Sulfamide derivatives, their preparation and their medicinal uses

Abstract

The present invention provides sulfamide derivatives of general formula (I), processes for their preparation and pharmaceutical compositions containing said derivatives, as well as their use as therapeutic agents, in particular as lysine acetyltransferase (KAT) inhibitors and in the preparation of medicaments for treating and / or preventing cancer. [Formula 1] TIFF2024529068000185.tif3564

Description

[Technical field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to sulfamide derivatives, their preparation methods and their pharmaceutical uses. In particular, the present disclosure relates to sulfamide derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions comprising said derivatives, and their use as KAT inhibitors in the preparation of medicaments for treating and / or preventing cancer. [Background technology]

[0002] Lysine acetyltransferases (KATs) are a class of enzymes that can catalyze the transfer of an acetyl group from acetyl coenzyme A to the lysine ε-amino group in protein substrates. Lysine acetylation can affect protein function, thereby exerting important regulatory effects on chromosome structure, gene transcription regulation, DNA binding ability, enzyme activity and stability, protein interactions and subcellular localization. KATs are divided into several subfamilies, among which MYST (MOZ, YBF2 / SAS3, SAS2, TIP60) is the largest one, including KAT5 (TIP60), KAT6A (MOZ, MYST3), KAT6B (MORF, MYST4), KAT7 (HBO, MYST2) and KAT8 (MOF, MYST1). KAT6A / B, as the main member of the MYST family, plays a crucial role in development, maintenance of stem cells in the hematopoiesis and immune systems, and in tumor formation, progression and drug resistance.

[0003] TCGA database analysis revealed that KAT6A and KAT6B are amplified in many types of tumors. Among them, KAT6A is located in the amplicon region of chromosome 8p11-p12, is amplified in 10-15% of breast cancers, its copy number is positively correlated with mRNA expression, and leads to poor cure. Meanwhile, both KAT6A and KAT6B are significantly highly expressed in breast cancer. Further isoform analysis showed a correlation between high expression of KAT6A / B and ERα expression level, and KAT6A / B are involved in ERα expression.+ / HER2 - This may be a potential target for breast cancer.

[0004] It has been reported in the literature that knocking down KAT6A in KAT6A-amplified luminal breast cancer cells SUM-52 significantly inhibited clone formation compared to non-tumor cells MCF10A. RNAseq analysis showed that knocking down KAT6A downregulated several genes, including ESR1 and genes related to the hormone stress pathway. Further studies showed that ER cells with high KAT6A expression were downregulated by KAT6A. +KAT6A knockdown inhibited clonogenesis in breast cancer cell lines T47D and CAMA1, but not in low-expressing cell lines MCF7 and SKBR3. KAT6A knockdown downregulated ERα expression in T47D and CAMA1, whereas overexpression of wild-type KAT6A upregulated Erα in MCF7 and LY2, but not in mutants that had lost KAT activity, highlighting the importance of KAT function. Overexpression of Erα in T47D reversed the inhibitory effect of KAT6A knockdown on clonogenesis, suggesting that KAT6A function may be mediated by regulation of ERα expression. Similarly, KAT6A was enriched in the promoter region of the ESR1 gene. In vivo efficacy studies in the T47D model also showed tumor inhibition and downregulation of ERα by KAT6A knockdown. In T47D, knockdown of KAT6A and KAT6B can both downregulate ERα expression and inhibit clone formation, and the effect of KAT6A is stronger than that of KAT6B. When both are knocked down simultaneously, the effect is more obvious and a synergistic effect is observed. CTx-648, a selective KAT6A / B inhibitor, shows antitumor activity in ER+ breast cancer both in vitro and in vivo, and the expression level of KAT6A is associated with the sensitivity of CTx-648. ER with high expression of KAT6A is + In breast cancer cells, CTx-648 can downregulate ERα expression, and H3K23Ac can serve as a pharmacodynamic biomarker for KAT6 inhibitors. As mentioned above, KAT6A / B inhibitors can be used as single agents or as a pharmacodynamic biomarker for ERα expression in breast cancer cells. + / HER2 - Combinations with conventional breast cancer therapies, such as fulvestrant, CDK4 / 6 inhibitors, and even SERD and SERCA, are also worthy of clinical development.

[0005] KAT6A / B inhibitors are + / HER2- In addition to breast cancer, there is potential for use in other tumor types, including brain glioma, B-cell lymphoma, liver cancer, and ovarian cancer, allowing for a wide range of indications.

[0006] Patent applications that have disclosed inhibitors of KAT6 include WO2016198507A1, WO2019243491A1, WO2019043139A1, WO2019108824A1, WO2020216701A1, WO2020002587A1, WO2020254946A1, and WO2020254989A1, among others. Summary of the Invention

[0007] The present disclosure aims to provide compounds of general formula (I) or medicamentable salts thereof: [ka] Among them, Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is a cycloalkyl group or a heterocyclyl group; L is a chemical bond, an alkylene group, or a heteroalkylene group, wherein the alkylene group or the heteroalkylene group is each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, or a haloalkoxy group; Each R 1 , each R 2 , R 3 are the same or different and each independently represent a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -NHC(O)OR 6 , -NR 7 R 8, -C(O)NR 7 R 8 , -S(O) r R 6 or -S(O) r NR 7 R 8 wherein the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from hydroxy group, halogen, cyano group, amino group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group and heterocyclyloxy group; R 4 is a hydrogen atom or [ka] and Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R 0 is selected from a hydrogen atom, a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, or a cycloalkyl group, Each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxy group, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, or -NR 9 R 10 Selected from R 5 , R 6are the same or different and each independently selected from a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkenyl group, the alkynyl group, the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; R 7 , R 8 , R 9 , R 10 are the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R 7 and R 8 form a heterocyclyl group together with the N atom to which it is linked, or R 9 and R 10form a heterocyclyl group together with the N atom to which it is linked, said heterocyclyl group being optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, amino, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy or heterocyclyloxy; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4, and r is 0, 1 or 2.

[0008] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is Among them, Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is selected from a cycloalkyl group or a heterocyclyl group; L is a chemical bond, an alkylene group, or a heteroalkylene group, wherein the alkylene group or the heteroalkylene group is each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, or a haloalkoxy group; Each R 1 , each R 2 , R 3 are the same or different and each independently represent a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -NHC(O)OR6 , -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O) r R 6 or -S(O) r NR 7 R 8 wherein the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from hydroxy group, halogen, cyano group, amino group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group and heterocyclyloxy group; R 4 is a hydrogen atom or [ka] and Ring C is an aryl group or a heteroaryl group; R 0 is selected from a hydrogen atom, a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, or a cycloalkyl group, Each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxy group, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, or -NR 9 R 10 Selected from R 5 , R 6are the same or different and each independently selected from a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkenyl group, the alkynyl group, the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; R 7 , R 8 , R 9 , R 10 are the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R 7 and R 8 form a heterocyclyl group together with the N atom to which it is linked, or R 9 and R 10form a heterocyclyl group together with the N atom to which it is linked, said heterocyclyl group being optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, amino, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy or heterocyclyloxy; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4, and r is 0, 1 or 2.

[0009] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 3 is a hydrogen atom, a hydroxyl group, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or 3- to 8-membered cycloalkyl group, preferably R 3 is a hydrogen atom.

[0010] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, preferably ring C is a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, more preferably ring C is a 5- or 6-membered heteroaryl group, and most preferably ring C is a pyrazolyl group.

[0011] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein ring C is a 5- or 6-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, preferably, ring C is selected from a pyrazolyl group, a pyridyl group, a furanyl group, or a tetrahydrofuranyl group, more preferably, ring C is a pyrazolyl group.

[0012] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein ring C is [ka] is selected from the group consisting of:

[0013] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 4 teeth [ka] Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; R 0 , R 4a , m and n are as defined in general formula (I).

[0014] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 4 teeth [ka] Ring C is a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group; R 0 , R 4a , m and n are as defined in general formula (I).

[0015] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 0is a hydrogen atom, a hydroxyl group, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or 3- to 8-membered cycloalkyl group, preferably R 0 are hydrogen atoms, hydroxyl groups, halogens and C 1-6 alkyl group, preferably R 0 is selected from a hydrogen atom, a hydroxyl group or Cl, more preferably, R 0 is a hydrogen atom.

[0016] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein m is 0 or 1, and preferably 1.

[0017] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 4 teeth [ka] Ring C is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group; R 4a and n are as defined in general formula (I), Preferably, R 4 teeth [ka] and R 4a and n are as defined in general formula (I), More preferably, R 4 teeth [ka] It is.

[0018] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (II) or a medicamentable salt thereof: [ka] Among them, Ring C is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group; Ring A, Ring B, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (I).

[0019] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 4 teeth [ka] Ring C is a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heterocyclyl group or a 5- or 6-membered heteroaryl group; R 4a and n are as defined in general formula (I), Preferably, R 4 teeth [ka] and R 4a and n are as defined in general formula (I), More preferably, R 4 teeth [ka] and R 4a and n are as defined in general formula (I), More preferably, R 4 teeth [ka] and Even more preferably, R 4 teeth [ka] It is.

[0020] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (Ii) or a medicamentable salt thereof: [ka] Among them, Ring C is a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heterocyclyl group or a 5- or 6-membered heteroaryl group; Ring A, Ring B, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (I).

[0021] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein R 4 teeth [ka] and preferably R 4 teeth [ka] It is.

[0022] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably the 6- to 10-membered aryl group is a phenyl group or a naphthyl group, and preferably the 5- to 10-membered heteroaryl group is a pyridyl group, a quinolyl group or a benzoxazolyl group.

[0023] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, and preferably, the 6- to 10-membered aryl group is a phenyl group, a naphthyl group, [ka] Preferably, the 5- to 10-membered heteroaryl group is a pyridyl group, a quinolyl group, or a benzoxazolyl group.

[0024] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring A is a 6-10 membered aryl group, preferably a phenyl group, [ka] and is preferably a phenyl group, more preferably a phenyl group.

[0025] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof is [ka] teeth [ka] p1 is 0, 1, 2 or 3; R 1 and p are as defined in general formula (I).

[0026] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof is [ka] teeth [ka] and R 1 and p are as defined in general formula (I).

[0027] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring B is a 3- to 8-membered heterocyclyl group or a 3- to 8-membered cycloalkyl group; Preferably, ring B is a 4- to 7-membered heterocyclyl group or a 4- to 7-membered cycloalkyl group. More preferably, Ring B is a 4- to 7-membered heterocyclyl group. Even more preferably, Ring B is a 4- to 7-membered heterocyclyl group, wherein the 4- to 7-membered heterocyclyl group contains 1 to 3 oxygen atoms; Most preferably, Ring B is a 5- or 6-membered heterocyclyl group, wherein said 5- or 6-membered heterocyclyl group contains 1 or 2 oxygen atoms.

[0028] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring B is [ka] and preferably selected from the group consisting of [ka] and R 2 may be substituted at any substitutable position of ring B.

[0029] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein ring B is [ka] Preferably, ring B is selected from the group consisting of [ka] More preferably, ring B is selected from the group consisting of [ka] and R 2 may be substituted at any substitutable position of ring B.

[0030] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is a compound represented by general formula (III) or a medicamentable salt thereof: [ka] Among them, X is O, CR a R b or C=O, Each R a , R b , R c and R d are the same or different and each independently selected from a hydrogen atom, a hydroxy group, a halogen, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R c , R d forms one C=O together with the carbon atom to which it is linked, s is 0, 1, 2 or 3; L, R 1 , R 4a , p and n are as defined in general formula (I).

[0031] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein each R c and Rd are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, 3- to 8-membered cycloalkyloxy group, or 3- to 8-membered heterocyclyloxy group, or R c , R d forms one C=O together with the carbon atom to which it is linked, Preferably, each R c and R d are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, or R c , R d forms one C=O together with the carbon atom to which it is linked, More preferably, each R c and R d are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, More preferably, each R c and R d are the same or different and each independently represent a hydrogen atom or a halogen atom; Even more preferably, each R c and R d are the same or different and each independently represent a hydrogen atom or a fluorine atom, Most preferably, R c and R d are all hydrogen atoms.

[0032] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II) or general formula (III) or a medicamentable salt thereof is a compound represented by general formula (IV) or a medicamentable salt thereof: [ka] Among them, L, X, R 1 , R 4a , p, n and s are as defined in general formula (III).

[0033] In some embodiments of the present disclosure, the compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein X is O or CR a R b And each R a and R b are the same or different, and each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 is selected from a haloalkoxy group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered cycloalkyloxy group, or a 3- to 8-membered heterocyclyloxy group, preferably each R a and R b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 More preferably, each R a and R b are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group or C 1-6 alkoxy groups, most preferably R a and R b are both hydrogen atoms.

[0034] In some embodiments of the present disclosure, the compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein X is O or CH 2 and preferably X is CH 2 It is.

[0035] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein s is 1 or 2, preferably 1.

[0036] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein R c and R d are the same or different and each independently represent a hydrogen atom or a halogen, and / or X represents O or CH 2 and / or s is 1 or 2.

[0037] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein X is O or CH 2 and / or s is 1 or 2.

[0038] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein q is 0, 1 or 2, preferably q is 0.

[0039] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II) or general formula (Ii), or a medicamentable salt thereof, wherein q is 1.

[0040] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein each R 1are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), preferably each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 More preferably, each R 1 are the same or different, and each independently C 1-6 An alkoxy group, most preferably R 1 is a methoxy group.

[0041] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -NR 7 R 8 , -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), Preferably, each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl groups, -C(O)OCH 3 or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, More preferably, each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, More preferably, each R 1 are the same or different, and each independently C 1-6 It is an alkoxy group.

[0042] Most preferably, each R 1 are the same or different and each independently a methoxy group.

[0043] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a monomethylamino group, a dimethylamino group, or [ka] Preferably, R 1 is a methoxy group.

[0044] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II) or general formula (Ii) or a medicamentable salt thereof, wherein each R 2 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, oxo group, 3- to 8-membered cycloalkyloxy group, or 3- to 8-membered heterocyclyloxy group, preferably each R 2 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6More preferably, each R 2 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group or C 1-6 More preferably, each R 2 are the same or different and each independently represent a hydrogen atom or a halogen atom, and even more preferably, each R 2 are the same or different and each independently represent a hydrogen atom or a fluorine atom, and most preferably, R 2 is a hydrogen atom.

[0045] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, -NR 9 R 10 , a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered cycloalkyloxy group, or a 3- to 8-membered heterocyclyloxy group; R 9 and R 10 is as defined in general formula (I), preferably each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 More preferably, R 4a is a hydrogen atom.

[0046] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein p is 0, 1, 2 or 3, preferably, p is 1, 2 or 3, and more preferably, p is 2.

[0047] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein p is 0, 1 or 2, and preferably, p is 1 or 2.

[0048] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein L is a chemical bond or C 1-6 An alkylene group, preferably a chemical bond, -CH 2 -or-CH 2 CH 2 -, more preferably a chemical bond and -CH 2 -, and most preferably a chemical bond.

[0049] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV), or a medicamentable salt thereof, wherein n is 1 or 2.

[0050] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein n is 0, 1, 2 or 3, and preferably, n is 0.

[0051] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein each R 4aare the same or different and each independently represent a halogen, a hydroxyl group, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, and n is 1 or 2; or R 4a are both hydrogen atoms, and n is 3.

[0052] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein R 4a are both hydrogen atoms, and n is 3.

[0053] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein R 5 , R 6 are the same or different and each independently represent a hydrogen atom, C 1-6 an alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, among which 1-6 The alkyl group, the 3- to 8-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group and the 5- to 10-membered heteroaryl group each independently optionally include a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 substituted with one or more substituents selected from a haloalkoxy group and a 3- to 8-membered cycloalkyl group; Preferably, R 5 , R 6 are the same or different, and each independently C 1-6 Alkyl group, C 1-6 It is selected from a haloalkyl group and a 3- to 8-membered cycloalkyl group.

[0054] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein R 7 and R 8 are the same or different and each independently represent a hydrogen atom, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 hydroxyalkyl group, 3- to 8-membered cycloalkyl group, or 3- to 12-membered heterocyclyl group, preferably R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 More preferably, R 7 and R 8 is a hydrogen atom.

[0055] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III) or general formula (IV) or a medicamentable salt thereof, wherein R 9 and R 10 are the same or different and each independently represent a hydrogen atom, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 is selected from the group consisting of a hydroxyalkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 12-membered heterocyclyl group, preferably R 9 and R 10 is a hydrogen atom.

[0056] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (II) and general formula (Ii) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 1a and R 1bare the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), preferably R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 More preferably, R 1a is C 1-6 and / or R is an alkoxy group; 1b is C 1-6 An alkoxy group, most preferably R 1a and R 1b are both methoxy groups.

[0057] In some embodiments of the present disclosure, the compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof is [ka] teeth [ka] and R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), preferably R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 More preferably, R 1a is C 1-6 and / or R is an alkoxy group; 1b is C 1-6 An alkoxy group, most preferably R 1a and R 1b are both methoxy groups.

[0058] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (II) and general formula (Ii) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), preferably R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 More preferably, R 1a is a hydrogen atom or C 1-6 and / or R is an alkoxy group; 1b is a hydrogen atom or C1-6 An alkoxy group, most preferably R 1a and R 1b are both methoxy groups, or R 1a is a hydrogen atom, and R 1b is a methoxy group.

