Sulfamide derivatives, methods for preparing the same, and their pharmaceutical use

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] This disclosure belongs to the pharmaceutical field and relates to sulfamide derivatives, methods for preparing them, and their pharmaceutically acceptable uses. In particular, this disclosure relates to sulfamide derivatives represented by general formula (I), methods for preparing them, pharmaceutical compositions containing said derivatives, and their use as KAT inhibitors in the preparation of agents for treating and / or preventing cancer. [Background technology]

[0002] Lysine acetyltransferases (KATs) are a type of enzyme that can catalyze the transfer of acetyl groups from acetyl coenzyme A to lysine ε-amino groups 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 intracellular localization. KATs are divided into several subfamilies, one of which MYST (MOZ, YBF2 / SAS3, SAS2, TIP60) is the largest, and includes KAT5 (TIP60), KAT6A (MOZ, MYST3), KAT6B (MORF, MYST4), KAT7 (HBO, MYST2), and KAT8 (MOF, MYST1). KAT6A / B, as a major member of the MYST family, plays a crucial role in development, maintenance of stem cells in hematopoiesis and the immune system, and tumor formation, progression, and drug resistance.

[0003] Analysis of the TCGA database revealed that KAT6A and KAT6B are amplified in various tumors. Of these, KAT6A is located in the amplicon region of chromosome 8p11-p12, is amplified in 10-15% of breast cancers, and its copy number is positively correlated with mRNA expression and associated with poor healing. On the other hand, both KAT6A and KAT6B are significantly high in breast cancer. Further isoform analysis showed a correlation between high KAT6A / B expression and ERα expression levels, indicating that KAT6A / B are associated with ERα+ / HER2 - It has been revealed that it may be a potential target for breast cancer.

[0004] The literature has reported that knockdown of KAT6A in luminal breast cancer cells SUM-52, which amplify KAT6A, significantly inhibits clonal formation compared to non-tumor cells MCF10A. Furthermore, RNA-seq analysis showed that knockdown of KAT6A downregulates several genes, including those related to ESR1 and the hormonal stress pathway. Further research suggests that ER cells that highly express KAT6A may be affected. +In breast cancer cell lines T47D and CAMA1, knockdown of KAT6A inhibited clonal formation, but this was not the case in cell lines MCF7 and SKBR3, which exhibit low KAT6A expression. In T47D and CAMA1, knockdown of KAT6A downregulated ERα expression, while in MCF7 and LY2, overexpression of wild-type KAT6A upregulated Erα. However, mutants lacking KAT activity did not exhibit this effect, highlighting the importance of KAT function. In T47D, overexpression of Erα reversed the inhibitory effect on clonal formation caused by KAT6A knockdown, suggesting that KAT6A function may be mediated by the regulation of ERα expression. Similarly, enrichment of KAT6A was observed in the promoter region of the ESR1 gene. In vivo efficacy studies of the T47D model also showed tumor inhibition and downregulation of ERα by KAT6A knockdown. In T47D, knockdown of both KAT6A and KAT6B could downregulate ERα expression and inhibit clonal formation. Furthermore, KAT6A had a greater effect than KAT6B, and when both were knocked down simultaneously, the effect became more pronounced, and a synergistic effect was observed. CTx-648, a selective inhibitor of KAT6A / B, showed antitumor activity in ER+ breast cancer both in vitro and in vivo, and the expression level of KAT6A was correlated with the sensitivity to CTx-648. ER with high KAT6A expression + In breast cancer cells, CTx-648 can downregulate ERα expression, and H3K23Ac can function as a pharmacodynamic biomarker for KAT6 inhibitors. As mentioned above, KAT6A / B inhibitors can be used as monotherapy or in combination with ERα. + / HER2 - It is clinically worth developing this drug in combination with conventional breast cancer therapies, such as fulvestrant, CDK4 / 6 inhibitors, and even SERD and SERCA.

[0005] KAT6A / B inhibitors, ER + / HER2- In addition to breast cancer, it has potential prospects for use in any of the tumor types such as glioblastoma, B-cell lymphoma, liver cancer, ovarian cancer, etc., and the indication can be expanded.

[0006] Patent applications for the disclosed inhibitors of KAT6 include WO2016198507A1, WO2019243491A1, WO2019043139A1, WO2019108824A1, WO2020216701A1, WO2020002587A1, WO2020254946A1 and WO2020254989A1, etc.

Summary of the Invention

[0007] The present disclosure aims to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0008] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, Eventually, 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, where the alkylene group or heteroalkylene group is independently and optionally substituted with one or more substituents selected from a hydroxyl group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, or haloalkoxy group. Each R 1 , each R 2 , R 3 They are the same or different, and each is independently a hydrogen atom, halogen, cyano group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, 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 Selected from, of which the above alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from hydroxyl 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 or heterocyclyloxy group. R 4 is a hydrogen atom or [ka] And, The ring C is an aryl group or a heteroaryl group. R 0 This is selected from hydrogen atoms, hydroxyl groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, or cycloalkyl groups. Each R 4a These are identical or different, and each is independently a hydrogen atom, hydroxyl group, halogen, cyano 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, heterocyclyloxy group, or -NR 9 R 10 Selected from, R 5 , R 6These groups are identical or different, and each is 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, and among these, the alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are independently and optionally substituted with one or more substituents selected from a hydroxyl 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, or heterocyclyloxy group. R 7 , R 8 , R 9 , R 10 They are identical or different, and each is independently selected from a hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, of which the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are independently and optionally substituted with one or more substituents selected from a hydroxyl 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 or heterocyclyloxy group, Alternatively, R 7 and R 8 It forms a heterocycline group with the linked N atom, or R 9 and R 10forms a heterocyclyl group together with the N atom to be linked, and the heterocyclyl group is 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, 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, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 is 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 or a 3- to 8-membered cycloalkyl group, preferably, R 3 is a hydrogen atom.

[0010] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable 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-membered or 6-membered heteroaryl group, and most preferably, ring C is a pyrazolyl group. <​​In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable 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, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is

Chemical formula

[0013] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is

Chemical formula

[0014] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is

Chemical formula

[0015] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 0is selected from a hydrogen atom, a hydroxy group, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group or a 3- to 8-member cycloalkyl group, preferably, R 0 is selected from a hydrogen atom, a hydroxy group, a halogen and a C 1-6 alkyl group, preferably, R 0 is selected from a hydrogen atom, a hydroxy group or Cl, more preferably, R 0 is a hydrogen atom.

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

[0017] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is

Chemical formula

Chemical formula

Chemical formula

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

[0019] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, among which, R 4 is [Chemical formula] and Ring C is a 3- to 8-member heterocyclyl group or a 5- to 10-member heteroaryl group, preferably a 5- or 6-member heterocyclyl group, a 5- or 6-member heteroaryl group, R 4a and n are as defined in the general formula (I), Preferably, R 4 is [Chemical formula] and R 4a and n are as defined in the general formula (I), More preferably, R 4 is [Chemical formula] and R 4a and n are as defined in the general formula (I), Even more preferably, R 4 is ​​​​​​​More preferably, R 4 teeth [ka] That is the case.

[0020] In some embodiments of this disclosure, the compound represented by the above general formula (I) or a medicinal salt thereof is the compound represented by the general formula (Ii) or a medicinal salt thereof: [ka] Eventually, Ring C is a 3-8 membered heterocyclyl group or a 5-10 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 this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, among which R 4 teeth [ka] Preferably, R 4 teeth [ka] That is the case.

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

[0023] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-10 membered aryl group or a 5-10 membered heteroaryl group, preferably the 6-10 membered aryl group is a phenyl group, a naphthyl group, [ka] Selected from the group consisting of the above, preferably the 5-10 membered heteroaryl group is a pyridyl group, a quinolyl group, and a benzoxazolyl group.

[0024] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-10 membered aryl group, preferably a phenyl group. [ka] Selected from the group consisting of the following, it is a phenyl group, and more preferably a phenyl group.

[0025] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] Selected from the group consisting of, p1 is 0, 1, 2 or 3, R 1 p is defined as shown in general formula (I).

[0026] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] And R 1 p is defined as shown in general formula (I).

[0027] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a pharmaceutically acceptable 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 4-7 membered heterocyclyl group or a 4-7 membered cycloalkyl group. More preferably, ring B is a 4-7 membered heterocyclyl group. More preferably, ring B is a 4-7 membered heterocyclyl group, of which the above 4-7 membered heterocyclyl group contains 1-3 oxygen atoms. Most preferably, ring B is a 5-membered or 6-membered heterocyclyl group, of which the 5-membered or 6-membered heterocyclyl group contains one or two oxygen atoms.

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

[0029] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a medicinal salt thereof, wherein ring B is [ka] Selected from the group consisting of, preferably, ring B is [ka] Selected from the group consisting of, more preferably, ring B is [ka] And R 2 may be substituted at any substitutable position in ring B.

[0030] In some embodiments of this disclosure, a compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof: [ka] Eventually, X is O, CR a R b Or selected from C=O, Each R a , R b , R c and R d They are identical or different, and each is independently selected from a hydrogen atom, a hydroxyl 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. Alternatively, R c , R d It forms one C=O with the linked carbon atoms, 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 this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, of which each R c and Rd They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from a haloalkoxy group, a 3-8 member cycloalkyl group, a 3-8 member heterocyclyl group, a 3-8 member cycloalkyloxy group, or a 3-8 member heterocyclyloxy group, or R c , R d It forms one C=O with the linked carbon atoms, Preferably, each R c and R d They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, or R c , R d It forms one C=O with the linked carbon atoms, Comfortable, each R c and R d They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl or C 1-6 Selected from alkoxy groups, More preferably, each R c and R d They are identical or different, and each is independently a hydrogen atom or a halogen. More preferably, each R c and R d These are either the same or different, and each is independently a hydrogen atom or a fluorine atom. Most preferably, R c and R d These are all hydrogen atoms.

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

[0033] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is O or CR a R b And each R a and R b They are the same or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from a haloalkoxy group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group, a 3-8 membered cycloalkyloxy group, or a 3-8 membered heterocycloxy group, preferably each R a and R b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, more preferably each R a and R b They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl or C 1-6 Selected from alkoxy groups, most preferably R a and R b They are all hydrogen atoms.

[0034] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is O or CH2, preferably X is CH2.

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

[0036] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, among which R c and R d X is either the same or different, and each is independently a hydrogen atom or a halogen, and / or X is O or CH2, and / or s is 1 or 2.

[0037] In some embodiments of the present disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein X is O or CH2, and / or s is 1 or 2.

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

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

[0040] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl alkyl group, C1-6 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 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 This is as defined by general formula (I), and preferably each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, more preferably each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, most preferably R 1 This is a methoxy group.

[0041] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which each R 1 They are the same or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, and C 1-6 Alkyl 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, C1-6 Alkoxy C 1-6 Alkyl alkyl, -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 This is defined in general formula (I), Preferably, each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 alkyl groups, -C(O)OCH3, or -NR 7 R 8 Selected from, R 7 and R 8 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, More preferably, each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl 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 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, Comfortable, each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group.

[0042] Most preferably, each R 1 These are identical or different, and each is independently a methoxy group.

[0043] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which each R 1 They are the same or different, and each is independently a hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, trifluoromethoxy group, monomethylamino group, dimethylamino group or [ka] Selected from, preferably R 1 This is a methoxy group.

[0044] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), or general formula (Ii), or a pharmaceutically acceptable salt thereof, among which each R 2 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from a haloalkoxy group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group, an oxo group, a 3-8 membered cycloalkyloxy group, or a 3-8 membered heterocyclyloxy group, preferably each R 2 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Selected from alkoxy groups or oxo groups, more preferably each R 2 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl or C1-6 Selected from alkoxy groups, more preferably each R 2 are the same or different and each is independently a hydrogen atom or a halogen, more preferably each R 2 These are the same or different, and each is independently a hydrogen atom or a fluorine atom, most preferably R 2 It is a hydrogen atom.

