Sulfonamide compound, pharmaceutical composition and application thereof

Abstract

The invention relates to a sulfonyl compound and a pharmaceutical composition and application thereof. The sulfonamide compound comprises a compound as shown in formula I: # imgabs0 #. The sulfonamide compound has a benzyne structure located on the left side of sulfonyl and a pyridino isoxazole structure located on the right side of sulfonyl. Through the synergistic effect of sulfonyl, a benzyne structure and a pyridoisoxazole structure, the druggability of the compound and the capability of competitively combining with acetyl coenzyme to KAT6A / KAT6B can be remarkably improved, the acetyl coenzyme is inhibited from combining with KAT6A / KAT6B to catalyze histone related sites, and gene expression inducing cancer cell growth is prevented; further, the KAT6A / KAT6B gene can be used for treating related tumor diseases caused by KAT6A / KAT6B gene amplification or KAT6A / KAT6B protein overexpression.

Description

[0001] This application claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on June 21, 2023, with patent application number 202310744705.3 and title “Sulfonamide compounds, pharmaceutical compositions and their applications”. The entire text of the prior application is incorporated into this disclosure by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to a sulfonamide compound and a pharmaceutical composition and application thereof. Background Art

[0003] KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (LysineAcetyltransferase6B, also known as MORF) are acetyltransferases of the MYST family. KAT6A has chromosomal translocations in acute myeloid leukemia and has amplification mutations in cancer types such as lung cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, and esophageal cancer. Similarly, KAT6B also has chromosomal translocation mutations in multiple cancer types. MOZ and MORF-linked fusion proteins identified in acute myeloid leukemia include MOZ-CBP, MOZ-p300, MOZ-TIF2, MOZ-NcoA3, MOZ-LEUTX, and MORF-CBP. Among them, MOZ-TIF2 has transforming activity in cultured cells and can induce acute myeloid leukemia in mice. In tumor cells with amplified KAT6A and KAT6B, the expression of KAT6A and KAT6B was closely correlated with the gene copy number, indicating that there is selective pressure to maintain their activity during tumorigenesis. In addition, in cell proliferation assays, tumor cells with high expression of KAT6A and KAT6B were generally more dependent on the activity of KAT6A and KAT6B.

[0004] KAT6A and KAT6B usually extensively acetylate the lysine 23 site (H3K23) of histone H3, and KAT6A can also modify the acetylation of the H3K9 site of its regulatory genes only. KAT6A interacts with some transcription factors such as p53 and RUNX1, acetylates histones, and regulates the expression of downstream genes. KAT6A binds to the proximal promoter region of the estrogen receptor ERa (Estrogen Receptor a) and activates the expression of the ERa gene. In the MYC-induced lymphoma mouse model, the loss of one KAT6A allele can significantly prolong the median survival of mice. In mice, mutations in the KAT6B allele lead to a significant reduction in the division and differentiation of cortical progenitor cells, which seriously affects the development of the cerebral cortex. KAT6B also plays an important role in maintaining the number of adult neural stem cells.

[0005] In summary, the development of inhibitors targeting KAT6A and KAT6B can not only meet the unmet clinical needs of ER+ breast cancer, triple-negative breast cancer and acute myeloid leukemia (AML), but also has broad clinical value in other cancers. Therefore, a lot of work is still needed to develop and optimize KAT6A and KAT6B inhibitors. Summary of the invention

[0006] The present invention provides a sulfonamide compound, a pharmaceutical composition and application thereof. The sulfonamide compound can inhibit histone acetylation, inhibit transcription of related genes and inhibit cell growth, thereby being used for treating related cancer diseases.

[0007] In a first aspect, an embodiment of the present application provides a sulfonamide compound, wherein the sulfonamide compound includes a compound shown in Formula I:

[0008]

[0009] In Formula I:

[0010] R1 is selected from the group consisting of none, methoxy, ethoxy, halogen, cyano, nitro, hydroxyl, alkynyl, 11 Alkynyl, aryl, R-containing 11 The aryl, heteroaryl, R-containing 11 Substituents of heteroaryl, alkyl, containing R 11 Alkyl, cycloalkyl, R-containing 11 Substituents of cycloalkyl, alkoxy, R 11 Alkoxy, alkoxyalkyl, R-containing 11 Alkoxyalkyl, alkyl nitrogen, R 11 Substituents of alkyl nitrogen, alkyl mercapto, R 11 Substituted alkylthiol, cycloalkoxy, containing R11 Substituted cycloalkyloxy, cycloalkylthiol, containing R 11 Substituted cycloalkylthiol, sulfonamide, containing R 11 The sulfonamide, phosphorus oxy or R-containing substituent 11 A phosphorus oxy group of a substituent; wherein R 11 is selected from halogen, cyano, nitro, hydroxy, alkynyl, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, alkylnitro, alkylthiol, cycloalkyloxy, sulfonamide, ester, amide or phosphorus, and R1 and R 11 different;

[0011] R2 and R3 are each independently selected from methyl, fluorine or hydrogen;

[0012] R4 is selected from alkyl, alkoxy, alkoxyalkyl, alkylnitrogen, alkylcycloalkoxy, oxy, 12 Substituted oxy, amino, R 12 Substituted amino, cycloalkyl, R 12 Substituted cycloalkyl, azacycloalkyl, R 12 Substituted nitrogen heterocyclic alkyl, aryl, R 12 Substituted aryl, heteroaryl or R 12 Substituted heteroaryl; wherein R 12 is selected from methyl, fluorine, difluorine, cyano, alkyl, cycloalkyl, alkoxy, alkyl nitrogen, alkyl mercapto or hydrogen, and R4 and R 12 different;

[0013] R5 is selected from none, methoxy, ethoxy or alkyl;

[0014] m is selected from 0, 1, 2 or 3, wherein when m is 2 or 3, two or three R1 groups cannot form a ring.

[0015] In a second aspect, the present application provides a pharmaceutical composition, comprising the sulfonamide compound of formula I described in the first aspect, any one of the enantiomers, diastereomers, pharmaceutical salts, solvent compounds and pharmaceutically acceptable carriers of the sulfonamide compound of formula I.

[0016] In a third aspect, the present application also provides the use of the pharmaceutical composition described in the second aspect in a drug for treating diseases related to KAT6 amplification or overexpression.

[0017] The technical solution of this application has at least the following beneficial effects:

[0018] The sulfonamide compound of the present application has a benzyne structure located on the left side of the sulfonyl group and a pyridoisoxazole structure on the right side of the sulfonyl group, so that the sulfonamide compound can competitively target and bind to the substrate KAT6A / KAT6B in the binding pocket of the acetyl coenzyme of the KAT6A / KAT6B substrate, wherein the benzyne structure can effectively increase the electron cloud density of the sulfonamide part, effectively enhance the ability of the two oxygens in the sulfonyl group to act as hydrogen bond receptors, and increase the affinity of the sulfonamide compound to bind to the pocket. At the same time, the benzyne structure can also significantly increase the exposure of the sulfonamide compound in rats and significantly improve the drugability of the compound; the pyridoisoxazole structure can effectively enhance the ability of the pyridoisoxazole structure to bind to the sulfonamide compound in rats and significantly enhance the drugability of the compound. Pyridine can effectively reduce the electron cloud density of NO in isoxazole, reduce the space and freedom of the lone pair of oxygen electrons, reduce spatial conflicts, and make the sulfonamide compound fit better with the pocket. The synergistic effect of sulfonyl, benzyne structure and pyridoisoxazole structure can significantly improve the drugability of this type of compound and its ability to competitively bind to KAT6A / KAT6B with acetyl coenzyme, inhibit the binding of acetyl coenzyme with KAT6A / KAT6B to catalytic histone-related sites, prevent the expression of genes that induce cancer cell growth, and then be used to treat tumor diseases related to KAT6A / KAT6B gene amplification or KAT6A / KAT6B protein overexpression. DETAILED DESCRIPTION

