1H), 1.87-1.78 (m, 2H), 0.91-0.88 (m, 2H), 0.67-0.65 (m, 2H).

[0370] Example 107 Compound 1-107: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-cyano-3,4-dihydro-1H-benzopyran-8-sulfonamide [ka]

[0371] Synthesis pathway [ka]

[0372] Steps 1-3: Preparation of Compound 1-107-C Compound 1-107-C was synthesized using SM1 as the starting material, following the steps 1 to 3 of compound D-31. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 8.10 (d, J =2.0Hz, 1H), 7.66 (d, J =2.0Hz, 1H), 4.59-4.56 (m, 2H), 2.97-2.91 (m, 2H), 2.22-2.16 (m, 2H).

[0373] Step 4: Preparation of Compound 1-107 The mixture of the main intermediate C08 and 1-107-C was subjected to a condensation reaction and purified by high-pressure preparative liquid chromatography to obtain compound 1-107. [M+1] + : 467.15. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (d, J=1.6 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J=1.6 Hz, 1H), 6.52 (s, 1H), 6.32-6.31 (m, 1H), 5.37 (s, 2H), 4.18-4.16 (m, 2H), 3.92 (s, 3H), 2.77-2.74 (m, 2H), 1.87-1.82 (m, 2H).

[0374] Example 108 Compound 1-108: N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridine-3-yl)-6-methoxybenzofuran-5-sulfonamide [ka]

[0375] Synthesis pathway [ka]

[0376] Steps 1-3: Preparation of Compound 1-108-C Compound 1-108-C was obtained by preparing SM1 as the starting material according to a manufacturing method similar to that of D-15. 1 H NMR (400 MHz, CDCl3-d) δ (ppm): 8.28 (s, 1H), 7.70 (s, 1H), 7.24 (s, 1H), 6.85 (s, 1H), 4.12 (s, 3H).

[0377] Step 4: Preparation of Compound 1-108 Following the procedure in step-1 of 1-1, the mixture of the main intermediate C08 and 1-108-C was condensed and purified by high-pressure preparative liquid chromatography to obtain compound 1-108. [M+1] + : 456.15. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (s, 1H), 7.95 (s, 1H), 7.87 (d, J =2.0 Hz, 1H), 7.50 (d, J =1.6 Hz, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 6.63-6.61 (m, 1H), 6.32-6.31 (m, 1H), 5.41 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H).

[0378] Pharmacological Experiment 1: Enzymatic Activity Measurement of Acetyltransferase 1.1 Experimental measurement of the enzymatic activity of KAT6A acetyltransferase The acetylation effect of KAT6A on the histone substrate H3 was measured using the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method.

[0379] 1.2 Preparation of the compound 1) The compounds prepared in the examples of this disclosure were each dissolved in dimethyl sulfoxide to obtain a solution with a concentration of 10 mmol / L, which was then further diluted to 0.2 mmol / L, i.e., 1 μL of the compound was taken and added to 49 μL of DMSO, and then a 3-fold dilution was started to obtain 10 concentrations. 2) Using Echo, 50 nL of the sample to be measured (compounds from the example) was transferred to a 384 reaction plate, two overlapping wells were set for each compound, and the plates were centrifuged at a rotation speed of 1000 rpm for 1 minute to obtain a final concentration of dimethyl sulfoxide (DMSO) of 0.5% in all cases. 3) 2.5 μL of the reaction product obtained in step 2 was added to the 384 reaction plate from step 2), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 4) Add 2.5 μL of Bio-H3 & AcCOA (acetyl coenzyme A) reaction solution to the 384 reaction plate from step 3), centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 90 minutes. 5) Add 5 μL of Eu-Ab&Ulight-SA detection solution to the 384 reaction plate from step 4), centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. 6) HTRF 665 nM / 615 nM signals were read using a BMG high-throughput drug screening multi-function microplate reader.