[0045] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which each R 4a They are the same or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, and C 1-6 Alkyl 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 , selected from a 3-8 member cycloalkyl group, a 3-8 member heterocyclyl group, a 3-8 member cycloalkyloxy group, or a 3-8 member heterocycloxy group, R 9 and R 10 This is as defined by general formula (I), and preferably each R 4a They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, more preferably R 4a It is a hydrogen atom.

[0046] In some embodiments of this disclosure, a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV) or a pharmaceutically acceptable 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 this disclosure, a compound represented by general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV) above, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2, preferably p is 1 or 2.

[0048] In some embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond or C 1-6 It is an alkylene group, preferably a chemical bond, selected from -CH2- or -CH2CH2-, more preferably a chemical bond and -CH2-, and most preferably a chemical bond.

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

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

[0051] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 4a They are the same or different, and each is independently a halogen, a hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, and n is 1 or 2, or R 4a All of these are hydrogen atoms, and n is 3.

[0052] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, among which R 4a All of these are hydrogen atoms, and n is 3.

[0053] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which R 5 , R 6 They are identical or different, and each is independently a hydrogen atom, C 1-6 Selected from alkyl groups, 3-8 membered cycloalkyl groups, 3-12 membered heterocyclyl groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups, of which the above C 1-6 Alkyl groups, 3-8 membered cycloalkyl groups, 3-12 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups can each be independently and optionally selected as a hydroxyl group, halogen, cyano group, amino group, nitro group, oxo group, or C 1-6 Alkyl 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 They are identical or different, and each is independently C 1-6 Alkyl alkyl group, C 1-6 Selected from haloalkyl groups or 3- to 8-membered cycloalkyl groups.

[0054] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which R 7 and R 8 They are identical or different, and each is independently a hydrogen atom, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6Selected from a hydroxyalkyl group, a 3-8 membered cycloalkyl group, or a 3-12 membered heterocyclyl group, preferably R 7 and R 8 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, more preferably R 7 and R 8 It is a hydrogen atom.

[0055] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), general formula (Ii), general formula (III), or general formula (IV), or a pharmaceutically acceptable salt thereof, among which R 9 and R 10 They are identical or different, and each is independently a hydrogen atom, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Selected from hydroxyalkyl groups, 3-8 membered cycloalkyl groups, and 3-12 membered heterocyclyl groups, preferably R 9 and R 10 It is a hydrogen atom.

[0056] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), and general formula (Ii), or a medicinal salt thereof, among which, [ka] teeth [ka] And R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl 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 alkyl group, -OR5 , -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), and preferably R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, more preferably R 1a is C 1-6 It is an alkoxy group, and / or R 1b is C 1-6 It is an alkoxy group, most preferably R 1a and R 1b All of these are methoxy groups.

[0057] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] And R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C1-6 Haloalkoxy group, oxo group, 3-8 membered cycloalkyl group, C 1-6 Alkoxy C 1-6 Alkyl 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), and preferably R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, more preferably R 1a is C 1-6 It is an alkoxy group, and / or R 1b is C 1-6 It is an alkoxy group, most preferably R 1a and R 1b All of these are methoxy groups.

[0058] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (II), and general formula (Ii), or a medicinal salt thereof, among which, [ka] teeth [ka] And R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C1-6 Alkyl 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 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), and preferably R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, more preferably R 1a is a hydrogen atom or C 1-6 It is an alkoxy group, and / or R 1b is a hydrogen atom or C 1-6 It is an alkoxy group, most preferably R 1a and R 1b Both are methoxy groups, or R 1a R is a hydrogen atom, 1b This is a methoxy group.

[0059] In some embodiments of this disclosure, a compound represented by the above general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] And R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, and C 1-6 Alkyl 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 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), and preferably R 1a and R 1b They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, more preferably R 1a is a hydrogen atom or C 1-6 It is an alkoxy group, and / or R 1b is a hydrogen atom or C 1-6 It is an alkoxy group, most preferably R 1a and R 1b Both are methoxy groups, or R 1a R is a hydrogen atom, 1b This is a methoxy group.

[0060] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, among which, [ka] teeth [ka] Preferably, [ka] teeth [ka] Selected from the group consisting of, more, [ka] teeth [ka] That is the case.

[0061] In some embodiments of this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, among which, [ka] teeth [ka] Selected from the group consisting of, preferably, [ka] teeth [ka] Selected from the group consisting of, more, [ka] teeth [ka] That is the case.

[0062] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, among which, [ka] teeth [ka] Selected from the group consisting of, L is a chemical bond, and ring B is [ka] And each R 2 are the same or different and each is independently a hydrogen atom or a fluorine atom, q is 0, 1 or 2, R 3 R is a hydrogen atom, 4 teeth [ka] The ring C is a 5-membered or 6-membered heterocyclyl group, a 5-membered or 6-membered heteroaryl group, m is 0 or 1, n is 0, R 0 R is selected from a hydrogen atom, a hydroxyl group, or Cl, and each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl 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 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, where p is 0, 1, or 2, and p1 is 0, 1, 2, or 3.

[0063] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, p is 1, 2, or 3, and each R 2 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl or C 1-6 Selected from alkoxy groups, q is 1, R 3 R is a hydrogen atom, 4 teeth [ka] And each R 4a They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, n is 1 or 2, ring C is a 5-10 membered heteroaryl group, ring A is a 6-10 membered aryl group, ring B is a 4-7 membered heterocyclyl group, and L is a chemical bond or -CH2-.

[0064] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 1-6Alkyl alkyl groups, -C(O)OCH3, or -NR 7 R 8 Selected from, R 7 and R 8 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and p is 0, 1, 2, 3 or 4, and each R 2 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl and C 1-6 Selected from alkoxy groups, q is 0, 1, 2, 3 or 4, R 3 R is a hydrogen atom, 4 teeth [ka] And each R 4a They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, n is 0, 1, 2, 3 or 4, m is 0 or 1, ring C is selected from 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups, R 0 is a hydrogen atom, hydroxyl group, halogen or C 1-6 Selected from alkyl groups, ring A is a 6-10 membered aryl group, ring B is a 4-7 membered heterocyclyl group, and L is a chemical bond or -CH2-.

[0065] In some embodiments of this disclosure, a compound represented by the above general formula (II) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 1-6Selected from alkyl groups or -C(O)OCH3, p is 1, 2, or 3, and each R 2 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl or C 1-6 Selected from alkoxy groups, q is 1, and each R 4a They are identical or different, and each is independently a hydrogen atom, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, n is 1 or 2, ring A is a 6-10 membered aryl group, ring B is a 4-7 membered heterocyclyl group, ring C is a 5-10 membered heteroaryl group, and L is a chemical bond or -CH2-.

[0066] In some embodiments of this disclosure, a compound represented by the above general formula (II) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl 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 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and p is 0, 1, 2, or 3, and each R 2 are the same or different and each is independently a hydrogen atom or a halogen, q is 0, 1 or 2, and each R 4a They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 The group is selected from alkoxy groups, n is 0, 1, 2, or 3, ring A is a 6-10 membered aryl group, ring B is a 4-7 membered heterocyclyl group, ring C is a 5- or 6 membered heteroaryl group, and L is a chemical bond.

[0067] In some embodiments of this disclosure, a compound represented by the above general formula (Ii) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl 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 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and p is 0, 1, 2, or 3, and each R 2 are the same or different and each is independently a hydrogen atom or a halogen, q is 0, 1 or 2, and each R 4a They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 The group is selected from alkoxy groups, n is 0, 1, 2, or 3, ring A is a 6-10 membered aryl group, ring B is a 4-7 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 this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, p is 1, 2, or 3, X is O or CH2, R c and R d These are all hydrogen atoms, and each R 4aThey are the same or different, and each is independently a halogen, a hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, and n is 1 or 2, or R 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond or -CH2-.

[0069] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl 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 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, where p is 0, 1, 2, or 3, and X is O or CH2, and each R c and R d R is either the same or different, and each is independently a hydrogen atom or a halogen. 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0070] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, p is 2, X is O or CH2, and each R c and R d R is either the same or different, and each is independently a hydrogen atom or a fluorine atom. 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0071] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, of which each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, p is 1 or 2, X is CH2, and each R c and R d are identical or different and are independently either 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 this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently a hydrogen atom, a hydroxyl group, a halogen, and C 1-6 Alkyl 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 Selected from alkyl groups or -C(O)OCH3, p is 1, 2, or 3, X is O or CH2, and each R 4a They are the same or different, and each is independently a halogen, a hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Hydroxyalkyl group or C 1-6 Selected from alkoxy groups, and n is 1 or 2, or R 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond or -CH2-.

[0073] In some embodiments of this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently a hydrogen atom, halogen, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or -NR 7 R8 Selected from, R 7 and R 8 They are identical or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, where p is 0, 1, 2, or 3, and X is O or CH2, R 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0074] In some embodiments of this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, p is 1 or 2, X is CH2, R 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0075] In some embodiments of this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, p is 2, X is O or CH2, R 4a All of these are hydrogen atoms, n is 3, s is 1 or 2, and L is a chemical bond.

[0076] In some embodiments of this disclosure, a compound represented by the above general formula (IV) or a medicinal salt thereof, wherein each R 1 They are identical or different, and each is independently C 1-6 It is an alkoxy group, where p is 1 or 2, X is CH2, n is 0, s is 1 or 2, and L is a chemical bond.

[0077] Table A Typical compounds in this disclosure include, but are not limited to, the following: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

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

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

[0080] Another aspect of this disclosure relates to a compound represented by general formula (IiA) or a salt thereof: [ka] Eventually, Ring B, Ring C, R 2 , R4a q and n are as defined in general formula (Ii).

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

[0082] Another aspect of this disclosure relates to compounds represented by general formula (IVA) or salts thereof: [ka] Eventually, X, R 4a n and s are as defined in general formula (IV).

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

[0085] Another aspect of this disclosure relates to a compound represented by general formula (IIIA') or a salt thereof: [ka] Eventually, 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 this disclosure relates to a compound represented by general formula (IVA') or a salt thereof: [ka] Eventually, X 1 is a halogen, preferably bromine, R 1 s, p, X, and L are as defined in general formula (IV).

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

[0088] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I) or a medicinal salt thereof, the method being: [ka] The process includes 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, Eventually, Ring A, Ring B, L, R 1 ~R 4 p and q are as defined in general formula (I).

[0089] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method being: [ka] The process includes 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 pharmaceutically acceptable salt thereof, Eventually, 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 this disclosure relates to a method for preparing a compound represented by general formula (Ii) or a pharmaceutically acceptable salt thereof, the method being: [ka] The process includes 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 pharmaceutically acceptable salt thereof, Eventually, 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 this disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method being: [ka] The process includes 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 pharmaceutically acceptable salt thereof, Eventually, 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 this disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method being: [ka] The process includes 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 pharmaceutically acceptable salt thereof, Eventually, X, L, R 1 , R 4a p, n, and s are as defined in general formula (IV).

[0093] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (Ii) or a pharmaceutically acceptable salt thereof, the method being: [ka] The process includes the 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 pharmaceutically usable salt thereof, Eventually, Ring D is a 3- to 8-membered heterocyclyl group containing at least one intraring double bond, preferably a 5- or 6-membered heterocyclyl group containing at least one intraring 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 this disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (I), general formula (II), general formula (II), general formula (III), general formula (IV), or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

[0095] This disclosure further relates to the use of compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for inhibiting KAT, wherein KAT6 is preferred, and KAT6A and / or KAT6B is more preferred.