[0059] In some embodiments of the present disclosure, the compound represented by the above general formula (III) or general formula (IV) or a medicamentable salt thereof is [ka] teeth [ka] and R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, -OR 5 , -C(O)R 6 , -C(O)OR 6 , -C(O)NR 7 R 8 or -S(O) r R 6 Selected from r, R 5 , R 6 , R 7 and R 8 is as defined in general formula (I), preferably R 1a and R 1b are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 More preferably, R 1a is a hydrogen atom or C 1-6 and / or R is an alkoxy group; 1b is a hydrogen atom or C 1-6 An alkoxy group, most preferably R 1a and R 1b are both methoxy groups, or R 1a is a hydrogen atom, and R 1b is a methoxy group.

[0060] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and preferably [ka] teeth [ka] More preferably, selected from the group consisting of: [ka] teeth [ka] It is.

[0061] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein: [ka] teeth [ka] Preferably, the compound is selected from the group consisting of [ka] teeth [ka] More preferably, selected from the group consisting of: [ka] teeth [ka] It is.

[0062] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein: [ka] teeth [ka] wherein L is a chemical bond and ring B is selected from the group consisting of [ka] And each R 2 are the same or different and each independently represent a hydrogen atom or a fluorine atom; q is 0, 1 or 2; R 3 is a hydrogen atom, and R 4 teeth [ka] wherein ring C is a 5- or 6-membered heterocyclyl group or a 5- or 6-membered heteroaryl group, m is 0 or 1, n is 0, and R 0 is selected from a hydrogen atom, a hydroxyl group, or Cl, and each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, p is 0, 1 or 2, and p1 is 0, 1, 2 or 3.

[0063] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 where p is 1, 2 or 3, and each R 2 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group or C 1-6 alkoxy groups, q is 1, and R 3 is a hydrogen atom, and R 4 teeth [ka] And each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, n is 1 or 2, ring C is a 5- to 10-membered heteroaryl group, ring A is a 6- to 10-membered aryl group, ring B is a 4- to 7-membered heterocyclyl group, and L is a chemical bond or -CH 2 -It is.

[0064] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl groups, -C(O)OCH 3 or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 alkyl group, p is 0, 1, 2, 3, or 4, and each R 2 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl groups and C 1-6 alkoxy groups, q is 0, 1, 2, 3 or 4, and R 3 is a hydrogen atom, and R 4 teeth [ka] And each R 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, n is 0, 1, 2, 3 or 4, m is 0 or 1, ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, R 0 is a hydrogen atom, a hydroxyl group, a halogen or C 1-6 alkyl group, ring A is a 6- to 10-membered aryl group, ring B is a 4- to 7-membered heterocyclyl group, and L is a chemical bond or -CH 2 -It is.

[0065] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 where p is 1, 2 or 3, and each R 2 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group or C 1-6 alkoxy groups, q is 1, and each R 4a are the same or different and each independently represent a hydrogen atom, a halogen, a hydroxyl group, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, n is 1 or 2, ring A is a 6- to 10-membered aryl group, ring B is a 4- to 7-membered heterocyclyl group, ring C is a 5- to 10-membered heteroaryl group, and L is a chemical bond or -CH 2 -It is.

[0066] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, p is 0, 1, 2, or 3, and each R2 are the same or different and each independently represents a hydrogen atom or a halogen atom; q is 0, 1 or 2; 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, n is 0, 1, 2 or 3, ring A is a 6- to 10-membered aryl group, ring B is a 4- to 7-membered heterocyclyl group, ring C is a 5- or 6-membered heteroaryl group, and L is a chemical bond.

[0067] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (Ii) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, p is 0, 1, 2, or 3, and each R 2 are the same or different and each independently represents a hydrogen atom or a halogen atom; q is 0, 1 or 2; 4a are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, n is 0, 1, 2 or 3, ring A is a 6- to 10-membered aryl group, ring B is a 4- to 7-membered heterocyclyl group, ring C is a 5- or 6-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, and L is a chemical bond.

[0068] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein each R1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 where p is 1, 2 or 3, and X is O or CH 2 and R c and R d are all hydrogen atoms, and each R 4a are the same or different and each independently represent a halogen, a hydroxyl group, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, and n is 1 or 2; or R 4a are each a hydrogen atom, n is 3, s is 1 or 2, and L is a chemical bond or -CH 2 -It is.

[0069] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, p is 0, 1, 2 or 3, and X is O or CH 2 And each R c and R d are the same or different and each independently represent a hydrogen atom or a halogen atom; R 4aare both hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0070] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein each R 1 are the same or different, and each independently C 1-6 is an alkoxy group, p is 2, and X is O or CH 2 And each R c and R d are the same or different and each independently represent a hydrogen atom or a fluorine atom; R 4a are both hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0071] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein each R 1 are the same or different, and each independently C 1-6 is an alkoxy group, p is 1 or 2, and X is CH 2 And each R c and R d are the same or different and each independently represent a hydrogen atom or a fluorine atom, n is 0, s is 1 or 2, and L is a chemical bond.

[0072] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a hydroxyl group, a halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Alkyl group or -C(O)OCH 3 where p is 1, 2 or 3, and X is O or CH 2 And each R 4aare the same or different and each independently represent a halogen, a hydroxyl group, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 alkoxy groups, and n is 1 or 2; or R 4a are each a hydrogen atom, n is 3, s is 1 or 2, and L is a chemical bond or -CH 2 -It is.

[0073] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R 8 Selected from R 7 and R 8 are the same or different and each independently represent a hydrogen atom or C 1-6 is an alkyl group, p is 0, 1, 2 or 3, and X is O or CH 2 and R 4a are both hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0074] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different, and each independently C 1-6 is an alkoxy group, p is 1 or 2, and X is CH 2 and R 4a are both hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0075] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different, and each independently C 1-6is an alkoxy group, p is 2, and X is O or CH 2 and R 4a are both hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0076] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (IV) or a medicamentable salt thereof, wherein each R 1 are the same or different, and each independently C 1-6 is an alkoxy group, p is 1 or 2, and X is CH 2 where n is 0, s is 1 or 2, and L is a chemical bond.

[0077] Table A Exemplary compounds of the present disclosure include, but are not limited to: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0078] Another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a salt thereof: [ka] Among them, Ring B, R 2 , R 3 , R 4 and q are as defined in general formula (I).

[0079] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof: [ka] Among them, Ring B, Ring C, R 2 , R 4a , q and n are as defined in general formula (II).

[0080] Another aspect of the present disclosure relates to a compound represented by the general formula (IiA) or a salt thereof: [ka] Among them, Ring B, Ring C, R 2 , R 4a , q and n are as defined in general formula (Ii).

[0081] Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA) or a salt thereof: [ka] Among them, X, R 4a , R c , R d , n and s are as defined in general formula (III).

[0082] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof: [ka] Among them, X, R 4a , n and s are as defined in general formula (IV).

[0083] Another aspect of the present disclosure relates to a compound represented by the general formula (IA') or a salt thereof: [ka] Among them, X 1 is a halogen, preferably bromine; Ring A, Ring B, R 1 , R 2 , R 3 , L, p and q are as defined in general formula (I).

[0084] Another aspect of the present disclosure relates to a compound represented by general formula (IIA') or a salt thereof: [ka] Among them, X 1 is a halogen, preferably bromine; Ring A, Ring B, R 1 , R 2 , L, p and q are as defined in general formula (II).

[0085] Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA') or a salt thereof: [ka] Among them, X 1 is a halogen, preferably bromine; R 1 , R c , R d , s, p, X and L are as defined in general formula (III).

[0086] Another aspect of the present disclosure relates to a compound represented by general formula (IVA') or a salt thereof: [ka] Among them, X 1 is a halogen, preferably bromine; R 1 , s, p, X and L are as defined in general formula (IV).

[0087] Table B Exemplary intermediate compounds of the present disclosure include, but are not limited to, the following: [Table 9] [Table 10]

[0088] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I) or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of reacting a compound represented by general formula (IA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a medicamentable salt thereof, Among them, Ring A, Ring B, L, R 1 ~R 4 , p and q are as defined in general formula (I).

[0089] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (II) or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of reacting a compound represented by general formula (IIA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (II) or a medicamentable salt thereof, Among them, Ring A, Ring B, Ring C, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (II).

[0090] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (Ii) or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of reacting a compound represented by general formula (IiA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (Ii) or a medicamentable salt thereof, Among them, Ring A, Ring B, Ring C, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (Ii).

[0091] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III) or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of reacting a compound represented by general formula (IIIA) or a salt thereof with a compound represented by general formula (IIIB) or a salt thereof to obtain a compound represented by general formula (III) or a medicamentable salt thereof, Among them, L, X, R 1 , R 4a , R c , R d , p, n and s are as defined in general formula (III).

[0092] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IV) or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of reacting a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IIIB) or a salt thereof to obtain a compound represented by general formula (IV) or a medicamentable salt thereof, Among them, X, L, R 1 , R 4a, p, n and s are as defined in general formula (IV).

[0093] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (Ii) or a medicamentable salt thereof, the method comprising: [ka] The method includes a step of coupling a compound represented by general formula (IIA') or a salt thereof with a compound represented by general formula (IiB') or a salt thereof to obtain a compound represented by general formula (Ii) or a medicamentable salt thereof, Among them, Ring D is a 3- to 8-membered heterocyclyl group containing at least one endocyclic double bond, preferably a 5- or 6-membered heterocyclyl group containing at least one endocyclic double bond, more preferably [ka] and Ring C is a 3- to 8-membered heterocyclyl group, preferably a 5- or 6-membered heterocyclyl group, more preferably [ka] and X 1 is a halogen, preferably bromine; Ring A, Ring B, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (Ii).

[0094] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A according to the present disclosure, or a medicamentable salt thereof, and one or more pharma- ceutically acceptable vectors, diluents or excipients.

[0095] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for inhibiting a KAT, wherein said KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0096] The present disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing a KAT-mediated disease, wherein said KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0097] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A or a medicament salt thereof or a pharmaceutical composition comprising same in the preparation of a medicament for treating and / or preventing cancer, wherein said cancer is preferably lung cancer (e.g., NCSLC, SCLC), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, colorectal cancer. , small intestine cancer, gastric cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma or squamous cell carcinoma, preferably breast cancer, prostate cancer, lung cancer (e.g., NCSLC, SCLC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer and leukemia, among which breast cancer is ER + Breast cancer or ER + / HER2 -Breast cancer is preferred, of which the lung cancer (eg, NCSLC, SCLC) is preferably non-small cell lung cancer, and of which the prostate cancer is preferably castration-resistant prostate cancer.

[0098] The present disclosure further relates to a method for inhibiting a KAT, comprising administering to a patient in need thereof an inhibitory effective amount of a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein said KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0099] The present disclosure further relates to a method for treating and / or preventing a KAT-mediated disease, comprising administering to a patient in need thereof a therapeutically and / or prophylactically effective amount of a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein said KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0100] The present disclosure further relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective and / or prophylactically effective amount of a compound of general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein the cancer is preferably lung cancer (e.g., NCSLC, SCLC), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, or the like.

[0023] The present invention relates to a cancer treatment method for treating pulmonary hypertension, pulmonary hypertension, and pulmonary edema, and is preferably selected from the group consisting of cancers of the esophagus, colorectum, small intestine, stomach, thyroid, parathyroid, adrenal, soft tissue sarcoma, penile, testicular, prostate, leukemia, B-cell lymphoma, bladder, urethra, ureter, renal cell, renal pelvis, central nervous system (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma, and squamous cell carcinoma, and is preferably selected from the group consisting of breast cancer, prostate, lung cancer (e.g., NCSLC, SCLC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder, brain glioma, B-cell lymphoma, liver cancer, and leukemia, among which the above-mentioned breast cancer is selected from the group consisting of ER, ER, ER-associated lymphoma, and endothelial cell carcinoma. + Breast cancer or ER + / HER2 - Breast cancer is preferred, of which the lung cancer (eg, NCSLC, SCLC) is preferably non-small cell lung cancer, and of which the prostate cancer is preferably castration-resistant prostate cancer.

[0101] The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use as a medicament.

[0102] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing the same, for use as a drug for inhibiting a KAT, wherein the KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0103] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting a KAT, wherein the KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0104] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing the same, for use as a KAT inhibitor, wherein the KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0105] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing a KAT-mediated disease, wherein the KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0106] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing cancer, wherein the cancer is preferably lung cancer (e.g., NCSLC, SCLC), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, colorectal cancer, small intestine cancer, The cancer is selected from gastric cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma and squamous cell carcinoma, and preferably selected from breast cancer, prostate cancer, lung cancer (e.g., NCSLC, SCLC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer or leukemia, among which, the breast cancer is ER + Breast cancer or ER + / HER2 - Breast cancer is preferred, of which the lung cancer (eg, NCSLC, SCLC) is preferably non-small cell lung cancer, and of which the prostate cancer is preferably castration-resistant prostate cancer.

[0107] In some embodiments of the present disclosure, the KAT6 is KAT6A and / or KAT6B.

[0108] In some embodiments of the present disclosure, the cancer is breast cancer.

[0109] In some embodiments of the present disclosure, the breast cancer is ER + It's breast cancer.

[0110] In some embodiments of the present disclosure, the breast cancer is ER + / HER2 - It's breast cancer.

[0111] In some embodiments of the present disclosure, the breast cancer is locally advanced or metastatic ER cancer. + / HER2 - It's breast cancer.

[0112] In some embodiments of the present disclosure, the lung cancer (eg, NCSLC, SCLC) is non-small cell lung cancer.

[0113] In some embodiments of the present disclosure, the lung cancer (eg, NCSLC, SCLC) is locally advanced or metastatic non-small cell lung cancer.

[0114] In some embodiments of the disclosure, the prostate cancer is castration-resistant prostate cancer.

[0115] In some embodiments of the disclosure, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0116] For convenience, estrogen receptor positive (ER) + ), human epidermal growth factor receptor 2 negative (HER2 - ), non-small cell lung cancer (NSCLC), and castration-resistant prostate cancer (CRPC).

[0117] The active compound can be prepared in a suitable form for administration by any suitable route, and the composition of the present disclosure can be prepared by one or more pharma- ceutically acceptable vectors in a conventional manner. Thus, the active compound of the present disclosure can be prepared in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation administration. The compound of the present disclosure can be prepared in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, tablets for external application, or syrups.

[0118] As a general guideline, it is preferred that the active compound be in a unit dose form or in a form that the patient can self-administer as a single agent. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled liquid, drug powder, granule, topical tablet, suppository, reconstituted powder or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0119] The pharmaceutical composition according to the present disclosure may contain one or more additives in addition to the active compound, and the additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, or excipients. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0120] The tablets contain the active ingredient and non-toxic medicamentous excipients suitable for mixing in the preparation of tablets. These excipients may be inert diluents, granulating agents, disintegrating agents, binding agents and lubricants. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over an extended period of time.

[0121] Oral formulations may be provided by soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or with a water-soluble vector or oil-based solvent.

[0122] Aqueous suspensions contain the active substances and mixing excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0123] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oil suspensions can also contain thickening agents.To provide a palatable preparation, the above-mentioned sweeteners and flavorings can also be added.These compositions can be preserved by adding antioxidants.

[0124] The pharmaceutical compositions according to the present disclosure may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain demulcents, preservatives, colorants and antioxidants.

[0125] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion can be injected into the patient's bloodstream by local injection of large amounts. Alternatively, it is preferable to administer the solutions and microemulsions in a manner that allows a constant cyclic concentration of the compounds of the present disclosure to be maintained. To maintain such a constant concentration, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

[0126] The pharmaceutical composition according to the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable. Sterile fixed oils may also be conveniently used as a solvent or suspension medium. Any fixed oil for formulation may be used for this purpose. Fatty acids may also be used to prepare an injectable.

[0127] The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore melts in the rectum to release the drug.

[0128] The compounds of the present disclosure can be administered by adding water to prepare dispersible powders and granules in an aqueous suspension. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0129] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, the severity of the disease, etc., and the optimal treatment method, such as the treatment mode, the daily dosage of the compound or the type of medicinal salt, can be verified according to conventional treatment plans. Explanation of terms

[0130] Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0131] The term “alkyl group” refers to a saturated aliphatic hydrocarbon group, straight or branched, containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkyl group), preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-20 alkyl group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhexyl, 44-methylhexyl, 45-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0132] The term "alkylene group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group, the residue derived by removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene group), preferably having 1 to 12 carbon atoms (i.e., C 1-12 alkylene group), more preferably 1 to 6 carbon atoms (i.e., C 1-6 A non-limiting example is methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 The alkylene group may be substituted or unsubstituted, and if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0133] The term "heteroalkylene group" refers to one or more -CH 2 - N, O, S, S(O) and S(O) 2wherein the alkyl group is as defined above, and the heteroalkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably one or more selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0134] The term "alkenyl group" refers to an alkyl group compound containing at least one carbon-carbon double bond in the molecule, where alkyl is as defined above, and having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 An alkenyl group) is preferred. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more selected from an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0135] The term "alkynyl group" refers to an alkyl group compound in which the molecule contains at least one carbon-carbon triple bond, where alkyl is as defined above, and which has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6An alkynyl group) is preferred. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more selected from an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0136] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 3-20 membered cycloalkyl group), preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered cycloalkyl group). ) carbon atoms (i.e., 3-12 membered cycloalkyl groups), preferably 3-8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3-8 membered cycloalkyl groups), more preferably 4-7 (e.g., 4, 5, 6, and 7) carbon atoms (i.e., 4-7 membered cycloalkyl groups), and even more preferably 3-6 (e.g., 3, 4, 5, and 6) carbon atoms (i.e., 3-6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0137] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., 5- to 20-membered spirocycloalkyl group), in which the monocyclic rings share one carbon atom (referred to as a spiro atom), which may contain one or more double bonds. It is preferably 6 to 14 members (i.e., 6- to 14-membered spirocycloalkyl group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members, i.e., 7- to 10-membered spirocycloalkyl group). Depending on the number of spiro atoms shared between the rings, the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bisspirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a monospirocycloalkyl group or a bisspirocycloalkyl group. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0138] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 5- to 20-membered fused cycloalkyl group), in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and in which one or more rings may contain one or more double bonds. It is preferably 6 to 14 members (i.e., a 6- to 14-membered fused cycloalkyl group), and more preferably 7 to 10 members (e.g., a 7-, 8-, 9- or 10-membered fused cycloalkyl group, i.e., a 7- to 10-membered fused cycloalkyl group). Depending on the number of rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0139] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, i.e., a 5-20 membered bridged cycloalkyl group), in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. It is preferably 6 to 14 members (i.e., a 6-14 membered bridged cycloalkyl group), more preferably 7 to 10 members (e.g., a 7-, 8-, 9- or 10-membered bridged cycloalkyl group, i.e., a 7-10 membered bridged cycloalkyl group). Depending on the number of rings that constitute it, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] Includes.