[0380] 1.3 Data Analysis Using GraphPad Prism 8 software, histone H3 acetylation levels were analyzed. The reading for the negative control (0.5% DMSO well) was set to 0% inhibition, and the reading for the positive control (highest concentration well of the control compound) was set to 100% inhibition. After calculating the inhibition rates, the IC of the compounds awaiting measurement was determined using a software nonlinear fitting formula. 50 Obtain the value (median inhibitory concentration),

number

[0381] [Table 3]

[0382] The reagents used in the experiment are shown in Table 4. [Table 4]

[0383] Pharmacological Experiment 2, Enzymatic Activity Measurement of Other Isoforms of Acetyltransferase 1.1 Enzymatic Activity Measurement Experiment of KAT6B, KAT5, KAT7, and KAT8 Acetyltransferases The acetylating effects of KAT6B on histone substrate H3, and the acetylating effects of KAT5, KAT7, and KAT8 on histone substrate H4 were measured using the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method. The measurements were performed following experimental procedures similar to those in "Pharmacological Experiment 1".

[0384] 1.2 Preparation of the compound The compounds prepared in the examples were each dissolved in dimethyl sulfoxide to obtain solutions with a concentration of 10 mmol / L. 1) The concentration of the compound in the example was diluted from a stock solution of 10 mmol / L to 0.2 mmol / L, that is, 1 μL of the compound was taken and added to 49 μL of DMSO, and then a 3-fold dilution was started to obtain 10 concentrations. 2) Using Echo, 50 nL of the sample awaiting measurement was transferred to a 384 reaction plate. Two overlapping wells were set for each compound, and the plates were centrifuged at a rotation speed of 1000 rpm for 1 minute to obtain a final concentration of dimethyl sulfoxide (DMSO) of 0.5% in all cases. Regarding KAT6B, 3) 2.5 μL of KAT6B enzyme solution with a final concentration of 3 nM was added to the 384 reaction plate from step 2), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 4) 2.5 μL of the reaction solution of Bio-H3 at a final concentration of 400 nM and AcCOA (acetyl coenzyme A) at a final concentration of 2 μM was added to the 384 reaction plate from step 3), centrifuged at a rotation speed of 1000 rpm for 1 minute, and incubated at 25°C for 90 minutes. Regarding KAT-D, 3) 2.5 μL of KAT5 enzyme solution with a final concentration of 1.5 nM was added to the 384 reaction plate from step 2), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 4) 2.5 μL of the reaction solution of H4 at a final concentration of 200 nM and AcCOA (acetyl coenzyme A) at a final concentration of 2 μM was added to the 384 reaction plate from step 3), centrifuged at a rotation speed of 1000 rpm for 1 minute, and incubated at 25°C for 90 minutes. Regarding KAT7, 3) 2.5 μL of KAT7 enzyme solution with a final concentration of 15 nM was added to the 384 reaction plate from step 2), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 4) 2.5 μL of the reaction solution of H4 at a final concentration of 300 nM and AcCOA (acetyl coenzyme A) at a final concentration of 2 μM was added to the 384 reaction plate from step 3), centrifuged at a rotation speed of 1000 rpm for 1 minute, and incubated at 25°C for 90 minutes. About KAT8, 3) 2.5 μL of KAT8 enzyme solution with a final concentration of 10 nM was added to the 384 reaction plate from step 2), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 4) 2.5 μL of the reaction solution of Bio-H3 at a final concentration of 300 nM and AcCOA (acetyl coenzyme A) at a final concentration of 2 μM was added to the 384 reaction plate from step 3), centrifuged at a rotation speed of 1000 rpm for 1 minute, and incubated at 25°C for 90 minutes. 5) 5 μL of Eu-Ab&Ulight-SA detection solution was added to each of the four sets of 384 reaction plates from step 4) above, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. 6) HTRF 665 nM / 615 nM signals were read using a BMG high-throughput drug screening multi-function microplate reader.

