Sulfonamide derivative and pharmaceutical use thereof

Abstract

The present invention relates to the technical field of pharmaceutics, and in particular, to a KAT inhibitor, a preparation method therefor, and pharmaceutical use thereof. Provided in the present invention are a sulfonamide derivative of formula (I), and a composition and use thereof. The compound can be used for treating or preventing KAT-mediated diseases or disorders and related diseases or disorders.

Description

Sulfonamide derivatives and their pharmaceutical uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a sulfonamide derivative, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt; a method for preparing such compounds; compositions comprising such compounds and their therapeutic uses. Background Technology

[0002] Lysine acetyltransferases (KATs) are a class of enzymes that catalyze the acetylation of lysine residues on histones and non-histone proteins, enabling them to epigenetically regulate gene transcription by altering chromatin structure. The MYST family of KATs includes KAT5 (TIP60), KAT6A (MOZ / MYST3), KAT6B (MORF / MYST4), KAT7 (HBO / MYST2), and KAT8 (MOF / MYST1). KAT6A / B, as an epigenetic oncoprotein associated with various cancers, acetylates different lysine residues on histone H3 (K9 and K23) and participates in the regulation of fundamental cellular processes, including gene transcription, cellular senescence, tissue development, and the maintenance of normal hematopoietic stem cells.

[0003] Dysregulation of KAT6A / B activity has been found in many cancers, including breast cancer, including gene amplification, overexpression, fusion, and mutation. In some breast cancer subtypes, KAT6A is amplified as part of the 8p11-p12 amplicon, and is amplified or overexpressed in 11% to 15% of the breast cancer population. Studies have shown that KAT6A / B overexpression is associated with poor clinical outcomes in patients with estrogen receptor-positive (ER+) / human epidermal growth factor receptor 2-negative (HER2-) breast cancer (the most common subtype). In ER-positive, KAT6A-overexpressing breast cancer, KAT6A regulates ERα expression by binding to the ERα gene promoter. By inhibiting KAT6A expression and downregulating estrogen receptors, endocrine receptors can be blocked at the transcriptional level, thereby inhibiting breast cancer cell proliferation without inhibiting cells with low KAT6A expression or normal cells. Furthermore, KAT6B chromosome translocations have been confirmed in various cancers, and it is locally amplified in breast cancer, ovarian cancer, uterine cancer, gastric cancer, bladder cancer, and lung cancer. In addition to ESR1 regulation, KAT6A / B is associated with the downregulation of cell cycle-related genes. Studies have shown that KAT6A is a key regulator of cell cycle and senescence, along with the inhibition of MYC signaling and stem cell pathways. Notably, the reduction of KAT6A activity has been shown to prolong the survival of MYC-overexpressing lymphoma models.

[0004] HR+ / HER2- breast cancer is the most common subtype of breast cancer. Approximately 70% of breast cancers are estrogen receptor-positive (ER+), and endocrine therapy remains the primary treatment for ER+ breast cancer patients. Despite the effectiveness of current treatment strategies, drug resistance remains a significant challenge, and HR+ / HER2- metastatic breast cancer (mBC) is incurable. KAT6A / B is an epigenetic target associated with multiple cancers. Inhibiting KAT6A / B at the transcriptional level and blocking endocrine receptors may overcome resistance to endocrine therapy. KAT6A / B inhibitors have clinical development value as monotherapy or in combination with existing therapies for ER+ / HER2- breast cancer (such as fulvestrant, CDK4 / 6 inhibitors, and selective estrogen receptor downregulators such as SERD). In addition to ER+ / HER2- breast cancer, KAT6A / B inhibitors also show potential applications in prostate cancer, glioma, ovarian cancer, and lung cancer.

[0005] The most advanced KAT6A / B inhibitor currently in clinical trials is Pfizer's PF-07248144 (Example 45 disclosed in WO2020 / 254946A1, namely 2-methoxy-N-(4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide). This molecule is in Phase III clinical trials, but in clinical trials, it has been found that the median effective half-life is too long, and accumulation occurs after repeated daily oral administration. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a novel sulfonamide derivative that can inhibit the activity of KAT6A and / or KAT6B and has significant antitumor activity.

[0007] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0008] On the one hand, the present invention provides a sulfonamide derivative, which is a compound having the following general structural formula (I), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0009] in:

[0010] R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0011] m is selected from 0, 1, 2, 3 or 4;

[0012] X is selected from -C(R1)(R2)-, -NR3-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0013] Y 1 Selected from CR4 or N; Y 2 Selected from CR5 or N; Y 3 Selected from CR6 or N;

[0014] It is an aromatic ring or a heterocyclic aromatic ring;

[0015] X 1 Selected from CR7, NR7, N, O, or S; X 2 Selected from CR8, NR8, N, O, or S; X 3 Selected from CR9, NR9, N, O, or S; X 4 Selected from CR 10 NR 10 , N, O or S;

[0016] R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0017] Alternatively, R4 and R5, along with the atoms they are attached to, together form a 6-10 membered heterocyclic group or a 5-14 membered heteroaryl group, which may optionally be further substituted by one or more groups selected from: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0018] R7, R8, R9, R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C6-14 Aryl, C 6-14 Mixed aromatics, -OR 11 -SR 11 -SF5, -N(R) 11 (R) 12 -C(O)OR 11 -OC(O)-N(R) 11 (R) 12 ), -N(R 13 )C(O)N(R 11 (R) 12 ), -N(R 13 )C(O)OR 14 -N(R) 13 )S(O)2R 14 -C(O)R 14 -OC(O)R 14 -C(O)N(R) 11 (R) 12 ), -S(O)R 14 -C(O)C(O)N(R) 11 (R) 12 ), -N(R 13 )C(O)R 14 -S(O)2R 14 -S(O)2N(R) 11 (R) 12 )-、S(=O)(=NH)N(R 11 (R) 12 -CH2C(O)N(R) 11 (R) 12 ), -CH2N(R 13 )C(O)R 14 -CH2S(O)2R 14 or -CH2S(O)2N(R) 11 (R) 12 ), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics;

[0019] R 11 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, C 6- 14 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics;

[0020] R 12 R 13 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0021] R 14 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, C 6-14 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics;

[0022] Ring A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C6-14 The aryl and 5-14 heteroaryl groups may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0023] n is selected from 0 or 1.

[0024] In some embodiments, the compound having the following general structural formula (II) or (III), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0025] in:

[0026] X is selected from -C(R1)(R2)-, -NR3-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-;

[0027] Y 1 Selected from CR4 or N; Y 2 Selected from CR5 or N; Y 3 Selected from CR6 or N;

[0028] R1, R2, R3, R4, R5, and R6 are each independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group;

[0029] R a m, X 1 X 2 X 3 X 4 The definition of ring A is as described in general formula (I).

[0030] In some embodiments, the compound having the following general structural formula (II-1), (II-2), or (III-1), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0031] Among them, R b Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0032] p is selected from 0, 1, or 2;

[0033] R a m, X, Y 2 X 1 X 2 X 3 X 4 The definition of ring A is as described in general formula (I).

[0034] In some embodiments, the compound having the general structural formula (II-1-1) or (III-1-1), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof are:

[0035] Among them, R b Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0036] p is selected from 0, 1, or 2;

[0037] R a m, X, Y 2 X 1 X 2 X 3 X 4 The definition of ring A is as described in general formula (I).

[0038] In some implementations, X is selected from CH2 or O.

[0039] In some implementation schemes, Y 1 Y 2 Y 3 Each can be independently selected from -CH, -COCH3, or N.

[0040] In some implementation schemes, R7, R8, R9, R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -OR 11 -N(R) 11 (R) 12), the C 1-6 Alkyl, C 3-8 The cycloalkyl or 3-10 membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatic compounds.

