KAT6 inhibitors

Abstract

The invention provides a novel compound with KAT6 inhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound and application of the compound to preparation of cancer treatment drugs.

Description

KAT6 inhibitors

[0001] This application claims priority to Chinese patent applications filed with the Patent Office of China on July 4, 2023, with application number CN202310816102X and the invention name “KAT6 inhibitor”, filed with the Patent Office of China on September 8, 2023, with application number CN2023111614487 and the invention name “KAT6 inhibitor”, filed with the Patent Office of China on November 29, 2023, with application number CN2023116187290 and the invention name “KAT6 inhibitor”, filed with the Patent Office of China on January 8, 2024, with application number CN2024100246927 and the invention name “KAT6 inhibitor”, and filed with the Patent Office of China on April 15, 2024, with application number CN2024104524832 and the invention name “KAT6 inhibitor”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present application belongs to the field of medicinal chemistry and relates to a KAT6 inhibitor, specifically a novel compound with KAT6 inhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound, and a method for using the compound of the present application to treat related diseases mediated by KAT6. Background Art

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

[0004] KAT6A and KAT6B typically extensively acetylate histone H3 at lysine 23 (H3K23), but KAT6A can also modify acetylation specifically at H3K9 on genes it regulates. KAT6A interacts with transcription factors such as p53 and RUNX1, acetylating histones and regulating the expression of downstream genes. KAT6A binds to the proximal promoter region of the estrogen receptor α (ERα), activating ERα expression. In breast cancer cells harboring ER+, KAT6A amplification, mutations, or high expression, inhibiting KAT6A acetyltransferase activity or knocking down KAT6A significantly inhibits breast cancer cell proliferation. Furthermore, KAT6A acetyltransferase activity is crucial for promoting the expression of MEIS1 and HOXa9, genes often overexpressed in some lymphomas and leukemias. In a mouse model of MYC-induced lymphoma, deletion of one KAT6A allele significantly prolongs median survival. In mice, mutations in the KAT6B allele significantly reduce the division and differentiation of cortical progenitor cells, severely impacting the development of the cerebral cortex. KAT6B also plays an important role in maintaining the number of adult neural stem cells. KAT6B is also mutated in some rare types of leukemia.

[0005] Currently, there are many studies based on this mechanism of action, but no KAT6 inhibitor drugs have been found on the market. Therefore, there is an urgent need to develop effective KAT6 inhibitors for clinical patients.

[0006] Summary of the Invention

[0007] The present application provides a compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof,

[0008] in,

[0009] R1 and R2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, hydroxyl, -C 1-4 Alkyl hydroxyl, -C 1-4 Alkyl-SC 1-4 Alkyl, amino, C 1-4 Alkylamino;

[0010] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy, hydroxyl, amino, R4, R5 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0011] or R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxyl, amino, R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0012] R a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0013] m is selected from 1, 2, 3, and 4;

[0014] R6, R7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, deuterated C 1-4 Alkoxy; or R6, R7 and the carbon atom to which they are connected form a 5-8 membered heterocyclic group, which may be optionally replaced by n R b replaced by;

[0015] R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0016] n is selected from 1, 2, 3, 4;

[0017] L1 is selected from C 1-4Alkylene or -O-, deuterated C 1-4 alkylene;

[0018] Ring A is selected from 5-6 membered heteroaryl;

[0019] R8 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, amino, -C 1-4 Alkylamino, hydroxyl;

[0020] P is selected from 1, 2, 3, 4.

[0021] The present application provides a compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof,

[0022] in,

[0023] R1 and R2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, hydroxyl, -C 1-4 Alkyl hydroxyl, -C 1-4 Alkyl-SC 1-4 Alkyl, amino, C 1-4 Alkylamino;

[0024] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxyl, amino, R4, R5 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0025] or R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxyl, amino, R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same Ca Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0026] R a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0027] m is selected from 1, 2, 3, and 4;

[0028] R6, R7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, deuterated C 1-4 Alkoxy; or R6, R7 and the carbon atom to which they are connected form a 5-8 membered heterocyclic group, which may be optionally replaced by n R b replaced by;

[0029] R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0030] n is selected from 1, 2, 3, 4;

[0031] L1 is selected from C 1-4 Alkylene or -O-, deuterated C 1-4 alkylene;

[0032] Ring A is selected from a 5-6 membered heteroaryl group; the heteroatoms in the 5-6 membered heteroaryl group are each independently selected from S or N;

[0033] R8 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, amino, -C 1-4 Alkylamino, hydroxyl;

[0034] P is selected from 1, 2, 3, 4;

[0035] The heteroatoms in the heterocyclic group are each independently selected from O, S or N.

[0036] The present application provides a compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof,

[0037] in,

[0038] R1 and R2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, hydroxyl, -C 1-4 Alkyl hydroxyl, -C 1-4 Alkyl-SC 1-4 Alkyl, amino, C 1-4 Alkylamino;

[0039] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxyl, amino, R4, R5 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0040] or R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxyl, amino, R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0041] R a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0042] m is selected from 1, 2, 3, and 4;

[0043] R6, R7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy; or R6, R7 and the carbon atom to which they are connected form a 5-8 membered heterocyclic group, the heterocyclic group can be arbitrarily replaced by n R b replaced by;

[0044] R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy, amino;

[0045] n is selected from 1, 2, 3, 4;

[0046] L1 is selected from C 1-4 Alkylene or -O-;

[0047] Ring A is selected from 5-6 membered heteroaryl;

[0048] R8 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, amino, -C 1-4 Alkylamino, hydroxyl;

[0049] P is selected from 1, 2, 3, 4.

[0050] In some embodiments of the present application, in the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, R1 is selected from CH3O- and hydrogen.

[0051] In some embodiments of the present application, the compound of the above formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R1 is selected from CH3O-.

[0052] In some embodiments of the present application, the compound of the above formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R2 is selected from H.

[0053] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated products and pharmaceutically acceptable salts thereof, wherein R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group selected from

[0054] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated products and pharmaceutically acceptable salts thereof, wherein R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group selected from

[0055] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the 7-8 membered heterocyclic group formed by R4, R5 and the carbon atoms to which they are connected is selected from

[0056] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R4, R5 and the carbon atoms to which they are connected form a 7-8 membered heterocyclic group selected from

[0057] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R4, R5 and the carbon atoms to which they are connected form a 7-8 membered heterocyclic group selected from

[0058] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R4, R5 and the carbon atoms to which they are connected form a 7-8 membered heterocyclic group selected from

[0059] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated products and pharmaceutically acceptable salts thereof, wherein R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group selected from

[0060] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R a Selected from -F.

[0061] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R a Selected from -CH3.

[0062] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from

[0063] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from

[0064] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from

[0065] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from

[0066] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the structural unit Selected from

[0067] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R6 and R7 are each independently selected from -F, -CH3, CH3O-, C2H5O-, CHF2O-, Preferably, R6 is selected from CH3O-.

[0068] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein R6 and R7 are each independently selected from -C2H5 and -OCD3.

[0069] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the 5-8 membered heterocyclic group formed by R6, R7 and the carbon atoms to which they are connected is selected from

[0070] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the 5-8 membered heterocyclic group formed by R6, R7 and the carbon atoms to which they are connected is selected from

[0071] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the 5-8 membered heterocyclic group formed by R6, R7 and the carbon atoms to which they are connected is selected from

[0072] In some embodiments of the present application, the compound of the above formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein L1 is selected from -CH2-.

[0073] In some embodiments of the present application, the compound of the above formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein L1 is selected from -CD2-.

[0074] In some embodiments of the present application, the compound of the above formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein L1 is selected from -O-.

[0075] In some embodiments of the present application, the compound of formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein ring A is selected from

[0076] The present application provides a benzisoxazole derivative and a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and use thereof in medicine.

[0077] The present application provides compounds, isomers, deuterated substances and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the following compounds:

[0078] The present application also provides a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned compound, its isomers, deuterated substances or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0079] In certain embodiments of the present application, in the pharmaceutical composition, the content of the compound, its isomers, deuterated substances and pharmaceutically acceptable salts thereof is selected from 0.1 mg to 1000 mg.

[0080] In certain embodiments of the present application, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0081] The present application also provides the use of the above-mentioned compound, its isomers, deuterated substances and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition in the preparation of drugs for treating KAT6-mediated diseases, wherein the KAT6-mediated related diseases include cancer.

[0082] The present application also provides a method for treating a KAT6-mediated disease, comprising administering a therapeutically effective amount of the above-mentioned compound, its isomer, deuterated substance or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a subject in need thereof; preferably, the KAT6-mediated related disease includes cancer.

[0083] Technical Effects

[0084] The compounds provided in this application have significant KAT6 enzymatic inhibitory activity and can be used to treat cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0086] FIG1 is a graph showing the weight changes of mice in different groups in the in vivo pharmacodynamic study of the present application;

[0087] FIG2 is a graph showing the tumor growth curves of mice in different groups in the in vivo pharmacodynamic study of this application. DETAILED DESCRIPTION

[0088] Description and Definition

[0089] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0090] The compounds of the present application have isomers including geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, all of which fall within the scope of the present application.

[0091] The term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0092] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0093] The term "cis-trans isomers" refers to configurations in which a molecule cannot rotate freely about a double bond or a single bond of a ring-forming carbon atom.

[0094] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter. For example The methyl group and the amino group are located on the same side of the cyclopentane. Stereoisomers of the compounds of the present application can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound of the present application can be prepared by asymmetric catalysis or chiral auxiliary derivatization. Alternatively, a compound with a single stereo configuration can be obtained from a mixture by chiral resolution technology. Alternatively, it can be directly prepared using chiral starting materials. The separation of optically pure compounds in the present application is usually achieved by preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.

[0095] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Compounds labeled "absolute configuration not determined" herein are typically resolved from racemic compounds by chiral preparative SFC into individual isomers, which are then characterized and tested.

[0096] Unless otherwise specified, "substituted or unsubstituted" means that it may be substituted or unsubstituted. 3-6 Examples of "cycloalkyl" include, but are not limited to

[0097] The term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.

[0098] The term "C 1-4 "Alkyl" is used to represent C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

[0099] The term "C 1-4 "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0100] The term "C 1-4 "Alkylene" is used to represent C 1-4 Straight-chain or branched saturated alkylene group. 1-4 Examples of alkylene include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3, -(CH2)4-, -CH(CH3)-, and -C(CH3)2-.

[0101] The term "C 1-4 "Deuterated alkylene" is used to represent C 1-4 The hydrogen atoms in the straight or branched saturated alkylene groups are replaced by D atoms. 1-4Examples of deuterated alkylene groups include, but are not limited to, -CD2-, -CH(CD3)-.

[0102] The term "C 1-4 "Alkoxy" refers to a C 1-4 Alkyl. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.

[0103] The term "deuterated alkoxy" refers to a deuterated C 1-4 wherein the deuterated C 1-4 Alkyl means that the hydrogen atoms in a straight or branched hydrocarbon group are completely or partially replaced by D atoms. 1-4 Examples of alkoxy groups include, but are not limited to, -OCD3, -OCD2CD3, -OCD2(CD3), and -OCH2(CD3).

[0104] The term "C 3-6 "Cycloalkyl" refers to a 3-6 membered monocyclic alkyl group. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0105] The term "heterocyclyl" refers to a non-aromatic cyclic group containing at least one heteroatom as a ring atom and derived by removing one hydrogen atom; it includes saturated or partially saturated monocyclic heterocyclyls and bicyclic heterocyclyls. The terms "5-8 membered heterocyclyl" and "7-8 membered heterocyclyl" refer to substituted or unsubstituted 5-8 membered saturated or unsaturated non-aromatic rings or substituted and unsubstituted 7-8 membered saturated or unsaturated non-aromatic rings, and contain 1-3 heteroatoms selected from N, O or S. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The heterocyclic group is not related to the position of attachment (i.e., it can be attached through a carbon atom or a heteroatom). Examples of "heterocyclic group" include but are not limited to

[0106] The term "spiroheterocyclyl" refers to a saturated or partially saturated cyclic structure formed by two or more cyclic structures sharing a ring atom, containing at least one heteroatom. The heteroatom is generally selected from CO, N, O, S, NO, SO, S(O)2. The "7-10 membered spiroheterocyclyl" described herein includes "7-10 membered saturated spiroheterocyclyl" and "7-10 membered partially saturated spiroheterocyclyl", preferably a 7-10 membered oxygen-containing saturated spiroheterocyclyl. Specific examples include but are not limited to: wait.

[0107] The term "fused heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms, containing at least one ring atom that is a heteroatom; the heteroatom is generally selected from N, O, and S; the ring carbon atoms and heteroatoms in the fused heterocyclic ring may be further oxidized to form cyclic groups containing C(O), NO, SO, and S(O)2 groups, which are also included in the definition of heterocyclic groups described in this application. The "non-aromatic" mentioned in this definition means that the group does not have aromaticity when it exists independently. This application does not limit the group to being connected to other structures through an endocyclic or exocyclic unsaturated bond, or to being connected to other unsaturated structures through a single bond, or to being aromatic under specific conditions (such as in a special solvent). The "7-10 membered fused heterocyclic group" mentioned in this application includes "7-10 membered saturated fused heterocyclic group" and "7-10 membered partially saturated fused heterocyclic group". The fused form can be a 5-6 membered heterocyclic group and a 3-4 membered heterocyclic group, a 5-6 membered heterocyclic group and a 3-4 membered cycloalkyl group, a 5-6 membered heteroaryl group and a 3-4 membered heterocyclic group, or a 5-6 membered heteroaryl group and a 3-4 membered cycloalkyl group. Specific examples of the fused heterocyclic group include, but are not limited to:

[0108] The term "heteroaryl" refers to a monocyclic group with aromatic properties in which at least one ring atom is a heteroatom and / or a heteroatom group, wherein the heteroatom and / or heteroatom group is generally selected from N, O, S, P, NO, SO, S(O)2, P(O) and NR, R is H or any substituent group, wherein the carbon atoms in the heterocyclic ring are optionally oxidized, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heteroaryl group includes "5-6 membered heteroaryl"; specific examples include but are not limited to pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, pyridinyl, and pyrimidinyl.

[0109] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0110] The term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present invention prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains relatively acidic functional groups, base addition salts are obtained by reaction with alkali metal or alkaline earth metal hydroxides or organic amines. These salts include cations based on alkali and alkaline earth metals, as well as nontoxic ammonium, quaternary ammonium, and amine cations, and also encompass salts of amino acids. When the compound contains relatively basic functional groups, acid addition salts are obtained by reaction with organic or inorganic acids.

[0111] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0112] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0113] The solvents used in this application are commercially available.

[0114] The structures of the compounds described herein are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O) as the internal standard, with tetramethylsilane (TMS) as the internal standard.

[0115] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer (electrospray ionization as the ion source).

[0116] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (electrospray ionization as the ion source).

[0117] HPLC analysis was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0118] Preparative HPLC was performed using a Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or a GILSON Trilution LC.

[0119] Chiral HPLC was performed using Waters Acquity UPC2 and a Daicel chi-ring Clpak AD-H column (5 μm, 4.6×250 mm).

[0120] Supercritical fluid chromatography (SFC) was performed using a Waters SFC 80Q.

[0121] The starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0122] Unless otherwise specified, all reactions in this application were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was a dry solvent, and the reaction temperature was expressed in degrees Celsius.

[0123] The reaction progress in the examples can be monitored by conventional methods such as thin layer chromatography (TLC) and LC-MS. The eluent system for column chromatography and the developing solvent system for thin layer chromatography used for purification can be composed of one or more of the following solvents: dichloromethane, methanol, n-hexane, ethyl acetate, petroleum ether, ethyl acetate, acetone, chloroform, etc. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine, acetic acid, trifluoroformic acid, etc. can also be added for adjustment.

[0124] Intermediate INT-1: 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine

[0125] Reaction route:

[0126] Steps:

[0127] Step A: Under nitrogen protection, 1H-pyrazole (5 g, 73.5 mmol) and triethylamine (11.1 g, 110.3 mmol) were dissolved in dichloromethane (50 mL). After cooling to 0°C, methanesulfonyl chloride (10.9 g, 95.6 mmol) was added dropwise. The system was stirred at room temperature for 1 hour.

[0128] After LCMS monitoring showed that the raw material reaction was complete, the reaction solution was quenched by adding saturated ammonium chloride solution, and dichloromethane (300 mL) was added. The mixture was washed with water (100 mL) and saturated brine (100 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.7 g of 1-(methylsulfonyl)-1H-pyrazole.

[0129] LCMS (ESI) M / Z: 147.3 [M+H] + .

[0130] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=2.6Hz,1H),7.96(d,J=1.2Hz,1H),6.61(dd,J=2.6,1.6Hz,1H),3.52(s,3H).

[0131] Step B: Under nitrogen protection, 2,6-difluoro-4-formylbenzonitrile (1 g, 6.0 mmol) was dissolved in ethanol (10 mL), cooled to 0°C, and sodium borohydride (226.5 mg, 6.0 mmol) was added dropwise. The system was stirred at 0°C for 2 hours.

[0132] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to a saturated citric acid solution. The ethanol was then dried by spin drying, and the mixture was extracted with dichloromethane (50 mL x 3). The mixture was washed with saturated sodium bicarbonate (100 mL), water (100 mL), and saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 680 mg of 2,6-difluoro-4-(hydroxymethyl)benzonitrile.

[0133] LCMS (ESI) M / Z: 170.1 [M+H] + .

[0134] Step C: Under nitrogen protection, dissolve 2,6-difluoro-4-(hydroxymethyl)benzonitrile (1 g, 5.9 mmol) in methanol (10 mL), cool to 0°C, add sodium methoxide solution (4.26 g, 23.67 mmol) dropwise, warm to room temperature and stir for 8 hours.

[0135] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into saturated aqueous citric acid (50 mL) for quenching, and extracted with ethyl acetate (100 mL). The mixture was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 990 mg of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile.

[0136] LCMS (ESI) M / Z: 182.1 [M+H] + .

[0137] 1 H NMR (400MHz, DMSO-d6) δ7.05 (s, 1H), 6.98 (d, J = 10.0Hz, 1H), 5.68 (t, J = 5.8Hz, 1H), 4.58 (d, J = 5.8Hz, 2H), 3.94 (s, 3H).

[0138] Step D: Under nitrogen protection, 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (6.33 g, 35 mmol), 1-(methylsulfonyl)-1H-pyrazole (6.13 g, 42 mmol) and cesium carbonate (13.7 g, 42 mmol) were dissolved in acetonitrile (80 mL), and the system was stirred at 70 ° C for 1 hour.

[0139] After LCMS monitoring indicated complete reaction of the starting material, the reaction solution was added to ethyl acetate (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to afford 6.2 g of 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile.

[0140] LCMS (ESI) M / Z: 232.2 [M+H] + .

[0141] 1 H NMR(400MHz,DMSO-d6)δ7.90(d,J=2.2Hz,1H),7.53(d,J=1.4Hz,1H),6.99(s ,1H),6.69(d,J=9.6Hz,1H),6.33(t,J=2.0Hz,1H),5.44(s,2H),3.91(s,3H).

[0142] Step E: Under nitrogen protection, N-hydroxyacetamide (6.8 g, 90.9 mmol) and potassium tert-butoxide (10.2 g, 90.9 mmol) were dissolved in N,N-dimethylformamide (70 mL), and the system was stirred at room temperature for 1 hour. 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile (7 g, 30.3 mmol) was added, and the system was stirred at 60 ° C for 4 hours.

[0143] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with water (100 mL), extracted with dichloromethane (100 mL), washed with saturated brine (100 mL x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 4 g of 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine.

[0144] LCMS (ESI) M / Z: 245.3 [M+H] + .

[0145] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,J=2.0Hz,1H),7.50(d,J=1.4Hz,1H),6.69(s,1 H), 6.63 (s, 1H), 6.30 (t, J = 2.0Hz, 1H), 5.95 (s, 2H), 5.41 (s, 2H), 3.86 (s, 3H).

[0146] Intermediate INT-2: 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride

[0147] Reaction route:

[0148] Steps:

[0149] Step A: Under nitrogen protection, 2-hydroxy-4-methoxybenzaldehyde (15 g, 98.7 mmol) and aluminum chloride (13.17 g, 98.7 mmol) were dissolved in dichloromethane (150 mL). After cooling to -20 °C, bromine (15.8 g, 98.7 mmol) was added dropwise. The system was stirred at room temperature for 16 hours.

[0150] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with 1M hydrochloric acid (200 mL), extracted with dichloromethane (150 mL x 3), and washed with a saturated aqueous sodium sulfite solution (100 mL), water (100 mL), and saturated brine (150 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 9.5 g of 3-bromo-2-hydroxy-4-methoxybenzaldehyde.

[0151] MS (ESI) M / Z: 231.0, 233.0 [M+H] + .

[0152] 1 H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.88(s,1H),7.82(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),3.97(s,3H).

[0153] Step B: Under nitrogen protection, 3-bromo-2-hydroxy-4-methoxybenzaldehyde (9.5 g, 41.09 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium hydroxide solution (32 mL) and hydrogen peroxide (5.59 g, 49.18 mmol) were added to the reaction solution at 0°C, and the system was stirred at 0°C for 40 minutes.

[0154] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with saturated sodium sulfite solution (200 mL), diluted with dichloromethane (300 mL), and washed with 1M aqueous hydrochloric acid (100 mL), water (100 mL), and saturated brine (100 mL x 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 9 g of 3-bromo-4-methoxybenzene-1,2-diol.

[0155] MS (ESI) M / Z: 219.0, 220.9 [M+H] + .

[0156] 1 H NMR (400MHz, DMSO-d6): δ9.22(s,1H),9.12(s,1H),6.70(d,J=8.8Hz,1H),6.37(d,J=8.8Hz,1H),3.70(s,3H).

[0157] Step C: Under nitrogen protection, 3-bromo-4-methoxybenzene-1,2-diol (9 g, 41.1 mmol), 1,3-dibromopropane (12.45 g, 61.5 mmol), potassium carbonate (11.4 g, 82.2 mmol) and potassium fluoride (1.19 g, 20.4 mmol) were dissolved in N,N-dimethylformamide (90 mL), and the system was stirred at 135 ° C for 2 hours.

[0158] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to saturated ammonium chloride solution (500 mL), diluted with ethyl acetate (300 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 6.7 g of 6-bromo-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0159] MS (ESI) M / Z: 259.0, 261.0 [M+H] + .

[0160] 1 H NMR (400MHz, DMSO-d6): δ6.98(d,J=9.0Hz,1H),6.70(d,J=9.0Hz,1H),4.18-4.02(m,4H),3.78(s,3H),2.14-2.04(m,2H).

[0161] Step D: Under nitrogen protection, 6-bromo-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (6.7 g, 25.8 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78°C, tert-butyl lithium (17.74 mL, 28.38 mmol, 1.6 M) was added dropwise, and stirred at this temperature for 30 minutes. A solution of 1,2-dibenzyldisulfane (7.64 g, 30.82 mmol) in tetrahydrofuran (15 mL) was added dropwise at -78°C, stirred at the same temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0162] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate (150 mL) and saturated ammonium chloride (150 mL), extracted, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 5.5 g of 6-(benzylthio)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0163] MS (ESI) M / Z: 303.1 [M+H] + .

[0164] 1 H NMR (400MHz, DMSO-d6): δ7.25-7.11(m,5H),6.90(d,J=8.8Hz,1H),6.61(d,J =9.0Hz,1H),3.99(s,2H),3.96-3.79(m,4H),3.75(s,3H),2.03-1.92(m,2H).

[0165] Step E: Under nitrogen protection, 6-(benzylthio)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (1.7 g, 5.63 mmol) and acetic acid (2.7 g, 45.03 mmol) were dissolved in water (5.6 mL) and acetonitrile (61.9 mL), cooled to 0°C, and dichlorohydantoin (2.2 g, 11.26 mmol) was added. The system was stirred at 0°C for 1 hour.

[0166] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 1.49 g of 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride.

[0167] 1 H NMR (400MHz, DMSO-d6): δ6.93 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.00-3.86 (m, 4H), 3.66 (s, 3H), 2.05-1.94 (m, 2H).

[0168] Intermediates INT-3 and 4:

[0169] 6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-amine

[0170] 6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-amine

[0171] Reaction route:

[0172] Steps:

[0173] Step A: To a solution of 4-bromo-2,6-difluorobenzonitrile (20 g, 91.74 mmol) and methylboronic acid (16.47 g, 275.22 mmol) in dioxane (360 mL) and water (40 mL) were added tetrakis(triphenylphosphine)palladium (0.80 g, 0.69 mmol) and potassium carbonate (25.36 g, 183.48 mmol). The atmosphere was then replaced with nitrogen three times and stirred at 100°C for 12 hours. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. The solvent was removed by concentration under reduced pressure, and the product was purified by column chromatography to yield 8.5 g of 2,6-difluoro-4-methylbenzonitrile.

[0174] 1 H NMR(400MHz,Chloroform-d)δ6.83-6.74(m,2H),2.37(s,3H).

[0175] Step B: To a solution of 2,6-difluoro-4-methylbenzonitrile (6.5 g, 42.45 mmol) in sulfuric acid (32.5 mL) at 0°C was added N-bromosuccinimide (8.31 g, 46.70 mmol), followed by stirring at room temperature for 12 hours. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. The reaction mixture was poured into 150 mL of ice water and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 8.4 g of 3-bromo-2,6-difluoro-4-methylbenzonitrile.

[0176] 1 H NMR (400MHz, Chloroform-d) δ6.93 (dt, J = 9.0, 1.1Hz, 1H), 2.45 (s, 3H).

[0177] Step C: To a solution of 3-bromo-2,6-difluoro-4-methylbenzonitrile (2 g, 8.62 mmol) in methanol (15 mL) was added sodium methoxide (651.91 mg, 12.07 mmol) at 0°C and the reaction continued for 3 hours. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. The solvent was removed by concentration under reduced pressure, followed by the addition of 20 mL of water and extraction with 20 mL of ethyl acetate. The organic phase was washed with saturated brine, filtered, concentrated, and purified by column chromatography to yield 1.4 g of 3-bromo-6-fluoro-2-methoxy-4-methylbenzonitrile.

[0178] 1 H NMR(400MHz,Chloroform-d)δ6.88-6.78(m,1H),4.02(s,3H),2.41(s,3H).

[0179] Step D: To a solution of 3-bromo-6-fluoro-2-methoxy-4-methylbenzonitrile (1.38 g, 5.65 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.093 g, 0.57 mmol) in carbon tetrachloride (25 mL) was added N-bromosuccinimide (1.01 g, 5.65 mmol). The atmosphere was purged with nitrogen three times, and the mixture was reacted at 80°C for 3 hours. Thin-layer chromatography indicated the formation of new spots. The solvent was removed by concentration under reduced pressure, and the product was purified by column chromatography to yield 0.88 g of 3-bromo-4-(bromomethyl)-6-fluoro-2-methoxybenzonitrile.

[0180] 1 H NMR (400MHz, Chloroform-d) δ7.06 (d, J = 8.7Hz, 1H), 4.49 (s, 2H), 4.06 (s, 3H).

[0181] Step E: To a solution of 3-bromo-4-(bromomethyl)-6-fluoro-2-methoxybenzonitrile (610 mg, 1.89 mmol) and 1H-pyrazole (141.54 mg, 2.08 mmol) in acetonitrile (15 mL) was added cesium carbonate (677.38 mg, 2.08 mmol), followed by reaction at 80°C for 1.5 hours. After completion of the reaction, monitored by LCMS, 20 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 390 mg of 3-bromo-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile.

[0182] MS (ESI) M / Z: 310.0 [M+H] + .

[0183] Step F: To a solution of 3-bromo-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (130 mg, 0.42 mmol), methylboronic acid (50.28 mg, 0.84 mmol), and potassium carbonate (174.14 mg, 1.26 mmol) in dioxane (4 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (30.73 mg, 0.042 mmol). The atmosphere was purged with nitrogen three times and the mixture was reacted at 90°C for 3 hours. LCMS showed residual starting material and the desired peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to yield 37 mg of 6-fluoro-2-methoxy-3-methyl-4-[(1H-pyrazol-1-yl)methyl]benzonitrile.

[0184] MS (ESI) M / Z: 246.1 [M+H] + .

[0185] Step G: To a solution of 6-fluoro-2-methoxy-3-methyl-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (37 mg, 0.15 mmol) and N-hydroxyacetamide (33.78 mg, 0.45 mmol) in N,N-dimethylformamide (1.5 mL) and water (0.22 mL) was added potassium carbonate (124.39 mg, 0.90 mmol) and reacted at 60°C for 12 hours. LCMS showed the disappearance of the starting material and the formation of the desired peak. The product was concentrated under reduced pressure and removed. The residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with 10 mL of saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to yield 30 mg of 6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-amine.