[0140] The cycloalkyl rings include the above cycloalkyl groups (including monocyclic cycloalkyl groups, spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups) fused to an aryl group, heteroaryl group or heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include: [ka] Including, [ka] is preferred.

[0141] The cycloalkyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0142] The term "alkoxy group" refers to -O-(alkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, is preferably one or more groups independently selected from D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group.

[0143] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 3- to 20-membered heterocyclyl group), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, which sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), but does not include -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., a 3- to 12-membered heterocyclyl group), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms, more preferably it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8, i.e., a 3- to 8-membered heterocyclyl group), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, and even more preferably it contains 4 to 7 ring atoms (e.g., 4 , 5, 6 and 7, i.e., 4-7 membered heterocyclyl groups), of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms, even more preferably 3 to 6 ring atoms (e.g., 3, 4, 5 and 6, i.e., 3-6 membered heterocyclyl groups), of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms, and most preferably 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl groups), of which 1 to 2 (e.g., 1 or 2) are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups and bridged heterocyclyl groups.

[0144] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 ring members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 5- to 20-membered spiroheterocyclyl group), in which the monocyclic rings share one atom (called a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 ring members (i.e., a 6- to 14-membered spiroheterocyclyl group), more preferably 7 to 10 ring members (e.g., a 7-, 8-, 9- or 10-membered spiroheterocyclyl group). Spiroheterocyclyl groups are classified into monospiroheterocyclyl groups, bisspiroheterocyclyl groups and polyspiroheterocyclyl groups according to the number of spiro atoms shared between the rings, and are preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferably, they are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0145] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 5- to 20-membered fused heterocyclyl group), in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, which may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably 7 to 10 members (e.g., a 7-, 8-, 9- or 10-membered fused heterocyclyl group, i.e., a 7- to 10-membered fused heterocyclyl group). Depending on the number of rings, the heterocyclyl groups can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0146] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, i.e., a 5- to 14-membered bridged heterocyclyl group), in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably 7 to 10 members (e.g., a 7-, 8-, 9- or 10-membered bridged heterocyclyl group). Depending on the number of rings that they consist of, they can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0147] The heterocyclyl rings include those in which the heterocyclyl groups (including monocyclic, spiro, fused and bridged heterocyclyl groups) are fused to an aryl, heteroaryl or cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0148] The heterocyclyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0149] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system with 6-14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, i.e., a 6-14 membered aryl group), preferably 6-10 members (i.e., a 6-10 membered aryl group), such as, for example, phenyl and naphthyl groups. The aryl rings include those in which the aryl rings are fused to a heteroaryl group, heterocyclyl group or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes.

[0150] The aryl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0151] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, i.e., a 5-14 membered heteroaryl group), in which the heteroatoms are selected from oxygen, sulfur, or nitrogen. Heteroaryl groups are preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, or 10 members, i.e., a 5-10 membered heteroaryl group), and more preferably 5 or 6 members (i.e., a 5 or 6 membered heteroaryl group), such as, for example, a furanyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, and the like. The heteroaryl rings include those in which the heteroaryl group is fused to an aryl group, a heterocyclyl group, or a cycloalkyl ring, in which the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0152] The heteroaryl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0153] The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each a residue derived by removing one hydrogen atom from a parent ring atom, or a residue derived by removing two hydrogen atoms from the same parent ring atom or two different parent ring atoms, i.e., a "divalent cycloalkyl group," a "divalent heterocyclyl group" (e.g., [ka] etc.), including "arylene groups" and "heteroarylene groups".

[0154] The term "cycloalkylalkyl group" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0155] The term "heterocyclylalkyl group" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the heterocyclyl and alkyl groups are as defined above.

[0156] The term "heteroarylalkyl group" refers to an alkyl group substituted with one or more heteroaryl groups, where the heteroaryl and alkyl groups are as defined above.

[0157] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0158] The term "heterocyclyloxy" refers to a heterocyclyl-O- group, in which the heterocyclyl group is as defined above.

[0159] The term "alkylthio group" refers to an alkyl-S- group, in which the alkyl group is as defined above.

[0160] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0161] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0162] The term "alkoxyalkyl group" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are defined above.

[0163] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

[0164] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0165] The term "hydroxy group" refers to --OH.

[0166] The term "mercapto" refers to -SH.

[0167] The term "amino group" means -NH 2 Refers to...

[0168] The term "cyano" refers to -CN.

[0169] The term "nitro group" means -NO 2 Refers to...

[0170] The term "oxo group" or "oxo" refers to "=O".

[0171] The term "carbonyl group" refers to C=O.

[0172] The term "aldehyde group" refers to -C(O)H.

[0173] The term "carboxy" refers to -C(O)OH.

[0174] The term "carboxylic acid ester group" refers to a -C(O)O(alkyl), -C(O)O(cycloalkyl)(alkyl)C(O)O- or -(cycloalkyl)C(O)O-, where alkyl and cycloalkyl are defined above.

[0175] However, compounds of the present disclosure may be in particular geometric or stereoisomeric forms. The present disclosure contemplates that all such compounds are within the scope of the present disclosure, including cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and mixtures thereof, both racemic and otherwise, such as mixtures enriched in enantiomers or diastereomers. Substituents such as alkyl groups may have other asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present disclosure. Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. One enantiomer of a compound of the present disclosure can be prepared by asymmetric synthesis or induction with a chiral auxiliary, where the resulting diastereomeric mixture is isolated and the resulting mixture is cleaved by assisted group splitting to provide the desired enantiomer in pure form. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base and diastereomeric separation can be carried out by conventional methods well known in the art, followed by recovery to obtain the pure enantiomers. Note that separation of the enantiomers and diastereomers is typically accomplished by chromatography employing chiral stationary phases, optionally coupled with chemical derivatization methods (e.g., formation of carbamates from amines).

[0176] In the chemical structures of the compounds described in this disclosure, [ka] indicates that the configuration is not specified, i.e., if chiral isomers are present in the chemical structure, [ka] The bond [ka] or [ka] In the chemical structure of the compound described in the present disclosure, [ka] The bond "Z" is not specified, i.e., it may be in the Z or E configuration, or it may include the two configurations simultaneously.

[0177] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions by protolysis, such as keto-enol and imine-enamine isomerizations. An example of lactam-lactim equilibrium is between A and B as shown below. [ka]

[0178] All of the compounds in this disclosure can be depicted in Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of a compound does not exclude any tautomeric form.

[0179] The present disclosure further includes certain isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative examples of isotopes that can be attached to the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0180] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 Compounds may be labeled with radioactive isotopes such as 3H, and deuterium may be substituted for hydrogen to form deuterated drugs, where the bond between deuterium and carbon is stronger than the normal hydrogen and carbon bond, and deuterated drugs have the advantages of reduced toxicity and side effects, increased drug stability, improved therapeutic efficacy, and increased biological half-life compared to non-deuterated drugs. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0181] In addition, relatively heavy isotopes (e.g., deuterium (i.e., 2Substitution with deuterium (H)) can provide several therapeutic advantages arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and thus may be preferred in some cases, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0182] Unless otherwise stated, when a position is specifically designated as deuterium (D), it should be understood that the position is deuterium (i.e., at least 10% deuterium incorporated) with an abundance at least 1000 times higher than the natural abundance of deuterium (which is 0.015%). In the example compounds, having an abundance higher than the natural abundance of deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or even more abundant deuterium. The present disclosure further includes various deuterated forms of the compound of formula (I). Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compound of formula (I) by referring to the relevant literature. Deuterated forms of the compounds of formula (I) may be prepared using commercially available deuterated starting materials or may be synthesized by conventional techniques with deuterated reagents including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, lithium aluminum deuteride, deuterated iodoethane, deuterated iodomethane, and the like.

[0183] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0184] "Substituted" refers to one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group being independently replaced with a corresponding number of substituents. A person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having a free hydrogen may be unstable if it is attached to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0185] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity.

[0186] A "pharmaceutical salt" refers to a salt of a compound according to the present disclosure, which is safe and effective when used in a mammalian body and has the desired biological activity. The salt may be prepared during the final isolation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. In general, bases for forming pharmaceutical acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. In general, acids for forming pharmaceutical acceptable salts include inorganic acids and organic acids.

[0187] The terms "therapeutically effective amount," "inhibitory effective amount," or "prophylactically effective amount" of a drug or pharmacologically active agent refer to a dose of the drug or agent sufficient to achieve or partially achieve a desired effect. The effective amount is determined by the person and depends on the age and general condition of the recipient, and also on the specific active agent, and the appropriate effective amount for an individual can be determined by one skilled in the art through routine testing.

[0188] As used herein, the term "pharmacologically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, applicable for contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0189] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0190] The term "about" when used with respect to parameters such as pH, concentration, temperature, etc., indicates that the parameter in question may be varied within ±10%, and in some cases more preferably ±5%. As will be appreciated by those skilled in the art, when a parameter is not critical, generally numbers are given merely for illustration, not limitation. Methods for synthesizing compounds according to the present disclosure

[0191] In order to achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions: Technical proposal 1

[0192] A process for preparing a compound of general formula (I) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the step of subjecting a compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof to a nucleophilic substitution reaction under the action of a base, optionally with microwaves, to obtain a compound represented by general formula (I) or a medicamentable salt thereof, Among them, L, ring A, ring B, R 1 ~R 4 , p and q are as defined in general formula (I). Technical proposal 2

[0193] A method for preparing a compound of general formula (II) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the step of subjecting a compound represented by general formula (IIA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof to a nucleophilic substitution reaction under the action of a base, optionally with microwaves, to obtain a compound represented by general formula (II) or a medicamentable salt thereof, Among them, Ring A, Ring B, Ring C, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (II). Technical proposal 2-1

[0194] A process for preparing a compound of general formula (Ii) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the step of subjecting a compound represented by general formula (IiA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof to a nucleophilic substitution reaction under the action of a base, optionally with microwaves, to obtain a compound represented by general formula (Ii) or a medicamentable salt thereof, Among them, Ring A, Ring B, Ring C, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (Ii). Technical proposal 3

[0195] A process for preparing a compound of general formula (III) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the step of subjecting a compound represented by general formula (IIIA) or a salt thereof and a compound represented by general formula (IIIB) or a salt thereof to a nucleophilic substitution reaction under the action of a base, optionally with microwaves, to obtain a compound represented by general formula (III) or a medicamentable salt thereof, Among them, L, X, R 1 , R 4a , R c , R d , p, n and s are as defined in general formula (III). Technical proposal 4

[0196] The present disclosure relates to a method for preparing a compound of general formula (IV) or a medicamentable salt thereof, which comprises: [ka] The method comprises the step of subjecting a compound represented by general formula (IVA) or a salt thereof and a compound represented by general formula (IIIB) or a salt thereof to a nucleophilic substitution reaction under the action of a base, optionally with microwaves, to obtain a compound represented by general formula (IV) or a medicamentable salt thereof, Among them, X, L, R 1 , R 4a , p, n and s are as defined in general formula (IV). Technical proposal 5

[0197] A method for preparing a compound of general formula (II) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] Step 1: A compound represented by general formula (IIA') or a salt thereof and a compound represented by general formula (IIB') or a salt thereof are subjected to a nucleophilic addition reaction under the action of a base (e.g., n-butyl lithium) to obtain a compound represented by general formula (IIa) or a medicamentable salt thereof; The compound represented by the general formula (IIa) or a salt thereof is subjected to a chlorination reaction (e.g., PCl 3 or SOCl 2 Step 2, under the action of (IIb) to obtain a compound of general formula (IIb) or a medicamentable salt thereof; Step 3 of reducing the compound represented by general formula (IIb) or a medicament salt thereof under the action of a metal (e.g., zinc powder or iron powder) to obtain the compound represented by general formula (II) or a medicament salt thereof; Among them, X 1 is a halogen, preferably bromine; Ring A, Ring B, Ring C, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (II). Technical proposal 6

[0198] A process for preparing a compound of general formula (Ii) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method includes a step of coupling a compound represented by general formula (IIA') or a salt thereof with a compound represented by general formula (IiB') or a salt thereof under the action of a base and a metal catalyst, and optionally adding a ligand, to obtain a compound represented by general formula (Ii) or a medicamentable salt thereof; Among them, Ring D is a 3- to 8-membered heterocyclyl group containing at least one endocyclic double bond, preferably a 5- or 6-membered heterocyclyl group containing at least one endocyclic double bond, more preferably [ka] and Ring C is a 3- to 8-membered heterocyclyl group, preferably a 5- or 6-membered heterocyclyl group, more preferably [ka] and X 1 is a halogen, preferably bromine; Ring A, Ring B, L, R 1 , R 2 , R 4a , p, q and n are as defined in general formula (Ii).

[0199] In the reaction of the above technical schemes 1 to 6, the base includes organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, pyridine, 3,5-dimethylpyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-biazadicycloundec-7-ene, the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide, the base in the technical schemes 1 to 4 is preferably selected from pyridine, lithium bis(trimethylsilyl)amide or 3,5-dimethylpyridine, the base in the technical scheme 5 is preferably n-butyllithium, and the base in the technical scheme 6 is preferably potassium carbonate.

[0200] In the above-mentioned technical proposal 6, the above-mentioned metal catalyst includes, but is not limited to, palladium acetate, tetrakis(triphenylphosphino)palladium, tris(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II), bis(acetonitrile)chloropalladium(II) and palladium / carbon, preferably palladium acetate.

[0201] In the above Technical Scheme 6, the ligand includes, but is not limited to, triphenylphosphine, tris(o-tolyl)phosphine and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably triphenylphosphine.

[0202] The reactions in the above Technical Schemes 1 to 4 are optionally carried out under the action of a catalyst, and the catalyst includes but is not limited to 4-dimethylaminopyridine and dimethylsulfoxide (DMSO).

[0203] When the reactions of the above Technical Schemes 1 to 6 are carried out using microwaves, the reaction temperature is 100 to 150°C, preferably 120°C.

[0204] When the reactions of the above Technical Schemes 1 to 6 are carried out using microwaves, the reaction time is 0.5 to 6 hours, preferably 2 to 3 hours, and more preferably 3 hours.

[0205] The reactions of the above-mentioned technical schemes 1 to 6 are preferably carried out in a solvent, and the solvents used include, but are not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, pyridine and mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0206] The present disclosure will be further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure. Working Example

[0207] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are within the range of 10 -6The units are shown in ppm. The NMR measurements were performed using a Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) and the internal standard is tetramethylsilane (TMS).

[0208] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0209] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

[0210] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD was used.

[0211] For preparative high performance liquid chromatography, preparative chromatographs Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 were used.

[0212] For chiral preparative chromatography, a preparative chromatograph Shimadzu LC-20AP was used.

[0213] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0214] As the silica gel plate for thin layer chromatography, Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used, the specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15-0.2 mm, and the specification for separation and purification of products by thin layer chromatography is 0.4-0.5 mm.

[0215] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0216] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0217] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Technology (Shanghai) Co., Ltd., Darui Chemicals, Shanghai Taitan Technology, Aldrich, Ananji Chemical, China National Pharmaceutical Group Co., Ltd., Adamas Reagents Co., Ltd., Sigma-Aldrich (Shanghai) Trading Co., Ltd., Shanghai BiDe Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biopharmaceutical Technology Co., Ltd., Thermo Fisher Scientific (China) Co., Ltd., and the like.

[0218] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0219] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume attached to the reaction flask.

[0220] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume connected to the reaction flask.

[0221] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0222] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0223] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0224] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0225] In the examples, unless otherwise specified, the reaction temperature was room temperature, 20 to 30°C.

[0226] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin layer chromatography included A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system, and the volume ratio of the solvents was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0227] Example 1 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 1 [ka] [ka]

[0228] Step 1 4-Bromo-2-((2,4-dimethoxybenzyl)oxy)-6-fluorobenzonitrile 1b 4-Bromo-2,6-difluorobenzonitrile 1a (22 g, 101 mmol) and 2,4-dimethoxybenzyl alcohol (18.5 g, 110 mmol) were dissolved in N,N-dimethylformamide (200 mL), and cesium carbonate (49 g, 150 mmol) was added. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, suction filtered under reduced pressure, and the filtrate was diluted with ethyl acetate (500 mL) and washed with saturated sodium chloride solution (30 mL x 5). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1b (36.9 g, yield: 100%). The product was used in the next reaction without purification.

[0229] Step 2 4-Bromo-2-fluoro-6-hydroxybenzonitrile 1c Compound 1b (36.9 g, 100.7 mmol) was dissolved in dichloromethane (250 mL) and cooled to 0° C. Trifluoroacetic acid (39 g, 342 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1c (9.7 g, yield: 44.5%).