[0041] In a further implementation scheme, R 11 R 12 Each is independently selected from hydrogen or C. 1-6 alkyl.

[0042] In some implementation schemes, Selected from

[0043] In some embodiments, ring A is selected from 5-14-membered heteroaryl groups, which may optionally be further substituted by one or more groups selected from: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group.

[0044] In a further embodiment, ring A is selected from...

[0045] In some embodiments, the compounds of the present invention are compounds having the following general structural formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), or (IV-9), their stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0046] Among them, R 8 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or -N(R) 11 (R) 12 ), the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups may optionally be further surrounded by one or more groups selected from hydrogen, halogen, or C. 1-6 Substituents of alkyl groups;

[0047] R 11 R 12 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0048] R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl or C 1-3 Alkoxy;

[0049] m and q are each independently selected from 0, 1, or 2.

[0050] In some embodiments, the compound having the following general structural formula (V-1), (V-2), or (V-3), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0051] Among them, R8 is selected from C 1-3 Alkoxy, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups or -N(R) 11 (R) 12 ), the C 1-3 Alkoxy, C 3-5 The cycloalkyl group and the 3-5 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, halogen, or C. 1-6 Substituents of alkyl groups;

[0052] R 11 R 12 Each is independently selected from hydrogen or C 1-6 alkyl;

[0053] R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl or C 1-3 Alkoxy;

[0054] m and q are each independently selected from 0, 1, or 2.

[0055] In some implementations, R8 is selected from H, -CH3, -OCH3, -NH2, -NHCH3, -N(CH3)2,

[0056] In some implementation schemes, R a R b It is a methoxy group; m is selected from 1 or 2; p is 1.

[0057] This invention also provides a sulfonamide derivative comprising the compounds numbered 1-34 shown below, their stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0058] In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound, stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof as described above, and at least one pharmaceutically acceptable carrier.

[0059] In another aspect, the present invention provides the use of the compounds, stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof as described above, and the use of the above pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of diseases related to the receptor KAT.

[0060] The present invention also provides the compounds, stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof as described above, and the use of the above pharmaceutical compositions in the prevention or treatment of diseases related to the receptor KAT.

[0061] The present invention provides a method for treating and / or preventing disease, comprising administering to a subject a therapeutically effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition thereof.

[0062] In some embodiments, the receptor KAT is KAT6A and / or KAT6B.

[0063] In some implementations, the disease is cancer.

[0064] In some implementations, the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, colorectal cancer, small bowel cancer, gastric cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, spinal cord tumor, glioma, brain glioma, pituitary adenoma, or squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer, or leukemia.

[0065] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0066] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0067] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0068] In this invention, "isomer" refers to stereoisomers or tautomers unless otherwise specified. Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and transisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons.

[0069] In this invention, "isotope" refers to a compound of this invention, unless otherwise specified, existing in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling include hydrogen isotopes, including but not limited to... 2 H and 3 H; Carbon isotopes: including but not limited to13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18 F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O、 17 O and 18 O; sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues, especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0070] In this invention, "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which are compounds with specific substituents discovered in this invention, and are compatible with 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, and dodecyl sulfonic acid. A base addition salt can be obtained by contacting a compound in its neutral form with a sufficient amount of base in a pure solution or a suitable inert solvent when it contains a relatively acidic functional group, such as maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, or organic amine salts. Examples include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkyl sulfonates, aryl sulfonates, organic acid salts, and amino acid salts.

[0071] The terms used in this article have the following meanings:

[0072] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0073] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group composed of carbon and hydrogen atoms, such as C... 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), and hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl).

[0074] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, possessing at least one double bond. For example, "C..." 2- "6-Alkenyl" means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, etc.

[0075] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, with at least one triple bond. For example, "C..." 2- "6-Hydynyl" means that the group is ynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of ynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 1,3-butyrynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentyrynyl, 1,5-hexadiynyl, etc.

[0076] The term "cycloalkyl" refers to a monocyclic alkyl group composed of carbon and hydrogen atoms, such as C1. 3-8 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "alkoxy" refers to a straight-chain or branched alkyl group linked by an oxygen atom, such as C... 1-6 Alkoxy groups, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, and neopentoxy), and hexoxy (n-hexoxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy, and 2,2-dimethylbutoxy).

[0078] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0079] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, including monosubstituted and disubstituted alkylamine groups, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0080] The term "aryl" refers to a monocyclic or fused polycyclic group with 6-14 carbon atoms, possessing a fully conjugated π-electron system, including but not limited to phenyl, naphthyl, anthracene, etc., with phenyl being preferred.

[0081] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., spirocyclic, bridged, etc.) group containing 3-10 ring atoms, and having a non-aromatic structure. The polycyclic group may consist entirely of non-aromatic rings, or at least one ring may be aromatic while the rest are non-aromatic. The aforementioned 3-10 ring atoms contain one or more (e.g., 2, 3, 4, or more) heteroatoms, with the remainder being carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heterocyclic group" include, but are not limited to, azirropropyl, oxadiropropyl, thioherropropyl, azirrobutyl, oxadirobutyl, thioherrobutyl, furanyl, piperidinyl, piperazinyl, morpholinyl, pyrroleyl, and thiomorpholinyl.

[0082] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic (e.g., fused ring) group containing 5-14 ring atoms, wherein the aforementioned 5-14 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the remainder are carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaryl" preferably contains 5-14, 5-12, 5-10, or 5-8 ring atoms, more preferably 5-6 ring atoms. Non-limiting examples of "heteroaryl" include, but are not limited to, tetrahydrofuranyl, thiophenyl, oxazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, etc.

[0083] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0084] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate drug delivery to the organism.

[0085] The present invention also provides the administration routes of the above-mentioned pharmaceutical compositions, including but not limited to oral, rectal, transmucosal, enteric administration, or local transdermal, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0086] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0087] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0088] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0089] This invention, based on the target design of KAT6A / B, has discovered a series of novel sulfonamide derivatives. Related biological experiments show that the compounds of this invention can significantly inhibit KAT6A enzyme activity and tumor cell proliferation, and also possess good hepatic microsomal metabolic stability, exhibiting superior in vivo pharmacokinetic properties compared to the clinical molecule PF-07248144. Simultaneously, the compounds demonstrate excellent in vivo antitumor activity and good safety. Furthermore, the synthetic route provided by this invention is novel, safe, environmentally friendly, and feasible for production. Detailed Implementation

[0090] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0091] Furthermore, all operations involving readily oxidizable or hydrolyzable raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0092] All reaction starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared in-house. The preparation process of the starting materials and common intermediates that need to be prepared in-house is detailed below:

[0093] Explanation of abbreviations related to chemical reagents:

[0094] DCDMH: 1,3-Dichloro-5,5-Dimethylhydantoin; DAST: Diethylaminosulfur trifluoride; MTBE: Methyl tert-butyl ether; NMM: N-Methylmorpholine; PF6 --Hexafluorophosphate; NaOMe: sodium methoxide; THF: tetrahydrofuran; MeOH: methanol; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; dioxane: 1,4-dioxane; H2O: water; NaIO4: sodium periodate; K2OsO4·H2O: potassium osmium tetroxide dihydrate; NaBH4: sodium borohydride; K2CO3: potassium carbonate; ACN: acetonitrile; Cs2CO3: cesium carbonate; DMF: N,N-dimethylformamide; NaHMDS: sodium bis(trimethylsilyl)aminoacetamide; EA: ethyl acetate; NaCl: sodium chloride; DCM: dichloromethane; Na2SO4: sodium sulfate; N2: nitrogen; HCl: hydrochloric acid; NH4Cl: ammonium chloride; TEA: triethylamine; tert-Butyl nitrite: tert-butyl nitrite; HOAc: acetic acid; Acetyl chloride: acetyl chloride; NH3·MeOH: ammonia-methanol solution; DMA: N,N-dimethylaniline; Pd2(dba)3: tris(dibenzylacetone)dipalladium; X-phos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; KOAc: potassium acetate; TFA: trifluoroacetic acid; Zn: zinc powder; NaI: sodium iodide; NiCl2 glyme: nickel chloride dimethoxyethane.