[0385] 1.3 Data Analysis Using GraphPad Prism 8 software, each histone acetylation level was analyzed. The reading for the negative control (0.5% DMSO well) was set to 0% inhibition, and the reading for the positive control (highest concentration well of the control compound) was set to 100% inhibition. After calculating the inhibition rate, the IC of the compounds awaiting measurement was determined using a software nonlinear fitting formula. 50 Obtain the value (median inhibitory concentration),

number

[0386] [Table 5]

[0387] The reagents used in the experiment are shown in Table 6. [Table 6]

[0388] Pharmacological experiment 3: Measurement of cell proliferation inhibitory activity 1.1 Cell Culture Human breast cancer cell line ZR-75-1 (100 mm diameter cells per Petri dish, 1 × 10⁶ cells) 6 Cells were cultured in 1640 medium, and simultaneously, 1% of biantibodies (streptomycin and penicillin), 10% fetal bovine serum (FBS), and 1% glutamine (Glumax) were added. The cells were then cultured in a Petri dish at 37°C and 5% CO2 until 80-90% full for 2 days to obtain cells in the logarithmic growth phase.

[0389] 1.2 Preparation of the compound 1) The compounds from the examples were each dissolved in dimethyl sulfoxide to obtain a 10 mmol / L solution, which was further diluted to 250 μmol / L. Gradient dilution was then performed at a 10-fold ratio to five concentrations: 0.2 nmol / L, 2 nmol / L, 20 nmol / L, 200 nmol / L, and 2000 nmol / L. 2) Blank control wells were prepared by adding 0.1% dimethyl sulfoxide to cultured cells and used as high-readability control wells, while 3D hydrogels without cells were used as background wells. 3) The cultured cells were added to the example compounds at concentrations of 0.2 nmol / L, 2 nmol / L, 20 nmol / L, 200 nmol / L, and 2000 nmol / L, respectively, which were the same as the original culture fluid volume, to create measurement wells.

[0390] 1.3 Cell Plating 1) Cells were collected, resuspended in PBS equilibrium salt solution, counted, and mixed with 3D hydrogel stock solution to prepare a hydrogel cell suspension of appropriate density. 2) 3D hydrogel cell suspension (5 × 10) per well 4 The cells were added to a 96-cell culture plate with low surface adsorption and incubated at 37°C and 5% CO2 for 20 minutes. 3) A complete medium of the same volume of compound as the cell suspension in Step 2, prepared at 1.2 per well, was added to a 96-cell culture plate. 4) Cells were cultured for 96 hours at 37°C in a 5% CO2 incubator.

[0391] 1.4 Cell detection 1) Carefully aspirate the complete medium from the upper hydrogel layer of each well of the 96-cell culture plate using a vacuum pump or manual pipette, taking care not to damage the hydrogel layer below. 2) Complete medium containing the CCK-8 substrate was added to each well in the same volume as the original hydrogel. 3) The cells were incubated at 37°C and 5% CO2 for 1 hour. 4) A 96-well cell culture plate was placed in a microplate reader, and the A450 and A630 values ​​were measured, respectively.

[0392] Data Analysis Using Excel software, we analyzed the relative inhibition levels and obtained cell viability under different compound culture conditions. Survival rate (%) = (Compound well reading in example - Background well reading) / (High reading control well reading - Background well reading) × 100 The high-reading control well contained cells with dimethyl sulfoxide added, while the background well was a hydrogel without cells. The measurement results are shown in Table 7.

[0393] [Table 7]

[0394] As can be seen from Tables 3 and 5, the compounds of this disclosure have relatively high cell proliferation inhibitory activity and can effectively inhibit the proliferation of breast cancer cells ZR-75-1, demonstrating that the compounds of this disclosure can very effectively treat or prevent KAT6A-dependent cancers.