[0230] Step 3 2-(Allyloxy)-4-bromo-6-fluorobenzonitrile 1d Compound 1c (10.7 g, 49.5 mmol) was dissolved in N,N-dimethylformamide (120 mL), the reaction solution was cooled to 0°C, cesium carbonate (24 g, 73.7 mmol) and allyl bromide (11.2 g, 92.6 mmol) were added, the reaction solution was warmed to room temperature and stirred for 4 hours. The reaction solution was suction filtered under reduced pressure, the filtrate was diluted with ethyl acetate (400 mL), washed with saturated sodium chloride solution (30 mL x 3), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1d (11.7 g, yield: 92%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.02 (dt, 1H), 6.95 (t, 1H), 6.04 (m, 1H), 5.57-5.47 (m, 1H), 5.41 (dt, 1H), 4.75-4.64 (m, 2H).

[0231] Step 4 3-Allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile 1e Compound 1d (3.35 g, 13.1 mmol) was dissolved in 1,2-dichlorobenzene (80 mL), purged with nitrogen gas three times, and the reaction solution was stirred at 180° C. for 13 hours. The reaction solution was cooled to room temperature, and the resulting residue was purified by silica gel column chromatography (wet column) with eluent system A to give the title product 1e (2.77 g, yield: 82.7%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.07 (dd, 1H), 6.45 (s, 1H), 5.90 (dddd, 1H), 5.24-5.10 (m, 2H), 3.68-3.55 (m, 2H).

[0232] Step 5 3-Allyl-4-bromo-6-fluoro-2-(methoxymethoxy)benzonitrile 1f Compound 1e (1 g, 3.91 mmol) was dissolved in acetonitrile (15 mL), potassium carbonate (1.07 g, 7.74 mmol) and bromo(bromomethoxy)methane (MOMBr, 634 mg, 5.08 mmol) were added, and the mixture was stirred for 2 hours. The reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained with eluent system A was purified by silica gel column chromatography to give the title product 1f (1.11 g, yield: 94.7%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.28 (d, 1H), 5.89 (ddt, 1H), 5.26 (d, 2H), 5.08-4.98 (m, 2H), 3.66 (s, 3H), 3.58 (s, 2H).

[0233] Step 6 4-Bromo-6-fluoro-3-(2-hydroxyethyl)-2-(methoxymethoxy)benzonitrile 1g Compound 1f (1.1 g, 3.66 mmol) was dissolved in 50 mL of a mixed solvent of methanol and tetrahydrofuran (V:V=1:1), and the reaction solution was cooled to -78°C, and dried ozone was passed through and aerated for 1 hour. The reaction solution was quenched by adding triphenylphosphine (1.05 g, 4.0 mmol), gradually warmed to room temperature, and reacted with stirring for 0.5 hours. The reaction solution was further cooled to 0°C, and sodium borohydride (560 mg, 14.8 mmol) was added in several portions, and reacted with stirring for 1 hour. The reaction solution was quenched by adding water (5 mL), concentrated under reduced pressure, diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride solution (10 mL x 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1g (800 mg, yield: 71.8%). 1 H NMR (500 MHz, CDCl3 ) δ 7.28 (d, 1H), 5.32 (s, 2H), 3.82 (t, 2H), 3.67 (s, 3H), 3.10 (t, 2H), 2.39 (s, 1H).

[0234] Step 7 4-Bromo-6-fluoro-2-hydroxy-3-(2-hydroxyethyl)benzonitrile 1H Compound 1g (800 mg, 2.63 mmol) was dissolved in methanol (25 mL), the reaction solution was cooled to 0° C., and a solution of hydrochloric acid in dioxane (4 M, 24 mmol, 6 mL) was added. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1h (680 mg, yield: 99%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.07-6.95 (m, 1H), 4.01 (t, 2H), 3.14 (t, 2H).

[0235] Step 8 4-Bromo-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile 1i Compound 1h (680 mg, 2.61 mmol) was dissolved in tetrahydrofuran (100 mL), the reaction mixture was cooled to 0° C., triphenylphosphine (2.05 g, 7.81 mmol) and diisopropyl azodicarboxylate (1.58 g, 7.81 mmol) were added, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1i (570 mg, yield: 90%). 1 H NMR (500 MHz, CDCl 3 ) δ 6.84 (dd, 1H), 4.84 (td, 2H), 3.24 (tt, 2H).

[0236] Step 9 Methyl 7-cyano-6-fluoro-2,3-dihydrobenzofuran-4-carboxylate 1j Compound 1i (615 mg, 2.54 mmol) was dissolved in 20 mL of a mixed solvent of methanol and N,N-dimethylformamide (V:V=1:3), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (185 mg, 252 mmol) and triethylamine (771 mg, 7.62 mmol) were added in that order. The mixture was purged with carbon monoxide three times, and the reaction solution was stirred at 80°C for 12 hours under carbon monoxide protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with saturated sodium chloride solution (20 mL x 3), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1j (289 mg, yield: 51.4%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.24 (d, 1H), 4.84 (td, 2H), 3.94 (s, 3H), 3.57 (td, 2H).

[0237] Step 10 6-Fluoro-4-(hydroxymethyl)-2,3-dihydrobenzofuran-7-carbonitrile 1k Compound 1j (436 mg, 1.97 mmol) was dissolved in dried tetrahydrofuran (10 mL), purged with nitrogen gas three times, cooled to 0°C, and lithium borohydride (2 M, 5 mmol, 2.5 mL) was added. The reaction was heated to 70°C and stirred for 2 hours. The reaction was cooled to room temperature, quenched by adding water (1 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL x 2), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1k (350 mg, yield: 91.9%). 1 H NMR (500 MHz, CDCl3 ) δ 6.76 (dd, 1H), 4.81 (td, 2H), 4.66 (s, 2H), 3.20 (t, 2H).

[0238] Step 11 Methyl (7-cyano-6-fluoro-2,3-dihydrobenzofuran-4-yl)methanesulfonate 1l Compound 1k (350 mg, 1.81 mmol) was dissolved in dichloromethane (20 mL), cooled to 0° C., and triethylamine (2.2 g, 21.74 mmol) and methanesulfonyl chloride (1.24 g, 10.82 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched by adding saturated sodium bicarbonate solution (10 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL×2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1l (491 mg, yield: 99%). The product was used in the next reaction without purification.

[0239] Step 12 4-((1H-pyrazol-1-yl)methyl)-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile 1m Compound 1l (491 mg, 1.81 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.25 g, 9.04 mmol) and pyrazole (369 mg, 5.42 mmol) were added. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was filtered, and the obtained filtrate was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL x 3), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1m (361 mg, yield: 82%). MS m / z (ESI): 244.0 [M+1].

[0240] Step 13 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-amine 1n Compound 1m (361 mg, 1.48 mmol) and acetohydroxamic acid (334 mg, 4.45 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.0 g, 7.23 mmol) was added. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was filtered, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL x 3), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1n (189 mg, yield: 49.7%). MS m / z (ESI): 257.0 [M+1].

[0241] Step 14 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 1 Compound 1n (189 mg, 737 μmol) and 2,6-dimethoxybenzenesulfonyl chloride 1o (265 mg, 1.12 mmol, prepared by the method disclosed in the patent application "Technical Proposal 15 on page 70 of the specification in WO2020254946A1") were dissolved in pyridine (8 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120 ° C. in a microwave for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Welch Xtimate C18 5 μm 30 × 150 mm, mobile phase: A-aqueous phase (0.1% formic acid): B-acetonitrile = 30% ~ 45% (15 min), flow rate: 30 mL / min), and the title product 1 (44 mg, yield: 13%) was obtained. MS m / z (ESI): 457.0 [M+1]. 1 H NMR (500 MHz, CD 3OD) δ 7.71 (s, 1H), 7.55 (s, 1H), 7.47 (td, 1H), 6.74 (dd, 2H), 6.58 (s, 1H), 6.36 (q, 1H), 5.42 (s, 2H), 4.80 (td, 2H), 3.83 (s, 6H), 3.10 (t, 2H).

[0242] Example 2 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfamide 2 [ka] [ka]

[0243] Step 1 4-Bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile 2a Compound 1e (4.8 g, 18.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and borane tetrahydrofuran solution (1.0 M, 22 mL, 22 mmol) was added dropwise at 0°C. The reaction solution was stirred in an ice bath for 2 hours. 3 M aqueous sodium hydroxide solution (13 mL, 39 mmol) and 30% hydrogen peroxide (3.0 mL) were added in turn in an ice bath, and the mixture was stirred for 10 min after addition was complete. The reaction solution was adjusted to pH=2 with 2 M hydrochloric acid, extracted with ethyl acetate (100 mL×2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2a (3.5 g, yield: 68.1%). MS m / z (ESI): 275.8 [M+1]. 1 H NMR (500 MHz, CDCl 3) δ 7.04 (d, 1H), 3.71 (t, 2H), 3.00-2.98 (m, 2H), 2.01-1.96 (m, 2H).

[0244] Step 2 5-Bromo-7-fluorochroman-8-carbonitrile 2b Compound 2a (3.8 g, 13.9 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), the reaction solution was cooled to 0° C., triphenylphosphine (4.4 g, 16.8 mmol) and diisopropyl azodicarboxylate (3.4 g, 16.8 mmol) were added, the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 2b (3.0 g, yield: 84.5%). MS m / z (ESI): 257.8 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.03 (d, 1H), 4.33 (t, 2H), 2.77-2.74 (m, 2H), 2.12-2.08 (m, 2H).

[0245] Step 3 Methyl 8-cyano-7-fluorochroman-5-carboxylate 2c Compound 2b (2.6 g, 10.2 mmol) was dissolved in 40 mL of a mixed solvent of methanol and N,N-dimethylformamide (V:V=1:3), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (800 mg, 1.09 mmol) and triethylamine (3.0 g, 2.93 mmol) were added in that order. The mixture was purged with carbon monoxide three times and stirred at 10 bar and 90°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with saturated sodium chloride solution (50 mL×3), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 2c (2.1 g, yield: 87.9%). MS m / z (ESI): 235.9 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.26 (d, 1H), 4.38-4.36 (m, 2H), 3.93 (s, 3H),3.10-3.07 (m, 2H), 2.08-2.03 (m, 2H).

[0246] Step 4 7-Fluoro-5-(hydroxymethyl)chroman-8-carbonitrile 2d Compound 2c (2.1 g, 8.93 mmol) was dissolved in dried tetrahydrofuran (40 mL), purged with nitrogen gas three times, cooled to 0°C, and lithium borohydride (2 M, 18 mmol, 9.0 mL) was added. The reaction was heated to 70°C and stirred for 2 hours. The reaction was cooled to room temperature, quenched by adding water (1 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography using eluent system A to obtain the title product 2d (1.84 g, yield: 99.5%). MS m / z (ESI): 207.9 [M+1].

[0247] Step 5 5-((1H-pyrazol-1-yl)methyl)-7-fluorochroman-8-carbonitrile 2f Compound 2d (1.8 g, 8.69 mmol) and 1-(methylsulfonyl)-1H-pyrazole 2e (1.5 g, 10.3 mmol, prepared by the method disclosed in the patent application "Intermediate 13 of Technical Scheme 8 on page 63 of the specification in WO2020254946A1") were dissolved in acetonitrile (30 mL), cesium carbonate (4.2 g, 12.9 mmol) was added, and the mixture was reacted at 70 ° C for 1 hour. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2f (1.9 g, yield: 85.0%). MS m / z (ESI): 258.0 [M+1].

[0248] Step 6 5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-amine 2g Compound 2f (1.9 g, 7.39 mmol) and acetohydroxamic acid (1.7 g, 22.2 mmol, Adamas) were dissolved in N,N-dimethylformamide (30 mL) and water (4.0 mL), and potassium carbonate (6.2 g, 44.9 mmol) was added. The reaction was stirred at 70° C. for 24 hours. The reaction was cooled to room temperature, water (100 mL) was added, filtered, and the filter cake was collected and dried to give the title product 2g (1.65 g, yield: 82.7%). MS m / z (ESI): 271.0 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.78 (d, 1H), 7.52 (d, 1H), 6.34 (s, 1H), 6.32 (t, 1H), 5.85 (s, 2H), 5.39 (s, 2H), 4.25-4.23 (m, 2H), 2.68 (t, 2H), 2.03-1.98 (m, 2H).

[0249] Step 7 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfamide 2 Compound 2g (200 mg, 0.740 mmol) and compound 1o (300 mg, 1.27 mmol) were dissolved in pyridine (5.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120 ° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 2 (40 mg, yield: 11.5%). MS m / z (ESI): 470.8 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.40 (s, 1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.48 (t, 1H), 6.77 (d, 2H), 6.43 (s, 1H), 6.32 (t, 1H), 5.42 (s, 2H), 4.25 (t, 2H), 3.78 (s, 6H), 2.70 (t, 2H), 2.04-1.99 (m, 2H).

[0250] Example 3 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2-methoxybenzenesulfamide 3 [ka] [ka] Compound 2g (300 mg, 1.11 mmol) and 2-methoxybenzenesulfonyl chloride 3a (460 mg, 2.22 mmol) were dissolved in pyridine (6.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120°C in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30 × 150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 3 (100 mg, yield: 20.5%). MS m / z (ESI): 440.8 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 7.81-7.78 (m, 2H), 7.62 (d, 1H), 7.51 (d, 1H), 7.20 (d, 1H), 7.09 (d, 1H), 6.45 (s, 1H), 6.32 (t, 1H), 5.41 (s, 2H), 4.19 (t, 2H), 3.81 (s, 3H), 2.69 (t, 2H), 2.01-1.96 (m, 2H).

[0251] Example 4 N-(5-((1H-pyrazol-1-yl)methyl)-2,3-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]isoxazol-9-yl)-2-methoxybenzenesulfamide 4 [ka] [ka]

[0252] Step 1 Methyl 4-bromo-5-fluoro-2,3-dihydroxybenzoate 4b Compound 5-fluoro-2,3-dihydrobenzoic acid methyl ester 4a (2.26 g, 12.1 mmol, prepared according to the method disclosed in the literature "J. Med. Chem. 2010, 53, 7035-7047") was dissolved in dichloromethane (60 mL), the reaction solution was cooled to 0°C, N-bromosuccinimide (2.6 g, 14.6 mmol) was added in several portions, and the reaction solution was stirred at room temperature for 3 days. The reaction solution was washed with saturated sodium hydrogen sulfite solution (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4b (1.8 g, yield: 55.9%). 1 H NMR (500 MHz, CDCl 3 ) δ 10.84 (s, 1H), 7.14 (d, 1H), 3.97 (s, 3H).

[0253] Step 2 8-Bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-methylformate 4c Compound 4b (1.0 g, 3.77 mmol) and 1,2-dibromoethane (1.1 g, 5.85 mmol) were dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (2.46 g, 7.55 mmol) was added, and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 4c (873 mg, yield: 79.5%). MS m / z (ESI): 292.9 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.26 (d, 1H), 4.45-4.43 (m, 2H), 4.39-4.36 (m, 2H), 3.91 (s, 3H).

[0254] Step 3 Methyl 8-cyano-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate 4d Compound 4c (708 mg, 2.43 mmol), zinc cyanide (714 mg, 6.08 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium (306 mg, 0.365 mmol, Bide) were dissolved in N,N-dimethylformamide (15 mL) and purged with nitrogen gas three times. The reaction mixture was reacted at 110 °C for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4d (503 mg, yield: 87.2%). MS m / z (ESI): 238.0 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.20 (d, 1H), 4.51 - 4.48 (m, 2H), 4.42 - 4.40 (m, 2H), 3.94 (s, 3H).

[0255] Step 4 6-Fluoro-8-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carbonitrile 4e Compound 4d (500 mg, 2.1 mmol) was dissolved in dry tetrahydrofuran (15 mL), purged with nitrogen gas three times, cooled to 0 °C, and lithium borohydride (2 M, 4 mmol, 2.0 mL) was added. The reaction mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, quenched by adding water (1 mL), diluted by adding ethyl acetate (30 mL), washed with saturated sodium chloride solution (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4e (323 mg, yield: 73.2%). 1 H NMR (500 MHz, CDCl3 ) δ 6.87 (dd, 1H), 4.72 (s, 2H), 4.46-4.42 (m, 2H), 4.36-4.32 (m, 2H).

[0256] Step 5 (8-cyano-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanesulfonate methyl ester 4f Compound 4e (323 mg, 1.54 mmol) was dissolved in dichloromethane (10 mL), cooled to 0° C., and triethylamine (780 mg, 7.71 mmol) and methanesulfonyl chloride (355 mg, 3.1 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched by adding saturated sodium bicarbonate solution (5 mL), diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4f (200 mg, yield: 45.1%). The product was used in the next reaction without purification.

[0257] Step 6 8-((1H-pyrazol-1-yl)methyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-carbonitrile 4g Compound 4f (200 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (7 mL), and potassium carbonate (240 mg, 1.73 mmol) and pyrazole (120 mg, 1.76 mmol) were added. The reaction solution was stirred at 60° C. for 12 hours. The reaction solution was filtered, and the obtained filtrate was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 4g (155 mg, yield: 85.8%). MS m / z (ESI): 260.0 [M+1]. 1H NMR (500 MHz, CDCl 3 ) δ 7.63 (d, 1H), 7.48 (dd, 1H), 6.34 (t, 1H), 6.22 (d, 1H), 5.34 (s, 2H), 4.47-4.42 (m, 2H), 4.38-4.35 (m, 2H).

[0258] Step 7 5-((1H-pyrazol-1-yl)methyl)-2,3-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]isoxazol-9-amine 4H Compound 4g (155 mg, 0.6 mmol) and acetohydroxamic acid (135 mg, 1.8 mmol) were dissolved in 4 mL of a mixed solvent of N,N-dimethylformamide and water (V:V=7:1), and potassium carbonate (495 mg, 3.58 mmol) was added. The reaction solution was stirred at 70° C. for 24 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 4h (110 mg, yield: 67.5%). MS m / z (ESI): 273.0 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.61-7.55 (m, 1H), 7.49 (d, 1H), 6.51 (s, 1H), 6.32 (t, 1H), 5.39 (s, 2H), 4.60 (s, 2H), 4.42 (dd, 2H), 4.37 (dd, 2H).