[0095] All reaction starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared in-house. The preparation process of the common intermediate that needs to be prepared in-house is detailed below:

[0096] I. Preparation of common intermediate A:

[0097] Step 1: Synthesis of compound 4-bromo-2-fluoro-6-methoxybenzonitrile (Int1)

[0098] Compound I-1: 4-bromo-2,6-difluoronitrobenzene (4.0 g, 1.0 eq) was dissolved in a mixed solution of THF:MeOH = 3:1. The mixture was placed in an ice bath at 0°C, and sodium methoxide (2.97 g, 2.0 eq) was added in small, multiple batches. The mixture was stirred overnight at room temperature. TLC analysis was performed. The reaction was quenched with a small amount of water, extracted with EA, and the organic phases were combined. The mixture was backwashed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the solution was rapidly passed through a column using 0–10% EA Flash to obtain 2.8 g of white solid, which was intermediate Int1, with a yield of 66%.

[0099] 1H NMR (600MHz, DMSO-d6) δ7.49 (dd, J=8.8, 1.5Hz, 1H), 7.42-7.39 (m, 1H), 3.98 (s, 3H).

[0100] Step 2: Synthesis of compound 2-fluoro-6-methoxy-4-vinylbenzonitrile (Int2)

[0101] Intermediate Int1 (2.0 g, 1.0 eq), compound M1: potassium vinyltrifluoroborate (1.4 g, 1.2 eq), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (636.16 mg, 0.1 eq), and cesium carbonate (8.50 g, 3.0 eq) were dissolved in a mixed solution of DMF:H2O = 6:1. After nitrogen purging, the mixture was heated to reflux at 90 °C overnight. LC-MS analysis was performed. The reaction solution was cooled to room temperature, a small amount of water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, backwashed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the solution was rapidly passed through a column using 0–10% EA Flash to obtain 1.2 g of white solid, which was intermediate Int2, with a yield of 78%.

[0102] 1 H NMR (600MHz, DMSO-d6) δ7.27 (dd, J=10.5, 1.3Hz, 1H), 7.20 (s, 1H), 6.79 (dd, J= 17.6,10.9Hz,1H),6.18(d,J=17.6Hz,1H),5.58(d,J=10.9Hz,1H),3.98(s,3H).

[0103] Step 3: Synthesis of compound 2-fluoro-6-methoxy-4-vinylbenzonitrile (Int3)

[0104] Intermediate Int2 (1.2 g, 1.0 eq) was dissolved in THF. Under 0°C ice bath conditions, an aqueous solution of potassium osmium tetroxide dihydrate (49.92 mg, 0.02 eq) was added. After maintaining the temperature at 0°C for half an hour, an aqueous solution of sodium periodate (3.62 g, 2.5 eq) was added, and the reaction was carried out at room temperature for 1 hour. TLC detection was performed. The reaction was quenched with a small amount of water, extracted with EA, and the organic phases were combined. The mixture was backwashed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the sample was rapidly passed through a column using 0–10% EA Flash to obtain 870 mg of white solid, which was intermediate Int3, with a yield of 71%.

[0105] 1H NMR (600MHz, DMSO-d6) δ10.04(d,J=1.7Hz,1H),7.63(s,1H),7.57(dd,J=8.7,1.1Hz,1H),4.06(s,3H).

[0106] Step 4: Synthesis of compound 2-fluoro-4-hydroxymethyl-6-methoxybenzonitrile (Int4)

[0107] Intermediate Int3 (870 mg, 1.0 eq) was dissolved in methanol. Sodium borohydride (367 mg, 2.0 eq) was added under 0°C ice bath conditions. After maintaining the temperature at 0°C for one hour, a small amount of water was added to quench the reaction. The pH was adjusted to approximately 2 with 1 M HCl. Extraction was performed with EA. The organic phases were combined, backwashed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, diluted with DCM, and mixed. The sample was then rapidly passed through a column using 0–10% EA Flash to obtain 750 mg of white solid, which was intermediate Int4, with a yield of 85%.

[0108] 1 H NMR (600MHz, DMSO-d6) δ7.05 (s, 1H), 7.00-6.96 (m, 1H), 5.59 (t, J = 5.8Hz, 1H), 4.58 (d, J = 5.8Hz, 2H), 3.94 (s, 3H).

[0109] Step 5: Synthesis of compound 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile (Int5)

[0110] Intermediate Int4 (750 mg, 1.0 eq), intermediate Int8 (667 mg, 1.1 eq), and cesium carbonate (2.71 g, 2.0 eq) were dissolved in acetonitrile and refluxed at 70 °C for 2 hours. LC-MS analysis was performed. After cooling the reaction solution to room temperature, a small amount of water was added to quench the reaction. The solution was extracted with EA, and the organic phases were combined. The solution was backwashed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the solution was rapidly passed through a column using 0–30% EA Flash to obtain 790 mg of white solid, which was intermediate Int5, with a yield of 82%.

[0111] 1 H NMR(600MHz,DMSO-d6)δ7.90(d,J=2.1Hz,1H),7.53(d,J=1.5Hz,1H),6.99( s,1H),6.70(d,J=9.8,1H),6.33(t,J=2.1Hz,1H),5.44(s,2H),3.91(s,3H).

[0112] Step 6: Synthesis of compound 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-amine (Int6)

[0113] Intermediate Int5 (790 mg, 1.0 eq), compound M2: N-hydroxyacetamide (750 mg, 3.0 eq), and K2CO3 (2.83 g, 6.0 eq) were dissolved in DMF and heated under reflux at 60 °C overnight. LC-MS analysis was performed. After cooling the reaction solution to room temperature, a small amount of water was added to quench the reaction. The mixture was extracted with EA, and the organic phases were combined. The solution was backwashed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the solution was rapidly passed through a column using 0–30% EA Flash to obtain 630 mg of a white solid, which was intermediate Int6, with a yield of 75%.

[0114] 1 H NMR(600MHz,DMSO-d6)δ7.87(d,J=2.2Hz,1H),7.50(d,J=1.8Hz,1H),6.69(s,1 H), 6.62 (s, 1H), 6.30 (t, J = 2.1Hz, 1H), 5.93 (s, 2H), 5.41 (s, 2H), 3.86 (s, 3H).

[0115] Step 7: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-bromo-2-methoxybenzenesulfonamide (A)

[0116] Intermediate Int6 (300 mg, 1.0 eq) was placed in a three-necked flask, purged with N2, and anhydrous THF was added. The flask was then pre-cooled in a -60°C cold trap. NaHMDS (0.9 mL, 2 M) was slowly added dropwise, ensuring the temperature did not exceed -40°C. After the addition was complete, the mixture was stirred at -60°C for 30 min. Subsequently, Int10 (700 mg, 2.0 eq) was slowly added dropwise. The mixture was stirred at -60°C for 1 h, then slowly raised to room temperature and reacted overnight at room temperature. LC-MS analysis was performed. The reaction was quenched with saturated NH4Cl solution, extracted with EA, backwashed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. A small amount of EA was added to dissolve the solid, followed by a large amount of methanol for slurry purification. The filter cake was collected by vacuum filtration, washed with methanol, and dried in a 50°C oven. After drying, 264 mg of a white solid, which was intermediate A, was obtained, with a yield of 44%.

[0117] MS (m / z): 492.9 [M+H] + .