[0096] This disclosure further relates to the use of compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or medicinal salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating and / or preventing KAT-mediated diseases, wherein KAT6 is preferred, and KAT6A and / or KAT6B is more preferred.

[0097] This disclosure further relates to the use of compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating and / or preventing cancer, wherein the cancers are 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 lymphoma, esophageal cancer, and colorectal cancer. Selected from small intestine cancer, stomach 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 tumors (CNS), primary CNS lymphoma, spinal tumor, glioma, cranial 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, cranial glioma, B-cell lymphoma, liver cancer, and leukemia, of which breast cancer is ER + Breast cancer or ER + / HER2 - Breast cancer is preferred, of which lung cancer (e.g., NCSLC, SCLC) is preferred as non-small cell lung cancer, and of which prostate cancer is preferred as castration-resistant prostate cancer.

[0098] This disclosure further relates to a method for inhibiting KAT, which includes administering to a patient in need an inhibitory 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0099] This disclosure further relates to a method for treating and / or preventing a KAT-mediated disease, which comprises administering to a patient in need a therapeutically effective amount 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 medicinal salt thereof, or a pharmaceutical composition containing the same, wherein the KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0100] This disclosure further relates to a method for treating and / or preventing cancer, which comprises administering to a patient in need a therapeutically effective dose and / or prophylactically effective dose 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 medicinal salt thereof, or a pharmaceutical composition containing the same, wherein the cancers are 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 A selection from tumors, esophageal cancer, colorectal cancer, small intestine cancer, stomach 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 tumors (CNS), primary CNS lymphoma, spinal tumors, glioma, cranial glioma, pituitary adenoma, and squamous cell carcinoma, preferably selected from breast cancer, prostate cancer, lung cancer (e.g., NCSLC, SCLC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, cranial glioma, B-cell lymphoma, liver cancer, or leukemia, of which breast cancer is treated in the ER. + Breast cancer or ER + / HER2 - Breast cancer is preferred, of which lung cancer (e.g., NCSLC, SCLC) is preferred as non-small cell lung cancer, and of which prostate cancer is preferred as castration-resistant prostate cancer.

[0101] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (IIi), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, used as pharmaceuticals.

[0102] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, which are used as agents that inhibit KAT, of which KAT6 is preferred, and KAT6A and / or KAT6B is more preferred.

[0103] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing the same, wherein KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0104] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, of which KAT is preferably KAT6, and more preferably KAT6A and / or KAT6B.

[0105] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or medicinal salts thereof, or pharmaceutical compositions containing the same, for treating and / or preventing KAT-mediated diseases, wherein KAT6 is preferred, and KAT6A and / or KAT6B is more preferred.

[0106] This disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (Ii), general formula (III), general formula (IV) or Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing the same, for the treatment and / or prevention of cancer, wherein the cancers are 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 lymphoma, esophageal cancer, colorectal cancer, small intestine cancer, 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 tumors (CNS), primary CNS lymphoma, spinal tumors, glioma, cranial glioma, pituitary adenoma, and squamous cell carcinoma, preferably selected from breast cancer, prostate cancer, lung cancer (e.g., NCSLC, SCLC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, cranial glioma, B-cell lymphoma, liver cancer, or leukemia, of which breast cancer is treated with ER. + Breast cancer or ER + / HER2 - Breast cancer is preferred, of which lung cancer (e.g., NCSLC, SCLC) is preferred as non-small cell lung cancer, and of which prostate cancer is preferred as castration-resistant prostate cancer.

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

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

[0109] In some embodiments of this disclosure, the breast cancer is referred to as ER + I have breast cancer.

[0110] In some embodiments of this disclosure, the breast cancer is referred to as ER + / HER2 - I have breast cancer.

[0111] In some embodiments of this disclosure, the breast cancer is locally advanced or metastatic ER + / HER2 - I have breast cancer.

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

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

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

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

[0116] For convenience, in this specification, estrogen receptor-positive (ER) + ), human epidermal growth factor receptor 2 negative (HER2 - Several well-known abbreviations may be used, including non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer (CRPC).

[0117] The active compound can be prepared in a form suitable for administration by any suitable route, and the composition of this disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable vectors. Accordingly, the active compound of this disclosure can be prepared in dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation. The compound of this disclosure may be prepared in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, topical tablets, or syrups.

[0118] As a general guideline, the active compound is preferably in the form of a unit dose or in a form that the patient can administer to themselves as a monotherapy. The unit dose of the compound or composition relating to this disclosure may be expressed as a tablet, capsule, cachet, bottled solution, drug powder, granules, topical tablet, suppository, regenerated powder, or liquid formulation. A preferred unit dose may be 0.1 to 1000 mg.

[0119] The pharmaceutical composition relating to this 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. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0120] The tablets comprise an active ingredient and a non-toxic, medicinal excipient suitable for mixing in the preparation of the tablets. These excipients may be inert excipients, granulators, disintegrants, binders, and lubricants. These tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period.

[0121] An oral formulation may be provided in the form of a soft gelatin capsule containing the active ingredient and an inert solid diluent, or the active ingredient and a water-soluble vector or oily solvent.

[0122] The aqueous suspension comprises an active substance and excipients suitable for mixing in the preparation of the aqueous suspension. Such excipients are suspending agents, dispersing agents, or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0123] An oil suspension can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oil suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0124] The pharmaceutical compositions relating to this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0125] The pharmaceutical compositions relating to this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection formulation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by local injection in large quantities. Alternatively, it is preferable to administer the solution and microemulsion in a manner that can maintain a constant cycle concentration of the compound relating to this disclosure. A continuous intravenous infusion device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

[0126] The pharmaceutical compositions relating to this disclosure may be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the appropriate dispersants or wetting agents and suspending agents described above, according to known techniques. The sterile injection formulation may also be a sterile injection solution or suspension prepared in a parenterally acceptable, non-toxic diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any compounding fixative oil can be used. Fatty acids can also be used to prepare injection formulations.

[0127] The compounds relating to this 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 dissolves in the rectum to release the drug.

[0128] The compounds relating to this disclosure can be administered by adding water to prepare aqueous suspensions, dispersible powders, and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a 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, weight, physical condition, behavior, diet, administration time, method of administration, excretion rate, drug composition, and disease severity. Furthermore, the optimal treatment method, such as the mode of treatment, the daily dose of the compound, or the type of medicinal salt, can be determined according to conventional treatment plans. Explanation of terms

[0130] Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0131] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, a linear or branched group containing 1 to 20 carbon atoms (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). 1-20 The alkyl group is preferably an alkyl group containing 1 to 12 carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atoms). 1-20 It is an alkyl group, more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6(alkyl group). Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl This includes n-octyl groups, 2,3-dimethylpentyl groups, 2,4-dimethylpentyl groups, 2,2-dimethylpentyl groups, 3,3-dimethylpentyl groups, 2-ethylpentyl groups, 3-ethylpentyl groups, n-octyl groups, 2,3-dimethylhexyl groups, 2,4-dimethylhexyl groups, 2,5-dimethylhexyl groups, 2,2-dimethylhexyl groups, 3,3-dimethylhexyl groups, 4,4-dimethylhexyl groups, 2-ethylhexyl groups, 3-ethylhexyl groups, 4-ethylhexyl groups, 2-methyl-2-ethylpentyl groups, 2-methyl-3-ethylpentyl groups, n-nonyl groups, 2-methyl-2-ethylhexyl groups, 2-methyl-3-ethylhexyl groups, 2,2-diethylpentyl groups, n-decyl groups, 3,3-diethylhexyl groups, 2,2-diethylhexyl groups, and various branched isomers thereof. The alkyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from a 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, and heteroaryl group.

[0132] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and has 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 1 to 12 carbon atoms (i.e., C 1-12 Alkylene group), more preferably 1 to 6 carbon atoms (i.e., C 1-6 The alkylene group has an alkylene group. Non-limiting examples include methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linkage point, and the substituent is preferably one or more selected from a 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, and heteroaryl group.

[0133] The term "heteroalkylene group" refers to an alkylene group in which one or more -CH2- groups are substituted with one or more selected from N, O, S, S(O), and S(O)2, where the alkyl group is as defined above. The heteroalkylene group may or may not be substituted, and if substituted, the substituent may be substituted at any available linking point. Preferably, the substituent is one or more selected from a 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.

[0134] The term "alkenyl group" refers to alkyl group compounds that contain at least one carbon-carbon double bond in the molecule, of which the definition of an alkyl group is as described above, and which have 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 Alkenyl group). The above 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 or may not be substituted. If substituted, the substituent is preferably one or more selected from an alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and 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, of which the definition of an alkyl group is as described above, and it 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 Alkynyl group). The above alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl groups are preferred. The alkynyl group may be substituted or not. If substituted, the substituent is preferably one or more selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

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

[0137] The term "spirocycloalkyl group" refers to a polycyclic group with 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 spirocycloalkyl group) in which monocyclic rings share one carbon atom (called a spiro atom), and which may contain one or more double bonds. Preferably, it is a 6 to 14-membered group (i.e., a 6 to 14-membered spirocycloalkyl group), more preferably a 7 to 10-membered group (e.g., 7, 8, 9, or 10 members, i.e., a 7 to 10-membered spirocycloalkyl group). Spirocycloalkyl groups are classified into monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferably, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

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

[0139] The term "crosslinked cycloalkyl group" refers to a 5-20 member (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 crosslinked cycloalkyl group) with any two rings sharing two carbon atoms that are not directly linked, and which may contain one or more double bonds. Preferably, they are 6-14 member (i.e., 6-14 membered crosslinked cycloalkyl groups), more preferably 7-10 member (e.g., 7, 8, 9, or 10 membered, i.e., a 7-10 membered crosslinked cycloalkyl group). Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] Includes.

[0140] The above cycloalkyl rings include those in which the above cycloalkyl group (including monocyclic cycloalkyl groups, spirocycloalkyl groups, condensed cycloalkyl groups, and crosslinked cycloalkyl groups) is condensed to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples are: [ka] This includes, [ka] It is preferable.

[0141] The cycloalkyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0142] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or not substituted. If substituted, it is preferable that the substituted group is one or more groups independently selected from a 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 substituent comprising 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 3-20 membered heterocyclyl group), of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, the sulfur being optionally substituted with an oxo group (i.e., forming a sulfoxide or sulfone), but without the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (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 A monocyclic heterocyclyl group may have 5, 6, or 7 members, i.e., a 4- to 7-membered heterocyclyl group, of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, more preferably 3 to 6 ring atoms (e.g., 3, 4, 5, and 6 members, i.e., a 3- to 6-membered heterocyclyl group), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, and most preferably 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclyl group), of which 1 to 2 (e.g., 1, 2) are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, tetrahydropyranyl group, 1,2,3,6-tetrahydropyridyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, condensed heterocyclyl groups, and cross-linked heterocyclyl groups.

[0144] The term "spiroheterocyclyl 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 spiroheterocyclyl group) in which monocyclic rings share one atom (called a spiro atom), of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the sulfur may optionally be 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. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered spiroheterocyclyl group), more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members, i.e., a 7 to 10-membered spiroheterocyclyl group). Spiroheterocyclyl groups are classified into monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between the rings, 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 "condensed 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 condensed heterocyclyl group) in which each ring in the system shares one pair of adjacent atoms with the other rings in the system, and one or more rings may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered condensed heterocyclyl group), more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members, i.e., a 7 to 10-membered condensed heterocyclyl group). Depending on the number of rings that make up the group, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl groups, preferably bicyclic or tricyclic, and 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 condensed heterocyclyl groups. Non-limiting examples of condensed 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 which may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is a 6 to 14-membered group (i.e., a 6 to 14-membered bridged heterocyclyl group), more preferably a 7 to 10-membered group (e.g., 7, 8, 9, or 10 members, i.e., a 7 to 10-membered bridged heterocyclyl group). Depending on the number of rings that make up the structure, the cross-linked heterocyclyl group can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic types, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of cross-linked heterocyclyl groups are: [ka] Includes.