[0019] In order to better illustrate the present application and facilitate understanding of the technical solution of the present application, the present application is further described in detail below. It should be clear that the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] The present application provides a sulfonamide compound, which includes a compound shown in Formula I:

[0021]

[0022] In Formula I:

[0023] R1 is selected from the group consisting of none, methoxy, ethoxy, halogen, cyano, nitro, hydroxyl, alkynyl, 11 Alkynyl, aryl, R-containing 11 The aryl, heteroaryl, R-containing 11 Substituents of heteroaryl, alkyl, containing R 11 Alkyl, cycloalkyl, R-containing 11 Substituents of cycloalkyl, alkoxy, R 11 Alkoxy, alkoxyalkyl, R-containing 11 Alkoxyalkyl, alkyl nitrogen, R 11Substituents of alkyl nitrogen, alkyl mercapto, R 11 Substituted alkylthiol, cycloalkoxy, containing R 11 Substituted cycloalkyloxy, cycloalkylthiol, containing R 11 Substituted cycloalkylthiol, sulfonamide, containing R 11 The sulfonamide, phosphorus oxy or R-containing substituent 11 A phosphorus oxy group of a substituent; wherein R 11 is selected from halogen, cyano, nitro, hydroxy, alkynyl, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, alkylnitro, alkylthiol, cycloalkyloxy, sulfonamide, ester, amide or phosphorus, and R1 and R 11 different;

[0024] R2 and R3 are each independently selected from methyl, fluorine or hydrogen;

[0025] R4 is selected from alkyl, alkoxy, alkoxyalkyl, alkylnitrogen, alkylcycloalkoxy, oxy, 12 Substituted oxy, amino, R 12 Substituted amino, cycloalkyl, R 12 Substituted cycloalkyl, azacycloalkyl, R 12 Substituted nitrogen heterocyclic alkyl, aryl, R 12 Substituted aryl, heteroaryl or R 12 Substituted heteroaryl; wherein R 12 is selected from methyl, fluorine, difluorine, cyano, alkyl, cycloalkyl, alkoxy, alkyl nitrogen, alkyl mercapto or hydrogen, and R4 and R 12 different;

[0026] R5 is selected from none, methoxy, ethoxy or alkyl;

[0027] m is selected from 0, 1, 2 or 3, wherein when m is 2 or 3, two or three R1 groups cannot form a ring.

[0028] In the above scheme, the sulfonamide compound has a benzyne structure located on the left side of the sulfonyl group and a pyridoisoxazole structure on the right side of the sulfonyl group, so that the sulfonamide compound can competitively target and bind to the substrate KAT6A / KAT6B in the binding pocket of the acetyl coenzyme of the KAT6A / KAT6B substrate, wherein the benzyne structure can effectively increase the electron cloud density of the sulfonamide part, effectively enhance the ability of the two oxygens in the sulfonyl group to act as hydrogen bond receptors, and increase the affinity of the sulfonamide compound to bind to the pocket. At the same time, the benzyne structure can also significantly increase the exposure of the sulfonamide compound in rats, significantly improving the drugability of the compound; the pyridoisoxazole structure The pyridine can effectively reduce the electron cloud density of NO in isoxazole, reduce the space and freedom of the lone pair of oxygen electrons, reduce spatial conflicts, and make the sulfonamide compound fit better with the pocket. The synergistic effect of the sulfonyl group, benzylene structure and pyridoisoxazole structure can significantly improve the drugability of this type of compound and its ability to competitively bind to KAT6A / KAT6B with acetyl coenzyme, inhibit the binding of acetyl coenzyme to KAT6A / KAT6B catalytic histone-related sites, prevent the expression of genes that induce cancer cell growth, and then be used to treat tumor diseases related to KAT6A / KAT6B gene amplification or KAT6A / KAT6B protein overexpression.

[0029] In some embodiments, the R1 group in the sulfonamide compound of the present application plays a decisive role in improving the binding ability of the sulfonamide compound to the target protein. By setting the R1 group and limiting its position, the sulfonamide compound molecule can be locked in a dominant conformation for binding to the target protein. At the same time, the electron cloud density of the benzyne structure can be controlled, thereby improving the ability of the compound to bind to the target protein.

[0030] In some embodiments, the sulfonamide compound of the present application may also be an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative and a solvate of the compound of formula I. It can be understood that the compound of formula I of the present application is used as an active reaction substance, and conventional design can be performed on the basis thereof, so that the designed compound can still maintain the efficacy of the compound of formula I.

[0031] In some embodiments, A is selected from Formula (Ia), Formula (Ib), or Formula (Ic):

[0032]

[0033] in Table: The site of attachment of fragment A to the alkynyl terminal of the compound of formula I;

[0034] R6 is selected from hydrogen, C 1-4 Alkyl, alkoxy, carboxyl, R 13 Substituted ester groups, amide groups, R 13 Substituted amide, hydroxyl, Cyano, amino, R 13 Substituted amino, C 3-8 Cycloalkyl, R 13 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 13 Substituted C 3-9 Heterocyclic group, aryl group, R 13 Substituted aryl, heteroaryl or R 13 Substituted heteroaryl; wherein R 13 is selected from halogen, cyano, nitro, hydroxy, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, alkylnitro, alkylthiol, cycloalkyloxy, cycloalkylthiol, sulfonamide, sulfonyl or phosphino, and R6 and R 13 different;

[0035] R7 and R8 are each independently selected from methyl, ethyl, aryl, fluorine or hydrogen;

[0036] Ring B is selected from C 3-8 Cycloalkyl;

[0037] R9 is selected from hydrogen, C 1-4 Alkyl, cyano, alkoxy, sulfonyl, alkylsulfonyl, carboxyl, R 14 Substituted ester groups, amide groups, R 14 Substituted amide, hydroxyl, Amino, R 14 Substituted nitrogen groups, C 3-8 Cycloalkyl, R 14 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 14 Substituted C 3-9 Heterocyclic group, aryl group, R 14 Substituted aryl, heteroaryl or R 14 Substituted heteroaryl; wherein R 14 is selected from halogen, cyano, nitro, hydroxy, alkynyl, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkylnitro, cycloalkyloxy, sulfonamido, sulfonyl or phosphino, and R9 and R 14 different;

[0038] R 10 Selected from hydrogen, C 1-4 Alkyl, alkoxy, cyano, sulfonyl, alkylsulfonyl, carboxyl, R 14 Substituted ester groups, amide groups, R 14 Substituted amide, hydroxyl, Amino, R 15 Substituted nitrogen, aryl, R 15Substituted aryl, heteroaryl or R 15 Substituted heteroaryl; wherein R 15 is selected from halogen, cyano, hydroxy, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, cycloalkyloxy, alkoxyalkyl, alkylnitrogen, acyl, sulfonamido, sulfonyl or phosphino, and R 10 and R 15 different.

[0039] In the A group, the sulfonamide compound in which the H of the acetylene in formula (Ia) is replaced only by R6, the presence of the R6 group can effectively prevent the alkynyl group from undergoing Michael addition with the non-conserved cysteine ​​residues in the body or the sulfhydryl group in glutathione, thereby avoiding the metabolism or unpredictable toxicity of the sulfonamide compounds designed in the present invention.

[0040] In the A group, after the H of acetylene in formula (Ib) is replaced by a methyl group containing three substituents, the Michael addition of the alkynyl group with the non-conserved cysteine ​​residues in the body or the thiol group in glutathione can be effectively avoided, and the oxidative metabolism of the unsubstituted hydrogen on the alkynyl methyl group can be avoided, thereby avoiding the metabolic or unpredictable toxicity of the sulfonamide compounds designed in the present invention. In addition, by modifying the methyl group with three substituents, it is helpful to solve the problem of the drugability of the sulfonamide compounds.