[0395] Pharmacological experiment 4: Measurement of plasma protein binding rate 1.1 Preparation of the compound The compounds prepared in the examples were each dissolved in dimethyl sulfoxide to obtain solutions with a concentration of 10 mmol / L. 1) The compound from the example was diluted from a 10 mmol / L stock solution to 0.2 mmol / L, i.e., 1 μL of the compound was taken and added to 49 μL of DMSO. 2) 3 μL of the compound awaiting measurement (0.2 mmol / L) was taken and added to 597 μL of plasma, then vortexed at 1000 rpm for 2 minutes. 3) Take 50 μL of drug-added plasma from 2), add 50 μL of PBS, and add 300 μL of methanol internal standard* to prepare sample T0. 4) Take 120 μL of drug-added plasma from 2) and add it to one side of the HTD instrument film, add 120 μL of PBS to the other side, cover with a gas-permeable film, and equilibrate with the remaining sample from 2) at 37°C (100 rpm, 5% CO2) for 6 hours. 5) A 50 μL post-dialysis plasma sample was taken, 50 μL of PBS was added, and 300 μL of methanol internal standard* was added to prepare sample P. 6) A 50 μL post-dialysis PBS sample was taken, 50 μL of blank plasma was added, and 300 μL of methanol internal standard* was added to create sample B. 7)2) 50 μL of drug-added plasma was taken, 50 μL of PBS was added, and 300 μL of methanol internal standard* was added to prepare sample T6. 8) All samples were vortexed and homogenized, then centrifuged at 3220 g at 4°C for 40 minutes. 9) 100 μL of the supernatant was taken and homogeneously mixed with 100 μL of pure water, and then used for liquid mass spectrometry. The methanol internal standard* demonstrated that an appropriate internal standard and concentration can be selected depending on the properties of the substance to be measured.

[0396] 1.2 Data Analysis Using an internal standard method, the binding rate, recovery rate, and residual percentage of plasma proteins were calculated using Excel based on the ratio of the sample peak area to the internal standard peak area.

number

number

number

number

[0397] [Table 8]

[0398] As can be seen from the data in Table 8, the plasma protein binding rates of the compounds disclosed herein showed relatively little difference across different species, indicating that the compounds disclosed herein have relatively high drug potential.

[0399] Pharmacological Experiment 5: In vivo pharmacokinetic studies in rats 1.1 Equipment A high-performance liquid chromatograph (SHIMADZU LC-30AD) was used, and mass spectrometry was performed using an AB SCIEX Triple Quad 5500 mass spectrometer. All measured data were calculated and processed in Microsoft Excel, and correlated pharmacokinetic parameters were calculated using WinNonlin software. The main pharmacokinetic parameters obtained were T max , T 1 / 2 , C max AUC 0~24 h and AUC inf The column used was an XSelect Hss T3 2.5 μm (2.1 × 50 mm) Column XP, the column temperature was 40°C, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the flow rate was 0.60 mL / min, and gradient elution was employed with 5%B at 0.30 min, 98%B at 1.00 min, 98%B at 1.48 min, 5%B at 1.51 min, and stop at 2.00 min. The injection volume was 1 μL.

[0400] 1.2 Animals Three female SD rats, weighing between 180 g and 300 g, were used in the study after being kept at the laboratory animal center for two days following purchase. They were fasted for 12 hours before administration and for 4 hours after administration, and were given free access to water during the study period. Blood samples were taken from the rats at predetermined points after intragastric administration.

[0401] 1.3 Solvents The intragastric solution was prepared as follows: 0.5% HPMC (hydroxypropyl methylcellulose) + 0.4% Tween 80 + 99.1% water. The compound was precisely weighed, the solvent was added, and the drug was sonicated at room temperature for 5 minutes to completely dissolve it, preparing a 0.5 mg / mL solution.

[0402] After intragastric administration, blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 7.0 h, and 24 h, respectively. The blood collection method involved collecting 0.2 mL of jugular vein blood, and the anticoagulant used was EDTA-K2. The collected blood samples were transferred to microcentrifuge tubes containing the anticoagulant, and the plasma was separated after centrifugation at 4°C and 4000 g for 5 minutes. All collected plasma samples were stored at -75±15°C until analysis.