[0259] Step 8 N-(5-((1H-pyrazol-1-yl)methyl)-2,3-dihydro-[1,4]dioxino[2',3':5,6]benzo[1,2-d]isoxazol-9-yl)-2-methoxybenzenesulfamide 4 Compound 4h (40 mg, 0.147 mmol) and compound 3a (152 mg, 0.735 mmol) were dissolved in pyridine (3.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 15% to 35% (20 min), flow rate: 30 mL / min) to obtain the title product 4 (25 mg, yield: 38.4%). MS m / z (ESI): 443.0 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 7.80 (d, 1H), 7.77 (dd, 1H), 7.58 (s, 1H), 7.50 (d, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 6.41 (s, 1H), 6.30 (t, 1H), 5.37 (s, 2H), 4.33 (q, 4H), 3.80 (s, 3H).

[0260] Example 5 N-(4-((1H-pyrazol-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 5 [ka] [ka]

[0261] Step 1 7-Bromo-6-fluoro-2-sulfanylidenebenzo[d][1,3]dioxole-4-methylformate 5a Compound 4b (16.7 g, 63 mmol) was dissolved in tetrahydrofuran (200 mL), the reaction mixture was cooled to 0° C., N,N'-thiocarbonyldiimidazole (18 g, 101 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 5a (9.1 g, yield: 47.0%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.71 (d, 1H), 4.05 (s, 3H).

[0262] Step 2 7-Bromo-2,2,6-trifluorobenzo[d][1,3]dioxole-4-methylformate 5b Compound 5a (9.1 g, 29.6 mmol) was dissolved in dichloromethane (160 mL) at -40°C, and hydrogen fluoride pyridine solution (42.3 g, 427 mmol) was added under nitrogen protection, and the reaction solution was reacted at -40°C for 5 minutes. Then, N-iodosuccinimide (20 g, 88.9 mmol) was added in several portions, and the reaction solution was continued to react at -40°C for 30 minutes. The reaction solution was quenched by adding saturated sodium bisulfite solution (20 mL), washed with saturated sodium chloride solution (60 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5b (4.8 g, yield: 51.7%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.49 (d, 1H), 4.00 (s, 3H).

[0263] Step 3 (7-Bromo-2,2,6-trifluorobenzo[d][1,3]dioxol-4-yl)methanol 5c Compound 5b (4.8 g, 15.3 mmol) was dissolved in dried tetrahydrofuran (150 mL), purged with nitrogen gas three times, cooled to 0° C., and lithium borohydride (2 M, 27.6 mmol, 13.8 mL) was added. The reaction was heated to 70° C. and stirred for 2 hours. The reaction was cooled to room temperature, quenched by adding water (5 mL), diluted with ethyl acetate (60 mL), washed with saturated sodium chloride solution (30 mL×2), combined organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5c (3.2 g, yield: 73.2%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.04 (d, 1H), 4.76 (d, 2H).

[0264] Step 4 1-((7-bromo-2,2,6-trifluorobenzo[d][1,3]dioxol-4-yl)methyl)-1H-pyrazole 5d Compound 5c (3.2 g, 11.2 mmol) and compound 2e (1.8 g, 12.3 mmol) were dissolved in acetonitrile (55 mL), and cesium carbonate (5.5 g, 16.9 mmol) was added and reacted at 70° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5d (2.61 g, yield: 69.3%). MS m / z (ESI): 336.9 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.59 (d, 1H), 7.51 (d, 1H), 6.67 (d, 1H), 6.35 (t, 1H), 5.33 (s, 2H).

[0265] Step 5 7-((1H-pyrazol-1-yl)methyl)-2,2,5-trifluorobenzo[d][1,3]dioxole-4-carbonitrile 5e Compound 5d (1.6 g, 4.77 mmol) and cuprous cyanide (3.2 g, 11.2 mmol) were dissolved in N-methylpyrrolidone (50 mL), and the reaction solution was reacted at 200° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with dichloromethane (60 mL), washed with saturated sodium chloride solution (60 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5e (465 mg, yield: 34.6%). MS m / z (ESI): 282.0 [M+1].

[0266] Step 6 4-((1H-pyrazol-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazol-8-amine 5f Compound 5e (1 g, 3.55 mmol) and acetohydroxamic acid (800 mg, 10.66 mmol) were dissolved in 20 mL of a mixture of N,N-dimethylformamide and water (V:V=7:1), and potassium carbonate (2.95 g, 21.33 mmol) was added. The reaction mixture was stirred at 70° C. for 30 min. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 5f (60 mg, yield: 5.7%). MS m / z (ESI): 295.0 [M+1].

[0267] Step 7 N-(4-((1H-pyrazol-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 5 Compound 5f (60 mg, 0.20 mmol) and compound 1o (144 mg, 0.61 mmol) were dissolved in acetonitrile (5 mL), dimethyl sulfoxide (1 mg, 0.01 mmol) and 3,5-dimethylpyridine (87 mg, 0.81 mmol) were added, and the reaction solution was reacted at 35 ° C for 2 days. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (welch Prep C18 5 μm 30 × 150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 25% ~ 45% (20 min), flow rate: 30 mL / min) to obtain the title product 5 (55 mg, yield: 54.5%). MS m / z (ESI): 495.0 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.65-7.41 (m, 2H), 7.29 (m, 2H), 6.90 (s, 1H), 6.65 (t, 2H), 6.35 (s, 1H), 5.48 (s, 2H), 3.99-3.89 (s, 6H).

[0268] Example 6 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-6-methoxy-2,3-dihydro-1H-indene-5-sulfamide 6 [ka] [ka] Compound 2g (50 mg, 0.185 mmol) and 6-methoxy-2,3-dihydro-1H-indene-5-sulfonyl chloride 6a (200 mg, 0.811 mmol, obtained by preparation according to the method disclosed in the patent application "Intermediate I108 on page 114 of the specification in WO2019243491A1") were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120 ° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30 × 150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% ~ 45% (15 min), flow rate: 30 mL / min), and the title product 6 (30 mg, yield: 33.7%) was obtained. MS m / z (ESI): 480.8 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.59 (s, 1H), 7.78 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 7.08 (s, 1H), 6.44 (s, 1H), 6.31 (d, 1H), 5.41 (s, 2H), 4.24 (t, 2H), 3.79 (s, 3H), 2.89 (t, 2H), 2.83 (t, 2H), 2.69 (t, 2H), 2.04-1.99 (m, 4H).

[0269] Example 7 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2-ethoxy-4-toluenesulfamide 7 [ka] [ka]

[0270] Step 1 5-Bromo-2-ethoxy-4-toluenesulfonic acid 7b Compound 1-bromo-4-ethoxy-2-toluene 7a (2.0 g, 9.30 mmol) was dissolved in concentrated sulfuric acid (3.6 mL) and stirred at room temperature overnight. The reaction mixture was poured into ice water (20 mL), concentrated under reduced pressure to remove most of the water, washed with cyclohexane (20 mL), filtered, the filter cake was washed with ethyl acetate (20 mL), and then washed with diethyl ether (20 mL), the filter cake was collected and dried under vacuum to give the title product 7b (2.5 g, yield: 91.1%). MS m / z (ESI): 295.1 [M-1]

[0271] Step 2 2-Ethoxy-4-toluenesulfonic acid 7c Compound 7b (2.5 g, 8.47 mmol) was dissolved in methanol (20 mL), palladium carbon (226 mg, 50% water) was added, hydrogen gas was passed through, and the mixture was heated to 70° C. and reacted for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the title product 7c (1.8 g, yield: 98.3%). MS m / z (ESI): 215.1 [M-1]

[0272] Step 3 2-Ethoxy-4-toluenesulfonyl chloride 7d Compound 7c (200 mg, 0.92 mmol) was placed in a flask, thionyl chloride (771 mg, 6.48 mmol) was slowly added dropwise, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 7d (200 mg, yield: 92.1%).

[0273] Step 4 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2-ethoxy-4-toluenesulfamide 7 Compound 2g (50 mg, 0.185 mmol) and compound 7d (100 mg, 0.426 mmol) were dissolved in pyridine (2.0 mL) and replaced with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 7 (30 mg, yield: 34.6%). MS m / z (ESI): 468.8 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.32 (s, 1H), 7.78 (d, 1H), 7.71 (d, 1H), 7.51 (d, 1H), 7.01 (s, 1H), 6.89 (d, 1H), 6.44 (s, 1H), 6.32 (t, 1H), 5.41 (s, 2H), 4.25-4.19 (m, 2H), 4.10 (q, 2H), 2.70 (t, 2H), 2.34 (s, 3H), 2.02-1.97 (m, 2H), 1.26 (t, 3H).

[0274] Example 8 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-methyl-2-(2,2,2-trifluoroethoxy)benzenesulfamide 8 [ka] [ka]

[0275] Step 1 5-Bromo-4-methyl-2-(2,2,2-trifluoroethoxy)benzenesulfonic acid 8b 1-Bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene 8a (1.2 g, 4.46 mmol, obtained by preparation according to the method disclosed in patent application "Intermediate A30 on page 71 of the specification in WO2020069322A1") was dissolved in concentrated sulfuric acid (2 mL) and stirred at room temperature overnight. The reaction solution was poured into ice water (20 mL), concentrated under reduced pressure to remove most of the water, washed with cyclohexane (20 mL), filtered, the filter cake was washed with ethyl acetate (20 mL), and then washed with diethyl ether (20 mL), the filter cake was collected and dried under vacuum to obtain the title product 8b (1.5 g, yield: 96.3%). MS m / z (ESI): 349.1 [M-1]

[0276] Step 2 4-Methyl-2-(2,2,2-trifluoroethoxy)benzenesulfonic acid 8c Compound 8b (1.7 g, 4.87 mmol) was dissolved in methanol (10 mL), palladium carbon (130 mg, 50% water) was added, hydrogen gas was passed through, and the mixture was heated to 70° C. and reacted for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the title product 8c (1.3 g, yield: 98.8%). MS m / z (ESI): 269.2[M-1]

[0277] Step 3 4-Methyl-2-(2,2,2-trifluoroethoxy)benzenesulfonyl chloride 8d Compound 8c (500 mg, 1.85 mmol) was placed in a flask, and thionyl chloride (1.55 g, 13.02 mmol) was slowly added dropwise to the flask, followed by reaction at 85° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 8d (400 mg, yield: 74.9%). MS m / z (ESI): 287.2 [M-1]

[0278] Step 4 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-methyl-2-(2,2,2-trifluoroethoxy)benzenesulfamide 8 Compound 2g (50 mg, 0.185 mmol) and compound 8d (130 mg, 0.450 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 8 (10 mg, yield: 10.3%). MS m / z (ESI): 522.8 [M+1]. 1H NMR (500 MHz, DMSO-d 6 ) δ 9.39 (s, 1H), 7.79-7.77 (m, 2H), 7.51 (d, 1H), 7.20 (s, 1H), 7.04 (d, 1H), 6.44 (s, 1H), 6.32 (t, 1H), 5.41 (s, 2H), 4.89 (d, 2H), 4.21 (t, 2H), 2.69 (t, 2H), 2.37 (s, 3H), 2.01-1.98 (m, 2H).

[0279] Example 9 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-5-fluoro-2-methoxybenzenesulfamide 9 [ka] [ka] Compound 2g (50 mg, 0.185 mmol) and 5-fluoro-2-methoxybenzenesulfonyl chloride 9a (200 mg, 0.890 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120°C in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 30% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 9 (15 mg, yield: 17.6%). MS m / z (ESI): 458.9 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 7.79 (d, 1H), 7.57 (dd, 1H), 7.58-7.56 (m, 2H),7.27 (m, 1H), 6.47 (s, 1H), 6.32 (t, 1H), 5.42 (s, 2H), 4.17 (t, 2H), 3.79 (s, 3H), 2.69 (t, 2H), 2.10-1.94 (m, 2H).

[0280] Example 10 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2-methoxy-6-(trifluoromethoxy)benzenesulfamide 10 [ka] [ka]

[0281] Step 1 2-Methoxy-6-(trifluoromethoxy)benzenesulfonyl chloride 10b 1-Methoxy-3-(trifluoromethoxy)benzene 10a (500 mg, 2.55 mmol), anhydrous tetrahydrofuran (10 mL) and tetramethylethylenediamine (616 mg, 5.30 mmol) were added to a 100 mL three-neck flask, cooled to -78 °C under nitrogen atmosphere, n-butyllithium (1.3 mL, 2.5 M, 3.25 mmol) was added dropwise, and after addition, the reaction was stirred at -78 °C for 1 h, sulfuryl chloride (0.3 mL, 3.71 mmol) was added, and after addition, the reaction was warmed to room temperature and stirred for 1 h. Water (20 mL) was added, extracted with ethyl acetate (20 mL), concentrated, and the obtained residue was purified by silica gel column chromatography using eluent system A to give the title product 10b (200 mg, yield: 26.9%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.70 (t, 1H), 7.12 (d, 1H), 7.05 (dt, 1H),4.10 (s, 3H).

[0282] Step 2 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2-methoxy-6-(trifluoromethoxy)benzenesulfamide 10 Compound 2g (50 mg, 0.185 mmol) and compound 10b (200 mg, 0.688 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 10 (3.0 mg, yield: 3.09%). MS m / z (ESI): 524.8 [M+1]. 1 H NMR (500 MHz, CD3 OD) δ 7.66 (d, 1H), 7.60-7.56 (m, 2H),7.15 (d, 1H), 7.02 (d, 1H), 6.40-6.38 (m, 2H), 5.43 (s, 2H), 4.28-4.26 (m, 2H), 3.85 (s, 3H), 2.69 (t, 2H), 2.12-2.07 (m, 2H).

[0283] Example 11 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-(dimethylamino)-2-methoxybenzenesulfamide 11 [ka] [ka]

[0284] Step 1 4-Bromo-3-methoxy-N,N-dimethylaniline 11b In a 100 mL flask, 4-bromo-3-methoxyaniline 11a (2.0 g, 9.90 mmol), 37% aqueous formaldehyde solution (9.0 g, 97.8 mmol), acetic acid (9.0 g, 150 mmol), and acetonitrile (30 mL) were added and stirred at room temperature for 30 min., and sodium cyanoborohydride (800 mg, 12.7 mmol) was added in an ice bath and stirred at room temperature for 16 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 11b (930 mg, yield: 40.8%). MS m / z (ESI): 230.0 [M+1]. 1 H NMR (500 MHz, CDCl 3) δ 7.33 (d, 1H), 6.28 (d, 1H), 6.24 (dd, 1H), 3.91 (s, 3H), 2.97 (s, 6H).

[0285] Step 2 4-(Dimethylamino)-2-methoxybenzenesulfonyl chloride 11c In a 100 mL three-neck flask, 11b (900 mg, 3.91 mmol) and anhydrous tetrahydrofuran (15 mL) were added, and the mixture was cooled to -70°C under nitrogen atmosphere, and n-butyllithium (2.0 mL, 2.5 M, 5.0 mmol) was added dropwise. After the addition, the mixture was stirred at -70°C for 1 hour, self-prepared sulfur dioxide was passed through for 10 minutes, and then stirred for 30 minutes. N-chlorosuccinimide (700 mg, 5.24 mmol) was added, and after the addition, the mixture was warmed to room temperature and reacted for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL), concentrated, and the obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 11c (50 mg, yield: 5.11%). MS m / z (ESI):232.0 [M-Cl+OH+1].

[0286] Step 3 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-(dimethylamino)-2-methoxybenzenesulfamide 11 Compound 2g (40 mg, 0.148 mmol) and compound 11c (50 mg, 0.200 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 10% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 11 (2.0 mg, yield: 2.79%). MS m / z (ESI): 483.9 [M+1]. 1 H NMR (500 MHz, CD 3 OD) δ 7.72 (d, 1H), 7.66 (d, 1H), 7.57 (d, 1H), 6.43-6.38 (m, 2H), 6.33 (dd, 1H), 6.19 (d, 1H), 5.42 (s, 2H), 4.38 (t, 2H), 3.87 (s, 3H), 3.03 (s, 6H), 2.70 (t, 2H), 2.18-2.12 (m, 2H).

[0287] Example 12 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,3-dihydrobenzofuran-7-sulfamide 12 [ka] [ka]

[0288] Step 1 2,3-Dihydrobenzofuran-7-sulfonyl chloride 12b In a 100 mL flask, 2,3-dihydrobenzofuran 12a (2.0 g, 16.6 mmol), sulfur trioxide N,N-dimethylformamide complex (3.0 g, 19.6 mmol), and 1,2-dichloroethane (10 mL) were added, and the reaction was stirred at 80° C. for 1 h. After cooling to room temperature, sulfoxide chloride (2.2 g, 18.5 mmol) was added dropwise, and after the addition was completed, the reaction was heated to 70° C. and reacted for 2 h. After that, it was cooled to room temperature, poured into ice water (50 mL), extracted with ethyl acetate (50 mL), concentrated, and the obtained residue was purified by silica gel column chromatography using eluent system A to give the title product 12b (3.2 g, yield: 87.9%). 1H NMR (500 MHz, CDCl 3) δ 7.89-7.86 (m, 2H), 6.93 (d, 1H), 4.78 (t, 2H), 3.35 (t, 2H).