[0186] MS (ESI) M / Z: 259.1 [M+H] + .

[0187] Step H: To a solution of 3-bromo-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (100 mg, 0.32 mmol), ethylboronic acid (4.73 mg, 0.064 mmol), and potassium carbonate (132.68 mg, 0.96 mmol) in dioxane (4 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (23.41 mg, 0.032 mmol). The atmosphere was purged with nitrogen three times and the mixture was reacted at 90°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the desired peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to yield 65 mg of 3-vinyl-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile.

[0188] MS (ESI) M / Z: 258.1 [M+H] + .

[0189] Step I: To a solution of 3-vinyl-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (65 mg, 0.25 mmol) in methanol (5 mL) was added wet palladium on carbon (6.5 mg, 0.0061 mmol) under a nitrogen atmosphere. The atmosphere was replaced with hydrogen three times, and then stirred under a hydrogen atmosphere (15 psi) for 0.5 hour. LCMS showed disappearance of the starting material and formation of the desired peak. The mixture was filtered and the filtrate was concentrated to yield 70 mg of 3-ethyl-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile.

[0190] MS (ESI) M / Z: 260.2 [M+H]+ .

[0191] Step J: To a solution of 3-ethyl-6-fluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (70 mg, 0.27 mmol) and N-hydroxyacetamide (60.81 mg, 0.81 mmol) in N,N-dimethylformamide (3 mL) and water (0.44 mL) was added potassium carbonate (186.58 mg, 1.35 mmol) and reacted at 60°C for 12 hours. LCMS showed the disappearance of the starting material and the formation of the desired peak. The product was concentrated under reduced pressure and removed. The residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with 10 mL of saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to yield 50 mg of 6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-amine.

[0192] MS (ESI) M / Z: 273.1 [M+H] + .

[0193] Intermediate INT-5: 6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-amine

[0194] Reaction route:

[0195] Steps:

[0196] Step A: To a solution of 2,3,5-trifluorobenzaldehyde (5 g, 31.23 mmol) in tetrahydrofuran (100 mL) was added sodium borohydride (1.30 g, 34.35 mmol) at 0°C, followed by reaction at 0°C for 2 hours. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. Saturated ammonium chloride (5 mL) was slowly added dropwise to the reaction solution to quench the reaction. The mixture was then filtered and concentrated to yield 5 g of (2,3,5-trifluorophenyl)methanol.

[0197] 1 H NMR (400MHz, Chloroform-d) δ6.93 (ddt, J = 10.8, 5.1, 2.3Hz, 1H), 6.83-6.74 (m, 1H), 4.81-4.62 (m, 2H).

[0198] Step B: To a solution of (2,3,5-trifluorophenyl)methanol (5 g, 30.84 mmol), triethylamine (4.68 g, 46.26 mmol), and 4-dimethylaminopyridine (0.38 g, 3.08 mmol) in dichloromethane (80 mL) was added tert-butyldimethylsilyl chloride (6.04 g, 40.09 mmol), followed by reaction at room temperature for 2 hours. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. The reaction mixture was added with 50 mL of water, then extracted with dichloromethane (50 mL). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 7.9 g of tert-butyldimethyl[(2,3,5-trifluorophenyl)methoxy]silane.

[0199] 1 H NMR(400MHz,Chloroform-d)δ6.92-6.83(m,1H),6.67(dddd,J=10.1,8.1,6.1,3.2Hz,1H),4.78-4.50(m,2H),0.82(s,9H),-0.00(s,6H).

[0200] Step C: To a solution of tert-butyldimethyl[(2,3,5-trifluorophenyl)methoxy]silane (3 g, 10.86 mmol) in tetrahydrofuran (30 mL) at -70°C was added diisopropylamino (1.40 g, 13.03 mmol) dropwise. The mixture was stirred for 2 hours, followed by the dropwise addition of a solution of 4-toluene-1-sulfonyl cyanide (2164.73 mg, 11.95 mmol) in tetrahydrofuran (3 mL). The mixture was stirred for 1 hour. Thin-layer chromatography indicated the disappearance of the starting material and the formation of new spots. Saturated ammonium chloride (5 mL) and water (20 mL) were added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 2 g of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-2,3,6-trifluorobenzonitrile.

[0201] 1 H NMR (400MHz, Chloroform-d) δ7.07 (dddd, J=8.8, 4.7, 2.1, 1.0Hz, 1H), 4.69 (q, J=1.1Hz, 2H), 0.81 (s, 9H), -0.00 (s, 6H).

[0202] Step D: To a solution of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-2,3,6-trifluorobenzonitrile (2 g, 6.64 mmol) in tetrahydrofuran (20 mL) was added sodium methoxide (286.85 mg, 5.31 mmol) at 0°C, followed by stirring at 0°C for 1 hour. Thin-layer chromatography showed the disappearance of the starting material and the formation of new spots. Dilute hydrochloric acid was added dropwise to the reaction solution at 0°C to adjust the pH to 6-7. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 0.8 g of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-3,6-difluoro-2-methoxybenzonitrile.

[0203] 1 H NMR (400MHz, Chloroform-d) δ6.96 (dd, J=8.9, 4.8Hz, 1H), 4.71 (t, J=1.2Hz, 2H), 4.07 (d, J=3.0Hz, 3H), 0.88 (s, 9H), 0.06 (s, 6H).

[0204] Step E: To a solution of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-3,6-difluoro-2-methoxybenzonitrile (300 mg, 0.96 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (502.00 mg, 1.92 mmol) and stirred at room temperature for 1 hour. Thin-layer chromatography showed the disappearance of the starting material and the formation of new spots. Add 20 mL of water to the reaction solution, then extract with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yield 0.3 g of 3,6-difluoro-4-(hydroxymethyl)-2-methoxybenzonitrile.

[0205] 1 H NMR (400MHz, Chloroform-d) δ7.02-6.95 (m, 1H), 4.75 (dd, J = 1.6, 0.8Hz, 2H), 4.09 (d, J = 3.1Hz, 3H).

[0206] Step F: To a solution of 3,6-difluoro-4-(hydroxymethyl)-2-methoxybenzonitrile (300 mg, 1.51 mmol) and 1-methanesulfonyl-1H-pyrazole (264.86 mg, 1.81 mmol) in acetonitrile (20 mL) was added cesium carbonate (590.39 mg, 1.81 mmol) and stirred at 70°C for 1 hour. Thin-layer chromatography showed the disappearance of the starting material and the formation of new spots. The reaction mixture was added with 20 mL of water, followed by extraction with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 0.28 g of 3,6-difluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile.

[0207] MS (ESI) M / Z: 250.1 [M+H] + .

[0208] Step G: To a solution of 3,6-difluoro-2-methoxy-4-[(1H-pyrazol-1-yl)methyl]benzonitrile (250 mg, 1.00 mmol) and N-hydroxyacetamide (225.21 mg, 3 mmol) in N,N-dimethylformamide (4 mL) and water (0.57 mL) was added potassium carbonate (691.05 mg, 5 mmol) and reacted at 60°C for 5 hours. The solvent was removed by concentration under reduced pressure, and 20 mL of water was added. The mixture was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to afford 0.2 g of 6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-amine.

[0209] MS (ESI) M / Z: 263.1 [M+H] + .

[0210] Intermediate INT-6: 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofurano[7,6-d]isoxazol-8-amine (see patent WO2023016484)

[0211] Reaction route:

[0212] Steps:

[0213] Step A: Under nitrogen, dissolve methyl 7-cyano-6-fluoro-2,3-dihydrobenzofuran-4-carboxylate (200 mg, 0.905 mmol) in methanol (2 mL). Add sodium borohydride (138 mg, 3.62 mmol) in an ice bath and heat to 50°C for 18 hours. Monitor the reaction by LCMS. After completion, quench with ice water and extract with 10 mL of ethyl acetate and 10 mL of water. Dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and analyze by column chromatography to yield 98 mg of the desired product, 6-fluoro-4-hydroxymethyl-2,3-dihydrobenzofuran-7-carbonitrile.

[0214] MS (ESI) M / Z: 194.2 [M+H] + .

[0215] Step B: Dissolve 6-fluoro-4-hydroxymethyl-2,3-dihydrobenzofuran-7-carbonitrile (95 mg, 0.492 mmol), 1-(methylsulfonyl)-1H-pyrazole (86 mg, 0.591 mmol), and cesium carbonate (240 mg, 0.738 mmol) in acetonitrile (1 mL) and react at 80°C for 2 hours. Monitor the reaction by LCMS. After the starting material is consumed, the reaction mixture is extracted with ethyl acetate (10 mL) and water (10 mL), and the organic phase is dried over anhydrous sodium sulfate. Column chromatography yields 88 mg of 4-((1H-pyrazol-1-yl)methyl)-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile.

[0216] MS (ESI) M / Z: 244.1 [M+H] + .

[0217] Step C: To a solution of 4-((1H-pyrazol-1-yl)methyl)-6-fluoro-2,3-dihydrobenzofuran-7-carbonitrile (88 mg, 0.362 mmol) in N,N-dimethylformamide (1 mL) were added acetohydroxamic acid (82 mg, 1.09 mmol) and potassium carbonate (250 mg, 1.81 mmol) and reacted at 60°C for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction solution was distilled under reduced pressure. The resulting residue was extracted with 10 mL of ethyl acetate and 10 mL of water, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and subjected to column chromatography to afford 44 mg of 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-amine.

[0218] MS (ESI) M / Z: 257.1 [M+H] + .

[0219] Intermediate INT-7: 6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-amine

[0220] Reaction route:

[0221] Steps:

[0222] Step A: To a solution of 2-bromo-6-fluoro-3-methoxybenzaldehyde (4 g, 17.17 mmol) in water (20 mL) was added sulfamic acid (3.40 g, 30.05 mmol) in an ice bath. The mixture was allowed to react at 50°C for 12 hours. After LCMS indicated complete consumption of the starting material, the reaction mixture was filtered and washed with water to yield 3.8 g of 2-bromo-6-fluoro-3-methoxybenzonitrile.

[0223] 1 H NMR(400MHz,DMSO-d6)δ7.64-7.48(m,2H),3.91(s,3H).

[0224] Step B: Dissolve 2-bromo-6-fluoro-3-methoxybenzonitrile (3.8 g, 16.59 mmol), methylboronic acid (3.13 g, 49.78 mmol), bis(diphenylphosphino)ferrocenepalladium dichloride (0.64 g, 0.87 mmol), and potassium carbonate (4.58 g, 33.2 mmol) in 1,4-dioxane (50 mL) and water (5 mL). Reflux at 110°C overnight. Monitor the reaction by thin-layer chromatography. After the starting material is consumed, extract the reaction solution with ethyl acetate (150 mL) and water (150 mL). The combined organic phases are washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to yield 2.47 g of 6-fluoro-3-methoxy-2-methylbenzonitrile.

[0225] 1 H NMR (400MHz, DMSO-d6) δ7.39-7.29(m,2H),3.84(s,3H),2.33(s,3H).

[0226] Step C: To a solution of 6-fluoro-3-methoxy-2-methylbenzonitrile (330 mg, 2.00 mmol) in dichloromethane (5 mL) was added N-bromosuccinimide (388.00 mg, 2.18 mmol) and allowed to react at room temperature. The reaction was monitored by thin-layer chromatography. After complete consumption of the product, the reaction solution was poured into ice water to quench the reaction. The mixture was extracted with ethyl acetate (10 mL) and water (10 mL). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography afforded 426 mg of 4-bromo-6-fluoro-3-methoxy-2-methylbenzonitrile.

[0227] 1 H NMR (400MHz, DMSO-d6) δ7.84 (d, J = 8.6Hz, 1H), 3.76 (s, 3H), 2.46 (s, 3H).

[0228] Step D: To a solution of 4-bromo-6-fluoro-3-methoxy-2-methylbenzonitrile (2.79 g, 11.48 mmol) in methanol (20 mL) was added tetrakistriphenylphosphine palladium (663 mg, 0.574 mmol) and triethylamine (2.3 g, 22.96 mmol) under a standard atmospheric pressure carbon monoxide atmosphere. The reaction was allowed to react at 65°C for 12 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction solution was extracted with ethyl acetate (60 mL) and water (60 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography using petroleum ether / ethyl acetate = 3:1 to afford 2.1 g of methyl 4-cyano-5-fluoro-2-methoxy-3-methylbenzoate.

[0229] 1 H NMR (400MHz, Chloroform-d) δ7.43 (d, J = 8.6Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 2.53 (s, 3H).

[0230] Step E: Dissolve methyl 4-cyano-5-fluoro-2-methoxy-3-methylbenzoate (600 mg, 2.69 mmol) in methanol (10 mL). Add sodium borohydride (407.05 mg, 10.76 mmol) under ice-cooling conditions. Heat the temperature to 50°C and react for 18 hours. Monitor the reaction by LCMS. After completion, quench the reaction with ice-cold water and extract with ethyl acetate (10 mL) and water (10 mL). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 420 mg of 6-fluoro-4-hydroxymethyl-3-methoxy-2-methylbenzonitrile.

[0231] MS (ESI) M / Z: 196.1 [M+H] + .

[0232] Step F: Dissolve 6-fluoro-4-hydroxymethyl-3-methoxy-2-methylbenzonitrile (420 mg, 2.15 mmol), 1-(methylsulfonyl)-1H-pyrazole (0.38 g, 2.58 mmol), and cesium carbonate (1050.77 mg, 3.22 mmol) in acetonitrile (10 mL) and react at 80°C for 2 hours. Monitor the reaction by LCMS. After the starting material is consumed, the reaction mixture is extracted with ethyl acetate (30 mL) and water (30 mL), and the organic phase is dried over anhydrous sodium sulfate. Column chromatography affords 570 mg of 4-((1H-pyrazol-1-yl)methyl)-6-fluoro-3-methoxy-2-methylbenzonitrile.

[0233] MS (ESI) M / Z: 246.1 [M+H] + .

[0234] Step G: To a solution of 4-((1H-pyrazol-1-yl)methyl)-6-fluoro-3-methoxy-2-methylbenzonitrile (570 mg, 2.32 mmol) in N,N-dimethylformamide (10 mL) were added acetohydroxamic acid (0.70 g, 9.28 mmol) and potassium carbonate (1.92 g, 13.92 mmol). The mixture was reacted at 60°C for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to yield 310 mg of 6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-amine.

[0235] MS (ESI) M / Z: 259.1 [M+H] + .

[0236] Intermediate INT-8: 6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-amine

[0237] Reaction route:

[0238] Steps:

[0239] Step A: Under nitrogen, dissolve methyl 7-cyano-6-fluoro-2,3-dihydrobenzofuran-4-carboxylate (418 mg, 2 mmol) in deuterated methanol (2 mL). Add sodium borodeuteride (336 mg, 8 mmol) in an ice bath and heat to 50°C for 18 hours. Monitor the reaction by LCMS. After completion, quench with deuterated water and extract with ethyl acetate (10 mL) and deuterated water (10 mL). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 390 mg of 2-fluoro-4-(hydroxymethyl-d2)-6-methoxybenzonitrile.

[0240] MS (ESI) M / Z: 184.1 [M+H] + .

[0241] Step B: To a solution of 2-fluoro-4-(hydroxymethyl-d2)-6-methoxybenzonitrile (390 mg, 2.12 mmol) in N,N-dimethylformamide (10 mL) was added acetohydroxamic acid (480 mg, 6.32 mmol) and potassium carbonate (1.47 g, 10.6 mmol). The mixture was reacted at 60°C for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction solution was distilled under reduced pressure. The resulting residue was extracted with ethyl acetate (10 mL) and water (10 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and subjected to column chromatography to yield 198 mg of (3-amino-4-methoxybenzo[d]isoxazol-6-yl)methane-d2-ol.

[0242] MS (ESI) M / Z: 197.1 [M+H] + .

[0243] Step C: Dissolve (3-amino-4-methoxybenzo[d]isoxazol-6-yl)methane-d2-ol (196 mg, 1 mmol), 1-(methylsulfonyl)-1H-pyrazole (175 mg, 1.2 mmol), and cesium carbonate (487 mg, 1.5 mmol) in acetonitrile (1 mL) and react at 80°C for 2 hours. Monitor the reaction by LCMS. After the starting material is consumed, the reaction mixture is extracted with ethyl acetate (10 mL) and water (10 mL), and the organic phase is dried over anhydrous sodium sulfate. Column chromatography affords 200 mg of 6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-amine.

[0244] MS (ESI) M / Z: 247.1 [M+H] + .

[0245] Intermediate INT-9: 6-(pyrazol-1-yl)methyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-amine

[0246] Reaction route:

[0247] Steps:

[0248] Step A: Dissolve 2,6-difluoro-4-formylbenzonitrile (5 g, 29.92 mmol) in ethanol (50 mL), cool to 0°C, and slowly add sodium borohydride (2.3 g, 60.79 mmol) in portions. Stir the mixture at 0°C for 2 hours. After LCMS monitoring indicates complete reaction of the starting material, the reaction solution is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield 5.01 g of 2,6-difluoro-4-(hydroxymethyl)benzonitrile.

[0249] MS (ESI) M / Z: 170.0 [M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d6) δppm 4.60 (d, J = 5.8Hz, 2H), 5.63-5.75 (m, 1H), 7.16-7.42 (m, 2H).

[0251] Step B: Dissolve 2,6-difluoro-4-(hydroxymethyl)benzonitrile (500 mg, 2.96 mmol) in deuterated methanol (2.5 mL), cool to 0°C, and add sodium hydride (177.36 mg, 4.43 mmol, 60 wt% purity) portionwise. The mixture is stirred at 20°C for 12 hours. After LCMS monitoring indicates complete reaction of the starting material, the reaction solution is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting mixture is purified by silica gel column chromatography to yield 303 mg of 2-fluoro-4-(hydroxymethyl)-6-(trideuteriomethoxy)benzonitrile.

[0252] MS (ESI) M / Z: 185.1 [M+H] + .

[0253] 1 H NMR (400MHz, DMSO-d6) δppm 4.51-4.60(m,2H),5.55-5.61(m,1H),6.94-7.01(m,1H),7.04(s,1H).

[0254] Step C: 2-Fluoro-4-(hydroxymethyl)-6-(trideuteriomethoxy)benzonitrile (300 mg, 1.60 mmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (676.11 mg, 2.08 mmol) and 1-methylsulfonylpyrazole (256.65 mg, 1.76 mmol) were added. The mixture was stirred at 70°C for 1 hour. After LCMS monitoring indicated complete reaction of the starting material, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 345 mg of 2-fluoro-4-(pyrazol-1-ylmethyl)-6-(trideuteriomethoxy)benzonitrile.

[0255] MS (ESI) M / Z: 235.1 [M+H] + .

[0256] 1H NMR (400MHz, DMSO-d6) δppm 5.36-5.49(m,2H),6.28-6.37(m,1H),6.62-6.75(m,1H),6.91-7.03(m,1H),7.48-7.56(m,1H),7.85-7.92(m,1H).

[0257] Step D: Dissolve 2-fluoro-4-(pyrazol-1-ylmethyl)-6-(trideuteriomethoxy)benzonitrile (340 mg, 1.45 mmol), potassium carbonate (1.20 g, 8.71 mmol), and acetohydroxamic acid (326.87 mg, 4.35 mmol) in N,N-dimethylformamide (6 mL) and water (0.9 mL) and stir at 60°C for 12 hours. After LCMS monitoring indicated complete reaction, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 256 mg of 6-(pyrazol-1-ylmethyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-amine.

[0258] MS (ESI) M / Z: 247.7 [M+H] + .

[0259] 1 H NMR(400MHz,DMSO-d6)δppm 5.35-5.45(m,2H),5.86-5.98(m,2H),6.30(t,J=1.9Hz,1H),6.59-6.65(m,1H),6.69(s,1H),7.43-7.52(m,1H),7.87(d,J=2.0Hz,1H).

[0260] Intermediate INT-10-P1: (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonyl chloride / (1aS,7bR)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonyl chloride

[0261] Reaction route:

[0262] Steps:

[0263] Step A: Dissolve 2-hydroxy-4-methoxybenzaldehyde (10.0 g, 66 mmol) and 3-bromo-1-propene (12.0 g, 99 mmol) in acetone (100 mL). Then add anhydrous potassium carbonate (18.2 g, 132 mmol). The reaction mixture is gradually heated to 70°C and reacted for 3 hours. After LCMS monitoring shows the disappearance of the starting material, the mixture is cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase is washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2-(allyloxy)-4-methoxybenzaldehyde (13 g).

[0264] MS (ESI) M / Z: 193.3 [M+H] + .

[0265] Step B: Under ice, sodium hydride (3.5 g, 88 mmol, 60 wt%) was added to a solution of bromo(methyl)triphenyl-15-phosphine (31 g, 88 mmol) in anhydrous N,N-dimethylformamide (100 mL). The mixture was stirred for half an hour. 2-(Allyloxy)-4-methoxybenzaldehyde (13 g, 67.7 mmol) dissolved in N,N-dimethylformamide (30 mL) was slowly added dropwise to the mixture. The reaction system was slowly warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to 0°C and quenched with water dropwise. The filtrate was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 2-(allyloxy)-4-methoxy-1-vinylbenzene (11 g).

[0266] MS (ESI) M / Z: 191.2 [M+H] + .

[0267] Step C: Dissolve 2-(allyloxy)-4-methoxy-1-vinylbenzene (11 g, 57.9 mmol) in dichloromethane (80 mL) and add (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium (1.8 g, 2.9 mmol). The reaction mixture is stirred at room temperature for 1 hour. After LCMS monitoring shows the disappearance of the starting material, the crude product is concentrated under reduced pressure and purified by flash silica gel chromatography to provide 7-methoxy-2H-chromene (8.2 g).

[0268] MS (ESI) M / Z: 163.3 [M+H] + .

[0269] 1H NMR (500MHz, CDCl3): δ6.87 (d, J=8.0Hz, 1H), 6.42 (dd, J=8.0, 2.4Hz, 1H), 6. 40-6.35(m,2H),5.65-5.60(m,1H),4.79(dd,J=3.6,2.0Hz,2H),3.77(s,3H).

[0270] Step D: Dissolve 7-methoxy-2H-chromene (8.2 g, 50.6 mmol) and benzyltriethylammonium chloride (1.2 g, 5.1 mmol) in chloroform (80 mL). Slowly add 33 wt% aqueous sodium hydroxide solution dropwise at room temperature. Stir the reaction mixture at room temperature for 2 hours. After LCMS monitoring shows the disappearance of the starting material, pour the reaction mixture into water (100 mL) and extract with dichloromethane (50 mL x 3). The organic phase is washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product is purified by flash silica gel chromatography to yield 1,1-dichloro-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]chromene (9.5 g).

[0271] MS (ESI) M / Z: 245.1 [M+H] + .

[0272] Step E: Dissolve sodium metal (7.1 g, 310 mmol) in anhydrous ether (70 mL) at room temperature. Dissolve 1,1-dichloro-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]chromene (9.5 g, 38.8 mmol) in a mixture of anhydrous ether (30 mL) and anhydrous methanol (15 mL). Slowly add the mixture dropwise to the reaction mixture, adding additional 5 mL of methanol every hour until the starting material disappears. After LCMS monitoring indicates the disappearance of the starting material, quench the reaction with anhydrous ethanol (20 mL), dilute with water (50 mL), and extract with ethyl acetate (50 mL x 3). The organic phase is washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography to afford 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]chromene (5.5 g).

[0273] MS (ESI) M / Z: 244.2 [M+H] + .

[0274] Step F: 5-Methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]chromene (30 g, 170.25 mmol, 1 eq) was separated and purified by SFC to yield 12.4 g of intermediate P1. (Retention time: 2.651 min, chromatographic conditions: Column: DAICEL CHIRALCELOJ (250 mm × 50 mm, 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₃·H₂O)]; B%: 20%, isocratic elution mode. [CO₂-EtOH (0.1% NH₃·H₂O)] means CO₂ as phase A and EtOH containing 0.1 vol% NH₃·H₂O as phase B; B%: 20% means A%:B% = 80%:20% (volume ratio).

[0275] Step G: Under nitrogen protection, the intermediate product (3g, 17.03mmol) isolated above and N,N,N',N'-tetramethylethane-1,2-diamine (197.85mg, 1.70mmol) were dissolved in tetrahydrofuran (45mL), cooled to 0°C, and n-butyllithium (2.5M, 10.22mL) was added dropwise. The mixture was stirred at this temperature for 1 hour. A solution of 1,2-dibenzyldisulfane (6.29g, 25.54mmol) in tetrahydrofuran (45mL) was added dropwise at 0°C, the mixture was warmed to room temperature, and stirred for 3 hours. After LCMS monitoring showed that the raw materials were completely reacted, the reaction solution was poured into a mixed solution of ethyl acetate and saturated ammonium chloride, extracted, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column to obtain 3.3g of the intermediate product.

[0276] MS (ESI) M / Z: 299.3 [M+H] + .

[0277] 1 H NMR(400MHz,CHLOROFORM-d)δ0.86-0.98(m,2H),1.63(br d,J=6.1Hz,1H),1.83-1.93(m,1H),3.54(d,J=10.5Hz,1H),3.80(s,3H),3.86-3.93(m,1 H),3.96-4.03(m,1H),4.32(d,J=10.5Hz,1H),6.46(d,J=8.3Hz,1H),7.06-7.24(m,6H).

[0278] Step H: The intermediate product obtained in step G (3.3 g, 11.06 mmol) was dissolved in acetic acid (50 mL) and water (5 mL), cooled to 0°C, and N-chlorosuccinimide (4.43 g, 33.18 mmol) was added. The system was stirred at 0°C for 0.5 hours.

[0279] After thin-layer chromatography monitoring indicated complete reaction of the starting material, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 × 2 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 10 / 1) to yield 2.44 g of INT-10-P1.

[0280] 1 H NMR(400MHz,CHLOROFORM-d)δ1.04-1.13(m,2H),1.75-1.84(m,1H),1.94-2.03(m,1H),3.94(s,3H) ,4.00(dd,J=10.7,1.9Hz,1H),4.56(d,J=10.5Hz,1H),6.60(d,J=8.6Hz,1H),7.45(d,J=8.6Hz,1H).

[0281] Example 1:

[0282] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonamide

[0283] Reaction route:

[0284] Steps:

[0285] Step A: Under nitrogen protection, 3-bromobenzene-1,2-diol (1 g, 5.3 mmol), 1,3-dibromopropane (1.6 g, 8.0 mmol), potassium carbonate (1.46 g, 10.6 mmol) and potassium fluoride (153 mg, 2.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the system was stirred at 135 ° C for 2 hours.

[0286] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to saturated ammonium chloride solution (100 mL), diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 750 mg of 6-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxirane.

[0287] MS (ESI) M / Z: 229.1, 231.0 [M+H] + .

[0288] 1 H NMR (400MHz, DMSO-d6) δ7.26(dd,J=7.8,1.6Hz,1H),6.99(dd,J=8.2,1.6Hz,1H),6.88(t,J=8.0Hz,1H),4.23-4.10(m,4H),2.19-2.06(m,2H).

[0289] Step B: Under nitrogen protection, 6-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxirane (640 mg, 2.8 mmol) was dissolved in tetrahydrofuran (8 mL), cooled to -78 ° C, tert-butyl lithium (1.93 mL) was added dropwise, and stirred at this temperature for 30 minutes. A solution of 1,2-dibenzyldisulfane (825 mg, 3.4 mmol) in tetrahydrofuran (2 mL) was added dropwise at -78 ° C, stirred at the same temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0290] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate and saturated ammonium chloride, extracted, washed with saturated brine (100 mL x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 320 mg of 6-(benzylthio)-3,4-dihydro-2H-benzo[b][1,4]dioxythiophene.

[0291] MS (ESI) M / Z: 273.1 [M+H] + .

[0292] 1 H NMR (400MHz, DMSO-d6) δ7.42-7.16(m,5H),6.99-6.82(m,2H),6.78(dd,J=7.8,1.6Hz,1H),4.14(s,2H),4.08(t,J=5.2Hz,4H),2.16-1.98(m,2H).

[0293] Step C: Under nitrogen protection, 6-(benzylthio)-3,4-dihydro-2H-benzo[b][1,4]dioxythiophene (320 mg, 1.2 mmol) and N-chlorosuccinimide (802.6 mg, 6.0 mmol) were dissolved in acetic acid (1.2 mL), water (1.2 mL) and acetonitrile (9 mL), and the system was stirred at room temperature for 16 hours.

[0294] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 200 mg of 3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride.