[0403] Compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions at different concentrations. Blank plasma was added to prepare plasma standard curves and quality control samples. After pretreatment by protein precipitation, LC / MS / MS analysis was performed, and the concentrations of the plasma compounds were then measured. All measurement data were collected and processed using correlated software, and pharmacokinetic parameters were calculated using Winnonlin software. The pharmacokinetic parameters of some representative compounds are shown in Table 9.

[0404] [Table 9]

[0405] As can be seen from the data in Table 9, pharmacokinetic studies in rats showed that the sulfonamide compounds of this disclosure had relatively high exposure levels after oral intragastric administration and were well-absorbed orally. In particular, compared to conventionally known compounds, the compounds of Examples 2, 4, 5, 9, 10, 11, 59, 60, 62, 75, and 76 had even better pharmacokinetic parameters, i.e., better biological exposure levels, and their T 1 / 2All of these observations occurred within 10 hours, making the drug even more suitable for once-daily administration, and resulting in even lower in vivo accumulation, thereby effectively reducing the safety risks associated with high accumulation of the compound.

[0406] Pharmacological Experiment 6: In vivo pharmacokinetic studies in beagle dogs 1.1 Equipment A high-performance liquid chromatograph (SHIMADZU LC-30AD) was used, and mass spectrometry was performed using an AB SCIEX Triple Quad 5500 mass spectrometer. All measured data were processed and calculated using Microsoft Excel, and correlated pharmacokinetic parameters were calculated using WinNonlin software. The main kinetic parameters obtained were: T max , T 1 / 2 , C max AUC 0~24 h and AUC inf The column was an Agilent EC-C18 2.7 μm (50 × 2.1 mm), the column temperature was 40°C, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the flow rate was 0.60 mL / min, and gradient elution was employed with 5%B at 0.30 min, 95%B at 1.90 min, 95%B at 2.20 min, 5%B at 2.21 min, and stop at 2.50 min. The injection volume was 10 μL.

[0407] 1.2 Animals Three male Beagle dogs, weighing between 8 and 15 kg, were fasted for 12 hours before administration and 4 hours after administration, and were given free access to water during the study period.

[0408] 1.3 Solvents 0.5% HPMC (hydroxypropyl methylcellulose) + 0.4% Tween80 + 99.1% water.

[0409] After intragastric administration, blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h, respectively. Blood collection was performed by venous puncture, and EDTA-K2 was used as the anticoagulant. The collected blood samples were transferred to a microcentrifuge tube containing the anticoagulant and centrifuged for 10 minutes at 4°C and 2000 g to separate the plasma. All collected plasma samples were stored at -75±15°C until analysis.

[0410] 1.4 Pretreatment of Plasma Samples A 50 μL plasma sample was taken, 200 μL of an internal standard solution prepared with acetonitrile was added to allow precipitation, and the sample was then vortexed for 1 minute to mix thoroughly and uniformly. The precipitated sample was centrifuged at 4°C and 3900 rpm for 15 minutes, the supernatant was aspirated, diluted 3-fold with water, and 10 μL of the sample was injected. Quantitative analysis was performed using liquid chromatography-mass spectrometry.

[0411] All measurement data were collected and processed by correlated software, and pharmacokinetic parameters were calculated using Winnonlin software. The kinetic parameters of some representative compounds are shown in Table 10.

[0412] [Table 10]

[0413] As can be seen from the data in Table 10, pharmacokinetic studies in beagle dogs showed that the sulfonamide compounds of this disclosure have relatively high exposure levels after oral intragastric administration and are well-absorbed orally. In particular, compared to conventionally known compounds, the compounds of Examples 9, 10, and 59 have even better pharmacokinetic parameters, i.e., they have better biological exposure levels, and their T 1 / 2 All of these observations occurred within 15 hours, making the drug even more suitable for once-daily administration, and resulting in even lower in vivo accumulation, thereby effectively reducing the safety risks associated with high accumulation of the compound.