[0041] In the A group, the H of acetylene in formula (Ic) is replaced by C 3-8 After the cycloalkyl substitution, the metabolic stability of the sulfonamide compound is improved, and the exposure amount of the sulfonamide compound in the body can be significantly increased, thereby improving the drugability of the compound.

[0042] In some embodiments, R6 is selected from hydrogen, C 3-8 Cycloalkyl, R 13 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 13 Substituted C 3-9 Heterocyclic group, aryl group, R 13 Substituted aryl, heteroaryl or R 13 Substituted heteroaryl, wherein R 13 Selected from halogen, cyano, hydroxy, alkyl or alkoxy.

[0043] In some embodiments, R7 is selected from methyl.

[0044] In some embodiments, R8 is selected from methyl.

[0045] In some embodiments, R9 is selected from alkoxy, sulfonyl, alkylsulfonyl, C 3-9 Heterocyclic or R 14 Substituted C 3-9 Heterocyclic group.

[0046] In some embodiments, R 10 Selected from hydroxyl, amino or R 15 Substituted nitrogen radical, wherein R 15 Selected from alkyl groups.

[0047] In some embodiments, R4 is selected from any one of the following groups:

[0048]

[0049] Wherein, n=0, 1 or 2.

[0050] In some embodiments, R2 is methyl and R3 is methyl or hydrogen.

[0051] In some embodiments, R2 is fluorine and R3 is fluorine or hydrogen.

[0052] In some embodiments, R2 is hydrogen and R3 is hydrogen, methyl or fluoro.

[0053] The present application also discloses a method for preparing the above-mentioned sulfonyl compound, which comprises the following reaction route and preparation steps:

[0054]

[0055] Specifically, the preparation method comprises the following steps:

[0056] (1) dissolving SM1 and malonic acid in a first solvent, adding a first alkaline reagent, and reacting at -5°C to -20°C to obtain compound C01;

[0057] (2) Compound C01 is mixed with a hydrochloric acid solution and reacted at 50° C. to 80° C. to obtain compound C02;

[0058] (3) dissolving compound C02, PCl5 and POCl3 in a second solvent and reacting at 20°C to 80°C to obtain compound C03;

[0059] (4) dissolving compound C03 in a third solvent, adding an alkylating agent, and reacting at 0° C. to 50° C. to obtain compound C04;

[0060] (5) dissolving compound C04 and N-bromosuccinimide (NBS) in a fourth solvent, adding a free radical initiator, and reacting at 30° C. to 100° C. to obtain compound C05;

[0061] (6) dissolving compound C05 and compound SM2 in a fifth solvent, adding a second alkaline reagent to carry out an alkylation reaction, and obtaining compound C06;

[0062] (7) dissolving compound C06 and compound SM3 in a sixth solvent, adding a third alkaline reagent, and reacting at 20° C. to 60° C. to obtain compound C07;

[0063] (8) dissolving compound C07 and compound SM4 in a seventh solvent, adding a fourth alkaline reagent, and reacting at 0° C. to 60° C. to obtain compound C08;

[0064] (9) Compound C08 and SM5 are dissolved in an eighth solvent, and a fifth alkaline reagent and a first catalyst are added, and the reaction is carried out at 20° C. to 80° C. to obtain compound C09, that is, the sulfonamide compound of the present application.

[0065] In some embodiments, in step (1), the first solvent includes at least one of tetrahydrofuran, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and acetonitrile.

[0066] In some embodiments, in step (1), the first alkaline reagent includes at least one of sodium hydride, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide.

[0067] In some embodiments, in step (3), the second solvent includes at least one of dichloromethane and chloroform.

[0068] In some embodiments, in step (4), the third solvent includes at least one of dichloromethane, chloroform, tetrahydrofuran and methyltetrahydrofuran.

[0069] In some embodiments, in step (4), the alkylating agent comprises at least one of trimethyloxonium tetrafluoroborate, methyl iodide, dimethyl sulfate, and ethyl iodide.

[0070] In some embodiments, in step (5), the fourth solvent includes at least one of carbon tetrachloride and benzene.

[0071] In some embodiments, in step (5), the free radical initiator includes at least one of dibenzoyl peroxide (BPO) and azobisisobutyronitrile (AIBN).

[0072] In some embodiments, in step (6), the fifth solvent includes at least one of tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane, chloroform, N-methylpyrrolidone (NMP) and acetonitrile.

[0073] In some embodiments, in step (6), the second alkaline reagent includes at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, sodium hydride and N,N-diisopropylethylamine.

[0074] In some embodiments, in step (7), the sixth solvent includes at least one of methanol, ethanol, tert-butanol, isopropanol and water.

[0075] In some embodiments, in step (7), the third alkaline reagent includes at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

[0076] In some embodiments, in step (8), the seventh solvent includes at least one of tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and acetonitrile.

[0077] In some embodiments, in step (8), the fourth alkaline reagent includes at least one of 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.

[0078] In some embodiments, in step (9), the eighth solvent includes at least one of tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and acetonitrile.

[0079] In some embodiments, in step (9), the fifth alkaline reagent includes at least one of triethylamine, diethylamine, piperidine and N,N-diisopropylethylamine.

[0080] In some embodiments, in step (9), the first catalyst includes at least one of cuprous iodide, cuprous chloride, cuprous oxide, bistriphenylphosphine palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)palladium and 1,1-bis(diphenylphosphine)diferroni palladium(II) dichloride.

[0081] In some embodiments, SM1, SM2, SM3, SM4 and SM5 can be directly purchased.

[0082] The following is a further description of the embodiments of the present application in multiple embodiments. The embodiments of the present application are not limited to the following specific embodiments. Within the scope of the unchanged main rights, appropriate changes can be made to the implementation.

[0083] 1. Pyridoisoxazolamide common intermediates I-1 to I-8 and their synthesis methods:

[0084] I-1(C07): 6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine:

[0085]

[0086] Synthesis route:

[0087]

[0088] Step-1 and Step-2 (preparation of intermediate I-1B): At 0°C, under nitrogen protection, add sodium hydride (78.6g, 1.3eq) to a reaction device containing tetrahydrofuran (THF, 1.6L), cool to -10°C, slowly add malononitrile (99.8g, 1eq), stir and react for 1.5h, then add diketene (127.1g, 1eq) at -10°C, cool to -10°C, and mechanically stir and react for 1.5h. LCMS shows that all of them are I-1A products, and then add hydrochloric acid aqueous solution (4M, 2L) to the above system. After the addition is completed, the system is heated to 80°C and continued to stir and reflux for 5h. LCMS indicates that the reaction is complete, wait for it to cool to room temperature, filter, collect the filter cake and wash with water, ethanol and ethyl acetate in turn. Dry to obtain the crude intermediate I-1B (111g, yield: 46.2%), which is directly used in the next step without further treatment. MS:[M+1] + :151.

[0089] Step-3 (Preparation of intermediate I-1C): Dissolve intermediate I-1B (105.1g, 1eq) in 1.5L chloroform, add POCl3 (223.1g, 2.08eq) and PCl5 (302.9g, 2.08eq) to the system at 0°C, and heat the mixture to 70°C under nitrogen protection and mechanically stir for 5h. LCMS characterization After the reaction is completed, slowly cool to room temperature, distill off part of the solvent and reactants under reduced pressure, cool the residue to 0°C, quench with crushed ice, and then neutralize with ammonia water. Solids precipitate, filter, collect the filter cake and wash with water, dichloromethane and ethanol in turn, dry the solid to obtain the crude intermediate I-1C (75.1g, yield: 63.61%), which is used directly in the next step without further treatment. MS: [M+1] + :169.