[0295] 1 H NMR (400MHz, DMSO-d6) δ7.36(dd,J=7.6,1.8Hz,1H),6.96(dd,J=7.8,1.8Hz,1H),6.86(t,J=7.8Hz,1H),4.10-3.94(m,4H),2.11-2.01(m,2H).

[0296] Step D: Under nitrogen protection, 3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (200 mg, 0.81 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (131 mg, 0.54 mmol) were dissolved in pyridine (5 mL), and the system was stirred at 120 ° C for 2 hours.

[0297] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to water (20 mL), diluted with ethyl acetate (20 mL), washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column and plated to yield 5.5 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonamide.

[0298] MS (ESI) M / Z: 457.1 [M+H] + .

[0299] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.87(d,J=2.2Hz,1H),7.48(dd,J=7.8,1.6Hz,2H),7.27(s,1H),7.09(s,1H) ,6.82(s,1H),6.72(s,1H),6.30(t,J=2.0Hz,1H),5.43(s,2H),4.21-4.05(m,4H),3.80(s,3H),2.15-2.02(m,2H).

[0300] Example 2:

[0301] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0302] Reaction route:

[0303] Steps:

[0304] Step A: Under nitrogen protection, 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (1.0 g, 3.60 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (439 mg, 1.80 mmol) were dissolved in pyridine (8 mL), and the system was stirred at 130 ° C under microwave conditions for 12 hours.

[0305] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to water (50 mL), diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was separated by silica gel column chromatography and reverse phase preparative separation to afford 90 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0306] MS (ESI) M / Z: 487.2 [M+H] + .

[0307] 1H NMR (400MHz, DMSO-d6): δ9.95(s,1H),7.88(d,J=2.0Hz,1H),7.50(d,J=1.4Hz,1H),7.23(d,J=9.2Hz,1H),6.79(dd,J= 21.6, 12.6Hz, 3H), 6.30 (t, J = 2.0Hz, 1H), 5.45 (s, 2H), 4.10-3.97 (m, 4H), 3.83 (s, 3H), 3.69 (s, 3H), 2.07-2.01 (m, 2H).

[0308] Examples 3 and 4:

[0309] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide

[0310] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-5-sulfonamide

[0311] Reaction route:

[0312] Steps:

[0313] Step A: Under nitrogen, suspend aluminum trichloride (11.82 g, 88.61 mmol) in dichloromethane (100 mL) and slowly add methyl oxalyl chloride (10.85 g, 88.61 mmol) in an ice bath. Stir in an ice bath until the reaction solution becomes clear. Then, slowly add 3-methoxyphenol (5.0 g, 40.28 mmol) dropwise to the reaction solution. Slowly warm the system to 25°C and stir for 2 hours.

[0314] After the reaction was completed, LCMS monitoring was performed. Ice was slowly added to the reaction solution under an ice bath, followed by 2M hydrochloric acid (50 mL). The mixture was extracted with dichloromethane solution (100 mL × 3). The organic phases were collected and combined, washed with 2M sodium hydroxide solution (100 mL × 2) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 9.0 g of methyl 2-(2-hydroxy-4-methoxyphenyl)-2-oxoacetate.

[0315] MS (ESI) M / Z: 211.1 [M+H] + .

[0316] 1H NMR (500MHz, CDCl3): δ11.74(s,1H),7.67(d,J=9.0Hz,1H),6.51-6.45(m,2H),4.12(d,J=7.2Hz,1H),3.98(s,3H),3.88(s,3H).

[0317] Step B: Under nitrogen protection, methyl 2-(2-hydroxy-4-methoxyphenyl)-2-oxoacetate (10.0 g, 47.58 mmol) and potassium carbonate (13.13 g, 95.15 mmol) were dissolved in N,N-dimethylformamide (80 mL). Bromomethyl methyl ether (5.02 mL, 61.85 mmol) was slowly added dropwise at 0°C. The reaction solution was slowly heated to 25°C and stirred for 1 hour.

[0318] After the reaction was completed, as monitored by LCMS, saturated aqueous sodium bicarbonate solution (100 mL) was slowly added dropwise to the reaction solution at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (120 mL×3), washed with saturated aqueous sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 6.95 g of methyl 2-(4-methoxy-2-(methoxymethoxy)phenyl)-2-oxoacetate.

[0319] MS (ESI) M / Z: 255.1 [M+H] + .

[0320] Step C: To a solution of methyltriphenylphosphonium bromide (8431.82 mg, 23.60 mmol) in tetrahydrofuran (100 mL) at 0°C was added n-butyllithium (9.05 mL, 22.62 mmol, 2.5 M), the mixture was warmed to room temperature and stirred for 1 hour, then cooled to -78°C, a solution of methyl 2-(4-methoxy-2-(methoxymethoxy)phenyl)-2-oxoacetate (5000 mg, 19.67 mmol) in tetrahydrofuran (20 mL) was added to the reaction solution, the mixture was warmed to room temperature and stirred for 12 hours.

[0321] After the reaction was completed, LCMS monitored the reaction solution. 5 mL of saturated ammonium chloride and 100 mL of water were added to the reaction solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 4.3 g of methyl 2-(4-methoxy-2-(methoxymethoxy)phenyl)acrylate.

[0322] MS (ESI) M / Z: 253.1 [M+H] + .

[0323] Step D: To a solution of trimethylsulfoxide iodide (7504.39 mg, 34.1 mmol) in N,N-dimethylformamide (70 mL) was added potassium tert-butoxide (3826.36 mg, 34.1 mmol), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 20°C for 45 minutes. To the reaction solution was added methyl 2-(4-methoxy-2-(methoxymethoxy)phenyl)acrylate (4300 mg, 17.05 mmol) in N,N-dimethylformamide (30 mL), the temperature was raised to 45°C, and the reaction was carried out for 1 hour.

[0324] After the reaction was completed, the reaction solution was cooled to 0°C, and then dilute hydrochloric acid was added dropwise to adjust the pH to 6-7. Then, 200 mL of water was added to the reaction solution, and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 3.1 g of methyl 1-(4-methoxy-2-(methoxymethoxy)phenyl)cyclopropane-1-carboxylate.

[0325] MS (ESI) M / Z: 267.2 [M+H] + .

[0326] Step E: To a solution of methyl 1-(4-methoxy-2-(methoxymethoxy)phenyl)cyclopropane-1-carboxylate (3.1 g, 11.64 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum tetrahydride (12.8 mL, 12.80 mmol, 1 M) at 0°C, followed by reaction at 0°C for 1 hour.

[0327] After the reaction was completed, monitored by LCMS, 500 mL of water, 500 mL of a 15 wt% aqueous sodium hydroxide solution, and 1500 mL of water were added to the reaction solution at 0°C, followed by filtration. The filtrate was concentrated to obtain 2.7 g of (1-(4-methoxy-2-(methoxymethoxy)phenyl)cyclopropyl)methanol.

[0328] MS (ESI) M / Z: 251.2 [M+Na] +

[0329] Step F: To a solution of (1-(4-methoxy-2-(methoxymethoxy)phenyl)cyclopropyl)methanol (2.7 g, 11.33 mmol) in methanol (30 mL) was added a solution of hydrochloric acid (1652.37 mg, 45.32 mmol) in dioxane at 0°C, and the mixture was heated to 20°C for 1 hour.

[0330] After the reaction was completed, the solvent was removed by LCMS monitoring, and 20 mL of water was added. The mixture was then extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.9 g of 2-(1-(hydroxymethyl)cyclopropyl)-5-methoxyphenol.

[0331] MS (ESI) M / Z: 195.2 [M+H] + .

[0332] Step G: To a solution of 2-(1-(hydroxymethyl)cyclopropyl)-5-methoxyphenol (1600 mg, 8.24 mmol) in tetrahydrofuran (30 mL) was added triphenylphosphine (3241.90 mg, 12.36 mmol), stirred for 10 minutes, then added diisopropyl azodicarboxylate (2499.32 mg, 12.36 mmol), and continued stirring for 1 hour.

[0333] After the reaction was completed as monitored by LCMS, 90 mL of petroleum ether was added to the reaction solution, which was then filtered through 50 g of silica gel. The filtrate was concentrated and purified by column chromatography to obtain 960 mg of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane].

[0334] MS (ESI) M / Z: 177.1 [M+H] + .

[0335] Step H: To a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (300 mg, 1.70 mmol) and N,N,N',N'-tetramethylethylenediamine (0.22 g, 1.87 mmol) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium (0.75 mL, 1.87 mmol, 2.5 M) at 0°C. The mixture was kept warm for 0.5 h, cooled to -70°C, and then a solution of dibenzyl disulfide (460.75 mg, 1.87 mmol) in tetrahydrofuran (3 mL) was added dropwise. The mixture was reacted at -70°C for 0.5 h, and then heated to room temperature for 1 h.

[0336] After the reaction was completed, LCMS monitoring was performed. To the reaction solution were added 5 mL of saturated ammonium chloride and 10 mL of water, followed by extraction with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 380 mg of 7-(benzylthio)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane].

[0337] MS (ESI) M / Z: 299.2 [M+H] + .

[0338] Step I: To a solution of 7-(benzylthio)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (100 mg, 0.34 mmol) in acetic acid (3 mL) and water (0.3 mL) was added N-chlorosuccinimide (136.20 mg, 1.02 mmol) at 0°C, followed by reaction at 10°C for 1 hour.

[0339] Thin layer chromatography showed that the starting material disappeared. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL×2), washed with saturated aqueous sodium carbonate solution (10 mL×2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 60 mg of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride.

[0340] 1 H NMR (400MHz, Chloroform-d): δ6.74 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 4.65 (s, 2H), 3.90 (s, 3H), 1.00 (dt, J = 5.7, 2.1 Hz, 4H).

[0341] Step J: To a solution of 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (20 mg, 0.082 mmol) in pyridine (1 mL) was added 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (33.79 mg, 0.12 mmol) and the mixture was microwaved at 100°C for 3 h.

[0342] LCMS showed the formation of the target peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative separation to give 13 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0343] MS (ESI) M / Z: 483.1 [M+H] + .

[0344] 1H NMR (400MHz, DMSO-d6): δ7.86(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),6.84(s,1H),6.76(s,1H),6.68(s,1H),6.4 5(d,J=8.2Hz,1H),6.29(t,J=2.1Hz,1H),5.42(s,2H),4.47(s,2H),3.84(s,3H),3.65(s,3H),1.08-0.91(m,4H).

[0345] Step K: To a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (300 mg, 1.70 mmol) in acetonitrile (3 mL) was added N-bromosuccinimide (332.82 mg, 1.87 mmol) and reacted at room temperature for 3 hours.

[0346] Thin layer chromatography showed that the starting material was consumed. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 360 ​​mg of 5-bromo-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane].

[0347] 1 H NMR (400MHz, Chloroform-d): δ6.71 (s, 1H), 6.38 (s, 1H), 4.43 (s, 2H), 3.78 (s, 3H), 0.96-0.93 (m, 2H), 0.91 (dd, J = 3.9, 1.4Hz, 2H).

[0348] Step L: To a solution of 5-bromo-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (360 mg, 1.41 mmol) and N,N,N',N'-tetramethylethylenediamine (0.18 g, 1.55 mmol) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium (0.62 mL, 1.55 mmol, 2.5 M) at 0°C. The mixture was kept at this temperature for 0.5 h, then cooled to -70°C. A solution of dibenzyl disulfide (382.15 mg, 1.55 mmol) in tetrahydrofuran (3 mL) was then added dropwise. The mixture was reacted at -70°C for 0.5 h, and then heated to room temperature for 1 h.

[0349] After the reaction was completed, LCMS monitoring was performed. To the reaction solution were added 5 mL of saturated ammonium chloride and 10 mL of water, followed by extraction with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 200 mg of 5-(benzylthio)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane].

[0350] MS (ESI) M / Z: 299.2 [M+H] + .

[0351] Step M: To a solution of 5-(benzylthio)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (170 mg, 0.57 mmol) in acetic acid (5 mL) and water (0.5 mL) at 0°C was added N-chlorosuccinimide (228.34 mg, 1.71 mmol).

[0352] Thin layer chromatography showed that the starting material disappeared. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL×2), washed with saturated aqueous sodium carbonate solution (10 mL×2), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 60 mg of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-5-sulfonyl chloride.

[0353] 1 H NMR(400MHz,Chloroform-d)δ7.14(s,1H),6.44(s,1H),4.56(s,2H),3.94(s,3H),1.09-0.96(m,4H).

[0354] Step N: To a solution of 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (20 mg, 0.082 mmol) in pyridine (1 mL) was added 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-5-sulfonyl chloride (33.79 mg, 0.12 mmol) and the mixture was microwaved at 100°C for 3 h.

[0355] LCMS showed the formation of the target peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative separation to give 18 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-5-sulfonamide.

[0356] MS (ESI) M / Z: 483.1 [M+H] + .

[0357] 1 H NMR(400MHz, DMSO-d6)δ9.65(s,1H),7.86(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.18(s,1H),6.80(s,1H),6.71(s, 1H), 6.64 (s, 1H), 6.30 (t, J = 2.1Hz, 1H), 5.43 (s, 2H), 4.56 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 1.03 (d, J = 11.2Hz, 4H).

[0358] Example 5:

[0359] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocycloprop[c]benzopyran-4-sulfonamide

[0360] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-6-sulfonamide

[0361] Reaction route:

[0362] Steps:

[0363] Step A: Dissolve 2-hydroxy-4-methoxybenzaldehyde (10.0 g, 66 mmol) and 3-bromo-1-propene (12.0 g, 99 mmol) in acetone (100 mL), then add anhydrous potassium carbonate (18.2 g, 132 mmol), and gradually raise the reaction temperature to 70°C for 3 hours.

[0364] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 13 g of crude 2-(allyloxy)-4-methoxybenzaldehyde.

[0365] MS (ESI) M / Z: 193.3 [M+H] + .

[0366] Step B: Under ice bath, sodium hydride (3.5 g, 88 mmol, 60 wt%) was added to a solution of (bromomethyl)triphenylphosphonium bromide (31 g, 71 mmol) dissolved in anhydrous N,N-dimethylformamide (100 mL) and stirred for half an hour. 2-(Allyloxy)-4-methoxybenzaldehyde (13 g, 67.7 mmol) was dissolved in N,N-dimethylformamide (30 mL) and slowly added dropwise to the mixture. The reaction system was slowly warmed to room temperature and stirred for 2 hours.

[0367] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to 0°C and quenched with water dropwise. The filtrate was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 11 g of 2-(allyloxy)-4-methoxy-1-vinylbenzene.

[0368] MS (ESI) M / Z: 191.2 [M+H] + .

[0369] Step C: Dissolve 2-(allyloxy)-4-methoxy-1-vinylbenzene (11 g, 57.9 mmol) in dichloromethane (80 mL) and add (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium (1.8 g, 2.9 mmol). Stir the reaction at room temperature for 1 hour.

[0370] After LCMS monitoring showed the disappearance of the starting material, the crude product was concentrated under reduced pressure and purified by flash silica gel chromatography to obtain 8.2 g of 7-methoxy-2H-benzopyran.

[0371] MS (ESI) M / Z: 163.3 [M+H] + .

[0372] 1 H NMR (500MHz, CDCl3): δ6.87 (d, J=8.0Hz, 1H), 6.42 (dd, J=8.0, 2.4Hz, 1H), 6. 40-6.35(m,2H),5.65-5.60(m,1H),4.79(dd,J=3.6,2.0Hz,2H),3.77(s,3H).

[0373] Step D: Dissolve 7-methoxy-2H-benzopyran (8.2 g, 50.6 mmol) and benzyltriethylammonium chloride (1.2 g, 5.1 mmol) in chloroform (80 mL). Slowly add 33 wt% sodium hydroxide aqueous solution dropwise at room temperature. Stir the reaction mixture at room temperature for 2 hours.

[0374] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 9.5 g of 1,1-dichloro-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran.

[0375] MS (ESI) M / Z: 245.1 [M+H] + .

[0376] Step E: Sodium metal (7.1 g, 310 mmol) was dissolved in anhydrous ether (70 mL) at room temperature. 1,1-Dichloro-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (9.5 g, 38.8 mmol) was dissolved in a mixture of anhydrous ether (30 mL) and anhydrous methanol (15 mL). The mixture was slowly added dropwise to the reaction solution. Methanol was added every hour (5 mL) until the starting material disappeared.

[0377] After LCMS monitoring showed the disappearance of the starting material, the reaction was quenched with anhydrous ethanol (20 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 5.5 g of 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran.

[0378] MS (ESI) M / Z: 244.2 [M+H] + .

[0379] Step F: Dissolve the raw material 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (600 mg, 3.4 mmol) in anhydrous tetrahydrofuran (10 mL), replace nitrogen three times, add n-butyl lithium (1.6 mL, 4.1 mmol) dropwise under ice bath, stir for 1 hour, then dissolve 1,2-dibenzyl disulfide (1.0 g, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL) and add dropwise to the reaction solution, gradually warm to room temperature and react for 2 hours.

[0380] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system for dilution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL x 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 250 mg of 4-(benzylthio)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran.

[0381] MS (ESI) M / Z: 299.1 [M+H] + .

[0382] 1 H NMR (500MHz, DMSO-d6): δ7.24-7.10(m,6H),6.54(d,J=8.0Hz,1H),4.29(d,J=10.2Hz,1H),3.96(d,J=12.4Hz,1H),3.88(d,J=12 .4Hz,1H),3.72(s,3H),3.51(d,J=10.0Hz,1H),1.96-1.91(m,1H),1.72(d,J=8.0Hz,1H),0.97-0.91(m,1H),0.72-0.69(m,1H).

[0383] Step G: Dissolve 4-(benzylthio)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (250 mg, 0.84 mmol) in acetonitrile (5 mL) and water (0.5 mL), add acetic acid (403 mg, 6.7 mmol), cool in an ice bath, and then add dichlorohydantoin (331 mg, 1.7 mmol) to the reaction solution, and react in an ice bath for half an hour.

[0384] After thin-layer chromatography monitoring indicated the disappearance of the starting material, water (30 mL) was added to the reaction system for dilution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 100 mg of 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonyl chloride.

[0385] MS (ESI) M / Z: 275.1 [M+H] + .

[0386] Step H: Dissolve 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonyl chloride (100 mg, 0.36 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (57 mg, 0.24 mmol) in anhydrous pyridine (1.0 mL) and react at 100°C under microwave conditions for 3 hours.

[0387] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system to dilute it. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by liquid phase preparative purification to obtain 12.3 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide.

[0388] MS (ESI) M / Z: 483.1 [M+H] + .

[0389] 1 H NMR (400MHz, DMSO-d6): δ9.69(s,1H),7.88(d,J=2.0Hz,1H),7.50(d,J=1.6Hz,1H),7. 44(d,J=8.4Hz,1H),6.83(s,1H),6.76(s,1H),6.71(d,J=8.4Hz,1H),6.31(t,J=2.0Hz ,1H),5.45(s,2H),4.27(d,J=10.8Hz,1H),3.87(s,3H),3.72(s,3H),3.59(d,J=10.4H z,1H),2.04-1.98(m,1H),1.75(d,J=5.6Hz,1H),0.98-0.91(m,1H),0.67-0.65(m,1H).

[0390] Step I: Dissolve 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (600 mg, 3.4 mmol) in anhydrous acetonitrile (10 mL), add N-bromosuccinimide (666 mg, 3.7 mmol), and react at room temperature for 3 hours.

[0391] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system for dilution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL x 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to obtain 700 mg of 6-bromo-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran.

[0392] MS (ESI) M / Z: 255.1 [M+H] + .

[0393] Step J: Dissolve 6-bromo-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (700 mg, 2.8 mmol) in anhydrous tetrahydrofuran (20 mL), replace nitrogen three times, add n-butyllithium (1.2 mL, 3.0 mmol) dropwise in a dry ice acetone bath, stir for 1 hour, then dissolve 1,2-dibenzyl disulfide (738 mg, 3.0 mmol) in anhydrous tetrahydrofuran (10 mL) and add dropwise to the reaction solution, gradually warm to room temperature and react for 2 hours.

[0394] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system for dilution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL x 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 350 mg of 6-(benzylthio)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran.

[0395] MS (ESI) M / Z: 299.1 [M+H] + .

[0396] 1 H NMR (400MHz, DMSO-d6): δ7.28(d,J=4.4Hz,4H),7.25-7.19(m,1H),7.15(s,1H),6.44(s,1H),4.25(d,J=10.4Hz,1H),4.04(s,2 H),3.77(d,J=10.8Hz,1H),3.73(s,3H),1.94-1.87(m,1H),1.74(dd,J=13.6,8.4Hz,1H),1.00-0.93(m,1H),0.71-0.68(m,1H).

[0397] Step K: Dissolve 6-(benzylthio)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran (350 mg, 1.2 mmol) in acetonitrile (5 mL) and water (0.5 mL), add acetic acid (564 mg, 9.4 mmol), cool in an ice bath, then add dichlorohydantoin (427 mg, 2.4 mmol) to the reaction solution, and react in an ice bath for half an hour.

[0398] After thin-layer chromatography monitoring indicated the disappearance of the starting material, water (30 mL) was added to the reaction system for dilution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 200 mg of 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-6-sulfonyl chloride.

[0399] MS (ESI) M / Z: 297.1 [M+Na] + .

[0400] Step L: Dissolve 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-6-sulfonyl chloride (200 mg, 0.73 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (119 mg, 0.49 mmol) in anhydrous pyridine (1.0 mL) and react at 100°C under microwave conditions for 3 hours.

[0401] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system to dilute it. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (10 mL × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by liquid phase preparative purification to obtain 14.8 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-6-sulfonamide.

[0402] MS (ESI) M / Z: 483.1 [M+H] + .

[0403] 1H NMR (500MHz, DMSO-d6): δ9.77(s,1H),7.87(s,1H),7.72(s,1H),7.49(s,1 H),6.82(s,1H),6.73(s,1H),6.56(s,1H),6.30(t,J=2.0Hz,1H),5.43(s, 2H),4.33(d,J=11.0Hz,1H),3.89(d,J=11.0Hz,1H),3.86(s,3H),3.69(s, 3H),2.10(s,1H),1.85-1.76(m,1H),1.08-0.99(m,1H),0.73-0.71(m,1H).

[0404] Example 6:

[0405] (1aS,7bR)-N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide (Compound 5-P1 or Compound 5-P2)

[0406] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide (Compound 5-P2 or Compound 5-P1)

[0407] Reaction route:

[0408] Steps:

[0409] Step A: 498 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide was purified and separated by supercritical fluid chromatography (chromatographic column: REGIS(S,S)WHELK-O1 (250 mm×25 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH 3· H2O)]; B%: 50%, isocratic elution mode) to give 124.45 mg of 5-P1 (retention time: 2.650 minutes) and 90.10 mg of 5-P2 (retention time: 2.912 minutes).

[0410] Compound 5-P1:

[0411] MS (ESI) M / Z: 483.1 [M+H] + .

[0412] 1 H NMR(400MHz,METHANOL-d4)δppm 7.77(d,J=2.3Hz,1H),7.56(d,J=1.6Hz,1H),7.36(d,J=8.6Hz,1H),6.76(s,1H),6.62-6.70(m,2H),6.37(t,J=2.1Hz,1H), 5.46(s,2H),4.32(d,J=10.8Hz,1H),3.99(s,3H),3.79(s,3H),3.72(d,J=10.5Hz,1H),1.96(td,J=8.5,4.4Hz,1H),1.72(br d, J=5.5Hz, 1H), 0.95 (td, J=8.2, 4.7Hz, 1H), 0.73 (q, J=4.8Hz, 1H).

[0413] Compound 5-P2:

[0414] MS (ESI) M / Z: 483.1 [M+H] + .

[0415] 1 H NMR(400MHz,METHANOL-d4)δppm 7.77(d,J=2.3Hz,1H),7.56(d,J=1.6Hz,1H),7.37(d,J=8.6Hz,1H),6.77(s,1H),6.63-6.70(m,2H),6.37(t,J=2.1Hz,1H), 5.47(s,2H),4.33(d,J=10.4Hz,1H),3.99(s,3H),3.79(s,3H),3.73(d,J=10.1Hz,1H),1.96(td,J=8.5,4.3Hz,1H),1.73(br d, J=5.4Hz, 1H), 0.95 (td, J=8.2, 4.7Hz, 1H), 0.73 (q, J=4.8Hz, 1H).

[0416] Example 7:

[0417] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-sulfonamide

[0418] Reaction route:

[0419] Steps:

[0420] Step A: Under nitrogen protection, 2-hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol) was dissolved in dichloromethane (50 mL), cooled to 0°C, and bromine (5.26 g, 32.9 mmol) was added dropwise. The system was stirred at room temperature for 16 hours.

[0421] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with 1M hydrochloric acid (100 mL), extracted with dichloromethane (100 mL), and washed with saturated sodium sulfite (100 mL), water (100 mL), and saturated brine (100 mL x 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 3.0 g of 5-bromo-2-hydroxy-4-methoxybenzaldehyde.

[0422] MS (ESI) M / Z: 231.1 [M+H] + .

[0423] Step B: Under nitrogen protection, 5-bromo-2-hydroxy-4-methoxybenzaldehyde (5.4 g, 23.5 mmol) was dissolved in tetrahydrofuran (50 mL). Sodium hydroxide solution (18.8 mL) and hydrogen peroxide (3.2 g, 28.2 mmol) were added to the reaction solution at 0°C, and the system was stirred at 0°C for 40 minutes.

[0424] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with saturated sodium sulfite solution (100 mL), diluted with dichloromethane (100 mL), and washed with 1M aqueous hydrochloric acid (100 mL), water (100 mL × 3), and saturated brine (100 mL × 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 5 g of 4-bromo-5-methoxybenzene-1,2-diol.

[0425] MS (ESI) M / Z: 219.0 [M+H] + .

[0426] Step C: Under nitrogen protection, 4-bromo-5-methoxybenzene-1,2-diol (5 g, 22.9 mmol), 1,3-dibromopropane (6.9 g, 34.4 mmol), potassium carbonate (6.3 g, 45.9 mmol) and potassium fluoride (664.1 mg, 11.5 mmol) were dissolved in N,N-dimethylformamide (50 mL), and the system was stirred at 135 ° C for 2 hours.

[0427] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to a saturated ammonium chloride solution (100 mL), diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 380 mg of 7-bromo-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0428] MS (ESI) M / Z: 259.0 [M+H] + .

[0429] Step D: Under nitrogen protection, 7-bromo-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (380 mg, 2.1 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to -78°C, tert-butyl lithium (1.4 mL, 2.3 mmol) was added dropwise, and stirred at this temperature for 30 minutes. A mixed solution of 1,2-dibenzyldisulfane (618 mg, 2.5 mmol) and tetrahydrofuran (2 mL) was added dropwise at -78°C, stirred at the same temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0430] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate and saturated ammonium chloride, extracted, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 220 mg of 7-(benzylthio)-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0431] MS (ESI) M / Z: 303.2 [M+H] + .

[0432] Step E: Under nitrogen protection, 7-(benzylthio)-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (220 mg, 0.73 mmol) and acetic acid (350 mg, 5.8 mmol) were dissolved in water (0.7 mL) and acetonitrile (8 mL), cooled to 0°C, and dichlorohydantoin (287 mg, 1.46 mmol) was added. The system was stirred at 0°C for 1 hour.

[0433] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 170 mg of 8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-sulfonyl chloride.

[0434] 1 H NMR (500MHz, DMSO-d6): δ7.26(s,1H),6.55(s,1H),4.12-4.08(m,2H),4.04-4.00(m,2H),3.67(s,3H),2.10 -2.03(m,2H).

[0435] Step F: Under nitrogen protection, 8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-sulfonyl chloride (170 mg, 0.61 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (74.6 mg, 0.31 mmol) were dissolved in pyridine (2 mL) and the system was stirred at 100 °C under microwave conditions for 3 hours.

[0436] After LCMS monitoring showed that the starting material was completely reacted, the reaction solution was added to water (50 mL), diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to the reverse reaction to obtain 47 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-sulfonamide.

[0437] MS (ESI) M / Z: 487.2 [M+H] + .

[0438] 1 H NMR (400MHz, DMSO-d6): δ10.10(s,1H),7.88(d,J=2.2Hz,1H),7.50(d,J=1.6Hz,1H),7.34(s,1H),6.84(s,1H),6.75(d,J=4.0Hz,2 H),6.30(t,J=2.0Hz,1H),5.44(s,2H),4.23(t,J=5.2Hz,2H),4.10(t,J=5.4Hz,2H),3.84(s,3H),3.69(s,3H),2.16-2.07(m,2H).