[0414] Pharmacological Experiment 7: Inhibitory Effect of Inhydro-P450 Enzymes 1.1 Preparation of Compounds The compounds prepared in the examples were each dissolved in dimethyl sulfoxide to obtain solutions with a concentration of 2 mmol / L.

[0415] 1.2 Test Method 1) The incubation system was as follows: Human liver microsomes, MgCl2 solution, phosphate buffer, and substrate solution were added to 96-well deep-well plates and mixed uniformly. The final concentration of human liver microsomes in the incubation system was 0.2 mg / mL, and the final concentrations of MgCl2 solution and phosphate buffer were 5 mM and 100 mM, respectively. 2) 1 μL of each substrate solution was added to the incubation system, and the final concentrations of the CYP1A2 phenacetin, 2C8 paclitaxel mephenytoin, 2C19 mephenytoin, 2D6 midazolam, and 3A midazolam substrates were 40 μM (phenacetin), 5 μM (paclitaxel), 50 μM (mephenytoin), 10 μM (mephenytoin), 5 μM (midazolam), and 50 μM (midazolam), respectively. 3) Before adding 1 μL of the compound solution or solvent (DMSO) of the example to the incubation system and then 20 μL of 10 mM NADPH solution to start the reaction, the incubation system was first preheated in a 37°C water bath for 5 minutes.

[0416] 1.3 Sample Processing Within the specified time (20 min for phenacetin, 10 min for paclitaxel, 20 min for mephenytoin, 20 min for dextromethorphan, 5 min for midazolam, and 10 min for testosterone), the reaction was stopped by adding 400 μL of methanol containing the internal standard. After vortexing to ensure homogeneity, the deep-well plates were centrifuged at 4°C and 3220 g for 40 min. 100 μL of the supernatant was transferred to a new plate, 150 μL of pure water was added and mixed homogeneously, and the plate was used for LC / MS / MS analysis.

[0417] [Table 11]

[0418] As can be seen from the data in Table 11, the compounds in the examples all showed relatively weak inhibitory effects on CYP enzymes, and IC 50 All of these were larger than 10 μM.

[0419] Pharmacological experiment 8, hERG channel detection 1.1 Test Method In this experiment, manual patch-clamp technology was used to detect the current-blocking effect of compounds on HEK-293 cell lines that stably express hERG channels, and the risk of the compounds inhibiting cardiac hERG potassium channels was evaluated by fitting the concentration-effect relationship.

[0420] 1.2 Experimental Procedure The patch clamp procedure was as follows: First, a micropipette puller was used to pull the capillary glass tube to the recording electrode. Then, the electrode, filled with intracellular fluid, was placed in a microelectrode holder, and under an inverted microscope, a microelectrode manipulator was used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). Next, the electrode was slowly brought into contact with the cell surface, negative pressure was applied, and a suction was performed to form a GΩ seal. At this point, fast capacitance compensation was performed, and negative pressure was continuously applied to disrupt the cell membrane by suction, creating a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was provided. Administration was started after the hERG current stabilized in the whole-cell recording, and each drug concentration was measured after approximately 5 minutes (or until the current stabilized), with multiple concentrations being measured for each compound. The coverslips containing the cells were placed in a recording bath under an inverted microscope. A blank control solution and the compound working solution awaiting measurement were passed through the recording bath in order from low to high concentration using gravity perfusion, and the cells were subjected to fluid exchange using a peristaltic pump during recording. For each cell, the current measured in the compound-free solution was used as its control group. Each concentration was independently measured and repeated three times. All electrophysiological tests were performed at room temperature.

[0421] The data processing was as follows: First, the tail current after the action of each drug concentration. [ka] and blank reference tail current [ka] Normalize the results, and then determine the inhibition rate corresponding to each drug concentration.

number

[0422] [Table 12]

[0423] conclusion As shown in the data in Table 12, the sulfonamide compounds in this disclosure are IC2 for hERG. 50 All of these levels were greater than 30 μM, and there was no hERG toxicity.