[0118] The intermediate Int8 mentioned above is commercially available or can be prepared by the following methods:

[0119] Step 1: Synthesis of compound 1-(methanesulfonyl)-1H-pyrazole (Int8)

[0120] Compound M3: pyrazole (1.0 g, 1.0 eq) and TEA (2.97 g, 2.0 eq) were dissolved in DCM. Compound M4: methanesulfonic anhydride (3.33 g, 1.5 eq) was added dropwise under 0°C ice bath conditions. The mixture was slowly heated to room temperature and incubated overnight. TLC detection was performed, followed by quenching with saturated NH4Cl solution, extraction with DCM, backwashing with saturated NaCl, drying with anhydrous Na2SO4, concentration under reduced pressure, dilution with DCM, mixing, and rapid column chromatography with 0–10% EA Flash to obtain 1.80 g of a yellow oily liquid, which was intermediate Int8, with a yield of 84%.

[0121] 1 H NMR (600MHz, Chloroform-d) δ8.06 (d, J = 2.8Hz, 1H), 7.84 (d, J = 1.6Hz, 1H), 6.49-6.45 (m, 1H), 3.34 (s, 3H).

[0122] The intermediate Int10 is commercially available or can be prepared by the following methods:

[0123] Step 1: Synthesis of the compound benzyl(4-bromo-2-methoxyphenyl)thione (Int9)

[0124] Compound I-2: 4-bromo-2-methoxyaniline (500 mg, 1.0 eq) and compound M5: dibenzyl disulfide (488 mg, 0.8 eq) were dissolved in acetonitrile. The mixture was heated and stirred at 60 °C, and tert-butyl nitrite (326 μL, 1.1 eq) was slowly added. The reaction mixture was heated at 60 °C for 2 h. TLC monitoring was performed, and the solvent was removed by concentration under reduced pressure. After dilution with DCM and mixing, the sample was rapidly passed through a column at 0–5% EA Flash to obtain 234 mg of a yellow oily liquid, which was intermediate Int9, with a yield of 31%.

[0125] 1 H NMR(600MHz,DMSO-d6)δ7.37-7.33(m,2H),7.29(t,J=7.6Hz,2H),7.26-7.20(m ,1H),7.19-7.14(m,2H),7.07(dd,J=8.2,2.0Hz,1H),4.15(s,2H),3.83(s,3H).

[0126] Step 2: Synthesis of compound 4-bromo-2-methoxybenzenesulfonyl chloride (Int10)

[0127] Intermediate Int9 (234 mg, 1.0 eq) was dissolved in a mixed solvent of acetonitrile:water:glacial acetic acid = 20:1:0.5 and cooled in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (224 mg, 1.5 eq) was added in small batches. TLC was performed, and the solution was extracted with EA. The organic phases were combined, backwashed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. After dilution with DCM and mixing, the solution was rapidly passed through a column using 0–1% EA Flash to obtain 180 mg of a yellow solid, which was intermediate Int10, with a yield of 84%.

[0128] 1 H NMR (600MHz, Chloroform-d) δ7.82 (d, J = 8.6Hz, 1H), 7.29-7.26 (m, 2H), 4.07 (s, 3H).

[0129] II. Preparation of common intermediate B:

[0130] Step 1: Synthesis of compound 2,4-dihydroxy-6-methylnicotinamide (Int11)

[0131] Compound I-3 (34 g, 1.0 eq.) was added to ammonia water (100 mL). Under nitrogen protection, the reaction system was heated to 50 °C and stirred for 16 h. A solid precipitated out, and the reaction was monitored by LC-MS to indicate completion. The mixture was filtered, the filter cake was washed with water, and the solid was collected to obtain 24.5 g of white solid, which was the intermediate Int11.

[0132] MS (m / z): 169.0 [M+H] + .

[0133] Step 2: Synthesis of compound 2,4-dichlorobenzene-6-methylnicotinonitrile (Int12)

[0134] Intermediate Int11 (24.5 g, 1.0 eq.) and POCl3 (265 mL) were placed in a single-necked flask. Under nitrogen protection, the mixture was heated to 70 °C and stirred for 30 min, then heated to 90 °C. DMF (1.4 mL, 0.12 eq.) was added, and the mixture was stirred for 2 h. The reaction was monitored by LC-MS until complete. The mixture was quenched with crushed ice, adjusted to alkalinity with saturated sodium carbonate solution, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 15.5 g of a pale yellow solid, which was intermediate Int12.

[0135] 1 H NMR (600MHz, DMSO-d6) δ7.85 (s, 1H), 2.56 (s, 3H).

[0136] Step 3: Synthesis of compound 2-chloro-4-hydroxy-6-methylnicotinonitrile (Int13)

[0137] Intermediate Int13 (15.26 g, 1.0 eq.) and CsOAc (45.9 g, 3.0 eq.) were dissolved in DMF (190 mL). The mixture was heated to 70 °C under nitrogen protection and stirred for 16 h. The reaction was monitored by LC-MS until completion. The reaction solution was quenched in an ice-water mixture, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was slurried with a 1:1 PE / EA mixture. The filter cake was collected after filtration and dried in a 50 °C oven to obtain 9.1 g of a yellow solid, which was intermediate Int13.

[0138] MS (m / z): 169.0 [M+H] + .

[0139] 1 H NMR (600MHz, DMSO-d6) δ6.81 (s, 1H), 2.40 (s, 3H).

[0140] Step 4: Synthesis of compound 4-hydroxy-2-methoxy-6-methylnicotinonitrile (Int14)

[0141] Intermediate Int13 (9.1 g, 1.0 eq.), sodium methoxide (23.5 g, 3.0 eq.), and methanol (300 mL) were added to an autoclave. The mixture was heated to 150 °C under nitrogen protection and stirred for 16 h. The reaction was monitored by LC-MS until completion. The reaction solution was quenched with a small amount of water, concentrated under reduced pressure to remove most of the methanol, and the pH was adjusted to acidic with hydrochloric acid. The solution was extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried in a 50 °C oven to obtain 8.6 g of a yellow solid, which was intermediate Int14.

[0142] MS (m / z): 165.0 [M+H] + .

[0143] Step 5: Synthesis of compound 4-chloro-2-methoxy-6-methylnicotinonitrile (Int15)

[0144] Intermediate Int14 (8.1 g, 1.0 eq.), POCl3 (7.57 g, 1.0 eq.), and PCl5 (10.3 g, 1 eq.) were added to a single-necked flask, and DMF (50 mL) and DCM (200 mL) were added and stirred to dissolve. The mixture was heated to 40 °C under nitrogen protection and stirred for 40 min. The reaction was monitored by LC-MS until complete. The reaction solution was quenched with a small amount of water, adjusted to alkalinity with saturated sodium carbonate solution, and then extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by column chromatography (PE / EA = 10:1) to obtain 3.1 g of a yellow solid, which was intermediate Int15.

[0145] MS (m / z): 181.0 [MH] + .

[0146] Step 6: Synthesis of compound 6-(bromomethyl)-4-chloro-2-methoxynicotinonitrile (Int16)

[0147] Intermediate Int15 (3.1 g, 1.0 eq.), NBS (3.02 g, 1.0 eq.), and BPO (0.82 g, 0.2 eq.) were added to a single-necked flask, and CCl4 (300 mL) was added and stirred to dissolve. The mixture was heated to 90 °C under nitrogen protection and stirred for 2 h. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 50:1) to give 2.9 g of a yellow solid, which was intermediate Int16.

[0148] MS (m / z): 260.8 [MH] + .

