Sulfonamide compound, and preparation method therefor and use thereof

Abstract

The present disclosure relates to a substituted sulfonamide derivative of formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the treatment and / or prevention of cancers in which lysine acetyltransferase 6A / B (KAT6A / B) plays a role.

Description

A sulfonamide compound, its preparation method and use Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a method for preparing a substituted sulfonamide compound and its use. Specifically, the present disclosure relates to a substituted sulfonamide compound of formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use for treating and / or preventing cancers in which lysine acetyltransferase 6A / B (KAT6A / B) plays a role. Background Art

[0002] Lysine acetyltransferases (KATs) catalyze the acetylation of the ε-amino group of lysine residues on histone and non-histone proteins using acetyl-CoA as an acetyl donor. Acetylation, as a reversible post-translational modification, affects protein function and gene expression through multiple mechanisms, including regulation of protein stability, enzyme activity, subcellular localization, interactions with other types of post-translational modifications, and protein-DNA interactions.

[0003] Based on amino acid sequence homology, KATs can be divided into four subfamilies: the MYST family, the p300 / CBP family, the SRC / p160 family, and the GNAT family. The largest subfamily is the MYST family, whose name is composed of the initial letters of four previously discovered members: MOZ, Ybf2, Sas2, and Tip60. The mammalian MYST family has five members: KAT5 (TIP60), KAT6A (MOZ; MYST3), KAT6B (MORF; MYST4), KAT7 (HBO; MYST2), and KAT8 (MOF; MYST1). All of these genes have homologous genes in humans.

[0004] Members of the MYST family of proteins all contain a highly conserved MYST domain. This domain functions as an adaptor protein, interacting with other proteins to form protein complexes. Reports have also suggested that the MYST domain may possess DNA binding capabilities. Furthermore, zinc finger and chromatin binding domains are characteristic domains of KATs in this family. MYST family proteins regulate gene transcriptional activity by modulating the acetylation levels of lysine residues on histones (H2A, H3, and H4). Downstream biological functions implicated include the initiation of DNA replication, regulation of gene expression, repair of DNA damage, regulation of Treg cells, maintenance of cell stemness, and the development and differentiation of the central nervous system and hematopoietic system. Abnormal activation of MYST family KATs or their associated complexes can easily lead to uncontrolled cell growth and apoptosis, ultimately contributing to the development of malignant tumors.

[0005] KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (Lysine Acetyltransferase 6B, also known as MORF), key members of the MYST family, are primarily responsible for acetylation of lysine 23 (H3K23) on histone H3. KAT6A also acetylates H3K9 and H3K14. KAT6A and KAT6B regulate a wide range of physiological and pathological functions. They are involved in the development of the nervous system, the development of the cardiac septum, the proliferation and differentiation of hematopoietic progenitor cells, the maintenance of cell stemness, and the development and progression of various tumors and the development of drug resistance.

[0006] Abnormal alterations in the KAT6A gene are closely associated with the development and progression of human tumors. Chromosomal translocations of KAT6A have been reported in hematological malignancies, such as acute myeloid leukemia, forming fusion genes such as KAT6A-CBP, KAT6A-TIF2, KAT6A-NcoA3, KAT6A-LEUTX, and KAT6A-EP300. KAT6A gene amplification has also been observed in various solid tumors, such as breast, ovarian, cervical, lung, colon, and rectal cancers. In breast cancer, KAT6A is located in a region called 8p11-12, where duplications have been found in 10-15% of patients. Chromosomal rearrangements of the KAT6B gene have also been reported in acute myeloid leukemia (e.g., KAT6B-CBP), and upregulation of KAT6B expression has also been observed in breast cancer. In tumor cells harboring KAT6A / B amplification, gene expression is closely correlated with gene copy number. Studies have shown that in breast cancer cells harboring 8p11 amplification, KAT6A protein localizes to the promoter region of the estrogen receptor α (ERα), promoting ERα expression. ShRNA-mediated knockdown of KAT6A reduced ERα mRNA and protein levels. These data suggest that KAT6A positively regulates ERα gene expression and that the growth of ER-positive breast cancer cells is dependent on this gene's expression. Molecular genetic studies have shown that KAT6A knockdown can induce downregulation of ERα expression and inhibit T47D tumor growth in vivo. CTx-648, a small molecule inhibitor of KAT6A / B, has also demonstrated excellent in vitro and in vivo antitumor activity against ER-positive breast cancer in preclinical studies. Beyond ER-positive breast cancer, KAT6A / B inhibitors have shown potential for expanded indications in a variety of other solid tumors. For example, in glioma, KAT6A exerts a pro-oncogenic function, promoting PI3K / AKT signaling activity by binding to TRIM24, thereby promoting glioma cell proliferation and tumor growth.

[0007] Given the important role of KAT6A / B in human diseases such as cancer, inhibitors targeting KAT6A / B have broad application prospects.

[0008] Summary of the Invention

[0009] The application relates to a compound of formula (I) as defined herein, which can be used as a lysine acetyltransferase 6A / B (KAT6A / B) inhibitor. The application is characterized in that the method for treating and / or preventing the cancer in which lysine acetyltransferase 6A / B (KAT6A / B) plays a role is provided, comprising administering a compound of formula (I) as defined herein (including formulas II-1 to VII-3) or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug to a subject in need thereof. The method of the application can be used for treating the cancer in which lysine acetyltransferase 6A / B (KAT6A / B) plays a role by suppressing its activity.

[0010] The first aspect of the present application relates to compounds of formula (I):

[0011] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 7 , X1, X2, X3, Y, Ring A and Z are as described in detail herein below.

[0012] Another aspect of the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0013] Another aspect of the present application relates to a method for inhibiting lysine acetyltransferase 6A / B (KAT6A / B). The method comprises administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same.

[0014] Another aspect of the present application relates to a method for treating cancer in which lysine acetyltransferase 6A / B (KAT6A / B) plays a role. The method comprises administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same. The cancer is preferably selected from the group consisting of lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial carcinoma, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer / endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinus node cell tumor, and tenosynovial giant cell tumor; more preferably selected from the group consisting of breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer / endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer and leukemia; wherein the breast cancer is preferably ER + Breast cancer or ER + / HER2 - Breast cancer; wherein the lung cancer is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.

[0015] The present application further provides compounds and compositions having significantly improved inhibitory activity against lysine acetyltransferase 6A / B (KAT6A / B), significantly improved pharmacodynamics and pharmacokinetics, and / or significantly improved safety profiles relative to known KAT6A / B inhibitors.

[0016] The details of the present application are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. Other features, objects and advantages of the present application will be apparent from the specification and claims. In the specification and the appended claims, the singular also includes the plural, unless the context clearly provides otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present application belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0017] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG1 is a graph showing the effects of compounds on histone acetylation in estrogen receptor-positive breast cancer cells.

[0019] Figure 2 shows the compound in Test Example 5 in ER + KAT6 high Figure 2. Results of tumor volume changes in a tumor inhibition experiment using a xenograft tumor model derived from breast cancer cells.

[0020] Figure 3 shows the compound in Test Example 5 in ER + KAT6 high Figure 2. Results of mouse body weight changes in a tumor inhibition experiment using a xenograft tumor model derived from breast cancer cells.

[0021] Figure 4 shows the compound in Test Example 6 in ER + KAT6 high Figure 2. Results of tumor volume changes in a tumor inhibition experiment using a xenograft tumor model derived from breast cancer cells.

[0022] Figure 5 shows the compound in Test Example 6 in ER + KAT6 high Figure 2. Results of mouse body weight changes in a tumor inhibition experiment using a xenograft tumor model derived from breast cancer cells. DETAILED DESCRIPTION

[0023] definition

[0024] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0025] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight chain or branched chain group (i.e., C 20) containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 alkyl), preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0026] The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon radical, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, and having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 Alkylene), preferably 1 to 12 carbon atoms (ie C 1-12 Alkylene), more preferably 1 to 6 carbon atoms (ie C 1-6Alkylene). 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. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0027] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- is replaced by one or more selected from N, O, S, S(O) and S(O)2; wherein the alkyl group is as defined above; the heteroalkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0028] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0029] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Alkynyl may be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0030] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 3-20 membered cycloalkyl), preferably containing 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., 3-12 membered cycloalkyl), preferably containing 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) carbon atoms (i.e., 3-8 membered cycloalkyl), further preferably containing 4 to 7 (e.g., 4, 5, 6 and 7) carbon atoms (i.e., 4-7 membered cycloalkyl), more preferably containing 3 to 6 (e.g., 3, 4, 5 and 6) carbon atoms (i.e., 3-6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0031] The term " spiroalkyl " refers to 5 to 20 yuan (for example 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e. 5 to 20 yuan spiroalkyl), a polycyclic group sharing a carbon atom (claiming spiral atom) between monocycles, which can contain one or more double bonds. Preferably it is 6 to 14 yuan (i.e. 6 to 14 yuan spiroalkyl), more preferably 7 to 10 yuan (for example 7, 8, 9 or 10 yuan, i.e. 7 to 10 yuan spiroalkyl). According to the number of spiral atoms shared between rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0032] The term "fused cycloalkyl" refers to a full-carbon polycyclic group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 5 to 20-membered fused cycloalkyl), wherein each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered fused cycloalkyl), and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members, i.e., a 7 to 10-membered fused cycloalkyl). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic condensed cycloalkyl groups. Non-limiting examples of condensed cycloalkyl groups include:

[0033] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, i.e., a 5 to 20-membered bridged cycloalkyl), any two rings sharing two carbon atoms that are not directly connected, which may contain one or more double bonds. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members, i.e., a 7 to 10-membered bridged cycloalkyl). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0034] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferably

[0035] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0036] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, it is preferably one or more of the following groups independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0037] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 3- to 20-membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., to form a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms (i.e., 3 to 12-membered heterocyclic 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., 3 to 8-membered heterocyclic group), of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; further preferably, it contains 4 to 7 ring atoms (e.g., 3 to 8-membered heterocyclic group), of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms. Atoms (e.g., 4, 5, 6, and 7, i.e., 4 to 7-membered heterocyclyls), of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, 3 to 6 ring atoms (e.g., 3, 4, 5, and 6, i.e., 3 to 6-membered heterocyclyls), of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; most preferably, 5 or 6 ring atoms (i.e., 5-membered or 6-membered heterocyclyls), of which 1-2 (e.g., 1, 2) are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0038] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic 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), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming 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), and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members, i.e., a 7 to 10-membered spiroheterocyclyl). Spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl according to the number of spirohetero atoms shared between the rings, preferably monospiroheterocyclyl and dispiroheterocyclyl. More preferably, it is a 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. Non-limiting examples of spiroheterocyclyl include:

[0039] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, i.e., a 5 to 20-membered fused heterocyclyl), wherein each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered fused heterocyclyl), and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members, i.e., a 7 to 10-membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0040] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic 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 heterocyclic group), any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered bridged heterocyclic group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members, i.e., a 7 to 10-membered bridged heterocyclic group). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0041] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0042] wait.

[0043] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0044] The term "aryl" refers to a 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, i.e., a 6- to 14-membered aryl) all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered (i.e., a 6- to 10-membered aryl), such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0045] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0046] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 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), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered, i.e., a 5- to 10-membered heteroaryl), more preferably 5 or 6-membered (i.e., a 5- or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0047] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0048] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic" (e.g. etc.), “arylene” and “heteroarylene”.

[0049] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0050] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0051] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0052] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0053] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0054] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0055] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0056] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0057] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0058] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0059] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0060] The term "hydroxy" refers to -OH.

[0061] The term "mercapto" refers to -SH.

[0062] The term "amino" refers to -NH2.

[0063] The term "cyano" refers to -CN.

[0064] The term "nitro" refers to -NO2.

[0065] The term "oxo" or "oxo" refers to "=0".

[0066] The term "carbonyl" refers to C=O.

[0067] The term "aldehyde group" refers to -C(O)H

[0068] The term "carboxy" refers to -C(O)OH.

[0069] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl)(alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0070] On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods well known in the art, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually achieved by using chromatography using a chiral stationary phase and optionally combined with a chemical derivatization method (such as the formation of carbamates from amines).

[0071] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be Or it contains both configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0072] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0073] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0074] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0075] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 Deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds of this disclosure, whether radioactive or not, are encompassed within the scope of this disclosure.

[0076] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0077] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is to be understood as having at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound having at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium can be present. The present disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0078] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0079] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0080] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0081] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and possess the desired biological activity. Salts can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0082] With respect to a drug or pharmacologically active agent, the terms "therapeutically effective amount," "inhibitory effective amount," or "prophylactically effective amount" refer to an amount of the drug or agent sufficient to achieve or partially achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0083] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0084] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0085] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0086] It should be noted that, in the event that the structure of a compound described in this specification is inconsistent with the chemical formula, the structure shall prevail.

[0087] Compounds of the present disclosure

[0088] In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof:

[0089] in:

[0090] Dashed lines are optional chemical bonds;

[0091] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, 6 to 10 membered aryl, 5 to 10 membered heteroaryl and C 1-6 Hydroxyalkyl, or R 4 and R 5 Together with the carbon atoms to which they are attached, they form a 4- to 10-membered heterocyclic group, a 5- to 6-membered heteroaryl group, a 7- to 12-membered spiro heterocyclic group, and an 8- to 15-membered fused heterocyclic group, wherein the 4- to 10-membered heterocyclic group, the 5- to 6-membered heteroaryl group, the 7- to 12-membered spiro heterocyclic group, and the 8- to 15-membered fused heterocyclic group are optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 Cycloalkyl)2, oxo, =CH2, =CHC 1-6 Alkyl, =C(C 1-6 alkyl)2, =CHC 1-6 Haloalkyl, =C(C 1-6 Haloalkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, cyano, benzyl, C 3-6Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated heterocyclic group, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, 6 to 10 membered aryl, 5 to 10 membered heteroaryl and C 2-6 alkenyl;

[0092] Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 10 membered aryl groups, 5 to 10 membered heteroaryl groups containing at least one nitrogen atom, and 6 to 12 membered fused heterocyclic groups; the ring A is optionally substituted by one or more substituents selected from the following: halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkoxy, C 1-6 Haloalkoxy, 3 to 8-membered halocycloalkoxy, oxo and C 2-6 alkenyl;

[0093] X1 is O, S, C or N;

[0094] X2 is N or C;

[0095] X3 is N or CR6;

[0096] R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 Halogenated cycloalkoxy;

[0097] R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 halocycloalkoxy; and

[0098] Y is O or NH; and

[0099] Z is -CH2-, -CF2-, -C(O)-, O, -S(O)-, -S(O)2- or -NH-.

[0100] In some embodiments of the compound of formula (I), X1 is O. In some embodiments of the compound of formula (I), X1 is S. In some embodiments of the compound of formula (I), X1 is C. In some embodiments of the compound of formula (I), X1 is N.

[0101] In some embodiments of the compound of formula (I), X2 is N. In some embodiments of the compound of formula (I), X2 is C.

[0102] In some embodiments of the compound of Formula (I), X3 is N.

[0103] In some embodiments of the compound of formula (I), X3 is CR6, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 Halogenated cycloalkoxy.

[0104] In some embodiments of the compound of formula (I), Z is -CH2-. Alternatively, in some embodiments of the compound of formula (I), Z is -CF2-. Alternatively, in some embodiments of the compound of formula (I), Z is -C(O)-. Alternatively, in some embodiments of the compound of formula (I), Z is O. Alternatively, in some embodiments of the compound of formula (I), Z is -S(O)-. Alternatively, in some embodiments of the compound of formula (I), Z is -S(O)2-. Alternatively, in some embodiments of the compound of formula (I), Z is -NH-.

[0105] In some aspects, the present disclosure provides a compound of formula (II-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0106] in:

[0107] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0108] R 4Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and C 1-6 hydroxyalkyl;

[0109] R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Halogenated cycloalkoxy;

[0110] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0111] Ring M is selected from 4 to 7 membered cycloalkyl and 4 to 7 membered halocycloalkyl;

[0112] Y is O or NH.

[0113] In some embodiments of the compound of Formula (II-1), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (II-1), R 2 and R 3 are the same or different and are each independently selected from hydrogen and halogen. More preferably, in some embodiments of the compound of formula (II-1), R 2 and R 3 All are hydrogen atoms.

[0114] In some embodiments of the compound of Formula (II-1), R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C1-6 Preferably, in some embodiments of the compound of formula (II-1), R 4 is selected from the group consisting of hydrogen, ethyl, isopropyl and tert-butyl. More specifically, in some embodiments of the compound of formula (II-1), R 4 In some other embodiments of the compound of formula (II-1), R 4 In some other embodiments of the compound of formula (II-1), R 4 In some other embodiments of the compound of formula (II-1), R 4 For tert-butyl.

[0115] In some embodiments of the compound of Formula (II-1), R 5 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and Preferably, in some embodiments of the compound of formula (II-1), R 5 is a hydrogen atom or a methoxy group. More specifically, in some embodiments of the compound of formula (II-1), R 5 In some other embodiments of the compound of formula (II-1), R 5 It is a methoxy group.

[0116] In some embodiments of the compound of Formula (II-1), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

[0117] In some embodiments of the compound of formula (II-1), ring M is selected from cyclobutyl and More specifically, in some embodiments of the compound of formula (II-1), ring M is cyclobutyl. In other embodiments of the compound of formula (II-1), ring M is

[0118] In some embodiments of the compound of formula (II-1), Y is O. In other embodiments of the compound of formula (II-1), Y is NH.

[0119] In some aspects, the present disclosure provides a compound of formula (II-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0120] in:

[0121] R 1 Selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0122] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0123] R 4A and R 4B The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 alkyl halide;

[0124] R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Halogenated cycloalkoxy;

[0125] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy;

[0126] Ring M is selected from 4 to 7 membered cycloalkyl and 4 to 7 membered halocycloalkyl;

[0127] Y is O or NH.

[0128] In some embodiments of the compound of formula (II-2), R 1 Selected from methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and

[0129] In some embodiments of the compound of formula (II-2), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (II-2), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom and halogen. More preferably, in some embodiments of the compound of formula (II-2), R 2 and R 3 All are hydrogen atoms.

[0130] In some embodiments of the compound of formula (II-2), R 4A and R 4B All are methyl.

[0131] In some embodiments of the compound of formula (II-2), R 5 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and Preferably, in some embodiments of the compound of formula (II-2), R 5 More specifically, in some embodiments of the compound of formula (II-2), R 5 In some other embodiments of the compound of formula (II-2), R 5 It is a methoxy group.

[0132] In some embodiments of the compound of formula (II-2), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

[0133] In some embodiments of the compound of formula (II-2), ring M is cyclobutyl. In other embodiments of the compound of formula (II-2), ring M is

[0134] In some embodiments of the compound of formula (II-2), Y is O. In other embodiments of the compound of formula (II-2), Y is NH.

[0135] In some aspects, the present disclosure provides a compound of formula (II-3) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0136] in:

[0137] R 1 Selected from C 1-4 Alkoxy, C1-4 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0138] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0139] R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and C 1-6 hydroxyalkyl;

[0140] R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Halogenated cycloalkoxy;

[0141] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy.

[0142] In some embodiments of the compound of formula (II-3), R 1 Selected from methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and

[0143] In some embodiments of the compound of formula (II-3), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (II-3), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom and halogen. More preferably, in some embodiments of the compound of formula (II-3), R 2 and R 3 All are hydrogen atoms.

[0144] In some embodiments of the compound of formula (II-3), R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C 1-6 Preferably, in some embodiments of the compound of formula (II-3), R 4 is selected from the group consisting of a hydrogen atom, an ethyl group, an isopropyl group and a tert-butyl group.

[0145] In some embodiments of the compound of formula (II-3), R 5 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and Preferably, in some embodiments of the compound of formula (II-3), R 5 is a hydrogen atom or a methoxy group.

[0146] In some embodiments of the compound of formula (II-3), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

[0147] In some aspects, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0148] in:

[0149] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0150] R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkoxy and C 1-6 hydroxyalkyl;

[0151] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0152] Y is O or NH.

[0153] In some embodiments of the compound of formula (III), R 1 Selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy.

[0154] In some embodiments of the compound of formula (III), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl.

[0155] Preferably, in some embodiments of the compound of formula (III), R 1 is methoxy, R 2 and R 3 All are hydrogen atoms.

[0156] In some embodiments of the compound of formula (III), R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C 1-6 Hydroxyalkyl.

[0157] Preferably, in some embodiments of the compound of formula (III), R 4 Selected from hydrogen atoms, ethyl, isopropyl, tert-butyl and More preferably, in some embodiments of the compound of formula (III), R 4 A hydrogen atom.

[0158] In some embodiments of the compound of formula (III), R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Preferably, in some embodiments of the compound of formula (III), R 5 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (III), R 5 In some other embodiments of the compound of formula (III), R 5 It is a methoxy group.

[0159] In some embodiments of the compound of formula (III), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

[0160] In some embodiments of the compound of formula (III), Y is O. In other embodiments of the compound of formula (III), Y is NH.

[0161] In some aspects, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0162] in:

[0163] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0164] R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkoxy and C 1-6 hydroxyalkyl;

[0165] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0166] X1 is C or N;

[0167] Y is O or NH.

[0168] In some embodiments of the compound of Formula (IV), R 1 Selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Preferably, in some embodiments of the compound of formula (IV), R 1 It is a methoxy group.

[0169] In some embodiments of the compound of Formula (IV), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Preferably, in some embodiments of the compound of formula (IV), R 2 and R 3 All are hydrogen atoms.

[0170] In some embodiments of the compound of Formula (IV), R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6Heterocyclic and C 1-6 Preferably, in some embodiments of the compound of formula (IV), R 4 Selected from hydrogen atom, ethyl, isopropyl, tert-butyl, and More preferably, in some embodiments of the compound of formula (IV), R 4 A hydrogen atom.

[0171] In some embodiments of the compound of Formula (IV), R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkoxy and C 3-6 Preferably, in some embodiments of the compound of formula (IV), R 5 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (IV), R 5 In some other embodiments of the compound of formula (IV), R 5 It is a methoxy group.

[0172] In some embodiments of the compound of Formula (IV), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

[0173] In some embodiments of the compound of formula (IV), X1 is C. In other embodiments of the compound of formula (IV), X1 is N.

[0174] In some embodiments of the compound of formula (IV), Y is O. In other embodiments of the compound of formula (IV), Y is NH.

[0175] In some aspects, the present disclosure provides a compound of formula (V) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0176] in:

[0177] Dashed lines are optional chemical bonds;

[0178] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; Ring B is selected from 4 to 10 membered heterocyclic groups, 5 to 6 membered heteroaryl groups and 7-12 membered spiroheterocyclic groups; Ring B is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 Cycloalkyl)2, oxo, =CH2, =CHC 1-6 Alkyl, =C(C 1-6 alkyl)2, =CHC 1-6 Haloalkyl, =C(C 1-6 Haloalkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, cyano, benzyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, 6 to 10 membered aryl, 5 to 10 membered heteroaryl and C 2-6 Alkenyl.

[0179] R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 Halogenated cycloalkoxy;

[0180] R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 Halogenated cycloalkoxy;

[0181] X1 is O, S, C or N;

[0182] X2 is N or C;

[0183] Y is O or NH;

[0184] Z is -CH2-, -CF2-, -C(O)-, O, -S(O)-, -S(O)2- or -NH-.

[0185] In some embodiments of the compound of formula (V), X1 is O. In some embodiments of the compound of formula (V), X1 is S. In some embodiments of the compound of formula (V), X1 is C. In some embodiments of the compound of formula (V), X1 is N.