[0289] Step 2 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,3-dihydrobenzofuran-7-sulfamide 12 Compound 2g (50 mg, 0.185 mmol) and compound 12b (200 mg, 0.915 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 30% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 12 (20.0 mg, yield: 23.9%). MS m / z (ESI): 452.9 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.76 (d, 1H), 7.52 (d, 1H), 6.93 (d, 1H), 6.44 (s, 1H), 6.32 (t, 1H), 5.42 (s, 2H), 4.64 (t, 2H), 4.30-4.20 (m, 2H), 3.25 (t, 2H), 2.69 (t, 2H), 2.17-1.95 (m, 2H).

[0290] Example 13 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-ethyl-2-methoxybenzenesulfamide 13 [ka] [ka]

[0291] Step 1 4-Bromo-3-ethylphenol 13b Compound 3-ethylphenol 13a (4.0 g, 32.7 mmol, adamas) was dissolved in dichloromethane (30 mL), tetrabutylammonium tribromide (16.0 g, 33.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 1 M dilute hydrochloric acid (50 mL), water, and saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 13b (6.3 g, yield: 95.7%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 (d, 1H), 6.76 (d, 1H), 6.58 (dd, 1H), 4.83 (s, 1H), 2.71 (q, 2H), 1.23 (t, 3H).

[0292] Step 2 1-Bromo-2-ethyl-4-methoxybenzene 13c Compound 13b (3.0 g, 14.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (4.1 g, 29.7 mmol) and iodomethane (2.6 g, 18.3 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), respectively, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using eluent system A to give the title product 13c (2.5 g, yield: 77.9%). 1 H NMR (500 MHz, CDCl 3) δ 7.42 (d, 1H), 6.81 (d, 1H), 6.64 (dd, 1H), 3.81 (s, 3H), 2.74 (q, 2H), 1.24 (t, 3H).

[0293] Step 3 5-Bromo-4-ethyl-2-methoxybenzenesulfonic acid 13d Compound 13c (2.5 g, 11.6 mmol) was slowly added to concentrated sulfuric acid (6.0 mL) in an ice bath and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (90 mL), and the reaction mixture was adjusted to pH=3 with 20% aqueous sodium hydroxide solution, filtered, and the filter cake was washed with water (100 mL) and dried to obtain the title product 13d (1.5 g, yield: 43.7%). MS m / z (ESI): 293.1 [M-1].

[0294] Step 4 4-Ethyl-2-methoxybenzenesulfonic acid 13e Compound 13d (1.5 g, 5.08 mmol) was dissolved in methanol (20 mL), palladium on carbon (600 mg, 10%, 50% water) was added, hydrogen gas was passed through, and the reaction was heated to 60° C. and stirred for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give the title product 13e (1.1 g, yield: 100%). MS m / z (ESI): 215.2 [M-1].

[0295] Step 5 4-Ethyl-2-methoxybenzenesulfonyl chloride 13f Compound 13e (400 mg, 1.85 mmol) was added to a flask, thionyl chloride (4.0 mL) was slowly added dropwise, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 13f (200 mg, yield: 46.1%). MS m / z (ESI):215.2 [M-Cl+OH-1].

[0296] Step 6 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-ethyl-2-methoxybenzenesulfamide 13 Compound 13f (200 mg, 0.852 mmol) and compound 2g (60 mg, 0.222 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 15% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 13 (15.0 mg, yield: 14.4%). MS m / z (ESI): 468.9 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.03 (s, 1H), 6.92 (d, 1H), 6.43 (s, 1H), 6.31 (t, 1H), 5.40 (s, 2H), 4.24-4.18 (m, 2H), 3.81 (s, 3H), 2.69 (t, 2H), 2.64 (t, 2H), 2.01-1.97 (m, 2H), 1.19 (t, 3H).

[0297] Example 14 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-isopropyl-2-methoxybenzenesulfamide 14 [ka] [ka]

[0298] Step 1 4-Bromo-3-isopropylphenol 14b Compound 3-isopropylphenol 14a (2.0 g, 14.7 mmol) was dissolved in dichloromethane (30 mL) and methanol (10 mL), tetrabutylammonium tribromide (7.1 g, 14.7 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1 M dilute hydrochloric acid (50 mL), water, and saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 14b (2.9 g, 1 NMR showed that the isomer contained ∼20% Br para to the isopropyl group, total yield: 95.7%, carried directly to the next step). 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 (d, 1H), 6.79 (d, 1H), 6.57 (dd, 1H), 4.99 (s, 1H), 3.31 (m, 1H), 1.24 (d, 6H).

[0299] Step 2 1-Bromo-2-isopropyl-4-methoxybenzene 14c Compound 14b (2.9 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (3.7 g, 26.8 mmol) and iodomethane (2.28 g, 16.1 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), respectively, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using eluent system A to give the title product 14c (2.4 g, 1 NMR showed that the isomer contained ∼10% Br para to the isopropyl group, total yield: 77.7%, carried on directly to the next step). 1 H NMR (500 MHz, CDCl3 ) δ 7.44 (d, 1H), 6.86 (d, 1H), 6.64 (dd, 1H), 3.81 (s, 3H), 3.33 (m, 1H), 1.25 (d, 6H).

[0300] Step 3 5-Bromo-4-isopropyl-2-methoxybenzenesulfonic acid 14d Compound 14c (2.4 g, 10.5 mmol) was slowly added to concentrated sulfuric acid (6.0 mL) in an ice bath and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (90 mL), adjusted to pH=3 with 20% aqueous sodium hydroxide solution, filtered, and the filter cake was washed with water (100 mL) and dried to give the title product 14d (2.4 g, yield: 74.1%). MS m / z (ESI): 307.1 [M-1].

[0301] Step 4 -Isopropyl-2-methoxybenzenesulfonic acid 14e Compound 14d (2.4 g, 7.76 mmol) was dissolved in methanol (30 mL), palladium carbon (1.0 g, 10%, 50% water) was added, hydrogen gas was passed through, and the mixture was heated to 60° C. and reacted for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the title product 14e (1.3 g, yield: 72.7%). MS m / z (ESI): 229.2 [M-1].

[0302] Step 5 4-Isopropyl-2-methoxybenzenesulfonyl chloride 14f Compound 14e (360 mg, 1.56 mmol) was added to a flask, thionyl chloride (4.0 mL) was slowly added dropwise, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 14f (250 mg, yield: 64.3%). MS m / z (ESI): 229.2 [M-Cl+OH-1].

[0303] Step 6 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-isopropyl-2-methoxybenzenesulfamide 14 Compound 14f (250 mg, 1.01 mmol) and compound 2g (60 mg, 0.222 mmol) were dissolved in pyridine (2.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 15% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 14 (10.0 mg, yield: 9.34%). MS m / z (ESI): 482.9 [M+1]. 1H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.75 (d, 1H), 7.68 (d, 1H), 7.51 (d, 1H), 6.94 (s, 1H), 6.87 (d, 1H), 6.31 (d, 2H), 5.37 (s, 2H), 4.24-4.16 (m, 2H), 3.77 (s, 3H), 2.91 (m, 1H), 2.67 (t, 2H), 2.06-1.94 (m, 2H), 1.21 (d, 6H).

[0304] Example 15 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-6-methoxy-2,3-dihydro-1H-indene-5-sulfamide 15 [ka] [ka] Compound 6a (289 mg, 1.17 mmol) and compound 1n (150 mg, 0.59 mmol) were dissolved in pyridine (5.0 mL), 4-dimethylaminopyridine (15 mg, 0.12 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120 ° C. for 3 hours in a microwave. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 15 (30 mg, yield: 11.0%). MS m / z (ESI): 467.5 [M+1]. 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (s, 1H), 7.57-7.56 (d, 1H), 7.42-7.41 (d, 1H), 6.84 (s, 1H),6.64 (s, 1H), 6.33-6.32 (m, 1H), 5.33 (s, 2H), 4.83-4.80 (m, 2H), 3.94 (s, 3H), 3.09-3.05 (m, 2H), 2.94-2.88 (m, 4H), 2.13-2.07 (m, 2H).

[0305] Example 16 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-ethoxy-4-methylbenzenesulfamide 16 [ka] [ka] Compound 7d (92 mg, 0.39 mmol) and compound 1n (50 mg, 0.20 mmol) were dissolved in pyridine (5.0 mL), 4-dimethylaminopyridine (3 mg, 0.02 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120 ° C. for 3 hours in a microwave. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 16 (10 mg, yield: 11.3%). MS m / z (ESI): 455.5 [M+1]. 1 H NMR (400 MHz, CDCl 3 ): δ 7.97-7.96 (d, 1H), 7.56-7.55 (d, 1H), 7.42-7.41 (d, 1H), 6.89-6.87 (d, 1H),6.75 (s, 1H), 6.66 (s, 1H), 6.33-6.32 (m, 1H), 5.33 (s, 2H), 4.83-4.79 (m, 2H), 4.19-4.15 (m, 2H), 3.09-3.06 (m, 2H),2.37 (s, 3H), 1.53-1.50 (m, 3H).

[0306] Example 17 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxy-6-methylbenzenesulfamide 17 [ka] [ka]

[0307] Step 1 2-Methoxy-6-methylbenzenesulfonyl chloride 17b At -70°C, n-butyllithium (1.0 mL, 2.5 mmol, 2.5 M n-hexane solution) was added dropwise to a solution of 2-bromo-1-methoxy-3-methylbenzene 17a (500.0 mg, 2.5 mmol) in anhydrous diethyl ether (10 mL). The reaction was allowed to proceed with stirring at -70°C for 1 hour under nitrogen protection. Sulfur dioxide gas was passed through the reaction solution at -70°C for 30 minutes. N-chlorosuccinimide (496.0 g, 3.8 mmol) was added, and the mixture was gradually warmed to room temperature, and then allowed to proceed with the reaction at room temperature for 2 hours. The reaction solution was washed with saturated sodium hydrogen sulfite solution (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 17b (390.0 mg, yield: 78.0%).

[0308] Step 2 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxy-6-methylbenzenesulfamide 17 At -70°C, lithium bis(trimethylsilyl)amide (0.4 mL, 0.4 mmol, 1 M tetrahydrofuran solution) was added dropwise to a solution of compound 1n (60.0 mg, 0.24 mmol) in anhydrous tetrahydrofuran (3 mL). The mixture was stirred at -70°C for 1 hour under nitrogen protection. At -70°C, a solution of compound 17b (78.0 mg, 0.35 mmol) in tetrahydrofuran (0.5 mL) was added dropwise. The reaction system was gradually warmed to room temperature, and then the mixture was reacted at room temperature for 16 hours while stirring. Saturated ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Xtimate C18, 5 μm, 30×150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 20% (v / v) to 34% (v / v) within 14 minutes, detection wavelength 214&254 nm) to obtain the title product 17 (25.0 mg, yield: 23.7%). MS m / z (ESI): 440.9 [M+1]. 1 H NMR (500 MHz, CD 3 OD): δ 7.70 (d, 1H), 7.54 (d, 1H), 7.36 (dd, 1H), 6.95 (d, 1H), 6.87 (d, 1H), 6.53 (s, 1H), 6.36 (t, 1H), 5.40 (s, 2H), 4.77 (t, 2H), 3.82 (s, 3H), 3.07 (t, 2H), 2.65 (s, 3H).

[0309] Example 18 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxy-5-methylbenzenesulfamide 18 [ka] [ka] Compound 2-methoxy-5-methylbenzenesulfonyl chloride 18a (130 mg, 0.59 mmol) and compound 1n (50 mg, 0.20 mmol) were dissolved in pyridine (5.0 mL), 4-dimethylaminopyridine (5 mg, 0.04 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120 ° C. for 3 hours in a microwave. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 18 (3 mg, yield: 3.5%). MS m / z (ESI): 441.3 [M+1]. 1 H NMR (400 MHz, CDCl 3): δ 7.80 (s, 1H), 7.57-7.56(m, 2H), 7.49-7.48 (m, 2H), 6.30-6.29 (m, 2H), 5.37 (s, 2H), 4.70-4.67 (m, 2H), 3.71 (s, 3H), 3.09-3.06 (m, 2H),2.25 (s, 3H).

[0310] Example 19 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-5-methoxy-2,3-dihydrobenzofuran-6-sulfamide 19 [ka] [ka]

[0311] Step 1 6-Bromo-5-methoxy-2,3-dihydrobenzofuran 19b 5-Methoxy-2,3-dihydrobenzofuran 19a (250 mg, 1.66 mmol, obtained by preparation according to the method disclosed in the patent application "Intermediate 1D on page 65 of the specification in WO2017218960A1") was added to dichloromethane (5 mL), and 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione (291 mg, 0.67 mmol) was added slowly at 0° C., and the reaction was carried out at 0° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title product 19b (330 mg, yield: 86.5%). MS m / z (ESI): 229.1 [M+1].

[0312] Step 2 5-Methoxy-2,3-dihydrobenzofuran-6-sulfonyl chloride 19c Compound 19b (390 mg, 1.70 mmol) was dissolved in diethyl ether (10 mL), n-butyllithium (0.69 mL, 1.72 mmol, 2.5 M tetrahydrofuran solution) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. Sulfur dioxide gas was passed through the reaction mixture for 30 minutes, N-chlorosuccinimide (342 mg, 2.56 mmol) was added, the mixture was stirred at room temperature for 2 hours, saturated ammonium chloride solution (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 19c (200 mg, yield: 47.2%).

[0313] Step 3 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-5-methoxy-2,3-dihydrobenzofuran-6-sulfamide 19 Compound 19c (194 mg, 0.78 mmol), compound 1n (100 mg, 0.39 mmol), 3,5-dimethylpyridine (168 mg, 1.57 mmol), and dimethyl sulfoxide (2 mg, 0.03 mmol) were dissolved in acetonitrile (10 mL), and the reaction solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-aqueous phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 19 (50 mg, yield: 27.3%). MS m / z (ESI): 469.1 [M+1]. 1 H NMR (400 MHz, DMSO-d 6): δ 7.80 (s, 1H), 7.49-7.48 (m, 1H), 7.09-7.06 (m, 3H), 6.29-6.28 (m, 1H), 5.36 (s, 2H), 4.70-4.67 (m, 2H), 4.52-4.48 (m, 2H), 3.68 (s, 3H), 3.08-3.07 (m, 2H), 3.06-3.05(m, 2H).

[0314] Example 20 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxybenzenesulfamide 20 [ka] [ka] Compound 1n (100 mg, 0.39 mmol) and compound 3a (120 mg, 0.58 mmol) were dissolved in pyridine (5.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 20 (19 mg, yield: 11.4%). MS m / z (ESI): 427.1 [M+1]. 1 H NMR (500 MHz, CD 3 OD) δ7.91 (dd, 1H), 7.72 (d, 1H), 7.62-7.57 (m, 1H), 7.56 (d, 1H), 7.14 (d, 1H), 7.07 (t, 1H), 6.59 (s, 1H), 6.38 (t, 1H), 5.42 (s, 2H), 4.78 (t, 2H), 3.87 (s, 3H), 3.09 (t, 2H).

[0315] Example 21 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-4-methyl-2-(2,2,2-trifluoroethoxy)benzenesulfamide 21 [ka] [ka] Compound 8d (113 mg, 0.39 mmol) and compound 1n (50 mg, 0.20 mmol) were dissolved in pyridine (5.0 mL), 4-dimethylaminopyridine (5 mg, 0.04 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120 ° C. for 3 hours in a microwave. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 21 (35 mg, yield: 35.3%). MS m / z (ESI): 509.3 [M+1]. 1 H NMR (400 MHz, CDCl 3 ): δ 8.07-8.05 (d, 1H), 7.56-7.55 (d, 1H), 7.41-7.40 (d, 1H), 7.06-7.04 (d, 1H),6.78 (s, 1H), 6.64 (s, 1H), 6.33-6.32 (m, 1H), 5.33 (s, 2H), 4.82-4.78 (m, 2H), 4.52-4.48 (m, 2H), 3.08-3.04 (m, 2H),2.42 (s, 3H).

[0316] Example 22 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxy-4-methylbenzenesulfamide 22 [ka] [ka] 2-Methoxy-4-methylbenzenesulfonyl chloride 22a (78 mg, 35 mmol) and compound 1n (30 mg, 0.12 mmol) were dissolved in pyridine (5.0 mL), 4-dimethylaminopyridine (3 mg, 0.02 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120 °C in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high-performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-water phase (0.1% ammonia water): B-acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 22 (5 mg, yield: 9.7%). MS m / z (ESI): 441.5 [M+1]. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.82 (s, 1H), 7.62-7.60(m,1H), 7.50-7.49 (m, 1H), 6.99-6.97 (m, 1H), 6.84-6.82 (m, 1H), 6.65-6.63 (m, 1H), 6.30 (s, 1H),5.40 (s, 2H), 4.73-4.69 (m, 2H), 3.76 (s, 3H), 3.11-3.08 (m, 2H),2.35 (s, 3H).

[0317] Example 23 N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxy-6-(trifluoromethoxy)benzenesulfamide 23 [ka] [ka] Compound 1n (80 mg, 0.31 mmol) and compound 10b (185 mg, 0.63 mmol) were dissolved in acetonitrile (3 mL), dimethyl sulfoxide (3 mg, 0.04 mmol) and 3,5-dimethylpyridine (135 mg, 1.26 mmol) were added, and the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30 × 150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 20% to 40% (10 min), flow rate: 30 mL / min), and the title product 23 (16 mg, yield: 10.0%) was obtained. MS m / z (ESI): 511.0 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.79 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.10 (s, 2H), 6.86 (s, 1H), 6.37 (s, 1H), 6.29 (m, 1H), 5.34 (s, 2H), 4.65 (t, 2H), 3.68 (s, 3H), 3.05 (t, 2H).