[0090] Step-4 (Preparation of intermediate I-1D): Add I-1C (75.1g, 1eq) to a 5L four-necked flask and dissolve it in 3L of ultra-dry dichloromethane. Add trimethyloxonium tetrafluoroborate (82.3g, 1.25eq) under mechanical stirring. Under nitrogen protection, heat to 45°C, mechanically stir and react overnight. LCMS characterizes the reaction as complete, and cool the mixture to room temperature. At 0°C, add 1mol / L NaOH solution to the reaction mixture to adjust pH=8, stir freely for 20 minutes, separate the organic layer, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate I-1D (58g, yield: 71.39%) as a white solid. MS: [M+1] + :183, 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.33 (s, 1H), 4.00 (s, 3H), 2.48 (s, 3H).

[0091] Step-5 (Preparation of intermediate I-1E): Dissolve intermediate I-1D (52.1 g, 1 eq), N-bromosuccinimide (NBS, 51.2 g, 1 eq) and dibenzoyl peroxide (BPO, 13.8 g, 0.2 eq) in carbon tetrachloride (4 L), and heat to 90 ° C under N2 protection and stir for 3 h. LCMS characterizes the product at 57%. Stop the reaction and cool to room temperature, add saturated sodium bisulfite solution to quench, and then extract with a large amount of ethyl acetate for 3 times, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, spin dry, and purify by normal phase column chromatography to obtain intermediate I-1E (28.9 g, yield: 38.4%).

[0092] Step-6 (Preparation of intermediate I-1F): Dissolve intermediate I-1E (28.9 g, 1 eq), pyrazole (11.4 g, 1.5 eq), and N,N-diisopropylethylamine (DIEA) (28.1 g, 2 eq) in acetonitrile. Under N2 protective atmosphere, heat to 90°C, reflux and stir the mixed solution to react overnight. LCMS characterizes the reaction as complete, stop the reaction and cool to room temperature, spin dry, and purify with normal phase column chromatography to obtain intermediate I-1F (18.4 g, yield: 66.2%).

[0093] Step-7 (Preparation of key intermediate I-1): Dissolve intermediate I-1F (18.1g, 1eq) in tert-butanol (2L), then add acetohydroxamic acid (11.1g, 2eq) and potassium carbonate (19.3g, 2eq) to the solution. Slowly heat to 30°C under N2 protection, and stir the mixed solution to react overnight. LCMS characterizes the reaction as complete, stop the reaction and cool to room temperature. Dilute with ethyl acetate, filter out the carbonate, wash the filter cake with ethyl acetate 3 times, and combine the filtrate and spin dry. The resulting residue is purified by normal phase column chromatography to obtain the key intermediate I-1 (11.2g, yield: 62.9%) as a light yellow solid. MS: [M+1] + :246.1, 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=2.4Hz,1H),7.52(d,J=1.6Hz,1H),6.54(s,1H),6.33(t,J=2.0Hz,1H),6.21(s,2H),5.42(s,2H),3.98(s,3H).

[0094] I-2: 6-(Fluoro(1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0095] I-3: 6-(difluoro(1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0096]

[0097] Synthesis route:

[0098]

[0099] Step-1: Dissolve the intermediate I-1F (1g, 1eq) in freshly distilled tetrahydrofuran (50mL), cool to -78°C under N2 protection, add n-butyl lithium n-hexane solution (2.5M in hexane, 4.8mL, 3eq) dropwise with stirring, stir at -78°C for 5min, add N-fluorobisbenzenesulfonamide (3.8g, 3eq) in tetrahydrofuran (30mL), and slowly warm from -78°C to room temperature overnight with stirring. LCMS characterization: After the reaction is complete, the reaction system is added to saturated ammonium chloride aqueous solution for quenching, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried, and the crude product is purified by high pressure preparative liquid chromatography to obtain compound I-2A (195mg, yield 18.1%), [M+1] + :267.10. and I-3A (98 mg, yield 8.1%), [M+1] + :285.10.

[0100] Step-2: According to the steps of Step-7 in I-1, the intermediate I-2A is reacted with acetohydroxamic acid to obtain the key intermediate I-2, [M+1] + :264.10; the intermediate I-3A is reacted with acetohydroxamic acid to obtain the key intermediate I-3, [M+1] + :282.05.

[0101] I-2: 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.03 (d, J = 2.8Hz, 1H), 7.66 (s, 1H), 7.51 (s, 1H),

[0102] 7.45(d,J=46.8Hz,1H),6.42(s,1H),6.30(s,2H),3.90(s,3H).

[0103] I-3: 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.18 (d, J = 2.4Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H),

[0104] 6.52-6.51(m,1H),6.39(s,2H),3.91(s,3H).

[0105] I-4: 6-((3,3-difluoroazetidin-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0106]

[0107] Synthesis route:

[0108]

[0109] Step-1: Dissolve the intermediate I-1E (1.8g, 1eq) and 3,3-difluorotrimethylimide hydrochloride (SM1, 1.34g, 1.5eq) in dichloromethane (70mL), add N,N-diisopropylethylamine (DIEA, 2.68g, 3eq) in dichloromethane (10mL) dropwise at 0°C, stir at 0°C for 5h under N2 protection, and LCMS shows that the reaction is complete. Add water to quench the reaction, extract with dichloromethane three times, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and spin dry. The solid is purified by normal phase column chromatography to obtain intermediate I-4A (0.85g, yield: 45.5%). [M+1] + :273.05.

[0110] Step-2: According to the steps of Step-7 in I-1, the intermediate I-4A (0.85 g, 1 eq) was reacted with acetohydroxamic acid to obtain the key intermediate I-4 (0.33 g, yield: 41.6%). [M+1] + :271.10.

[0111] I-5: 6-((dimethylamino)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0112]

[0113] Synthesis route:

[0114]

[0115] The difference from the key intermediate I-4 is that the "3,3-difluorotrimethylimide hydrochloride" in step-1 of compound I-4 is replaced with "dimethylamine hydrochloride" to obtain intermediate I-5. [M+1] + :223.10.

[0116] I-6: 6-(azetidin-1-ylmethyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0117]

[0118] Synthesis route:

[0119]

[0120] The difference from the key intermediate I-4 is that the "3,3-difluorotrimethylimide hydrochloride" in step-1 of compound I-4 is replaced with "azetidine hydrochloride" to obtain intermediate I-6. [M+1] + :235.20

[0121] I-7: 6-((2H-1,2,3-triazol-2-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-amine

[0122]

[0123] Synthesis route:

[0124]

[0125] The difference from the key intermediate I-4 is that the "3,3-difluorotrimethylimide hydrochloride" in step-1 of compound I-4 is replaced with "triazole" to obtain intermediate I-7. [M+1] + :246.20.

[0126] 1-8: 4-methoxy-6-((3-methoxyoxetane-1-yl)methyl)isoxazolo[4,5-c]pyridin-3-amine:

[0127]

[0128] Synthesis route:

[0129]

[0130] The difference from the key intermediate I-4 is that the "3,3-difluorotrimethylimide hydrochloride" in step-1 of compound I-4 is replaced with "3-methoxy-azetidine" to obtain intermediate I-8. [M+1] + :265.20.