[0439] Example 8:

[0440] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-8-sulfonamide

[0441] Reaction route:

[0442] Steps:

[0443] Step A: Under nitrogen protection, 4-bromo-2,5-dimethoxybenzaldehyde (10.0 g, 40.80 mmol) and anhydrous zinc chloride (33.36 g, 244.83 mmol) were dissolved in nitromethane (100 mL). Boron trichloride (244.83 mL, 244.83 mmol) was slowly added dropwise at 0°C. The reaction solution was slowly heated to 25°C and stirred for 8 hours.

[0444] After LCMS showed the reaction was complete, methanol (200 mL) and water (150 mL) were slowly added dropwise at 0°C. The mixture was vortexed to remove most of the solvent, and the residue was extracted with dichloromethane (100 mL x 3). The organic phase was collected, washed with saturated sodium bicarbonate aqueous solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, and the resulting residue was purified by column chromatography to obtain 3.1 g of the desired product, 4-bromo-2-hydroxy-5-methoxybenzaldehyde.

[0445] MS (ESI) M / Z: 231.0, 233.0 [M+H] + .

[0446] 1 H NMR (500MHz, CDCl3): δ10.73(s,1H),9.85(s,1H),7.28(s,1H),6.99(s,1H),3.91(s,3H).

[0447] Step B: Under nitrogen, potassium carbonate (3.70 g, 26.84 mmol) was added to a solution of 4-bromo-2-hydroxy-5-methoxybenzaldehyde (3.1 g, 13.42 mmol) and 2-bromoethane-1-ol (2.01 g, 16.10 mmol) in acetonitrile (25 mL). The reaction system was stirred at 80°C for 16 hours.

[0448] After LCMS monitoring showed that most of the starting material had disappeared, the reaction solution was added to ethyl acetate (30 mL) and filtered. The filter cake was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.09 g of the desired product, 4-bromo-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde.

[0449] MS (ESI) M / Z: 275.0, 277.0 [M+H] + .

[0450] Step C: Under nitrogen, triethylamine (3.2 mL, 22.79 mmol) was slowly added dropwise to a solution of 4-bromo-2-(2-hydroxyethoxy)-5-methoxybenzaldehyde (2.09 g, 7.60 mmol) in dichloromethane (20 mL) at 0°C. After stirring at 0°C for 15 minutes, p-toluenesulfonyl chloride (2.17 g, 11.40 mmol) was added. The reaction system was slowly warmed to 25°C and stirred for 16 hours.

[0451] After LCMS showed completion of the reaction, saturated aqueous sodium bicarbonate was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, and the resulting residue was purified by column chromatography to yield 2.2 g of the desired product, 2-(5-bromo-2-formyl-4-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0452] MS (ESI) M / Z: 429.0, 431.0 [M+H] + .

[0453] Step D: Under nitrogen protection, lithium aluminum tetrahydride (7.7 mL, 7.69 mmol) was slowly added dropwise to a solution of 2-(5-bromo-2-formyl-4-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (2.2 g, 5.12 mmol) in anhydrous tetrahydrofuran (20 mL) in an ice bath, and the reaction solution was stirred at 0°C for 0.5 h.

[0454] After LCMS showed that the reaction was completed, 8 mL of water, 8 mL of 10 wt% NaOH aqueous solution and 24 mL of water were slowly added dropwise to the reaction solution, and the mixture was extracted with ethyl acetate solution (50 mL×3). The organic phase was collected and washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give 1.2 g of the target product, 2-(5-bromo-2-(hydroxymethyl)-4-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0455] MS(ESI)M / Z:413.0,415.0[M+H-18] + .

[0456] Step E: To a suspension of sodium hydride (200 mg, 5.01 mmol, 60 wt% in mineral oil) and potassium iodide (208 mg, 1.25 mmol) in anhydrous N,N-dimethylformamide (10 mL) was slowly added dropwise a solution of 2-(5-bromo-2-(hydroxymethyl)-4-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (1.8 g, 4.17 mmol) in anhydrous N,N-dimethylformamide (5 mL) under nitrogen. The reaction was stirred at 80°C for 1 hour.

[0457] After the reaction was completed as monitored by LCMS, the reaction solution was returned to room temperature and water (30 mL) was slowly added, extracted with ethyl acetate (50 mL×3), the organic phase was collected and washed with saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 520 mg of the target product 8-bromo-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0458] MS (ESI) M / Z: 259.0, 261.0 [M+H] + .

[0459] 1 H NMR (400MHz, CDCl3): δ7.28(s,1H),6.71(s,1H),4.63(s,2H),4.06-4.02(m,2H),3.99-3.98(m,2H),3.86(s,3H).

[0460] Step F: Dissolve 8-bromo-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (350 mg, 1.36 mmol) in tetrahydrofuran (4 mL). Cool the mixture to -78°C and add n-butyllithium (0.6 mL, 1.49 mmol, 2.5 M) dropwise. Stir the mixture for 40 minutes. Then, add a solution of dibenzyldisulfane (401 mg, 1.63 mmol) in tetrahydrofuran (1 mL) dropwise. The resulting mixture is slowly warmed to -30°C under argon. The entire reaction takes 1.5 hours.

[0461] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was poured into an icy ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 3) and dried over anhydrous sodium sulfate. Filtered and spin-dried, the crude product was purified using normal phase chromatography to yield 110 mg of 8-(benzylthio)-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0462] MS (ESI) M / Z: 303.1 [M+H] + .

[0463] 1 H NMR (400MHz, DMSO-d6): δ7.33-7.21(m,5H),6.95(s,1H),6.64(s,1H),4.62(s,2H),4.11(s,2H),4.08-3.98(m,4H),3.79(s,3H).

[0464] Step G: Dissolve 8-(Benzylthio)-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (110 mg, 0.36 mmol) in acetonitrile / water (2.2 mL / 0.2 mL). Cool the mixture to 0°C and add acetic acid (160 mg). Finally, add dichlorohydantoin (142 mg, 0.72 mmol). Stir the mixture at 0°C for 1 hour.

[0465] After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added, and the aqueous layer was washed with ethyl acetate (10 mL × 2), then with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude product, which was purified by normal phase to give 60 mg of 7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-8-sulfonyl chloride.

[0466] MS (ESI) M / Z: 301.0 [M+Na] + .

[0467] Step H: Dissolve 7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-8-sulfonyl chloride (60 mg, 0.22 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (27 mg, 0.11 mmol) in pyridine (1 mL), replace the atmosphere with nitrogen, and heat in a microwave oven at 100°C for 4 hours.

[0468] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase preparative chromatography to give 10 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-8-sulfonamide.

[0469] MS (ESI) M / Z: 487.2 [M+H]+ .

[0470] 1 H NMR (400MHz, DMSO-d6): δ10.04(s,1H),7.88(d,J=2.2Hz,1H),7.71(s,1H),7.49(s,1H),6.83(d,J=4.6Hz,2H),6.74(s,1H ), 6.30 (t, J = 2.0Hz, 1H), 5.44 (s, 2H), 4.63 (s, 2H), 4.14 (d, J = 4.8Hz, 2H), 3.91 (d, J = 4.8Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H).

[0471] Example 9:

[0472] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-7-sulfonamide

[0473] Reaction route:

[0474] Steps:

[0475] Step A: Dissolve 5-bromo-2-hydroxy-4-methoxybenzaldehyde (6 g, 25.97 mmol) in N,N-dimethylformamide (50 mL). Add bromoethanol (4.22 g, 33.76 mmol) and potassium carbonate (10.75 g, 77.92 mmol) to the reaction solution, and then add potassium iodide (0.2 g). Heat the mixture to 80°C and continue stirring for 48 hours.

[0476] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to zero degrees, quenched with aqueous ammonium chloride solution (250 mL), and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with water (50 mL) and brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by normal phase purification to give 4.5 g of 5-bromo-2-(2-hydroxyethoxy)-4-methoxybenzaldehyde.

[0477] MS (ESI) M / Z: 275.0 [M+H] + .

[0478] Step B: Dissolve 5-bromo-2-(2-hydroxyethoxy)-4-methoxybenzaldehyde (4.5 g, 16.3 mmol) in dichloromethane (50 mL), then add triethylamine (11.31 mL, 81.52 mmol) and p-toluenesulfonyl chloride (3.73 g, 19.56 mmol). Stir the resulting mixture at room temperature for 16 hours.

[0479] After LCMS monitoring showed the disappearance of the starting material, the mixture was quenched with aqueous ammonium chloride solution (250 mL), and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with water (50 mL) and brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by normal phase purification to obtain 4.8 g of 2-(4-bromo-2-formyl-5-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0480] MS (ESI) M / Z: 429.0 [M+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6): δ9.81 (s, 1H), 7.78 (d, J = 6.4Hz, 2H), 7.74 (s, 1H), 7.4 2(d,J=6.8Hz,2H),6.81(s,1H),4.46-4.43(m,4H),3.96(s,3H),2.40(s,3H).

[0482] Step C: Dissolve 2-(4-bromo-2-formyl-5-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (4.8 g, 11.21 mmol) in tetrahydrofuran (50 mL), and add lithium aluminum tetrahydride (16.82 mL, 16.82 mmol) dropwise to the reaction mixture at 0°C. Stir the resulting mixture at 0°C for 1 hour.

[0483] After LCMS monitoring showed the disappearance of the starting material, the mixture was diluted with tetrahydrofuran (50 mL) and quenched with sodium sulfate decahydrate (about 30 g). The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated to give a crude product, which was purified by normal phase chromatography to give 2.7 g of 2-(4-bromo-2-(hydroxymethyl)-5-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0484] MS (ESI) M / Z: 453.1 [M+Na] + .

[0485] 1H NMR (400MHz, DMSO-d6): δ7.79(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),7.43(s,1H),6.6 5(s,1H),4.36-4.31(m,2H),4.29(s,2H),4.26-4.22(m,2H),3.81(s,3H),2.41(s,3H).

[0486] Step D: Sodium hydride (0.31 g, 7.53 mmol, 60 wt%) was dissolved in N,N-dimethylformamide (20 mL). A solution of 2-(4-bromo-2-(hydroxymethyl)-5-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (2.7 g, 6.27 mmol) in N,N-dimethylformamide (10 mL) was added dropwise to the above solution. Potassium iodide (0.1 g) was then added to the reaction solution. The resulting mixture was heated to 80°C and stirred for 2 hours.

[0487] LCMS monitoring indicated the reaction was complete, and the reaction mixture was cooled to room temperature. Water (150 mL) was added for dilution, followed by extraction with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3) and dried over anhydrous sodium sulfate. Filtered and spin-dried. The crude product was purified by normal phase chromatography to yield 1.3 g of 7-bromo-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0488] MS (ESI) M / Z: 259.0 [M+H] + .

[0489] 1 H NMR (400MHz, DMSO-d6): δ7.49(s,1H),6.80(s,1H),4.55(s,2H),4.05-4.04(m,2H),3.90-3.88(m,2H),3.81(s,3H).

[0490] Step E: Dissolve 7-bromo-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (1.3 g, 5.04 mmol) in tetrahydrofuran (20 mL). Cool the mixture to -78°C and add n-butyllithium (2.22 mL, 5.54 mmol, 2.5 M) dropwise. Stir the mixture for 40 minutes. Then, add a solution of dibenzyldisulfane (1.49 g, 6.05 mmol) in tetrahydrofuran (5 mL) dropwise. The resulting mixture is slowly heated to -30°C under argon. The entire reaction takes 1.5 hours.

[0491] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was poured into an icy ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3) and dried over anhydrous sodium sulfate. Filtered and spin-dried, the crude product was purified using normal phase chromatography to yield 1.0 g of 7-(benzylthio)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0492] MS (ESI) M / Z: 303.0 [M+H] + .

[0493] 1 H NMR (400MHz, DMSO-d6): δ7.29-7.21(m,5H),7.16(s,1H),6.69(s,1H),4.5 1(s,2H),4.08(s,2H),4.02-4.00(m,2H),3.88-3.78(m,2H),3.79(s,3H).

[0494] Step F: Dissolve 7-(Benzylthio)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (400 mg, 1.32 mmol) in acetonitrile / water (8.8 mL / 0.8 mL). Cool the mixture to 0°C and add acetic acid (640 mg). Finally, add dichlorohydantoin (520 mg, 2.64 mmol). Stir the mixture at 0°C for 1 hour.

[0495] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added, and the aqueous layer was washed with ethyl acetate (100 mL×2), then with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude product, which was purified twice using normal phase to give 160 mg of 8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-7-sulfonyl chloride.

[0496] MS (ESI) M / Z: 301.1 [M+Na] + .

[0497] 1 H NMR (400MHz, DMSO-d6): δ7.78(s,1H),6.78(s,1H),4.66(s,2H),4.23-4.21(m,2H),4.15-4.02(m,5H),3.79(s,3H).

[0498] Step G: 8-Methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-7-sulfonyl chloride (160 mg, 0.58 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (70 mg, 0.29 mmol) were dissolved in pyridine (2 mL), replaced with nitrogen, and heated in a microwave oven to 100 °C for 4 h.

[0499] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase preparative chromatography to give 30 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-7-sulfonamide.

[0500] MS (ESI) M / Z: 487.2 [M+H] + .

[0501] 1 H NMR (400MHz, DMSO-d6): δ10.04(s,1H),7.88(d,J=2.2Hz,1H),7.71(s,1H),7.49(s,1H),6.83(d,J=4.6Hz,2H),6.74(s,1H ), 6.30 (t, J = 2.0Hz, 1H), 5.44 (s, 2H), 4.63 (s, 2H), 4.14 (d, J = 4.8Hz, 2H), 3.91 (d, J = 4.8Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H).

[0502] Example 10:

[0503] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-9-sulfonamide

[0504] Reaction route:

[0505] Steps:

[0506] Step A: Under nitrogen protection, 2-hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol) and aluminum chloride (4.39 g, 32.9 mmol) were dissolved in dichloromethane (50 mL). After cooling to -20 °C, bromine (5.26 g, 32.9 mmol) was added dropwise. The system was stirred at room temperature for 16 hours.

[0507] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with 1M hydrochloric acid (100 mL), extracted with dichloromethane (100 mL), and washed with saturated sodium sulfite (100 mL), water (100 mL), and saturated brine (100 mL x 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 3.26 g of 3-bromo-2-hydroxy-4-methoxybenzaldehyde.

[0508] MS (ESI) M / Z: 231.0, 233.0 [M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.88(s,1H),7.82(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),3.97(s,3H).

[0510] Step B: To a solution of 3-bromo-2-hydroxy-4-methoxybenzaldehyde (7 g, 30.4 mmol) and 2-bromo-1-ol (5.7 g, 45.6 mmol) in acetonitrile (70 mL) was added potassium carbonate (12.6 g, 91.3 mmol) and potassium iodide (0.5 g, 3.0 mmol) under nitrogen. The reaction was stirred at 80°C for 16 hours.

[0511] After LCMS monitoring showed that most of the starting material had disappeared, the reaction solution was added to ethyl acetate (100 mL) and filtered. The filter cake was washed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6 g of the desired product, 3-bromo-2-(2-hydroxyethoxy)-4-methoxybenzaldehyde.

[0512] MS (ESI) M / Z: 275.0, 277.0 [M+H] + .

[0513] Step C: Under nitrogen protection, 3-bromo-2-(2-hydroxyethoxy)-4-methoxybenzaldehyde (6 g, 21.9 mmol) and triethylamine (6.6 g, 65.7 mmol) were dissolved in dichloromethane (60 mL). After cooling to 0°C, p-toluenesulfonyl chloride (6.2 g, 32.8 mmol) was slowly added dropwise. The system was stirred at room temperature for 16 hours.

[0514] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with water (200 mL) and extracted with dichloromethane (200 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to afford 5 g of 2-(2-bromo-6-formyl-3-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0515] MS (ESI) M / Z: 427.0, 429.0 [M+H] + .

[0516] Step D: Under nitrogen protection, lithium aluminum tetrahydride (14 mL, 14 mmol) was slowly added dropwise to a solution of 2-(2-bromo-6-formyl-3-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (5 g, 11.7 mmol) in anhydrous tetrahydrofuran (50 mL) in an ice bath, and the reaction solution was stirred at 0°C for half an hour.

[0517] After LCMS showed that the reaction was completed, sodium thiosulfate decahydrate (50 g) was added, stirred for 30 minutes until clear, filtered, and the filter cake was washed with ethyl acetate (100 mL×3). The filtrate was concentrated and the resulting residue was purified by column chromatography to obtain the target product 3 g of 2-(2-bromo-6-(hydroxymethyl)-3-methoxyphenoxy)ethyl-4-methylbenzenesulfonate.

[0518] MS(ESI)M / Z:413.0,415.0[M-18+H] + .

[0519] Step E: To a suspension of sodium hydride (335 mg, 8.4 mmol, 60 wt%) and potassium iodide (116 mg, 0.7 mmol) in anhydrous N,N-dimethylformamide (20 mL) was slowly added dropwise a solution of 2-(2-bromo-6-(hydroxymethyl)-3-methoxyphenoxy)ethyl-4-methylbenzenesulfonate (3 g, 7.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) under nitrogen. The reaction was stirred at 70°C for 1 hour.

[0520] After the reaction was completed, the reaction solution was cooled to room temperature and water (100 mL) was slowly added, extracted with ethyl acetate (100 mL × 3), and the organic phase was collected and washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target product 1 g 9-bromo-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0521] MS (ESI) M / Z: 259.0, 261.0 [M+H] + .

[0522] Step F: Under nitrogen, 9-bromo-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (630 mg, 2.4 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to -78°C, tert-butyl lithium (2.1 mL, 2.68 mmol) was added dropwise, and stirred at this temperature for 30 minutes. A mixed solution of 1,2-dibenzyldisulfane (720 mg, 2.9 mmol) and tetrahydrofuran (5 mL) was added dropwise at -78°C, stirred at the same temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0523] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate and saturated ammonium chloride, extracted, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 300 mg of 9-(benzylthio)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane.

[0524] MS (ESI) M / Z: 303.1 [M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6): δ7.26-7.08(m,6H),6.69(d,J=8.4Hz,1H),4.49(s,2H),4.01(s,2H),3.81(s,5H),3.74-3.64(m,2H).

[0526] Step G: Under nitrogen protection, 9-(benzylthio)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane (150 mg, 0.44 mmol) and acetic acid (213 mg, 3.55 mmol) were dissolved in water (0.44 mL) and acetonitrile (4.84 mL), cooled to 0°C, and dichlorohydantoin (174.8 mg, 0.89 mmol) was added. The system was stirred at 0°C for 1 hour.

[0527] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 110 mg of 8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-9-sulfonyl chloride.

[0528] MS (ESI) M / Z: 301.0 [M+Na] + .

[0529] Step H: Under nitrogen protection, 8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-9-sulfonyl chloride (110 mg, 0.39 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (48.3 mg, 0.20 mmol) were dissolved in pyridine (2 mL) and the system was stirred at 100 °C under microwave conditions for 3 hours.

[0530] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to water (50 mL), diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to the reverse reaction to afford 13.6 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3-dihydro-5H-benzo[e][1,4]dioxepane-9-sulfonamide.

[0531] MS (ESI) M / Z: 487.2 [M+H] + .

[0532] 1 H NMR (400MHz, DMSO-d6): δ10.01 (s, 1H), 7.88 (d, J = 2.2Hz, 1H), 7.49 (t, J = 5.6Hz, 2H), 6.85 (d, J = 8.8Hz, 2H),6.75(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),4.57(s,2H),4.06-3.99(m,2H),3.93-3.87(m,2H),3.82(s,3H),3.74(s,3H).

[0533] Example 11:

[0534] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0535] Reaction route:

[0536] Steps:

[0537] Step A: Under nitrogen protection, 2,2-difluoroalkane-1,3-diol (1 g, 8.9 mmol) and triethylamine (6.2 mL, 44.6 mmol) were dissolved in dichloromethane (10 mL). After cooling to 0°C, p-toluenesulfonyl chloride (5.1 g, 26.8 mmol) was slowly added dropwise. The system was stirred at room temperature for 16 hours.

[0538] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 4.39 g of 2,2-difluoropropane-1,3-diylbis(4-methylbenzenesulfonate).

[0539] MS (ESI) M / Z: 421.0 [M+H] + .

[0540] Step B: Under nitrogen protection, 3-bromo-4-methoxybenzene-1,2-diol (7 g, 32.1 mmol), 2,2-difluoropropane-1,3-diylbis(4-methylbenzenesulfonate) (20.3 g, 48.2 mmol) and potassium carbonate (6.7 g, 48.2 mmol) were dissolved in N,N-dimethylformamide (70 mL), and the system was stirred at 120 ° C for 1 hour.

[0541] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to saturated ammonium chloride solution (200 mL), diluted with ethyl acetate (200 mL), washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 2.12 g of 6-bromo-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0542] MS (ESI) M / Z: 295.0, 297.0 [M+H] + .

[0543] Step C: Under nitrogen protection, 6-bromo-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (1.95 g, 6.6 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78°C, tert-butyl lithium (5.6 mL) was added dropwise, and stirred at this temperature for 30 minutes. A mixed solution of 1,2-dibenzyldisulfane (1.96 g, 8.0 mmol) and tetrahydrofuran (5 mL) was added dropwise at -78°C, stirred at the same temperature for 30 minutes, and then heated to room temperature and stirred for 1 hour.

[0544] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate and saturated ammonium chloride, extracted, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 650 mg of 6-(benzylthio)-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane.

[0545] MS (ESI) M / Z: 339.1 [M+H] + .

[0546] Step D: Under nitrogen protection, 6-(benzylthio)-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane (150 mg, 0.44 mmol) and acetic acid (213 mg, 3.55 mmol) were dissolved in water (0.44 mL) and acetonitrile (4.84 mL), cooled to 0°C, and dichlorohydantoin (174.8 mg, 0.89 mmol) was added. The system was stirred at 0°C for 1 hour.

[0547] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to afford 120 mg of 3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride.

[0548] MS (ESI) M / Z: 337.0 [M+Na] + .

[0549] Step E: Under nitrogen protection, 3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (120 mg, 0.38 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (46.6 mg, 0.19 mmol) were dissolved in pyridine (2 mL) and the system was stirred at 100 °C under microwave conditions for 3 hours.

[0550] After LCMS monitoring showed that the starting material was completely reacted, the reaction solution was added to water (50 mL), diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to the reverse preparation to obtain 15.7 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3,3-difluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0551] MS (ESI) M / Z: 523.2 [M+H] + .

[0552] 1 H NMR (400MHz, DMSO-d6): δ10.32(s,1H),7.88(d,J=2.2Hz,1H),7.50(s,1H),7.36(d,J=9.2Hz,1H),6.92(d,J=9.2H z,1H),6.84(s,1H),6.75(s,1H),6.30(t,J=1.8Hz,1H),5.45(s,2H),4.36-4.30(m,4H),3.82(s,3H),3.72(s,3H).

[0553] Example 12:

[0554] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0555] Reaction route:

[0556] Steps:

[0557] Step A: Dissolve 4-bromo-2,5-difluorobenzaldehyde (5 g, 22.62 mmol) in tetrahydrofuran (50 mL), cool the system to 0°C, and then add lithium aluminum tetrahydride (24.88 mL, 24.88 mmol) dropwise to the solution. Stir the resulting mixture at the same temperature for 30 minutes.

[0558] LCMS showed that the reaction was complete, and sodium sulfate decahydrate (20 g) was added, stirred for 30 minutes, and filtered. The filter cake was washed twice with tetrahydrofuran (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 4.3 g of crude 4-bromo-2,5-difluorobenzyl alcohol.

[0559] MS (ESI) M / Z: 205.0 [M-18+H] + .

[0560] Step B: Dissolve 4-bromo-2,5-difluorobenzyl alcohol (3.8 g, 17.04 mmol) in acetonitrile (50 mL). Add cesium carbonate (8.33 g, 25.56 mmol) and N-methylsulfonylpyrazole (2.74 g, 18.74 mmol) to the reaction solution. Heat the mixture to 70°C and continue stirring for 2 hours.

[0561] After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain a crude product, which was purified by normal phase chromatography to obtain 3.5 g of 1-(4-bromo-2,5-difluorobenzyl)-1H-pyrazole.

[0562] MS (ESI) M / Z: 273.0 [M+H] + .

[0563] 1 H NMR (400MHz, DMSO-d6): δ7.85(d,J=2.2Hz,1H),7.77(dd,J=9.0,5.8Hz,1H),7.49 (d, J=1.6Hz, 1H), 7.16 (dd, J=8.8, 6.4Hz, 1H), 6.29 (t, J=2.0Hz, 1H), 5.37 (s, 2H).

[0564] Step C: Dissolve 1-(4-bromo-2,5-difluorobenzyl)-1H-pyrazole (3.5 g, 12.86 mmol) in N,N-dimethylformamide (20 mL), then add cuprous cyanide (2.3 g, 25.72 mmol). Heat the resulting mixture to 150°C and stir for 7 hours.

[0565] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (50 mL × 3), washed with water (30 mL × 2), washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by normal phase column chromatography to obtain 1.05 g of 4-((1H-pyrazol-1-yl)methyl)-2,5-difluorobenzonitrile.

[0566] MS (ESI) M / Z: 220.0 [M+H] + .

[0567] 1 H NMR (400MHz, CDCl3): δ7.61 (d, J=1.6Hz, 1H), 7.50 (d, J=2.2Hz, 1H), 7.35 (dd, J= 8.4, 5.0Hz, 1H), 6.80 (dd, J=8.4, 5.6Hz, 1H), 6.36 (t, J=2.2Hz, 1H), 5.41 (s, 2H).

[0568] Step D: Dissolve 4-((1H-pyrazol-1-yl)methyl)-2,5-difluorobenzonitrile (150 mg, 0.68 mmol) in N,N-dimethylformamide and water (2.1 mL / 0.3 mL). Add N-hydroxyacetamide (154 mg, 2.05 mmol) and potassium carbonate (283 mg, 2.05 mmol). Stir the resulting mixture at 60°C for 2 hours.

[0569] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (30 mL×3). The organic layer was then washed with brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography to give 80 mg of 6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-amine.

[0570] MS (ESI) M / Z: 233.2 [M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6): δ7.85(d,J=2.2Hz,1H),7.65(d,J=9.2Hz,1H),7.49(d,J=1 .6Hz,1H),7.13(d,J=5.6Hz,1H),6.45(s,2H),6.30(t,J=2.0Hz,1H),5.48(s,2H).

[0572] Step E: 7-Methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (120 mg, 0.42 mmol) and 6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-amine (50 mg, 0.21 mmol) were dissolved in pyridine (2 mL), replaced with nitrogen, and heated in a microwave oven to 100 °C for 4 h.

[0573] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase column preparative chromatography to give 50 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0574] MS (ESI) M / Z: 475.2 [M+H] + .

[0575] 1 H NMR (400MHz, DMSO-d6): δ11.66(s,1H),7.88-7.84(m,2H),7.49(d,J=1.6Hz,1H),7.27(d,J=5.4Hz,1H),7.21(d,J=9.2Hz,1H),6 .76(d,J=9.2Hz,1H),6.30(t,J=2.2Hz,1H),5.51(s,2H),4.10-4.03(m,2H),4.01-3.94(m,2H),3.66(s,3H),2.09-1.98(m,2H).

[0576] Example 13:

[0577] N-(6-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)benzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0578] Reaction route:

[0579] Steps:

[0580] Step A: Dissolve methyl 4-bromo-5-fluoro-2-hydroxybenzoate (4 g, 16.1 mmol) in N,N-dimethylformamide (40 mL) at room temperature, add potassium hydroxide solution (10 mL, 2 M), add diethyl (bromodifluoromethyl)phosphonate (6.4 g, 24.1 mmol) under ice-water bath, and stir under ice-water bath for 2 hours.

[0581] LCMS monitoring showed that the reaction of the starting material was complete. The reaction solution was added with ammonium chloride solution (100 mL) and extracted twice with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g of 4-bromo-2-(difluoromethoxy)-5-fluorobenzoic acid.

[0582] MS (ESI) M / Z: 285.0 [M+H] + .

[0583] Step B: Dissolve 4-bromo-2-(difluoromethoxy)-5-fluorobenzoic acid (4 g, 14.1 mmol) in N,N-dimethylformamide (30 mL), add potassium carbonate (3.9 g, 28.2 mmol), add iodomethane (3.0 g, 21.1 mmol) dropwise, and stir at room temperature for 2 hours.

[0584] LCMS monitoring showed that the reaction of the starting material was complete. The reaction solution was added with water (150 mL) and extracted twice with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain 3.2 g of methyl 4-bromo-2-(difluoromethoxy)-5-fluorobenzoate.

[0585] MS (ESI) M / Z: 299.1 [M+H] + .