[0149] Step 7: Synthesis of compound 6-((1H-pyrazol-1-yl)methyl)-4-chloro-2-methoxynicotinonitrile (Int17)

[0150] Intermediate Int16 (2.9 g, 1.0 eq.), pyrazole (1.13 g, 1.5 eq.), and DIPEA (2.87 g, 2.0 eq.) were added to a single-necked flask, and ACN (100 mL) was added and stirred to dissolve. The reaction was carried out overnight at 90 °C, and the reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 100:0-93:7) to obtain 880 mg of a yellow solid, which was intermediate Int17.

[0151] MS (m / z): 249.0 [M+H] + .

[0152] Step 8: Synthesis of compound 6-((1H-pyrazol-1-yl)methyl)-4-methoxyisoxazole-[4,5-c]pyridyl-3-amine (Int18)

[0153] Intermediate Int17 (880 mg, 1.0 eq.) was dissolved in tert-butanol (100 mL). Acetoxyxamic acid (533 mg, 2.0 eq.) and K2CO3 (980 mg, 2.0 eq.) were added to the solution. The reaction was carried out overnight at 30 °C under nitrogen protection, and the reaction was monitored by LC-MS until completion. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 3:1) to obtain 480 mg of a yellow solid, which was intermediate Int18.

[0154] MS (m / z): 246.1 [M+H] + .

[0155] Step 9: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxyisoxazole[4,5-c]pyridin-3-yl)-4-bromo-2-methoxybenzenesulfonamide (B)

[0156] Intermediate Int18 (200 mg, 1.0 eq.) was dissolved in THF (20 mL), purged with nitrogen three times, and the internal temperature was lowered to -60 °C. NaHMDS (1.2 mL, 1.5 eq.) was slowly added dropwise to the solution, and the reaction was continued at -60 °C for 1 h. A THF solution of Int10 (582 mg, 2.0 eq.) was slowly added dropwise to the reaction solution, and after the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction was monitored by LC-MS until completion. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. Ethyl acetate was then added for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. 123 mg of a yellow solid was obtained, which was intermediate B.

[0157] MS (m / z): 496.0 [M+H] + .

[0158] III. Preparation of common intermediate C:

[0159] Step 1: Synthesis of compound 2-fluoro-4-hydroxy-6-methoxybenzonitrile (Int19)

[0160] Intermediate Int1 (5 g, 1.0 eq.), Xphos (2.5 g, 0.2 eq.), KOH (9.6 g, 8.0 eq.), and Pd2(dba)3 (1.0, 0.05 eq.) were dissolved in a mixed solution of 1,4-dioxane and H2O (V:V = 5:1). The mixture was heated to reflux at 100 °C under N2 protection. The reaction was monitored by TLC. When the reactants had completely reacted, a small amount of water was added to quench the reaction. The pH was adjusted to approximately 5 with 1 M HCl solution. The aqueous phase was extracted three times with ethyl acetate and backwashed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was rapidly passed through a column at 0–40% EA Flash to obtain 1.9 g of a yellow solid, which was intermediate Int19.

[0161] Step 2: Synthesis of compound 2-fluoro-6-methoxy-4-(thiazol-2-oxy)benzonitrile (Int20)

[0162] Intermediate Int19 (1.0 g, 1.0 eq), cesium carbonate (6.0 g, 3.0 eq), 2-bromothiazole (2.16 mL, 4.0 eq), and J009 PreCat (800 mg, 0.15 eq) were dissolved in xylene, and the mixture was purged with nitrogen and reacted at 150 °C for 12 h. The reaction was monitored by TLC, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure (using a pump to evaporate to dryness). The filtrate was then rapidly purified by column chromatography (0–10% EA Flash) to obtain product Int20 (460 mg), a brown solid.

[0163] Step 3: Synthesis of compound 4-methoxy-6-(thiazol-2-oxy)methoxybenzo[d]isoxazole-3-amine (Int21)

[0164] Intermediate Int20 (400 mg, 1.0 eq), acetyloxyoxime acid (360 mg, 3.0 eq), and TMG (1.2 mL, 6.0 eq) were dissolved in MeCN / H2O (9:1), and nitrogen was purged. The reaction was carried out at 60 °C for 12 h. The reaction was stopped by TLC. The solution was concentrated under reduced pressure and purified by rapid column chromatography (0–50% EA Flash) to obtain product Int21 (148.8 mg), which was a yellow oily liquid.

[0165] MS (m / z): 264.0 [M+H] + .

[0166] Step 4: Synthesis of compound 4-bromo-2-methoxy-N-(4-methoxy-6-(thiazol-2-yl)oxy)methoxybenzo[d]isoxazol-3-yl)benzenesulfonamide (C)

[0167] Referring to the synthesis of intermediate A in step 7 of intermediate A, only "intermediate Int6" is replaced with "intermediate Int21", and the rest of the method is the same. Intermediate C (80mg) is synthesized from intermediate Int21 (150mg, 1.0eq).

[0168] MS (m / z): 513.1 [M+H] + .

[0169] IV. Preparation of common intermediate D:

[0170] Step 1: Synthesis of compound 4-bromo-2-fluoro-5-hydroxybenzoic acid (Int22)

[0171] At 0°C, 60 mL of liquid bromine (3.0 eq) was dissolved in 150 mL of glacial acetic acid to obtain solution A. Compound I-4 (60 g, 1.0 eq) was dissolved in 150 mL of chloroform. Under an ice bath at 0°C, solution A was slowly added dropwise to the chloroform. After the addition was complete, the mixture was allowed to stand at room temperature overnight. The reaction was confirmed by LC-MS. After the reactants had reacted completely, saturated sodium sulfite solution was added to quench the reaction until the reaction solution was completely colorless. The mixture was extracted with EA / H2O, then extracted with saturated NaCl solution, dried over anhydrous NaSO4, concentrated under reduced pressure to remove the solvent, and then stirred at room temperature overnight with approximately 30 mL of EA. The mixture was filtered, and the filter cake was dried to obtain 35 g of white solid.

[0172] MS (m / z): 234.9 [M+H] + .

[0173] Step 2: Synthesis of compound (4-bromo-2-fluoro-5-hydroxyphenyl)(1H-imidazol-1-yl)methyl ketone (Int23)

[0174] Dissolve Int22 (35g, 1.0eq) in 150mL of DMF. Add CDI (26.6g, 1.1eq) in small amounts several times under an ice bath at 0℃. Stir at 0℃ for more than 2 hours. Monitor the reaction by TLC. After the reaction with the starting material is complete, the reaction solution is ready for use.

[0175] Step 3: Synthesis of compound 4-bromo-2-fluoro-5-hydroxybenzamide (Int24)

[0176] At room temperature, the reaction solution of Int23 was slowly added to 175 mL of ammonia water and stirred at room temperature for 1 h. The reaction was monitored by LC-MS, extracted with EA / H2O, extracted with saturated NaCl solution, dried over anhydrous NaSO4, and concentrated under reduced pressure to remove the solvent, yielding 36.4 g of an oily orange liquid.

[0177] MS (m / z): 233.9 [M+H] + .

[0178] Step 4: Synthesis of compound 4-bromo-2-fluoro-5-hydroxybenzonitrile (Int25)

[0179] In a cold trap at -20℃, 40 mL of POCl3 was slowly added dropwise to Int24 (36.4 g, 1.0 eq). After the addition was complete, the mixture was heated to 60℃ for 2 hours (note the need to set up a tail gas absorption device). The reaction was monitored by TLC until the reactants were completely reacted. The mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The reaction solution was then quenched in room temperature water, extracted with EA / H2O, extracted with saturated NaCl solution, dried over anhydrous NaSO4, concentrated under reduced pressure to remove the solvent, mixed with water, and passed through a column at a PE:EA ratio of 10:1 to obtain 7.2 g of white solid.

[0180] 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 7.86 (d, J = 8.7Hz, 1H), 7.26 (d, J = 5.8Hz, 1H).