[0147] The above heterocyclyl ring includes those in which the above heterocyclyl group (including monocyclic heterocyclyl group, spiroheterocyclyl group, condensed heterocyclyl group, and crosslinked heterocyclyl group) is condensed to an aryl group, a heteroaryl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0148] The heterocyclyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is 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 a 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, i.e., a 6-14 membered aryl group) all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6-10 membered (i.e., a 6-10 membered aryl group), such as a phenyl group and a naphthyl group. The above aryl rings include those in which the above aryl rings are fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes.

[0150] The aryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from halogens, alkyl groups, 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.

[0151] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3 and 4) 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- to 14 membered heteroaryl group), where the heteroatoms are selected from oxygen, sulfur, or nitrogen. Heteroaryl groups are preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered, i.e., a 5- to 10 membered heteroaryl group), and more preferably 5 or 6 membered (i.e., a 5 or 6 membered heteroaryl group), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. The above heteroaryl ring includes those in which the heteroaryl group is condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are: [ka] Includes.

[0152] The heteroaryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is 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 groups, heterocyclyl groups, aryl groups, and heteroaryl groups are residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, i.e., "divalent cycloalkyl groups," "divalent heterocyclyl groups" (for example, [ka] (etc.) Contains "arylene groups" and "heteroarylene groups".

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

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

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

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

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

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

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

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

[0162] The term "alkoxyalkyl group" refers to a group in which an alkyl group is substituted with one or more alkoxy groups, where the alkyl group and alkoxy group are as defined above.

[0163] The term "hydroxyalkyl group" refers to a group in which an alkyl group is substituted with one or more hydroxyl groups, where the alkyl group is as defined above.

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

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

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

[0167] The term "amino group" refers to -NH2.

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

[0169] The term "nitro group" refers to -NO2.

[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 "carboxyl group" refers to -C(O)OH.

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

[0175] On the other hand, the compounds relating to this disclosure may have specific geometric or stereoisomeric forms. This disclosure includes all cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as mixtures rich in enantiomers and diastereomers, and all such compounds are intended to be within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this 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. To obtain one enantiomer of a compound of this disclosure, it can be prepared by asymmetric synthesis or by inductive action with a chiral aid, thereby providing the required pure enantiomer by isolating the resulting diastereomer mixture and assisting in the fission of the groups. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is then divided by a conventional method well known in this field, after which it is recovered to obtain the pure enantiomer. The isolation of the enantiomer and diastereomer is generally completed by chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivation method (e.g., generating a carbamate from an amine).

[0176] In the chemical structure of the compounds described in this disclosure, [ka] This type of bond indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, [ka] The combination is [ka] It may be so, or [ka] The following two configurations may be included simultaneously. In the chemical structure of the compounds described herein, [ka] This combination does not specify an arrangement, meaning it may be a Z arrangement or an E arrangement, or it may include both arrangements simultaneously.

[0177] Furthermore, the compounds and intermediates of this disclosure may exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that can be interconverted over a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions by protrics, such as keto-enol and imine-enamine isomerization. An example of lactam-lactim equilibrium is between A and B as shown below. [ka]

[0178] All compounds in this disclosure can be described as either type A or type B. All tautomer forms are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomer.

[0179] This disclosure is the same as described herein, but further includes several isotopically labeled compounds in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be bound to the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively 2 H, 3 H, 11 C, 13C, 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 Examples include Cl.

[0180] The compounds of this disclosure may contain non-natural ratio atomic isotopes in one or more atoms constituting the compound. For example, tritium ( 3 Compounds may be labeled with radioactive isotopes such as ¹H, or hydrogen may be substituted with deuterium to form deuterated agents. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon, and compared to undeuterated agents, deuterated agents have advantages such as reduced toxicity and side effects, increased drug stability, improved therapeutic effect, and extended biological half-life. All isotopic transformations of the compounds relating to this disclosure, whether radioactive or not, are included within the scope of this disclosure.

[0181] Furthermore, relatively heavy isotopes (for example, deuterium (i.e., 2 Substitution with H)) can provide several therapeutic benefits resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose demand), and may therefore be preferable in some cases, where the deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.

[0182] Unless otherwise specified, where one position is specifically designated as deuterium (D), that position should be understood to be deuterium having an abundance at least 1000 times higher than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporated). Having an abundance higher than the natural abundance of deuterium in the example compounds may mean deuterium with an abundance of at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even greater. This disclosure further includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom bonded to a carbon atom may be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds of formula (I) in deuterated forms by referring to relevant literature. When preparing the deuterated compound of formula (I), commercially available deuterated starting materials may be used, or it may be synthesized using deuterated reagents by conventional techniques. Deuterated reagents include, but are not limited to, borane deuterated, borane trihydrofuran solution, lithium aluminum hydride deuterated, iodoethane deuterated, and iodomethane deuterated.

[0183] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both cases in which the event or situation occurs and cases in which it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may or may not be present, and this description includes both cases in which the heterocyclyl group is substituted with an alkyl group and cases in which the heterocyclyl group is not substituted with an alkyl group.

[0184] "Substituting" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3, are substituted with a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

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

[0186] "Medicinal salt" refers to a salt of a compound relating to this disclosure, which is safe and effective when used in the body of a mammal and possesses the desired biological activity. Salts may be prepared individually during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for forming pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0187] With respect to drugs or pharmacological activators, the terms “therapeutic effective dose,” “inhibitory effective dose,” or “preventive effective dose” refer to a dose of the drug or agent sufficient to produce, or partially produce, the desired effect. The effective dose is determined on a person-by-person basis, depending on the age and general condition of the recipient, as well as the specific active substance. A suitable effective dose for an individual can be determined by ordinary testing by those skilled in the art.

[0188] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to contact with patient tissue, have a reasonable cost-benefit ratio, and are effective for the desired use.

[0189] As used herein, the singular forms "one," "one type," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0190] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that the parameter may vary within ±10%, and in some cases, more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, the number is generally given for illustrative purposes only, not as a limitation. Synthesis method of the compound related to this disclosure

[0191] To achieve the objectives of this disclosure, this disclosure adopts the following technical proposals. Technical proposal 1

[0192] A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] The process includes the step of optionally performing a nucleophilic substitution reaction with a compound represented by general formula (IA) or a salt thereof using microwaves under the action of a base to obtain a compound represented by general formula (I) or a pharmaceutically usable salt thereof. Eventually, 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 represented by general formula (II) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] The method includes the step of optionally performing a nucleophilic substitution reaction with a compound represented by general formula (IIA) or a salt thereof using microwaves under the action of a base to obtain a compound represented by general formula (II) or a pharmaceutically usable salt thereof. Eventually, 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 method for preparing a compound represented by general formula (Ii) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] The method includes the step of optionally performing a nucleophilic substitution reaction with a compound represented by general formula (IiA) or a salt thereof using microwaves under the action of a base to obtain a compound represented by general formula (Ii) or a pharmaceutically usable salt thereof. Eventually, 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 method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof as relating to this disclosure, is provided, [ka] The process includes the step of optionally performing a nucleophilic substitution reaction with a compound represented by general formula (IIIA) or a salt thereof using microwaves under the action of a base to obtain a compound represented by general formula (III) or a pharmaceutically usable salt thereof. Eventually, L, X, R1 , R 4a , R c , R d p, n, and s are as defined in general formula (III). Technical proposal 4

[0196] A method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein the preparation is as follows: [ka] The process includes the step of optionally performing a nucleophilic substitution reaction with a compound represented by general formula (IVA) or a salt thereof using microwaves under the action of a base to obtain a compound represented by general formula (IV) or a pharmaceutically usable salt thereof. Eventually, 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 represented by general formula (II) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] Step 1 involves a nucleophilic addition reaction between a compound represented by general formula (IIA') or a salt thereof and a compound represented by general formula (IIB') or a salt thereof, under the action of a base (e.g., n-butyllithium), to obtain a compound represented by general formula (IIa) or a pharmaceutically usable salt thereof. Step 2 involves chlorinating a compound represented by general formula (IIa) or a salt thereof (for example, under the action of PCl3 or SOCl2) to obtain a compound represented by general formula (IIb) or a pharmaceutically acceptable salt thereof, Step 3 involves reducing a compound represented by general formula (IIb) or a pharmaceutically acceptable salt thereof under metallic action (e.g., zinc powder or iron powder) to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. Eventually, X 1is 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 method for preparing a compound represented by general formula (Ii) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] The process includes the 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, by optionally adding a ligand under the action of a base and a metal catalyst, to obtain a compound represented by general formula (Ii) or a pharmaceutically usable salt thereof. Eventually, Ring D is a 3- to 8-membered heterocyclyl group containing at least one intraring double bond, preferably a 5- or 6-membered heterocyclyl group containing at least one intraring 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 reactions of Technical Options 1 to 6 described above, 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 described in Technical Options 1 to 4 is preferably selected from pyridine, lithium bis(trimethylsilyl)amide, or 3,5-dimethylpyridine. The base described in Technical Options 5 is preferably n-butyllithium, and the base described in Technical Options 6 is preferably potassium carbonate.

[0200] In the above technical proposal 6, the 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. Palladium acetate is preferred.

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

[0202] The reactions in Technical Proposals 1 to 4 described above are carried out by the action of a catalyst in an optional manner, and the catalyst includes, but is not limited to, 4-dimethylaminopyridine and dimethyl sulfoxide (DMSO).

[0203] When carrying out the reactions described in Technical Proposals 1 to 6 above using microwaves, the reaction temperature is 100 to 150°C, preferably 120°C.

[0204] When carrying out the reactions described in Technical Options 1 to 6 using microwaves, the reaction time is 0.5 to 6 hours, preferably 2 to 3 hours, and more preferably 3 hours.

[0205] The reactions described in Technical Options 1 to 6 above are preferably carried out in a solvent. 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. [Modes for carrying out the invention]

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

[0207] The structure of a compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The values ​​are expressed in units of ppm. A Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer was used for the NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

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

[0209] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

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

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

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

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

[0214] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography are 0.4 to 0.5 mm.

[0215] In silica gel column chromatography, silica gel of 200-300 mesh size, manufactured by Yantai Huanghai Silica Gel, was commonly used as a vector.

[0216] Kinase mean inhibition rate and IC 50 A plate reader, NovoStar (BMG GmbH, Germany), was used to measure the values.

[0217] The known starting materials relating to this disclosure may be synthesized by or in accordance with 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, Aladdin, Annaij Chemical, China National Pharmaceutical Group Limited, Adamas Reagents Co., Ltd., Sigma-Aldrich (Shanghai) Trading Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., and Thermo Fisher Scientific (China) Co., Ltd.