[0586] 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 6.54 (t, J = 74 Hz, 1H), 3.93 (s, 3H).

[0587] Step C: To a solution of methyl 4-bromo-2-(difluoromethoxy)-5-fluorobenzoate (3.2 g, 10.7 mmol) in N,N-dimethylformamide (15 mL) was added cuprous cyanide (1.93 g, 21.4 mmol), heated to 150° C. in a microwave oven, and stirred for 5 hours.

[0588] After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography to give 2.1 g of methyl 4-cyano-2-(difluoromethoxy)-5-fluorobenzoate.

[0589] MS (ESI) M / Z: 246.1 [M+H] + .

[0590] Step D: Methyl 4-cyano-2-(difluoromethoxy)-5-fluorobenzoate (500 mg, 2.04 mmol) was dissolved in methanol (10 mL) at room temperature, sodium borohydride (155 mg, 4.08 mmol) was added, and the mixture was stirred at room temperature for 2 hours.

[0591] LCMS monitoring showed that the reaction of the starting material was complete. Water (50 mL) was added to the reaction solution and stirred for 10 minutes. The mixture was extracted twice with dichloromethane (50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 420 mg of crude 5-(difluoromethoxy)-2-fluoro-4-(hydroxymethyl)benzonitrile.

[0592] MS (ESI) M / Z: 218.3 [M+H] + .

[0593] Step E: Dissolve 5-(difluoromethoxy)-2-fluoro-4-(hydroxymethyl)benzonitrile (420 mg, 1.94 mmol) in acetonitrile (10 mL) at room temperature, add cesium carbonate (1.26 g, 3.88 mmol) and 1-(methylsulfonyl)-1H-pyrazole (340 mg, 2.33 mmol), warm to 70°C, and stir for 2 hours.

[0594] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and concentrated. The crude product was purified by silica gel column chromatography to give 380 mg of 4-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)-2-fluorobenzonitrile.

[0595] MS (ESI) M / Z: 268.1 [M+H] + .

[0596] 1H NMR (400MHz, CDCl3): δ7.61(d,J=1.6Hz,1H),7.49(d,J=2.4Hz,1H),7.44(d,J=5.6Hz ,1H),6.72(d,J=8.8Hz,1H),6.57(t,J=72Hz,1H),6.37(t,J=2.0Hz,1H),5.41(s,2H).

[0597] Step F: Dissolve 4-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)-2-fluorobenzonitrile (380 mg, 1.42 mmol) in N,N-dimethylformamide (7 mL) and water (1 mL) at room temperature, add N-hydroxyacetamide (427 mg, 5.68 mmol) and potassium carbonate (783 mg, 5.68 mmol), raise the temperature to 60°C, and stir for 3 hours.

[0598] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and concentrated. The crude product was purified by silica gel column chromatography to give 280 mg of 6-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)benzo[d]isoxazol-3-amine.

[0599] MS (ESI) M / Z: 281.3 [M+H] + .

[0600] 1 H NMR (400MHz, DMSO-d6): δ7.84(d,J=2.0Hz,1H),7.74(s,1H),7.51(d,J=1.6Hz,1H), 7.15(t,J=74Hz,1H),6.95(s,1H),6.50(s,2H),6.32(t,J=2.0Hz,1H),5.46(s,2H).

[0601] Step G: Dissolve 6-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)benzo[d]isoxazol-3-amine (50 mg, 0.179 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (99 mg, 0.358 mmol) in anhydrous pyridine (1.5 mL) and react at 100 °C under microwave conditions for 3 hours.

[0602] After LCMS monitoring showed the disappearance of the starting material, ammonium chloride solution (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined. The organic phases were washed with water (30 mL), then with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to yield 55 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-(difluoromethoxy)benzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0603] MS (ESI) M / Z: 523.2 [M+H] + .

[0604] 1 H NMR (500MHz, DMSO-d6): δ11.69(s,1H),7.98(s,1H),7.84(d,J=2.0Hz,1H),7.51(d,J=1.2Hz,1H),7.21(d,J=9.2Hz,1H),7.18(t,J=73.2Hz,1H),7. 07(s,1H),6.75(d,J=9.2Hz,1H),6.32(t,J=2.0Hz,1H),5.48(s,2H),4.0 6(t,J=5.2Hz,2H),3.98(t,J=5.6Hz,2H),3.64(s,3H),2.06-2.02(m,2H).

[0605] Example 14:

[0606] N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0607] Reaction route:

[0608] Steps:

[0609] Step A: Under nitrogen protection, methyl 2-amino-4-bromo-5-fluorobenzoate (5.0 g, 20.2 mmol) was added to a mixed solution of 6 M aqueous HCl solution (100 mL) and acetonitrile (50 mL), and the temperature was lowered to 0°C. A solution of sodium nitrite (1.47 g, 21.2 mmol) in water (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. A solution of potassium iodide (6.7 g, 40.5 mmol) in water (10 mL) was then slowly added dropwise to the reaction solution. The reaction solution was slowly heated to 25°C and stirred for 16 hours.

[0610] After LCMS monitoring showed that the reaction of the starting material was complete, the reaction solution was added to ethyl acetate (100 mL), filtered, the filter cake was washed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.4 g of methyl 4-bromo-5-fluoro-2-iodobenzoate.

[0611] MS (ESI) M / Z: 358.9, 360.9 [M+H] + .

[0612] Step B: Under nitrogen protection, methyl 4-bromo-5-fluoro-2-iodobenzoate (6.4 g, 17.9 mmol), cyclopropylboronic acid (1.84 g, 21.5 mmol), cesium carbonate (11.6 g, 42.4 mmol) and 1,1-bis(diphenylphosphine)dibrominated iron palladium dichloride (1.3 g, 1.8 mmol) were dissolved in 1,4-dioxane (100 mL), and the reaction solution was stirred at 100 ° C for 3 hours.

[0613] After LCMS monitoring showed that the reaction of the starting material was complete, the reaction solution was added to ethyl acetate (100 mL), filtered, the filter cake was washed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.5 g of methyl 4-bromo-2-cyclopropyl-5-fluorobenzoate.

[0614] MS (ESI) M / Z: 273.0, 275.0 [M+H] +

[0615] Step C: Under nitrogen protection, cuprous cyanide (2.3 g, 25.7 mmol) was added to a solution of methyl 4-bromo-2-cyclopropyl-5-fluorobenzoate (3.5 g, 12.9 mmol) in anhydrous N,N-dimethylformamide (30 mL). The reaction solution was stirred at 130°C for 16 hours.

[0616] After LCMS showed that the reaction was completed, saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution to quench the reaction, and the mixture was filtered. The filtrate was extracted with ethyl acetate (100 mL×3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vortexing. The mixture was purified by column chromatography to obtain 1.3 g of methyl 4-cyano-2-cyclopropyl-5-fluorobenzoate.

[0617] MS (ESI) M / Z: 220.1 [M+H] + .

[0618] Step D: Under nitrogen, methyl 4-cyano-2-cyclopropyl-5-fluorobenzoate (1.3 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Lithium borohydride (5.9 mL, 11.9 mmol, 2 M in tetrahydrofuran) was slowly added dropwise at 0°C. The reaction solution was slowly heated to 25°C and stirred for 2 hours.

[0619] After the reaction was completed as monitored by LCMS, 30 mL of water was slowly added dropwise to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate (50 mL×3), washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.1 g of 5-cyclopropyl-2-fluoro-4-(hydroxymethyl)benzonitrile.

[0620] MS (ESI) M / Z: 192.1 [M+H] + .

[0621] 1 H NMR (400MHz, DMSO-d6): δ7.46 (dd, J=19.6, 8.6Hz, 2H), 5.60 (t, J=5.4Hz, 1H), 4 .75(d,J=5.4Hz,2H),1.89-1.78(m,1H),0.93-0.86(m,2H),0.72-0.64(m,2H).

[0622] Step E: Under nitrogen protection, 5-cyclopropyl-2-fluoro-4-(hydroxymethyl)benzonitrile (1.1 g, 5.7 mmol), 1-(methylsulfonyl)-1H-pyrazole (1.0 g, 6.9 mmol) and cesium carbonate (3.75 g, 11.5 mmol) were dissolved in acetonitrile (10 mL), and the system was stirred at 70 ° C for 2 hours.

[0623] After LCMS monitoring indicated complete reaction of the starting material, the reaction solution was added to ethyl acetate (50 mL), filtered, the filter cake washed with ethyl acetate (100 mL), and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.0 g of 4-((1H-pyrazol-1-yl)methyl)-5-cyclopropyl-2-fluorobenzonitrile.

[0624] MS (ESI) M / Z: 242.2 [M+H] + .

[0625] Step F: Under nitrogen protection, N-hydroxyacetamide (186.7 mg, 2.5 mmol) and potassium carbonate (342.7 mg, 2.5 mmol) were dissolved in a mixed solution of N,N-dimethylformamide (7 mL) and water (1 mL), and 4-((1H-pyrazol-1-yl)methyl)-5-cyclopropyl-2-fluorobenzonitrile (200 mg, 0.83 mmol) was added, and the system was stirred at 60 ° C for 3 hours.

[0626] After LCMS monitoring showed that the starting material was completely reacted, the reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 60 mg of 6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-amine.

[0627] MS (ESI) M / Z: 255.2 [M+H] + .

[0628] Step G: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-amine (50 mg, 0.20 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (85 mg, 0.31 mmol) were dissolved in anhydrous pyridine (1 mL). The reaction was stirred at 100°C in a microwave oven for 4 hours.

[0629] After the reaction was completed as monitored by LCMS, 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL×3), washed with saturated ammonium chloride solution (50 mL×3) and saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparation (formic acid system) to give 58.5 mg of the target product N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0630] MS (ESI) M / Z: 497.3 [M+H] + .

[0631] 1H NMR (400MHz, DMSO-d6): δ11.50(s,1H),7.86(d,J=2.0Hz,1H),7.79(s,1H),7.54(s,1H),7.21(d,J=9.2Hz,1H),6.82-6.71(m,2H ), 6.34 (t, J = 2.0Hz, 1H), 5.66 (s, 2H), 4.10-3.93 (m, 4H), 3.64 (s, 3H), 2.08-1.98 (m, 3H), 1.02-0.95 (m, 2H), 0.65-0.54 (m, 2H).

[0632] Example 15:

[0633] N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0634] Reaction route:

[0635] Steps:

[0636] Step A: To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (4.0 g, 16.06 mmol) and potassium carbonate (4.43 g, 32.12 mmol) in acetone (35 mL) was slowly added dropwise iodomethane (1.20 mL, 19.27 mmol) under nitrogen protection and an ice bath. The reaction solution was slowly heated to 25°C and stirred for 16 hours.

[0637] After LCMS monitoring showed that the reaction of the starting materials was complete, the reaction solution was added to ethyl acetate (30 mL), filtered, the filter cake was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography gave 3.9 g of methyl 4-bromo-5-fluoro-2-methoxybenzoate.

[0638] MS (ESI) M / Z: 263.0, 265.0 [M+H] + .

[0639] Step B: Under nitrogen protection, cuprous cyanide (2.66 g, 29.66 mmol) was slowly added to a solution of methyl 4-bromo-5-fluoro-2-methoxybenzoate (3.9 g, 14.83 mmol) in anhydrous N,N-dimethylformamide (30 mL). The reaction solution was stirred at 130°C for 16 hours.

[0640] After LCMS showed that the reaction was completed, saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate solution (100 mL×3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vortexing and purified by column chromatography to obtain 1.6 g of methyl 4-cyano-5-fluoro-2-methoxybenzoate.

[0641] MS (ESI) M / Z: 210 [M+H] + .

[0642] 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 3.92 (d, J = 2.4 Hz, 6H).

[0643] Step C: Under nitrogen protection, methyl 4-cyano-5-fluoro-2-methoxybenzoate (1.65 g, 7.89 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Lithium borohydride (7.89 mL, 7.89 mmol, 2 M) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was slowly heated to 25°C and stirred for 6 hours.

[0644] After the reaction was completed, as monitored by LCMS, 30 mL of water was slowly added dropwise to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.05 g of the target product, 2-fluoro-4-(hydroxymethyl)-5-methoxybenzonitrile.

[0645] MS (ESI) M / Z: 182.1 [M+H] + .

[0646] Step D: Under nitrogen protection, 2-fluoro-4-(hydroxymethyl)-5-methoxybenzonitrile (300 mg, 1.66 mmol), 1-(methylsulfonyl)-1H-pyrazole (291 mg, 1.99 mmol) and cesium carbonate (812 mg, 2.49 mmol) were dissolved in acetonitrile (10 mL), and the system was stirred at 70 ° C for 3 hours.

[0647] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was added to ethyl acetate (30 mL), filtered, the filter cake washed with ethyl acetate (50 mL), and the filtrate concentrated under reduced pressure. Purification by silica gel column chromatography afforded 200 mg of 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-5-methoxybenzonitrile.

[0648] MS (ESI) M / Z: 232.2 [M+H] + .

[0649] Step E: Under nitrogen protection, N-hydroxyacetamide (259 mg, 3.46 mmol) and potassium carbonate (477 mg, 3.46 mmol) were dissolved in a mixed solution of N,N-dimethylformamide (7 mL) and water (1 mL), and 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-5-methoxybenzonitrile (200 mg, 0.86 mmol) was added, and the system was stirred at 60 ° C for 16 hours.

[0650] After LCMS monitoring showed that the starting material was completely reacted, the reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography gave 50 mg of 6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-amine.

[0651] MS (ESI) M / Z: 245.1 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6): δ7.80(d,J=2.2Hz,1H),7.50(d,J=1.6Hz,1H),7.42(s,1H),6.72(s,1H),6.30(s,3H),5.38(s,2H),3.84(d,J=12.6Hz,3H).

[0653] Step F: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-amine (50 mg, 0.20 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (85 mg, 0.31 mmol) were dissolved in anhydrous pyridine (1 mL). The reaction was stirred at 100°C in a microwave oven for 4 hours.

[0654] After the reaction was completed, as monitored by LCMS, 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3), washed with saturated ammonium chloride solution (10 mL×3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to give 49.2 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0655] MS (ESI) M / Z: 487.2 [M+H]+ .

[0656] 1 H NMR (400MHz, DMSO-d6): δ11.44(s,1H),7.82(d,J=1.6Hz,1H),7.62(s,1H),7.50(d,J=1.6Hz,1H),7.21(d,J=9.2Hz,1H),6.82(s,1H),6.7 5(d,J=9.2Hz,1H),6.30(t,J=2.0Hz,1H),5.40(s,2H),4.09-4.05(m,2H),4.00-3.97(m,2H),3.86(s,3H),3.66(s,3H),2.07-2.02(m,2H).

[0657] Example 16:

[0658] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepane-9-sulfonamide

[0659] Reaction route:

[0660] Steps:

[0661] Step A: Dissolve 2-bromo-3-methoxyphenol (2 g, 9.9 mmol) in N,N-dimethylformamide (50 mL). Add potassium carbonate (2.8 g, 20 mmol) and ethyl 4-bromobutyrate (1.7 mL, 12 mmol). Stir the reaction system at room temperature overnight.

[0662] After LC-MS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (70 mL × 2 times), and the organic phases were combined, washed with saturated brine (50 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3 g of ethyl 4-(2-bromo-3-methoxyphenoxy)butyrate.

[0663] MS (ESI) M / Z: 317.1 [M+H] + .

[0664] Step B: Dissolve ethyl 4-(2-bromo-3-methoxyphenoxy)butanoate (3 g, 9.49 mmol) in ethanol (20 mL), add sodium hydroxide (1.14 g, 28.475 mmol), and react at room temperature overnight.

[0665] After LC-MS monitoring showed the disappearance of the starting material, dilute hydrochloric acid was added to the reaction system to adjust the pH to acidic. The mixture was extracted with ethyl acetate (70 mL x 2), and the organic phases were combined and washed with saturated brine (50 mL x 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was slurried with petroleum ether and dichloromethane to obtain 2.9 g of 4-(2-bromo-3-methoxyphenoxy)butyric acid.

[0666] MS (ESI) M / Z: 289.1 [M+H] + .

[0667] Step C: Dissolve 4-(2-bromo-3-methoxyphenoxy)butanoic acid (2.9 g, 10.09 mmol) in TFA (trifluoroacetic acid, 50 mL), then add TFAA (trifluoroacetic anhydride, 4.2 mL, 30 mmol), and stir the reaction system at room temperature overnight.

[0668] After LC-MS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (70 mL x 2), and the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.0 g of 9-bromo-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one.

[0669] 1 H NMR(400MHz,Chloroform-d): δ7.78(d,J=8.8Hz,1H),6.71(d,J=8.8Hz,1H),4.3 3(t,J=6.7Hz,2H),3.96(s,3H),2.89(dd,J=7.4,6.2Hz,2H),2.30-2.10(m,2H).

[0670] Step D: Dissolve 9-bromo-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.0 g, 7.4 mmol) in methanol (30 mL), add sodium borohydride (0.14 g, 7.4 mmol), and stir the reaction at room temperature for 3 hours.

[0671] After LC-MS monitoring showed the disappearance of the starting material, dilute HCl (5 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.53 g of 9-bromo-8-methoxy-2,3-dihydrobenzo[b]oxepin.

[0672] MS (ESI) M / Z: 255.1 [M+H] + .

[0673] Step E: Dissolve 9-bromo-8-methoxy-2,3-dihydrobenzo[b]oxepin (0.53 g, 2.1 mol) in methanol (10 mL), add 60 mg of palladium on carbon, replace the hydrogen with air under vacuum 3-4 times, and stir the reaction system at room temperature for 3 hours.

[0674] After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was filtered through celite to obtain a reaction residue which was purified by silica gel column chromatography to obtain 0.44 g of 8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin.

[0675] 1 H NMR (400MHz, DMSO-d6): δ6.57-6.48(m,1H),3.97-3.88(m,1H),3.69(s,1H),2.76-2.63(m,1H),1.95-1.81(m,1H),1.66-1.55(m,1H).

[0676] Step F: Under nitrogen protection, 8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin (0.44 g, 2.44 mmol) and N,N,N',N'-tetramethylethylenediamine (0.42 mL, 2.68 mol) were dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and n-butyllithium (1.68 mL, 2.68 mmol, 1.6 M) was added dropwise. The mixture was stirred at this temperature for 20 minutes. A solution of 1,2-dibenzyldisulfane (0.66 g, 2.69 mmol) in tetrahydrofuran (5 mL) was added dropwise at -78°C, stirred at the same temperature for 30 minutes, and then warmed to room temperature and stirred for 1 hour.

[0677] After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was poured into a mixture of ethyl acetate (50 mL) and saturated ammonium chloride (50 mL), extracted, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 10) to yield 0.42 g of 9-(benzylthio)-8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin.

[0678] MS (ESI) M / Z: 301.1 [M+H] + .

[0679] Step G: Under nitrogen protection, 9-(benzylthio)-8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin (0.10 g, 0.33 mmol) was dissolved in acetic acid (3 mL), cooled to 0°C, and dichlorohydantoin (0.13 g, 11.26 mmol) was added. The system was stirred at 0°C for 1 hour.

[0680] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL x 3) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 3 / 1) to yield 0.043 g of 8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxazepine-9-sulfonyl chloride.

[0681] 1 H NMR (400MHz, DMSO-d6): δ7.10(d,J=8.4Hz,1H),6.62(d,J=8.4Hz,1H),3.81(t,J=5.1Hz,1H),2.69-2.61(m,1H),1.87-1.78(m,1H),1.60-1.54(m,1H).

[0682] Step H: Under nitrogen protection, 8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxazepine-9-sulfonyl chloride (0.035 g, 0.127 mmol) and 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (0.015 g, 0.063 mmol) were dissolved in pyridine (0.5 mL) and the system was stirred at 100 °C under microwave conditions for 3 hours.

[0683] After LCMS monitoring indicated complete reaction of the starting material, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 4 / 5) and by reverse phase chromatography (eluent: 0.01 vol% formic acid in water / acetonitrile = 1 / 1) to afford 16 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepane-9-sulfonamide.

[0684] MS (ESI) M / Z: 485.2 [M+H] + .

[0685] 1H NMR (400MHz, DMSO-d6): δ7.87(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.33(d,J=8.5Hz,1H),6.76(dd,J=19.2,10.7Hz,3H), 6.30(t,J=2.1Hz,1H),5.43(s,2H),3.93(s,2H),3.84(s,3H),3.68(s,3H),2.69(d,J=9.9Hz,2H),1.85(s,2H),1.58(s,2H).

[0686] Example 17:

[0687] N-(6-((1H-pyrazol-1-yl)methyl)-5-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0688] Reaction route:

[0689] Steps:

[0690] Step A: 4-Bromo-2-fluoro-5-methylbenzonitrile (500 mg, 2.34 mmol) was dissolved in methanol (15 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (382 mg, 0.47 mmol) and triethylamine (0.98 mL, 7.02 mmol) were added. After purging with a carbon monoxide balloon three times, the reaction solution was stirred at 65°C under a carbon monoxide atmosphere for 16 hours.

[0691] After the reaction was completed, the reaction was monitored by LCMS and concentrated under reduced pressure to remove methanol. Ethyl acetate solution (30 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate solution (50 mL×3). The mixture was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 330 mg of methyl 4-cyano-5-fluoro-2-methylbenzoate.

[0692] MS (ESI) M / Z: 194.1 [M+H] + .

[0693] 1 H NMR (400MHz, DMSO-d6): δ7.98(d,J=6.4Hz,1H),7.83(d,J=9.8Hz,1H),3.87(s,3H),2.48(s,3H).

[0694] Step B: Under nitrogen, methyl 4-cyano-5-fluoro-2-methylbenzoate (330 mg, 1.71 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Lithium borohydride (1.71 mL, 3.42 mmol) was slowly added dropwise at 0°C. The reaction solution was slowly heated to 25°C and stirred for 2 hours.

[0695] After the reaction was completed as monitored by LCMS, 15 mL of water was slowly added dropwise to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate (30 mL×3), washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 190 mg of 2-fluoro-4-(hydroxymethyl)-5-methylbenzonitrile.

[0696] MS (ESI) M / Z: 166.1 [M+H] + .

[0697] Step C: Under nitrogen protection, 2-fluoro-4-(hydroxymethyl)-5-methylbenzonitrile (190 mg, 1.15 mmol), 1-(methylsulfonyl)-1H-pyrazole (402 mg, 1.38 mmol) and cesium carbonate (562 mg, 1.73 mmol) were dissolved in acetonitrile (10 mL), and the system was stirred at 70 ° C for 3 hours.

[0698] After LCMS monitoring indicated complete reaction of the starting material, the reaction mixture was added to ethyl acetate (30 mL), filtered, the filter cake washed with ethyl acetate (50 mL), and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield 220 mg of 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-5-methylbenzonitrile.

[0699] MS (ESI) M / Z: 216.2 [M+H] + .

[0700] 1 H NMR (400MHz, DMSO-d6): δ7.85(d,J=1.8Hz,1H),7.78(d,J=6.6Hz,1H),7.54(d,J=1 .4Hz,1H),6.70(d,J=10.2Hz,1H),6.34(t,J=2.2Hz,1H),5.46(s,2H),2.31(s,3H).

[0701] Step D: Under nitrogen protection, N-hydroxyacetamide (307 mg, 4.09 mmol) and potassium tert-butoxide (459 mg, 4.09 mmol) were dissolved in N,N-dimethylformamide (10 mL) solution. After the system was stirred at room temperature for 1 hour, 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-5-methylbenzonitrile (220 mg, 1.02 mmol) was added, and the system was stirred at 60 ° C for 2 hours.

[0702] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield 110 mg of 6-((1H-pyrazol-1-yl)methyl)-5-methylbenzo[d]isoxazol-3-amine.

[0703] MS (ESI) M / Z: 229.2 [M+H] + .

[0704] Step E: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-methylbenzo[d]isoxazol-3-amine (50 mg, 0.22 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (91 mg, 0.33 mmol) were dissolved in anhydrous pyridine (1 mL). The reaction was stirred at 100°C in a microwave oven for 3 hours.

[0705] After the reaction was completed, as monitored by LCMS, 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated ammonium chloride solution (50 mL × 3) and saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative method to obtain 14.8 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0706] MS (ESI) M / Z: 471.2 [M+H] + .

[0707] 1H NMR (400MHz, DMSO-d6): δ11.52(s,1H),7.83(s,1H),7.81(d,J=1.8Hz,1H),7.52(d,J=1.4Hz,1H),7.20(d,J=9.2Hz,1H),6.86(s,1H),6.7 5(d,J=9.2Hz,1H),6.32(t,J=2.0Hz,1H),5.48(s,2H),4.07-4.03(m,2H),4.00-3.96(m,2H),3.66(s,3H),2.36(s,3H),2.07-2.01(m,2H).

[0708] Example 18:

[0709] N-(6-(1H-pyrazol-1-yl)methyl)-5-ethoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0710] Reaction route:

[0711] Steps:

[0712] Step A: Dissolve methyl 4-bromo-5-fluoro-2-hydroxybenzoate (2.0 g, 8.0 mmol) and bromoethane (1.1 g, 10.4 mmol) in acetonitrile (30 mL), then add potassium carbonate (2.2 g, 16.0 mmol), and gradually raise the reaction temperature to 70°C for 3 hours.

[0713] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.0 g of crude methyl 4-bromo-2-ethoxy-5-fluorobenzoate.

[0714] MS (ESI) M / Z: 279.0 [M+H] + .

[0715] Step B: Methyl 4-bromo-2-ethoxy-5-fluorobenzoate (2.0 g, 7.2 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL) at room temperature. Cuprous cyanide (1.7 g, 14.4 mmol) was added to the mixture. The reaction system was slowly heated to 150°C and stirred for 5 hours.

[0716] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature and quenched with water dropwise. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography to yield 850 mg of methyl 4-cyano-2-ethoxy-5-fluorobenzoate.

[0717] MS (ESI) M / Z: 224.3 [M+H] + .

[0718] Step C: Dissolve methyl 4-cyano-2-ethoxy-5-fluorobenzoate (350 mg, 1.6 mmol) in anhydrous tetrahydrofuran (10 mL), add lithium borohydride (2.0 mL, 4 mmol) dropwise under ice-cooling, and warm the reaction system to room temperature and stir for 4 hours.

[0719] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to 0°C and quenched with water dropwise. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 250 mg of 5-ethoxy-2-fluoro-4-(hydroxymethyl)benzonitrile.

[0720] MS (ESI) M / Z: 196.1 [M+H] + .

[0721] Step D: 5-Ethoxy-2-fluoro-4-(hydroxymethyl)benzonitrile (250 mg, 1.3 mmol) and 1-(methylsulfonyl)-1H-pyrazole (209 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (848 mg, 2.6 mmol) was added. The reaction mixture was gradually heated to 70°C for 3 hours.

[0722] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography to give 350 mg of 4-(1H-pyrazol-1-yl)methyl)-5-ethoxy-2-fluorobenzonitrile.

[0723] MS (ESI) M / Z: 246.2 [M+H] + .

[0724] 1H NMR (400MHz, DMSO-d6): δ7.83(d,J=2.0Hz,1H),7.56(d,J=5.2Hz,1H),7.51(d,J=1.2Hz,1H),6.75 (d,J=9.6Hz,1H),6.31(t,J=2.0Hz,1H),5.36(s,2H),4.12(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H).

[0725] Step E: Dissolve 4-(1H-pyrazol-1-ylmethyl)-5-ethoxy-2-fluorobenzonitrile (200 mg, 0.82 mmol) and N-hydroxyacetamide (184 mg, 2.4 mmol) in N,N-dimethylformamide (8 mL), then add anhydrous potassium carbonate (338 mg, 2.4 mmol), and gradually raise the reaction temperature to 70°C for overnight reaction.

[0726] After LCMS monitoring showed that the reaction had stopped, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography to give 350 mg of 6-(1H-pyrazol-1-yl)methyl)-5-ethoxybenzo[d]isoxazol-3-amine.

[0727] MS (ESI) M / Z: 259.2 [M+H] + .

[0728] Step F: Dissolve the raw materials 6-(1H-pyrazol-1-yl)methyl)-5-ethoxybenzo[d]isoxazol-3-amine (40 mg, 0.16 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (86 mg, 0.32 mmol) in anhydrous pyridine (1.0 mL) and react at 100°C under microwave conditions for 3 hours.

[0729] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system to dilute it. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by liquid phase preparative purification to obtain 41.9 mg of N-(6-(1H-pyrazol-1-yl)methyl)-5-ethoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0730] MS (ESI) M / Z: 501.2 [M+H]+ .