[0131] 2. Synthesis of sulfonamide compounds

[0132] Example 1

[0133] 1-1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-ethynyl-2,6-dimethoxybenzenesulfonamide

[0134]

[0135] Synthesis route:

[0136]

[0137] Step-1 (Preparation of tert-butyl((3,5-dimethoxyphenyl)ethynyl)dimethylsilane (1-1A)): 3,5-dimethoxyiodobenzene (SM1, 5.1 g, 1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.5 g, 0.1 eq), CuI (360.6 mg, 0.1 eq) and N,N-diisopropylethylamine (DIEA, 10 mL) were dissolved in tetrahydrofuran (THF, 40 mL). Under nitrogen protection, a tetrahydrofuran solution of (tert-butyldimethylsilyl)acetylene (SM2, 3.9 g, 1.5 eq) was added dropwise at 0°C. After the addition was complete, the mixture was reacted at room temperature for 4 h. The reaction was monitored by GCMS. The reaction mixture was quenched with water at room temperature, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Intermediate 1-1A (3.6 g, yield: 68.77%) was obtained by silica gel column chromatography. GCMS (ES, m / z): 276 [M] + .

[0138] 1H NMR (400MHz, DMSO-d6) δ6.58-6.53(m,3H),3.74(s,6H),0.96(s,9H),0.16(s,6H).

[0139] Step-2 (Preparation of 4-((tert-butyldimethylsilyl)ethynyl)-2,6-dimethoxybenzenesulfonyl chloride (1-1B)): Under nitrogen protection, intermediate 1-1A (1.1 g, 1 eq) and tetramethylethylenediamine (TMEDA, 503.2 mg, 1.1 eq) were dissolved in 10 mL of n-hexane, cooled to 0°C, and n-butyllithium (2.5 M in n-hexane, 1.6 mL, 1 eq) was added dropwise. After stirring for 20 minutes, the reaction system was cooled to -78°C, and sulfur dioxide gas was bubbled for 20 minutes. The system was heated to -20°C, and then the reaction mixture was slowly heated to room temperature and stirred for 1 hour. Solid precipitated from the system, filtered, the filter cake was collected and washed with ether to obtain 1.78 grams of crude product. Under stirring, the solid was suspended in 10 mL of n-hexane, cooled to 0°C, sulfonyl chloride (488.2 mg, 1 eq) was added dropwise, and the reaction was stirred for 1 hour. The solid was filtered and the filter cake was collected. The filter cake was dissolved in water / ethyl acetate, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by silica gel column chromatography to obtain intermediate 1-1B (480.2 mg, yield: 35.4%).

[0140] 1 H NMR (400MHz, DMSO-d6) δ6.71(s,2H),4.01(s,6H),1.03(s,9H),0.25(s,6H).

[0141] Step-3 (Preparation of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((tert-butyldimethylsilyl)ethynyl)-2,6-dimethoxybenzenesulfonamide (1-1C)): Intermediate C07 (50.2 mg, 1.00 eq) was dissolved in 5 mL of tetrahydrofuran, and sodium hydride (60% in oil, 49.1 mg, 6 eq) was slowly added at 0°C. After stirring for 30 minutes, intermediate 1-1B (228.1 mg, 3 eq) was added and stirred at room temperature overnight. The reaction mixture was quenched with ice water at room temperature. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude intermediate 1-1C (120 mg), which was used directly in the next step without further treatment. MS: [M+1] + :584.1.

[0142] Step-4 (Preparation of sulfonamide compound 1-1): At room temperature, intermediate 1-1C (80.1 mg, 1 eq) was completely dissolved in dichloromethane (5 mL), tetramethylammonium fluoride (76.6 mg, 6 eq) was added at 0°C, and the reaction was allowed to react overnight at room temperature under nitrogen protection. The reaction mixture was quenched with water at room temperature, extracted with dichloromethane 3 times, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and dried. The crude product was purified by high-performance liquid chromatography to obtain compound 1-1 ((37.5 mg, yield: 57.6%) as a white solid. MS: [M+1] + :470.2.

[0143] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.90 (s.1H), 7.51 (s, 1H), 7.16 (s, 1H), 6.77 (s, 2H) ),6.54(s,1H),6.33(s,1H),5.42(s,2H),4.37(s,1H),3.94(s,3H),3.68(s,6H).

[0144] According to the preparation method similar to that of Example 1, (tert-butyldimethylsilyl)acetylene is replaced with other alkynyl substituents to generate benzenesulfonyl chloride compounds which react with intermediate C07 to prepare the following sulfonamide compounds of Examples 1 to 4 as shown in Table 1:

[0145] Table 1. Sulfonamide compounds prepared in Examples 1 to 4

[0146]

[0147]

[0148] Example 5

[0149] Sulfonamide compound 1-5: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-3-ethynyl-2,6-dimethoxybenzenesulfonamide;

[0150]

[0151] Synthesis route:

[0152]

[0153] The difference from Example 1 is that 3,5-dimethoxyiodobenzene (SM1) in Step-1 of 1-1 is replaced by 2,4-dimethoxy-1-iodobenzene and the same four-step reaction as in Example 1 is performed to prepare sulfonamide compound 1-5. MS: [M+1] + :470.2.

[0154] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.89 (d, J = 2.4Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 6.99 (s, 1H), 6.75 (d, J = 8.4Hz,1H),6.36(s,1H),6.32(t,J=2.0Hz,1H),5.38(s,2H),4.13(s,1H),3.94(s,3H),3.79(s,3H),3.61(s,3H).

[0155] Example 6

[0156] Sulfonamide compound 1-6: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-ethynyl-2-methoxybenzenesulfonamide;

[0157]

[0158] Synthesis route:

[0159]

[0160] Step-1 (Preparation of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-bromo-2-methoxybenzenesulfonamide (1-6A)): Dissolve intermediate C07 (0.98 g, 1 eq) in ultra-dry tetrahydrofuran (50 mL), slowly add sodium hydride (60% in oil, 160.2 mg, 1 eq) at 0°C under nitrogen protection, stir for 30 minutes, then add 4-bromo-2-methoxybenzene-1-sulfonyl chloride (1.13 g, 1 eq), slowly warm to room temperature and stir for 3 hours. LCMS characterizes the reaction, and the reaction mixture is quenched with ice water at room temperature. Extract with ethyl acetate three times, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, spin dry, and purify by silica gel column chromatography to obtain intermediate 1-6A (930.2 mg, yield: 47.2%). MS: [M+1] + :494.0.

[0161] 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.12 (s, 1H), 7.90 (d, J = 2.0Hz, 1H), 7.73 (t, J = 4.4Hz, 1H), 7.52 (s, 1H) ,7.44(s,1H),7.31(d,J=4.0Hz,1H),6.71(s,1H),6.34(s,1H),5.45(s,2H),3.93(s,3H),3.78(s,3H).

[0162] Step-2 (Preparation of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((tert-butyldimethylsilyl)ethynyl)-2-methoxybenzenesulfonamide (1-6B)): Intermediate 1-6A (0.73 g, 1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.12 g, 0.1 eq), CuI (20.1 mg, 0.1 eq), N,N-diisopropylethylamine (DIEA, 5 mL) and (tert-butyldimethylsilyl)acetylene (SM2, 0.42 g, 2 eq) were dissolved in tetrahydrofuran (THF, 40 mL) and refluxed with stirring under nitrogen protection for 4 h. LCMS characterization: After the reaction was completed, the reaction mixture was quenched with ice water at room temperature, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and dried by spin drying. The intermediate 1-6B (0.34 g, yield: 46.2%) was obtained by purification by silica gel column chromatography. MS: [M+1] + :554.2.

[0163] Step-3 (Preparation of sulfonamide compound 1-6): Dissolve intermediate 1-6B (110 mg, 1 eq) in 10 mL of dichloromethane, add tetramethylammonium fluoride (0.11 g, 6 eq) at room temperature, and stir at room temperature overnight. After LCMS characterization, the reaction was completed, water was added to quench the reaction, and dichloromethane was extracted 3 times. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by high-performance liquid chromatography to obtain compound 1-1 (45.5 mg, yield: 51.8%) as a white solid. MS: [M+1] + :440.25.