[0181] Step 5: Synthesis of compound 5-(allyloxy)-4-bromo-o-fluorobenzonitrile (Int26)

[0182] In t25 (6.5 g, 1.0 eq), 3-bromopropene (5.2 mL, 2.0 eq), and K2CO3 (8.3 g, 2.0 eq) were dissolved in 25 mL of DMF. The mixture was heated at 40 °C for 2 hours under N2 protection, and the reaction was monitored by LC-MS. The solution was extracted with EA / H2O, then with a saturated NaCl solution. The mixture was dried over anhydrous NaSO4, concentrated under reduced pressure to remove the solvent, and then passed through a 0–5% EA / PE Flash column to obtain 7.5 g of a white solid.

[0183] 1 H NMR (400MHz, Chloroform-d) δ7.48(d,J=7.9Hz,1H),7.02(d,J=5.4Hz,1H),6.10–5.96(m,1H),5.53–5.45(m,1H),5.41–5.33(m,1H),4.64–4.58(m,2H).

[0184] Step 6: Synthesis of compound 2-allyl-4-bromo-6-fluoro-3-hydroxybenzonitrile (Int27)

[0185] Int26 (2.0 g) was dissolved in 5 mL of o-dichlorobenzene under N2 protection and microwaved at 200 °C for 4 hours. A total of 6.5 g of Int26 was added in batches. The reaction was detected by TLC. The mixture was heated in an oil bath at 120 °C, concentrated under reduced pressure to remove the solvent, mixed, and then passed through a column at 0–10% EA / PE Flash to obtain 6.0 g of white solid.

[0186] MS (m / z): 255.9 [M+H] + .

[0187] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 7.77 (d, J = 8.6Hz, 1H), 5.97–5.83 (m, 1H), 5.15–4.90 (m, 2H), 3.60–3.54 (m, 2H).

[0188] Step 7: Synthesis of compound 4-bromo-6-fluoro-3-hydroxy-2-(3-hydroxypropyl)benzonitrile (Int28)

[0189] Int27 (6.0 g, 1.0 eq) was dissolved in anhydrous THF under N2 protection in an ice bath at 0°C. Boranetetrahydrofuran solution (30 mL, 1 M, 1.5 eq) was slowly added, and the mixture was stirred in an ice bath for 2 hours. Then, NaOH aqueous solution (13 mL, 3 M, 2.0 eq) was slowly added, followed by hydrogen peroxide (3.2 mL, 30%). The mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS. The pH was adjusted to 2–3 with 1 M HCl solution, and the mixture was extracted with EA / H2O, then with a saturated NaCl solution. The sample was dried over anhydrous NaSO4, concentrated under reduced pressure to remove the solvent, and then passed through a 0–30% EA / PE Flash column to obtain 4.15 g of a white solid.

[0190] MS (m / z): 273.9 [M+H] + .

[0191] Step 8: Synthesis of compound 8-bromo-6-fluorobenzene-5-nitrile (D)

[0192] Int28 (4.15 g, 1.0 eq) and PPh3 (4.76 g, 1.2 eq) were dissolved in anhydrous THF under N2 protection and stirred for 10 min in an ice bath at 0 °C. DIAD (3 mL, 1.2 eq) was added dropwise, and the mixture was allowed to react at room temperature for 1 hour after the addition was complete. The reaction was monitored by LC-MS. The solvent was evaporated, and the mixture was diluted with DCM and stirred. The solution was then passed through a 0–5% EA / PE Flash column to obtain 3.8 g of a white solid.

[0193] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.6Hz,1H),4.31–4.24(m,2H),2.91(t,J=6.5Hz,2H),2.05–1.94(m,2H).

[0194] V. Preparation of common intermediate E:

[0195] Step 1: Synthesis of compound 2-fluoro-4-methyl-5-(4,4,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (Int29)

[0196] Compound I-5 (8.8 g, 1.0 eq, 41.11 mmol) was dissolved in dioxane (120 mL), and then 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (15.66 g, 1.5 eq, 61.61 mmol), Pd(dppf)Cl2 (3.01 g, 0.1 eq, 4.11 mmol), and potassium acetate (10.09 g, 103 mmol) were added sequentially. The reaction mixture was stirred at 95 °C for 2 hours. After cooling to room temperature, the mixture was evaporated to dryness, and the crude product was purified by column chromatography to give the final product (6.2 g, yield: 58%) as a yellow solid.

[0197] 1 H NMR (600MHz, DMSO-d6) δ7.95 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 11.0 Hz, 1H), 2.56 (s, 3H), 1.31 (s, 12H).

[0198] Step 2: Synthesis of compound 2-fluoro-5-hydroxy-4-methylbenzonitrile (Int30)

[0199] Compound Int29 (6.2 g, 1.0 eq, 23.75 mmol) was dissolved in acetic acid (60 mL), and 30% hydrogen peroxide (6 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, evaporated to dryness, and extracted with ethyl acetate (200 mL) and water (200 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the product (4.7 g), which was a white solid.

[0200] 1 H NMR (600MHz, DMSO-d6) δ10.12(s,1H),7.28(d,J=9.9Hz,1H),7.05(d,J=5.5Hz,1H),2.19(s,3H).

[0201] Step 3: Synthesis of compound 2-fluoro-5-methoxy-N-acetyltryptamine-4-methylbenzonitrile (Int31)

[0202] Compound Int30 (4.7 g, 1.0 eq, 31.10 mmol) was dissolved in THF (70 mL). 60% NaH (2.49 g, 2.0 eq, 62.19 mmol) was added in portions at 0 °C and stirred at room temperature for 20 minutes. Iodomethane (22.07 g, 5.0 eq, 155.48 mmol) was added and stirred at room temperature for 1 hour and 40 minutes. The mixture was then poured into a saturated ammonium chloride aqueous solution (300 mL) and extracted with ethyl acetate (300 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the product (3.9 g, yield: 76%), which was a white solid.

[0203] 1 H NMR (600MHz, DMSO-d6) δ7.42 (d, J = 5.3Hz, 1H), 7.39–7.35 (m, 1H), 3.83 (s, 3H), 2.22 (s, 3H).

[0204] Step 4: Synthesis of compound 4-(bromomethyl)-2-fluoro-5-methoxybenzonitrile (Int32)

[0205] Compound Int31 (3.5 g, 1.0 eq, 21.19 mmol) was dissolved in carbon tetrachloride (50 mL), and NBS (3.96 g, 1.1 eq, 22.25 mmol) and AIBN (348 mg, 0.1 eq, 2.12 mmol) were added sequentially. The mixture was purged with nitrogen three times, stirred at 80 °C for 5 hours, cooled to room temperature, and evaporated to dryness. The crude product was purified by column chromatography to obtain the final product (4.6 g, yield: 89%), which was a white solid.

[0206] 1 H NMR (600MHz, DMSO-d6) δ7.66 (d, J = 9.4Hz, 1H), 7.60 (d, J = 5.2Hz, 1H), 4.62 (s, 2H), 3.90 (s, 3H).

[0207] Step 5: Synthesis of compound 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-5-methoxybenzonitrile (Int33)

[0208] Compound Int32 (4.6 g, 18.85 mmol) was dissolved in acetonitrile (100 mL), and pyrazole (1.41 g, 1.0 eq, 20.73 mmol) and cesium carbonate (7.98 g, 1.2 eq, 24.50 mmol) were added sequentially. The mixture was stirred at room temperature for 5 hours, poured into water (300 mL), and extracted with ethyl acetate (300 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the product (3.34 g, yield: 77%), which was a yellow solid.

[0209] 1 H NMR (600MHz, DMSO-d6) δ7.83(d,J=2.3Hz,1H),7.59(d,J=5.1Hz,1H),7.52(d,J=1 .8Hz,1H),6.70(d,J=9.5Hz,1H),6.32(t,J=2.1Hz,1H),5.37(s,2H),3.88(s,3H).