[0186] In some embodiments of the compound of formula (V), X2 is N. In other embodiments of the compound of formula (V), X2 is C.

[0187] In some embodiments of the compound of formula (V), X1 is O or S; X2 is C. Preferably, in some embodiments of the compound of formula (V), X1 is O; X2 is C.

[0188] In some embodiments of the compound of Formula (V), Y is O. In other embodiments of the compound of Formula (V), Y is NH.

[0189] In some embodiments of the compound of formula (V), Z is -CH2-. Alternatively, in some embodiments of the compound of formula (V), Z is -CF2-. Alternatively, in some embodiments of the compound of formula (V), Z is -C(O)-. Alternatively, in some embodiments of the compound of formula (V), Z is O. Alternatively, in some embodiments of the compound of formula (V), Z is -S(O)-. Alternatively, in some embodiments of the compound of formula (V), Z is -S(O)2-. Alternatively, in some embodiments of the compound of formula (V), Z is -NH-.

[0190] In some embodiments of the compound of Formula (V), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (V), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (V), R 1 In some other embodiments of the compound of formula (V), R 1 It is a methoxy group.

[0191] In some embodiments of the compound of Formula (V), R 2 and R 3 are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (V), R 2 and R 3 All are hydrogen atoms.

[0192] In some embodiments of the compound of Formula (V), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. Preferably, in some embodiments of the compound of formula (V), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group. More preferably, in some embodiments of the compound of formula (V), R 6 In some embodiments of the compound of formula (V), R 7 In some other embodiments of the compound of formula (V), R 7 is a fluorine atom.

[0193] In some embodiments of the compound of Formula (V), Ring B is The dotted line represents the chemical bond shared by ring B and the benzene ring, and W is selected from -O-, -NR 9C -、-CR 9D R 9E -、 and -C(O)-, and W is connected to the benzene ring R 3 The adjacent carbon atom of the carbon atom where it is located; p is 0, 1 or 2; R 9A and R 9B are the same or different and are independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 cycloalkyl)2, benzyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl and C 2-6 Alkenyl; R 9D and R9E are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and hydroxy; Ring C is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 12 membered spirocyclyl, 6 to 12 membered heterospirocyclyl and 5 to 12 membered heterobridged ring group; the ring C is optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents of a haloalkyl group; R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group and hydroxyl group, said C 3-6 Cycloalkyl and C 3-6 The heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, methyl and methoxy; R 9M and R 9L are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 Preferably, W is selected from -O-, -NR 9C -、 and -C(O)-. Preferably, W is selected from -O-, -NR 9C -、 More preferably, W is selected from -O- and -NR 9C -. In some embodiments of the compound of formula (V), W is -O-. In some embodiments of the compound of formula (V), W is -NR 9C -.

[0194] Preferably, R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group. More preferably, R 9Aand R 9B All are hydrogen atoms.

[0195] Preferably, R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, heteroaryl and More preferably, R 9C is selected from the group consisting of a hydrogen atom, a methyl group, a deuterated methyl group, an ethyl group, a trifluoroethyl group, a benzyl group, -C(O)OCH3, -C(O)CH3 and -S(O)2CH3.

[0196] Preferably, R 9D and R 9E are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a methyl group and a hydroxyl group. More preferably, R 9D and R 9E are the same or different and are each independently selected from a hydrogen atom, a methyl group and a hydroxyl group.

[0197] Preferably, ring C is selected from and ring C is optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl and C 1-6 More preferably, ring C is selected from

[0198] Preferably, in some embodiments of the compound of formula (V), p is 2. In some embodiments of the compound of formula (V), p is 0 or 1. In some embodiments of the compound of formula (V), p is 1. In other embodiments of the compound of formula (V), p is 0.

[0199] In some aspects, the present disclosure provides a compound of formula (VI-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0200] in:

[0201] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0202] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0203] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0204] R 9A and R 9B are the same or different and are independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0205] Y is O or NH;

[0206] p is 0, 1 or 2.

[0207] In some embodiments of the compound of Formula (VI-1), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VI-1), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (VI-1), R 1 In some other embodiments of the compound of formula (VI-1), R 1 It is a methoxy group.

[0208] In some embodiments of the compound of Formula (VI-1), R 2 and R 3 are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VI-1), R 2 and R 3 All are hydrogen atoms.

[0209] In some embodiments of the compound of Formula (VI-1), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. Preferably, in some embodiments of the compound of formula (VI-1), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group. More preferably, in some embodiments of the compound of formula (VI-1), R 6 In some embodiments of the compound of formula (VI-1), R 7 In some other embodiments of the compound of formula (VI-1), R 7 is a fluorine atom.

[0210] In some embodiments of the compound of Formula (VI-1), R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group. Preferably, in some embodiments of the compound of formula (VI-1), R 9A and R 9B All are hydrogen atoms.

[0211] In some embodiments of the compound of formula (VI-1), Y is O. In other embodiments of the compound of formula (VI-1), Y is NH.

[0212] In some embodiments of the compound of formula (VI-1), p is 2. In some embodiments of the compound of formula (VI-1), p is 0 or 1. In some embodiments of the compound of formula (VI-1), p is 1. In some other embodiments of the compound of formula (VI-1), p is 0.

[0213] In some aspects, the present disclosure provides a compound of formula (VI-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0214] in:

[0215] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0216] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0217] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0218] R 9A and R 9B are the same or different and are independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0219] R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1- 6-haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 cycloalkyl)2, benzyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl and C 2-6 alkenyl;

[0220] Y is O or NH;

[0221] p is 0, 1 or 2.

[0222] In some embodiments of the compound of formula (VI-2), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VI-2), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (VI-2), R 1 In some other embodiments of the compound of formula (VI-2), R 1 It is a methoxy group.

[0223] In some embodiments of the compound of formula (VI-2), R 2 and R 3are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VI-2), R 2 and R 3 All are hydrogen atoms.

[0224] In some embodiments of the compound of formula (VI-2), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. Preferably, in some embodiments of the compound of formula (VI-2), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group. More preferably, in some embodiments of the compound of formula (VI-2), R 6 In some embodiments of the compound of formula (VI-2), R 7 In some other embodiments of the compound of formula (VI-2), R 7 is a fluorine atom.

[0225] In some embodiments of the compound of formula (VI-2), R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group. Preferably, in some embodiments of the compound of formula (VI-2), R 9A and R 9B All are hydrogen atoms.

[0226] In some embodiments of the compound of formula (VI-2), R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, heteroaryl and Preferably, in some embodiments of the compound of formula (VI-2), R 9C is selected from the group consisting of a hydrogen atom, a methyl group, a deuterated methyl group, an ethyl group, a trifluoroethyl group, a benzyl group, -C(O)OCH3, -C(O)CH3 and -S(O)2CH3.

[0227] In some embodiments of the compound of formula (VI-2), R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, 6 to 10 membered aryl, 5 to 10 membered heteroaryl and C 2-6 In some embodiments of the compound of formula (VI-2), R 9C Selected from C 1-6 Alkyl, heteroaryl and Preferably, in some embodiments of the compound of formula (VI-2), R 9C It is a methyl group.

[0228] In some embodiments of the compound of formula (VI-2), R 9C Selected from -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 cycloalkyl)2 and benzyl; In some embodiments of the compound of formula (VI-2), R 9C Selected from hydrogen atoms, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl and -S(O)2C 1-6 Preferably, in some embodiments of the compound of formula (VI-2), R 9C is a hydrogen atom, a deuterated methyl group, an ethyl group, a trifluoroethyl group, a benzyl group, -C(O)OCH3, -C(O)CH3, and -S(O)2CH3. In some embodiments of the compound of formula (VI-2), Y is O. In other embodiments of the compound of formula (VI-2), Y is NH.

[0229] In some embodiments of the compound of formula (VI-2), p is 2. In some embodiments of the compound of formula (VI-2), p is 0 or 1. In some embodiments of the compound of formula (VI-2), p is 1. In some other embodiments of the compound of formula (VI-2), p is 0.

[0230] In some aspects, the present disclosure provides a compound of formula (VI-3) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0231] in:

[0232] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0233] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0234] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0235] R 9A and R 9B are the same or different and are independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0236] R 9D and R 9E are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and hydroxy groups;

[0237] Y is O or NH;

[0238] p is 0, 1 or 2.

[0239] In some embodiments of the compound of formula (VI-3), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VI-3), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (VI-3), R 1 In some other embodiments of the compound of formula (VI-3), R 1 It is a methoxy group.

[0240] In some embodiments of the compound of formula (VI-3), R 2 and R 3 are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VI-3), R 2 and R3 All are hydrogen atoms.

[0241] In some embodiments of the compound of formula (VI-3), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. Preferably, in some embodiments of the compound of formula (VI-3), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group. More preferably, in some embodiments of the compound of formula (VI-3), R 6 In some embodiments of the compound of formula (VI-3), R 7 In some other embodiments of the compound of formula (VI-3), R 7 is a fluorine atom.

[0242] In some embodiments of the compound of formula (VI-3), R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group. Preferably, in some embodiments of the compound of formula (VI-3), R 9A and R 9B All are hydrogen atoms.

[0243] In some embodiments of the compound of formula (VI-3), R 9D and R 9E are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a methyl group and a hydroxyl group. In some embodiments of the compound of formula (VI-3), R 9D and R 9E are the same or different and are each independently selected from a fluorine atom and a methyl group. Specifically, in some embodiments of the compound of formula (VI-3), R 9D and R 9E are fluorine atoms or methyl groups.

[0244] In some embodiments of the compound of formula (VI-3), Y is O. In other embodiments of the compound of formula (VI-3), Y is NH.

[0245] In some embodiments of the compound of formula (VI-3), p is 2. In some embodiments of the compound of formula (VI-3), p is 0 or 1. In some embodiments of the compound of formula (VI-3), p is 1. In some other embodiments of the compound of formula (VI-3), p is 0.

[0246] In some aspects, the present disclosure provides a compound of formula (VI-4) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0247] in:

[0248] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0249] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0250] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0251] R 9A and R 9B are the same or different and are independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0252] Ring C is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 12 membered spirocyclyl, 6 to 12 membered heterospirocyclyl and 5 to 12 membered heterobridged cyclyl; the ring C is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkyl and C 1-6 substituted by one or more substituents of a haloalkyl group;

[0253] Y is O or NH;

[0254] p is 0, 1 or 2.

[0255] In some embodiments of the compound of formula (VI-4), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VI-4), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More specifically, in some embodiments of the compound of formula (VI-4), R 1 In some other embodiments of the compound of formula (VI-4), R 1 It is a methoxy group.

[0256] In some embodiments of the compound of formula (VI-4), R 2 and R 3 are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VI-4), R 2 and R 3 All are hydrogen atoms.

[0257] In some embodiments of the compound of formula (VI-4), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. Preferably, in some embodiments of the compound of formula (VI-4), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group. More preferably, in some embodiments of the compound of formula (VI-4), R 6 In some embodiments of the compound of formula (VI-4), R 7In some other embodiments of the compound of formula (VI-4), R 7 is a fluorine atom.

[0258] In some embodiments of the compound of formula (VI-4), R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group. Preferably, in some embodiments of the compound of formula (VI-4), R 9A and R 9B All are hydrogen atoms.

[0259] In some embodiments of the compound of formula (VI-4), ring C is selected from and ring C is optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl and C 1-6 Preferably, ring C is selected from

[0260] In some embodiments of the compound of formula (VI-4), Y is O. In other embodiments of the compound of formula (VI-4), Y is NH.

[0261] In some embodiments of the compound of formula (VI-4), p is 2. In some embodiments of the compound of formula (VI-4), p is 0 or 1. In some embodiments of the compound of formula (VI-4), p is 1. In some other embodiments of the compound of formula (VI-4), p is 0.

[0262] In some aspects, the present disclosure provides a compound of formula (VII-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0263] in:

[0264] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0265] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0266] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0267] R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group and hydroxyl group, said C 3-6 Cycloalkyl and C 3-6 The heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, methyl and methoxy;

[0268] Y is O or NH.

[0269] In some embodiments of the compound of Formula (VII-1), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VII-1), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More preferably, in some embodiments of the compound of formula (VII-1), R 1 It is a methoxy group.

[0270] In some embodiments of the compound of Formula (VII-1), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl and C 1-4Preferably, in some embodiments of the compound of formula (VII-1), R 2 and R 3 are the same or different and are each independently selected from hydrogen and halogen. More preferably, in some embodiments of the compound of formula (VII-1), R 2 and R 3 All are hydrogen atoms.

[0271] In some embodiments of the compound of Formula (VII-1), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. In some embodiments of the compound of formula (VII-1), R 6 In some embodiments of the compound of formula (VII-1), R 7 In some other embodiments of the compound of formula (VII-1), R 7 is a fluorine atom.

[0272] In some embodiments of the compound of Formula (VII-1), R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Preferably, in some embodiments of the compound of formula (VII-1), R 9K is selected from the group consisting of a hydrogen atom, a methyl group and a hydroxyl group.

[0273] In some embodiments of the compound of formula (VII-1), Y is O. In other embodiments of the compound of formula (VII-1), Y is NH.

[0274] In some aspects, the present disclosure provides a compound of formula (VII-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0275] in:

[0276] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0277] R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0278] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0279] R 9M and R 9L are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and C 1-6 alkyl halide;

[0280] Y is O or NH.

[0281] In some embodiments of the compound of Formula (VII-2), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VII-2), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More preferably, in some embodiments of the compound of formula (VII-2), R 1 It is a methoxy group.

[0282] In some embodiments of the compound of Formula (VII-2), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VII-2), R 2 and R 3are the same or different and are each independently selected from hydrogen atom and halogen. More preferably, in some embodiments of the compound of formula (VII-2), R 2 and R 3 All are hydrogen atoms.

[0283] In some embodiments of the compound of Formula (VII-2), R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. In some embodiments of the compound of formula (VII-2), R 6 In some embodiments of the compound of formula (VII-2), R 7 In some other embodiments of the compound of formula (VII-2), R 7 is a fluorine atom.

[0284] In some embodiments of the compound of Formula (VII-2), R 9M and R 9L are the same or different and are each independently selected from hydrogen atom and C 1-6 Preferably, in some embodiments of the compound of formula (VII-2), R 9M and R 9L are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group.

[0285] In some embodiments of the compound of formula (VII-2), Y is O. In other embodiments of the compound of formula (VII-2), Y is NH.

[0286] In some aspects, the present disclosure provides a compound of formula (VII-3) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0287] in:

[0288] R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0289] R 2 and R3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0290] R 6 and R 7 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy;

[0291] Y is O or NH.

[0292] In some embodiments of the compound of formula (VII-3), R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, in some embodiments of the compound of formula (VII-3), R 1 Selected from hydrogen atom, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More preferably, in some embodiments of the compound of formula (VII-3), R 1 It is a methoxy group.

[0293] In some embodiments of the compound of formula (VII-3), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-4 Alkyl and C 1-4 Preferably, in some embodiments of the compound of formula (VII-33), R 2 and R 3 are the same or different and are each independently selected from hydrogen atom and halogen. More preferably, in some embodiments of the compound of formula (VII-3), R 2 and R 3 All are hydrogen atoms.

[0294] In some embodiments of the compound of formula (VII-3), R 6 and R 7are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group. In some embodiments of the compound of formula (VII-3), R 6 In some embodiments of the compound of formula (VII-3), R 7 In some other embodiments of the compound of formula (VII-3), R 7 is a fluorine atom.

[0295] In some embodiments of the compound of formula (VII-3), Y is O. In other embodiments of the compound of formula (VII-2), Y is NH.

[0296] In some embodiments, the present disclosure provides a compound of Table 1 below, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0297] Table 1. Typical compounds of the present disclosure including but not limited to:

[0298] Compounds of Formula (I) (including any applicable subformula as described herein or compounds of Table 1) can exist as individual enantiomers, diastereomers, atropisomers, and / or geometric isomers (as applicable) or as mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some embodiments, compounds of Formula (I) (including any applicable subformula as described herein or compounds of Table 1) can exist as mixtures of atropisomers in any ratio (including about 1:1) when applicable. In some embodiments, compounds of Formula (I) (including any applicable subformula as described herein or compounds of Table 1) can exist as isolated individual atropisomers that are substantially free of other atropisomers (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other atropisomers by weight, by HPLC area, or both).

[0299] In some embodiments, the above compounds are substituted with isotopes. Preferably, in some embodiments, the isotope substitution is deuterium atom substitution.

[0300] Surprisingly, the compounds of the present disclosure exhibit significantly improved inhibitory activity against KAT6A / B, significantly improved pharmacodynamics and pharmacokinetics, and / or significantly improved safety profiles relative to KAT6A / B inhibitors known in the prior art.

[0301] Synthesis method of the disclosed compound

[0302] Given this disclosure, one skilled in the art can readily synthesize the disclosed compounds. Exemplary syntheses are shown in the Examples section.

[0303] The following synthesis methods of the compounds are illustrative and can be similarly applied by those skilled in the art to synthesize other compounds by using appropriate synthetic starting materials or intermediates.

[0304] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0305] The method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0306] reacting a compound of formula (IA) or a salt thereof with a compound of formula (IB) or a salt thereof in the presence of a base to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0307] in:

[0308] The dotted lines are optional chemical bonds.

[0309] Ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 , X1, X2, X3, Y and Z are as defined above in the compound of formula (I); or

[0310] reacting a compound of formula (VA) or a salt thereof with a compound of formula (VB) or a salt thereof in the presence of a base to obtain a compound of formula (V) or a pharmaceutically acceptable salt thereof;

[0311] in:

[0312] The dotted lines are optional chemical bonds, ring A, ring B, R 1 、R 2 、R 3、R 6 、R 7 , X1, X2, Y and Z are as defined above in the compound of formula (V); or

[0313] The compound of formula (VI-1A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain the compound of formula (VI-1) or a pharmaceutically acceptable salt thereof;

[0314] in:

[0315] R 1 、R 2 、R 3 、R 6 、R 7 、R 9A 、R 9B , Y and p are as defined above in the compound of formula (VI-1); or

[0316] The compound of formula (VI-1A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain the compound of formula (VI-1) or a pharmaceutically acceptable salt thereof;

[0317] in:

[0318] R 1 、R 2 、R 3 、R 6 、R 7 、R 9A 、R 9B 、R 9C , Y and the above-mentioned compound of formula (VI-2); or

[0319] The compound of formula (VI-3A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-3) or a pharmaceutically acceptable salt thereof;

[0320] in:

[0321] R 1 、R 2 、R 3 、R 6 、R 7 、R 9A 、R 9B 、R 9D 、R 9E , Y and p are as defined above in the compound of formula (VI-3); or

[0322] The compound of formula (VI-4A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-4) or a pharmaceutically acceptable salt thereof;

[0323] in:

[0324] Ring C, R 1 、R 2 、R 3 、R 6 、R 7 、R 9A 、R 9B , Y and p are as defined above in the compound of formula (VI-4); or

[0325] Step a: reacting a compound of formula (VII-3A) or a salt thereof with a compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VII-3B) or a pharmaceutically acceptable salt thereof;

[0326] Step b: reacting the compound of formula (VII-3B) or a salt thereof with a deprotecting agent to remove the hydroxy protecting group to obtain a compound of formula (VII-3C) or a pharmaceutically acceptable salt thereof;

[0327] Step c: reacting a compound of formula (VII-3C) or a salt thereof with an oxidizing agent to obtain a compound of formula (VII-3) or a pharmaceutically acceptable salt thereof;

[0328] in:

[0329] R 1 、R 2 、R 3 、R 6 、R 7 and Y are as defined above in the compound of formula (VII-3);

[0330] R a is a hydroxyl protecting group; preferably (trimethylsilyl)ethoxymethyl;

[0331] Step b: the deprotecting reagent is an acid or a fluorine-containing reagent, preferably trifluoroacetic acid or tetrabutylammonium fluoride;

[0332] The oxidizing reagent in step c is a reagent that oxidizes hydroxyl groups to ketones, preferably manganese dioxide or Dess-Martin reagent.

[0333] The base used in the reaction of the above scheme is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-lutidine, 2,6-lutidine, n-butyllithium, lithium bistrimethylsilylamide, sodium hydride, sodium hydroxide, cesium carbonate and potassium carbonate.

[0334] The reaction of the above scheme is preferably carried out in a solvent, and the solvent used is selected from: ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, toluene, pyridine and mixtures thereof.

[0335] It will be apparent to those skilled in the art that conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in “Protective Groups in Organic Synthesis”, 4th ed. PGM Wuts; TW Greene, John Wiley, 2007 and references cited therein. The reagents used for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, some reagents suitable for the reactions described herein can be prepared by following the corresponding procedures described in WO2019 / 103952, the contents of which are incorporated herein by reference in their entirety. In addition, many reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference books, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), or obvious modifications thereof, as of the time of this application.

[0336] Pharmaceutical composition

[0337] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0338] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., a compound of formula (I) to (VII-3), any one of compound numbers 1-132, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives, such as absorption enhancers, antioxidants, adhesives, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, wetting agents, lubricants, spices, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st ed., AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients for formulating pharmaceutical compositions and known techniques for preparing pharmaceutical compositions.

[0339] The pharmaceutical composition may include any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises, for example, a therapeutically effective amount of a compound of Formula (I) to (VII-3), any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof. In any embodiment described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from Compound Nos. 1-132 or a pharmaceutically acceptable salt thereof.

[0340] The pharmaceutical compositions may also be formulated for delivery by any known route of delivery, including but not limited to oral, parenteral, inhalation, and the like.

[0341] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be presented as discrete units such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil emulsions. Excipients used to prepare orally administrable compositions are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, peanut oil, hydroxypropyl methylcellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth gum, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0342] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, glucose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0343] In some embodiments, the pharmaceutical composition is formulated for inhalation administration. For example, the inhalable formulation can be formulated into a nasal spray, a dry powder, or an aerosol that can be administered by a metered dose inhaler. Excipients for the preparation of inhalation formulations are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, as well as mixtures of these substances. Sprays can also include propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0344] Pharmaceutical compositions can include various amounts of compounds of the present disclosure, depending on various factors, such as the intended use and efficacy and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I to VII-3, any one of compound numbers 1-132, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a cancer as described herein, e.g., lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial cancer, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer / endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinus node cell tumor, tenosynovial giant cell tumor, which may depend on the recipient of the treatment, the cancer being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound (e.g., potency for inhibiting KAT6A / B), its clearance rate, and whether it is co-administered with another drug.

[0345] For veterinary use, the compounds of the present disclosure can be administered in an appropriately acceptable formulation according to normal veterinary practice. A veterinarian can readily determine the dosing regimen and route of administration that is most suitable for a particular animal.

[0346] In some embodiments, all necessary components for treating a disease associated with a KAT6A / B-related cancer using a compound of the present invention, alone or in combination with another agent or intervention conventionally used to treat such a disease, can be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for therapeutic intervention of a disease, comprising a packaged set of medicaments comprising a compound disclosed herein and a buffer and other components for preparing a deliverable form of the medicament, and / or a device for delivering such medicament, and / or any agent for combination therapy with a compound of the present invention, and / or instructions for use for treating the disease packaged with the medicament. The instructions can be fixed in any tangible medium, such as printed paper, or a computer-readable magnetic or optical medium, or directed to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0347] Treatment methods / uses

[0348] The compounds of the present disclosure can be used as therapeutically active substances for treating and / or preventing cancers associated with KAT6A / B. In particular, the compounds of the present disclosure can be used to treat conditions associated with regulating KAT6A / B function, particularly inhibiting KAT6A / B function, by acting on KAT6A / B to mediate signal transduction. Such conditions include diseases in which the pathogenic mechanism is related to these cytokines of KAT6A / B, including any of those known in the art and those described herein.