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

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

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

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

[0222] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

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

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

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

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

[0227] Example 1 N-(4-((1H-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, filtered by suction under reduced pressure, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride solution (30 mL x 5), the resulting 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%). This product was used directly 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), cooled to 0°C, and trifluoroacetic acid (39 g, 342 mmol) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain 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 mixture was cooled to 0°C, cesium carbonate (24 g, 73.7 mmol) and allyl bromide (11.2 g, 92.6 mmol) were added, and the reaction mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was filtered by suction under reduced pressure, the filtrate was diluted with ethyl acetate (400 mL), washed with saturated sodium chloride solution (30 mL x 3), the resulting organic phase was 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 1d (11.7 g, yield: 92%). 1H NMR (500 MHz, CDCl3) 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 three times with nitrogen gas, and the reaction mixture was stirred at 180°C for 13 hours. The reaction mixture was cooled to room temperature, and the resulting residue was purified with eluent system A by silica gel column chromatography (wet method) to obtain the title product 1e (2.77 g, yield: 82.7%). 1 H NMR (500 MHz, CDCl3) 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 reacted with stirring for 2 hours. Water (10 mL) was added to the reaction mixture to quench it, and the mixture was 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 obtain the title product 1f (1.11 g, yield: 94.7%). 1H NMR (500 MHz, CDCl3) 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). The reaction mixture was cooled to -78°C and passed through with dry ozone for 1 hour. The reaction mixture was added to triphenylphosphine (1.05 g, 4.0 mmol) and quenched. The temperature was gradually raised to room temperature, and the reaction was carried out with stirring for 0.5 hours. The reaction mixture was then cooled to 0°C, and sodium borohydride (560 mg, 14.8 mmol) was added in several batches, and the reaction was carried out with stirring for 1 hour. Water (5 mL) was added to the reaction mixture and quenched. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride solution (10 mL x 2). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with eluent system A by silica gel column chromatography to obtain 1 g (800 mg, yield: 71.8%) of the title product. 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 1 g (800 mg, 2.63 mmol) of the compound was dissolved in methanol (25 mL), the reaction mixture was cooled to 0°C, and a 4 M, 24 mmol, 6 mL solution of dioxane hydrochloride was added. The reaction mixture was then heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 1 h (680 mg, yield: 99%). 1 H NMR (500 MHz, CDCl3) 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-carbonitriel 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 azodicarboxylic acid (1.58 g, 7.81 mmol) were added, and the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 1i (570 mg, yield: 90%). 1 H NMR (500 MHz, CDCl3) δ 6.84 (dd, 1H), 4.84 (td, 2H), 3.24 (tt, 2H).

[0236] Step 9 7-Cyano-6-fluoro-2,3-dihydrobenzofuran-4-carboxylate methyl 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'-bisdiphenylphosphinoferocenedichloropalladium (185 mg, 252 mmol) and triethylamine (771 mg, 7.62 mmol) were added in sequence. The reaction mixture was stirred at 80°C for 12 hours under carbon monoxide protection after three substitutions with carbon monoxide. The reaction mixture 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 resulting organic phase was 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 1j (289 mg, yield: 51.4%). 1 H NMR (500 MHz, CDCl3) 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 three times with nitrogen gas, the reaction mixture was cooled to 0°C, and lithium borohydride (2 M, 5 mmol, 2.5 mL) was added. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 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 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 (7-Cyano-6-Fluoro-2,3-Dihydrobenzofuran-4-yl)Methyl Methanesulfonate 1 liter 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 heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL x 2), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 l (491 mg, yield: 99%) of the title product. This product was used directly in the next reaction without purification.

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

[0240] Step 13 4-((1H-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was stirred at 60°C for 12 hours. The reaction mixture was filtered, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL x 3), the resulting organic phase was 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 1n (189 mg, yield: 49.7%). MS m / z (ESI): 257.0 [M+1].

[0241] Step 14 N-(4-((1H-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 "Technical Proposal 15 on page 70 of the specification in patent application WO2020254946A1") were dissolved in pyridine (8 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting 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) to obtain title product 1 (44 mg, yield: 13%). MS m / z (ESI): 457.0 [M+1]. 1H NMR (500 MHz, CD3OD) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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 boranetetrahydrofuran solution (1.0 M, 22 mL, 22 mmol) was added dropwise at 0°C. The reaction mixture was stirred in an ice bath for 2 hours. In an ice bath, 3 M aqueous sodium hydroxide solution (13 mL, 39 mmol) and 30% hydrogen peroxide (3.0 mL) were added sequentially, and the mixture was stirred for 10 minutes after the addition was complete. The reaction mixture was adjusted to pH=2 with 2 M hydrochloric acid, extracted with ethyl acetate (100 mL × 2), and the organic phase was collected. The organic phase was 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 2a (3.5 g, yield: 68.1%). MS m / z (ESI): 275.8 [M+1]. 1H NMR (500 MHz, CDCl3) 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 mixture was cooled to 0°C, triphenylphosphine (4.4 g, 16.8 mmol) and diisopropyl azodicarboxylic acid (3.4 g, 16.8 mmol) were added, and the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 2b (3.0 g, yield: 84.5%). MS m / z (ESI): 257.8 [M+1]. 1 H NMR (500 MHz, CDCl3) δ 7.03 (d, 1H), 4.33 (t, 2H), 2.77-2.74 (m, 2H), 2.12-2.08 (m, 2H).

[0245] Step 3 8-Cyano-7-Fluorochroman-5-carboxylate methyl 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'-bisdiphenylphosphinoferocenedichloropalladium (800 mg, 1.09 mmol) and triethylamine (3.0 g, 2.93 mmol) were added sequentially. The mixture was substituted three times with carbon monoxide and stirred for 16 hours under conditions of 10 bar and 90°C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with saturated sodium chloride solution (50 mL x 3), the resulting organic phase was 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 2c (2.1 g, yield: 87.9%). MS m / z (ESI): 235.9 [M+1]. 1 H NMR (500 MHz, CDCl3) 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 three times with nitrogen gas, cooled the reaction mixture to 0°C, and lithium borohydride (2 M, 18 mmol, 9.0 mL) was added. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (50 mL x 2), dried the resulting organic phase over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography 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-pyrazole-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, obtained by the method disclosed in "Intermediate 13 of Technical Proposal 8 on page 63 of Specification in Patent Application 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. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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 mixture was stirred at 70°C for 24 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was filtered. The filtered cake was collected and dried to obtain 2 g of the title product (1.65 g, yield: 82.7%). MS m / z (ESI): 271.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-2,6-dimethoxybenzenesulfamide 2 Two g (200 mg, 0.740 mmol) of compound 10 (300 mg, 1.27 mmol) were dissolved in pyridine (5.0 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-2-methoxybenzenesulfamide 3 [ka] [ka] Two g (300 mg, 1.11 mmol) of the compound and 2-methoxybenzenesulfonyl chloride 3a (460 mg, 2.22 mmol) were dissolved in pyridine (6.0 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) 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-d6) 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-pyrazole-1-yl)methyl)-2,3-dihydro-[1,4]dioxyno[2',3':5,6]benzo[1,2-d]isoxazole-9-yl)-2-methoxybenzenesulfamide 4 [ka] [ka]

[0252] Step 1 4-Bromo-5-fluoro-2,3-dihydroxybenzoate methyl 4b Compound methyl 5-fluoro-2,3-dihydrobenzoate 4a (2.26 g, 12.1 mmol, prepared by the method disclosed in the literature "J. Med. Chem. 2010, 53, 7035-7047") was dissolved in dichloromethane (60 mL), the reaction mixture was cooled to 0°C, N-bromosuccinimide (2.6 g, 14.6 mmol) was added in several batches, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was washed with saturated sodium bisulfite solution (30 mL x 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 4b (1.8 g, yield: 55.9%). 1 H NMR (500 MHz, CDCl3) 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]dioxin-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 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 4c (873 mg, yield: 79.5%). MS m / z (ESI): 292.9 [M+1]. 1 H NMR (500 MHz, CDCl3) δ 7.26 (d, 1H), 4.45-4.43 (m, 2H), 4.39-4.36 (m, 2H), 3.91 (s, 3H).

[0254] Step 3 8-Cyano-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-methyl formate 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) were dissolved in N,N-dimethylformamide (15 mL) and substituted three times with nitrogen gas. The reaction mixture was allowed to react at 110°C for 16 hours. 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 using 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, CDCl3) 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]dioxin-5-carbonitrili 4e Compound 4d (500 mg, 2.1 mmol) was dissolved in dried tetrahydrofuran (15 mL), purged three times with nitrogen gas, and the reaction mixture was cooled to 0°C. Lithium borohydride (2 M, 4 mmol, 2.0 mL) was added. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (30 mL x 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 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)Methyl Methanesulfonate 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 heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL), diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL x 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%). This product was used directly in the next reaction without purification.

[0257] Step 6 8-((1H-pyrazole-1-yl)methyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-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 mixture was stirred at 60°C for 12 hours. The reaction mixture was filtered, and the resulting filtrate was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL x 3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain 4 g (155 mg, yield: 85.8%) of the title product. MS m / z (ESI): 260.0 [M+1]. 1H NMR (500 MHz, CDCl3) 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-pyrazole-1-yl)methyl)-2,3-dihydro-[1,4]dioxyno[2',3':5,6]benzo[1,2-d]isoxazole-9-amine 4h Four g (155 mg, 0.6 mmol) of the compound 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 mixture was stirred at 70°C for 24 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 4h (110 mg, yield: 67.5%). MS m / z (ESI): 273.0 [M+1]. 1 H NMR (500 MHz, CDCl3) 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-pyrazole-1-yl)methyl)-2,3-dihydro-[1,4]dioxyno[2',3':5,6]benzo[1,2-d]isoxazole-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 three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting 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%~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-d6) 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-pyrazole-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazole-8-yl)-2,6-dimethoxybenzenesulfamide 5 [ka] [ka]

[0261] Step 1 7-Bromo-6-fluoro-2-sulfanylidenebenzo[d][1,3]dioxol-4-methylformate 5a Compound 4b (16.7 g, 63 mmol) was dissolved in tetrahydrofuran (200 mL), the reaction mixture was cooled to 0°C, and N,N'-thiocarbonyldiimidazole (18 g, 101 mmol) was added in several portions. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 5a (9.1 g, yield: 47.0%). 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, 1H), 4.05 (s, 3H).

[0262] Step 2 7-Bromo-2,2,6-trifluorobenzo[d][1,3]dioxol-4-methylformate 5b Compound 5a (9.1 g, 29.6 mmol) was dissolved in dichloromethane (160 mL) at -40°C, and under nitrogen protection, pyridine hydrofluoride solution (42.3 g, 427 mmol) was added, and the reaction mixture was allowed to react at -40°C for 5 minutes. Then, N-iodosuccinimide (20 g, 88.9 mmol) was added in several portions, and the reaction mixture was continued at -40°C for 30 minutes. The reaction mixture was quenched with 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, 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 5b (4.8 g, yield: 51.7%). 1 H NMR (500 MHz, CDCl3) 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 three times with nitrogen gas, the reaction mixture was cooled to 0°C, and lithium borohydride (2 M, 27.6 mmol, 13.8 mL) was added. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (5 mL), diluted with ethyl acetate (60 mL), washed with saturated sodium chloride solution (30 mL x 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 5c (3.2 g, yield: 73.2%). 1 H NMR (500 MHz, CDCl3) 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), cesium carbonate (5.5 g, 16.9 mmol) was added, and the mixture was reacted at 70°C for 1 hour. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography 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, CDCl3) 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-pyrazole-1-yl)methyl)-2,2,5-trifluorobenzo[d][1,3]dioxol-4-carbonitrili 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 mixture was allowed to react at 200°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with dichloromethane (60 mL), washed with saturated sodium chloride solution (60 mL x 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 using eluent system A by silica gel column chromatography to obtain the title product 5e (465 mg, yield: 34.6%). MS m / z (ESI): 282.0 [M+1].

[0266] Step 6 4-((1H-pyrazole-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazole-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 mixed solvent 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 minutes. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 5f (60 mg, yield: 5.7%). MS m / z (ESI): 295.0 [M+1].