[0424] The foregoing are merely preferred embodiments of the Disclosure and do not limit the scope of the claims of the Disclosure. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art, without departing from the spirit and principles of the Disclosure, are all included within the scope of the claims of the Disclosure.

Claims

1. Formula (IV): 【Chemistry 1】 (IV) [In the formula, Ring B, together with its fused phenyl group, forms a 9-10 membered fused heterocycle, and the fused heterocycle is a partially saturated or aromatic fused heterocycle, and the ring B portion contains 1-3 heteroatoms selected from N, O, or S, or the ring B portion, together with its fused phenyl group, forms a C9-C10 fused carbon ring, and the fused carbon ring is a partially saturated or aromatic fused carbon ring. R 11 、R 12 、R 13 、R 14 、R x are the same or different and are each independently selected from hydrogen, deuterium, halogen, hydroxy group, cyano group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkynyl group, preferably, R 11 、R 12 、R 13 、R 14 、R x are the same or different and are each independently selected from hydrogen, deuterium, halogen, hydroxy group, cyano group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C2-C6 alkynyl group, more preferably, R 11 、R 12 、R 13 、R 14 、R x are the same or different and are each independently selected from hydrogen, halogen, hydroxy group, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted C1-C3 alkoxy group or substituted or unsubstituted C2-C4 alkynyl group, still more preferably, R 11 、R 12 、R 13 、R 14 、R x The substituents are homologous or homologous, and each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted methyl group, substituted or unsubstituted ethyl group, substituted or unsubstituted methoxy group, substituted or unsubstituted ethoxy group, or substituted or unsubstituted ethynyl group, and the substituents on the group are independently selected from halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, or C3-C6 cycloalkyl group, preferably, if the group is substituted, the substituents are homologous or homologous, and each is independently selected from halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C1-C3 alkoxy group, or C3-C4 cycloalkyl group, and more preferably, if the group is substituted, the substituents are homologous or homologous, and each is independently selected from halogen, hydroxyl group, cyano group, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, or cyclobutyl group, R 15 R is chosen at will. 6 A group selected from substituted hydroxyl groups, amino groups, alkoxy groups, heterocyclyl groups, and heteroaryl groups, preferably R 15 R is chosen at will. 6 The group is selected from substituent-substituted hydroxyl groups, amino groups, C1-C6 alkoxy groups, 4-6 membered heterocyclyl groups, and 5-6 membered heteroaryl groups, of which the heterocyclyl group contains 1-2 heteroatoms selected from N, O, or S, and the heteroaryl group contains 1, 2, or 3 heteroatoms selected from N, O, or S, and the R 6 The substituents are selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, and C1-C6 alkylcarbonyl group. X is selected from O or S. m and n are either homologous or different, and are independently chosen from the integers 0, 1, 2, and 3. Sulfonamide compounds represented by [formula], their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