[0349] In some embodiments, the present disclosure provides a method of inhibiting KAT6A / B, comprising treating cells with an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formulas I to VII-3, any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof).

[0350] In some embodiments, the present disclosure provides a method of inhibiting KAT6A / B function in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formulas I to VII-3, any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof).

[0351] In some embodiments, the present disclosure provides a method for treating or preventing a cancer mediated by KAT6A / B in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formulas I to VII-3, any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof). Suitable KAT6A / B-mediated cancers that can be treated with the methods herein include any of those known in the art. Exemplary KAT6A / B-mediated cancers that can be treated using the methods herein also include, but are not limited to, lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial cancer, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer / endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinoatrial node cell tumor, and tenosynovial giant cell tumor as described herein.

[0352] In some embodiments, the present disclosure provides a method for treating or preventing a cancer, such as that described herein, in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formulas I to VII-3, any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof).

[0353] In some embodiments, the present disclosure provides a method for treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formulas I to VII-3, any one of Compound Nos. 1-132, or a pharmaceutically acceptable salt thereof), wherein the cancer may be one or more selected from the following cancers: lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial cancer, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer / endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, brain glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinoatrial node cell tumor, tendon sheath giant cell tumor; wherein the breast cancer is preferably ER + Breast cancer or ER + / HER2 - Breast cancer; wherein the lung cancer is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.

[0354] Administration herein is not limited to any specific route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, oral, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In some embodiments, administration is oral administration.

[0355] The dosing regimen, including dosage, can vary and be adjusted depending on the recipient of treatment, the cancer being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0356] Example

[0357] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0358] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0359] MS was measured using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0360] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0361] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0362] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0363] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0364] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0365] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0366] Silica gel column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel as a carrier.

[0367] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0368] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bidex Pharmaceuticals.

[0369] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0370] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0371] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0372] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0373] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0374] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0375] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0376] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0377] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0378] Example 1

[0379] Synthesis of intermediate 1

[0380] 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine

[0381] Step a:

[0382] 4-Bromo-2-fluoro-6-methoxybenzonitrile

[0383] To a solution of 4-bromo-2,6-difluorobenzonitrile (10.00 g, 45.87 mmol) in tetrahydrofuran (60 mL) was added sodium methoxide solution (9.92 g, 55.09 mmol, 30 wt% in methanol) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to provide compound Int 1-a (2.72 g, 25.8% yield).

[0384] 1 H NMR (300MHz, CDCl3): δ7.02-6.99(m,1H),6.94(s,1H),3.96(s,3H).

[0385] Step b:

[0386] Methyl 4-cyano-3-fluoro-5-methoxybenzoate

[0387] To a solution of compound Int 1-a (8.00 g, 34.78 mmol) in methanol (80 mL) were added triethylamine (14 mL, 100.07 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (2.55 g, 3.49 mmol). The reaction system was stirred at 80°C under a carbon monoxide (3.0 MPa) atmosphere for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound Int 1-b (6.43 g, 88.4% yield).

[0388] 1 HNMR (300MHz, CDCl3): δ7.46-7.38 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H).

[0389] Step c:

[0390] 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile

[0391] To a solution of compound Int1-b (3.57 g, 17.07 mmol) in tetrahydrofuran (30 mL) was added lithium borohydride (0.74 g, 33.98 mmol) at 0°C. The reaction system was heated to 80°C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature and the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), washed with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound Int1-c (2.14 g, 69.2% yield).

[0392] 1 HNMR (300 MHz, DMSO-d6): δ 7.05 (s, 1H), 6.98 (d, 1H), 5.60 (t, 1H), 4.57 (d, 2H), 3.94 (s, 3H). Step d:

[0393] 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile

[0394] To a solution of compound Int1-c (2.14 g, 11.81 mmol) and 1-(methylsulfonyl)-1H-pyrazole (2.07 g, 14.16 mmol) in tetrahydrofuran (30 mL) was added cesium carbonate (4.61 g, 14.15 mmol). The reaction system was heated to 70°C and stirred for 1 hour. After the reaction was completed, it was cooled to room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound Int1-d (2.15 g, 78.7% yield). MS m / z (ESI): 232.0 [M+H] + .

[0395] Step e:

[0396] 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine

[0397] To a mixed solution of compound Int1-d (2.59 g, 11.20 mmol) and acetohydroxamic acid (2.52 g, 33.57 mmol) (N,N-dimethylformamide:water ratio 9:1, 30 mL) was added tetramethylguanidine (8.5 mL, 67.60 mmol) dropwise. The reaction system was heated to 60°C and stirred for 7 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound Intermediate 1 (2.17 g, 79.3% yield).

[0398] 1 HNMR (300MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),6.69(s,1H),6.63(s,1H),6.30(t,1H),5.95(s,2H),5.41(s,2H),3.85(s,3H).

[0399] MS m / z(ESI):245.1[M+H] + .

[0400] Example 2

[0401] Synthesis of intermediate 2

[0402] 6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-amine

[0403] Step a:

[0404] (2,3,5-Trifluorophenyl)methanol

[0405] To a solution of 2,3,5-trifluorobenzoic acid (7.20 g, 40.89 mmol) in tetrahydrofuran (70 mL) was added a borane tetrahydrofuran solution (1.0 M in tetrahydrofuran, 123 mL, 122.66 mmol) at 25°C. The reaction system was heated to 50°C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with 1N aqueous hydrochloric acid (50 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound Int2-a (6.03 g, 91.0% yield).

[0406] 1 H NMR (400MHz, CDCl3): δ7.01-6.97(m,1H),6.89-6.82(m,1H),4.79(s,2H).

[0407] Step b:

[0408] tert-Butyldimethyl((2,3,5-trifluorobenzyl)oxy)silane

[0409] Compound Int2-a (7.48 g, 46.14 mmol), tert-butyldimethylsilyl chloride (8.34 g, 55.33 mmol), triethylamine (7.00 g, 69.18 mmol), and 4-dimethylaminopyridine (0.56 g, 4.58 mmol) were dissolved in dichloromethane (80 mL). The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound Int2-b (11.40 g, 89.4% yield).

[0410] 1 H NMR (400MHz, CDCl3): δ7.02-6.98(m,1H), 6.82-6.77(m,1H), 4.79(s,2H), 0.95(s,9H), 0.13(s,6H).

[0411] Step c:

[0412] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,3,6-trifluorobenzonitrile

[0413] To a solution of compound Int2-b (6.80 g, 24.60 mmol) in tetrahydrofuran (80 mL) at -78°C was added lithium diisopropylamide (2.0 M in n-hexane, 18.50 mL, 37.00 mmol). The reaction system was stirred at -78°C for 1 hour, followed by the addition of 4-toluenesulfonyl cyanide (4.90 g, 27.04 mmol) and continued stirring for 2 hours. After the reaction was returned to room temperature, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound Int2-c (3.60 g, 48.5% yield).

[0414] 1 H NMR (400MHz, CDCl3): δ7.23-7.19(m,1H),4.83(s,2H),0.95(s,9H),0.14(s,6H).

[0415] Step d:

[0416] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-3,6-difluoro-2-methoxybenzonitrile

[0417] Compound Int2-c (3.60 g, 11.94 mmol) and sodium methoxide (1.93 g, 35.72 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction system was heated to 80°C and stirred for 4 hours. After the reaction was completed and returned to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound Int2-d (1.60 g, 42.7% yield).

[0418] 1 H NMR (400MHz, CDCl3): δ6.91-6.87(m,1H),4.78(s,2H),4.14(d,3H),0.95(s,9H),0.13(s,6H).

[0419] Step e:

[0420] 3,6-Difluoro-4-(hydroxymethyl)-2-methoxybenzonitrile

[0421] To a solution of compound Int2-d (1.60 g, 5.10 mmol) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (2.67 g, 10.21 mmol), and the reaction system was stirred at 25°C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound Int2-e (0.79 g, 77.7% yield).

[0422] 1 H NMR (400MHz, CDCl3): δ7.06-7.03 (m, 1H), 4.81 (s, 2H), 4.15 (d, 3H).

[0423] Step f:

[0424] 4-((1H-pyrazol-1-yl)methyl)-3,6-difluoro-2-methoxybenzonitrile

[0425] To a solution of compound Int2-e (0.79 g, 3.97 mmol) and 1-(methylsulfonyl)-1H-pyrazole (0.70 g, 4.76 mmol) in acetonitrile (20 mL) was added cesium carbonate (2.58 g, 7.92 mmol). The reaction system was heated to 75°C and stirred for 4 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound Int2-f (0.81 g, 81.9% yield).

[0426] MS m / z(ESI):250.0[M+H] + .

[0427] Step g:

[0428] 6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-amine

[0429] Compound Int2-f (810 mg, 3.25 mmol), acetohydroxamic acid (732 mg, 9.75 mmol), and 2-tert-butyl-1,1,3,3-tetramethylguanidine (557 mg, 3.25 mmol) were dissolved in acetonitrile (15 mL). The reaction system was heated to 80°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to provide compound Intermediate 2 (440 mg, 51.6% yield).

[0430] 1 HNMR (400MHz, DMSO-d6): δ7.86(d,1H),7.54(d,1H),6.72(d,1H),6.31(t,1H),6.11(s,2H),5.47(s,2H),4.06(d,3H).

[0431] Example 3

[0432] Synthesis of intermediate 3

[0433] 6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-amine

[0434] Step a:

[0435] 4-Bromo-3-chloro-2,5-difluorobenzoic acid

[0436] Under nitrogen, N-chlorosuccinimide (5.63 g, 42.16 mmol) was added to a solution of 4-bromo-2,5-difluorobenzoic acid (5.00 g, 21.10 mmol) in 98% concentrated sulfuric acid (30 mL) at 80°C. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was poured into ice water and concentrated under reduced pressure. The resulting filter cake was purified by flash C18 reverse-phase column chromatography (methanol:water (0.1% trifluoroacetic acid) = 3:2) to afford compound Int 3-a (2.30 g, 40.2% yield).

[0437] 1 HNMR(400MHz, DMSO-d6): δ14.05(brs,1H),7.80(dd,1H).

[0438] Step b:

[0439] (4-Bromo-3-chloro-2,5-difluorophenyl)methanol

[0440] Under nitrogen, a borane tetrahydrofuran solution (1.0 M in tetrahydrofuran, 28.74 mL, 28.74 mmol) was added dropwise to a solution of compound Int3-a (3.90 g, 14.37 mmol) in tetrahydrofuran (60 mL) at 0°C. The reaction system was heated to 50°C and stirred for 2.5 hours. After completion of the reaction, the reaction system was quenched with methanol at 0°C and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 9:1) to afford compound Int3-b (3.26 g, 88.1% yield).

[0441] 1 HNMR (400MHz, DMSO-d6): δ7.44(dd,1H),5.61(t,1H),4.56(d,2H).

[0442] Step c:

[0443] ((4-Bromo-3-chloro-2,5-difluorobenzyl)oxy)(tert-butyl)dimethylsilane

[0444] To a solution of compound Int3-b (3.26 g, 12.66 mmol) and pyrazole (1.72 g, 25.32 mmol) in dichloromethane (60 mL) was added tert-butyldimethylsilyl chloride (2.10 g, 13.93 mmol) at 25°C. The reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the reaction system was poured into ice water and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether) to give compound Int3-c (4.56 g, 96.9% yield).

[0445] 1 HNMR (400MHz, DMSO-d6): δ7.38(dd,1H),4.75(s,2H),0.89(s,9H),0.10(s,6H).

[0446] Step d:

[0447] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloro-3,6-difluorobenzonitrile

[0448] Under nitrogen, compound Int3-c (4.65 g, 12.51 mmol) and cuprous cyanide (5.60 g, 62.55 mmol) were dissolved in N,N-dimethylformamide (25 mL). The reaction system was heated to 140°C and stirred for 16 hours. After completion of the reaction, the reaction system was quenched with water and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 9:1) to obtain compound Int3-d (1.89 g, 47.5% yield).

[0449] 1 HNMR (400MHz, DMSO-d6): 7.48 (dd, 1H), 4.86 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H).

[0450] Step e:

[0451] 2-Chloro-3,6-difluoro-4-(hydroxymethyl)benzonitrile

[0452] To a solution of compound Int3-d (1.89 g, 5.95 mmol) in tetrahydrofuran (38 mL) was added tetrabutylammonium fluoride (2.18 g, 8.33 mmol) at 0°C. The reaction system was stirred at 0°C for 1 hour. After completion of the reaction, the reaction system was poured into ice water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 4:1) to give compound Int3-e (0.84 g, 69.4% yield).

[0453] 1 HNMR(400MHz, DMSO-d6):7.55(dd,1H),5.81(t,1H),4.65(d,2H).

[0454] Step f:

[0455] 2-Chloro-4-(chloromethyl)-3,6-difluorobenzonitrile

[0456] Under nitrogen, N,N-dimethylformamide (0.15 g, 2.04 mmol) was added to a solution of compound Int3-e (4.15 g, 20.39 mmol) and thionyl chloride (12.13 g, 101.96 mmol) in dichloromethane (40 mL). The reaction system was heated to 40°C and stirred for 3 hours. After completion of the reaction, the reaction system was diluted with water and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 9:1) to obtain compound Int3-f (4.35 g, 96.1% yield).

[0457] 1 HNMR (400MHz, DMSO-d6): 7.84 (dd, 1H), 4.88 (s, 2H).

[0458] Step g:

[0459] 4-((1H-pyrazol-1-yl)methyl)-2-chloro-3,6-difluorobenzonitrile

[0460] Under nitrogen, compound Int3-f (2.25 g, 10.13 mmol), pyrazole (0.76 g, 11.16 mmol), 18-crown-6 (0.80 g, 3.03 mmol), and potassium carbonate (2.80 g, 20.26 mmol) were dissolved in acetonitrile (24 mL). The reaction system was heated to 80°C and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 9:1) to afford compound Int3-g (1.00 g, 38.9% yield).

[0461] 1 HNMR (400MHz, DMSO-d6): δ7.89(d,1H),7.53(d,1H),7.21(dd,1H),6.33(t,1H),5.54(s,2H).

[0462] Step h:

[0463] 6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-amine

[0464] Compound Int3-g (21.34 g, 5.28 mmol), acetohydroxamic acid (1.19 g, 15.85 mmol), and potassium carbonate (2.19 g, 15.85 mmol) were dissolved in a mixed solution (5:1 N,N-dimethylformamide:water, 24 mL). The reaction system was heated to 80°C and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 9:1) to afford compound Intermediate 3 (0.94 g, 69.1% yield).

[0465] 1 HNMR (400MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),7.18(d,1H),6.31(t,1H),6.24(s,2H),5.52(s,2H).

[0466] MS m / z(ESI):267.2[M+H] + .

[0467] Example 4

[0468] Synthesis of intermediate 4

[0469] 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-amine

[0470] Step a:

[0471] 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-amine

[0472] Under nitrogen protection, sodium sulfide (157 mg, 2.02 mmol) was added to a solution of compound Int1-d (466 mg, 2.02 mmol) in dimethyl sulfoxide (15 mL). The reaction system was heated to 70°C and stirred for 7 hours. After the reaction was completed, it was cooled to 0°C. Then, ammonia water (6 mL) and sodium hypochlorite aqueous solution (6 mL) were slowly added to the reaction system and stirred for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane: methanol = 9:1) to give compound intermediate 4 (210 mg, yield 40.0%).

[0473] 1 HNMR (300MHz, DMSO-d6): δ7.87(d,1H),7.49(d,1H),7.13(s,1H),6.74(s,1H),6.50(s,2H),6.30(t,1H),5.42(s,2H),3.90(s,3H),2.54(s,2H).

[0474] Example 5

[0475] Synthesis of intermediate 5

[0476] 6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-amine

[0477] Step a:

[0478] Methyl 2-chloro-4-cyano-5-fluoro-3-methoxybenzoate

[0479] Compound Int1-b (2.10 g, 10.04 mmol), trichloroisocyanuric acid (1.16 g, 4.99 mmol), and trifluoromethanesulfonic acid (0.09 mL, 1.00 mmol) were dissolved in hexafluoroisopropanol (20 mL). The reaction system was heated to 60°C and stirred for 40 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether: dichloromethane = 4:1) to obtain compound Int5-a (1.45 g, 59.3% yield).

[0480] 1 H NMR (400MHz, CDCl3): δ7.34(d,1H), 4.14(s,3H), 3.97(s,3H).

[0481] Step b:

[0482] 3-Chloro-6-fluoro-4-(hydroxymethyl)-2-methoxybenzonitrile

[0483] To a solution of compound Int5-a (1.60 g, 6.57 mmol) in tetrahydrofuran (50 mL) was added lithium borohydride (2.0 M in tetrahydrofuran, 6.6 mL, 13.20 mmol) dropwise at 0°C. The reaction system was then heated to 50°C and stirred for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound Int5-b (1.37 g, 96.7% yield).

[0484] 1 HNMR (400MHz, DMSO-d6): δ7.28(d,1H), 4.82(d,2H), 4.10(s,3H).

[0485] Step c:

[0486] 3-Chloro-4-(chloromethyl)-6-fluoro-2-methoxybenzonitrile

[0487] To a solution of compound Int5-b (610 mg, 2.83 mmol) in dichloromethane (10 mL) was added sulfonyl chloride (10 mL) and a drop of N,N-dimethylformamide. The reaction system was heated to 40°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to give compound Int5-c (580 mg, 87.7% yield).

[0488] 1 HNMR (400MHz, DMSO-d6): δ7.19(d,1H),7.67(s,2H),7.13(s,3H).

[0489] Step d:

[0490] 4-((1H-pyrazol-1-yl)methyl)-3-chloro-6-fluoro-2-methoxybenzonitrile Compound Int5-c (960 mg, 4.10 mmol), pyrazole (838 mg, 12.31 mmol), cesium fluoride (1.87 g, 12.31 mmol), and tetrabutylammonium iodide (152 mg, 0.41 mmol) were dissolved in acetonitrile (40 mL). The reaction system was heated to 40°C and stirred for 16 hours. After completion of the reaction, the mixture was poured into ice water and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to afford compound Int5-d (770 mg, 70.7% yield). 1 HNMR (400MHz, DMSO-d6): δ7.90(d,1H),7.57(d,1H),6.55(d,1H),6.36(t,1H),5.55(s,2H),4.07(s,3H).

[0491] Step e:

[0492] 6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-amine

[0493] Compound Int5-d (1.61 g, 6.06 mmol), acetohydroxamic acid (1.37 g, 18.25 mmol), and potassium carbonate (2.53 g, 18.31 mmol) were dissolved in a mixed solution (55 mL of N,N-dimethylformamide and water, 10:1 ratio). The reaction system was heated to 70°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford Intermediate 5 (1.10 g, 65.1% yield).

[0494] 1 HNMR (400MHz, DMSO-d6): δ7.88(d,1H),7.55(d,1H),6.60(s 1H),6.34(t,1H),6.20(s,2H),5.53(s,2H),3.94(s,3H).

[0495] Example 6

[0496] Synthesis of intermediate 6

[0497] 6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-amine

[0498] Step a:

[0499] 4-Amino-2-chloro-6-fluorobenzonitrile

[0500] Under nitrogen, 4-bromo-3-chloro-5-fluoroaniline (21.70 g, 96.68 mmol) and cuprous cyanide (8.66 g, 96.69 mmol) were dissolved in N-methylpyrrolidone (100 mL). The reaction system was heated to 190°C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was quenched with 14% aqueous ammonia and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound Int 6-a (16.40 g, 99.5% yield).

[0501] 1 H NMR (300MHz, DMSO-d6): δ6.87(s,2H), 6.60(d,1H), 6.44(dd,1H).

[0502] Step b:

[0503] 2-Chloro-6-fluoro-4-iodobenzonitrile

[0504] To a solution of compound Int 6-a (10.00 g, 58.63 mmol) and 98% concentrated sulfuric acid (9.4 mL, 175.80 mmol) in acetonitrile (300 mL) and water (90 mL) at 0°C was slowly added a solution of sodium nitrite (4.45 g, 64.46 mmol) in water (100 mL). The reaction system was stirred at 10°C for 15 minutes, then returned to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was poured into an aqueous solution (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound Int 6-b (12.00 g, 72.7% yield).

[0505] 1 H NMR (300MHz, CDCl3): δ7.73 (s, 1H), 7.55 (dd, 1H).

[0506] Step c:

[0507] Methyl 3-chloro-4-cyano-5-fluorobenzoate

[0508] To a solution of compound Int 6-b (14.10 g, 50.10 mmol) in methanol (140 mL) were added triethylamine (15.21 g, 150.30 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (3.64 g, 4.97 mmol). The reaction system was stirred at 40°C under a carbon monoxide atmosphere (2.0 MPa) for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 92:8) to afford compound Int 6-c (8.40 g, 78.5% yield).

[0509] 1 HNMR (300MHz, CDCl3): δ7.99(s,1H),7.77(dd,1H),3.98(s,3H).

[0510] Step d:

[0511] 2-Chloro-6-fluoro-4-(hydroxymethyl)benzonitrile

[0512] Under nitrogen protection, a solution of compound Int 6-c (8.40 g, 39.33 mmol) in tetrahydrofuran (100 mL) was added with lithium borohydride (39.3 mL, 78.60 mmol) in tetrahydrofuran (100 mL). The reaction system was stirred at 25 ° C for 1 hour. After the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to give compound Int 6-d (5.00 g, yield 68.5%).

[0513] 1 HNMR (300MHz, CDCl3): δ7.34(s,1H),7.18(dd,1H),4.78(s,2H),1.86(s,1H).

[0514] Step e:

[0515] 2-Chloro-4-(chloromethyl)-6-fluorobenzonitrile

[0516] Under nitrogen protection, thionyl chloride (6.02 g, 50.61 mmol) in dichloromethane (10 mL) was added dropwise to a solution of compound Int6-d (4.70 g, 25.33 mmol) and N,N-dimethylformamide (0.02 g, 0.25 mmol) in dichloromethane (70 mL). The reaction system was heated to 40°C and stirred for 1 hour. After the reaction, the mixture was poured into ice water and extracted with dichloromethane (200 mL x 2). The combined organic layer was washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 92:8) to give compound Int6-e (4.74 g, 91.7% yield).

[0517] 1 HNMR (400MHz, CDCl3): δ7.37(s,1H),7.20(dd,1H),4.55(s,2H).

[0518] Step f:

[0519] 4-((1H-pyrazol-1-yl)methyl)-2-chloro-6-fluorobenzonitrile

[0520] Compound Int6-e (4.70 g, 23.04 mmol), pyrazole (4.70 g, 69.04 mmol), cesium fluoride (10.48 g, 68.99 mmol), and tetrabutylammonium iodide (0.85 g, 2.30 mol) were dissolved in acetonitrile (100 mL). The reaction system was heated to 50°C and stirred for 18 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 82:18) to afford compound Int6-f (3.61 g, 66.5% yield).

[0521] 1 HNMR (400MHz, DMSO-d6): δ7.91(d,1H),7.54(d,1H),7.35(s,1H),7.28(d,1H),6.34(t,1H),5.48(s,2H).

[0522] Step g:

[0523] 6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-amine

[0524] Compound Int6-f (3.61 g, 15.32 mmol), acetohydroxamic acid (3.45 g, 45.96 mmol), and tetramethylguanidine (10.57 g, 91.77 mmol) were dissolved in a 55 mL mixture (N,N-dimethylformamide:water ratio of 10:1). The reaction system was heated to 80°C and stirred for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to afford Intermediate 6 (2.90 g, 71.0% yield).