[0731] 1 H NMR (400MHz, DMSO-d6): δ7.77(d,J=2.0Hz,1H),7.47(d,J=1.6Hz,1H),7.11(s,1H),6.92(d,J=8.8Hz,1H),6.62-6.55(m,2H),6.2 7(t,J=2.0Hz,1H),5.34(s,2H),4.04(q,J=6.8Hz,2H),3.92-3.85(m,2H),3.84-3.77(m,2H),1.92(s,2H),1.36(t,J=6.8Hz,3H).

[0732] Example 19:

[0733] N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropyloxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0734] Reaction route:

[0735] Steps:

[0736] Step A: Dissolve methyl 4-bromo-5-fluoro-2-hydroxybenzoate (3.0 g, 12.0 mmol) and 2-chloroethyl 4-methylbenzenesulfonate (3.4 g, 14.5 mmol) in N,N-dimethylformamide (30 mL). Then add anhydrous potassium carbonate (3.3 g, 24.0 mmol). The reaction mixture is gradually heated to 70°C and reacted for 3 hours.

[0737] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.2 g of crude product methyl 4-bromo-2-(2-chloroethoxy)-5-fluorobenzoate.

[0738] MS (ESI) M / Z: 311.0 [M+H] + .

[0739] Step B: Dissolve methyl 4-cyano-2-ethoxy-5-fluorobenzoate (3.2 g, 10.3 mmol) in anhydrous tetrahydrofuran (30 mL) at room temperature. Add potassium tert-butoxide (13.4 mL, 13.4 mmol) dropwise to the mixture in an ice bath. The reaction system is slowly heated to room temperature and stirred for 3 hours.

[0740] After LCMS monitoring showed the disappearance of the starting material, water was added dropwise under an ice bath to quench the reaction and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 1.75 g of methyl 4-bromo-5-fluoro-2-(vinyloxy)benzoate.

[0741] MS (ESI) M / Z: 277.0 [M+H] + .

[0742] Step C: Methyl 4-bromo-5-fluoro-2-(vinyloxy)benzoate (1.75 g, 6.4 mmol) and chloroiodomethane (3.4 g, 19.1 mmol) were dissolved in anhydrous 1,2-dichloroethane (30 mL) at room temperature. Diethylzinc (1.3 g, 10.2 mmol) was added dropwise to the mixture under ice bath. The reaction system was slowly heated to room temperature and stirred for 2 hours.

[0743] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to 0°C and quenched with saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 860 mg of methyl 4-bromo-2-cyclopropyloxy-5-fluorobenzoate.

[0744] MS (ESI) M / Z: 289.1 [M+H] + .

[0745] 1 H NMR (400MHz, DMSO-d6): δ7.74(d,J=5.8Hz,1H),7.63(d,J=8.8Hz,1H),4.04-3.99(m,1H),3.77(s,3H),0.88-0.78(m,2H),0.71-0.64(m,2H).

[0746] Step D: Methyl 4-bromo-2-cyclopropyloxy-5-fluorobenzoate (860 mg, 3.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) at room temperature. Cuprous cyanide (696 mg, 6.0 mmol) was added to the mixture. The reaction mixture was slowly heated to 150° C. and stirred for 5 hours.

[0747] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature and quenched with water dropwise. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 360 mg of methyl 4-cyano-2-cyclopropyloxy-5-fluorobenzoate.

[0748] MS (ESI) M / Z: 236.3 [M+H] + .

[0749] Step E: Dissolve methyl 4-cyano-2-cyclopropyloxy-5-fluorobenzoate (360 mg, 1.5 mmol) in anhydrous tetrahydrofuran (10 mL), add lithium borohydride (1.5 mL, 3.0 mmol) dropwise under ice-cooling, and warm the reaction system to room temperature and stir for 4 hours.

[0750] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to 0°C and quenched with water dropwise. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography to yield 230 mg of 5-cyclopropyloxy-2-fluoro-4-(hydroxymethyl)benzonitrile.

[0751] MS (ESI) M / Z: 208.3 [M+H] + .

[0752] Step F: Dissolve 5-cyclopropyloxy-2-fluoro-4-(hydroxymethyl)benzonitrile (230 mg, 1.1 mmol) and 1-(methylsulfonyl)-1H-pyrazole (178 mg, 1.2 mmol) in N,N-dimethylformamide (8 mL). Then add anhydrous cesium carbonate (717 mg, 2.2 mmol). The reaction mixture is gradually heated to 70°C for 3 hours.

[0753] After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography to give 300 mg of 4-(1H-pyrazol-1-ylmethyl)-5-cyclopropyloxy-2-fluorobenzonitrile.

[0754] MS (ESI) M / Z: 258.2 [M+H] + .

[0755] 1H NMR (400MHz, DMSO-d6): δ7.78(t,J=4.0Hz,2H),7.53-7.46(m,1H),6.79(d,J=9.6Hz,1H),6 .30(t,J=2.0Hz,1H),5.30(s,2H),4.06-3.99(m,1H),0.86-0.79(m,2H),0.68-0.61(m,2H).

[0756] Step G: Dissolve N-hydroxyacetamide (88 mg, 1.2 mmol) in N,N-dimethylformamide (5 mL), then add potassium tert-butoxide (1.2 mL, 1.2 mmol), stir at room temperature for 1 hour, add 4-(1H-pyrazol-1-yl)methyl)-5-cyclopropyloxy-2-fluorobenzonitrile (100 mg, 0.39 mmol) to the mixture, and heat the reaction mixture to 60°C for 3 hours.

[0757] After LCMS monitoring showed that the reaction had stopped, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography to give 40 mg of 6-(1H-pyrazol-1-yl)methyl)-5-cyclopropyloxybenzo[d]isoxazole-3-amine.

[0758] MS (ESI) M / Z: 271.2 [M+H] + .

[0759] Step H: Dissolve the raw materials 6-(1H-pyrazol-1-yl)methyl)-5-cyclopropyloxybenzo[d]isoxazol-3-amine (40 mg, 0.15 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (83 mg, 0.3 mmol) in anhydrous pyridine (1.0 mL) and react at 100°C under microwave conditions for 3 hours.

[0760] After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction system to dilute it. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by liquid phase preparative purification to obtain 12.4 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-cyclopropyloxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0761] MS (ESI) M / Z: 513.2 [M+H] + .

[0762] 1 H NMR (400MHz, DMSO-d6): δ11.53(s,1H),7.93(s,1H),7.77(d,J=2.0Hz,1H),7.48(d,J =1.2Hz,1H),7.21(d,J=9.2Hz,1H),6.87(s,1H),6.75(d,J=9.2Hz,1H),6.29(t,J=2. 0Hz,1H),5.33(s,2H),4.10-4.04(m,2H),4.01-3.95(m,2H),3.90-3.84(m,1H),3.66 (s,3H),2.05(dd,J=10.4,5.2Hz,2H),0.85(dd,J=9.6,3.6Hz,2H),0.71-0.65(m,2H).

[0763] Example 20:

[0764] 7-Methoxy-N-(4-methoxy-6-(pyridin-2-oxy)benzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0765] Reaction route:

[0766] Steps:

[0767] Step A: Dissolve 4-bromo-2,6-difluorobenzonitrile (4.34 g, 20 mmol) in tetrahydrofuran (100 mL), add sodium methoxide (3.7 mL, 20 mmol) at 0°C, and react at this temperature for 1.5 hours.

[0768] After LC-MS monitoring showed the disappearance of the starting material, the mixed solution was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was used directly in the next reaction without further purification.

[0769] MS (ESI) M / Z: 230.1 [M+H] + .

[0770] Step B: Under nitrogen protection, 4-bromo-2-fluoro-6-methoxybenzonitrile (4.5 g, 19.65 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (2.5 g, 5.89 mmol), tris(dibenzylideneacetone)dipalladium (5.4 g, 5.89 mmol) and potassium hydroxide (3.3 g, 58.95 mmol) were dissolved in 1,4-dioxane (40 mL) and water (40 mL), and the reaction system was stirred at 100 ° C overnight.

[0771] After LC-MS monitoring indicated the disappearance of the starting material, the reaction solution was adjusted to an acidic pH with hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2 g of 2-fluoro-4-hydroxy-6-methoxybenzonitrile.

[0772] MS (ESI) M / Z: 168.1 [M+H] + .

[0773] Step C: Dissolve 2-fluoro-4-hydroxy-6-methoxybenzonitrile (0.8 g, 4.79 mmol), {[(R)-(-)-1[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldibutylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (0.44 g, 0.479 mmol), cesium carbonate (1.56 g, 4.79 mmol), and 2-bromopyridine (1.37 mL, 14.37 mmol) in toluene (20 mL). React at 100°C for 24 hours.

[0774] After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.16 g of 2-fluoro-6-methoxy-4-(pyridine-2-oxy)benzonitrile.

[0775] MS (ESI) M / Z: 245.1 [M+H] + .

[0776] Step D: Dissolve 2-fluoro-6-methoxy-4-(pyridin-2-yl)benzonitrile (1.16 g, 4.75 mmol), potassium carbonate (3.28 g, 23.75 mmol), and acetohydroxamic acid (1.07 g, 14.26 mmol) in N,N-dimethylformamide (21 mL) and water (3 mL). Stir the reaction at 60°C overnight.

[0777] After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was not further purified to yield 0.66 g of 4-methoxy-6-(pyridin-2-oxy)benzo[d]isoxazol-3-amine.

[0778] MS (ESI) M / Z: 258.1 [M+H] + .

[0779] Step E: Under nitrogen protection, 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (0.02 g, 0.072 mmol) and 4-methoxy-6-(pyridin-2-oxy)benzo[d]isoxazol-3-amine (0.016 g, 0.06 mmol) were dissolved in pyridine (0.5 mL) and the system was stirred at 100 °C under microwave conditions for 3 hours.

[0780] After LCMS monitoring indicated complete reaction of the starting material, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 4 / 5) and then on a reverse phase preparative chromatography (eluent: 0.01 vol% formic acid in water / acetonitrile = 1 / 1) to yield 2 mg of 7-methoxy-N-(4-methoxy-6-(pyridin-2-oxy)benzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0781] MS (ESI) M / Z: 500.1 [M+H] + .

[0782] 1 H NMR (400MHz, DMSO-d6): δ8.20(dd,J=5.0,1.9Hz,1H),7.90(td,J=7.7,2.0Hz,1H),7.27-7.15(m,2H),7.10(d,J=8. 2Hz,1H),6.89(s,1H),6.78(d,J=9.1Hz,1H),6.63(s,1H),4.04(dt,J=28.4,5.2Hz,4H),3.83(s,3H),3.71(s,3H).

[0783] Example 21:

[0784] 7-Methoxy-N-(4-methoxy-6-(thiazol-2-yl)benzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0785] Reaction route:

[0786] Steps:

[0787] Step A: Dissolve 2-fluoro-4-hydroxy-6-methoxybenzonitrile (1.0 g, 5.99 mmol), {[(R)-(-)-1[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldibutylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.66 g, 1.80 mmol), cesium carbonate (5.8 g, 17.96 mmol), and 2-bromothiazole (1.64 mL, 17.96 mmol) in toluene (20 mL). React at 149°C for 24 hours.

[0788] After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2 times). The organic phases were combined and washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.694 g of 2-fluoro-6-methoxy-4-(thiazole-2-oxy)benzonitrile.

[0789] MS (ESI) M / Z: 251.1 [M+H] + .

[0790] Step B: Dissolve 2-fluoro-6-methoxy-4-(thiazol-2-yloxy)benzonitrile (0.694 g, 2.78 mmol), potassium carbonate (1.92 g, 13.88 mmol), and acetohydroxamic acid (0.625 g, 8.33 mmol) in N,N-dimethylformamide (21 mL) and water (3 mL). Stir the reaction at 60°C overnight.

[0791] After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was not further purified to yield 0.31 g of 4-methoxy-6-(thiazole-2-oxy)benzo[d]isoxazol-3-amine.

[0792] MS (ESI) M / Z: 264.1 [M+H] + .

[0793] Step C: Under nitrogen protection, 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (0.06 g, 0.228 mmol) and 4-methoxy-6-(thiazole-2-oxy)benzo[d]isoxazol-3-amine (0.05 g, 0.19 mmol) were dissolved in pyridine (0.5 mL), and the system was stirred at 100 ° C under microwave conditions for 3 hours.

[0794] After LCMS monitoring indicated complete reaction of the starting material, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 4 / 5) and then subjected to reverse phase chromatography (eluent: 0.01 vol% formic acid in water / acetonitrile = 1 / 1) to afford 2 mg of 7-methoxy-N-(4-methoxy-6-(thiazol-2-oxy)benzo[d]isoxazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0795] MS (ESI) M / Z: 506.0 [M+H] + .

[0796] 1 H NMR (400MHz, DMSO-d6): δ7.36-7.28(m,2H),7.22-7.12(m,2H),6.87-6.73(m,2H),4.05-3.96(m,3H),3.87(s,3H),3.70(s,3H),2.12-1.96(m,2H).

[0797] Example 22:

[0798] N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzopyrano[8,7-d]isoxazol-9-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0799] Reaction route:

[0800] Steps:

[0801] Step A: Under nitrogen protection, 4-bromo-2,6-difluorobenzonitrile (5.0 g, 23.04 mmol) and allyl alcohol (1.36 g, 23.54 mmol) were dissolved in a mixed solution of tetrahydrofuran (25 mL) and dioxane (25 mL). Sodium hydride (942 mg, 23.54 mmol, 60 wt%) was slowly added at 0°C. The reaction solution was slowly heated to 25°C and stirred for 3 hours.

[0802] After LCMS showed completion of the reaction, the pH was adjusted to 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtered, dried, and purified by column chromatography to yield 6.3 g of 2-(allyloxy)-4-bromo-6-fluorobenzonitrile.

[0803] MS (ESI) M / Z: 256.0, 258.0 [M+H] + .

[0804] Step B: Under nitrogen protection, a solution of 2-(allyloxy)-4-bromo-6-fluorobenzonitrile (6.3 g, 24.61 mmol) in 1,2-dichlorobenzene (50 mL) was stirred at 175° C. for 8 hours.

[0805] After LCMS monitoring showed that most of the starting materials disappeared, the reaction solution was cooled to room temperature, the solution was spin-dried and purified by column chromatography to obtain 4.2 g of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile.

[0806] MS (ESI) M / Z: 256.0, 258.0 [M+H] + .

[0807] 1 H NMR (400MHz, DMSO-d6): δ11.49(s,1H),7.38(d,J=8.9Hz,1H),5.87-5.77(m,1H),5.04-5.01(m,1H),4.92-4.87(m,1H),3.52(d,J=5.7Hz,2H).

[0808] Step C: Under nitrogen, borane-tetrahydrofuran complex (18.1 mL, 18.07 mmol, 1 M dissolved in tetrahydrofuran) was slowly added dropwise to a solution of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (4.2 g, 16.41 mmol) in tetrahydrofuran at 0°C. After stirring at 0°C for 1 hour, 30 wt% hydrogen peroxide solution (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added and stirred at 0°C for 1 hour.

[0809] After LCMS showed completion of the reaction, the mixture was quenched with saturated aqueous sodium thiosulfate at 0°C and acidified to pH 2 with concentrated hydrochloric acid. Extraction was then performed with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtering, the solvent was removed by vortexing, and purification by column chromatography afforded 2.7 g of 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile.

[0810] MS (ESI) M / Z: 274.0 [M+H] + .

[0811] Step D: Under nitrogen protection, diethyl azodicarboxylate (1.43 mL, 9.85 mmol) was slowly added dropwise to a solution of 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile (2.7 g, 9.85 mmol) and triphenylphosphine (2.58 g, 9.85 mmol) in anhydrous tetrahydrofuran (100 mL) in an ice bath, and the reaction solution was stirred at 0°C for 0.5 h.

[0812] After LCMS showed that the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate solution (100 mL×3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vortexing and purified by column chromatography to obtain 1.5 g of 5-bromo-7-fluorochroman-8-carbonitrile.

[0813] MS (ESI) M / Z: 256.0, 258.0 [M+H] + .

[0814] Step E: 5-Bromo-7-fluorochroman-8-carbonitrile (1.5 g, 5.86 mmol) was dissolved in methanol (30 mL), and palladium acetate (263 mg, 1.17 mmol) and triethylamine (2.44 mL, 17.58 mmol) were added. The mixture was purged with a carbon monoxide balloon three times, and the reaction mixture was stirred at 65°C under a carbon monoxide atmosphere for 16 hours.

[0815] After the reaction was completed, the reaction was monitored by LCMS and concentrated under reduced pressure to remove methanol. Ethyl acetate solution (30 mL) and water (50 mL) were added, extracted with ethyl acetate solution (50 mL×3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.0 g of the target product, 8-cyano-7-fluorochroman-5-carboxylic acid methyl ester.

[0816] MS (ESI) M / Z: 236.1 [M+H] + .

[0817] 1H NMR (400MHz, DMSO-d6): δ7.32 (d, J=9.6Hz, 1H), 4.45-4.31 (m, 2H), 3.86 (s, 3H), 2.92 (t, J=6.0Hz, 2H), 1.99-1.90 (m, 2H).

[0818] Step F: Under nitrogen, methyl 8-cyano-7-fluorochroman-5-carboxylate (800 mg, 3.40 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Lithium borohydride (3.40 mL, 6.80 mmol, 2 M in tetrahydrofuran) was slowly added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour.

[0819] After the reaction was completed, as monitored by LCMS, 20 mL of water was slowly added dropwise to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 700 mg of the target product, 7-fluoro-5-(hydroxymethyl)chroman-8-carbonitrile.

[0820] MS (ESI) M / Z: 208.1 [M+H] + .

[0821] Step G: Under nitrogen protection, 7-fluoro-5-(hydroxymethyl)chroman-8-carbonitrile (700 mg, 3.38 mmol), 1-(methylsulfonyl)-1H-pyrazole (593 mg, 4.06 mmol) and cesium carbonate (1.65 g, 5.07 mmol) were dissolved in acetonitrile (10 mL), and the system was stirred at 70 ° C for 2 hours.

[0822] After LCMS monitoring indicated complete reaction of the starting material, the reaction solution was added to ethyl acetate (30 mL), filtered, the filter cake washed with ethyl acetate (50 mL), and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 546 mg of the desired product, 5-((1H-pyrazol-1-yl)methyl)-7-fluorochroman-8-carbonitrile.

[0823] MS (ESI) M / Z: 258.1 [M+H] + .

[0824] Step H: Under nitrogen protection, N-hydroxyacetamide (478 mg, 6.37 mmol) and potassium tert-butoxide (714 mg, 6.37 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the system was stirred at room temperature for 1 hour. 5-((1H-pyrazol-1-yl)methyl)-7-fluorochroman-8-carbonitrile (546 mg, 2.12 mmol) was added, and the system was stirred at 60°C for 6 hours.

[0825] After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of the desired product, 5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-amine.

[0826] MS (ESI) M / Z: 271.2 [M+H] + .

[0827] 1 H NMR (400MHz, DMSO-d6): δ7.78(d,J=2.2Hz,1H),7.51(d,J=1.6Hz,1H),6.33-6.31(m,2H) ,5.86(s,2H),5.38(s,2H),4.31-4.17(m,2H),2.67(t,J=6.4Hz,2H),2.06-1.92(m,2H).

[0828] Step I: Under nitrogen, 5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzopyrano[8,7-d]isoxazol-9-amine (50 mg, 0.18 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonyl chloride (78 mg, 0.28 mmol) were dissolved in anhydrous pyridine (1 mL). The reaction was stirred at 100°C for 16 hours.

[0829] After the reaction was completed, as monitored by LCMS, 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated ammonium chloride solution (50 mL × 3) and saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative purification to give 32.4 mg of the target product, N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzopyrano[8,7-d]isoxazol-9-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0830] MS (ESI) M / Z: 513.2 [M+H] + .

[0831] 1H NMR (400MHz, DMSO-d6): δ9.74(s,1H),7.79(d,J=2.2Hz,1H),7.51(d,J=1.6Hz ,1H),7.23(d,J=9.2Hz,1H),6.79(d,J=9.2Hz,1H),6.44(s,1H),6.32(t,J=2.0 Hz,1H),5.42(s,2H),4.21-4.15(m,2H),4.12-4.06(m,2H),4.02-3.97(m,2H) ,3.71(s,3H),2.69(t,J=6.4Hz,2H),2.05(d,J=5.0Hz,2H),2.02-1.96(m,2H).

[0832] Example 23:

[0833] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxetine-6-sulfonamide

[0834] Reaction route:

[0835] Steps:

[0836] Step A: To a solution of 4-methoxy-5-methyl-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (30 mg, 0.12 mmol) in pyridine (1 mL) was added 7-methoxy-3,4-dihydro-2H-1,5-benzodioxane-6-sulfonyl chloride (66.89 mg, 0.24 mmol). The reaction was microwaved at 100°C for 3 hours. LCMS showed residual starting material and the target peak was formed. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 3 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonamide.

[0837] MS (ESI) M / Z: 501.1 [M+H] + .

[0838] 1H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.75(d,J=2.3Hz,1H),7.50(d,J=1.8Hz,1H),6.95(s,1H),6.59(d,J=9.2Hz,1H),6.3 7(s,1H),6.30(t,J=2.1Hz,1H),5.39(s,2H),4.03(s,3H),3.89(d,J=16.7Hz,4H),3.56(s,3H),2.17(s,3H),1.94(s,2H).

[0839] Example 24:

[0840] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide

[0841] Reaction route:

[0842] Steps:

[0843] Step A: To a solution of 4-methoxy-5-methyl-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.077 mmol) in pyridine (0.3 mL) was added 9-methoxy-6-oxatricyclo[5.4.0.0^{2,4}]undecane-1(7),8,10-triene-8-sulfonyl chloride (31.73 mg, 0.12 mmol) and the mixture was microwaved at 100°C for 6 hours. LCMS showed that the starting material was consumed and the target peak was generated. The mixture was concentrated under reduced pressure to remove the solvent and purified by preparative separation to give 13 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide.

[0844] MS (ESI) M / Z: 497.1 [M+H] + .

[0845] 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.80(d,J=2.3Hz,1H),7.53(d,J=1.8Hz,1H),7.43(s,1H),6.69(s,2H),6.32(t,J=2.1Hz,1 H),5.48(s,2H),4.23(s,1H),3.76(d,J=34.1Hz,6H),2.23(s,3H),2.02(s,1H),1.75(s,1H),0.96(s,1H),0.73(q,J=4.6Hz,1H).

[0846] Example 25:

[0847] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide

[0848] Reaction route:

[0849] Steps:

[0850] Step A: To a solution of 4-methoxy-5-methyl-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.077 mmol) in pyridine (0.3 mL) was added 6-methoxy-2H-spiro[1-benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (25.38 mg, 0.092 mmol). The reaction was microwaved at 100°C for 6 hours. LCMS indicated residual starting material and the formation of the target molecule. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 8 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-5-methylbenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0851] MS (ESI) M / Z: 497.1 [M+H] + .

[0852] 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),7.79(s,1H),7.52(d,J=1.8Hz,1H),6.68(s,2H),6.52(s,1H),6.32( t,J=2.1Hz,1H),5.48(s,2H),4.48(s,2H),3.87(s,3H),3.71(s,3H),2.23(s,3H),1.01(d,J=12.2Hz,4H).

[0853] Example 26:

[0854] N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxetine-6-sulfonamide

[0855] Reaction route:

[0856] Steps:

[0857] Step A: To a solution of 5-ethyl-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.073 mmol) in pyridine (1 mL) was added 7-methoxy-3,4-dihydro-2H-1,5-benzodioxane-6-sulfonyl chloride (61.04 mg, 0.22 mmol). The mixture was microwaved at 100°C for 3 hours. LCMS indicated the formation of the desired peak. The solvent was removed by concentration under reduced pressure. The product was purified by preparative separation to give 13 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonamide.

[0858] MS (ESI) M / Z: 515.2 [M+H] + .

[0859] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.84(s,1H),7.51(s,1H),7.24(s,1H),6.79(s,2H),6.32(s,1H) ,5.52(s,2H),4.03(s,5H),3.87(s,3H),3.72(s,2H),2.75(s,2H),2.06(d,J=10.8Hz,2H),1.02(s,3H).

[0860] Example 27:

[0861] N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide

[0862] Reaction route:

[0863] Steps:

[0864] Step A: To a solution of 5-ethyl-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.073 mmol) in pyridine (0.3 mL) was added 5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonyl chloride (30.08 mg, 0.11 mmol). The mixture was microwaved at 100°C for 6 hours. LCMS showed residual starting material and the desired peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative separation to yield 12 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide.

[0865] MS (ESI) M / Z: 511.2 [M+H] + .

[0866] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.83(s,1H),7.51(d,J=1.8Hz,2H),6.71(s,2H),6.31(t,J=2.1Hz,1H),5.50(s,2H),4.24 (s,1H),3.88(s,3H),3.70(s,4H),2.74(d,J=7.7Hz,2H),2.01(s,1H),1.74(s,1H),1.01(t,J=7.3Hz,4H),0.73(q,J=4.6Hz,1H).

[0867] Example 28:

[0868] N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide

[0869] Reaction route:

[0870] Steps:

[0871] Step A: To a solution of 5-ethyl-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.073 mmol) in pyridine (0.3 mL) was added 6-methoxy-2H-spiro[1-benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (24.07 mg, 0.088 mmol). The reaction was microwaved at 100°C for 6 hours. LCMS showed residual starting material and the target peak was formed. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 8 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-ethyl-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0872] MS (ESI) M / Z: 511.2 [M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.49(d,J=1.8Hz,1H),6.54(d,J=125.0Hz,3H),6.30(d,J=2.1Hz ,1H),5.44(s,2H),4.39(s,2H),4.07(s,3H),3.59(s,3H),2.75-2.67(m,2H),0.97(d,J=11.3Hz,7H).

[0874] Example 29:

[0875] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxetine-6-sulfonamide

[0876] Reaction route:

[0877] Steps:

[0878] Step A: To a solution of 5-fluoro-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (60 mg, 0.23 mmol) in pyridine (1 mL) was added 7-methoxy-3,4-dihydro-2H-1,5-benzodioxane-6-sulfonyl chloride (76.92 mg, 0.28 mmol). The mixture was microwaved at 100°C for 3 hours. LCMS indicated complete consumption of the starting material, with the presence of product. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative separation to yield 35 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxane-6-sulfonamide.

[0879] MS (ESI) M / Z: 505.1 [M+H] + .

[0880] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),7.86(d,J=2.2Hz,1H),7.50(d,J=1.8Hz,1H),7.24(d,J=9.1Hz,1H),6.92(s,1H), 6.80(d,J=9.1Hz,1H),6.30(d,J=2.1Hz,1H),5.50(s,2H),4.04(d,J=19.0Hz,7H),3.71(s,3H),2.06(d,J=10.2Hz,2H).

[0881] Example 30:

[0882] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide

[0883] Reaction route:

[0884] Steps:

[0885] Step A: To a solution of 5-fluoro-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.076 mmol) in pyridine (0.3 mL) was added 5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonyl chloride (31.32 mg, 0.11 mmol). The mixture was microwaved at 100°C for 6 hours. LCMS showed consumption of the starting material and the formation of the desired peak. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative separation to give 8 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide.

[0886] MS (ESI) M / Z: 501.1 [M+H] + .

[0887] 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.3Hz,1H),7.50(d,J=1.8Hz,1H),7.35(s,1H),6.73(d,J=55.8Hz,2H),6.30(t,J=2.1H z,1H),5.48(s,2H),4.07(s,4H),3.68(s,3H),3.52(s,1H),1.98(s,1H),1.71(s,1H),0.93(s,1H),0.71(q,J=4.6Hz,1H).

[0888] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide / (1aS,7bR)-N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide

[0889] Reaction route:

[0890] Steps:

[0891] Step A: To a solution of 5-fluoro-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.076 mmol) in pyridine (0.5 mL) was added INT-10-P1 (31.32 mg, 0.11 mmol). The mixture was microwaved at 100°C for 6 hours. LCMS indicated residual starting material and the target peak. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 9 mg of compound 30-P1.

[0892] MS (ESI) M / Z: 501.1 [M+H] + .

[0893] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.85(d,J=2.3Hz,1H),7.55-7.35(m,2H),6.79(d,J=73.5Hz,2H),6.30(t,J=2.1Hz ,1H),5.49(s,2H),4.24(s,1H),4.05(s,3H),3.70(s,4H),2.01(s,1H),1.74(s,1H),0.95(s,1H),0.71(q,J=4.6Hz,1H).