[0210] Step 6: Synthesis of compound 6-((1H-pyrazol-1-yl)methyl)-5-methoxybenzo[d]isoxazole-3-amine (E)

[0211] Compound Int32 (3.34 g, 1.0 eq, 14.44 mmol) was dissolved in acetonitrile / water (7:1) (50 mL), followed by the addition of acetoxyxamic acid (5.42 g, 5.0 eq, 72.44 mmol) and tetramethylguanidine (11.65 g, 7.0 eq, 101.11 mmol). The mixture was stirred at 60 °C for 12 hours, then poured into water (300 mL) and extracted with ethyl acetate (300 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the product (1.1 g, yield: 35%), which was a white solid.

[0212] 1 H NMR (600MHz, DMSO-d6) δ7.80(d,J=2.2Hz,1H),7.50(d,J=1.8Hz,1H),7.42(s,1H),6.72(s,1H),6.33–6.28(m,3H),5.38(s,2H),3.86(s,3H).

[0213] VI. Preparation of common intermediate F:

[0214] Compound Int6 (200 mg, 1.0 eq) was dissolved in THF and placed in an ice bath at 0°C. 280 mg of potassium tert-butoxide was added and stirred for 5 minutes. Then, a THF solution of compound 4-bromo-2,6-dimethoxybenzenesulfonyl chloride was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for half an hour. The reaction was confirmed by TLC. The pH was adjusted to about 5 by adding 10% citric acid aqueous solution. Extraction was performed by adding EA / H2O, followed by backwashing with brine and drying with anhydrous sodium sulfate. The mixture was then purified by EA slurry to give 224 mg of a white solid, which was intermediate F.

[0215] Example 1: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-cyclopropylpyrimidin-5-yl)-2-methoxybenzenesulfonamide (1)

[0216] Common intermediate A (40 mg, 1.0 eq), (2-cyclopropyl-5-pyrimidinyl)boronic acid (20 mg, 1.5 eq), Pd(dppf)Cl2 (6 mg, 0.1 eq), and K2CO3 (45 mg, 4.0 eq) were placed in a pressure-resistant bottle, and approximately 1 mL of a mixed solution of 1,4-dioxane:water = 5:1 was added. The mixture was then purged with nitrogen and heated at 100°C with stirring for at least 2 hours. LC-MS analysis was performed, and the filtrate was collected, concentrated under reduced pressure, purified using preparative liquid chromatography, and freeze-dried to obtain 13.6 mg of a white powdery solid, which was compound 1, with a yield of 32%.

[0217] MS (m / z): 533.1 [M+H] + .

[0218] 1 H NMR (600MHz, DMSO-d6) δ10.34(s,1H),9.05(s,2H),7.90-7.86(m,2H),7.53(d,J=1.6Hz,1H),7.49(d,J=1.8Hz,1H),7.47(dd,J=8.1,1.5Hz,1H), 6.84(s,1H),6.75(s,1H),6.30(t,J=2.1Hz,1H),5.44(s,2H),3.89(s,3H ),3.83(s,3H),2.29-2.25(m,1H),1.12-1.09(m,2H),1.07-1.04(m,2H).

[0219] Example 2: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-cyclopropylpyridin-3-yl)-2-methoxybenzenesulfonamide (2)

[0220] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "6-cyclopropylpyridine-3-boronic acid pinacol ester", and the rest of the method was the same. Compound 2 (30.4 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 70%.

[0221] MS (m / z): 532.1 [M+H] + .

[0222] 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H),8.81(d,J=2.4Hz,1H),8.04(dd,J=8.2,2.5Hz,1H),7.89-7.84(m,2H),7.49(d,J=1.8Hz,1H),7.46-7.38( m,3H),6.84(s,1H),6.75(s,1H),6.30(d,J=2.1Hz,1H),5.44(s,2H),3. 89(s,3H),3.83(s,3H),2.17(tt,J=8.0,4.8Hz,1H),1.03-0.95(m,4H).

[0223] Example 3: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(azacyclobutane))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (3)

[0224] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(azacyclobutane-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronane-2-yl)pyrimidine", and the rest of the method was the same, compound 3 (16.1 mg) was prepared from common intermediate A (60 mg, 1.0 eq) with a yield of 24%.

[0225] MS (m / z): 548.0 [M+H] + .

[0226] 1H NMR (600MHz, DMSO-d6) δ10.18(s,1H),8.78(s,2H),7.87(d,J=2.3Hz,1H),7.82(d,J=8.2Hz,1H),7.49(d,J=1.8Hz,1H),7.39(d,J=1.6Hz,1H),7.36(dd ,J=8.2,1.6Hz,1H),6.83(s,1H),6.75(s,1H),6.30(t,J=2.1Hz,1H),5.44( s,2H),4.10(t,J=7.5Hz,4H),3.88(s,3H),3.85(s,3H),2.38-2.30(m,2H).

[0227] Example 4: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazo-3-yl)-2-methoxy-4-(2-(pyrrolidine-1-yl))pyrimidin-5-yl)benzenesulfonamide (4)

[0228] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(1-pyrrolidinyl)pyrimidin-5-boronic acid pinacol ester", and the rest of the method was the same. Compound 4 (3.8 mg) was prepared from common intermediate A (60 mg, 1.0 eq) with a yield of 5%.

[0229] MS (m / z): 562.1 [M+H] + .

[0230] 1 H NMR(600MHz,DMSO-d6)δ10.19(br s,1H),8.80(s,2H),7.92-7.79(m,2H),7.49(s,1H),7.45-7.29(m,2H),6.82-6.71(m, 2H),6.30(s,1H),5.44(s,2H),3.88(s,3H),3.85(s,3H),3.54(br,4H),1.95(br,4H).

[0231] Example 5: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(3,3-difluorocyclobutyl))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (5)

[0232] Step 1: Synthesis of compound 3,3-difluorocyclobutane-1-carboxynitrile (5-1)

[0233] Compound 5-0 (3-oxocyclobutane-1-carboxynitrile, 3.0 g, 1.0 eq) was dissolved in DCM. Ethylaminotrifluoride (10.2 g, 2.0 eq) was added dropwise under an ice bath at 0 °C, and the reaction was allowed to proceed overnight at room temperature. TLC detection was performed, followed by quenching with saturated NaHCO3 solution, extraction with DCM, backwashing with saturated NaCl, drying under anhydrous Na2SO4, and concentration under reduced pressure to obtain 3.3 g of a brown solid, which was compound 5-1.

[0234] Step 2: Synthesis of compound 3,3-difluorocyclobutane-1-formamidinyl ester (5-2)

[0235] Methyl tert-butyl ether (30 mL) and methanol (8.4 g, 10.0 eq) were added to a reaction flask. The mixture was placed in an ice bath at 0 °C, and acetyl chloride (18.8 g, 10.0 eq) was slowly added dropwise. The reaction was carried out at 0 °C for 1 h. Then, 5-1 (2.8 g, 1.0 eq) was slowly added, and the reaction was carried out at 0 °C for 5 h. The mixture was concentrated under reduced pressure to give 3.8 g of a yellow solid, which was compound 5-2.

[0236] Step 3: Synthesis of compound 3,3-difluorocyclobutane-1-amidinium (5-3)

[0237] Compound 5-2 (3.8 g) was dissolved in methanol, and the mixture was placed in an ice bath at 0°C. A methanol solution of ammonia (8.8 mL, 7 M) was added, and the reaction was carried out at 0°C for 3.5 h. The solution was concentrated under reduced pressure to give 3.4 g of a yellow solid, which was compound 5-3.