[0525] 1 HNMR (300MHz, DMSO-d6): δ7.90(d,1H),7.51(d,1H),7.24(s,1H),7.10(s,1H),6.31(t,1H),6.19(s,2H),5.46(s,2H).

[0526] Example 7

[0527] Synthesis of compound 1

[0528] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutyloxybenzenesulfonamide

[0529] Step a:

[0530] 1-Cyclobutyloxy-2-iodobenzene

[0531] Under nitrogen, potassium carbonate (5.30 g, 38.35 mmol) was added to a solution of 2-iodophenol (2.80 g, 12.73 mmol) and cyclobutyl bromide (3.41 g, 25.26 mmol) in N,N-dimethylformamide (40 mL). The reaction system was heated to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 1a (2.60 g, 74.5% yield).

[0532] 1 H NMR (300MHz, CDCl3): δ7.81(d,1H),7.32-7.27(m,1H),6.76-6.71(m,2H),4.76-4.68 (m,1H),2.57-2.48(m,2H),2.38-2.25(m,2H),1.99-1.89(m,1H),1.96-1.62(m,1H).

[0533] Step b:

[0534] Benzyl(2-cyclobutyloxyphenyl)sulfane

[0535] To a solution of compound 1a (2.60 g, 9.49 mmol) in N,N-dimethylformamide (50 mL) were added benzyl mercaptan (1.77 g, 14.25 mmol), cesium carbonate (6.18 g, 18.97 mmol), 1,4-diazabicyclo[2.2.2]octane (0.11 g, 0.98 mmol), and cuprous iodide (0.91 g, 4.78 mmol) under nitrogen. The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 1b (2.10 g, 81.9% yield).

[0536] MS m / z(ESI):271.0[M+H] + .

[0537] Step c:

[0538] 2-Cyclobutoxybenzenesulfonyl chloride

[0539] To a mixed solution of compound 1b (2.10 g, 7.77 mmol) (glacial acetic acid and water, 10:1 ratio, 33 mL) was added N-chlorosuccinimide (3.10 g, 23.22 mmol) at 0°C. The reaction system was stirred at 25°C for 12 hours. The reaction mixture was then cooled to 0°C with ice and stirred for 1 hour. The mixture was filtered under reduced pressure and dried in vacuo to afford compound 1c (1.36 g, 71.0% yield).

[0540] 1 HNMR (300MHz, CDCl3): δ7.59-7.49(m,1H),7.43-7.34(m,2H),7.03-6.91(m,1H),4.85-4 .73(m,1H),2.53-2.35(m,2H),2.36-2.16(m,2H),1.95-1.80(m,1H),1.77-1.57(m,1H).

[0541] Step d:

[0542] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxybenzenesulfonamide Compound 1c (870 mg, 3.53 mmol) and Intermediate 1 (250 mg, 1.02 mmol) were dissolved in pyridine (2 mL). The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5%-95%) to afford Compound 1 (61 mg, 13.1% yield).

[0543] 1HNMR (400MHz, DMSO-d6): δ9.82(s,1H),7.87-7.84(m,2H),7.58-7.50(t,1H),7.49(d,1H),7.10-7.06(t,1H),6.97-6.95(d,1H),6.83(s,1 H),6.75(s,1H),6.30-6.29(t,1H),5.44(s,2H),4.73-4.69(m,1H),3.81(s,3H),2.26-2.22(m,2H),1.82-1.77(m,2H),1.57-1.49(m,2H).

[0544] MS m / z(ESI):455.0[M+H] + .

[0545] Example 8

[0546] Synthesis of compound 2

[0547] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-(3,3-difluorocyclobutyloxy)benzenesulfonamide

[0548] Step a:

[0549] 1-(3,3-difluorocyclobutyloxy)-2-iodobenzene

[0550] Under nitrogen, triphenylphosphine (10.93 g, 41.67 mmol) and diisopropyl azodicarboxylate (5.62 g, 27.79 mmol) were added to a toluene (150 mL) solution of 2-iodophenol (4.89 g, 22.23 mmol) and 3,3-difluorocyclobutanol (2.00 g, 18.50 mmol). The reaction system was heated to 110°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 2a (2.70 g, 47.1% yield).

[0551] 1H NMR (300MHz, CDCl3): δ7.81-7.78(m,1H),7.37-7.33(m,1H),6.92-6.90(m,1H) ),6.81-6.77(m,1H),4.85-4.81(m,1H),3.32-3.19(m,2H),2.76-2.64(m,2H).

[0552] Step b:

[0553] Benzyl(2-(3,3-difluorocyclobutyloxy)phenyl)sulfane

[0554] To a solution of compound 2a (2.70 g, 8.71 mmol) in N,N-dimethylformamide (50 mL) under nitrogen was added benzyl mercaptan (1.63 g, 13.12 mmol), cesium carbonate (5.70 g, 17.49 mmol), 1,4-diazabicyclo[2.2.2]octane (0.10 g, 0.87 mmol), and cuprous iodide (0.84 g, 4.37 mmol). The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 2b (2.00 g, 75.0% yield).

[0555] 1 H NMR (300MHz, CDCl3): δ7.40-7.28(m,6H),7.27-7.16(m,1H),6.99-6.88(m, 2H),4.84-4.79(m,1H),4.19(s,2H),3.29-3.19(m,2H),2.76-2.66(m,2H).

[0556] Step c:

[0557] 2-(3,3-Difluorocyclobutyloxy)benzenesulfonyl chloride

[0558] To a mixed solution of compound 2b (2.00 g, 6.53 mmol) (glacial acetic acid and water, 10:1 ratio, 33 mL) was added N-chlorosuccinimide (2.62 g, 19.62 mmol) at 0°C. The reaction system was stirred at 25°C for 12 hours. The reaction mixture was then cooled to 0°C with ice and stirred for 1 hour. The mixture was filtered under reduced pressure and dried in vacuo to afford compound 2c (1.20 g, 65.0% yield).

[0559] 1HNMR (300MHz, CDCl3): δ8.08-8.06(d,1H),7.77-7.72(m,1H),7.26-7.21(m ,1H),7.00-6.98(d,1H),4.94(m,1H),3.33-3.20(m,2H),3.10-2.94(m,2H).

[0560] Step d:

[0561] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-(3,3-difluorocyclobutyloxy)benzenesulfonamide compound 2c (1.20 g, 4.24 mmol) and intermediate 1 (200 mg, 0.82 mmol) were dissolved in pyridine (2 mL). The reaction system was heated to 100°C and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to afford compound 2 (20 mg, 5.0% yield).

[0562] 1 HNMR (400MHz, DMSO-d6): δ10.35(s,1H),7.99-7.77(m,2H),7.69-7.41(m,2H),7.24-6.98(m,2H),6.78(s,1H),6. 70(s,1H),6.37-6.21(m,1H),5.43(s,2H),4.90-4.74(m,1H),3.78(s,3H),3.17-2.92(m,2H),2.74-2.56(m,2H).

[0563] MS m / z(ESI):491.0[M+H] + .

[0564] Example 9

[0565] Synthesis of compound 3

[0566] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0567] Step a:

[0568] 4-(tert-Butyl)-2-iodophenol

[0569] To a solution of 4-tert-butylphenol (5.00 g, 33.28 mmol) in acetonitrile (75 mL) at 20°C was added p-toluenesulfonic acid monohydrate (6.33 g, 33.28 mmol). After 30 minutes of reaction, N-iodosuccinimide (7.49 g, 33.29 mmol) was added and the reaction system was stirred for 16 hours. After completion of the reaction, the mixture was quenched with aqueous sodium sulfite (100 mL) and acidified with 1.0 M hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 3a (8.20 g, 89.2% yield).

[0570] 1 H NMR (300MHz, CDCl3): δ7.62(d,1H),7.27-7.24(m,1H),6.91(d,1H),5.17(s,1H),1.29(s,9H).

[0571] Step b:

[0572] 4-(tert-Butyl)-1-cyclobutoxy-2-iodobenzene

[0573] To a solution of compound 3a (2.00 g, 7.24 mmol) and potassium carbonate (2.99 g, 21.63 mmol) in N,N-dimethylformamide (35 mL) was added bromocyclobutane (2.92 g, 21.63 mmol) at 20°C. The reaction system was heated to 70°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 3b (2.20 g, 92.0% yield).

[0574] 1 H NMR (300MHz, CDCl3): δ7.75(d,1H),7.74-7.22(m,1H),6.59(d,1H),4.67-4.60(m,1H),2 .48-2.41(m,2H),2.28-2.19(m,2H),1.91-1.82(m,1H),1.73-1.61(m,1H),1.27(s,9H).

[0575] Step c:

[0576] Benzyl(5-(tert-butyl)-2-cyclobutyloxyphenyl)sulfane

[0577] To a solution of compound 3b (7.20 g, 21.80 mmol) in N,N-dimethylformamide (35 mL) were added benzyl mercaptan (5.42 g, 43.64 mmol), cesium carbonate (14.21 g, 43.61 mmol), 1,4-diazabicyclo[2.2.2]octane (0.12 g, 1.06 mmol), and cuprous iodide (0.21 g, 1.10 mmol) under nitrogen. The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 3c (1.90 g, 26.7% yield).

[0578] 1 H NMR (400MHz, CDCl3): δ7.40-7.24(m,6H),7.20-7.19(m,1H),6.69(d,1H),4.70-4.62(m,1H),4.10 (s,2H),2.50-2.42(m,2H),2.28-2.18(m,2H),1.90-1.83(m,1H),1.72-1.64(m,1H),1.20(s,9H).

[0579] Step d:

[0580] 5-(tert-Butyl)-2-cyclobutoxybenzenesulfonyl chloride

[0581] To a mixed solution of compound 3c (1.50 g, 4.59 mmol) (glacial acetic acid and water, 10:1 ratio, 18 mL) was added N-chlorosuccinimide (3.69 g, 27.63 mmol) at 0°C. The reaction system was stirred at 10°C for 1 hour. After completion of the reaction, the mixture was quenched with water (20 mL). The mixture was filtered under reduced pressure, and the filter cake was washed with water (3 mL x 5) and dried under vacuum to afford compound 3d (1.00 g, 71.9% yield).

[0582] 1HNMR(300MHz, CDCl3): δ7.80(d,1H),7.32-7.29(m,1H),6.65(d,1H),4.74-4.65(m,1H), 2.55-2.45(m,2H),2.36-2.22(m,2H),1.97-1.87(m,1H),1.78-1.61(m,1H),1.32(s,9H).

[0583] Step e:

[0584] To a solution of intermediate 1 (100 mg, 0.41 mmol) in pyridine (4 mL) at 10°C was added compound 3d (743 mg, 2.45 mmol) (N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutyloxybenzenesulfonamide). The reaction system was heated to 100°C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to afford compound 3 (64 mg, 37.9% yield).

[0585] 1 HNMR (400MHz, CDCl3): δ8.10(d,1H),8.00(s,1H),7.56(d,1H),7.49-7.46(m,1H),7.42(d,1H),6.77(s,1H),6.69(d,1H),6.44(s,1 H),6.32(t,1H),5.38(s,2H),4.72-4.69(m,1H),3.94(s,3H),2.42-2.38(m,2H),2.15-2.10(m,2H),1.80-1.63(m,2H),1.31(s,9H).

[0586] MS m / z(ESI):511.1[M+H] + .

[0587] Example 10

[0588] Synthesis of compound 4

[0589] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)benzo[d][1,3]dioxole-4-sulfonamide

[0590] Step a:

[0591] Benzo[d][1,3]dioxole-4-sulfonyl chloride

[0592] Thionyl chloride (5.3 mL, 73.06 mmol) was added dropwise to water (30 mL) at 25°C, and the mixture was stirred for 6 hours. 4-Amino-1,3-benzodioxole (1.00 g, 7.29 mmol) was added dropwise to concentrated hydrochloric acid (7 mL) at 0°C to obtain the hydrochloride salt. A solution of sodium nitrite (650 mg, 9.42 mmol) in water (2 mL) was then added dropwise to the hydrochloride salt. Subsequently, cuprous chloride (70 mg, 0.71 mmol) was added to the aqueous solution containing thionyl chloride at a temperature below 5°C, followed by the slowly added hydrochloride salt solution. The mixture was stirred at 40°C for 16 hours. The mixture was filtered under reduced pressure, and the filter cake was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 4a (680 mg, 42.3% yield).

[0593] Step b:

[0594] To a solution of intermediate 1 (80 mg, 0.33 mmol) in pyridine (2 mL) was added compound 3a (72 mg, 0.33 mmol). The reaction system was heated to 120°C and stirred for 5 hours. Compound 3a (72 mg, 0.33 mmol) was then added and stirred for 2 hours. A final batch of compound 3a (72 mg, 0.33 mmol) was then added and stirred for another 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the crude compound. The crude product was purified by high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound 4 (21 mg, yield 15.0%).

[0595] 1 HNMR (400MHz, DMSO-d6): δ7.85(d,1H),7.49(d,1H),7.30-7.19(m,1H),7.19-6.94(m,2H),6.9 1-6.82(m,1H),6.71(s,1H),6.62(s,1H),6.29(t,1H),6.02(s,2H),5.40(s,2H),3.80(s,3H). MS m / z(ESI): 428.9[M+H]+ .

[0596] Example 11

[0597] Synthesis of compound 5

[0598] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-4-sulfonamide

[0599] Step a:

[0600] 2,2-Difluorobenzo[d][1,3]dioxole-4-sulfonyl chloride

[0601] Thionyl chloride (5.96 mL, 82.16 mmol) was added dropwise to water (30 mL) at 25°C, and the mixture was stirred for 6 hours. 4-Amino-2,2-difluoro-1,3-benzodioxole (1.00 g, 5.78 mmol) was added dropwise to concentrated hydrochloric acid (7 mL) at 0°C to obtain the hydrochloride salt. A solution of sodium nitrite (523 mg, 7.58 mmol) in water (2 mL) was then added dropwise to the hydrochloride salt. Subsequently, cuprous chloride (10 mg, 0.10 mmol) was added to the aqueous solution containing thionyl chloride at a temperature below 5°C, and the prepared hydrochloride salt solution was slowly added. The mixture was stirred at 0°C for 2 hours. The mixture was extracted with dichloromethane (50 mL x 2), and the combined organic phases were concentrated under reduced pressure to afford compound 5a (1.00 g, 67.5% yield).

[0602] Step b:

[0603] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-4-sulfonamide

[0604] To a solution of intermediate 1 (100 mg, 0.41 mmol) in pyridine (2 mL) was added a solution of compound 5a (157 mg, 0.61 mmol) in pyridine (0.5 mL). The reaction system was heated to 80°C and stirred for 2 hours. Compound 3a (157 mg, 0.61 mmol) was then added and stirred for 2 hours. After the reaction was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to afford the crude compound. The crude product was purified by high-performance liquid chromatography (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 5 (30 mg, 15.8% yield).

[0605] 1 HNMR (400MHz, DMSO-d6): δ7.84(d,1H),7.57-7.44(m,2H),7.30-7.18(m,1H),7.15-7.05(m ,1H),7.05-6.94(m,1H),6.67(s,1H),6.59(s,1H),6.29(t,1H),5.39(s,2H),3.80(s,3H).

[0606] MS m / z(ESI):464.9[M+H] + .

[0607] Example 12

[0608] Synthesis of compound 6

[0609] N-(6-((1H-pyrazol-1-yl)methyl)-4-isopropoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0610] Step a:

[0611] 4-Bromo-2-fluoro-6-isopropoxybenzonitrile

[0612] Under nitrogen, 4-bromo-2,6-difluorobenzonitrile (2.40 g, 11.01 mmol) was added to a solution of sodium metal (280 mg, 11.67 mmol) in isopropanol (30 mL) at 0°C. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to give compound 6a (1.70 g, 59.8% yield).

[0613] 1 H NMR (400MHz, CDCl3): δ6.95(d,1H),6.9(s,1H),4.66-4.63(m,1H),1.41(d,6H).

[0614] Step b:

[0615] Methyl 4-cyano-3-fluoro-5-isopropoxybenzoate

[0616] To a solution of compound 6a (1.70 g, 6.59 mmol) in methanol (20 mL) were added triethylamine (4.6 mL, 34.09 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.24 g, 0.33 mmol). The reaction system was stirred at 80°C under a carbon monoxide atmosphere (1 atm) for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to afford compound 6b (1.20 g, 76.8% yield).

[0617] 1 HNMR (400MHz, CDCl3): δ7.40(s,1H),7.37(d,1H),4.66-4.63(m,1H),3.96(s,3H),1.44(d,6H).

[0618] Step c:

[0619] 2-Fluoro-4-(hydroxymethyl)-6-isopropoxybenzonitrile

[0620] To a solution of compound 6b (1.10 g, 4.64 mmol) in tetrahydrofuran (10 mL) at 10°C, lithium borohydride (0.40 g, 18.37 mmol) was added portionwise. The reaction system was heated to 70°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with dilute hydrochloric acid (1.0 M) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 6c (907 mg, 93.5% yield).

[0621] 1 HNMR (300MHz, CDCl3): δ7.31(s,1H),6.82(s,1H),6.77(d,1H),4.77(s,2H),4.73-4.69(m,1H),1.45(d,6H).

[0622] Step d:

[0623] 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-isopropoxybenzonitrile

[0624] To a solution of compound 6c (586 mg, 2.80 mmol) and 1-(methylsulfonyl)-1H-pyrazole (491 mg, 3.36 mmol) in acetonitrile (10 mL) was added cesium carbonate (1.09 g, 3.35 mmol) at 20°C. The reaction system was heated to 70°C and stirred for 1 hour. After the reaction was completed, it was cooled to room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (25 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1-2:1) to give compound 6d (700 mg, 96.4% yield).

[0625] 1 HNMR (400MHz, CDCl3): δ7.60(d,1H),7.45(d,1H),6.48(d,1H),6.45(s,1H),6.36(t,1H),5.32(s,2H),4.61-4.49(m,1H),1.35(d,6H).

[0626] Step e:

[0627] 6-((1H-pyrazol-1-yl)methyl)-4-isopropoxybenzo[d]isoxazol-3-amine

[0628] To a mixed solution of compound 6d (700 mg, 2.70 mmol) and acetohydroxamic acid (608 mg, 8.10 mmol) (N,N-dimethylformamide:water ratio 9:1, 8 mL) was added tetramethylguanidine (1.87 g, 16.20 mmol) dropwise. The reaction system was heated to 60°C and stirred for 7 hours. After completion of the reaction, it was cooled to room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 6e (500 mg, 68.0% yield).

[0629] 1HNMR (400MHz, DMSO-d6): δ7.86(d,1H),7.50(d,1H),6.67(s,1H),6.60(s,1 H),6.29(t,1H),5.80(s,2H),5.40(s,2H),4.72-4.66(m,1H),1.34(d,6H).

[0630] Step f:

[0631] N-(6-((1H-pyrazol-1-yl)methyl)-4-isopropoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0632] Compound 3d (336 mg, 1.11 mmol) was added to a solution of compound 6e (100 mg, 0.37 mmol) in pyridine (4 mL) at 10°C. The reaction system was heated to 100°C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5%-95%) to afford compound 6 (20 mg, 10.1% yield).

[0633] 1 HNMR (400MHz, DMSO-d6): δ9.62(s,1H),7.86(d,1H),7.83(d,1H),7.57(d,1H),7.48(d,1H), 6.88(s,1H),6.83(d,1H),6.68(s,1H),6.29(t,1H),5.43(s,2H),4.64-4.53(m,1H) ,4.49-4.46(m,1H),2.08-2.03(m,2H),1.53-1.31(m,4H),1.27(s,9H),1.09(d,6H).

[0634] MS m / z(ESI):539.2[M+H] + .

[0635] Example 13

[0636] Synthesis of compound 7

[0637] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0638] Step a:

[0639] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0640] To a solution of intermediate 2 (80 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added sodium hydride (60%, 37 mg, 0.93 mmol). The reaction system was stirred at 0°C for 10 minutes, followed by the addition of compound 3d (139 mg, 0.46 mmol) and continued stirring for 20 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 7 (22 mg, 13.6% yield).

[0641] 1 HNMR (400MHz, DMSO-d6): δ10.36(s,1H),7.96-7.75(m,2H),7.68-7.55(m,1H),7.49(d,1H),6.95(d,1H),6.90(d,1H),6.30 (t,1H),5.50(s,2H),4.66-4.62(m,1H),3.94(d,3H),2.20-2.16(m,2H),1.74-1.57(m,2H),1.57-1.48(m,2H),1.26(s,9H).

[0642] MS m / z(ESI):529.0[M+H] + .

[0643] Example 14

[0644] Synthesis of compound 8

[0645] N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutoxybenzenesulfonamide

[0646] Step a:

[0647] 5-Bromo-4-(bromomethyl)-2-fluorobenzonitrile: To a solution of 5-bromo-2-fluoro-4-methylbenzonitrile (1.00 g, 4.67 mmol) in acetonitrile (10 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (0.67 g, 2.34 mmol) and azobisisobutyronitrile (0.10 g, 0.61 mmol). The reaction system was heated to 80°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 8a (0.85 g, 62.1% yield).

[0648] 1 H NMR (400MHz, CDCl3): δ7.83(d,1H),7.37(d,1H),4.53(s,2H).

[0649] Step b:

[0650] 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzonitrile

[0651] To a solution of compound 8a (1.00 g, 3.41 mmol) in acetonitrile (16 mL) were added pyrazole (0.25 g, 3.67 mmol) and cesium carbonate (1.33 g, 4.08 mmol). The reaction system was stirred at 25°C for 5 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 8b (0.73 g, 76.3% yield).

[0652] 1 H NMR (300MHz, CDCl3): δ7.82(d,1H),7.64(d,1H),7.52(d,1H),6.50(d,1H),6.39(t,1H),5.42(s,2H).

[0653] MS m / z(ESI):281.0[M+H] + .

[0654] Step c:

[0655] 4-((1H-pyrazol-1-yl)methyl)-5-cyclopropyl-2-fluorobenzonitrile

[0656] To a solution of compound 8b (0.68 g, 2.43 mmol) in 1,4-dioxane (15 mL) under nitrogen was added cesium carbonate (1.58 g, 4.85 mmol), cyclopropylboronic acid (0.42 g, 4.89 mmol), tris(dibenzylideneindeneacetone)dipalladium (0.16 g, 0.17 mmol), and 2-(di-tert-butylphosphino)biphenyl (0.14 g, 0.47 mmol). The reaction system was heated to 90°C and stirred for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 8c (0.54 g, 92.2% yield).

[0657] 1 HNMR (300MHz, CDCl3): δ7.62(d,1H),7.46(d,1H),7.33(d,1H),6.49(d,1H),6.3 8(t,1H),5.56(s,2H),1.87-1.80(m,1H),1.07-1.03(m,2H),0.71-0.67(m,2H).

[0658] MS m / z(ESI):240.1[MH] + .

[0659] Step d:

[0660] 6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-amine

[0661] To a mixed solution of compound 8c (0.49 g, 2.03 mmol) (acetonitrile:water ratio 9:1, 10 mL) were added acetohydroxamic acid (0.46 g, 6.13 mmol) and tetramethylguanidine (2.08 g, 18.06 mmol). The reaction system was heated to 60°C and stirred under a nitrogen atmosphere for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 8d (0.35 g, 67.8% yield).

[0662] 1HNMR (400MHz, DMSO-d6): δ7.84(d,1H),7.58(s,1H),7.53(d,1H),6.71(s,1H),6.36 -6.28(m,3H),5.64(s,2H),2.10-1.99(m,1H),1.02-0.90(m,2H),0.69-0.56(m,2H).