[0894] Example 31:

[0895] N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide

[0896] Reaction route:

[0897] Steps:

[0898] Step A: To a solution of 5-fluoro-4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.076 mmol) in pyridine (0.3 mL) was added 6-methoxy-2H-spiro[1-benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (31.32 mg, 0.11 mmol). The mixture was microwaved at 100°C for 6 hours. LCMS indicated consumption of the starting material and formation of the desired peak. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 6 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-fluoro-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0899] MS (ESI) M / Z: 501.1 [M+H] + .

[0900] 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),6.81(s,2H),6.46(s,1H) ,6.30(t,J=2.1Hz,1H),5.47(s,2H),4.45(s,2H),4.09(s,3H),3.65(s,3H),1.10-0.90(m,4H).

[0901] Example 32:

[0902] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2H,4H-spiro[benzo[b][1,4]dioxane-3,3'-oxetane]-6-sulfonamide

[0903] Reaction route:

[0904] Steps:

[0905] Step A: To a solution of 2-hydroxy-4-methoxybenzaldehyde (5 g, 32.86 mmol) in tetrahydrofuran (125 mL) and water (50 mL) was added sodium percarbonate (2:3) (5.16 g, 16.43 mmol) at 0°C, followed by reaction at 25°C for 1 hour. LCMS indicated the disappearance of the starting material and the formation of the desired peak. The pH was adjusted to 2-3 with 6M hydrochloric acid, followed by extraction with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 3.8 g of 4-methoxybenzene-1,2-diol.

[0906] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.34(s,1H),6.61(d,J=8.6Hz,1H),6.34(d,J=2.9Hz,1H),6.18(dd,J=8.6,3.0Hz,1H),3.61(s,3H).

[0907] Step B: To a solution of 4-methoxybenzene-1,2-diol (2 g, 14.27 mmol) and 3,3-bis(bromomethyl)oxetane (5221.11 mg, 21.41 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (5916.77 mg, 42.81 mmol) and potassium iodide (236.88 mg, 1.43 mmol), followed by stirring at 100°C for 5 hours. LCMS indicated the main peak as the target peak. Water (80 mL) was added to the reaction solution, which was then extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (40 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 2.1 g of 7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane].

[0908] MS (ESI) M / Z: 223.1 [M+H] + .

[0909] Step C: To a solution of 7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane] (1000 mg, 4.50 mmol) and N,N,N',N'-tetramethylethylenediamine (575.19 mg, 4.95 mmol) in tetrahydrofuran (15 mL) at 0°C was added n-butyllithium (319.98 mg, 5.00 mmol) dropwise. The mixture was allowed to react at 0°C for 1 hour. The temperature was then lowered to -70°C, and a solution of [(benzyldisulfanyl)methyl]benzene (1219.63 mg, 4.95 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture. The mixture was allowed to react at -70°C for 0.5 hour, then warmed to room temperature and stirred for 1 hour. LCMS showed a major peak that was not the target molecule. At 0 ° C, 5 mL of saturated ammonium chloride and 20 mL of water were added to the reaction solution, followed by extraction with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.4 g of the product 6-(benzylthio)-7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane].

[0910] MS (ESI) M / Z: 345.1 [M+H] + .

[0911] Step D: To a solution of 6-(benzylthio)-7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane] (150 mg, 0.44 mmol) in acetic acid (5 mL) and water (0.5 mL) was added N-chlorosuccinimide (176.26 mg, 1.32 mmol) at 0°C. The mixture was stirred at 0-10°C for 1 hour. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the disappearance of the starting material and the formation of a new spot with the same polarity as the pilot product. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 75 mg of 7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane]-6-sulfonyl chloride.

[0912] 1 H NMR(400MHz,Chloroform-d)δ7.23(d,J=9.2Hz,1H),6.62(d,J=9.2Hz,1H),4.55 (d,J=6.7Hz,2H),4.48(d,J=6.8Hz,2H),4.43(s,2H),4.29(s,2H),3.87(s,3H).

[0913] Step E: To a solution of 4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (20 mg, 0.082 mmol) in pyridine (0.5 mL) was added 7-methoxy-2,4-dihydrospiro[1,5-benzodioxepane-3,3'-oxetane]-6-sulfonyl chloride (39.45 mg, 0.12 mmol). The mixture was stirred at 100°C for 12 hours. LCMS showed the desired peak. The mixture was concentrated under reduced pressure and purified by preparative isolation to afford 3.3 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-2H,4H-spiro[benzo[b][1,4]dioxane-3,3'-oxetane]-6-sulfonamide.

[0914] MS (ESI) M / Z: 529.2 [M+H] + .

[0915] 1H NMR(400MHz,DMSO-d6)δ7.85(d,J=2.3Hz,1H),7.48(d,J=1.9Hz,1H),7.05(s,1H),6.67-6.55(m,3H ), 6.28 (t, J = 2.1Hz, 1H), 5.39 (s, 2H), 4.32 (s, 4H), 4.13 (d, J = 7.8Hz, 4H), 3.83 (s, 3H), 3.59 (s, 3H).

[0916] Example 33:

[0917] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide / (1aS,7bR)-N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide

[0918] Reaction route:

[0919] Steps:

[0920] Step A: To a solution of 5-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (15 mg, 0.061 mmol) in pyridine (0.5 mL) was added (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonyl chloride (25.14 mg, 0.091 mmol). The mixture was microwaved at 100°C for 6 hours. Thin-layer chromatography (TLC) indicated the disappearance of the starting material and the formation of new spots. The solvent was removed by concentration under reduced pressure, and the product was purified by preparative isolation to yield 21 mg of (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide.

[0921] MS (ESI) M / Z: 483.1 [M+H] + .

[0922] 1H NMR (400MHz, DMSO-d6) δ11.35(s,1H),7.81(d,J=2.3Hz,1H),7.59(s,1H),7.50(d,J=1. 8Hz,1H),7.40(d,J=8.5Hz,1H),6.79(s,1H),6.67(d,J=8.6Hz,1H),6.30(t,J=2.1Hz,1H ),5.39(s,2H),4.22(s,1H),3.85(s,3H),3.69(s,3H),3.47(d,J=10.9Hz,1H),1.98(td ,J=8.4,4.3Hz,1H),1.72(d,J=6.7Hz,1H),0.93(q,J=3.8Hz,1H),0.64(q,J=4.7Hz,1H).

[0923] Example 34:

[0924] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide / (1aS,7bR)-N-(6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide

[0925] Reaction route:

[0926] Steps:

[0927] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-amine (9 mg, 0.039 mmol) and (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-sulfonyl chloride (16 mg, 0.058 mmol) were dissolved in pyridine (0.4 mL) and stirred in a microwave oven at 100°C for 6 hours. After LCMS monitoring indicated complete reaction, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 18 mg of (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-5-fluorobenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide.

[0928] MS (ESI) M / Z: 471.1 [M+H] + .

[0929] 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),7.85(d,J=2.3Hz,1H),7.77(s,1H),7.49(d,J=1.8Hz,1H),7.36(s,1H),7.19(s,1H),6.65(s,1H),6.30(t,J= 2.1Hz,1H),5.49(s,2H),4.16(s,1H),3.67(s,3H),2.00(dd,J=15.6,8.2 Hz,2H),1.73(d,J=18.0Hz,1H),0.98-0.88(m,1H),0.66(d,J=4.9Hz,1H).

[0930] Example 35:

[0931] N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0932] Reaction route:

[0933] Steps:

[0934] Step A: Under nitrogen, 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofurano[7,6-d]isoxazol-8-amine (8 mg, 0.031 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (20 mg, 0.072 mmol) were dissolved in pyridine (0.4 mL) and stirred in a microwave at 100°C for 6 hours. After LCMS monitoring showed that the starting materials were completely reacted, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 6 mg of N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0935] MS (ESI) M / Z: 499.1 [M+H] + .

[0936] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),7.82(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.20(s,1H),6.71(d,J=33.6Hz,2H),6.35 -6.23(m,1H),5.39(s,2H),4.68(d,J=10.7Hz,2H),3.98(s,4H),3.67(s,3H),3.14-3.01(m,2H),2.00(dd,J=13.8,6.8Hz,2H).

[0937] Example 36:

[0938] N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-6-methoxy-2H-spiro[benzofuran-3,1′-cyclopropane]-7-sulfonamide

[0939] Reaction route:

[0940] Steps:

[0941] Step A: Under nitrogen protection, 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofurano[7,6-d]isoxazol-8-amine (12 mg, 0.047 mmol) and 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (26 mg, 0.095 mmol) were dissolved in pyridine (0.4 mL) and the system was stirred under microwave conditions at 100°C for 6 hours. After LCMS monitoring showed that the raw materials were completely reacted, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 8 mg of N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0942] MS (ESI) M / Z: 495.1 [M+H] + .

[0943] 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.82(d,J=2.2Hz,1H),7.49(s,1H),6.88(s,1H),6.66(s,1H),6.49(d,J=8.3Hz,1H),6.3 0(t,J=2.2Hz,1H),5.40(s,2H),4.70(t,J=8.9Hz,2H),4.47(s,2H),3.68(s,3H),3.09(t,J=8.9Hz,2H),1.00(d,J=12.4Hz,4H).

[0944] Example 37:

[0945] N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-sulfonamide

[0946] Reaction route:

[0947] Steps:

[0948] Step A: Under nitrogen protection, 4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofurano[7,6-d]isoxazol-8-amine (12 mg, 0.047 mmol) and 5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonyl chloride (26 mg, 0.095 mmol) were dissolved in pyridine (0.4 mL) and the system was stirred under microwave conditions at 100 degrees for 6 hours. After LCMS monitoring showed that the raw materials were completely reacted, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 10 mg of N-(4-((1H-pyrazol-1-yl)methyl)-2,3-dihydrobenzofuro[7,6-d]isoxazol-8-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide.

[0949] MS (ESI) M / Z: 495.1 [M+H] + .

[0950] HNMR(400MHz,DMSO-d6)δ7.82(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.36(s,1H) ,6.72-6.50(m,2H),6.30(t,J=2.1Hz,1H),5.39(s,2H),4.70(t,J=8.9Hz,2H),4. 16(s,1H),3.67(s,3H),3.64-3.49(m,1H),3.09(t,J=8.9Hz,2H),1.99(q,J=4.4H z,1H),1.72(d,J=7.0Hz,1H),0.94(td,J=8.3,4.3Hz,1H),0.72(q,J=4.6Hz,1H).

[0951] Example 38:

[0952] N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide

[0953] Reaction route:

[0954] Steps:

[0955] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-amine (20 mg, 0.077 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (0.042 g, 0.15 mmol) were dissolved in pyridine (0.5 mL) and stirred in a microwave at 100°C for 6 hours. After LCMS monitoring showed complete reaction of the starting materials, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 20 mg of 7N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonamide.

[0956] MS (ESI) M / Z: 497.1 [M+H] + .

[0957] 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),7.86(d,J=2.3Hz,1H),7.50(d,J=1.9Hz,1H ),7.45(d,J=8.5Hz,1H),6.88(s,1H),6.72(d,J=8.6Hz,1H),6.31(t,J=2.1Hz,1H ),5.48(s,2H),4.26(d,J=10.8Hz,1H),3.70(d,J=3.0Hz,6H),2.56(s,3H),2.10- 1.96(m,2H),1.77(q,J=7.7Hz,1H),0.99(q,J=3.9Hz,1H),0.75(q,J=4.7Hz,1H).

[0958] Example 39:

[0959] N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide

[0960] Reaction route:

[0961] Steps:

[0962] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-amine (20 mg, 0.077 mmol) and 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonyl chloride (0.042 g, 0.15 mmol) were dissolved in pyridine (0.5 mL) and stirred in a microwave at 100°C for 6 hours. After LCMS monitoring showed that the reaction of the starting materials was complete, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 20 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-sulfonamide.

[0963] MS (ESI) M / Z: 497.1 [M+H] + .

[0964] 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.86(d,J=2.3Hz,1H),7.50(d,J=1.8Hz,1H),6.95-6.85(m,2H),6.55(d,J=8.3Hz ,1H),6.31(t,J=2.0Hz,1H),5.48(s,2H),4.47(s,2H),3.69(d,J=2.9Hz,6H),2.54(s,3H),1.01(dd,J=7.6,2.2Hz,4H).

[0965] Example 40:

[0966] N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide

[0967] Reaction route:

[0968] Steps:

[0969] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-amine (20 mg, 0.077 mmol) and 5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl-4-benzenesulfonyl chloride (0.042 g, 0.15 mmol) were dissolved in pyridine (0.5 mL) and stirred in a microwave at 100°C for 6 hours. After LCMS monitoring showed complete reaction of the starting materials, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 18 mg of N-(6-((1H-pyrazol-1-yl)methyl)-5-methoxy-4-methylbenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide.

[0970] MS (ESI) M / Z: 497.1 [M+H] + .

[0971] 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),7.86(d,J=2.3Hz,1H),7.50(d,J=1.9Hz,1H ),7.45(d,J=8.5Hz,1H),6.88(s,1H),6.72(d,J=8.6Hz,1H),6.31(t,J=2.1Hz,1H ),5.48(s,2H),4.26(d,J=10.8Hz,1H),3.70(d,J=3.0Hz,6H),2.56(s,3H),2.10- 1.96(m,2H),1.77(q,J=7.7Hz,1H),0.99(q,J=3.9Hz,1H),0.75(q,J=4.7Hz,1H).

[0972] Example 41:

[0973] N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-sulfonamide

[0974] Reaction route:

[0975] Steps:

[0976] Step A: Under nitrogen, dissolve 2-amino-5-methoxyphenol (2 g, 14.39 mmol) in formic acid (20 mL). Add sodium formate (988 mg, 14.5 mmol) and heat to 90°C for 16 hours. Monitor the reaction by LCMS. After completion, extract with ethyl acetate (60 mL) and water (60 mL). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography using petroleum ether / ethyl acetate (3:1) to yield 1.8 g of N-(2-hydroxy-4-methoxyphenyl)formamide.

[0977] MS (ESI) M / Z: 168.1 [M+H] + .

[0978] Step B: Dissolve N-(2-hydroxy-4-methoxyphenyl)formamide (1.8 g, 10.78 mmol) in N,N-dimethylformamide (20 mL). Add sodium hydride (2.59 g, 107.8 mmol, 60 wt%) and allow to react for 10 minutes. Then add 1,3-dibromopropane (1.64 mL, 16.17 mmol) and react at 120°C for 12 hours. Monitor the reaction by LCMS. After the starting material is consumed, the reaction mixture is quenched with water, extracted with ethyl acetate (60 mL) and water (60 mL), and the organic phase is dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 3 / 1 yields 400 mg of 8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine.

[0979] MS (ESI) M / Z: 180.1 [M+H] + .

[0980] Step C: To a solution of 8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (350 mg, 1.944 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (117 mg, 4.86 mmol, 60 wt%) under ice-cooling conditions. After 10 minutes, iodomethane (121 μL, 2.92 mmol) was added and the reaction was allowed to react at room temperature for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction solution was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (20 mL) and water (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography was performed using a 3:1 ratio of petroleum ether to ethyl acetate as the developing solvent to yield 218 mg of 8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine.

[0981] MS (ESI) M / Z: 194.2 [M+H] + .

[0982] Step D: To a solution of 8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (218 mg, 1.12 mmol) and N,N,N',N'-tetramethylethylenediamine (185 μL, 1.24 mmol) in tetrahydrofuran (5 mL) at 0°C was added n-butyllithium (494 μL, 1.24 mmol). After 20 minutes, the temperature was lowered to -78°C and a solution of dibenzyl sulfide (304 mg, 1.24 mmol) in tetrahydrofuran was added. The reaction was allowed to react at room temperature for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction mixture was quenched with water and distilled under reduced pressure. The resulting residue was extracted with ethyl acetate (20 mL) and water (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and subjected to column chromatography using a developing solvent of petroleum ether / ethyl acetate = 3:1. This gave 304 mg of 9-(benzylthio)-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine.

[0983] MS (ESI) M / Z: 316.1 [M+H] + .

[0984] Step E: Under nitrogen, to a solution of 9-(benzylthio)-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (10 mg, 0.317 mmol) in acetic acid (1.5 mL) and water (0.5 mL) was added N-chlorosuccinimide (187.6 mg, 0.952 mmol) and reacted at 0°C for 3 hours. After thin-layer chromatography indicated complete conversion of the starting material to product, the reaction solution was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (10 mL) and water (10 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and subjected to column chromatography to afford 38 mg of 8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-sulfonyl chloride.

[0985] MS (ESI) M / Z: 292.0 [M+H] + .

[0986] Step F: Under nitrogen, 6-((1H-pyrazol-6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine (12 mg, 0.025 mmol) and 8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-sulfonyl chloride (31 mg, 0.095 mmol) were dissolved in pyridine (0.4 mL) and stirred in a microwave oven at 100 °C for 6 hours. After LCMS monitoring showed the reaction was complete, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 6 mg of N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-sulfonamide.

[0987] MS (ESI) M / Z: 500.2 [M+H] + .

[0988] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=2.2Hz,1H),7.49(d,J=1.8Hz,1H),7.04(d,J=9.0Hz,1H),6.82-6.67(m,3H),6.30(t,J=2.1H z,1H),5.43(s,2H),3.97(t,J=5.2Hz,2H),3.85(s,3H),3.65(s,3H),2.90(t,J=5.5Hz,2H),2.74(s,3H),1.85(p,J=5.4Hz,2H).

[0989] Example 42:

[0990] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide

[0991] Reaction route:

[0992] Steps:

[0993] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-amine (20 mg, 0.081 mmol) and (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-sulfonyl chloride (33 mg, 0.12 mmol) were dissolved in pyridine (0.4 mL) and stirred in a microwave oven at 100°C for 6 hours. After LCMS monitoring indicated complete reaction of the starting materials, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 20 mg of (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-sulfonamide.

[0994] MS (ESI) M / Z: 485.1 [M+H] + .

[0995] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.88(d,J=2.2Hz,1H),7.50(d,J=1.8Hz,1H),7.43( d,J=8.5Hz,1H),6.83(s,1H),6.75(s,1H),6.70(d,J=8.5Hz,1H),6.30(t,J=2.1Hz,1H), 4.25(d,J=10.8Hz,1H),3.87(s,3H),3.72(s,3H),3.58(d,J=10.7Hz,1H),2.01(td,J=8. 6,4.1Hz,1H),1.75(q,J=7.5Hz,1H),0.95(td,J=8.2,4.5Hz,1H),0.65(q,J=4.7Hz,1H).

[0996] Example 43:

[0997] N-(6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-sulfonamide

[0998] Reaction route:

[0999] Steps:

[1000] Step A: Under nitrogen, 6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-amine (20 mg, 0.081 mmol) and 7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-sulfonyl chloride (34 mg, 0.12 mmol) were dissolved in pyridine (0.4 mL) and stirred in a microwave oven at 100°C for 6 hours. After LCMS monitoring showed complete reaction of the starting materials, the reaction solution was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography and reverse phase preparation to give 16 mg of N-(6-((1H-pyrazol-1-yl)methyl-d2)-4-methoxybenzo[d]isoxazol-3-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-sulfonamide.

[1001] MS (ESI) M / Z: 489.1 [M+H] + .

[1002] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),7.88(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.20(d,J=9.0Hz,1H),6.93-6 .67(m,3H),6.30(t,J=2.1Hz,1H),4.02(dt,J=26.1,5.2Hz,4H),3.83(s,3H),3.68(s,3H),2.05(q,J=5.3Hz,2H).

[1003] Example 44:

[1004] 4-Methoxy-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-3-sulfonamide

[1005] Reaction route:

[1006] Steps:

[1007] Step A: Dissolve 2-hydroxy-4-methoxybenzaldehyde (2 g, 13.15 mmol) in acetonitrile (30 mL), add potassium carbonate (3.63 g, 26.29 mmol) and 1,2-dibromoethane (24.69 g, 131.45 mmol, 9.92 mL), and stir at 90°C for 12 hours. After LCMS monitoring shows complete reaction of the starting material, the reaction solution is concentrated under reduced pressure. Extract with ethyl acetate and water, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting mixture is purified by silica gel column chromatography to yield 2.53 g of 2-(2-bromoethoxy)-4-methoxybenzaldehyde.

[1008] MS (ESI) M / Z: 260.5 [M+H] + .

[1009] 1 H NMR(400MHz,CHLOROFORM-d)δ3.65-3.76(m,2H),3.83-3.94(m,3H),4.34-4.44(m, 2H),6.38-6.46(m,1H),6.56-6.65(m,1H),7.81-7.89(m,1H),10.34-10.43(m,1H).

[1010] Step B: Dissolve 2-(2-bromoethoxy)-4-methoxybenzaldehyde (2.5 g, 9.65 mmol) in dimethyl sulfoxide (25 mL), add potassium tert-butoxide (1.30 g, 11.58 mmol), and stir at 25°C for 2 hours. After LCMS monitoring indicates complete reaction of the starting material, the reaction solution is extracted with ethyl acetate and water. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting mixture is purified by silica gel column chromatography to yield 495 mg of 4-methoxy-2-vinyloxybenzaldehyde.

[1011] MS (ESI) M / Z: 178.6 [M+H] + .

[1012] 1 H NMR(400MHz,CHLOROFORM-d)δ3.85-3.93(m,3H),4.60-4.68(m,1H),4.86-4.96(m,1H ),6.51-6.56(m,1H),6.64-6.75(m,2H),7.86(d,J=8.8Hz,1H),10.26-10.37(m,1H).

[1013] Step C: 4-Methoxy-2-vinyloxy-benzaldehyde (490 mg, 2.75 mmol) was dissolved in methanol (10 mL), and 4-methylbenzenesulfonylhydrazide (563.34 mg, 3.02 mmol) was added. The mixture was stirred at 25°C for 12 hours. After LCMS monitoring showed that the starting material was completely reacted, the reaction solution was filtered, and the residue was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1.1 g of N-[(E)-(4-methoxy-2-vinyloxy-phenyl)methyleneamino]-4-methyl-benzenesulfonamide.

[1014] MS (ESI) M / Z: 346.7 [M+H] + .

[1015] 1 H NMR(400MHz,CHLOROFORM-d)δ2.42(s,3H),3.82(s,3H),4.50(dd,J=6.0,1.8Hz,1H),4.68-4.78(m,1H),6.46(d,J=2.3Hz,1H),6.5 5(dd,J=13.8,6.0Hz,1H),6.65(dd,J=8.8,2.3Hz,1H),7.29-7.35(m,2H),7.51-7.64(m,1H),7.79-7.91(m,3H),8.00-8.05(m,1H).

[1016] Step D: Under nitrogen, N-[(E)-(4-methoxy-2-vinyloxy-phenyl)methyleneamino]-4-methyl-benzenesulfonamide (1090 mg, 3.15 mmol), lithium tert-butoxide (277.09 mg, 3.46 mmol), and bis[(α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid)rhodium (239.93 mg, 314.67 μmol) were dissolved in toluene (30 mL) and stirred at 110°C for 12 hours. After LCMS monitoring indicated complete reaction of the starting materials, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 409 mg of 4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran.

[1017] MS (ESI) M / Z: 162.6 [M+H] + .

[1018] 1H NMR(400MHz,CHLOROFORM-d)δ0.24-0.35(m,1H),0.89-1.00(m,1H),2.56(ddd,J=8.9,5.3,4.1Hz,1H),3.73(br d,J=5.8Hz,3H),4.75-4.87(m,1H),6.39-6.47(m,2H),7.16-7.23(m,1H).

[1019] Step E: Under nitrogen, 4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran (200 mg, 1.23 mmol) and N,N,N',N'-tetramethylethane-1,2-diamine (157.63 mg, 1.36 mmol, 204.71 μL) were dissolved in tetrahydrofuran (4 mL), cooled to 0°C, and n-butyllithium (1.6 M, 847.80 μL) was added dropwise. After stirring at this temperature for 1 hour, the temperature was lowered to -78°C, and a solution of 1,2-dibenzyldisulfane (334.22 mg, 1.36 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring at this temperature for 0.5 hour, the temperature was raised to room temperature and stirred for 1 hour. After LCMS monitoring showed that most of the starting materials had reacted, the reaction solution was slowly poured into ice water to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography to obtain 295 mg of 3-benzylsulfonyl-4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran.

[1020] MS (ESI) M / Z: 284.7 [M+H] + .

[1021] 1 H NMR(400MHz,CHLOROFORM-d)δ0.10-0.20(m,1H),0.86-0.96(m,1H),2.50-2.60(m,1H),3.7 5-3.82(m,3H),3.95-4.07(m,2H),4.77-4.86(m,1H),6.33-6.39(m,1H),7.12-7.23(m,6H).

[1022] Step F: Dissolve 3-benzylsulfonyl-4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran (290 mg, 1.02 mmol) in acetic acid (5 mL) and water (0.5 mL). The mixture was cooled to 10°C and N-chlorosuccinimide (408.53 mg, 3.06 mmol) was added. The mixture was stirred at 10°C for 1 hour. After TLC monitoring indicated complete reaction of the starting material, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 218 mg of 4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-3-sulfonyl chloride.

[1023] 1 H NMR(400MHz,CHLOROFORM-d)δ0.47(ddd,J=6.7,4.4,1.8Hz,1H),1.11(ddd,J=8.8,6.8,5.5Hz, 1H),2.60-2.69(m,1H),3.98(s,3H),5.06-5.15(m,1H),6.46-6.57(m,1H),7.48-7.55(m,1H).

[1024] Step G: Dissolve 4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-amine (170 mg, 696.01 μmol) and 4-methoxy-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-3-sulfonyl chloride (217.74 mg, 835.21 μmol, 1.2 eq) in pyridine (1.3 mL) and stir at 110°C for 12 hours. After LCMS monitoring indicated that most of the starting material had reacted, the reaction mixture was concentrated under reduced pressure. The resulting mixture was purified by high performance liquid chromatography (column: Xtimate C18 150×40 mm×10 μm; mobile phase: [water(FA)-ACN]; gradient: 31%-61% B over 10 min) to obtain 140 mg of 4-methoxy-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-3-sulfonamide.

[1025] MS (ESI) M / Z: 468.9 [M+H] + .

[1026] 1H NMR(400MHz, DMSO-d6)δ0.05(ddd,J=6.1,4.2,1.5Hz,1H),0.96-1.09(m,1H),2.62-2.72(m,1H),3.62-3.72(m,3H),3.84(s,3H),4.98-5.08(m,1 H),5.30-5.49(m,2H),6.23-6.33(m,1H),6.50-6.60(m,1H),6.68-6.77( m,1H),6.83(s,1H),7.33-7.55(m,2H),7.91(s,1H),9.73-10.04(m,1H).

[1027] Example 45:

[1028] (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-4-(methoxy-d3)benzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide

[1029] Reaction route:

[1030] Steps:

[1031] Step A: Dissolve 6-(pyrazol-1-ylmethyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-amine (40 mg, 161.77 μmol) and (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-sulfonyl chloride (57.77 mg, 210.30 μmol) in pyridine (0.3 mL) and stir at 100°C for 12 hours. After LCMS monitoring indicated complete reaction, the reaction mixture was concentrated under reduced pressure. The resulting mixture was purified by high performance liquid chromatography (column: Xtimate C18 150×40mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 31%-61% B over 10 min) to give 23.13 mg of (1aR,7bS)-N-(6-((1H-pyrazol-1-yl)methyl)-4-(methoxy-d3)benzo[d]isoxazol-3-yl)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-sulfonamide.

[1032] MS (ESI) M / Z: 485.9 [M+H] + .

[1033] 1H NMR(400MHz,DMSO-d6)δppm 0.58-0.71(m,1H),0.89-0.99(m,1H),1.68-1.82(m,1H),1.95-2.06(m ,1H),3.51-3.63(m,1H),3.66-3.79(m,3H),4.16-4.31(m,1H),5.44(s, 2H),6.27-6.34(m,1H),6.66-6.77(m,2H),6.78-6.85(m,1H),7.38-7. 46(m,1H),7.47-7.52(m,1H),7.87(d,J=2.3Hz,1H),9.49-9.87(m,1H).

[1034] Example 46:

[1035] 7-Methoxy-N-[6-(pyrazol-1-ylmethyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-yl]-3,4-dihydro-2H-1,5-benzodioxepin-6-sulfonamide

[1036] Reaction route:

[1037] Steps:

[1038] Step A: 6-(Pyrazol-1-ylmethyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-amine (40 mg, 161.77 μmol) and 7-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-sulfonyl chloride (54.10 mg, 194.12 μmol) were dissolved in pyridine (0.3 mL) and the system was stirred at 100 °C for 12 hours.