[0164] 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.08 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 7.16(d,J=8.0Hz,1H),6.97(s,1H),6.33-6.32(m,1H),5.44(s,2H),4.46(s,1H),3.93(s,3H),3.79(s,3H).

[0165] According to the general preparation method similar to Step-2 in Example 6, (tert-butyldimethylsilyl)acetylene is replaced with other alkynyl substituents to undergo coupling reaction with intermediate 1-6A to prepare the following sulfonamide compounds of Examples 6 to 20 as shown in Table 2:

[0166] Table 2. Sulfonamide compounds prepared in Examples 6 to 20

[0167]

[0168]

[0169]

[0170] Embodiment 21

[0171] Sulfonamide compound 1-21: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-ethynyl-2-methoxybenzenesulfonamide;

[0172]

[0173] Synthesis route:

[0174]

[0175] According to the preparation method similar to Example 6, 4-bromo-2-methoxybenzene-1-sulfonyl chloride in Step-1 was replaced with 5-bromo-2-methoxybenzene-1-sulfonyl chloride, and N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-ethynyl-2-methoxybenzenesulfonamide (1-21) was prepared through a similar four-step reaction. MS: [M+1] + :440.20.

[0176] 1H NMR (400MHz, DMSO-d6) δ (ppm): 7.89-7.86 (m, 2H), 7.51 (d, J = 1.6Hz, 1H), 7.22-6.97 (m, 3H ),6.44(s,1H),6.32(t,J=2.0Hz,1H),5.40(s,2H),4.06(s,1H),3.94(s,3H),3.76(s,3H).

[0177] According to the general preparation method similar to Step-1 in Example 21, the intermediate I-1 is replaced with I-2 to I-8; in the general preparation method of Step-2, (tert-butyldimethylsilyl)acetylene is replaced with other alkynyl substituents to undergo coupling reaction with the intermediate 1-21A to prepare the following sulfonamide compounds of Examples 21 to 41 as shown in Table 3:

[0178] Table 3. Sulfonamide compounds prepared in Examples 21 to 41

[0179]

[0180]

[0181]

[0182]

[0183] Pharmacological experiment 1: Determination of acetyltransferase enzymatic activity

[0184] 1.1KAT6A acetyltransferase enzymatic activity test

[0185] The TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method was used to measure the acetylation effect of KAT6A on the histone substrate H3.

[0186] 1.2 Compound preparation

[0187] The compounds prepared in Examples 1 to 41 were respectively dissolved in dimethyl sulfoxide to obtain solutions with a concentration of 10 mmol / L.

[0188] 1) The concentration of the compound of Examples 1 to 41 was diluted from 10 mmol / L stock solution to 0.2 mmol / L, i.e., 1 μL of the compound was added to 49 μL of DMSO, and then 3-fold dilution was started, with 10 concentrations;

[0189] 2) Use Echo to transfer 50 nL of the test substance (Examples 1 to 41) to a 384 reaction plate, with two replicate wells for each compound, and centrifuge at 1000 rpm for 1 minute. The final concentration of dimethyl sulfoxide (DMSO) is 0.5%.

[0190] 3) Add 2.5 μL of the reaction product obtained in step 2 to the 384 reaction plate in step 2), centrifuge at 1000 rpm for 1 min, and incubate at 25° C. for 10 min.

[0191] 4) Add 2.5 μL of Bio-H3 & AcCOA (acetyl coenzyme A) reaction solution to the 384 reaction plate in step 3), centrifuge at 1000 rpm for 1 min, and incubate at 25° C. for 90 min.

[0192] 5) Add 5 μL of Eu-Ab & Ulight-SA detection solution to the 384 reaction plate in step 4), centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min.

[0193] 6) Use BMG high-throughput drug screening multifunctional microplate reader to read HTRF 665nM / 615nM signal.

[0194] 1.3 Data Analysis

[0195] The acetylation level of KAT6A was analyzed using GraphPad Prism 8 software. The reading value of the negative control (0.5% DMSO well) was set to 0% inhibition rate, and the reading value of the positive control (the well with the highest concentration of the control compound) was set to 100% inhibition rate. After calculating the inhibition rate, the IC of the test compound was obtained using the nonlinear fitting formula of the software. 50 value (half-maximal inhibitory concentration);

[0196]

[0197] The average of the values ​​of the positive control wells; Average of the negative control well values

[0198] The test results are shown in Table 3.

[0199] Table 3. Enzyme inhibition activity of the compounds in the examples

[0200] sample IC50(nmol / L) sample IC50(nmol / L) sample IC50(nmol / L) Example 1 <1 Embodiment 14 <10 Embodiment 27 <100 Example 2 <5 Embodiment 15 <5 Embodiment 28 <10 Example 3 <5 Example 16 <5 Embodiment 29 <10 Example 4 <10 Embodiment 17 <10 Embodiment 30 <10 Example 5 <1 Embodiment 18 <10 Embodiment 31 <10 Example 6 <5 Embodiment 19 <10 Embodiment 32 <10 Example 7 <5 Embodiment 20 <10 Embodiment 33 <10 Example 8 <10 Embodiment 21 <5 Embodiment 34 <10 Example 9 <100 Embodiment 22 <5 Embodiment 35 <10 Example 10 <10 Embodiment 23 <10 Embodiment 36 <10 Embodiment 11 <10 Embodiment 24 <10 Embodiment 38 <100 Example 12 <10 Embodiment 25 <10 Embodiment 13 <10 Embodiment 26 <10

[0201] The reagent information used in the experiment is shown in Table 4:

[0202] Table 4. Information on reagents used in the experiment

[0203] Material factory Product Number KAT6A active motife 81223 AcCOA Sigma A2056 Bio-H3(1-21) GenScript / Eu-Ab PerkinElmer TRF0412-M Ulight-SA PerkinElmer TRF0102-M <![CDATA[LANCE TM Detection buffer(10x)]]> Perkinelmer CR97-100

[0204] Pharmacological experiment 2: Determination of cell proliferation inhibitory activity

[0205] 1.1 Cell culture

[0206] Human breast cancer cell line ZR-75-1 (1*10^ 6 Cells were cultured in 1640 medium (per 100 mm diameter cell culture dish), and 1% double antibody (streptomycin and penicillin), 10% fetal bovine serum (FBS), and 1% glutamine (Glumax) were added. The cell culture dish was placed at 37°C and 5% CO2 for 2 days until it grew to 80% to 90% confluence, and cells in the logarithmic growth phase were obtained.

[0207] 1.2 Compound preparation: The compounds prepared in Examples 1, 5, 6, 21, 31, 33 and 34 were respectively dissolved in dimethyl sulfoxide to obtain solutions with a concentration of 10 mmol / L.

[0208] 1) The compounds prepared in Examples 1, 5, 6, 21, 31, 33 and 34 were diluted from 10 mmol / L stock solution to 250 μmol / L, and then diluted to 5 concentrations in a 10-fold gradient, namely 0.2 nmol / L, 2 nmol / L, 20 nmol / L, 200 nmol / L and 2000 nmol / L;

[0209] 2) Prepare blank control wells, which are cultured cells plus 0.1% dimethyl sulfoxide, as high-reading value control wells; and use 3D hydrogels without cells as background wells.

[0210] 3) adding 0.2 nmol / L, 2 nmol / L, 20 nmol / L, 200 nmol / L and 2000 nmol / L of the compound of the example to the cultured cells in the same volume as the original culture medium, respectively, as test wells;

[0211] 1.3 Cell plating

[0212] 1) Collect cells, resuspend them in PBS balanced salt solution, count them, and mix them with 3D hydrogel stock solution to prepare a hydrogel cell suspension with appropriate density.