[0663] MS m / z(ESI):255.2[M+H] + .

[0664] Step e:

[0665] N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-yl)-5-(tert-butyl)-2-cyclobutyloxybenzenesulfonamide Compound 8d (100 mg, 0.39 mmol) and compound 3d (357 mg, 1.18 mmol) were dissolved in pyridine (6 mL). The reaction system was heated to 120°C and stirred under nitrogen for 56 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to obtain compound 8 (35 mg, 17.1% yield).

[0666] 1 HNMR (400MHz, DMSO-d6): δ11.48(s,1H),7.88-7.76(m,3H),7.56(d,1H),7.52(d,1H),6.86(d,1H),6.82(s,1H),6.32(t,1H),5.65(s,2H),4.7 4-4.60(m,1H),2.25-2.12(m,2H),2.12-2.10(m,1H),1.78-1.64(m,2H) ,1.53-1.37(m,2H),1.25(s,9H),1.02-0.93(m,2H),0.64-0.54(m,2H). MS m / z(ESI): 521.1[M+H] + .

[0667] Example 15

[0668] Synthesis of compound 9

[0669] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-yl)-2-methoxybenzenesulfonamide

[0670] Step a:

[0671] To a solution of intermediate 6 (80 mg, 0.31 mmol) in pyridine (5 mL) was added 2-methoxybenzenesulfonyl chloride (64 mg, 0.31 mmol) of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-yl)-2-methoxybenzenesulfonamide under nitrogen. The reaction system was heated to 70°C and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20*150mm, 5μm; mobile phase A: 5mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to afford compound 9 (23 mg, 17.4% yield).

[0672] 1 HNMR (400MHz, DMSO-d6): δ9.41(brs,1H),7.91-7.88(m,2H),7.62-7.58(m,1H),7.49(d,1H),7. 28(s,1H),7.15-7.09(m,2H),6.94(s,1H),6.30(t,1H),5.45(s,2H),4.05(s,3H),3.78(s,3H).

[0673] MS m / z(ESI):430.9[M+H] + .

[0674] Example 16

[0675] Synthesis of compound 10

[0676] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-(2,2-difluoroethoxy)-5-isopropylbenzenesulfonamide

[0677] Step a:

[0678] 2-iodo-4-isopropylphenol

[0679] To a solution of 4-isopropylphenol (1.36 g, 9.99 mmol) in dichloromethane (40 mL) at 10°C were added p-toluenesulfonic acid (0.17 g, 0.99 mmol) and N-iodosuccinimide (2.25 g, 9.99 mmol). The reaction system was stirred for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (150 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to afford compound 10a (1.72 g, 65.7% yield).

[0680] 1 H NMR (400MHz, CDCl3): δ7.49(d,1H),7.11-7.08(m,1H),6.91(d,1H),5.13(s,1H),2.83-2.80(m,1H),1.21(s,3H),1.20(s,3H).

[0681] Step b:

[0682] 1-(2,2-difluoroethoxy)-2-iodo-4-isopropylbenzene

[0683] Compound 10a (1.60 g, 6.10 mmol) and potassium carbonate (1.69 g, 12.20 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction system was stirred at 25°C for 5 minutes, followed by the addition of 1,1-difluoro-2-iodoethane (1.29 g, 6.72 mmol). The reaction system was heated to 100°C and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 10b (1.80 g, 90.4% yield).

[0684] 1 H NMR (400MHz, CDCl3): δ7.64(d,1H),7.17-7.14(m,1H),6.76(d,1H),6.29-5 .99(m,1H),4.23-4.16(m,2H),2.86-2.79(m,1H),1.22(s,3H),1.20(s,3H).

[0685] Step c:

[0686] Benzyl(2-(2,2-difluoroethoxy)-5-isopropylphenyl)sulfane

[0687] To a solution of compound 10b (1.56 g, 4.78 mmol) in N,N-dimethylformamide (15 mL) was added benzyl mercaptan (0.78 g, 6.20 mmol), potassium carbonate (1.33 g, 9.60 mmol), 1,4-diazabicyclo[2.2.2]octane (0.05 g, 0.48 mmol), and cuprous iodide (0.05 g, 0.24 mmol) under nitrogen. The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:dichloromethane = 30:1) to afford compound 10c (1.49 g, 96.6% yield).

[0688] 1 H NMR (400MHz, CDCl3) δ7.32-7.27(m,3H),7.26-7.19(m,2H),7.10(d,1H),7.04-7.01(m,1H),6.77(d, 1H),6.26-5.97(m,1H),4.23-4.15(m,2H),4.08(s,2H),2.82-2.75(m,1H),1.16(s,3H),1.15(s,3H).

[0689] MS m / z(ESI):321.1[MH] + .

[0690] Step d:

[0691] 2-(2,2-Difluoroethoxy)-5-isopropylbenzenesulfonyl chloride

[0692] To a mixed solution of compound 10c (1.49 g, 4.62 mmol) (glacial acetic acid and water, 10:1 ratio, 22 mL) was added N-chlorosuccinimide (3.69 g, 27.60 mmol) at 25°C. The reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 10d (1.12 g, 81.1% yield).

[0693] 1HNMR(400MHz, CDCl3): δ7.82(d,1H),7.56-7.54(m,1H),7.04(d,1H),6.37-6 .07(m,1H),4.42-4.34(m,2H),3.00-2.93(m,1H),1.28(s,3H),1.26(s,3H).

[0694] Step e:

[0695] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-(2,2-difluoroethoxy)-5-isopropylbenzenesulfonamide Intermediate 1 (50 mg, 0.20 mmol) and compound 10d (306 mg, 1.02 mmol) were dissolved in pyridine (5 mL). The reaction system was heated to 120°C and stirred for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to afford compound 10 (57 mg, 55.0% yield).

[0696] 1 HNMR (400MHz, DMSO-d6): δ9.93(s,1H),7.87(d,1H),7.69(d,1H),7.52-7.48(m,2H),7.22(s,1H),6.82-6.73(m,2 H),6.52-6.23(m,2H),5.43(s,2H),4.41-4.35(m,2H),3.80(s,3H),2.95-2.91(m,1H),1.18(s,3H),1.16(s,3H).

[0697] MS m / z(ESI):507.0[M+H] + .

[0698] Example 17

[0699] Synthesis of compound 11

[0700] N-(6-((1H-pyrazol-1-yl)methyl)-4-(difluoromethoxy)benzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide

[0701] Step a:

[0702] 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-hydroxybenzonitrile

[0703] Compound Int1-d (1.10 g, 4.76 mmol) was dissolved in pyridine hydrochloric acid solution (7 mL). The reaction system was heated to 180°C and stirred for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure to provide compound 11a (0.78 g, 75.5% yield).

[0704] MS m / z(ESI):218.0[M+H] + .

[0705] Step b:

[0706] 4-((1H-pyrazol-1-yl)methyl)-2-(difluoromethoxy)-6-fluorobenzonitrile

[0707] To a mixed solution of compound 11a (780 mg, 3.59 mmol) (N,N-dimethylformamide and water in a ratio of 30:1, 20 mL) was added sodium difluorochloroacetate (821 mg, 5.31 mmol) and potassium carbonate (745 mg, 5.39 mmol). The reaction system was heated to 120°C under nitrogen and stirred for 4 hours. After completion of the reaction, it was cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:tetrahydrofuran = 4:1) to afford compound 11b (650 mg, 67.7% yield).

[0708] 1 H NMR (300MHz, CDCl3): δ8.11(d,1H),7.98(d,1H),7.78-6.91(m,3H),6.87(t,1H),5.88(s,2H).

[0709] Step c:

[0710] 6-((1H-pyrazol-1-yl)methyl)-4-(difluoromethoxy)benzo[d]isoxazol-3-amine

[0711] Compound 11b (0.65 g, 2.43 mmol), acetohydroxamic acid (0.55 g, 7.30 mmol), and tetramethylguanidine (1.68 g, 14.60 mmol) were dissolved in a 5 mL mixture (acetonitrile:water ratio of 15:1). The reaction system was heated to 60°C and stirred under nitrogen for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:methanol = 20:1) to afford compound 11c (0.42 g, 61.6% yield).

[0712] MS m / z(ESI):281.0[M+H] + .

[0713] Step d:

[0714] To a solution of 11c (100 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 71 mg, 1.78 mmol) under nitrogen at 0°C. The reaction was stirred for 10 minutes, followed by the addition of 2-methoxybenzenesulfonyl chloride (111 mg, 0.54 mmol). The mixture was stirred at 0°C for 1 hour and then returned to 25°C for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound 11 (28 mg, yield 17.4%).

[0715] 1 HNMR (400MHz, DMSO-d6): δ10.67(s,1H),7.97-7.87(m,1H),7.77(d,1H),7.75-7.58( m,1H),7.51(s,1H),6.37-6.92(m,5H),6.37-6.28(m,1H),5.50(s,2H),3.75(s,3H).

[0716] MS m / z(ESI):450.9[M+H] + .

[0717] Example 18

[0718] Synthesis of compound 12

[0719] N-(6-((1H-pyrazol-1-yl)methyl)-4-(difluoromethoxy)benzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0720] Step a:

[0721] To a solution of 11c (100 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 71 mg, 1.78 mmol) under nitrogen at 0°C. The reaction was stirred for 10 minutes, followed by the addition of 2,6-dimethoxybenzenesulfonyl chloride (127 mg, 0.53 mmol). The mixture was stirred at 0°C for 1 hour and then returned to 25°C for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to give compound 11 (54 mg, yield 31.5%).

[0722] 1 HNMR (400MHz, DMSO-d6): δ10.22(s,1H),7.89(d,1H),7.51-7.11(m,4H),7.00(s,1H),6.77(d,2H),6.36-6.26(m,1H),5.50(s,2H),3.74(s,6H).

[0723] MS m / z(ESI):481.0[M+H] + .

[0724] Example 19

[0725] Synthesis of compound 13

[0726] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide

[0727] Step a:

[0728] 3-(Chlorosulfonyl)-4-methoxybenzoic acid

[0729] p-Anisic acid (500 mg, 3.29 mmol) was dissolved in chlorosulfonic acid (2 mL). The reaction system was heated to 65°C under nitrogen and stirred for 5 hours. After the reaction, the reaction mixture was slowly poured into ice water and filtered under reduced pressure to obtain compound 13a (610 mg, 74.1% yield).

[0730] 1 H NMR (400MHz, DMSO-d6): δ13.64(s,1H),8.30(d,1H),7.92-7.88(m,1H),7.06(d,1H),3.83(s,3H).

[0731] MS m / z(ESI):248.9[MH] + .

[0732] Step b:

[0733] Methyl 3-(chlorosulfonyl)-4-methoxybenzoate

[0734] Under nitrogen, compound 13a (4.00 g, 15.96 mmol) was dissolved in sulfonyl chloride (80 mL) at 20°C and stirred for 18 hours. Methanol (10 mL) was then added to the reaction system and stirred for another 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 13b (2.90 g, 68.7% yield).

[0735] 1 H NMR (400MHz, CDCl3): δ8.64(d,1H),8.39-8.35(m,1H),7.18(d,1H),4.14(s,3H),3.95(s,3H).

[0736] Step c:

[0737] Methyl 3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-4-methoxybenzoate. To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60%, 82 mg, 2.05 mmol) under nitrogen at 0°C. The reaction system was stirred for 1 hour, followed by the addition of compound 13b (217 mg, 0.82 mmol), and stirring continued at 0°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:tetrahydrofuran = 10:1) to give compound 13c (68 mg, 35.2% yield).

[0738] 1 HNMR (400MHz, DMSO-d6): δ10.67(s,1H),8.36(d,1H),8.22-8.18(m,1H),7.87(d,1H),7.50(d,1H),7. 35(d,1H),6.85(s,1H),6.75(s,1H),6.30(t,1H),5.44(s,2H),3.86(s,3H),3.85(s,3H),3.79(s,3H).

[0739] MS m / z(ESI):473.1[M+H] + .

[0740] Step d:

[0741] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide

[0742] Under nitrogen, methylmagnesium iodide (237 mg, 3.18 mmol) was added to a solution of compound 13c (150 mg, 0.32 mmol) in tetrahydrofuran (7 mL) at 20°C. The reaction was stirred at 20°C for 2 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 13 (21 mg, 14.0% yield).

[0743] 1 HNMR (400MHz, DMSO-d6): δ10.02(s,1H),7.92(d,1H),7.87(d,1H),7.64(d,1H),7.49(d,1H) ,7.10(d,1H),6.83(s,1H),6.73(s,1H),6.30(t,1H),5.43(s,2H),5.17(s,1H),3.80(s,3H), 3.74(s,3H),1.39(s,6H).

[0744] MS m / z(ESI):473.1[M+H] + .

[0745] Example 20

[0746] Synthesis of compound 14

[0747] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[0748] Step a:

[0749] 6-Methoxy-2,3-dihydrobenzo[b][1,4]dioxine

[0750] 6-Hydroxy-1,4-benzodioxane (500 mg, 3.29 mmol), iodomethane (700 mg, 4.93 mmol), and potassium carbonate (908 mg, 6.57 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction system was stirred at 20°C for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 14a (410 mg, 75.1% yield).

[0751] 1 H NMR (400 MHz, CDCl3): δ 6.79 (d, 1H), 6.46-6.41 (m, 2H), 4.26-4.20 (m, 4H), 3.75 (s, 3H). Step b:

[0752] 6-Methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonyl chloride

[0753] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 3.5 mL, 8.75 mmol) was added dropwise to a solution of compound 14a (1.20 g, 7.22 mmol) in tetrahydrofuran (25 mL) at 0°C. The reaction system was stirred at 0°C for 30 minutes, then cooled to -78°C and sulfuryl chloride (1.46 g, 10.82 mmol) was added. Stirring was continued at -78°C for 30 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 14b (0.25 g, 13.1% yield).

[0754] 1 H NMR (400MHz, CDCl3): δ7.15(d,1H), 6.57(d,1H), 4.47-4.45(m,2H), 4.31-4.29(m,2H), 3.86(s,3H).

[0755] Step c:

[0756] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[0757] Under nitrogen, sodium hydride (60%, 246 mg, 6.14 mmol) was added to a solution of intermediate 1 (150 mg, 0.61 mmol) in N,N-dimethylformamide (2 mL) at 25°C. The reaction was stirred for 1 hour, followed by the addition of compound 14b (195 mg, 0.73 mmol) and continued stirring at 25°C for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 14 (21 mg, 7.2% yield).

[0758] 1HNMR (400MHz, DMSO-d6): δ9.73(s,1H),7.87(d,1H),7.50(d,1H),7.04(d,1H),6.84(s,1H),6.75( s,1H),6.63(d,1H),6.31-6.30(m,1H),5.45(s,2H),4.20-4.15(m,4H),3.86(s,3H),3.69(s,3H).

[0759] MS m / z(ESI):473.0[M+H] + .

[0760] Example 21

[0761] Synthesis of compound 15

[0762] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclobutane]-8-sulfonamide

[0763] Step a:

[0764] Methyl 2-cyclobutylidene acetate

[0765] To a solution of trimethyl phosphate acetate (9.46 g, 51.95 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (60%, 2.08 g, 52.00 mmol) at 0°C. The reaction system was stirred at 0°C for 1 hour, followed by the addition of cyclobutanone (2.60 g, 37.10 mmol). The reaction system was stirred at 25°C for another 2 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 15a (3.00 g, 64.1% yield).

[0766] 1 H NMR (400MHz, CDCl3) δ5.59-5.58(m,1H),3.67(s,3H),3.12(t,2H),2.83(t,2H),2.12-2.04(m,2H)

[0767] Step b:

[0768] 7-Methoxyspiro[chroman-4,1'-cyclobutane]-2-one

[0769] 3-Methoxyphenol (6.88 g, 55.42 mmol), compound 15a (3.50 g, 27.74 mmol), and 98% concentrated sulfuric acid (0.54 g, 5.40 mmol) were mixed and heated to 130°C with stirring for 2 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 15b (0.74 g, 12.2% yield).

[0770] 1 H NMR (400MHz, CDCl3): δ7.38(d,1H),6.78-6.75(m,1H),6.64(d,1H),3.82(s,3H),2.89(s,2H),2.40-2.37(m,2H),2.13-2.03(m,4H).

[0771] Step c:

[0772] 2-(1-(2-hydroxyethyl)cyclobutyl)-5-methoxyphenol

[0773] To a solution of compound 15b (740 mg, 3.39 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (136 mg, 3.39 mmol) at 0°C, and the reaction system was stirred at 0°C for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 15c (570 mg, 75.6% yield).

[0774] 1 H NMR (400MHz, CDCl3): δ6.85(d,1H),6.50-6.47(m,1H),6.42(d,1H),3.79(s,3H),3.6 7(t,2H),2.55-2.47(m,2H),2.34-2.29(m,2H),2.22-2.07(m,3H).1.88-1.85(m,1H).

[0775] Step d:

[0776] 7-Methoxyspiro[chroman-4,1'-cyclobutane]

[0777] Compound 15c (570 mg, 2.56 mmol) and p-toluenesulfonic acid (88 mg, 0.51 mmol) were dissolved in toluene (10 mL). The reaction system was heated to 110°C and stirred for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 15d (360 mg, 68.7% yield).

[0778] 1 H NMR (400MHz, CDCl3): δ7.39(d,1H),6.55-6.53(m,1H),6.32(d,1H),4.12(t,2H),3.75(s,3H),2.43-2.38(m,2H),2.09-1.93(m,6H).

[0779] Step e:

[0780] 7-Methoxyspiro[chroman-4,1'-cyclobutane]-8-sulfonyl chloride

[0781] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 0.9 mL, 2.25 mmol) was added dropwise to a solution of compound 15d (300 mg, 1.47 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (297 mg, 2.20 mmol) was added. Stirring was continued at -78°C for 30 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 15e (190 mg, 42.7% yield).

[0782] 1 H NMR (400MHz, DMSO-d6): δ7.47(d,1H),6.58(d,1H),4.04-4.02(m,2H),3.67(s,3H),2.32-2.30(m,2H),2.01-1.88(m,6H).

[0783] Step f:

[0784] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclobutane]-8-sulfonamide

[0785] To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 82 mg, 2.05 mmol). The reaction system was stirred for 15 minutes, followed by the addition of compound 15e (186 mg, 0.61 mmol), and stirring continued at 0°C for 30 minutes. After completion of the reaction, the mixture was diluted with water, adjusted to pH 7 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 15 (100 mg, 47.8% yield).

[0786] 1 HNMR (400MHz, DMSO-d6): δ9.49(s,1H),7.87(d,1H),7.73(d,1H),7.49(d,1H),6.83(s,1H),6.76-6.72(m,2 H),6.30(s,1H),5.45(s,2H),4.05(t,2H),3.87(s,3H),3.73(s,3H),2.33-2.28(m,2H),2.02-1.87(m,6H).

[0787] MS m / z(ESI):511.0[M+H] + .

[0788] Example 22

[0789] Synthesis of compound 16

[0790] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[0791] Step a:

[0792] 7-Methoxy-4,4-dimethylchroman-2-one

[0793] 3-Methoxyphenol (8.69 g, 70.00 mmol), methyl 3,3-dimethacrylate (4.00 g, 35.04 mmol), and 98% concentrated sulfuric acid (0.69 g, 6.90 mol) were mixed and the reaction system was heated to 130°C and stirred for 3 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 16a (2.30 g, 31.8% yield).

[0794] 1 H NMR (400MHz, CDCl3): δ7.22(d,1H),6.74-6.71(m,1H),6.64(d,1H),3.82(s,3H),2.62(s,2H),1.35(s,6H).

[0795] Step b:

[0796] 2-(4-Hydroxy-2-methylbutan-2-yl)-5-methoxyphenol

[0797] To a solution of compound 16a (1.80 g, 8.73 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.33 g, 8.73 mmol) at 0°C, and the reaction system was stirred at 0°C for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 16b (1.39 g, 75.7% yield).

[0798] 1 H NMR (400MHz, CDCl3): δ7.09(d,1H),6.41-6.39(m,1H),6.24(d,1H),3.74(s,3H),3.54(t,2H),2.18(t,2H),1.38(s,6H).

[0799] Step c:

[0800] 7-Methoxy-4,4-dimethylchroman

[0801] Compound 16b (320 mg, 1.52 mmol) and p-toluenesulfonic acid (53 mg, 0.31 mmol) were dissolved in toluene (10 mL). The reaction system was heated to 120°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 16c (150 mg, 51.3% yield).

[0802] 1 H NMR (400MHz, CDCl3): δ7.15(d,1H),6.49-6.46(m,1H),6.34(d,1H),4.18(t,2H),3.74(s,3H),1.81(t,2H),1.30(s,6H).

[0803] Step d:

[0804] 7-Methoxy-4,4-dimethylchroman-8-sulfonyl chloride

[0805] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 1.1 mL, 2.75 mmol) was added dropwise to a solution of compound 16c (450 mg, 2.34 mmol) in tetrahydrofuran (3 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (474 ​​mg, 3.51 mmol) was added. Stirring was continued at -78°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 16d (125 mg, 18.4% yield).

[0806] 1 H NMR (400MHz, CDCl3): δ7.42(d,1H),6.50(d,1H),4.32(t,2H),3.87(s,3H),1.81(t,2H),1.26(s,6H).

[0807] Step e:

[0808] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[0809] Under nitrogen, sodium hydride (60%, 62 mg, 1.55 mmol) was added to a solution of intermediate 1 (75 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) at 25°C. The reaction was stirred for 1 hour, followed by the addition of compound 16d (112 mg, 0.38 mmol) and continued stirring at 25°C for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 16 (30 mg, 19.6% yield).

[0810] 1 HNMR (400MHz, DMSO-d6): δ9.51(s,1H),7.87(d,1H),7.50-7.48(m,2H),6.83(s,1H),6.75(s,1H),6.6 7(d,1H),6.31(t,1H),5.45(s,2H),4.08(t,2H),3.87(s,3H),3.71(s,3H),1.67(t,2H),1.20(s,6H).

[0811] MS m / z(ESI):499.0[M+H] + .

[0812] Example 23

[0813] Synthesis of compound 17

[0814] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxybenzo[d][1,3]dioxole-4-sulfonamide

[0815] Step a:

[0816] 5-Methoxybenzo[d][1,3]dioxole

[0817] Sesamol (2.00 g, 14.48 mmol), iodomethane (3.09 g, 21.77 mmol), and potassium carbonate (4.10 g, 29.67 mmol) were dissolved in acetone (30 mL). The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 17a (1.60 g, 72.6% yield).

[0818] 1 H NMR (400MHz, CDCl3): δ6.71(d,1H), 6.49(d,1H), 6.33-6.31(m,1H), 5.91(s,2H), 3.75(s,3H).

[0819] Step b:

[0820] 5-Methoxybenzo[d][1,3]dioxole-4-sulfonyl chloride

[0821] Under nitrogen, n-butyllithium (1.6 M in n-hexane, 0.98 mL, 1.58 mmol) was added dropwise to a solution of compound 17a (200 mg, 1.31 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (355 mg, 2.63 mmol) was added. Stirring was continued at -78°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 17b (110 mg, 33.4% yield).

[0822] 1 H NMR (400MHz, DMSO-d6): δ6.76(d,1H), 6.34(d,1H), 5.91(s,2H), 3.66(s,3H).