2. Formula (III): 【Chemistry 2】 (III) [In the formula, 【Transformation 3】 It is selected from single bonds or double bonds. R 11 , R 12 , R 13 , R 14 , R x Each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and substituted or unsubstituted C2-C6 alkynyl group, preferably R 11 , R 12 , R 13 , R 14 , R x Each is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted C1-C3 alkoxy group, or substituted or unsubstituted C2-C4 alkynyl group, and more preferably R 11 , R 12 , R 13 , R 14 , R x Each of the groups is independently selected from hydrogen, halogen, hydroxyl group, substituted or unsubstituted methyl group, substituted or unsubstituted ethyl group, substituted or unsubstituted methoxy group, substituted or unsubstituted ethoxy group, or substituted or unsubstituted ethynyl group, and each of the substituents on the group is independently selected from halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, or C3-C6 cycloalkyl group, preferably each of the substituents on the group is independently selected from halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C1-C3 alkoxy group, or C3-C4 cycloalkyl group, and more preferably each of the substituents on the group is independently selected from halogen, hydroxyl group, cyano group, methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, or cyclobutyl group. R 15 R 6 Selected from 5-6 member heteroaryl groups containing substituents, preferably R 15 R 6 Selected from a 5-membered heteroaryl group containing a substituent, R 6 The substituent is selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C6 alkyl group, C3-C6 cycloalkyl group or C1-C6 alkoxy group, preferably R 6 is selected from hydrogen, halogen, hydroxyl group, cyano group, C1-C3 alkyl group, C3-C4 cycloalkyl group or C1-C3 alkoxy group, and more preferably R 6 This is selected from hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl groups. X is chosen from either O or S. Sulfonamide compounds represented by [formula], their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts.

3. Ring B, together with its condensed phenyl group, forms a 9-10 membered condensed heterocycle, the condensed heterocycle being partially saturated or aromatic, the ring B portion containing 1-2 heteroatoms selected from N, O, or S, the heteroatoms being linked to the condensed phenyl group, or the ring B portion, together with its condensed phenyl group, forms a C9-C10 condensed carbon ring, the condensed carbon ring being partially saturated or aromatic, preferably the condensed carbon ring being partially saturated. A sulfonamide compound according to claim 1, its stereoisomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt. 【Request Item 4】 【Chemistry 4】 The following condensed bicyclic structures are selected: 【Transformation 5】 Here, 【Transformation 6】 The single or double bond is selected, preferably an aminosulfonyl fragment (-S(=O) 2 -NH-) and R 11 It has a condensed biringular structure. 【Transformation 7】 Located at the phenyl group in, more preferably R 11 If it is not hydrogen, an aminosulfonyl fragment and at least one R 11 It has a condensed biringular structure. 【Transformation 8】 Characterized by bonding to the ortho position of the phenyl group in The sulfonamide compound according to claim 3, its stereoisomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt.

5. The aminosulfonyl fragment in formula (III) (-S (=O) 2 -NH-) and R 11 The aminosulfonyl fragment is located at the phenyl group of the oxygen-containing condensed ring biring, preferably at the 6th or 7th position of the oxygen-containing condensed ring biring, R 11 It is located at the 5th or 6th position of the condensed ring biring, and more preferably an aminosulfonyl fragment and R 11 It is characterized by being located at the ortho position of the benzene ring in the oxygen-containing condensed ring biring, The sulfonamide compound according to claim 2, its stereoisomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt.

6. R 15 teeth, 【Chemistry 9】 Selected from, R 6 is selected from hydrogen, deuterium, halogen, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylcarbonyl group, preferably R 6 It is characterized by being selected from hydrogen, F, a methyl group or ethyl group, a methoxy group, an ethoxy group, and an acetyl group. A sulfonamide compound according to claim 1 or 2, a stereoisomer thereof, an isotopic derivative thereof, a hydrate, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.

7. Selected from the following compounds, their stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts: A compound according to any one of claims 1 to 6, its stereoisomer, isotope derivative, hydrate, solvate, prodrug or pharmaceutically usable salt: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】

8. A pharmaceutical composition comprising, as an active ingredient, one of the compounds described in any one of claims 1 to 7, a stereoisomer thereof, an isotopic derivative thereof, a hydrate, a solvate thereof, a prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of any one of the compounds described in any one of claims 1 to 7, stereoisomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, in the manufacture of a drug for treating and / or preventing diseases associated with KAT6 amplification or overexpression.

10. The disease associated with the amplification or overexpression of KAT6 is characterized by being at least one selected from breast cancer, triple-negative breast cancer, acute myeloid leukemia, lung adenocarcinoma, hematological malignancies, gastrointestinal tumors, reproductive system tumors, nervous system tumors, or head and neck cancers. The use described in claim 9.

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