[0267] Step 7 N-(4-((1H-pyrazole-1-yl)methyl)-2,2-difluoro-[1,3]dioxolo[4',5':5,6]benzo[1,2-d]isoxazole-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 mixture was allowed to react at 35°C for 2 days. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting 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, CDCl3) 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-pyrazole-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] Two g (50 mg, 0.185 mmol) of the compound and 6-methoxy-2,3-dihydro-1H-indene-5-sulfonyl chloride 6a (200 mg, 0.811 mmol, prepared by the method disclosed in "Intermediate I108 on page 114 of the specification in patent application WO2019243491A1") were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) to obtain the title product 6 (30 mg, yield: 33.7%). MS m / z (ESI): 480.8 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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 overnight at room temperature. 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 with diethyl ether (20 mL), the filter cake was collected, dried under vacuum to obtain 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. The mixture was filtered, and 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, and thionyl chloride (771 mg, 6.48 mmol) was gradually added dropwise. The mixture was reacted at 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 7d (200 mg, yield: 92.1%).

[0273] Step 4 N-(5-((1H-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-2-ethoxy-4-toluenesulfamide 7 Two g (50 mg, 0.185 mmol) of compound 7d (100 mg, 0.426 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) 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-d6) 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-pyrazole-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, prepared by the method disclosed in "Intermediate A30 on page 71 of the specification in patent application WO2020069322A1") was dissolved in concentrated sulfuric acid (2 mL) and stirred overnight at room temperature. 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 washed with ethyl acetate (20 mL), and then with diethyl ether (20 mL), the filter cake was collected, 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. The mixture was filtered, and 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 gradually added dropwise. The mixture was reacted at 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 8d (400 mg, yield: 74.9%). MS m / z (ESI): 287.2[M-1]

[0278] Step 4 N-(5-((1H-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-methyl-2-(2,2,2-trifluoroethoxy)benzenesulfamide 8 Two g (50 mg, 0.185 mmol) of compound 8d (130 mg, 0.450 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) to obtain the title product 8 (10 mg, yield: 10.3%). MS m / z (ESI): 522.8 [M+1]. 1H NMR (500 MHz, DMSO-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-5-fluoro-2-methoxybenzenesulfamide 9 [ka] [ka] Two g (50 mg, 0.185 mmol) of the compound and two (200 mg, 0.890 mmol) of 5-fluoro-2-methoxybenzenesulfonyl chloride 9a were dissolved in 2.0 mL of pyridine and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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%~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-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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-necked flask. The mixture was cooled to -78°C under a nitrogen atmosphere, and n-butyllithium (1.3 mL, 2.5 M, 3.25 mmol) was added dropwise. After addition was complete, the reaction was stirred at -78°C for 1 hour. Sulfuryl chloride (0.3 mL, 3.71 mmol) was added, and after addition was complete, the reaction was raised to room temperature and stirred for 1 hour. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The mixture was concentrated, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 10b (200 mg, yield: 26.9%). 1 H NMR (500 MHz, CDCl3) δ 7.70 (t, 1H), 7.12 (d, 1H), 7.05 (dt, 1H),4.10 (s, 3H).

[0282] Step 2 N-(5-((1H-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-2-methoxy-6-(trifluoromethoxy)benzenesulfamide 10 Two g (50 mg, 0.185 mmol) of compound 10b (200 mg, 0.688 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) to obtain the title product 10 (3.0 mg, yield: 3.09%). MS m / z (ESI): 524.8 [M+1]. 1H NMR (500 MHz, CD3OD) 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-pyrazole-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 (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 minutes. In an ice bath, sodium borohydride cyanohydride (800 mg, 12.7 mmol) was added and stirred at room temperature for 16 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) to concentrate the organic phase. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 11b (930 mg, yield: 40.8%). MS m / z (ESI): 230.0 [M+1]. 1 H NMR (500 MHz, CDCl3) 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 11b (900 mg, 3.91 mmol) and anhydrous tetrahydrofuran (15 mL) were added to a 100 mL three-necked flask. The mixture was cooled to -70°C under a nitrogen atmosphere, and n-butyllithium (2.0 mL, 2.5 M, 5.0 mmol) was added dropwise. After addition was complete, the mixture was stirred at -70°C for 1 hour. Homemade sulfur dioxide was passed through for 10 minutes, and the mixture was stirred for 30 minutes. N-chlorosuccinimide (700 mg, 5.24 mmol) was then added. After addition was complete, the mixture was raised to room temperature and reacted for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The mixture was concentrated, and the resulting residue was purified using eluent system A by silica gel column chromatography 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-4-(dimethylamino)-2-methoxybenzenesulfamide 11 Two g (40 mg, 0.148 mmol) of compound 11c (50 mg, 0.200 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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%~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]. 1H NMR (500 MHz, CD3OD) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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 hour. After cooling to room temperature, sulfoxide chloride (2.2 g, 18.5 mmol) was added dropwise, and after the addition was complete, the reaction was heated to 70°C and continued for 2 hours. Then, after cooling to room temperature, ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL), concentrated, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 12b (3.2 g, yield: 87.9%). 1H NMR (500 MHz, CDCl3) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-2,3-dihydrobenzofuran-7-sulfamide 12 Two g (50 mg, 0.185 mmol) of compound 12b and two (200 mg, 0.915 mmol) of compound 12b were dissolved in 2.0 mL of pyridine and purged three times with nitrogen gas. The reaction mixture was incubated at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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%~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-d6) 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-pyrazole-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 hours. The reaction solutions were washed with 1 M dilute hydrochloric acid (50 mL), water, and saturated sodium chloride aqueous solution, and concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 13b (6.3 g, yield: 95.7%). 1 H NMR (500 MHz, CDCl3) 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 sodium chloride aqueous solution (100 mL), respectively, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 13c (2.5 g, yield: 77.9%). 1 H NMR (500 MHz, CDCl3) 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 gradually 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), the pH of the reaction mixture was adjusted to 3 with 20% sodium hydroxide aqueous solution, filtered, 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 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 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 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, and thionyl chloride (4.0 mL) was gradually added dropwise. The reaction was carried out at 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain 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-pyrazole-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 2 g (60 mg, 0.222 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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%~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-d6) 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-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), and tetrabutylammonium tribromide (7.1 g, 14.7 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solutions were washed with 1 M dilute hydrochloric acid (50 mL), water, and saturated sodium chloride aqueous solution, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 14b (2.9 g, 1 An isomer was shown by NMR to contain approximately 20% Br at the para position of the isopropyl group; overall yield: 95.7%, proceeded directly to the next step. 1 H NMR (500 MHz, CDCl3) 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 sodium chloride aqueous solution (100 mL), respectively, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 14c (2.4 g, 1 An isomer was shown by NMR to contain approximately 10% Br at the para position of the isopropyl group; overall yield: 77.7%, proceeded 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 In an ice bath, compound 14c (2.4 g, 10.5 mmol) was gradually added to concentrated sulfuric acid (6.0 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (90 mL), the pH of the reaction mixture was adjusted to 3 with 20% aqueous sodium hydroxide solution, filtered, the filter cake was washed with water (100 mL), and dried to obtain 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. The mixture was filtered, and 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, and thionyl chloride (4.0 mL) was gradually added dropwise. The reaction was carried out at 85°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain 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-pyrazole-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazole-9-yl)-4-isopropyl-2-methoxybenzenesulfamide 14 Compound 14f (250 mg, 1.01 mmol) and compound 2 g (60 mg, 0.222 mmol) were dissolved in pyridine (2.0 mL) and purged three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting 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%~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-d6) 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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, CDCl3): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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, CDCl3): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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, in a 2.5 M solution of n-hexane) 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 carried out at -70°C for 1 hour with stirring under nitrogen protection. Sulfur dioxide gas was passed through the reaction mixture at -70°C for 30 minutes. N-chlorosuccinimide (496.0 g, 3.8 mmol) was added, and the temperature was gradually raised to room temperature, after which the reaction was carried out at room temperature for 2 hours. The reaction mixture was washed with saturated sodium bisulfite 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 using eluent system A to obtain the title product 17b (390.0 mg, yield: 78.0%).

[0308] Step 2 N-(4-((1H-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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, compound 17b (78.0 mg, 0.35 mmol) in tetrahydrofuran (0.5 mL) was added dropwise. The reaction system was gradually raised to room temperature, and then the reaction was carried out at room temperature with stirring for 16 hours. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by high-performance liquid chromatography (Welch Xtimate C18, 5 μm, 30 × 150 mm, eluent: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 20% (v / v) to 34% (v / v) within 14 minutes, detection wavelengths 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, CD3OD): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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]. 1H NMR (400 MHz, CDCl3): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazole-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, prepared by the method disclosed in "Intermediate 1D on page 65 of the specification in patent application WO2017218960A1") was added to dichloromethane (5 mL), and 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione (291 mg, 0.67 mmol) was gradually added at 0°C, and the mixture was reacted at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography 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), and n-butyllithium (0.69 mL, 1.72 mmol, in a 2.5 M solution of tetrahydrofuran) 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, and 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazole-8-yl)-5-methoxy-2,3-dihydrobenzofuran-6-sulfamide 19 Compound 19c (194 mg, 0.78 mmol) and 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 mixture was stirred overnight at room temperature. 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% aqueous ammonia): B - acetonitrile = 5%~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]. 1H NMR (400 MHz, DMSO-d6): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting 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) to obtain the title product 20 (19 mg, yield: 11.4%). MS m / z (ESI): 427.1 [M+1]. 1 H NMR (500 MHz, CD3OD) 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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, CDCl3): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature, 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% aqueous ammonia): B-acetonitrile = 5%~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-d6): 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-pyrazole-1-yl)methyl)-2,3-dihydrobenzofluoro[7,6-d]isoxazole-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 mixture was allowed to react at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting 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%~40% (10 min), flow rate: 30 mL / min) to obtain the title product 23 (16 mg, yield: 10.0%). MS m / z (ESI): 511.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 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-(pyridine-2-ylmethyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-8-yl)benzenesulfamide 24 [ka] [ka]

[0319] Step 1 4-Bromo-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture was stirred at 65°C for 16 hours. The reaction mixture 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-dihydrobenzofl[7,6-d]isoxazole-8-yl)-2,6-dimethoxybenzenesulfamide 24b Compound 24a (300 mg, 1.18 mmol) and compound 10 (835 mg, 3.53 mmol) were dissolved in pyridine (8 mL), 4-dimethylaminopyridine (29 mg, 0.24 mmol) was added, and the mixture was substituted three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting 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) 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(pyridine-2-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-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 mixture, and the mixture was stirred overnight at room temperature. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture, 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(pyridine-2-yl)methyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-8-yl)-2,6-dimethoxybenzenesulfamide 24d Compound 24c (5 mg, 0.01 mmol) was added to dichloromethane (5 mL), and thionyl chloride (13 mg, 0.1 mmol) was gradually added dropwise. The mixture was reacted 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 obtain 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-(pyridine-2-ylmethyl)-2,3-dihydrobenzofl[7,6-d]isoxazole-8-yl)benzenesulfamide 24 Compound 24d (5 mg, 0.01 mmol) was added to acetic acid (1 mL), and zinc powder (1 mg, 0.015 mmol) was added. The reaction was carried out at 60°C for 3 hours. The reaction 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% aqueous ammonia): 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-d6): 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-dihydrobenzofl[7,6-d]isoxazole-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), substituted three times with nitrogen gas, and palladium acetate (28 mg, 0.12 mmol), triphenylphosphine (65 mg, 0.24 mmol), and potassium carbonate (345 mg, 2.49 mmol) were added. The reaction mixture was allowed to react at 110°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain 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-dihydrobenzoflo[7,6-d]isoxazole-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 mixture was stirred at 70°C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 25c (22 mg, yield: 21.0%). MS m / z (ESI): 243.0 [M+1]. 1 H NMR (500 MHz, CDCl3) 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-dihydrobenzofl[7,6-d]isoxazole-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 three times with nitrogen gas. The reaction mixture was reacted at 120°C under microwave conditions for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting 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 25 (5 mg, yield: 13.3%). MS m / z (ESI): 413.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 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-dihydrobenzofl[7,6-d]isoxazole-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 three times with nitrogen gas, and palladium acetate (30 mg, 0.13 mmol), triphenylphosphine (60 mg, 0.22 mmol), and potassium carbonate (320 mg, 2.31 mmol) were added. The reaction mixture was allowed to react at 110°C for 16 hours. The reaction mixture was cooled to room temperature, purged three times with hydrogen gas, and allowed to continue reacting at room temperature for 6 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (Sharpsil-T Prep C18 8μm 50×250 mm, mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile = 18%~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, CDCl3) 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] Examples 26-1 and 26-2 (R)-2,6-dimethoxy-N-(4-(tetrahydrofuran-2-yl)-2,3-dihydrobenzofl[7,6-d]isoxazole-8-yl)benzenesulfamide 26-1 (S)-2,6-dimethoxy-N-(4-(tetrahydrofuran-2-yl)-2,3-dihydrobenzofl[7,6-d]isoxazole-8-yl)benzenesulfamide 26-2 [ka] [ka] Compound 26 (203 mg, 0.45 mmol) was chiral-parited (separation conditions: CHIRALPAK IE chiral preparative column, 20 × 250 mm, mobile phase: n-hexane / ethanol / trifluoroacetic acid = 60 / 40 / 0.1 (V / V / V), flow rate: 20 mL / min), the corresponding components were collected and concentrated under reduced pressure to obtain 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 minutes, 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, CDCl3) 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 minutes, 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)). 1H NMR (500 MHz, CDCl3) 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 following provides further details and explanations of this disclosure, along with examples of tests, but these examples are not intended to limit the scope of this 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 (Biotechnology B548140-0500) 4.5 M NaCl solution (Biological Engineering, 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. Biotin-labeled recombinant histone H3.1 (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 (CST 9441S) 15. PHERA star plate reader (BMG Labtech)