[1039] After LCMS monitoring indicated that most of the starting material had reacted, the reaction solution was concentrated under reduced pressure. The resulting mixture was purified by high-performance liquid chromatography to yield 17.82 mg of 7-methoxy-N-[6-(pyrazol-1-ylmethyl)-4-(trideuteriomethoxy)-1,2-benzoxazol-3-yl]-3,4-dihydro-2H-1,5-benzodioxepin-6-sulfonamide.

[1040] MS (ESI) M / Z: 489.9 [M+H] + .

[1041] 1H NMR(400MHz,DMSO-d6)δppm 1.98-2.12(m,2H),3.65-3.74(m,3H),3.94-4.13(m,4H),5.40-5.48(m,2H),6.26-6.33(m ,1H),6.70-6.90(m,3H),7.17-7.27(m,1H),7.47-7.54(m,1H),7.84-7.92(m,1H),9.89(br s,1H).

[1042] Example 47:

[1043] (1aR,7bS)-5-Methoxy-N-(4-methoxy-6-(thiazol-2-yloxy)benzo[d]isoxazol-3-yl)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide

[1044] Reaction route:

[1045] Steps:

[1046] Step A: Under nitrogen protection, (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonyl chloride (0.06 g, 0.228 mmol) and 4-methoxy-6-(thiazole-2-oxy)benzo[d]isoxazol-3-amine (0.05 g, 0.19 mmol) were dissolved in pyridine (0.5 mL) and the system was stirred at 100 ° C under microwave conditions for 6 hours.

[1047] After LCMS monitoring indicated complete reaction of the starting material, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column and reverse phase chromatography (eluent: 0.01 vol% formic acid in water / acetonitrile = 1 / 1) to yield 22 mg of (1aR,7bS)-5-methoxy-N-(4-methoxy-6-(thiazol-2-yloxy)benzo[d]isoxazol-3-yl)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide.

[1048] MS (ESI) M / Z: 502.0 [M+H] + .

[1049] 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),7.42(s,1H),7.38-7.31(m,2H),7.21(s,1H),6.86(s,1H),6.71(d,J=8.5Hz,1H),4.24(s,1H),3. 90(s,3H),3.72(s,3H),3.59(d,J=10.6Hz,1H),2.00(d,J=7.8Hz,1H),1.76(d,J=7.2Hz,1H),1.04-0.91(m,1H),0.68(q,J=4.6Hz,1H).

[1050] Example 48: (1aR,7bS)-5-methoxy-N-(4-methoxy-6-(pyridin-2-yloxy)benzo[d]isoxazol-3-yl)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide

[1051] Reaction route:

[1052] Steps:

[1053] Step A: Under nitrogen protection, (1aR,7bS)-5-methoxy-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonyl chloride (0.06 g, 0.228 mmol) and 4-methoxy-6-(pyridin-2-yloxy)benzo[d]isoxazol-3-amine (0.05 g, 0.19 mmol) were dissolved in pyridine (0.5 mL) and the system was stirred at 100 ° C under microwave conditions for 6 hours.

[1054] After LCMS monitoring indicated complete reaction of the starting material, the reaction mixture was added to water (5 mL), diluted with ethyl acetate (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column and reverse phase chromatography (eluent: 0.01% formic acid in water / acetonitrile = 1 / 1) to yield 32 mg of (1aR,7bS)-5-methoxy-N-(4-methoxy-6-(pyridin-2-yloxy)benzo[d]isoxazol-3-yl)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-sulfonamide.

[1055] MS (ESI) M / Z: 496.1 [M+H] + .

[1056] 1H NMR(400MHz, DMSO-d6)δ9.71(s,1H),8.21(dd,J=5.0,2.0Hz,1H),7.90(ddd,J=9.1,7.2,2.0Hz,1H) ,7.44(d,J=8.5Hz,1H),7.20(dd,J=7.2,5.0Hz,1H),7.11(d,J=8.2Hz,1H),6.92(s,1H),6.73(d,J=8 .5Hz,1H),6.67(s,1H),4.29(d,J=10.9Hz,1H),3.87(s,3H),3.75(s,3H),3.63(d,J=10.8Hz,1H),2. 03(td,J=8.3,4.0Hz,1H),1.77(q,J=7.8Hz,1H),0.99(dd,J=8.3,4.5Hz,1H),0.69(q,J=4.7Hz,1H).

[1057] Example 49: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,3'-oxetane]-7-sulfonamide

[1058] Reaction route:

[1059] Steps:

[1060] Step A: To a solution of ethyl 6-methoxy-1-benzofuran-3-carboxylate (5 g, 22.70 mmol) in methanol (80 mL) was added magnesium turnings (2.2 g, 90.8 mmol), followed by reaction at room temperature for 12 hours.

[1061] Thin layer chromatography showed that the starting material disappeared and new spots were generated. Dilute hydrochloric acid was added to the reaction solution at 0°C until the solution became clear. Then 50 mL of water was added and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated to obtain 4.5 g of methyl 6-methoxy-2,3-dihydro-1-benzofuran-3-carboxylate.

[1062] 1 H NMR(400MHz,DMSO-d6)δ7.18(dt,J=7.8,1.0Hz,1H),6.47-6.41(m,2H),4.76(dd,J=9.2,5 .9Hz,1H),4.66(t,J=9.4Hz,1H),4.37(ddd,J=9.6,5.9,1.1Hz,1H),3.69(d,J=9.6Hz,6H).

[1063] Step B: To a solution of methyl 6-methoxy-2,3-dihydro-1-benzofuran-3-carboxylate (4.5 g, 21.61 mmol) in dimethyl sulfoxide (90 mL) were added paraformaldehyde (713.13 mg, 23.77 mmol) and sodium methoxide (128.41 mg, 2.38 mmol) and reacted at room temperature for 2 hours.

[1064] LCMS showed the formation of the target peak. The temperature was lowered to 0°C, and 15 mL of dilute hydrochloric acid (1 M) was added to the reaction solution, followed by 60 mL of water. The mixture was extracted with ethyl acetate (80 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 4.2 g of methyl 3-(hydroxymethyl)-6-methoxy-2,3-dihydro-1-benzofuran-3-carboxylate.

[1065] 1 H NMR (400MHz, DMSO-d6) δ7.17(d,J=8.2Hz,1H),6.46-6.40(m,2H),5.32(t,J=5.4Hz,1H),4.92(d,J=9.4Hz,1 H), 4.57 (d, J = 9.3Hz, 1H), 3.94 (dd, J = 10.4, 5.7Hz, 1H), 3.69 (d, J = 6.7Hz, 6H), 3.54 (dd, J = 10.4, 5.2Hz, 1H).

[1066] Step C: To a solution of methyl 3-(hydroxymethyl)-6-methoxy-2,3-dihydro-1-benzofuran-3-carboxylate (2 g, 8.39 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum tetrahydride (0.32 g, 8.39 mmol) dropwise at 0°C, followed by reaction at 0°C for 1 hour.

[1067] LCMS showed that the starting material disappeared and the target peak was generated. 32 mL of water, 32 mL of sodium hydroxide aqueous solution, and 96 mL of water were added to the reaction solution in sequence, filtered, concentrated, and purified by column chromatography to obtain 1.1 g of the product (3-(hydroxymethyl)-6-methoxy-2,3-dihydro-1-benzofuran-3-yl)methanol.

[1068] MS (ESI) M / Z: 211.1 [M+H] + .

[1069] Step D: To a solution of (3-(hydroxymethyl)-6-methoxy-2,3-dihydro-1-benzofuran-3-yl)methanol (1 g, 4.76 mmol) in N,N-dimethylformamide (20 mL) at 0°C was added sodium hydride (0.23 g, 5.71 mmol, 60% purity). The mixture was stirred at 0°C for 20 minutes. Then, a solution of p-toluenesulfonyl chloride (952.87 mg, 5.00 mmol) in N,N-dimethylformamide (5 mL) was added to the reaction mixture and stirred at 0°C for 1 hour. Sodium hydride (0.23 g, 5.71 mmol, 60% purity) was added to the reaction mixture at 0°C and stirred at 0°C for 40 minutes. The mixture was then heated to 80°C and stirred for 1 hour.

[1070] LCMS showed the disappearance of the starting material and the formation of the target peak. The temperature was lowered to 0°C, and the reaction solution was added with 5 mL of saturated ammonium chloride and 50 mL of water. The mixture was then extracted with ethyl acetate (60 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 410 mg of the product 6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane].

[1071] 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=8.2Hz,1H),6.53(dd,J=8.3,2.3Hz,1H),6.39(d,J=2.3Hz,1H),4.79(s,2H),4.73(s,4H),3.71(s,3H).

[1072] Step E: To a solution of 6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane] (400 mg, 2.08 mmol) and N,N,N',N'-tetramethylethylenediamine (265.87 mg, 2.29 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (0.92 mL, 2.29 mmol, 2.5 M) dropwise at 0°C for 1 hour, then cooled to -70°C, and [(benzyldisulfide)methyl]benzene (563.74 mg, 2.29 mmol) in tetrahydrofuran (3 mL) was added dropwise to the reaction solution, which was then kept warm for 0.5 hour and then heated to 20°C for 1.5 hours.

[1073] LCMS showed residual starting material and the formation of the target peak. 2 mL of saturated ammonium chloride and 15 mL of water were added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 550 mg of 7-(benzylthio)-6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane].

[1074] MS (ESI) M / Z: 315.2 [M+H] + .

[1075] Step F: To a solution of 7-(benzylthio)-6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane] (100 mg, 0.32 mmol) in acetic acid (5 mL) and water (0.5 mL) was added N-chlorosuccinimide (128.19 mg, 0.96 mmol) at 0°C, and the mixture was reacted at 0-10°C for 1 hour.

[1076] Thin layer chromatography showed the disappearance of the starting material and the formation of new spots. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 80 mg of 6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane]-7-sulfonyl chloride.

[1077] 1 H NMR (400MHz, DMSO-d6) δ7.50 (d, J = 8.2Hz, 1H), 6.56 (d, J = 8.3Hz, 1H), 4.77-4.66 (m, 6H), 3.70 (s, 3H).

[1078] Step G: To a solution of 6-methoxy-2H-spiro[1-benzofuran-3,3'-oxetane]-7-sulfonyl chloride (20 mg, 0.069 mmol) and 4-dimethylaminopyridine (0.84 mg, 0.0069 mmol) in pyridine (1 mL) was added 4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (13.48 mg, 0.055 mmol), followed by reaction at 75°C for 12 hours.

[1079] LCMS showed residual starting material, and the target molecule peak was detected. The solvent was removed by concentration under reduced pressure, and preparative separation and purification were performed to obtain 3.5 mg of the product, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-6-methoxy-2H-spiro[benzofuran-3,3'-oxetane]-7-sulfonamide.

[1080] MS (ESI) M / Z: 499.0 [M+H] + .

[1081] 1H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.3Hz,1H),7.62(s,1H),7.48(d,J=1.8Hz,1H),6.67(s,1H),6.6 0(d,J=8.5Hz,2H),6.29(t,J=2.1Hz,1H),5.39(s,2H),4.80-4.63(m,6H),3.81(s,3H),3.64(s,3H).

[1082] Example 50: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin-3-sulfonamide

[1083] Reaction route:

[1084] Steps:

[1085] Step A: To a solution of 3-bromo-4-methoxybenzene-1,2-diol (6.4 g, 29.22 mmol) in N,N-dimethylformamide (120 mL) was added potassium carbonate (16.15 g, 116.88 mmol) at 0°C. 3-bromoprop-1-ene (12.37 g, 102.27 mmol) was then added to the reaction solution. The temperature was raised to 20°C and stirred for 12 hours.

[1086] Thin layer chromatography showed that the starting material disappeared and new spots were formed. 20 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 5.5 g of 1,2-bis(allyloxy)-3-bromo-4-methoxybenzene.

[1087] 1 H NMR (400MHz, DMSO-d6) δ7.04(d,J=9.1Hz,1H),6.79(d,J=9.1Hz,1H),6.14-5.97(m,2H),5.38(ddd,J=19. 2,17.3,1.8Hz,2H),5.23(ddd,J=21.0,10.5,1.7Hz,2H),4.53(ddt,J=18.7,5.8,1.5Hz,4H),3.78(s,3H).

[1088] Step B: Under nitrogen atmosphere, tris(triphenylphosphine)carbonylruthenium(II) chloride (1748.65 mg, 1.84 mmol) was added to a toluene (80 mL) solution of 1,2-bis(allyloxy)-3-bromo-4-methoxybenzene (5.5 g, 18.38 mmol), and the mixture was reacted at 80°C under nitrogen for 24 hours. [1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene]-dichloro-[(2-propan-2-yloxyphenyl)methylene]ruthenium (1.15 g, 1.84 mmol) was then added to the reaction solution and the mixture was reacted at 80°C for 1 hour.

[1089] LCMS showed that the starting material disappeared and a new spot was generated. The solvent was removed by concentration under reduced pressure and the residue was purified by column chromatography to obtain 3.5 g of 5-bromo-6-methoxybenzo[b][1,4]dioxin.

[1090] 1 H NMR (400MHz, DMSO-d6) δ6.74(d,J=9.0Hz,1H),6.61(d,J=9.0Hz,1H),6.32(d,J=3.6Hz,1H),6.26(d,J=3.6Hz,1H),3.77(s,3H).

[1091] Step C: To a solution of 5-bromo-6-methoxybenzo[b][1,4]dioxin (1 g, 4.11 mmol) in dichloromethane (20 mL) was added dropwise diethylzinc (20.55 mL, 20.55 mmol, 1 M) at 0°C, followed by the addition of chloroiodomethane (7.3 g, 41.1 mmol). The mixture was reacted at 0°C for 2 hours and at room temperature for 12 hours.

[1092] Thin-layer chromatography showed residual starting material and the formation of a new spot. 5 mL of saturated ammonium chloride and 50 mL of water were added to the reaction solution, followed by extraction with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 280 mg of 3-bromo-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin.

[1093] 1 H NMR(400MHz,DMSO-d6)δ6.92(d,J=9.0Hz,1H),6.64(d,J=9.0Hz,1H),4.13-4.0 7(m,1H),4.02-3.97(m,1H),3.76(s,3H),1.18-1.12(m,1H),1.11-1.06(m,1H).

[1094] Step D: To a solution of 3-bromo-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin (270 mg, 1.05 mmol) and N,N,N',N'-tetramethylethylenediamine (134.21 mg, 1.16 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (0.464 mL, 1.16 mmol, 2.5 M) dropwise at -70°C. The mixture was reacted for 0.5 h at -70°C. Then, [(benzyldisulfanyl)methyl]benzene (284.58 mg, 1.16 mmol) in tetrahydrofuran (3 mL) was added dropwise. The mixture was stirred for 0.5 h, and then the mixture was warmed to room temperature and stirred for 1.5 h.

[1095] LCMS showed the disappearance of the starting material and the formation of the target peak. 2 mL of ammonium chloride and 20 mL of water were added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 190 mg of 3-(benzylthio)-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin.

[1096] MS (ESI) M / Z: 301.2 [M+H] + .

[1097] Step E: To a solution of 3-(benzylthio)-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin (70 mg, 0.23 mmol) in acetic acid (2 mL) and water (0.2 mL) was added N-chlorosuccinimide (92.14 mg, 0.69 mmol) at 0°C and stirred at 0-10°C for 1 hour.

[1098] Thin-layer chromatography showed the disappearance of the starting material and the formation of new spots. 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 40 mg of 4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin-3-sulfonyl chloride.

[1099] 1H NMR (400MHz, DMSO-d6) δ6.84(d,J=8.8Hz,1H),6.49(d,J=8.9Hz,1H),3.93(ddd,J=6.2,5.4,3.4Hz,1H), 3.85(ddd,J=6.4,5.4,3.5Hz,1H),3.64(s,3H),1.04(dt,J=7.7,6.2Hz,1H),0.93(dt,J=7.4,3.5Hz,1H).

[1100] Step F: To a solution of 4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin-3-sulfonyl chloride (20 mg, 0.072 mmol) and 4-dimethylaminopyridine (0.88 mg, 0.0072 mmol) in pyridine (0.2 mL) was added 4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-amine (15.83 mg, 0.065 mmol) and the mixture was reacted at 80°C for 12 hours.

[1101] LCMS showed residual starting material and the target peak was detected. Concentration to remove the solvent was recommended, and preparative isolation yielded 9 mg of the product, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-methoxy-1a,7a-dihydro-1H-benzo[b]cyclopropyl[e][1,4]dioxin-3-sulfonamide.

[1102] MS (ESI) M / Z: 485.0 [M+H] + .

[1103] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.87(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),7.13(s,1H),6.89-6.6 1(m,3H),6.30(t,J=2.1Hz,1H),5.44(s,2H),3.84(s,5H),3.68(s,3H),1.06(d,J=7.5Hz,1H),0.96(s,1H).

[1104] Biological testing experiments

[1105] 1. KATs acetyltransferase activity assay

[1106] 1. The inhibitory effect of the compounds on KATs acetyltransferase activity was evaluated by TR-FRET (time-resolved fluorescence resonance energy transfer) in a 384-well plate using Tris-HCl buffer.

[1107] 2. Dilute the compound in DMSO, transfer the compound to a 384-well plate, add enzyme solution (KAT6: active motif (kit), 81223; KAT6B: active motif, 81224; KAT5: SignalChem, K314-380G; KAT7: ICE, S2210F-H21HF; KAT8: Active motif, 81225) and react at room temperature for 15 minutes.

[1108] 3. Then, 2.5 μl of a mixture of KAT6A / KAT6B:Biotin-H3 (1-21, Genscript, C6829GL060) or KAT5 / 7 / 8:Bio-H4 (1-25, Genscript, C736BGL100) AcCOA (Sigma, A2056) was added and reacted at room temperature for 90 minutes.

[1109] 4. After the reaction is completed, add Europium-anti-acetyl-Histone H4 Lysine (H4Kac pan) Antibody (Perkin Elmer, TRF0412) and LANCE Ultra ULight TM -Streptavidin detection reagent mixture, the detection reagent buffer solution is LANCETM Detection buffer (10x) (Perkin Elmer, CR97-100), and the reaction is carried out at room temperature for 60 minutes.

[1110] 5. HTRF signal values ​​(Ratio: 665nm / 620nm) were read by BMG PHERAstar FSX, and IC was calculated using the nonlinear fitting-four-parameter formula in GraphPad Prism 8 software. 50 Fitting.

[1111] The test results are shown in Table 1 below:

[1112] Table 1

[1113] The results showed that the compound of the present application had good enzyme inhibitory activity against KAT6A / 6B.

[1114] 2. ZR-75-1 cell proliferation assay

[1115] 1. Plant ZR-75-1 cells in a 96-well plate and culture overnight in a 37°C & 5% CO2 incubator.

[1116] 2. Dilute the compound with culture medium and add it to a 96-well plate. Continue culturing in an incubator. Re-digest the cells every 5 days, count and plate the cells. After the cells are fully attached, add the compound again and incubate for a total of 10 days.

[1117] 3. After the incubation period, add 60 μL of CellTiter-Glo reagent (Promega, G7573) to each well, shake in the dark for 2 minutes to lyse the cells, and continue incubation at room temperature in the dark for 30 minutes.

[1118] 4. Use BMG PHERAstar FSX to read the optical signal value and use the nonlinear fitting-four-parameter formula in GraphPad Prism 8 software to perform IC 50 Fitting.

[1119] The test results are shown in Table 2 below:

[1120] Table 2

[1121] Conclusion: The compounds described in this application have good cell proliferation inhibitory activity.

[1122] 3. Histone H3 acetylation assay

[1123] 1. Plant 5000 / 40 μL ZR-75-1 cells in a 384-well plate and culture in a 37°C & 5% CO2 incubator overnight.

[1124] 2. Add 40 nL of serially diluted compounds to a 384-well plate and continue incubation for 72 hours.

[1125] 3. Discard the supernatant, directly add 8w / v% paraformaldehyde (final concentration 4w / v%), and incubate at room temperature to fix the cells.

[1126] 4. After washing twice with PBS, add a membrane permeabilization agent (40 μL of methanol) and incubate for 10 minutes to permeabilize the cell membrane.

[1127] 5. After washing twice with PBS, add blocking solution and incubate at room temperature for 1 hour for blocking treatment.

[1128] 6. Discard the blocking solution and add 20 μL of primary antibodies (recombinant Anti-Histone H3 (acetyl K23) antibody and Anti-Histone H4 antibody) diluted in blocking solution (1:1000 volume ratio dilution) and incubate overnight at 4°C.

[1129] 7. After washing three times with PBST (0.05 vol% Tween-20 in PBS), add 20 μL of fluorescent secondary antibody (IRDye 680RD Goat anti-MOUSE, Licor, 926-68070; IRDye 800CW Goat anti-Rabbit, Licor, 926-32211) diluted in blocking buffer (1:2000 volume ratio), incubate at room temperature in the dark for 1 hour, and wash three times with PBST.

[1130] 8. Use Odyssey CLx to scan and quantify the fluorescence signal value of each well, and use the nonlinear fitting-four-parameter formula in GraphPad Prism 8 software to calculate IC 50 Fitting.

[1131] The test results are shown in Table 3 below:

[1132] Table 3

[1133] Conclusion: The data show that the compounds of the present application have obvious targeting cell activity.

[1134] IV. In vivo pharmacodynamic study of test drugs Compound 2, Compound 5-P2, Compound 3 and Compound A (Compound A) in a BALB / c nude mouse model with subcutaneous transplantation of human breast cancer ZR-75-1 cells

[1135] 1. Purpose of the experiment

[1136] The purpose of this experiment is to evaluate the in vivo efficacy of the test drugs Compound 2, Compound 5-P2, Compound 3 and Compound A on the BALB / c nude mouse model of subcutaneously transplanted tumors of human breast cancer ZR-75-1 cells.

[1137] 2. Experimental Animals

[1138] Species: Mouse;

[1139] Strain: BALB / c nude mice;

[1140] Age and weight: 6-8 weeks old, weight 19-26 grams;

[1141] Gender: female;

[1142] Supplier: Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[1143] Source of compound:

[1144] Compound A: Prepared with reference to patent CN114364672A.

[1145] 3. Experimental methods and steps

[1146] 3.1 Cell culture

[1147] Human breast cancer ZR-75-1 (ATCC, CRL-1500) cells were cultured adherently in 1640 medium supplemented with 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Cells were routinely passaged twice weekly. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[1148] 3.2 Estrogen tablet injection and urination

[1149] Three days before cell inoculation, 17β-estrogen tablets (0.36 mg) were inoculated on the left back of each mouse. One week after inoculation, the animals were allowed to urinate 2-3 times a week, and if necessary, daily.

[1150] 3.3 Tumor cell inoculation

[1151] will contain 10×10 6 100 μL of PBS containing 100 μL of ZR-75-1 cells was mixed with 100 μL of Matrigel (final volume was 200 μL) and inoculated subcutaneously on the right back (upper side) of each mouse. On the 18th day after cell inoculation, the average tumor volume reached 138 mm 3 The group administration was started at 14:00 pm, and the tumor volume range was 100-212 mm. 3 Mice were randomly divided into groups of 7 based on weight and tumor volume. The day of grouping was designated as PG-D0, and all groups began to receive the drug from PG-D0. The experimental groups and dosing schedule are shown in Table 4.

[1152] 3.4 Preparation of test substances

[1153] Table 4. Preparation method of test substances Note: The drug needs to be gently mixed thoroughly before administration; "-" represents 0.

[1154] 3.5 Tumor Measurement and Experimental Indicators

[1155] The experimental indicator is to examine whether tumor growth is inhibited, delayed, or cured. Tumor diameter is measured with a vernier caliper three times a week. The formula for calculating tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[1156] The tumor inhibition efficacy of a compound was evaluated using TGI (%) or relative tumor growth rate (T / C) (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [1 - (mean tumor volume at the end of dosing in a given treatment group - mean tumor volume at the start of dosing in that treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[1157] Relative tumor proliferation rate T / C (%): The calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV :RTV in treatment group; C RTV : RTV of negative control group). Relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV=V t / V0, where V0 is the tumor volume of each mouse measured at the time of group administration (i.e., d0), V t is the tumor volume of each mouse at a certain measurement. Then calculate the average value of each group. t The tumor volume data of the same mouse were obtained.

[1158] After the experiment, the tumor weight was measured and T was calculated. weight / C weight Percentage, T weight and C weight Represent the tumor weights of the drug-treated group and the vehicle control group, respectively.

[1159] 4. Experimental Results

[1160] 4.1 Weight changes

[1161] The effects of test drugs Compound 2, Compound 5-P2, Compound 3 and Compound A on the body weight of female BALB / c nude mice model with subcutaneous transplantation of human breast cancer ZR-75-1 cells are shown in Figure 1.

[1162] Figure 1 shows the weight changes of mice bearing human breast cancer ZR-75-1 cell transplant tumor models after administration of test drugs Compound 2, Compound 5-P2, Compound 3, and Compound A. As can be seen from the figure, there is no significant difference in weight changes among the groups.

[1163] 4.2 Tumor growth curve

[1164] Figure 2 shows the tumor growth curves of each group in the female BALB / c nude mouse model with subcutaneous ZR-75-1 cell transplanted tumors after treatment with the test drugs Compound 2, Compound 5-P2, Compound 3 and Compound A.

[1165] Figure 2 shows the tumor growth curves of mice bearing the ZR-75-1 transplanted tumor model after administration of the test drugs Compound 2, Compound 5-P2, Compound 3, and Compound A. As can be seen from the figure, Compound 2, Compound 5-P2, and Compound 3 all have more significant anti-tumor effects than Compound A.

[1166] 4.3 Anti-tumor efficacy evaluation indicators

[1167] Table 5 shows the anti-tumor efficacy evaluation of Compound 2, Compound 5-P2, Compound 3 and Compound A on the ZR-75-1 transplanted tumor model (calculated based on the tumor volume on the 21st day after administration).

[1168] Table 5

[1169] Note:

[1170] a. Detailed calculation of tumor growth inhibition T / C and TGI is shown in Section 3.5; “--” indicates absence.

[1171] 5. Conclusion

[1172] In summary, in this experiment, mice bearing the human breast cancer ZR-75-1 model were tolerant to the test drugs Compound 2, Compound 5-P2, and Compound 3, and all of the test drugs exhibited significant antitumor effects. Compared with Compound A, Compound 2, Compound 5-P2, and Compound 3 all exhibited more significant antitumor effects.

[1173] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A compound represented by formula (I), its isomers, deuterated substances and pharmaceutically acceptable salts thereof, in, R1 and R2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, hydroxyl, -C 1-4 Alkyl hydroxyl, -C 1-4 Alkyl-SC 1-4 Alkyl, amino, C 1-4 Alkylamino; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxyl, amino, R4, R5 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; or R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxyl, amino, R3, R4 and the carbon atom to which they are connected form a 7-8 membered heterocyclic group, which may be optionally replaced by m R a Replaced by two R on the same C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R located on adjacent C a Can form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxyl, amino; m is selected from 1, 2, 3, 4; R6 and R7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, deuterated C 1-4 or R6, R7 and the carbon atom to which they are connected form a 5-8 membered heterocyclic group, which may be optionally replaced by n R b replaced by; R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxyl, amino; n is selected from 1, 2, 3, 4; L1 is selected from C 1-4 Alkylene or -O-, deuterated C 1-4 Alkylene; Ring A is selected from 5-6 membered heteroaryl; R8 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, amino, -C 1-4 Alkylamino, hydroxyl; P is selected from 1, 2, 3, 4.

2. The compound according to claim 1, its isomers, deuterated substances and pharmaceutically acceptable salts thereof, characterized in that: R1 is selected from CH3O-, hydrogen.

3. The compound according to any one of claims 1 to 2, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: The 7-8 membered heterocyclic group formed by R3, R4 and the carbon atom to which they are connected is selected from 4. The compound according to any one of claims 1 to 2, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: The 7-8 membered heterocyclic group formed by R4, R5 and the carbon atom to which they are connected is selected from 5. The compound according to any one of claims 1 to 4, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: R a Selected from -F, -CH3.

6. The compound according to any one of claims 1 to 5, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: The structural unit Selected from 7. The compound according to any one of claims 1 to 6, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: R6 and R7 are each independently selected from -F, -CH3, CH3O-, C2H5O-, CHF2O-, -C2H5, -OCD3.

8. The compound according to any one of claims 1 to 6, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: The 5-8 membered heterocyclic group formed by R6, R7 and the carbon atom to which they are connected is selected from 9. The compound according to any one of claims 1 to 8, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: L1 is selected from -CH2-, -CD2-, and -O-.

10. The compound according to any one of claims 1 to 9, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from 11. A compound, its isomers, deuterated substances and pharmaceutically acceptable salts thereof, characterized in that: The compound is selected from the following compounds:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 12, its isomer, deuterated substance and pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating diseases mediated by KAT6 target.

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