[0823] Step c:

[0824] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxybenzo[d][1,3]dioxole-4-sulfonamide

[0825] To a solution of intermediate 1 (200 mg, 0.82 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added sodium hydride (60%, 164 mg, 4.09 mmol). The reaction system was stirred at 0°C for 10 minutes, followed by the addition of compound 17b (411 mg, 1.64 mmol) and continued stirring for 50 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 17 (92 mg, 24.5% yield).

[0826] 1 HNMR (400MHz, DMSO-d6): δ10.28(s,1H),7.88(d,1H),7.50(d,1H),7.08(d,1H),6.86(s,1H),6. 75(s,1H),6.49(d,1H),6.31-6.30(m,1H),6.07(s,2H),5.45(s,2H),3.82(s,3H),3.66(s,3H).

[0827] MS m / z(ESI):459.0[M+H] + .

[0828] Example 24

[0829] Synthesis of compound 18

[0830] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-2,2-dimethylbenzo[d][1,3]dioxole-4-sulfonamide

[0831] Step a:

[0832] 5-Methoxy-2,2-dimethylbenzo[d][1,3]dioxole

[0833] 4-Methoxy-1,2-benzenediol (1.00 g, 7.14 mmol), 2,2-dimethoxypropane (1.49 g, 14.27 mmol), and p-toluenesulfonic acid (0.12 g, 0.71 mmol) were dissolved in toluene (30 mL). The reaction system was heated to 120°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 18a (0.69 g, 53.7% yield).

[0834] 1 H NMR (400MHz, DMSO-d6): δ6.69(d,1H),6.50(d,1H),6.31-6.28(m,1H),3.66(s,3H),1.60(s,6H).

[0835] Step b:

[0836] 5-Methoxy-2,2-dimethylbenzo[d][1,3]dioxole-4-sulfonyl chloride

[0837] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 4.3 mL, 10.75 mmol) was added dropwise to a solution of compound 18a (1.60 g, 8.84 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (2.40 g, 17.78 mmol) was added. Stirring was continued at -78°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 18b (0.47 g, 19.0% yield).

[0838] 1 H NMR (400MHz, CDCl3): δ6.92(d,1H), 6.39(d,1H), 3.96(s,3H), 1.78(s,6H).

[0839] Step c:

[0840] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-2,2-dimethylbenzo[d][1,3]dioxole-4-sulfonamide

[0841] To a solution of intermediate 1 (140 mg, 0.57 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added sodium hydride (60%, 115 mg, 2.87 mmol). The reaction system was stirred at 0°C for 10 minutes, followed by the addition of compound 18b (320 mg, 1.15 mmol) and continued stirring for 50 minutes. After the reaction was returned to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (dichloromethane:methanol = 9:1) to afford compound 18 (30 mg, 10.8% yield).

[0842] 1 HNMR (400MHz, DMSO-d6): δ10.18(s,1H),7.81(d,1H),7.50(d,1H),6.97(d,1H),6.85(s, 1H),6.74(s,1H),6.45(d,1H),6.31-6.30(m,1H),5.45(s,2H),3.83(s,3H),3.66(s,3H),1.53(s,6H).

[0843] MS m / z(ESI):487.0[M+H] + .

[0844] Example 25

[0845] Synthesis of compound 19

[0846] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0847] Step a:

[0848] 1-(4-Methoxyphenyl)-2-methylpropan-2-ol

[0849] To a solution of p-methoxyphenylacetone (1.50 g, 9.14 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium chloride (3.0 M in tetrahydrofuran, 9.10 mL, 27.30 mmol) dropwise under a nitrogen atmosphere. The reaction was stirred at 0°C for 16 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 19a (1.05 g, 63.8% yield).

[0850] 1 H NMR (400MHz, CDCl3) δ7.15(d,2H),6.87(d,2H),3.82(s,3H),2.72(s,2H),1.20(s,6H).

[0851] Step b:

[0852] 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran

[0853] To a solution of compound 19a (2.00 g, 11.10 mmol) in perfluorobenzene (25 mL) under a hydrogen atmosphere were added lithium carbonate (1.23 g, 16.65 mmol), iodophenyl diacetic acid (5.36 g, 16.64 mmol), and palladium acetate (0.12 g, 0.53 mmol). The reaction system was heated to 120°C and stirred for 36 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 19b (0.55 g, 27.8% yield).

[0854] 1 H NMR (400MHz, CDCl3): δ6.92(d,1H),6.32-6.26(m,2H),3.68(s,3H),2.87(s,2H),1.39(s,6H).

[0855] Step c:

[0856] 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0857] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 0.8 mL, 2.00 mmol) was added dropwise to a solution of compound 19b (250 mg, 1.40 mmol) in tetrahydrofuran (5 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (227 mg, 1.68 mmol) was added. Stirring was continued at -78°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 19c (50 mg, 12.9% yield).

[0858] 1 H NMR (400MHz, CDCl3): δ7.30(d,1H), 6.43(d,1H), 3.96(s,3H), 2.98(s,2H), 1.55(s,6H).

[0859] Step d:

[0860] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0861] Under nitrogen, sodium hydride (60%, 50 mg, 1.24 mmol) was added to a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) at 0°C. The reaction was stirred for 1 hour, followed by the addition of compound 19c (170 mg, 0.61 mmol). The reaction was allowed to return to room temperature and stirred for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 19 (5 mg, 2.5% yield).

[0862] 1HNMR (400MHz, DMSO-d6): δ9.55(s,1H),7.87(d,1H),7.50(d,1H),7.29(d,1H),6.83(s,1H),6.76( s,1H),6.53(d,1H),6.30(t,1H),5.45(s,2H),3.88(s,3H),3.73(s,3H),2.88(s,2H),1.20(s,6H).

[0863] MS m / z(ESI):485.0[M+H] + .

[0864] Example 26

[0865] Synthesis of compound 20

[0866] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0867] Step a:

[0868] 2-(3-methoxyphenoxy)acetic acid methyl ester

[0869] 3-Methoxyphenol (8.00 g, 64.44 mmol), ethyl bromoacetate (16.13 g, 96.59 mmol), and potassium carbonate (17.80 g, 128.79 mmol) were dissolved in acetone (100 mL). The reaction system was heated to 60°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to provide compound 20a (12.30 g, 97.3% yield).

[0870] 1 H NMR (400MHz, CDCl3): δ7.20(t,1H),6.59-6.49(m,3H),4.62(s,2H),4.29(q,2H),3.80(s,3H)1.32(t,3H).

[0871] Step b:

[0872] 1-(3-Methoxyphenoxy)-2-methylpropan-2-ol

[0873] Methylmagnesium chloride (3.0 M in n-hexane, 4.76 mL, 14.27 mmol) was added dropwise to a solution of compound 20a (1.00 g, 4.76 mmol) in tetrahydrofuran (10 mL) at 0°C, and the reaction system was stirred at 0°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 20b (0.82 g, 82.0% yield).

[0874] 1 H NMR (400MHz, CDCl3): δ7.18(t,1H),6.54-6.48(m,3H),3.80(s,3H),3.78(s,2H),1.34(s,6H).

[0875] Step c:

[0876] 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran

[0877] To a solution of compound 20b (7.60 g, 38.73 mmol) in methanesulfonic acid (150 mL) was added phosphorus pentoxide (19.23 g, 135.48 mmol) under nitrogen, and the reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 20c (1.90 g, 27.5% yield).

[0878] MS m / z(ESI):179.1[M+H] + .

[0879] Step d:

[0880] 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0881] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 0.54 mL, 1.35 mmol) was added dropwise to a solution of compound 20c (200 mg, 1.12 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (227 mg, 1.68 mmol) was added. Stirring was continued at -78°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 20d (30 mg, 9.7% yield).

[0882] 1 H NMR (400MHz, CDCl3): δ7.23(d,1H), 6.36(d,1H), 3.89(s,3H), 2.90(s,2H), 1.48(s,6H).

[0883] Step e:

[0884] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0885] To a solution of intermediate 1 (130 mg, 0.53 mmol) in N,N-dimethylformamide (4 mL) at 0°C was added sodium hydride (60%, 106 mg, 2.66 mmol). The reaction system was stirred at 25°C for 1 hour, followed by the addition of compound 20d (198 mg, 0.72 mmol) and continued stirring for 1 hour. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 20 (75 mg, 29.1% yield).

[0886] 1HNMR (400MHz, DMSO-d6): δ9.56(s,1H),7.69(d,1H),7.50(d,1H),7.29(d,1H),6.83(s,1H),6.75( s,1H),6.52(d,1H),6.30(t,1H),5.45(s,2H),3.88(s,3H),3.73(s,3H),2.88(s,2H),1.20(s,6H).

[0887] MS m / z(ESI):485.0[M+H] + .

[0888] Example 27

[0889] Synthesis of compound 21

[0890] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-6-methoxybenzenesulfonamide

[0891] Step a:

[0892] 1-Cyclobutyloxy-3-methoxybenzene

[0893] To a solution of 3-methoxyphenol (1.00 g, 8.06 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (2.24 g, 16.21 mmol) and bromocyclobutane (1.31 g, 9.78 mmol). The reaction system was heated to 100°C and stirred for 40 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 21a (1.00 g, 69.7% yield).

[0894] 1 H NMR (400MHz, DMSO-d6): δ7.18-7.12(m,1H),6.51-6.48(m,1H),6.43-6.36(m,2H),4.7 1-4.61(m,1H),3.72(s,3H),2.46-2.36(m,2H),2.08-1.95(m,2H),1.82-1.58(m,2H).

[0895] Step b:

[0896] 2-Cyclobutoxy-6-methoxybenzenesulfonyl chloride

[0897] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 2.4 mL, 6.00 mmol) was added dropwise to a solution of compound 21a (900 mg, 5.05 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (1.36 g, 10.08 mmol) was added. Stirring was continued at -78°C for 2 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 21b (480 mg, 34.3% yield).

[0898] 1 H NMR (400MHz, DMSO-d6): δ7.25-7.19(m,1H),6.63(d,1H),6.47(d,1H),4.64( t,1H),3.72(s,3H),2.39-2.29(m,2H),2.13-2.00(m,2H),1.80-1.54(m,2H).

[0899] Step c:

[0900] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-6-methoxybenzenesulfonamide

[0901] To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (3 mL) at 0°C was added sodium hydride (60%, 82 mg, 2.05 mmol). The reaction system was stirred at 0°C for 1 hour, followed by the addition of compound 21b (227 mg, 0.82 mmol) and continued stirring for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 21 (45 mg, 22.7% yield).

[0902] 1HNMR (400MHz, DMSO-d6): δ9.53(s,1H),7.88(d,1H),7.50(d,1H),7.45(t,1H),6.82(s,1H),6.77-6.74(m,2H),6.54(d,1H),6. 31(t,1H),5.45(s,2H),4.73-4.64(m,1H),3.88(s,3H),3.78(s,3H),2.27-2.21(m,2H),1.94-1.81(m,2H),1.58-1.46(m,2H).

[0903] MS m / z(ESI):485.0[M+H] + .

[0904] Example 28

[0905] Synthesis of compound 22

[0906] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-5-ethylbenzenesulfonamide

[0907] Step a:

[0908] 4-Ethyl-2-iodophenol

[0909] To a solution of 4-ethylphenol (2.00 g, 16.37 mmol) in acetonitrile (50 mL) at 25°C was added p-toluenesulfonic acid (2.82 g, 16.38 mmol). After reacting for 10 minutes, N-iodosuccinimide (3.69 g, 16.40 mmol) was added and the reaction system was stirred for 16 hours. After completion, the reaction was quenched with aqueous sodium sulfite (100 mL) and acidified with 1 M hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 22a (2.80 g, 68.9% yield).

[0910] 1 H NMR (400MHz, DMSO-d6): δ10.00(s,1H),7.49(d,1H),7.03-7.01(m,1H),6.79(d,1H),2.49(q,2H),1.11(t,3H).

[0911] Step b:

[0912] 1-Cyclobutoxy-4-ethyl-2-iodobenzene

[0913] Compound 22a (1.00 g, 4.03 mmol), bromocyclobutane (0.66 g, 4.84 mmol), and cesium carbonate (2.63 g, 8.06 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction system was heated to 100°C and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound 22b (1.10 g, 90.3% yield).

[0914] 1 H NMR (400MHz, CDCl3): δ7.60(d,1H),7.07-7.05(m,1H),6.59(d,1H),4.66-4.63(m,1H),2.54(q ,2H),2.47-2.43(m,2H),2.27-2.22(m,2H),1.89-1.85(m,1H),1.71-1.66(m,1H),1.19(t,3H).

[0915] Step c:

[0916] Benzyl(2-cyclobutyloxy-5-ethylphenyl)sulfane

[0917] To a solution of compound 22b (200 mg, 0.66 mmol) in N,N-dimethylformamide (6 mL) was added benzyl mercaptan (90 mg, 0.73 mmol), potassium carbonate (182 mg, 1.32 mmol), 1,4-diazabicyclo[2.2.2]octane (7.4 mg, 0.066 mmol), and cuprous iodide (6.1 mg, 0.033 mmol) under nitrogen. The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 22c (140 mg, 70.9% yield).

[0918] 1H NMR (400MHz, CDCl3): δ7.24-7.14(m,5H),6.98(s,1H),6.87(d,1H),6.54(d,1H),4.60-4.56(m,1H),4 .03(s,2H),2.47-2.35(m,4H),2.17-2.12(m,2H),1.79-1.77(m,1H),1.61-1.59(m,1H),1.07(t,3H).

[0919] Step d:

[0920] 2-Cyclobutoxy-5-ethylbenzenesulfonyl chloride

[0921] To a mixed solution of compound 22c (780 mg, 2.61 mmol) (glacial acetic acid and water, 10:1 ratio, 10 mL) was added N-chlorosuccinimide (1.05 g, 7.84 mmol) at 25°C. The reaction system was stirred at 25°C for 3 hours. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 22d (460 mg, 64.1% yield).

[0922] 1 HNMR (400MHz, CDCl3): δ7.75(d,1H),7.44-7.41(m,1H),6.85(d,1H),4.87-4.82(m,1H),2.65(q ,2H),2.53-2.47(m,2H),2.38-2.30(m,2H),1.95-1.93(m,1H),1.76-1.72(m,1H),1.24(t,3H).

[0923] Step e:

[0924] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-5-ethylbenzenesulfonamide

[0925] To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added sodium hydride (60%, 82 mg, 2.05 mmol). The reaction system was stirred at 0°C for 10 minutes, followed by the addition of compound 22d (169 mg, 0.61 mmol) and continued stirring for 50 minutes. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride, adjusted to pH 5 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (dichloromethane:methanol = 20:1) to afford compound 22 (39 mg, 19.7% yield).

[0926] 1 HNMR (400MHz, DMSO-d6): δ9.73(s,1H),7.87-7.81(m,1H),7.67(d,1H),7. 49-7.48(m,1H),7.42-7.39(m,1H),6.88(d,1H),6.84(s,1H),6.75(s,1H) ,6.30-6.29(m,1H),5.44(s,2H),4.69-4.66(m,1H),3.81(s,3H),2.60(q, 2H),2.23-2.20(m,2H),1.80-1.75(m,2H),1.55-1.51(m,2H),1.15(t,3H).

[0927] MS m / z(ESI):483.0[M+H] + .

[0928] Example 29

[0929] Synthesis of compound 23

[0930] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-5-isopropylbenzenesulfonamide

[0931] Step a:

[0932] 1-Cyclobutoxy-2-iodo-4-isopropylbenzene

[0933] To a solution of compound 10a (850 mg, 3.24 mmol) in N,N-dimethylformamide (10 mL) were added bromocyclobutane (525 mg, 3.89 mmol) and cesium carbonate (2.11 g, 6.49 mmol). The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to afford compound 23a (884 mg, 86.2% yield).

[0934] 1 H NMR (400MHz, DMSO-d6): δ7.60(d,1H),7.19-7.16(m,1H),6.75(d,1H),4.74-4.65(m,1H),2.85- 2.73(m,1H),2.48-2.38(m,2H),2.11-1.98(m,2H),1.84-1.58(m,2H),1.16(s,3H),1.14(s,3H).

[0935] Step b:

[0936] Benzyl(2-cyclobutyloxy-5-isopropylphenyl)sulfane

[0937] To a solution of compound 23a (1.00 g, 3.16 mmol) in N,N-dimethylformamide (10 mL) were added benzyl mercaptan (0.52 g, 4.16 mmol), potassium carbonate (0.88 g, 6.40 mmol), 1,4-diazabicyclo[2.2.2]octane (0.04 g, 0.32 mmol), and cuprous iodide (0.03 g, 0.16 mmol) under nitrogen. The reaction system was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:dichloromethane = 10:1) to afford compound 23b (0.63 g, 63.7% yield).

[0938] 1H NMR (400MHz, DMSO-d6): δ7.37-7.20(m,5H),7.06(d,1H),6.97-6.94(m,1H),6.71(d,1H),4.71-4.62(m,1H),4.1 5(s,2H),2.81-2.72(m,1H),2.45-2.36(m,2H),2.09-1.96(m,2H),1.83-1.58(m,2H),1.12(s,3H),1.10(s,3H).

[0939] Step c:

[0940] 2-Cyclobutoxy-5-isopropylbenzenesulfonyl chloride

[0941] To a mixed solution of compound 23b (37 mg, 0.12 mmol) (glacial acetic acid and water, 10:1 ratio, 3 mL) was added N-chlorosuccinimide (95 mg, 0.71 mmol) at 25°C. The reaction system was stirred at 25°C for 3 hours. After completion of the reaction, water (50 mL) was added and stirring continued for 20 minutes. The reaction mixture was filtered under reduced pressure to provide compound 23c (20 mg, 58.5% yield).

[0942] 1 HNMR (400MHz, DMSO-d6): δ7.57(d,1H),7.14-7.12(m,1H),6.73(d,1H),4.70-4.61(m,1H),2.86- 2.78(m,1H),2.37-2.35(m,2H),2.12-2.02(m,2H),1.81-1.56(m,2H),1.17(s,3H),1.15(s,3H).

[0943] Step d:

[0944] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-cyclobutoxy-5-isopropylbenzenesulfonamide

[0945] To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (3 mL) at 0°C was added sodium hydride (60%, 82 mg, 2.05 mmol). The reaction system was stirred at 0°C for 1 hour, followed by the addition of compound 23c (236 mg, 0.82 mmol) and continued stirring for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 23 (40 mg, 19.7% yield).

[0946] 1 HNMR (400MHz, DMSO-d6): δ9.79(s,1H),7.87(d,1H),7.69(d,1H),7.50-7.44(m,2H),6.91-6.85(m,2H),6.76(s,1H),6.31-6.30(m,1H),5.45( s,2H),4.69-4.64(m,1H),3.79(s,3H),2.94-2.90(m,1H),2.23-2.17( m,2H),1.80-1.73(m,2H),1.57-1.48(m,2H),1.19(s,3H),1.17(s,3H). MS m / z(ESI): 497.0[M+H] + .

[0947] Example 30

[0948] Synthesis of compound 24

[0949] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0950] Step a:

[0951] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isothiazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0952] To a solution of intermediate 6 (120 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60%, 111 mg, 2.77 mmol) at 0°C. The reaction system was stirred at 0°C for 1 hour, followed by the addition of 2,6-dimethoxybenzenesulfonyl chloride (148 mg, 0.62 mmol), and the mixture was allowed to return to room temperature and stirred for another 1 hour. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 24 (20 mg, 9.4% yield).

[0953] 1 HNMR (400MHz, DMSO-d6): δ9.38(s,1H),7.89(d,1H),7.50(d,1H),7.45(t,1H),7.27( s,1H),6.95(s,1H),6.72(d,2H),6.31(t,1H),5.46(s,2H),4.06(s,3H),3.73(s,6H).

[0954] MS m / z(ESI):460.9[M+H] + .

[0955] Example 31

[0956] Synthesis of compound 25

[0957] N-(6-((1H-pyrazol-1-yl)methyl)benzo[d]isothiazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0958] Step a:

[0959] 4-(Bromomethyl)-2-fluorobenzonitrile

[0960] To a solution of 2-fluoro-4-methylbenzonitrile (1.00 g, 7.40 mmol) in chloroform (20 mL) were added dibenzoyl peroxide (0.09 g, 0.37 mmol) and N-bromosuccinimide (1.98 g, 11.12 mmol). The reaction system was heated to 75°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to afford compound 25a (0.78 g, 49.2% yield).

[0961] 1 H NMR (400 MHz, DMSO-d6): δ 7.97-7.92 (m, 1H), 7.65 (d, 1H), 7.53-7.50 (m, 1H), 4.77 (s, 2H). Step b:

[0962] 4-((1H-pyrazol-1-yl)methyl)-2-fluorobenzonitrile

[0963] To a solution of compound 25a (575 mg, 2.69 mmol) in acetonitrile (15 mL) was added pyrazole (201 mg, 2.95 mmol) and cesium carbonate (963 mg, 2.96 mmol) at 25°C. The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 25b (522 mg, 96.6% yield).

[0964] 1 H NMR (400MHz, DMSO-d6): δ7.92-7.89(m,2H),7.53-7.52(m,1H),7.27(d,1H),7.15-7.12(m,1H),6.33(d,1H),5.48(s,2H).

[0965] Step c:

[0966] 6-((1H-pyrazol-1-yl)methyl)benzo[d]isothiazol-3-amine

[0967] Under nitrogen protection, sodium sulfide (27 mg, 0.35 mmol) was added to a solution of compound 25b (70 mg, 0.35 mmol) in dimethyl sulfoxide (2 mL). The reaction system was heated to 70°C and stirred for 7 hours. After the reaction was completed, it was cooled to 0°C. Ammonia water (1 mL) and sodium hypochlorite aqueous solution (1 mL) were then slowly added to the reaction system and stirred for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:tetrahydrofuran = 8:1) to give compound 25c (49 mg, yield 61.1%).

[0968] 1 HNMR (400MHz, CDCl3): δ7.66(d,1H),7.61-7.55(m,2H),7.46(d,1H),7.22(d,1H),6.33(t,1H),5.48(s,2H).

[0969] MS m / z(ESI):231.2[M+H] + .

[0970] Step d:

[0971] N-(6-((1H-pyrazol-1-yl)methyl)benzo[d]isothiazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0972] To a solution of compound 25c (100 mg, 0.43 mmol) in N,N-dimethylformamide (3 mL) at 0°C was added sodium hydride (60%, 87 mg, 2.17 mmol). The reaction system was stirred at 0°C for 1 hour, followed by the addition of 2,6-dimethoxybenzenesulfonyl chloride (206 mg, 0.87 mmol) and continued stirring for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 25 (84 mg, 44.9% yield).

[0973] 1HNMR (400MHz, DMSO-d6): δ11.30(s,1H),8.36(d,1H),7.88(d,1H),7.82(s,1H),7.49(d,1H) ,7.45(t,1H),7.29(d,1H),6.72(s,1H),6.70(s,1H),6.30(t,1H),5.50(s,2H),3.67(s,6H). MS m / z(ESI): 430.9[M+H] + .

[0974] Example 32

[0975] Synthesis of compound 26

[0976] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopentane]-8-sulfonamide

[0977] Step a:

[0978] Methyl 2-cyclopentylidene acetate

[0979] Under nitrogen, sodium hydride (60%, 3.21 g, 80.25 mmol) was added to a solution of trimethyl phosphate acetate (15.14 g, 83.14 mmol) in tetrahydrofuran (150 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, followed by the dropwise addition of a solution of cyclopentanone (5.00 g, 59.44 mmol) in tetrahydrofuran (50 mL). The reaction system was returned to 25°C and stirred for another 2 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 20:1) to afford compound 26a (3.66 g, 43.9% yield).