[0334] 2. Experimental Method 1. Preparation of reagents a. 1× 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 of 1.25 nM, prepared with 1× detection buffer. c. Mixed substrate of Ac-CoA and H3: A mixed substrate of Ac-CoA with a final concentration of 1000 nM and H3 with a final concentration of 55 nM, prepared with 1× detection buffer. d. Compounds: Initial concentration 100 μM, 3-fold dilution, 10 concentration gradients. All concentration compounds were diluted 83-fold with 1× detection buffer and prepared for use. e. Detection reagent: AlphaScreen protein A acceptor beads with a final concentration of 8 ng / μL prepared with 1× detection buffer, 8 ng / μL of AlphaScreen streptavidin donor beads, acetylated lysine antibody diluted 1:1500, and 100 μM anacardic acid.

[0335] 2. Experimental Procedure a. 3 μL of the prepared enzyme solution was added to each well of a 384-well plate, and 3 μL of 1× detection buffer was added to the wells in rows 23 and 24 (min). b. Add 3 μL of compound solution to each well, add 3 μL of buffer to each well in the minimum row, and add 3 μL of DMSO solution as a control to each well in the first and second rows (maximum). Centrifuge, mix homogeneously, shake for 2 minutes, and incubate at room temperature for 15 minutes. c. Add 6 μL of the Ac-CoA and H3 mixed substrate to each well, centrifuge, mix uniformly, shake for 2 minutes, and incubate at room temperature for 20 minutes. d. Add 6 μL of detection reagent to each well, centrifuge, mix uniformly, shake for 2 minutes, and incubate in the dark at room temperature for 120 minutes. e. The plates were read using a plate reader, and the counted values ​​were recorded using AlphaScreen. f. Plotted using Graphpad software, compound IC 50 The value was calculated.

[0336] Table 1 IC of inhibition of human KAT6A enzyme by the compounds relating to this disclosure 50 value [Table 11] Conclusion: The compounds described 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 (Biotechnology, A500023-0100) 3. 2 M Tris-HCl solution, pH 7.8, sterile (Biotechnology 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. Biotin-labeled recombinant histone H3.1 (human) (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] 2. Experimental Method 1. Preparation of reagents a. 1× 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: Final concentration of 3 nM, prepared with buffer 2. c. Mixed substrate of Ac-CoA and H3: A mixed substrate of Ac-CoA with a final concentration of 30 nM and H3, prepared in buffer 2. d. Compounds: Initial concentration 10 mM, 4-fold dilution, 10 concentration gradients. All concentration compounds were diluted 2500-fold with buffer 2 and prepared for use. e. Detection reagent: AlphaScreen protein A acceptor beads at a final concentration of 8 ng / μL prepared in buffer 2, AlphaScreen streptavidin donor beads at 8 ng / μL, acetylated lysine antibody diluted 1:1000, and 100 μM anacardic acid.

[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 of the Min and Max wells as a control, and the plates were centrifuged. b. Add 2 μL of the prepared enzyme solution to each well, and add 2 μL of buffer 2 to the minimum. Centrifuge, mix homogeneously, shake for 2 minutes, and incubate at room temperature for 10 minutes. c. Add 4 μL of the Ac-CoA and H3 mixed substrate to each well, centrifuge, mix uniformly, shake for 2 minutes, and incubate at room temperature for 120 minutes. d. Add 4 μL of detection reagent to each well, centrifuge, mix uniformly, shake for 2 minutes, and incubate in the dark at room temperature for 120 minutes. e. The plates were read using a plate reader, and the counted values ​​were recorded using AlphaScreen. f. Using the log(inhibitor) vs. response function of GraphPad Prism software, plot the dose-response curve with the logarithmic value of compound concentration on the x-axis and the calculated enzyme activity inhibition rate on the y-axis. 50 The result was calculated.

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

[0341] Test Example 3: Acetylation IF assay (Immunofluorescence) of H3K23 in U2OS cells 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) 5.96-well assay plate with clear black bottom (Corning, 3603) 6. Bovine serum albumin (BSA) (Sangon Biotech, A500023-0100) 7. Methanol (GENMERAL-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 (1×) (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] 2. Experimental Method 1. Preparation of reagents a. Blocking buffer: PBS (Shanghai Yuanpei) + BSA (final concentration 1%) + Triton X-100 (final concentration 0.5%). b. Washing buffer: PBS (20×PBS diluted to 1×PBS) + Tween-20 (final concentration 0.1%). c. Primary antibody solution: Recombinant anti-histone H3 (acetyl group K23) antibody was diluted with blocking buffer at a dilution ratio of 1:1000. d. Secondary antibody solution: Goat anti-rabbit IgG (H+L), Superclonal® recombinant secondary antibody, and Alexa Fluor 488 were diluted at a 1:1000 ratio, and Hoechst 33342 was diluted at a 1:5000 ratio, using blocking buffer. e. Compounds: Initial concentration 100 μM, 3-fold dilution, 9 concentration gradients. All concentration compounds were diluted 500-fold in McCoy's 5A medium and prepared for use.

[0343] 2. Experimental Procedure 2.1 Cell processing (Day 1) a. The state of U-2 OS cells was observed under a microscope, and it was confirmed that the degree of cell fusion was approximately 90%. b. Remove the cell supernatant, rinse once with DPBS, and discard the DPBS. Add an appropriate amount of trypsin to digest the cells and let stand at room temperature or 37°C for 5 minutes. c. Digestion was stopped with a medium containing 10% of an equal volume of 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. The cell suspension was diluted and seeded into plates at a rate of 9000 cells / 50 μL / well. The surrounding wells were blocked with 100 μL of PBS. g. The cell culture plates were placed in an incubator at 37°C with 5% carbon dioxide and incubated overnight. 2.2 Medication administration (Day 2) a. In each cell plate, 50 μL of diluted compound was added to 50 μL / well of cell supernatant. b. Cell plates treated with the drug were incubated at 37°C in a 5% carbon dioxide incubator for 24 hours. 2.3 Immunofluorescence staining and detection (Days 3-4) a. After culturing the cells in the incubator for 24 hours, the cell plate was removed, the culture medium was removed, and pre-cooled methanol was added and the plate was fixed at room temperature for 10 minutes. b. Remove the fixative, perform three high-speed washes with washing buffer, and then three low-speed washes (5 minutes / wash). c. Remove the wash buffer, add the blocking buffer, and incubate at room temperature for 60 minutes. d. The blocking buffer was removed, and the prepared primary antibody solution was added and incubated overnight at 4°C. 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, perform three high-speed washes with washing buffer, and then five low-speed washes (5 minutes / wash). g. Detected using ImageXpress® Micro Confocal. h. Plot the average fluorescence intensity data of each cell using Graphpad software and analyze the IC of the compound. 50 The values ​​and Imax% were calculated.

[0344] Table 3 Inhibition of H3K23 acetylation of compounds related to this disclosure (IC) 50 Value and maximum inhibition rate [Table 13] Conclusion: The compounds described herein have excellent inhibitory activity against H3K23 acetylation.

[0345] Experiment Example 4: ZR-75-1 Propagation Experiment 1. Reagents and Equipment 1. ZR-75-1 (ATCC CRL1500) 2.1640 medium (Gibco, 22400-089) 3.0.25% trypsin-EDTA (1×) (Gibco, 25200-072) 4. Penicillin-streptomycin (Gibco, 15140-122) 5.DPBS(1×)(Gibco, 14190-144) 6. FBS (Gibco, 10091148) 7.96-well bottom transparent black detection plate (Corning, 3603) 8.96-well non-treated round bottom 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] 2. Experimental Method 1. Seeding of cells onto plates (Day 0) a. The state of the cells was observed under a microscope to ensure that the degree of cell fusion was approximately 90%. b. Remove the cell supernatant, rinse once with DPBS, and discard the DPBS. Add an appropriate amount of trypsin to digest the cells and let stand at 37°C for 5 minutes. c. Digestion was terminated with 1640 medium containing 10% of an equal volume of 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. Dissolve the cell suspension in 1640 medium containing 10% FBS in 5 × 10⁶ cells. 4 The solution was diluted to 50 μL / well at a concentration of 2500 cells / well for ZR-75-1. f. The cell culture plates were placed in an incubator at 37°C with 5% carbon dioxide and incubated overnight.

[0347] 2. Medication administration (Day 1) a. Each compound was gradient diluted with DMSO to nine concentration points (initial concentration 100 μM, 3-fold dilution; different compounds had different maximum concentrations at IC). 50 (Adjustable according to the requirements). For example, in a 96-well round-bottom plate, 3 μL of the compound was successively gradient-diluted in 6 μL of DMSO. b. Each concentration point of each compound was diluted 500-fold in the corresponding volume of 1640 medium. c. 50 μL of the diluted compound solution was sequentially added to 50 μL / well of the cell supernatant in each cell plate. d. Cell plates treated with the drug were cultured in an incubator at 37°C with 5% carbon dioxide.

[0348] 3. Further digestion, seeding onto plates, and application of pesticides (Day 7) a. Six days after drug addition, the culture medium containing the drug was removed, and after adding 150 μL / well of DPBS and rinsing once, the DPBS was immediately aspirated and removed. b. The cells were digested by adding 50 μL of trypsin, allowed to stand at 37°C for 3 minutes, and then digestion was stopped by adding 1640 medium containing 10% FBS at a rate of 150 μL / well. c. The cells were pipetted using a multichannel pipette to mix them uniformly and reseed onto plates in a 1:8 ratio, i.e., 25 μL of cell suspension was aspirated and placed into a new 96-well plate (25 μL of 1640 medium containing 10% FBS was pre-added to the new plate). d. Compound preparation and drug addition were carried out in 50 μL / wells according to steps a. to c. in 2. e. Cell plates treated with the drug were cultured in an incubator at 37°C with 5% carbon dioxide.

[0349] 4. CTG assay (Day 14) a. Before use, allow the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to equilibrate at room temperature, then mix them thoroughly and uniformly to prepare 100 mL of CellTiter-Glo reagent (or, remove the mixed CellTiter-Glo reagent from -20°C and equilibrate at room temperature). b. The 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 while shaking for 2 minutes. d. After leaving the samples at room temperature for 28 minutes and allowing the signal to stabilize, they were detected using PHERAstar FS.