[0213] 2) Add 3D hydrogel cell suspension (5*10^ 4 The cells were cultured in a 96-well plate with low surface adsorption and incubated at 37°C and 5% CO2 for 20 min.

[0214] 3) Add the complete medium containing the functional compound in step 2 in an equal volume to the cell suspension to each well of the 96-well cell culture plate.

[0215] 4) The cells were cultured in a 37°C, 5% CO2 incubator for 96 h.

[0216] 1.4 Cell detection

[0217] 1) Carefully use a vacuum pump or manual ejector to aspirate the complete medium on the top layer of the hydrogel in each well of the 96-well cell culture plate, taking care not to damage the hydrogel on the bottom layer.

[0218] 2) Add complete culture medium containing CCK-8 substrate in an equal volume to the original hydrogel to each well.

[0219] 3) Incubate at 37°C, 5% CO2 for 1 hour.

[0220] 4) Place the 96-well cell culture plate into an ELISA reader and detect the values ​​of A450 and A630 respectively.

[0221] Data analysis: Excel software was used to analyze the relative level of inhibition and obtain the cell survival rate under different compound culture conditions;

[0222] Survival rate (%) = (reading value of the example compound well - reading value of the background well) / (reading value of the high reading control well - reading value of the background well) * 100

[0223] High reading control well: cells plus dimethyl sulfoxide; background well: cell-free hydrogel. The test results are shown in Table 5.

[0224] Table 5. Cell proliferation inhibition activity of some of the compounds in the examples

[0225]

[0226] It can be seen from Tables 3 and 5 that the sulfonamide compounds of the present application have a high ability to inhibit acetylation and can effectively inhibit the proliferation of breast cancer cells ZR-75-1, indicating that the compounds of the present application can well treat or prevent cancers that depend on KAT6A. Similarly, since KAT6A and KAT6B are homologous genes, the compounds of the present application can also be used to treat or prevent cancers that depend on KAT6B, that is, the sulfonyl compounds of the present application can be used to regulate KAT6A / KAT6B gene amplification or KAT6A / KAT6B protein overexpression, thereby being used to treat tumors or cancer diseases related to KAT6A / KAT6B dependence, and have good application prospects.

[0227] Pharmacological Experiment III: Pharmacokinetic Study in Rats

[0228] 1.1 Instruments: High performance liquid chromatograph: SHIMADZU LC-30AD, mass spectrometer: AB SCIEX mass spectrometer TripleQuad5500, all measured data were calculated and processed using Microsoft Excel, and relevant pharmacokinetic parameters were calculated using WinNonlin software. The main kinetic parameters obtained were T max , T 1 / 2 , C max , AUC 0-24h and AUC inf . Chromatographic column: XSelect Hss T3 2.5μm (2.1x50 mm) Column XP, column temperature 40℃, mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.60 ml / min, gradient elution is adopted, the elution gradient is 0.30min: 5% B; 1.00min: 98% B; 1.48min: 98% B; 1.51min: 5% B; 2.00min: stop. Injection volume: 1μL.

[0229] 1.2 Animals: Three SD female rats, weighing 180 g to 300 g, were purchased and raised in the experimental animal center for two days before use. They were fasted for 12 hours before administration and within 4 hours after administration, and had free access to water during the experiment. Blood samples were collected at the specified time points after oral gavage.

[0230] 1.3 Solvent: 0.5% HPMC (hydroxypropyl methylcellulose) + 0.4% Tween80 + 99.1% water. Preparation of intragastric administration solution: accurately weigh the compound, add the solvent, and perform ultrasound at room temperature for 5 minutes to completely dissolve the drug, and prepare a 0.5 mg / ml solution.

[0231] Blood was 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 after oral administration. The blood collection method was as follows: 0.2 mL of blood was collected from the jugular vein. Anticoagulant: EDTA-K2. The collected blood samples were transferred to microcentrifuge tubes containing anticoagulants. After centrifugation at 4°C and 4000 g for 5 min, the supernatant was collected for LCMS / MS analysis.

[0232] The compounds were accurately weighed and prepared into different concentrations, and quantitative analysis was performed on the mass spectrometer to establish a standard curve. Then, the concentration of the above plasma compounds was tested to obtain the changes in compound concentrations at different time points. All the measured data were collected and processed by relevant software, and the pharmacokinetic parameters were calculated using the statistical moment method. The kinetic parameters of some representative compounds are shown in Table 6:

[0233] Table 6. Pharmacokinetic parameters of some compounds in rats

[0234]

[0235] According to the data in Table 6, the pharmacokinetic study in rats showed that the sulfonamide compounds of the present application were rapidly absorbed in the gastrointestinal tract, wherein the compound of Example 1 reached a peak at about 0.33 h after oral administration, and the compound of Example 6 reached a peak at about 0.83 h after oral administration. At the same time, the AUC of the compounds were all above 100,000 h*ng / mL, indicating that the sulfonamide compounds of the present application had good oral bioavailability.

[0236] The present application also provides a pharmaceutical composition, which comprises as an active ingredient a compound of formula I or any one of an enantiomer, a diastereomer, a pharmaceutical salt, a solvent compound, and a pharmaceutically acceptable carrier of the compound. The pharmaceutical composition of the present application can be used in drugs for treating diseases related to KAT6 amplification or overexpression.

[0237] The pharmaceutical composition disclosed in the present application may contain one or more excipients in addition to the above-mentioned sulfonamide compound active substance, including fillers, excipients, disintegrants, binders and wetting agents, etc. Depending on the different modes of administration, the composition of the present application may contain 10% to 90% of the above-mentioned sulfonamide compound by mass. The pharmaceutical composition of the present application is in the form of an oral preparation or an injection, wherein the oral preparation may be a capsule, a tablet, etc., and the injection may be an intravenous injection, an intramuscular injection or a subcutaneous injection, etc., which is not limited in the present application.

[0238] The pharmaceutical composition of the present application can be used to treat diseases including cancer, including at least one of breast cancer (e.g., triple-negative breast cancer), acute myeloid leukemia, lung adenocarcinoma, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors or head and neck cancer.

[0239] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the claims. Any person skilled in the art may make several possible changes and modifications without departing from the concept of the present application. Therefore, the scope of protection of the present application shall be based on the scope defined by the claims of the present application.

Claims

1. A sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, It is characterized in that The sulfonamide compound includes a compound shown in Formula I: In Formula I: R1 is selected from the group consisting of none, methoxy, ethoxy, halogen, cyano, nitro, hydroxyl, alkynyl, 11 Alkynyl, aryl, R-containing 11 The aryl, heteroaryl, R-containing 11 Substituents of heteroaryl, alkyl, containing R 11 Alkyl, cycloalkyl, R-containing 11 Substituents of cycloalkyl, alkoxy, R 11 Alkoxy, alkoxyalkyl, R-containing 11 Alkoxyalkyl, alkyl nitrogen, R 11 Substituents of alkyl nitrogen, alkyl mercapto, R 11 Substituted alkylthiol, cycloalkoxy, containing R 11 Substituted cycloalkyloxy, cycloalkylthiol, containing R 11 Substituted cycloalkylthiol, sulfonamide, containing R 11 The sulfonamide, phosphorus oxy or R-containing 11 the phosphorus oxygen group of the substituent; Among them, R 11 is selected from halogen, cyano, nitro, hydroxy, alkynyl, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, alkylnitro, alkylthiol, cycloalkyloxy, sulfonamide, ester, amide or phosphorus, and R1 and R 11 different; R2 and R3 are each independently selected from methyl, fluorine or hydrogen; R4 is selected from alkyl, alkoxy, alkoxyalkyl, alkylnitrogen, alkylcycloalkoxy, oxy, 12 Substituted oxy, amino, R 12 Substituted amino, cycloalkyl, R 12 Substituted cycloalkyl, azacycloalkyl, R 12 Substituted nitrogen heterocyclic alkyl, aryl, R 12 Substituted aryl, heteroaryl or R 12 Substituted heteroaryl; wherein R 12 is selected from methyl, fluorine, difluorine, cyano, alkyl, cycloalkyl, alkoxy, alkyl nitrogen, alkyl mercapto or hydrogen, and R4 and R 12 different; R5 is selected from none, methoxy, ethoxy or alkyl; m is selected from 0, 1, 2 or 3, wherein when m is selected from 2 or 3, two or three R1 groups cannot form a ring.