[0318] Example 24 2,6-Dimethoxy-N-(4-(pyridin-2-ylmethyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)benzenesulfamide 24 [ka] [ka]

[0319] Step 1 4-Bromo-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-amine 24a Compound 1i (2.3 g, 9.59 mmol) and acetohydroxamic acid (2.2 g, 28.85 mmol) were dissolved in a mixture of N,N-dimethylformamide (25 mL) and water (2.5 mL), and potassium carbonate (7.9 g, 57.54 mmol) was added. The reaction solution was stirred at 65° C. for 16 hours. The reaction solution was filtered to obtain the title product 24a (1.7 g, yield: 67.5%). MS m / z (ESI): 255.0 [M+1].

[0320] Step 2 N-(4-bromo-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 24b Compound 24a (300 mg, 1.18 mmol) and compound 1o (835 mg, 3.53 mmol) were dissolved in pyridine (8 mL), 4-dimethylaminopyridine (29 mg, 0.24 mmol) was added, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was reacted at 120°C in a microwave for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Welch Xtimate C18 5 μm 30 × 150 mm, mobile phase: A-water phase (0.1% formic acid): B-acetonitrile = 30% to 45% (15 min), flow rate: 30 mL / min) to obtain the title product 24b (130 mg, yield: 24.3%). MS m / z (ESI): 455.1 [M+1].

[0321] Step 3 (±)-N-(4-(hydroxy(pyridin-2-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 24c Compound 24b (30 mg, 0.065 mmol) was dissolved in tetrahydrofuran (5 mL), and n-butyllithium (0.06 mL, 0.16 mmol, 2.5 M tetrahydrofuran solution) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. Pyridine-2-formaldehyde (9 mg, 0.084 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Saturated ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 24c (5 mg, yield: 15.7%). MS m / z (ESI): 484.3 [M+1].

[0322] Step 4 (±)-N-(4-(chloro(pyridin-2-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2,6-dimethoxybenzenesulfamide 24d Compound 24c (5 mg, 0.01 mmol) was added to dichloromethane (5 mL), thionyl chloride (13 mg, 0.1 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 24d (5 mg, yield: 96.3%). MS m / z (ESI): 502.3 [M+1].

[0323] Step 5 2,6-Dimethoxy-N-(4-(pyridin-2-ylmethyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)benzenesulfamide 24 Compound 24d (5 mg, 0.01 mmol) was added to acetic acid (1 mL), zinc powder (1 mg, 0.015 mmol) was added, and the mixture was reacted at 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A-aqueous phase (0.1% ammonia water): B-acetonitrile = 5% ~ 45% (20 min), flow rate: 30 mL / min) to obtain the title product 24 (2.5 mg, yield: 53.7%). MS m / z (ESI): 468.4 [M + 1]. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.49-8.48 (m, 1H), 7.80-7.77(m,2H), 7.42 (s, 1H), 7.32-7.28 (m, 2H), 6.72-6.71 (m, 2H), 4.77-4.76 (m, 2H),4.60 (s, 3H), 4.20 (s, 2H), 3.78 (s, 3H), 3.13-3.10 (m, 2H).

[0324] Example 25 N-(4-(furan-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxybenzenesulfamide 25 [ka] [ka]

[0325] Step 1 4-(4,5-Dihydrofuran-2-yl)-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile 25b Compound 1i (300 mg, 1.24 mmol) and 2,3-dihydrofuran 25a (435 mg, 6.20 mmol) were dissolved in N,N-dimethylformamide (10 mL), purged with nitrogen gas three times, and palladium acetate (28 mg, 0.12 mmol), triphenylphosphine (65 mg, 0.24 mmol) and potassium carbonate (345 mg, 2.49 mmol) were added, and the reaction solution was reacted at 110° C. for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using eluent system A to give the title product 25b (100 mg, yield: 34.9%). MS m / z (ESI): 232.0 [M+1].

[0326] Step 2 4-(Furan-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-amine 25c Compound 25b (100 mg, 0.43 mmol) and acetohydroxamic acid (100 mg, 1.33 mmol) were dissolved in 4 mL of a mixed solvent of N,N-dimethylformamide and water (V:V=7:1), and potassium carbonate (360 mg, 2.60 mmol) was added. The reaction solution was stirred at 70° C. for 30 minutes. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using eluent system A to give the title product 25c (22 mg, yield: 21.0%). MS m / z (ESI): 243.0 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.56 (dd, 1H), 7.27 (s, 1H), 6.69 (dd, 1H), 6.56 (dd, 1H), 4.86 (t, 2H), 4.52 (s, 2H), 3.49 (t, 2H).

[0327] Step 3 N-(4-(furan-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-2-methoxybenzenesulfamide 25 Compound 25c (22 mg, 0.09 mmol) and compound 3a (95 mg, 0.46 mmol) were dissolved in pyridine (1.0 mL) and purged with nitrogen gas three times. The reaction solution was reacted at 120° C. in a microwave for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (welch Prep C18 5 μm 30×150 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 25% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 25 (5 mg, yield: 13.3%). MS m / z (ESI): 413.0 [M+1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 7.88 (s, 1H), 7.78 (dd, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 6.70 (dd, 1H), 4.79 (t, 2H), 3.79 (s, 3H), 3.44 (t, 2H).

[0328] Example 26 2,6-Dimethoxy-N-(4-(tetrahydrofuran-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)benzenesulfamide 26 [ka] [ka] Compound 24b (500 mg, 1.09 mmol) and compound 25a (430 mg, 6.13 mmol) were dissolved in N,N-dimethylformamide (10 mL), purged with nitrogen gas three times, palladium acetate (30 mg, 0.13 mmol), triphenylphosphine (60 mg, 0.22 mmol) and potassium carbonate (320 mg, 2.31 mmol) were added, and the reaction solution was reacted at 110° C. for 16 hours. The reaction solution was cooled to room temperature, purged with hydrogen gas three times, and continued to react at room temperature for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Sharpsil-T Prep C18 8 μm 50 × 250 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 18% to 38% (20 min), flow rate: 80 mL / min) to obtain the title product 26 (203 mg, yield: 41.4%). MS m / z (ESI): 447.0 [M+1]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.40 (t, 1H), 6.99 (s, 1H), 6.61 (d, 2H), 4.94 (t, 1H), 4.90-4.78 (m, 2H), 4.12 (dt, 1H), 3.96 (dt, 1H), 3.93 (s, 6H), 3.25 (t, 2H), 2.36 (dq, 1H), 2.09-1.99 (m, 2H), 1.76 (dq, 1H).

[0329] Example 26-1 and Example 26-2 (R)-2,6-Dimethoxy-N-(4-(tetrahydrofuran-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)benzenesulfamide 26-1 (S)-2,6-Dimethoxy-N-(4-(tetrahydrofuran-2-yl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)benzenesulfamide 26-2 [ka] [ka] Compound 26 (203 mg, 0.45 mmol) was subjected to chiral separation (separation conditions: CHIRALPAK IE chiral separation column, 20 × 250 mm, mobile phase: n-hexane / ethanol / trifluoroacetic acid = 60 / 40 / 0.1 (V / V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title products 26-1 (60 mg) and 26-2 (56 mg), respectively.

[0330] 26-1 (relatively long retention time, 60 mg): MS m / z (ESI): 447.0 [M+1]. Chiral HPLC analysis: retention time 36.6 min, chiral purity: 100% (column: CHIRALPAK IE, 20 × 250 mm, 5 μm, mobile phase: n-hexane / ethanol / trifluoroacetic acid = 60 / 40 / 0.1 (V / V / V)). 1 H NMR (500 MHz, CDCl 3 ) δ 7.40 (t, 1H), 6.99 (s, 1H), 6.61 (d, 2H), 4.94 (t, 1H), 4.90-4.78 (m, 2H), 4.12 (dt, 1H), 3.96 (dt, 1H), 3.93 (s, 6H), 3.25 (t, 2H), 2.36 (dq, 1H), 2.09-1.99 (m, 2H), 1.76 (dq, 1H).

[0331] 26-2 (relatively short retention time, 56 mg): MS m / z (ESI): 447.0 [M+1]. Chiral HPLC analysis: retention time 26.3 min, chiral purity: 100% (column: CHIRALPAK IE, 20 × 250 mm, 5 μm, mobile phase: n-hexane / ethanol / trifluoroacetic acid = 60 / 40 / 0.1 (V / V / V). 1 H NMR (500 MHz, CDCl 3) δ 7.40 (t, 1H), 6.99 (s, 1H), 6.61 (d, 2H), 4.94 (t, 1H), 4.90-4.78 (m, 2H), 4.12 (dt, 1H), 3.96 (dt, 1H), 3.93 (s, 6H), 3.25 (t, 2H), 2.36 (dq, 1H), 2.09-1.99 (m, 2H), 1.76 (dq, 1H).

[0332] Biological evaluation The present disclosure will be further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0333] Test Example 1 KAT6 enzyme activity assay (AlphaScreen method) 1. Reagents and equipment 1.KAT6A (Chempartner customization) 2. Ovalbumin (Sigma-Aldrich, A5378-5G) 3.2 M Tris-HCl solution, pH 7.8, sterile (Seiko B548140-0500) 4.5 M NaCl solution (Seiko, B548121-0100) 5.EDTA (0.5 M), pH8.0, RNase-free (Thermofisher, AM9260G) 6.Tween-20 (raw material, A100777-0500) 7.DTT, 1M (Invitrogen, P2325) 8. Acetyl coenzyme A (Ac-CoA, CAYMAN, Cat. No. 16160) 9. Recombinant Histone H3.1 biotinylated(Human) (Active Motif 31696) 10. 384-well plate, light gray (Perkin Elmer, Cat. No. 6005350) 11. Anacardic acid (MCE, Cat. No. HY-N2020) 12. AlphaScreen Streptavidin Donor beads, 5 mg (PerkinElmer, 6760002) 13. AlphaScreen Protein A Acceptor beads, 5 mg (PerkinElmer, 6760137M) 14. Acetylated-Lysine Antibody (#9441) (CST 9441S) 15. PHERA star plate reader (BMG labtech)

[0334] II. Experimental Method 1. Preparation of Reagents a. 1x Detection Buffer: 100 mM Tris-HCL, pH 7.8, 15 mM NaCl, 1 mM EDTA, 0.01% Tween-20, 1 mM DTT, 0.01% m / v ovalbumin. b. KAT enzyme solution: final concentration 1.25 nM prepared in 1× detection buffer. c. Mixed substrate of Ac-CoA and H3: Mixed substrate of Ac-CoA at a final concentration of 1000 nM and H3 at a final concentration of 55 nM prepared in 1× detection buffer. d. Compounds: initial concentration 100 μM, 3-fold dilutions, 10-fold concentration gradient. All compounds were diluted 83-fold in 1× detection buffer and ready for use. e. Detection Reagents: AlphaScreen Protein A Acceptor Beads (final concentration 8 ng / μL), AlphaScreen Streptavidin Donor Beads (final concentration 8 ng / μL), Acetylated Lysine Antibody (final concentration 1:1500), and 100 μM Anacardic Acid prepared in 1× Detection Buffer.

[0335] 2. Experimental Procedure a. Add 3 μL of prepared enzyme solution to each well of a 384-well plate, and add 3 μL of 1× detection buffer to wells in columns 23 and 24 (Min). b. 3 μL of compound solution was added to each well, 3 μL of buffer was added to each well of Min, and 3 μL of DMSO solution was added to each well of 1st and 2nd row (Max) as a control. Centrifugation was performed, and the wells were mixed uniformly and shaken for 2 minutes, and incubated at room temperature for 15 minutes. c. 6 μL of mixed substrate of Ac-CoA and H3 was added to each well, centrifuged, mixed evenly, shaken for 2 min, and incubated at room temperature for 20 min. d. 6 μL of detection reagent was added to each well, centrifuged, mixed evenly, shaken for 2 minutes, and incubated at room temperature in the dark for 120 minutes. e. The plate was read using a plate reader and the AlphaScreen counts were recorded. f. Plot using Graphpad software and compound IC 50 The value was calculated.

[0336] Table 1. IC of inhibition of human KAT6A enzyme for compounds according to the present disclosure 50 value [Table 11] Conclusion: The compounds disclosed herein have excellent inhibitory activity against KAT6A.

[0337] Test Example 2: Detection of KAT6B enzyme activity (AlphaScreen method) 1. Reagents and equipment 1. KAT6B(718-1008)(ActiveMotif, 81224) 2. Bovine serum albumin (Seiko, A500023-0100) 3. 2 M Tris-HCl solution, pH 7.8, sterile (Seiko B548140-0500) 4. EDTA (0.5 M), pH8.0, RNase-free (Thermofisher, AM9260G) 5. Tween-20 (raw material, A100777-0500) 6. DTT, 1M (Invitrogen, P2325) 7. Acetyl coenzyme A (Ac-CoA, CAYMAN, Cat. No. 16160) 8. Recombinant histone H3.1 (human) labeled with biotin (Active Motif 31696) 9. 384-well plate, light gray (Perkin Elmer, Cat. No. 6007290) 10. Anacardic acid (MCE, Cat. No. HY-N2020) 11. AlphaScreen Streptavidin Donor Beads 5 mg (PerkinElmer, 6760002) 12. AlphaScreen Protein A Acceptor Beads, 5 mg (PerkinElmer, 6760137M) 13. Acetylated Lysine Antibody #9441 (CST 9441S) 14. DMSO (Tansoole, G7592B) 15. PHERA star plate reader (BMG labtech)

[0338] II. Experimental Method 1. Preparation of Reagents a. 1x Buffer 2: 50 mM Tris-HCl, pH 7.8, 0.1 mM EDTA, 0.01% v / v Tween-20, 1 mM DTT, 0.01% m / v bovine serum albumin. b. KAT6B enzyme solution: Prepared in buffer 2, final concentration 3 nM c. Mixed substrate of Ac-CoA and H3: Mixed substrate of Ac-CoA (final concentration: 30 nM) and H3 (final concentration: 30 nM) prepared in buffer 2. d. Compounds: initial concentration 10 mM, 4-fold dilution, 10-fold concentration gradient. All compounds were diluted 2500-fold with buffer 2 and ready for use. e. Detection Reagents: AlphaScreen Protein A Acceptor Beads (final concentration 8 ng / μL), AlphaScreen Streptavidin Donor Beads (final concentration 8 ng / μL), Acetylated Lysine Antibody (final concentration 1:1000), and 100 μM Anacardic Acid prepared in Buffer 2.

[0339] 2. Experimental Procedure a. 2 μL of the prepared compound solution was added to each well of a 384-well plate, and 2 μL of buffer 2 (containing 0.04% DMSO) was added to each well of Min and Max as a control, followed by centrifugation. b. Add 2 μL of prepared enzyme solution to each well, and add 2 μL of buffer 2 to Min. Centrifuge, mix evenly, shake for 2 minutes, and incubate at room temperature for 10 minutes. c. 4 μL of mixed substrate of Ac-CoA and H3 was added to each well, centrifuged, mixed uniformly, shaken for 2 min, and incubated at room temperature for 120 min. d. 4 μL of detection reagent was added to each well, centrifuged, mixed evenly, shaken for 2 minutes, and incubated at room temperature in the dark for 120 minutes. e. The plate was read using a plate reader and the AlphaScreen counts were recorded. f. Using the log(inhibitor) vs. response software in GraphPad Prism, plot a dose-response curve with the compound concentration logarithm on the horizontal axis and the enzyme activity inhibition rate calculated on the vertical axis to obtain the IC 50 was calculated.

[0340] [Table 12] Conclusion: The compounds disclosed herein have excellent inhibitory activity against KAT6B.

[0341] Test Example 3 U2OS cell H3K23 acetylation IF assay (Immunofluorescence) 1. Reagents and equipment 1. U-2 OS (ATCC HTB-96) 2. Recombinant Anti-Histone H3(acetyl K23) antibody (Abcam, ab177275) 3. Goat anti-Rabbit IgG(H+L), Superclonal® Recombinant Secondary Antibody, Alexa Fluor 488 (Thermofisher, A27034) 4.Hoechst 33342 (Sigma-Aldrich, B2261-25MG) 5. Assay plate, 96 well, Black with clear bottom (Corning, 3603) 6. Bovine serum albumin (BSA) (Sangon Biotech, A500023-0100) 7. Methanol (GENERAL-REAGENT, G75851D) 8.Tween-20 (raw material, A100777-0500) 9.Triton X-100 (Solarbio, T8200) 10.PBS (Shanghai Yuanpei Biological Technology Co., Ltd., B320KJ) 11.20X PBS buffer (Sangon Biotech, B548117-0500) 12.McCoy's 5A medium (Gibco, 16600082) 13. 0.25% Trypsin-EDTA (1x) (Gibco, 25200-072) 14.Pen strep (Gibco, 15140-122) 15. DPBS (1x) (Gibco, 14190-144) 16.FBS (Gibco, 10091148) 17. Automated cell counter (Countstar, IC1000) 18. Constant temperature incubator (Thermo, I160) 19. ImageXpress® Micro Confocal (Molecular Device)

[0342] II. Experimental Method 1. Preparation of Reagents a. Blocking buffer: PBS (Shanghai Yuan Culture Medium) + BSA (final concentration 1%) + Triton X-100 (final concentration 0.5%). b. Washing buffer: PBS (20x PBS diluted in 1x PBS) + Tween-20 (final concentration 0.1%). c. Primary antibody solution: Recombinant anti-histone H3 (acetyl group K23) antibody was diluted in blocking buffer at a dilution ratio of 1:1000. d. Secondary antibody solution: Goat anti-rabbit IgG (H+L), Superclonal® recombinant secondary antibody, Alexa Fluor 488 at a dilution ratio of 1:1000, Hoechst 33342 at a dilution ratio of 1:5000, diluted in blocking buffer. e. Compounds: initial concentration 100 μM, 3-fold dilutions, 9 concentration gradients. All compounds were diluted 500-fold in McCoy's 5A medium and ready for use.