[0350] Table 4 IC of the inhibitory effect of the compounds relating to this disclosure on ZR-75-1 proliferation 50 Value and maximum inhibition rate [Table 14] Conclusion: The compounds described herein have excellent inhibitory effects on the proliferation of ZR-75-1.

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

[0352] 2. Test Plan 2.1 Test drug These were compound 2, compound 7, compound 21, and compound 23. 2.2 Test Animals Sixteen SD rats, with an equal number of males and females, provided by Weitong Lihua Laboratory Animal Technology Co., Ltd., were divided into four equal groups. After fasting overnight, each group received intragastric administration. 2.3 Preparation of drugs A fixed amount of each test compound was weighed, and 5% DMSO, 5% Tween 80, and 90% physiological saline were added to prepare a 0.2 mg / mL colorless, transparent solution. 2.4 Administration The administered dose was 2.0 mg / kg, and the administered volume was 10.0 mL / kg.

[0353] 3.Operation 0.1 mL of blood was collected from the orbit 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. The blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour. The plasma was then stored at -20°C for measurement. The entire process from blood collection to centrifugation was performed under ice bath conditions. The subjects were fed 2 hours after administration. The content of compounds awaiting measurement in the plasma of SD rats after administration of various drug concentrations was measured as follows: 25 μL of plasma samples were taken from SD rats at each time point after administration. 25 μL of camptothecin (internal standard for compound 2, 100 ng / mL), 50 μL of tolbutamide (internal standard for compound 7, 100 ng / mL), or 50 μL of verapamil (internal standard for compounds 21 and 23, 100 ng / mL) was added to each sample. 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 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. Results of pharmacokinetic parameters

[0355] Table 5 Compound Pharmacokinetic Parameters Related to This Disclosure [Table 15] Conclusion: The compounds described herein exhibit pharmacokinetic advantages in SD rats, including high blood drug concentrations, high exposure levels, and low clearance.

[0356] 2. C57 Mouse Test 1. Summary Using C57 mice as test animals, the drug concentrations in the plasma of C57 mice were measured at different time points after intragastric (ig) / intravenous (iv) administration of the compounds relating to this disclosure by LC / MS / MS. The pharmacokinetic behavior of the compounds relating to this disclosure in C57 mice was studied, and their pharmacokinetic characteristics were evaluated.

[0357] 2. Test Plan 2.1 Test drug These were compound 2 and compound 3. 2.2 Test Animals Thirty-six C57 rats, with an equal number of males and females, provided by Weitong Lihua Laboratory Animal Technology Co., Ltd., were divided equally into four groups of nine rats each, with three rats in each group at each time point. The rats were administered via intragastric and intravenous injection, respectively. 2.3 Preparation of drugs A fixed amount of each test compound was weighed, and 5% DMSO + 5% Tween 80 + 90% physiological saline was added to prepare a 0.1 mg / mL colorless transparent solution (intragastric administration group) and a 0.1 mg / mL colorless transparent solution (intravenous injection administration group). 2.4 Administration Intragastric administration group: The dose was 2.0 mg / kg, and the volume of administration was 0.2 mL / 10 g. Intravenous injection group: The dose was 1.0 mg / kg, and the volume of administration was 0.1 mL / 10 g.

[0358] 3.Operation Intragastric administration group: 0.1 mL of blood was collected 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. The blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour. The sample was then stored at -80°C for measurement. The process from blood collection to centrifugation was performed under ice bath conditions. Intravenous injection group: Blood samples were collected before administration, 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, and processed in the same manner as the gastric administration group. The content of compounds awaiting measurement in the plasma of C57 rats after administration of various drug concentrations was measured as follows: 25 μL of plasma samples were taken from C57 rats at each time point after administration. 50 μL of diclofenac (internal standard for compound 2, 100 ng / mL) or 25 μL of tolbutamide (internal standard for compound 3, 10 μg / mL, purchased from LGC, UK) was added to each sample. 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 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. Results of pharmacokinetic parameters Table 6 Compound Pharmacokinetic Parameters Related to This Disclosure [Table 16] Conclusion: The compounds described herein exhibit pharmacokinetic advantages in C57 rats, including high blood drug concentrations, high exposure levels, low clearance, and a relatively long half-life.

Claims

1. A compound represented by general formula (I) or a medicinal salt thereof, 【Chemistry 1】 Of these, ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group. Ring B is a 4- to 7-membered heterocyclyl group, and this 4- to 7-membered heterocyclyl group contains 1 to 3 oxygen atoms. L is a chemical bond, Each R １ and each R ２ are the same or different and each independently is a hydrogen atom, halogen, cyano group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, 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 selected from, 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 a 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 or heterocyclyloxy group, R3 can be a hydrogen atom, halogen, cyano group, nitro group, alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR5, -C(O)R6, -C(O)OR6, -OC(O)R6, -NHC(O)OR6, -NR7R8, -C(O)NR7R8, -S(O)rR6 or -S(O)rNR7R8 Selected from, of which the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from hydroxyl 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 or 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 This is selected from hydrogen atoms, hydroxyl groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, or cycloalkyl groups. Each R ４ａ They are the same or different, and each is independently a hydrogen atom, hydroxyl group, halogen, cyano 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, heterocyclyloxy group, or -NR ９ R １０ Selected from, R ５ , R ６ These groups are identical or different, and each is 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, and among these, the alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from a hydroxyl 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, or heterocyclyloxy group. R ７ , R ８ , R ９ , R １０ They are the same or different and each is independently selected from a hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and of which the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are independently and optionally substituted with one or more substituents selected from a hydroxyl 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 or heterocyclyloxy group, Or, R ７ and R ８ It forms a heterocycline group with the linked N atom, or R ９ and R １０ This group forms a heterocyclyl group together with the linked N atom, and the heterocyclyl group is optionally substituted with one or more substituents selected from a hydroxyl 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, or heterocyclyloxy group. 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 general formula (I) or a medicinal salt thereof.

2. A compound represented by general formula (I) or a medicinal salt thereof, 【Transformation 3】 Of these, ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group. Ring B is a 4- to 7-membered heterocyclyl group, and this 4- to 7-membered heterocyclyl group contains 1 to 3 oxygen atoms. L is a chemical bond, Each R １ , and each R ２ They are the same or different, and each is independently a hydrogen atom, halogen, cyano group, nitro group, oxo group, alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, 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 Selected from, of which the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from hydroxyl 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 or heterocyclyloxy group. R3 can be a hydrogen atom, halogen, cyano group, nitro group, alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -OR5, -C(O)R6, -C(O)OR6, -OC(O)R6, -NHC(O)OR6, -NR7R8, -C(O)NR7R8, -S(O)rR6 or -S(O)rNR7R8 Selected from, of which the alkenyl group, alkynyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from hydroxyl 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 or heterocyclyloxy group. R ４ is a hydrogen atom or 【Chemistry 4】 And, The ring C is an aryl group or a heteroaryl group. R ０ This is selected from hydrogen atoms, hydroxyl groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, or cycloalkyl groups. Each R ４ａ These are identical or different and independently hydrogen atoms, hydroxyl groups, halogens, cyano groups, nitro groups, oxo groups, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, cycloalkyloxy groups, heterocyclyloxy groups, or -NR ９ R １０ Selected from, R ５ , R ６ These groups are identical or different, and each is 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, and among these, the alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally substituted with one or more substituents selected from a hydroxyl 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, or heterocyclyloxy group. R ７ , R ８ , R ９ , R １０ They are the same or different and each is independently selected from a hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and of which the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are independently and optionally substituted with one or more substituents selected from a hydroxyl 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 or heterocyclyloxy group, Or, R ７ and R ８ It forms a heterocycline group with the linked N atom, or R ９ and R １０ This group forms a heterocyclyl group together with the linked N atom, and the heterocyclyl group is optionally substituted with one or more substituents selected from a hydroxyl 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, or heterocyclyloxy group. 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 general formula (I) or a medicinal salt thereof.

3. R ３ That is a hydrogen atom. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

4. R ４ but 【Transformation 5】 The ring C is a 5-membered or 6-membered heteroaryl group, and R ４ａ n is as defined in claim 1, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

5. A compound represented by general formula (II) or a medicinal salt thereof, 【Transformation 6】 Eventually, The ring C is a 5-membered 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. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

6. Ring A is a 6-10 membered aryl group. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

7. Ring A is a phenyl group, 【Transformation 7】 Selected from the group consisting of, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

8. Ring A is a phenyl group, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

9. Ring B is a 5- or 6-membered heterocyclyl group, the 5- or 6-membered heterocyclyl group contains 1 or 2 oxygen atoms. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

10. A compound represented by general formula (III) or a medicinal salt thereof, 【Transformation 8】 Eventually, X is O, CR ａ R ｂ Or selected from C=O, Each R ａ , R ｂ , R ｃ and R ｄ They are the same or different and independently selected from hydrogen atom, hydroxyl group, halogen, cyano group, amino group, alkenyl group, alkynyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkyloxy group or heterocyclyloxy group, Or, R ｃ , R ｄ It forms one C=O with the linked carbon atoms, s is 0, 1, 2, or 3. n is 0, 1, 2, or 3. L, R １ , R ４ａ p is as defined in claim 1 or 2, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

11. R ｃ and R ｄ are the same or different and each is independently a hydrogen atom or a halogen, and / or X is O or CH ２ And / or s is 1 or 2, A compound represented by general formula (I) as described in claim 10, or a medicinal salt thereof.

12. Each R １ is the same or different and independently is a hydrogen atom, a hydroxy group, a halogen, C １－６ ~ １－６ an alkyl group, C １－６ a haloalkyl group, C １－６ a hydroxyalkyl group, C １－６ an alkoxy group, C １－６ a haloalkoxy group, C １－６ an alkoxyC 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 is a hydrogen atom or a C １－６ alkyl group. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

13. Each R1 is the same or different and independently a C1-6 alkoxy group, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

14. Each R ２ is the same or different and independently is a hydrogen atom, halogen, C １－６ alkyl group or C １－６ alkoxy group, selected from A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

15. R2 is a hydrogen atom, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

16. Each R ４ａ They are the same or different, and independently of a hydrogen atom, hydroxyl group, halogen, C １－６ alkyl group, C １－６ Hydroxyalkyl group or C １－６ Selected from alkoxy groups, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

17. R 4a is a hydrogen atom, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

18. The following compounds: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof, selected from the group of compounds consisting of the above.

19. A compound represented by general formula (IA) or a salt thereof, 【Chemistry 12】 Eventually, Ring B, R ２ , R ３ , R ４ and q are as defined in claim 1 or 2, A compound represented by general formula (IA) or a salt thereof.

20. The following compounds or their salts: 【Chemistry 13】 Selected from the group consisting of, A compound or a salt thereof.

21. A method for preparing a compound represented by general formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, 【Chemistry 14】 The process includes 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, Eventually, Ring A, Ring B, L, R １ ~R ４ p and q are as defined in claim 1 or 2, method.

22. A compound represented by general formula (I) as described in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients, Pharmaceutical composition.

23. A compound represented by general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for inhibiting KAT.

24. The compound according to claim 23, wherein the KAT is KAT6.

25. A compound represented by general formula (I) according to any one of claims 1 to 18 or a medicinal salt thereof, or a pharmaceutical composition according to claim 22, for treating and / or preventing cancer.

26. The cancer is selected from 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 lymphoma, esophageal cancer, colorectal cancer, small intestine cancer, stomach 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 tumor, glioma, cerebral glioma, pituitary adenoma, or squamous cell carcinoma. The compound according to claim 25.

Images