[0980] 1 H NMR (300MHz, CDCl3) δ5.81-5.78(m,1H),3.68(s,3H),2.76(t,2H),2.43(t,2H),1.79-1.61(m,4H)

[0981] Step b:

[0982] 7-Methoxyspiro[chroman-4,1'-cyclopentane]-2-one

[0983] 3-Methoxyphenol (6.48 g, 52.20 mmol), compound 26a (3.66 g, 26.11 mmol), and 98% concentrated sulfuric acid (0.51 g, 5.10 mmol) were mixed and heated to 130°C with stirring for 3 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 20:1) to afford compound 26b (1.90 g, 31.3% yield).

[0984] 1 H NMR (300MHz, CDCl3): δ7.14(d,1H),6.70-6.62(m,2H),3.79(s,3H),2.66(s,2H),1.93-1.59(m,8H).

[0985] Step c:

[0986] 2-(1-(2-hydroxyethyl)cyclopentyl)-5-methoxyphenol

[0987] Under nitrogen, lithium aluminum hydride (0.27 g, 7.24 mmol) was added to a solution of compound 26b (1.60 g, 6.89 mmol) in tetrahydrofuran (30 mL) at 0°C, and the reaction system was stirred at 0°C for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 1:1) to afford compound 26c (1.60 g, 98.3% yield).

[0988] 1 H NMR (300MHz, CDCl3): 7.06(d,1H),6.43-6.37(m,1H),6.28(d,1H),3.74(s,3H),3.52(t,2H),2.04-1.93(m,6H),1.72-1.63(m,4H).

[0989] Step d:

[0990] 7-Methoxyspiro[chroman-4,1'-cyclopentane]

[0991] Compound 26c (1.60 g, 6.77 mmol) and p-toluenesulfonic acid (0.23 g, 1.34 mmol) were dissolved in toluene (32 mL). The reaction system was heated to 110°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 20:1) to afford compound 26d (1.26 g, 85.2% yield).

[0992] 1 H NMR (300MHz, CDCl3): δ7.13(d,1H),6.49(dd,1H),6.33(d,1H),4.17(t,2H),3.75(s,3H),1.93-1.69(m,10H).

[0993] Step e:

[0994] 7-Methoxyspiro[chroman-4,1'-cyclopentane]-8-sulfonyl chloride

[0995] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 2.5 mL, 6.25 mmol) was added dropwise to a solution of compound 26d (1.26 g, 5.77 mmol) in tetrahydrofuran (25 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (1.01 g, 7.48 mmol) was added. Stirring was continued at -78°C for 15 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 2:1) to afford compound 26e (0.77 g, 42.1% yield).

[0996] 1 H NMR (400MHz, CDCl3): δ7.45(d,1H),6.57(d,1H),4.37(t,2H),3.94(s,3H),1.88-1.77(m,10H).

[0997] Step f:

[0998] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopentane]-8-sulfonamide

[0999] To a solution of intermediate 1 (100 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60%, 82 mg, 2.05 mmol) at 0°C. The reaction system was stirred for 30 minutes, followed by the addition of compound 26e (195 mg, 0.62 mmol), and stirring continued at 0°C for 1 hour. After completion of the reaction, the mixture was diluted with 1N aqueous hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 26 (105 mg, 48.9% yield).

[1000] 1 HNMR (400MHz, DMSO-d6): δ9.47(s,1H),7.87(d,1H),7.50(d,1H),7.44(d,1H),6.85(s,1H),6.76(s,1 H),6.69(d,1H),6.30(t,1H),5.45(s,2H),4.07(t,2H),3.87(s,3H),3.72(s,3H),1.77-1.60(m,10H).

[1001] MS m / z(ESI):525.0[M+H] + .

[1002] Example 33

[1003] Synthesis of compound 27

[1004] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1005] Step a:

[1006] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1007] To a solution of intermediate 2 (80 mg, 0.31 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 61 mg, 1.52 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 16d (133 mg, 0.46 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 27 (88 mg, 55.8% yield).

[1008] 1 HNMR (400MHz, DMSO-d6): δ10.00(s,1H),7.85(d,1H),7.52-7.50(m,2H),6.91(d,1H),6.69(d,1H) ,6.32-6.31(m,1H),5.50(s,2H),4.10(t,2H),4.03(d,3H),3.72(s,3H),1.70(t,2H),1.23(s,6H).

[1009] MS m / z(ESI):517.1[M+H] + .

[1010] Example 34

[1011] Synthesis of compound 28

[1012] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1013] Step a:

[1014] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1015] To a solution of intermediate 2 (80 mg, 0.31 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 61 mg, 1.52 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 14b (121 mg, 0.46 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 28 (90 mg, 60.2% yield).

[1016] 1 HNMR (400MHz, DMSO-d6): δ10.23(s,1H),7.86(d,1H),7.50(d,1H),7.07(d,1H),6.92(d,1H) ,6.65(d,1H),6.31-6.30(m,1H),5.51(s,2H),4.22-4.16(m,4H),4.04(d,3H),3.70(s,3H). MS m / z(ESI): 491.1[M+H] + .

[1017] Example 35

[1018] Synthesis of compound 29

[1019] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1020] Step a:

[1021] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1022] To a solution of intermediate 5 (70 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 50 mg, 1.25 mmol). The reaction system was stirred at 0°C for 5 minutes, followed by the addition of compound 16d (110 mg, 0.38 mmol) and continued stirring for 10 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 29 (89 mg, 66.6% yield).

[1023] 1 HNMR (400MHz, DMSO-d6): δ10.30(s,1H),7.88(d,1H),7.54(d,1H),7.52(d,1H),6.79(s,1H) ,6.70(d,1H),6.34(t,1H),5.57(s,2H),4.12(t,2H),3.91(s,3H),3.72(s,3H),1.71(t,2H), 1.25(s,6H).

[1024] MS m / z(ESI):533.1[M+H] + .

[1025] Example 36

[1026] Synthesis of compound 30

[1027] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1028] Step a:

[1029] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1030] To a solution of intermediate 5 (51 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 37 mg, 0.93 mmol). The reaction system was stirred at 0°C for 5 minutes, followed by the addition of compound 14b (73 mg, 0.28 mmol) and continued stirring for 10 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 30 (63 mg, 67.9% yield).

[1031] 1 HNMR (400MHz, DMSO-d6): δ10.53(s,1H),7.88(d,1H),7.55(d,1H),7.08(d,1H),6.79(s, 1H),6.67(d,1H),6.34(t,1H),5.57(s,2H),5.20-5.16(m,4H),3.94(s,3H),3.71(s,3H).

[1032] MS m / z(ESI):507.0[M+H] + .

[1033] Example 37

[1034] Synthesis of compound 31

[1035] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1036] Step a:

[1037] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1038] To a solution of intermediate 3 (60 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 45 mg, 1.13 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 16d (73 mg, 0.25 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 31 (19 mg, 16.2% yield).

[1039] 1 HNMR (400MHz, DMSO-d6): δ10.28(s,1H),7.88(d,1H),7.54-7.44(m,3H),6.69(d,1 H),6.31(t,1H),5.57(s,2H),4.07(t,2H),3.71(s,3H),1.69(t,2H),1.25(s,6H).

[1040] MS m / z(ESI):521.1[M+H] + .

[1041] Example 38

[1042] Synthesis of compound 32

[1043] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1044] Step a:

[1045] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1046] To a solution of intermediate 3 (60 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 45 mg, 1.13 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 14b (89 mg, 0.34 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 32 (33 mg, 29.6% yield).

[1047] 1 HNMR (400MHz, DMSO-d6): δ10.48(s,1H),7.88(d,1H),7.50(d,1H),7.44(d,1H),7. 08(d,1H),6.66(d,1H),6.31(t,1H),5.57(s,2H),4.20-4.16(m,4H),3.68(s,3H).

[1048] MS m / z(ESI):495.0[M+H] + .

[1049] Example 39

[1050] Synthesis of compound 33

[1051] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1052] Step a:

[1053] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxy-4,4-dimethylchroman-8-sulfonamide

[1054] To a solution of intermediate 6 (56 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 48 mg, 1.20 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 16d (105 mg, 0.36 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 33 (79 mg, 69.7% yield).

[1055] 1 HNMR (400MHz, DMSO-d6): δ10.09(s,1H),7.90(d,1H),7.52-7.45(m,3H),7.25(s,1H),6. 68(d,1H),6.31(t,1H),5.50(s,2H),4.06(t,2H),3.70(s,3H),1.68(t,2H),1.24(s,6H).

[1056] MS m / z(ESI):503.1[M+H] + .

[1057] Example 40

[1058] Synthesis of compound 34

[1059] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1060] Step a:

[1061] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-sulfonamide

[1062] To a solution of intermediate 6 (56 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 48 mg, 1.20 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 14b (96 mg, 0.36 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 34 (52 mg, 48.4% yield).

[1063] 1 HNMR (400MHz, DMSO-d6): δ10.31(s,1H),7.91(d,1H),7.52(d,1H),7.47(s,1H),7.27(s, 1H),7.07(d,1H),6.66(d,1H),6.32(t,1H),5.51(s,2H),4.20-4.15(m,4H),3.68(s,3H).

[1064] MS m / z(ESI):477.0[M+H] + .

[1065] Example 41

[1066] Synthesis of compound 35

[1067] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1068] Step a:

[1069] 7-Bromo-4-methylenechroman

[1070] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 13.74 mL, 34.35 mmol) was slowly added dropwise to a solution of methyltriphenylphosphonium bromide (12.59 g, 35.24 mmol) in tetrahydrofuran (80 mL) at 0°C. The reaction system was stirred for 1 hour, followed by the dropwise addition of a solution of 7-bromo-2,3-dihydrochromen-4-one (4.00 g, 17.62 mmol) in tetrahydrofuran (20 mL), and stirring continued for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether) to afford compound 35a (2.43 g, 61.3% yield).

[1071] 1 HNMR (400MHz, DMSO-d6): δ7.60(d,1H),7.08-7.05(m,2H),5.63(s,1H),4.99(d,1H),4.19(t,2H),2.64(t,2H).

[1072] Step b:

[1073] 7-Bromospiro[chroman-4,1'-cyclopropane]

[1074] Under nitrogen, diethylzinc (1.0 M in n-hexane, 21.59 mL, 21.59 mmol) in dichloromethane (40 mL) was slowly added dropwise at -78°C. The reaction system was returned to 0°C and stirred for 20 minutes. Trifluoroacetic acid (3.69 g, 32.39 mmol) was then added to the reaction system at 0°C. Stirring continued for 15 minutes, followed by the dropwise addition of a solution of compound 35a (2.43 g, 10.80 mmol) in dichloromethane (12 mL). After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 99:1) to give compound 35b (1.60 g, yield 62.0%).

[1075] 1 HNMR (400MHz, CDCl3): δ6.97-6.91(m,2H),6.50(d,1H),4.27(t,2H),1.84(t,2H),1.04-1.01(m,2H),0.86-0.83(m,2H).

[1076] Step c:

[1077] 7-Methoxyspiro[chroman-4,1'-cyclopropane]

[1078] To a solution of compound 35b (1.80 g, 7.53 mmol) and cuprous bromide (0.43 g, 3.01 mmol) in N,N-dimethylformamide (10 mL) was added sodium methoxide (30% in methanol, 16.26 g, 90.34 mmol). The reaction system was then heated to 100°C and stirred for 4 hours. After completion of the reaction, the reaction mixture was quenched with aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 96:4) to afford compound 35c (1.40 g, 97.8% yield).

[1079] 1 HNMR (400MHz, DMSO-d6): δ6.61(d,1H),6.38(dd,1H),6.31(d,1H),4.19(t,2H),3.66(s,3H),1.77(t,2H),0.93-0.91(m,2H),0.80-0.77(m,2H).

[1080] Step d:

[1081] 7-Methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonyl chloride

[1082] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 0.64 mL, 1.16 mmol) was slowly added dropwise to a solution of compound 35c (0.20 g, 1.05 mmol) in tetrahydrofuran (4 mL) at 0°C. The reaction system was stirred for 1 hour, followed by the addition of sulfonyl chloride (213 mg, 1.58 mmol) and continued stirring for 30 minutes. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:tetrahydrofuran = 3:1) to afford compound 35d (60 mg, 19.8% yield).

[1083] 1HNMR (400MHz, CDCl3): δ6.86(d,1H),6.50(d,1H),4.49(t,2H),3.92(s,3H),1.89(t,2H),1.03-1.00(m,2H),0.90-0.87(m,2H).

[1084] Step e:

[1085] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1086] To a solution of intermediate 1 (50 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 41 mg, 1.03 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 35d (59 mg, 0.20 mmol) and continued stirring for 30 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was quenched with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 35 (22 mg, 21.6% yield).

[1087] 1 HNMR (400MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),6.88(d,1H),6.82(s,1H),6.75(s,1H),6.60(d,1H),6.30( t,1H),5.45(s,2H),4.17(t,2H),3.88(s,3H),3.70(s,3H),1.70(t,2H),0.96-0.94(m,2H),0.82-0.79(m,2H).

[1088] MS m / z(ESI):497.1[M+H] + .

[1089] Example 42

[1090] Synthesis of compound 36

[1091] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxychroman-8-sulfonamide

[1092] Step a:

[1093] 7-Methoxychroman-4-ol

[1094] To a solution of 7-methoxy-4H-chromen-4-one (9.10 g, 51.70 mmol) in methanol (100 mL) was added palladium on carbon (900 mg, 10% w / w) under a hydrogen atmosphere. The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 84:16) to afford compound 36a (7.90 g, 84.9% yield).

[1095] Step b:

[1096] tert-Butyl((7-methoxychroman-4-yl)oxy)dimethylsilane

[1097] To a solution of compound 36a (1.00 g, 5.55 mmol) and 1H-imidazole (604 mg, 8.88 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyldimethylsilyl chloride (1.25 g, 8.32 mmol), and the reaction system was stirred for 16 hours. After completion of the reaction, the reaction mixture was quenched with aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 91:9) to give compound 36b (1.40 g, 85.7% yield).

[1098] 1 HNMR (400 MHz, DMSO-d6): δ 7.08 (d, 1H), 6.48 (dd, 1H), 6.31 (d, 1H), 4.78 (t, 1H), 4.21-4.16 (m, 2H), 3.70 (s, 3H), 2.04-1.96 (m, 1H), 1.85-1.79 (m, 1H), 0.87 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H). Step c:

[1099] 4-((tert-Butyldimethylsilyl)oxy)-7-methoxychroman-8-sulfonyl chloride

[1100] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 4.89 mL, 12.23 mmol) was slowly added dropwise to a solution of compound 36b (3.00 g, 10.19 mmol) in tetrahydrofuran (60 mL) at 0°C. The reaction system was stirred for 1 hour, then cooled to -78°C and sulfuryl chloride (1.65 g, 12.22 mmol) was added dropwise. Stirring was continued for 15 minutes. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to afford compound 36c (1.40 g, 35.0% yield).

[1101] 1 HNMR (400MHz, CDCl3): δ7.43(d,1H),6.58(d,1H),4.75(t,1H),4.48-4.45(m,2H),3.9 6(s,3H),2.12-2.08(m,1H),2.07-1.97(m,1H),0.90(s,9H),0.16(s,3H),0.14(s,3H).

[1102] Step d:

[1103] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-((tert-butyldimethylsilyl)oxy)-7-methoxychroman-8-sulfonamide

[1104] To a solution of intermediate 1 (600 mg, 2.46 mmol) in N,N-dimethylformamide (3 mL) at 0°C was added sodium hydride (60%, 491 mg, 12.28 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 36c (1.35 g, 3.44 mmol) and continued stirring for 30 minutes. After the reaction was returned to room temperature, the reaction mixture was adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:tetrahydrofuran = 4:1) to afford compound 36d (680 mg, 46.1% yield).

[1105] MS m / z(ESI):601.1[M+H] + .

[1106] Step e:

[1107] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxychroman-8-sulfonamide

[1108] To a solution of compound 36d (50 mg, 0.08 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride trihydrate (70 mg, 0.25 mmol), and the reaction system was stirred for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to obtain compound 36 (30 mg, yield 74.1%).

[1109] 1 HNMR (400MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),7.42(d,1H),6.81(s,1H),6.75(s,1H),6.70(d,1H),6.30(t,1H),5.42 (s,2H),5.37(d,1H),4.57-4.52(m,1H),4.21-4.15(m,1H)4.12-4.07(m,1H),3.89(s,3H),3.73(s,3H),1.87-1.74(m,2H).

[1110] MS m / z(ESI):487.0[M+H] + .

[1111] Example 43

[1112] Synthesis of compound 37

[1113] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1114] Step a:

[1115] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1116] To a solution of compound 36 (50 mg, 0.10 mmol) in chloroform (5 mL) was added manganese dioxide (26.8 mg, 0.31 mmol). The reaction system was heated to 60°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5% to 95%) to obtain compound 37 (2.9 mg, 5.8% yield).

[1117] 1 HNMR (400MHz, DMSO-d6): δ10.24(s,1H),7.95(d,1H),7.87(d,1H),7.50-7.49(m,1H),6.92(d,1H),6. 82(s,1H),6.73(s,1H),6.30(t,1H),5.44(s,2H),4.47(t,2H),3.85(s,3H),3.83(s,3H),2.72(t,2H).

[1118] MS m / z(ESI):485.1[M+H] + .

[1119] Example 44

[1120] Synthesis of compound 38

[1121] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxy-4-methylchroman-8-sulfonamide

[1122] Step a:

[1123] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxy-4-methylchroman-8-sulfonamide

[1124] Under nitrogen, methylmagnesium bromide (1.0 M in tetrahydrofuran, 3.1 mL, 3.10 mmol) was added to a solution of compound 37 (150 mg, 0.31 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 38 (60 mg, 38.7% yield).

[1125] 1 HNMR (400MHz, DMSO-d6): δ9.39(s,1H),7.87(d,1H),7.61(d,1H),7.50(d,1H),6.82(s,1H),6.76(s,1H),6.71(d,1H) ,6.30(t,1H),5.45(s,2H),5.18(s,1H),4.18-4.13(m,2H),3.88(s,3H),3.73(s,3H),1.87-1.81(m,2H),1.39(s,3H).

[1126] MS m / z(ESI):501.1[M+H] + .

[1127] Example 45

[1128] Synthesis of compound 39

[1129] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1130] Step a:

[1131] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1132] To a solution of compound 37 (30 mg, 0.06 mmol) in dichloromethane (4 mL) was added 1,2-ethanedithiol (12 mg, 0.12 mmol) and boron trifluoride etherate (18 mg, 0.12 mmol) at 30°C. The reaction system was stirred at 30°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 39 (8.9 mg, 25.6% yield).

[1133] 1 HNMR (400MHz, DMSO-d6): δ9.77(s,1H),7.94(d,1H),7.87(d,1H),7.50(d,1H),6.85(s,1H),6.79-6.75(m,2H),6.30(t, 1H),5.45(s,2H),4.20-4.19(m,2H),3.84(s,3H),3.74(s,3H),3.64-3.57(m,2H),3.51-3.45(m,2H),2.41-2.38(m,2H).

[1134] MS m / z(ESI):561.1[M+H] + .

[1135] Example 46

[1136] Synthesis of compound 40

[1137] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2H-chromene-8-sulfonamide

[1138] Step a:

[1139] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2H-chromene-8-sulfonamide

[1140] To a solution of compound 36 (60 mg, 0.12 mmol) in toluene (2 mL) was added Burgess reagent (88 mg, 0.37 mmol), and the reaction system was heated to 80°C and stirred for 3 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Welchrom C18, 20*150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient ratio: phase B 5%-95%) to obtain compound 40 (4.3 mg, 7.4% yield).

[1141] 1 HNMR (400MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),7.17(d,1H),6.79(s,1H),6.71(s,1H),6.63(d,1H),6. 45-6.43(m,1H),6.30(t,1H),5.78-5.74(m,1H),5.44(s,2H),4.63-4.61(m,2H),3.86(s,3H),3.72(s,3H).

[1142] MS m / z(ESI):469.1[M+H] + .

[1143] Example 47

[1144] Synthesis of compound 41

[1145] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

[1146] Step a:

[1147] 7-Methoxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[1148] Under nitrogen, sodium hydride (60%, 0.58 g, 14.50 mmol) was added to a solution of 7-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (1.84 g, 10.27 mmol) in N,N-dimethylformamide (30 mL) at 0°C. The reaction system was stirred at 0°C for 30 minutes. Methyl iodide (1.61 g, 11.34 mmol) was then added and stirring continued for 3 hours. After the reaction was returned to room temperature, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 41a (1.86 g, 93.7% yield).

[1149] 1 HNMR (400MHz, DMSO-d6): δ7.06(d,1H),6.66-6.61(m,2H),4.61(s,2H),3.72(s,3H),3.24(s,3H).

[1150] Step b:

[1151] 7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

[1152] Under nitrogen protection, a solution of compound 41a (1.86 g, 9.63 mmol) in tetrahydrofuran (40 mL) was added with a borane dimethyl sulfide complex solution (19 mL) at 30°C. The reaction system was heated to 75°C and stirred for 3 hours. The temperature was then lowered to 0°C. The reaction mixture was quenched with ice water (40 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 41b (1.54 g, 89.3% yield).

[1153] 1 HNMR (400MHz, CDCl3): δ6.62(d,1H),6.45-6.41(m,2H),4.32-4.30(m,2H),3.73(s,3H),3.18-3.15(m,2H),2.82(s,3H).

[1154] Step c:

[1155] 7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonyl chloride

[1156] Under nitrogen, n-butyllithium (2.5 M in n-hexane, 0.67 mL, 1.68 mmol) was added dropwise to a solution of compound 41b (200 mg, 1.16 mmol) in tetrahydrofuran (6 mL) at 0°C. The reaction system was stirred at 0°C for 1 hour, then cooled to -78°C and sulfuryl chloride (181 mg, 1.34 mmol) was added. Stirring was continued at -78°C for 15 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 41c (80 mg, 25.8% yield).

[1157] 1 HNMR (400MHz, CDCl3): δ6.87(d,1H),6.53(d,1H),4.49-4.47(m,2H),3.89(s,3H),3.29-3.27(m,2H),2.88(s,3H).

[1158] Step d:

[1159] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-sulfonamide

[1160] To a solution of intermediate 1 (60 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 49 mg, 1.23 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 41c (82 mg, 0.30 mmol) and continued stirring for 15 minutes. After the reaction was allowed to cool to room temperature, the reaction mixture was added with 1N aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 41 (9.2 mg, 7.7% yield).

[1161] 1HNMR (400MHz, DMSO-d6): δ7.87(d,1H),7.50(d,1H),6.84-6.81(m,2H),6.74(s,1H),6.57(d,1 H),6.30(t,1H),5.44(s,2H),4.16(t,2H),3.89(s,3H),3.65(s,3H),3.10(t,2H),2.76(s,3H). MS m / z(ESI): 486.1[M+H] + .

[1162] Example 48

[1163] Synthesis of compound 42

[1164] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1165] Step a:

[1166] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1167] To a solution of compound 107 (100 mg, 0.20 mmol) in chloroform (10 mL) was added manganese dioxide (258.5 mg, 2.97 mmol). The reaction system was heated to 60°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient ratio: phase B 5% to 95%) to obtain compound 42 (80 mg, 80.3% yield).

[1168] 1 HNMR (400MHz, DMSO-d6): δ10.64(s,1H),7.96(s,1H),7.85(d,1H),7.49(d,1H),6.93-6.91( m,2H),6.30(t,1H),5.50(s,2H),4.49-4.47(m,2H),4.04(s,3H),3.85(s,3H),2.67(t,2H).