2. The sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate according to claim 1, characterized in that: The A is selected from Formula (Ia), Formula (Ib) or Formula (Ic): in Table: The site of attachment of fragment A to the alkynyl terminal of the compound of formula I; R6 is selected from hydrogen, C 1-4 Alkyl, alkoxy, carboxyl, R 13 Substituted ester groups, amide groups, R 13 Substituted amide, hydroxyl, Cyano, amino, R 13 Substituted amino, C 3-8 Cycloalkyl, R 13 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 13 Substituted C 3-9 Heterocyclic group, aryl group, R 13 Substituted aryl, heteroaryl or R 13 Substituted heteroaryl; wherein R 13 is selected from halogen, cyano, nitro, hydroxy, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, alkylnitro, alkylthiol, cycloalkyloxy, cycloalkylthiol, sulfonamide, sulfonyl or phosphino, and R6 and R 13 different; R7 and R8 are each independently selected from methyl, ethyl, aryl, fluorine or hydrogen; R9 is selected from hydrogen, C 1-4 Alkyl, cyano, alkoxy, sulfonyl, alkylsulfonyl, carboxyl, R 14 Substituted ester groups, amide groups, R 14 Substituted amide, hydroxyl, Amino, R 14 Substituted nitrogen groups, C 3-8 Cycloalkyl, R 14 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 14 Substituted C 3-9 Heterocyclic group, aryl group, R 14 Substituted aryl, heteroaryl or R 14 Substituted heteroaryl; wherein R 14 is selected from halogen, cyano, nitro, hydroxy, alkynyl, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, alkylnitro, cycloalkyloxy, sulfonamido, sulfonyl or phosphino, and R9 and R 14 different; Ring B is selected from C 3-8 Cycloalkyl; R 10 Selected from hydrogen, C 1-4 Alkyl, alkoxy, cyano, sulfonyl, alkylsulfonyl, carboxyl, R 14 Substituted ester groups, amide groups, R 14 Substituted amide, hydroxyl, Amino, R 15 Substituted nitrogen, aryl, R 15 Substituted aryl, heteroaryl or R 15 Substituted heteroaryl; wherein R 15 is selected from halogen, cyano, hydroxy, aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, cycloalkyloxy, alkoxyalkyl, alkylnitrogen, acyl, sulfonamido, sulfonyl or phosphino, and R 10 and R 15 different.

3. The sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate according to claim 1 or 2, characterized in that: The sulfonamide compound comprises at least one of the following features (1) to (5): (1) R6 is selected from hydrogen, C 3-8 Cycloalkyl, R 13 Substituted C 3-8 Cycloalkyl, C 3-9 Heterocyclic group, R 13 Substituted C 3-9 Heterocyclic group, aryl group, R 13 Substituted aryl, heteroaryl or R 13 Substituted heteroaryl, wherein R 13 is selected from halogen, cyano, hydroxy, alkyl or alkoxy; (2) R7 is selected from methyl; (3) R8 is selected from methyl; (4) R9 is selected from alkoxy, sulfonyl, alkylsulfonyl, C 3-9 Heterocyclic or R 14 Substituted C 3-9 Heterocyclic group; (5) R 10 Selected from hydroxyl, amino or R 15 Substituted nitrogen radical, wherein R 15 Selected from alkyl groups.

4. The sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 3, characterized in that: The R4 is selected from any one of the following groups: Wherein, n=0, 1 or 2.

5. The sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4, characterized in that: The R2 is methyl, R3 is methyl or hydrogen; or the R2 is fluorine, R3 is fluorine or hydrogen; or the R2 is hydrogen, R3 is hydrogen, methyl or fluorine.

6. The sulfonamide compound, its enantiomer, diastereomer, pharmaceutically acceptable salt or solvate according to any one of claims 1 to 5, characterized in that: The sulfonamide compound is selected from any one of the following compounds: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-ethynyl-2,6-dimethoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-(cyclopropylethynyl)-2,6-dimethoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2,6-dimethoxy-4-(phenylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2,6-dimethoxy-4-((2-methoxyphenyl)ethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-3-ethynyl-2,6-dimethoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-ethynyl-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-(cyclopropylalkynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-4-(pyridin-2-ylethynyl)benzenesulfonamide; N-(6-(difluoro(1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-ethynyl-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-4-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-hydroxycyclopentyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-4-(oxetanyl-3-ylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-4-(3-methoxy-3-methylbut-1-yn-1-yl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-4-(3-methyl-3-morpholinobut-1-yn-1-yl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-(3-(azetidin-1-yl)-3-methylbut-1-yn-1-yl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-hydroxycyclobutyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-aminocyclopropyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-hydroxycyclobutyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-hydroxycyclohexyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-4-((1-(dimethylamino)cyclopropyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-ethynyl-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-(cyclopropylalkynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(pyridin-3-ylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-((3-cyanophenyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-((4-methoxyphenyl)ethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-((4-methyl-4H-1,2,4-triazol-3-yl)ethynyl)benzenesulfonamide; N-(6-((2H-1,2,3-triazol-2-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(phenylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(m-tolylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-(furan-2-ylethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(oxazol-2-ylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(thiophen-2-ylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-((3,3-difluorocyclobutyl)ethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-5-(cyclopentylethynyl)-2-methoxybenzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(phenylethynyl)benzenesulfonamide; N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-((2-methoxyphenyl)ethynyl)benzenesulfonamide; 2-methoxy-N-(4-methoxy-6-(oxazol-4-ylmethyl)isoxazolo[4,5-c]pyridin-3-yl)-5-(phenylethynyl)benzenesulfonamide; N-(6-(azetidin-1-ylmethyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(phenylethynyl)benzenesulfonamide; N-(6-(difluoro(1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(phenylethynyl)benzenesulfonamide; N-(6-((3,3-difluoroazetidin-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxy-5-(phenylethynyl)benzenesulfonamide; 5-(Cyclopropylalkynyl)-N-(6-((dimethylamino)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxybenzenesulfonamide; 5-(Cyclopropylalkynyl)-N-(6-(fluoro(1H-pyrazol-1-yl)methyl)-4-methoxyisoxazolo[4,5-c]pyridin-3-yl)-2-methoxybenzenesulfonamide.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the sulfonamide compound of formula I as described in any one of claims 1 to 6, any one of its enantiomers, diastereomers, pharmaceutically acceptable salts, solvent compounds and pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition may be in the form of an oral preparation or an injection.

9. Use of the sulfonamide compound of formula I according to any one of claims 1 to 6, its enantiomer, diastereomer, pharmaceutically acceptable salt, solvate or the pharmaceutical composition according to claim 7 or 8 in the preparation of a drug for treating a disease associated with KAT6 amplification or KAT6 overexpression.

10. The use according to claim 9, characterized in that: The diseases associated with KAT6 amplification or KAT6 overexpression include at least one of breast cancer, acute myeloid leukemia, lung adenocarcinoma, blood tumors, digestive system tumors, reproductive system tumors, nervous system tumors and head and neck cancer.

Images