[0343] 2. Experimental Procedure 2.1 Treatment of cells (day 1) a. Observe the state of U-2 OS cells under a microscope to ensure that the cell confluence was about 90%. b. The supernatant of the cells was removed, the cells were rinsed once with DPBS, and the DPBS was discarded. An appropriate amount of trypsin was added to digest the cells, and the cells were left to stand at room temperature or 37°C for 5 minutes. c. The digestion was stopped by adding an equal volume of medium containing 10% FBS, and the cell suspension was collected and centrifuged at 300 g for 3 minutes. The cells were suspended in an appropriate amount of fresh medium. d. The resuspended cell suspension was taken and counted. e. The cell suspension was diluted and plated at 9000 cells / 50 μL / well. f. The surrounding wells were blocked with 100 μL of PBS. g. The cell culture plate was placed in a 37°C, 5% carbon dioxide incubator and cultured overnight. 2.2 Drug intake (2nd day) a. 50 μL of compound diluted in 50 μL / well of cell supernatant was added to each cell plate. b. The drug-added cell plates were placed in a 37°C, 5% carbon dioxide incubator and cultured for 24 hours. 2.3 Immunofluorescence staining and detection (Days 3-4) a. The cell plate cultured in the incubator for 24 hours was taken out, the medium was removed, and pre-chilled methanol was added to fix the cells at room temperature for 10 minutes. b. Remove fixative and wash 3 times with fast wash buffer followed by 3 times with slow wash (5 min each time). c. The washing buffer was removed and blocking buffer was added and incubated at room temperature for 60 minutes. d. The blocking buffer was removed, and the prepared primary antibody solution was added and incubated at 4°C overnight. e. The primary antibody was removed and the prepared secondary antibody was added and incubated at room temperature for 60 minutes. f. Remove the secondary antibody solution and wash with wash buffer 3 times at high speed followed by 5 times at low speed (5 min each time). g. Detection was performed by ImageXpress® Micro Confocal. h. Based on the data of the average fluorescence intensity of each cell, the IC of the compound was plotted using Graphpad software. 50 The value and Imax% were calculated.

[0344] Table 3. IC of compounds disclosed herein for inhibition of H3K23 acetylation 50 Value and maximum inhibition rate [Table 13] Conclusion: The compounds disclosed herein have excellent inhibitory effects on H3K23 acetylation.

[0345] Test Example 4 ZR-75-1 proliferation experiment 1. Reagents and Equipment 1. ZR-75-1 (ATCC CRL1500) 2.1640 medium (Gibco, 22400-089) 3. 0.25% Trypsin-EDTA (1x) (Gibco, 25200-072) 4. Penicillin-streptomycin (Gibco, 15140-122) 5.DPBS(1×)(Gibco, 14190-144) 6.FBS (Gibco, 10091148) 7. 96-well bottom clear black detection plate (Corning, 3603) 8. 96 well non-treated round bottom formulation plate (JET BIOFIL, TCP-002-096) 9.CellTiter-Glo buffer (Promega, G756B) 10.CellTiter-Glo substrate (Promega, G755B) 11. Automated cell counter (Countstar, IC1000) 12. Constant temperature incubator (Thermo, I160) 13.PHERAstar FS(BMG labtech, PHERAstar FS)

[0346] II. Experimental Method 1. Seeding cells onto plates (Day 0) a. Observe the cells under a microscope to ensure that the cell fusion rate is about 90%. b. The supernatant of the cells was removed, the cells were rinsed once with DPBS, and the DPBS was discarded. An appropriate amount of trypsin was added to digest the cells, and the cells were incubated at 37°C for 5 minutes. c. The digestion was stopped by adding an equal volume of 1640 medium containing 10% FBS, and the cell suspension was collected. It was centrifuged at 300 g for 3 minutes. The cells were suspended in an appropriate amount of fresh medium. d. The resuspended cell suspension was taken and counted. e. 5 × 10 cell suspension in 1640 medium containing 10% FBS. 4 / mL, 50 μL / well. ZR-75-1 is 2500 cells / well. f. The cell culture plate was placed in a 37°C, 5% carbon dioxide incubator and cultured overnight.

[0347] 2. Drug intake (Day 1) a. Each compound was diluted in DMSO to nine concentration points (initial concentration 100 μM, 3-fold dilution, different compounds were diluted to the highest concentration IC 50 For example, in a 96-well round-bottom formulation plate, 3 μL of compound was gradient-diluted into 6 μL of DMSO. b. Each concentration point of each compound was diluted 500-fold into the corresponding volume of 1640 medium. c. 50 μL / well of cell supernatant in each cell plate was added in turn with 50 μL of the diluted compound solution. d. The drug-added cell plates were placed in a 37°C, 5% carbon dioxide incubator and cultured.

[0348] 3. Digestion again, plating again, and drug addition (Day 7) a. Six days after drug addition, the drug-containing medium was removed and 150 μL / well of DPBS was added to rinse once, and the DPBS was immediately aspirated off. b. Cells were digested by adding 50 μL of trypsin, incubated at 37° C. for 3 min, and digestion was stopped by adding 150 μL / well of 1640 medium containing 10% FBS. c. The cells were pipetted with a multichannel pipette to mix evenly and re-plated at a ratio of 1:8, i.e., 25 μL of the cell suspension was aspirated and placed into a new 96-well plate (the new plate had previously been supplemented with 25 μL of 1640 medium containing 10% FBS). d. Compound preparation and drug addition were performed at 50 μL / well according to steps a.-c. in 2. e. The drug-added cell plates were placed in a 37°C, 5% carbon dioxide incubator and cultured.

[0349] 4. CTG assay (day 14) a. Before use, leave the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to equilibrate to room temperature, then mix the two thoroughly to homogenize to prepare 100 mL of CellTiter-Glo reagent (or remove the premixed CellTiter-Glo reagent from -20°C and equilibrate to room temperature). b. Plates awaiting detection were removed from the incubator, equilibrated to room temperature, and 50 μL of CellTiter-Glo reagent was added to each well. c. The cells were thoroughly lysed by mixing uniformly with shaking for 2 minutes. d. After leaving the plate at room temperature for 28 minutes, the signal was stabilized and detected using a PHERAstar FS.

[0350] Table 4. IC of compounds disclosed herein inhibiting ZR-75-1 proliferation 50 Value and maximum inhibition rate [Table 14] Conclusion: The compounds disclosed herein have excellent inhibitory effects on the proliferation of ZR-75-1.

[0351] Test Example 5 Pharmacokinetic evaluation 1. SD rat test 1. Summary Using SD rats as test animals, the plasma drug concentrations of the compounds of the present disclosure at different time points after intragastric administration (ig) were measured by LC / MS / MS. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied, and their pharmacokinetic characteristics were evaluated.

[0352] 2. Test plan 2.1 Study Drugs They were Compound 2, Compound 7, Compound 21 and Compound 23. 2.2 Test animals Sixteen SD rats, half male and half female, provided by Weitong Lihua Laboratory Animal Technology Co., Ltd. were divided into four groups. After fasting overnight, the rats were intragastrically administered the test compound. 2.3 Preparation of drugs A certain amount of each test compound was weighed out, and 5% DMSO+5% Tween 80+90% physiological saline was added to prepare a 0.2 mg / mL colorless, transparent solution. 2.4 Administration The dose was 2.0 mg / kg and the administration volume was 10.0 mL / kg.

[0353] 3.Operation Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C for measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. The animals were fed for 2 hours after administration. The content of compounds to be measured in the plasma of SD rats after administration of various concentrations of drugs was measured as follows: 25 μL of plasma samples of SD rats at each time point after administration were taken, and 25 μL of camptothecin (internal standard of compound 2, 100 ng / mL) or 50 μL of tolbutamide (internal standard of compound 7, 100 ng / mL) or 50 μL of verapamil (internal standard of compounds 21 and 23, 100 ng / mL) were added to each sample, and the proteins were precipitated with 200 μL of acetonitrile, mixed by vortex for 5 minutes, and centrifuged at 3700 rpm for 10 minutes. 120 μL of the supernatant was taken, 30 μL of water was added, mixed by vortex for 5 minutes, and 5 μL was injected for LC / MS / MS analysis.

[0354] 4. Pharmacokinetic parameters

[0355] Table 5. Pharmacokinetic parameters of compounds according to the present disclosure [Table 15] Conclusion: The compound according to the present disclosure has high blood drug concentrations, high exposure, low clearance, and pharmacokinetic advantages in SD rats.

[0356] II. C57 Mouse Test 1. Summary C57 mice were used as test animals, and the plasma drug concentrations of the compounds according to the present disclosure were measured at different times after intragastric (ig) / intravenous injection (iv) administration in C57 mice by LC / MS / MS. The pharmacokinetic behavior of the compounds according to the present disclosure in C57 mice was studied, and their pharmacokinetic characteristics were evaluated.

[0357] 2. Test plan 2.1 Study Drugs These were compound 2 and compound 3. 2.2 Test animals Thirty-six C57 rats, half male and half female, provided by Weitong Lihua Laboratory Animal Technology Co., Ltd., were equally divided into four groups, nine rats per group, with three rats per time point, and administered intragastric and intravenous injections, respectively. 2.3 Preparation of drugs A fixed amount of each test compound was weighed out, and 5% DMSO + 5% Tween 80 + 90% saline was added to prepare a 0.1 mg / mL colorless and transparent solution (intragastric administration group) and a 0.1 mg / mL colorless and transparent solution (intravenous administration group). 2.4 Administration Intragastric administration group: the dose was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g. Intravenous injection group: the dose was 1.0 mg / kg, and the administration volume was 0.1 mL / 10 g.

[0358] 3.Operation Intragastric administration group: 0.1 mL of blood was collected before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -80°C for measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. Intravenous injection group: Blood samples were taken before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours, and treated in the same manner as for the intragastric administration group. The content of compounds to be measured in plasma of C57 rats after administration of various concentrations of drugs was measured as follows: 25 μL of plasma samples of C57 rats at each time point after administration were taken, and 50 μL of diclofenac (internal standard of compound 2, 100 ng / mL) or 25 μL of tolbutamide (internal standard of compound 3, 10 μg / mL, purchased from LGC, UK) were added to each sample, and the proteins were precipitated with 200 μL of acetonitrile, mixed by vortex for 5 minutes, and centrifuged at 3700 rpm for 10 minutes. 120 μL of the supernatant was taken, 30 μL of water was added, mixed by vortex for 5 minutes, and 5 μL was injected for LC / MS / MS analysis.

[0359] 4. Pharmacokinetic parameters Table 6. Pharmacokinetic parameters of compounds according to the present disclosure [Table 16] Conclusion: The compounds disclosed herein have high blood drug concentrations, high exposure, low clearance, and relatively long half-life in C57 rats, and thus have pharmacokinetic advantages.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is a cycloalkyl group or a heterocyclyl group; L is a chemical bond, an alkylene group, or a heteroalkylene group, wherein the alkylene group or heteroalkylene group is each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, or a haloalkoxy group; Each R １ , each R ２ , R ３ are the same or different and each independently represent a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR ５ , -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NHC(O)OR ６ , -NR ７ R ８ , —C(O)NR ７ R ８ , -S(O) ｒ R ６ or -S(O) ｒ NR ７ R ８ wherein the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from hydroxy group, halogen, cyano group, amino group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group and heterocyclyloxy group; R ４ is a hydrogen atom or 【Chemistry 2】 and Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R ０ is selected from a hydrogen atom, a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, or a cycloalkyl group; Each R ４ａ are the same or different and each independently represent a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, or —NR ９ R １０ Selected from R ５ , R ６ are the same or different and each independently selected from a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group, or heterocyclyloxy group; R ７ , R ８ , R ９ , and R １０ are the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R ７ and R ８ form a heterocyclyl group together with the N atom to which it is linked, or R ９ and R １０ form a heterocyclyl group together with the N atom to which it is linked, and the heterocyclyl group is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, amino, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, and heterocyclyloxy groups; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4, and r is 0, 1 or 2; A compound represented by the general formula (I) or a medicamentable salt thereof:

2. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is selected from a cycloalkyl group or a heterocyclyl group; L is a chemical bond, an alkylene group, or a heteroalkylene group, wherein the alkylene group or heteroalkylene group is each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, or a haloalkoxy group; Each R １ , each R ２ , R ３ are the same or different and each independently represent a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -OR ５ , -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NHC(O)OR ６ , -NR ７ R ８ , —C(O)NR ７ R ８ , -S(O) ｒ R ６ or -S(O) ｒ NR ７ R ８ wherein the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from hydroxy group, halogen, cyano group, amino group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group and heterocyclyloxy group; R ４ is a hydrogen atom or 【Chemistry 2】 and Ring C is an aryl group or a heteroaryl group; R ０ is selected from a hydrogen atom, a hydroxy group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, or a cycloalkyl group; Each R ４ａ are the same or different and independently represent a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, or —NR ９ R １０ Selected from R ５ , R ６ are the same or different and each independently selected from a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, cycloalkyloxy group, or heterocyclyloxy group; R ７ , R ８ , R ９ , and R １０ are the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a hydroxy group, a halogen atom, a cyano group, an amino group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R ７ and R ８ form a heterocyclyl group together with the N atom to which it is linked, or R ９ and R １０ form a heterocyclyl group together with the N atom to which it is linked, and the heterocyclyl group is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, amino, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, and heterocyclyloxy groups; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4, and r is 0, 1 or 2; A compound represented by the general formula (I) or a medicamentable salt thereof:

3. R ３ is a hydrogen atom, 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

4. R ４ but 【Chemistry 3】 wherein ring C is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group, and R ４ａ and n is as defined in claim 1; 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

5. A compound represented by general formula (II) or a medicamentable salt thereof, 【Chemistry 4】 Among them, Ring C is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group; Ring A, Ring B, L, R １ , R ２ , R ４ａ , p, q and n are as defined in claim 1; 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

6. Ring A is a 6- to 10-membered aryl group, preferably a phenyl group; 【Chemistry 5】 and more preferably, ring A is phenyl.

3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

7. Ring B is a 4- to 7-membered heterocyclyl group; 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

8. A compound represented by general formula (III) or a medicamentable salt thereof, 【Chemistry 6】 Among them, X is O, CR ａ R ｂ or C═O, Each R ａ , R ｂ , R ｃ and R ｄ are the same or different and independently selected from a hydrogen atom, a hydroxy group, a halogen, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkyloxy group, or a heterocyclyloxy group; Or, R ｃ , R ｄ forms one C═O together with the carbon atom to which it is attached, s is 0, 1, 2 or 3; L, R １ , R ４ａ , p and n are as defined in claim 2; 3. A compound of formula (I) according to claim 2 or a medicamentable salt thereof.

9. R ｃ and R ｄ are the same or different and each independently represent a hydrogen atom or a halogen, and / or X represents O or CH ２ and / or s is 1 or 2; 9. A compound of formula (I) according to claim 8 or a medicamentable salt thereof.

10. Each R １ are the same or different and independently represent a hydrogen atom, a hydroxy group, a halogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Alkoxy C １－６ Alkyl group, —C(O)OCH ３ or -NR ７ R ８ Selected from R ７ and R ８ are the same or different and each independently represent a hydrogen atom or C １－６ is an alkyl group, and preferably, each R １ are the same or different and independently represent a hydrogen atom, a halogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ haloalkoxy group or —NR ７ R ８ Selected from R ７ and R ８ are the same or different and each independently represent a hydrogen atom or C １－６ is an alkyl group, and more preferably, each R １ are the same or different and independently C １－６ is an alkoxy group, 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

11. Each R ２ are the same or different and independently represent a hydrogen atom, a halogen, C １－６ Alkyl group or C １－６ is selected from alkoxy groups, preferably a hydrogen atom or a halogen atom, and more preferably R ２ is a hydrogen atom, 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

12. Each R ４ａ are the same or different and independently represent a hydrogen atom, a hydroxy group, a halogen, C １－６ Alkyl group, C １－６ Hydroxyalkyl group or C １－６ alkoxy groups, preferably hydrogen atoms; 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

13. L is a chemical bond or -CH ２ -, preferably a chemical bond; 3. A compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof.

14. The following compound: 【Chemistry 7】 【Chemistry 8】 3. The compound of formula (I) according to claim 1 or 2, or a medicamentable salt thereof, selected from the group consisting of:

15. A compound represented by general formula (IA) or a salt thereof, 【Chemistry 9】 Among them, Ring B, R ２ , R ３ , R ４ and q are as defined in claim 1; A compound represented by the general formula (IA) or a salt thereof:

16. The following compound or a salt thereof: 【Chemistry 10】 Selected from the group consisting of: A compound or a salt thereof.

17. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising: 【Chemistry 11】 The method comprises the step of reacting a compound represented by general formula (IA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, Among them, Ring A, Ring B, L, R １ ~R ４ , p and q are as defined in claim 1; method.

18. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions.

19. A compound represented by general formula (I) or a medicinal salt thereof according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 18, for use in inhibiting KAT, wherein the KAT is preferably KAT6, more preferably KAT6A and / or KAT6B.

20. A compound of general formula (I) according to any one of claims 1 to 14 or a medicamentable salt thereof, or a pharmaceutical composition according to claim 18, for use in treating and / or preventing cancer, wherein the cancer is preferably lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, colorectal cancer, small intestine cancer, stomach cancer, thyroid cancer, or parathyroid cancer. , adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma or squamous cell carcinoma, more preferably breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer or leukemia, among which, breast cancer is selected from ER cancer, ＋ Breast cancer or ER ＋ / HER2 － The compound represented by formula (I) or a salt thereof, or a pharmaceutical composition, is preferably a breast cancer, among which the lung cancer is preferably a non-small cell lung cancer, among which the prostate cancer is preferably a castration-resistant prostate cancer.

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