[1169] MS m / z(ESI):503.1[M+H] + .

[1170] Example 49

[1171] Synthesis of compound 43

[1172] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1173] Step a:

[1174] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1175] To a solution of intermediate 2 (50 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 38 mg, 0.95 mmol). The reaction was stirred at 0°C for 15 minutes, followed by the addition of compound 35d (66 mg, 0.23 mmol) and continued stirring for 15 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride. The mixture was adjusted to pH 5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 43 (29.3 mg, 29.9% yield).

[1176] 1 HNMR (400MHz, DMSO-d6): δ10.01(s,1H),7.86(d,1H),7.50-7.49(m,1H),6.91-6-89(m,2H),6.61(d,1H),6.31(t,1H),5. 50(s,2H),4.19-4.17(m,2H),4.06(d,3H),3.70(s,3H),6.92(d,1H),1.73(t,2H),0.98-0.96(m,2H),0.83-0.81(m,2H).

[1177] MS m / z(ESI):515.1[M+H] + .

[1178] Example 50

[1179] Synthesis of compound 44

[1180] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1181] Step a:

[1182] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1183] To a solution of compound 42 (60 mg, 0.12 mmol) in dichloromethane (5 mL) were added 1,2-ethanedithiol (24 mg, 0.24 mmol) and boron trifluoride etherate (34 mg, 0.24 mmol) at 25°C. The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 44 (25 mg, 36.2% yield).

[1184] 1 HNMR (400MHz, DMSO-d6): δ10.25(s,1H),7.96(d,1H),7.86(d,1H),7.50(d,1H),6.93-6.91(m,1H),6.79(d,1H),6. 31(t,1H),5.51(s,2H),4.22(t,2H),4.01(d,3H),3.75(s,3H),3.65-3.58(m,2H),3.52-3.46(m,2H),2.42(t,2H).

[1185] MS m / z(ESI):579.1[M+H] + .

[1186] Example 51

[1187] Synthesis of compound 45

[1188] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1189] Step a:

[1190] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-4-((tert-butyldimethylsilyl)oxy)-7-methoxychroman-8-sulfonamide

[1191] To a solution of intermediate 6 (140 mg, 0.56 mmol) in N,N-dimethylformamide (1.4 mL) at 0°C was added sodium hydride (60%, 113 mg, 2.83 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 36c (288 mg, 0.73 mmol) and continued stirring for 15 minutes. After the reaction was returned to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 45a (225 mg, 66.0% yield).

[1192] MS m / z(ESI):605.6[M+H] + .

[1193] Step b:

[1194] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxychroman-8-sulfonamide

[1195] To a solution of compound 45a (225 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride trihydrate (312 mg, 1.12 mmol), and the reaction system was stirred for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 45b (160 mg, 87.7% yield).

[1196] MS m / z(ESI):491.0[M+H] + .

[1197] Step c:

[1198] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1199] To a solution of compound 45b (160 mg, 0.33 mmol) in chloroform (10 mL) was added manganese dioxide (425 mg, 4.89 mmol). The reaction system was heated to 60°C and stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM formic acid in water, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 45 (90 mg, 56.5% yield).

[1200] 1 HNMR (400MHz, DMSO-d6): δ10.66(s,1H),7.97(d,1H),7.90(d,1H),7.51(d,1H),7.45-7.43(m,1 H),7.25(s,1H),6.93(d,1H),6.31(t,1H),5.50(s,2H),4.47(t,2H),3.83(s,3H),2.72(t,2H). MS m / z(ESI): 489.0[M+H] + .

[1201] Example 52

[1202] Synthesis of compound 46

[1203] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1204] Step a:

[1205] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1206] To a solution of intermediate 6 (50 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 40 mg, 1.00 mmol). The reaction was stirred at 0°C for 15 minutes, followed by the addition of compound 35d (76 mg, 0.26 mmol) and continued stirring for 15 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 46 (18 mg, 17.9% yield).

[1207] 1 HNMR (400MHz, DMSO-d6): δ10.11(s,1H),7.90(d,1H),7.51(d,1H),7.46(s,1H),7.26(s,1H),6.91(d,1H),6.61 (d,1H),6.32(t,1H),5.51(s,2H),4.17(t,2H),3.69(s,3H),1.73(t,2H),0.99-0.97(m,2H),0.84-0.81(m,2H).

[1208] MS m / z(ESI):501.0[M+H] + .

[1209] Example 53

[1210] Synthesis of compound 47

[1211] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1212] Step a:

[1213] N-(6-((1H-pyrazol-1-yl)methyl)-4-chlorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,2'-[1,3]dithiolane]-8-sulfonamide

[1214] To a solution of compound 45 (65 mg, 0.13 mmol) in dichloromethane (5 mL) was added 1,2-ethanedithiol (50 mg, 0.53 mmol) and boron trifluoride etherate (72 mg, 0.53 mmol) at 25°C. The reaction system was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 47 (13.9 mg, 18.5% yield).

[1215] 1 HNMR (400MHz, DMSO-d6): δ10.30(s,1H),7.96(d,1H),7.91(d,1H),7.51(d,1H),7.46(s,1H),7.25(s,1H),6.78(d, 1H),6.31(t,1H),5.50(s,2H),4.21-4.19(m,2H),3.73(s,3H),3.62-3.59(m,2H),3.52-3.46(m,2H),2.41(t,2H).

[1216] MS m / z(ESI):565.0[M+H] + .

[1217] Example 54

[1218] Synthesis of compound 49

[1219] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1220] Step a:

[1221] N-(6-((1H-pyrazol-1-yl)methyl)-4-chloro-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxyspiro[chroman-4,1'-cyclopropane]-8-sulfonamide

[1222] To a solution of intermediate 3 (50 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL) at 0°C was added sodium hydride (60%, 36 mg, 0.90 mmol). The reaction was stirred at 0°C for 15 minutes, followed by the addition of compound 35d (68 mg, 0.24 mmol) and continued stirring for 15 minutes. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by HPLC (Welchrom C18, 20 x 150 mm, 5 μm; mobile phase A: 5 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: phase B 5% to 95%) to afford compound 49 (7.0 mg, 7.2% yield).

[1223] 1 HNMR (400MHz, DMSO-d6): δ10.33(s,1H),7.88(d,1H),7.51(d,1H),7.42(s,1H),6.90(d,1H),6.61(d,1H) ,6.31(t,1H),5.56(s,2H),4.19(t,2H),3.70(s,3H),1.74(t,2H),0.99-0 / 97(m,2H),0.84-0.82(m,2H).

[1224] MS m / z(ESI):519.0[M+H] + .

[1225] Example 55

[1226] Synthesis of compound 51

[1227] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-4-oxochroman-8-sulfonamide

[1228] Step a:

[1229] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-4-((tert-butyldimethylsilyl)oxy)-7-methoxychroman-8-sulfonamide

[1230] To a solution of intermediate 5 (120 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added sodium hydride (60%, 86 mg, 2.15 mmol). The reaction system was stirred at 0°C for 15 minutes, followed by the addition of compound 36c (212 mg, 0.54 mmol) and continued stirring for 15 minutes. After the reaction was returned to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the mother liquor was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (dichloromethane:methanol = 49:1) to afford compound 51a (171 mg, 62.5% yield).

[1231] Step b:

[1232] N-(6-((1H-pyrazol-1-yl)methyl)-5-chloro-4-methoxybenzo[d]isoxazol-3-yl)-4-hydroxy-7-methoxychroman-8-sulfonamide

[1233] To a solution of compound 51a (171 mg, 0.27 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride trihydrate (226 mg, 0.81 mmol), and the reaction system was stirred for 18 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracte...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof: in: Dashed lines are optional chemical bonds; R 1 , R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 4 and R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 halocycloalkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C 1-6 Hydroxyalkyl, or R 4 and R 5 Together with the attached carbon atoms, they form a 4- to 10-membered heterocyclic group, a 5- to 6-membered heteroaryl group, a 7- to 12-membered spiro heterocyclic group, and an 8- to 15-membered fused heterocyclic group, wherein the 4- to 10-membered heterocyclic group, the 5- to 6-membered heteroaryl group, the 7- to 12-membered spiro heterocyclic group, and the 8- to 15-membered fused heterocyclic group are optionally substituted by one or more substituents selected from the group consisting of hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 Cycloalkyl)2, oxo, =CH2, =CHC 1-6 Alkyl, =C(C 1-6 Alkyl)2, =CHC 1-6 Haloalkyl, =C(C 1-6 Haloalkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, cyano, benzyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated heterocyclic group, C 3-6 Cycloalkoxy, C 3-6 halocycloalkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C 2-6 alkenyl; Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 10 membered aryl groups, 5 to 10 membered heteroaryl groups containing at least one nitrogen atom, and 6 to 12 membered fused heterocyclic groups; the ring A is optionally substituted by one or more substituents selected from the following: halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkoxy, C 1-6 haloalkoxy, 3 to 8 membered halocycloalkoxy, oxo and C 2-6 alkenyl; X1 is O, S, C or N; X2 is N or C; X3 is N or CR6; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 ring Alkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 Halogenated cycloalkoxy; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, C 3-8 Cycloalkoxy and C 3-8 halocycloalkoxy; and Y is O or NH; Z is -CH2-, -CF2-, -C(O)-, O, -S(O)-, -S(O)2- or -NH-.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, wherein the compound is a compound of formula (II-1), (II-2) or (II-3), in: R 1 Selected from C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 1 is selected from methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Preferably, R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Alkoxy; More preferably, R 2 and R 3 are the same or different and are each independently selected from hydrogen and halogen; most preferably, R 2 and R 3 All are hydrogen atoms; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C 1-6 More preferably, R 4 is selected from the group consisting of a hydrogen atom, an ethyl group, an isopropyl group and a tert-butyl group; R 4A and R 4B The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Preferably, R 4A and R 4B All are methyl; R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 4-6 Cycloalkoxy and C 4-6 Preferably, R 5 is selected from hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and More preferably, R 5 is a hydrogen atom or a methoxy group; R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group; Ring M is selected from 4 to 7 membered cycloalkyl and 4 to 7 membered halogenated cycloalkyl; preferably, ring M is selected from cyclobutyl and Y is O or NH; preferably, Y is O.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is a compound of formula (III), in: R 1 , R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 1 Selected from C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy, R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 More preferably, R 1 is methoxy, R 2 and R 3 All are hydrogen atoms; R 4 and R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C 1-6 Hydroxyalkyl, R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkoxy and C 3-6 More preferably, R 4 is selected from hydrogen, ethyl, isopropyl, tert-butyl and R 5 is selected from hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and Most preferably, R 4 is a hydrogen atom, R 5 is a hydrogen atom or a methoxy group; R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, chlorine atoms, fluorine atoms, methoxy groups, ethoxy groups 1-propyl, 1-isopropyl, 1-difluoromethoxy, and 1-cyclopropyl; Y is O or NH; preferably, Y is O.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is a compound of formula (IV), in: R 1 , R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 1 Selected from C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy, R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 More preferably, R 1 is methoxy, R 2 and R 3 All are hydrogen atoms; R 4 and R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Heterocyclic and C 1-6 Hydroxyalkyl, R 5 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkoxy and C 3-6 More preferably, R 4 is selected from hydrogen, ethyl, isopropyl, tert-butyl, and R 5 is selected from hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and Most preferably, R 4 is a hydrogen atom, R 5 is a hydrogen atom or a methoxy group; R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Preferably, R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group; X1 is C or N; Y is O or NH; preferably, Y is O.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is a compound of formula (V), in: Dashed lines are optional chemical bonds; R 1 , R 2 , R 3 , R 6 , R 7 , Y, X1, X2 and Z as defined in claim 1; Ring B is selected from 4-10 membered heterocyclyl, 5-6 membered heteroaryl and 7-12 membered spiro heterocyclyl; the ring B is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 Cycloalkyl)2, oxo, =CH2, =CHC 1-6 Alkyl, =C(C 1-6 Alkyl)2, =CHC 1-6 Haloalkyl, =C(C 1-6 Haloalkyl)2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, cyano, benzyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 halocycloalkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C 2-6 Alkenyl.

6. The compound according to claim 5 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, wherein in the compound of formula (V), ring B is The dotted line represents the chemical bond shared by ring B and the benzene ring, and W is selected from -O-, -NR 9C -、-CR 9D R 9E -、 and -C(O)-, and W is connected to the benzene ring R 3 The carbon atom adjacent to the carbon atom; p is 0, 1, or 2; R 9A and R 9B are the same or different and are each independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2,- PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 cycloalkyl)2, benzyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl and C 2-6 alkenyl; R 9D and R 9E are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and hydroxy groups; Ring C is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 12 membered spirocyclyl, 6 to 12 membered heterospirocyclyl and 5 to 12 membered heterobridged cyclyl; the ring C is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents of a haloalkyl group; R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group and hydroxyl group, the C 3-6 Cycloalkyl and C 3-6 The heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, methyl and methoxy; R 9M and R 9L are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and C 1-6 Halogenated alkyl.

7. The compound according to claim 6 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, wherein in the compound of formula (V), W is selected from -O-, -NR 9C -、 and -C(O)-; preferably, W is selected from -O-, -NR 9C -、 More preferably, W is selected from -O- and -NR 9C -.

8. A compound according to claim 1, 5 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is a compound of formula (VI-1), (VI-2), (VI-3) or (VI-4), in: R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy; R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 9A and R 9B are the same or different and are each independently selected from hydrogen, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -C(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, -PO(C 1-6 Alkyl)2, -PO(C 3-6 Cycloalkyl)2, -PO(halogenated C 1-6 Alkyl)2, -PO(halogenated C 3-6 cycloalkyl)2, benzyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl and C 2-6 alkenyl; R 9D and R 9E are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 1-6 Haloalkoxy, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, cyano, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy and hydroxy groups; Ring C is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 12 membered spirocyclyl, 6 to 12 membered heterospirocyclyl and 5 to 12 membered heterobridged cyclyl; the ring C is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkyl and C 1-6 is substituted by one or more substituents of a haloalkyl group; Y is O or NH; p is 0, 1 or 2.

9. The compound according to any one of claims 5 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 4-6 Cycloalkoxy and C 4-6 Halogenated cycloalkoxy.

10. The compound according to any one of claims 5 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1 is selected from hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and 11. The compound according to any one of claims 5 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1 It is cyclobutyloxy or methoxy.

12. A compound according to any one of claims 5 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 1 It is a methoxy group.

13. A compound according to any one of claims 5 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 2 and R 3 are independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Alkoxy.

14. A compound according to any one of claims 5 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 2 and R 3 All are hydrogen atoms.

15. The compound according to any one of claims 5 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

16. The compound according to any one of claims 5 to 15, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom and a methoxy group.

17. A compound according to any one of claims 5 to 16, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 6 It is a methoxy group.

18. A compound according to any one of claims 5 to 17, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 7 is a hydrogen atom or a fluorine atom.

19. A compound according to any one of claims 5 to 18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 7 A fluorine atom.

20. The compound according to any one of claims 6 to 19, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9A and R 9B are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group.

21. A compound according to any one of claims 6 to 20, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9A and R 9B All are hydrogen atoms.

22. A compound according to any one of claims 6 to 21, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Halogenated cycloalkoxy, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 3-6 Halogenated cycloalkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2halogenated C 1-6 Alkyl, -S(O)2halogenated C 3-6 Cycloalkyl, benzyl and 23. A compound according to any one of claims 6 to 22, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C A hydrogen atom.

24. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is methyl.

25. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is a deuterated methyl group.

26. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is ethyl.

27. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is trifluoroethyl.

28. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is -C(O)OCH3.

29. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is benzyl.

30. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9C It is -C(O)CH3.

31. A compound according to any one of claims 6 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R 9C It is -S(O)2CH3.

32. A compound according to any one of claims 6 to 21, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9D and R 9E are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a methyl group and a hydroxyl group.

33. A compound according to any one of claims 6-21 and 32, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9D and R 9E are the same or different and are each independently selected from a fluorine atom and a methyl group.

34. A compound according to any one of claims 6 to 21, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein ring C is selected from The ring C is optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl and C 1-6 Preferably, ring C is selected from 35. The compound according to any one of claims 5-34, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Y is O.

36. A compound according to any one of claims 6 to 35, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein p is 1.

37. A compound according to any one of claims 6 to 35, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein p is 2.

38. A compound according to claim 1, 5 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound is a compound of formula (VII-1), (VII-2) or (VII-3), in: R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy; R 6 and R 7 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkoxy and C 3-6 Halogenated cycloalkoxy; R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group and hydroxyl group, the C 3-6 Cycloalkyl and C 3-6 The heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, methyl and methoxy; R 9M and R 9L are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and C 1-6 Haloalkyl; Y is O or NH.

39. The compound of claim 38 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1 Selected from hydrogen atoms, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 4-6 Cycloalkoxy and C 4-6 Halogenated cycloalkoxy.

40. The compound of claim 38 or 39, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1 is selected from hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, -OCH2CHF2, cyclobutyloxy and 41. A compound according to any one of claims 38 to 40, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 1 It is a methoxy group.

42. A compound according to any one of claims 38 to 41, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 2 and R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-4 Alkyl and C 1-4 Alkoxy.

43. A compound according to any one of claims 38 to 42, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 2 and R 3 are the same or different and are each independently selected from a hydrogen atom and a halogen.

44. A compound according to any one of claims 38 to 43, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 2 and R 3 All are hydrogen atoms.

45. A compound according to any one of claims 38 to 44, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, an ethoxy group, an isopropoxy group, a difluoromethoxy group and a cyclopropyl group.

46. ​​A compound according to any one of claims 38 to 45, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 6 It is a methoxy group.

47. A compound according to any one of claims 38 to 46, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 7 is selected from hydrogen atoms and fluorine atoms.

48. A compound according to any one of claims 38 to 47, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 7 Fluorine atom.

49. A compound according to any one of claims 38 to 48, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9K Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and hydroxy.

50. A compound according to any one of claims 38 to 49, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9K is selected from the group consisting of a hydrogen atom, a methyl group and a hydroxyl group.

51. A compound according to any one of claims 38 to 50, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9K A hydrogen atom.

52. A compound according to any one of claims 38 to 47, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9M and R 9L are the same or different and are each independently selected from hydrogen atom and C 1-6 alkyl.

53. A compound according to any one of claims 38-47 and 52, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R 9M and R 9L are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methyl group.

54. A compound according to any one of claims 38-53, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Y is O.

55. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound is isotopically substituted, preferably, the isotope substitution is deuterium atom substitution.

56. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the structural formula of the compound is selected from Table 1.

57. A method of preparing a compound or a pharmaceutically acceptable salt thereof, the method comprising: Option I: The compound of formula (IA) or a salt thereof reacts with the compound of formula (IB) or a salt thereof in the presence of a base to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof; in: Dashed lines are optional chemical bonds. Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , X1, X2, X3, Y and Z as defined in claim 1; Option II: The compound of formula (VA) or its salt reacts with the compound of formula (VB) or its salt in the presence of a base to obtain the compound of formula (V) or its pharmaceutically acceptable salt; in: The dashed lines are optional chemical bonds. Ring A, Ring B, R 1 , R 2 , R 3 , R 6 , R 7 , X1, X2, Y and Z as defined in claim 5 or 6; Option III: The compound of formula (VI-1A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof; in: R 1 , R 2 , R 3 , R 6 , R 7 , R 9A , R 9B , Y and p are as defined in claim 8; Option IV: The compound of formula (VI-1A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof; in: R 1 , R 2 , R 3 , R 6 , R 7 , R 9A , R 9B , R 9C , Y and p are as defined in claim 8; Option V: The compound of formula (VI-3A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-3) or a pharmaceutically acceptable salt thereof; in: R 1 , R 2 , R 3 , R 6 , R 7 , R 9A , R 9B , R 9D , R 9E , Y and p are as defined in claim 8; Solution VI: The compound of formula (VI-4A) or a salt thereof reacts with the compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VI-4) or a pharmaceutically acceptable salt thereof; in: Ring C, R 1 , R 2 , R 3 , R 6 , R 7 , R 9A , R 9B , Y and p are as defined in claim 8; Scheme VII: Step a: reacting a compound of formula (VII-3A) or a salt thereof with a compound of formula (VI-3B) or a salt thereof in the presence of a base to obtain a compound of formula (VII-3B) or a pharmaceutically acceptable salt thereof; Step b: reacting a compound of formula (VII-3B) or a salt thereof with a deprotecting agent to remove the hydroxy protecting group to obtain a compound of formula (VII-3C) or a pharmaceutically acceptable salt thereof; Step c: reacting a compound of formula (VII-3C) or a salt thereof with an oxidizing agent to obtain a compound of formula (VII-3) or a pharmaceutically acceptable salt thereof; in: R 1 , R 2 , R 3 , R 6 , R 7 and Y as defined in claim 38; R a is a hydroxyl protecting group; preferably (trimethylsilyl)ethoxymethyl; Step b: the deprotecting group reagent is an acid or a fluorine-containing reagent, preferably trifluoroacetic acid or tetrabutylammonium fluoride; Step c: the oxidizing reagent is a reagent that oxidizes hydroxyl groups to ketones, preferably manganese dioxide or Dess-Martin reagent; The base used in the reaction of the above scheme is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-lutidine, 2,6-lutidine, n-butyl lithium, lithium bistrimethylsilylamide, sodium hydride, sodium hydroxide, cesium carbonate and potassium carbonate; The reaction of the above scheme is preferably carried out in a solvent selected from the group consisting of ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, toluene, pyridine and mixtures thereof.

58. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

59. A compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition according to claim 58 for use as a medicament, preferably for use in the treatment or prevention of cancer in which KATA / B plays a role.

60. Use of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 58 in the preparation of a medicament for inhibiting KAT; wherein the KAT is preferably KAT6, more preferably KAT6A and / or KAT6B.

61. The method of claim 60, wherein the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug or isotope-substituted product or pharmaceutical composition is used to treat or prevent cancer, wherein the cancer is selected from lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial carcinoma, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, brain glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinus node cell tumor, and tenosynovial giant cell tumor.

62. The use according to claim 61, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer and leukemia.

63. The use according to claim 61 or 62, wherein the breast cancer is ER + Breast cancer or ER + / HER2 - Breast cancer.

64. The use according to claim 61 or 62, wherein the lung cancer is non-small cell lung cancer.

65. The use according to claim 61 or 62, wherein the prostate cancer is castration-resistant prostate cancer.

66. A method of inhibiting KATA / B comprising administering a compound according to any one of claims 1-56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 58.

67. A method of treating or preventing a cancer in which KATA / B plays a role, comprising administering to a subject in need thereof a compound according to any one of claims 1-56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 58, wherein the cancer is selected from lung cancer, breast cancer, rectal cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, urothelial carcinoma, head and neck cancer, nasopharyngeal cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, bone cancer, mesothelioma, gastrointestinal stromal tumor, sarcoma, brain glioma, thyroid cancer, salivary gland tumor, glioblastoma, neuroblastoma, gastric myxoma, lymphoma, leukemia, plasmacytoma, sinus node cell tumor, tenosynovial giant cell tumor.

68. The method of claim 67, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, malignant lymphoma, liver cancer, and leukemia.

69. The method of claim 67 or 68, wherein the breast cancer is ER + Breast cancer or ER + / HER2 - Breast cancer.

70. The method of claim 67 or 68, wherein the lung cancer is non-small cell lung cancer.

71. The method of claim 67 or 68, wherein the prostate cancer is castration-resistant prostate cancer.

72. A kit comprising a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, hydrate, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition according to claim 58 and instructions for use.

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