[0238] Step 4: Synthesis of compound 5-chloro-2-(3,3-difluorocyclobutyl)pyrimidine (5-4)

[0239] Compound 5-3 (2 g, 1.0 eq) was dissolved in DMA, and hexafluorophosphate (4.3 g, 1.2 eq) and NMM (3 g, 3.0 eq) were added. The reaction was carried out at 80 °C for 1 h. DCM was added for extraction, and the organic phase was washed with 10% citric acid aqueous solution, dried over anhydrous Na₂SO₄, and purified by Flash column chromatography to give 0.65 g of white solid, which was compound 5-4, in 23% yield.

[0240] Step 5: Synthesis of compound 2-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyrimidine (5-5)

[0241] Compound 5-4 (0.64 g, 1.0 eq), pinacol diboronate (0.85 g, 1.3 eq), AcOK (0.5 g, 2.0 eq), Pd2(dba)3 (0.12 g, 0.05 eq), and X-phos (0.12 g, 0.1 eq) were dissolved in 1,4-dioxane and reacted at 80 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was compound 5-5.

[0242] MS (m / z): 297.1 [M+H] + .

[0243] Step 6: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(3,3-difluorocyclobutyl))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (5)

[0244] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "5-5", and the rest of the method was the same. Compound 5 (3.5 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 7%.

[0245] MS (m / z): 583.0 [M+H] + .

[0246] 1 H NMR (600MHz, DMSO-d6) δ10.39 (s, 1H), 9.21 (s, 2H), 7.91 (d, J = 8.1Hz, 1H), 7.89-7.85 (m, 1H), 7.56 (s, 1H), 7.52-7.48 (m, 2H), 6.83(s,1H),6.74(s,1H),6.30(t,J=2.1Hz,1H),5.44(s,2H),3.90(s,3H),3.84(s,3H),3.72-3.65(m,1H),3.11-2.92(m,4H).

[0247] Example 6: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2-methoxybenzenesulfonamide (6)

[0248] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-dimethylaminepyrimidin-5-boronic acid-2,3-dimethylbutanediol ester", and the rest of the method was the same. Compound 6 (9.4 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 22%.

[0249] MS (m / z): 536.1 [M+H] + .

[0250] 1 H NMR (600MHz, DMSO-d6) δ10.13(s,1H),8.80(s,2H),7.88-7.85(m,1H),7.81(d,J=8.2Hz,1H),7.49(d,J=1.8Hz,1H) ,7.41-7.30(m,2H),6.82-6.68(m,2H),6.29(t,J=2.1Hz,1H),5.43(s,2H),3.86(s,3H),3.85(s,3H),3.18(s,6H).

[0251] Example 7: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(dimethylamino)pyridin-3-yl)-2-methoxybenzenesulfonamide (7)

[0252] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(dimethylamino)pyridine-5-boronic acid pinacol ester", and the rest of the method was the same. Compound 7 (16.90 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 39%.

[0253] MS (m / z): 535.1 [M+H] + .

[0254] 1 H NMR (600MHz, DMSO-d6) δ10.11(s,1H),8.52(s,1H),8.02(s,1H),7.87(d,J=2.2Hz,1H),7.81(d,J=8.2Hz,1H),7.49(d,J=1.8Hz ,1H),7.38-7.33(m,2H),6.83(s,2H),6.75(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.89(s,3H),3.85(s,3H),3.12(s,6H).

[0255] Example 8: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4-(2-(oxecyclobutane-3-yl))pyrimidin-5-yl)benzenesulfonamide (8)

[0256] Step 1: Synthesis of compound 5-bromo-2-(oxetane-3-yl)pyrimidine (8-1)

[0257] 8-O: 5-bromo-2-iodopyrimidine (8.8 g, 1.0 eq) and 3-iodooxetine (6.82 g, 1.2 eq) were dissolved in DMA. Nickel chloride dimethoxyethane (0.68 g, 0.1 eq), 2-amidinylpyridine (0.49 g, 0.1 eq), TFA (0.37 g, 0.1 eq), NaI (2.32 g, 0.5 eq), and Zn (4.04 g, 2.0 eq) were added. The reaction was carried out at 60 °C for 4 h. TLC monitoring was performed. The reaction was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution. The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. Flash column chromatography was used to purify the crude compound to 0.64 g, with a yield of 9.7%.

[0258] MS (m / z): 214.9 [M+H] + .

[0259] Step 2: Synthesis of compound 2-(oxecyclobutane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentane-2-yl)pyrimidine (8-2)

[0260] 8-1 (0.64 g, 1.0 eq), pinacol diboronate (0.91 g, 1.2 eq), AcOK (0.59 g, 2.0 eq), and Pd(dppf)Cl2 (0.13 g, 0.1 eq) were dissolved in DMA and reacted at 85 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth liner, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification.

[0261] MS (m / z): 262.9 [M+H] + .

[0262] Step 3: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4-(2-(oxecyclobutane-3-yl))pyrimidin-5-yl)benzenesulfonamide (8)

[0263] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "8-2", and the rest of the method was the same. Compound 8 (4.5 mg) was prepared from common intermediate A (60 mg, 1.0 eq) with a yield of 7%.

[0264] MS (m / z): 549.1 [M+H] + .

[0265] 1 H NMR(600MHz,DMSO-d6)δ10.39(s,1H),9.24(s,2H),7.92(d,J=8.1Hz,1H),7 .88(d,J=2.2Hz,1H),7.59(s,1H),7.53(d,J=8.1Hz,1H),7.49(d,J=1.8Hz,1 H),6.84(s,1H),6.75(s,1H),6.30(t,J=2.2Hz,1H),5.44(s,2H),4.99-4.94 (m,2H),4.88(t,J=6.2Hz,2H),4.60-4.52(m,1H),3.92(s,3H),3.84(s,3H).

[0266] Example 9: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy4-(2-methoxypyrimidin-5-yl)benzenesulfonamide (9)

[0267] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-methoxypyrimidin-5-boronic acid pinacol ester", and the rest of the method was the same. Compound 9 (10.3 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 25%.

[0268] MS (m / z): 523.0 [M+H] + .

[0269] 1H NMR (600MHz, DMSO-d6) δ10.34(s,1H),9.05(s,2H),7.89-7.85(m,2H),7.52(s,1H),7.49(d,J=1.8Hz,1H),7.46(d ,J=8.2,1H),6.84(s,1H),6.75(s,1H),6.30(t,J=2.1Hz,1H),5.44(s,2H),3.98(s,3H),3.90(s,3H),3.84(s,3H).

[0270] Example 10: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazo-3-yl)-2-methoxy4-(6-methoxypyridin-3-yl)benzenesulfonamide (10)

[0271] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-methoxy-5-pyridineboronic acid pinacol ester", and the rest of the method was the same. Compound 10 (22.4 mg) was prepared from common intermediate A (40 mg, 1.0 eq) with a yield of 53%.

[0272] MS (m / z): 522.1 [M+H] + .

[0273] 1 H NMR (600MHz, DMSO-d6) δ10.24(s,1H),8.60(s,1H),8.13(d,J=8.7Hz,1H),7.89-7.82(m,2H),7.49(d,J=1.8Hz,1H),7.46-7.35(m,2H ),6.95(d,J=8.6Hz,1H),6.83(s,1H),6.75-6.72(m,1H),6.30(t,J=2.1Hz,1H),5.43(s,2H),3.91(s,3H),3.88(s,3H),3.84(s,3H).

[0274] Example 11: Preparation of compound N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxybenzenesulfonamide (11)

[0275] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole", and the rest of the method was the same, compound 11 (11.3 mg) was prepared from common intermediate A (60 mg, 1.0 eq) with a yield of 18%.

[0276] MS (m / z): 521.1 [M+H] + .

[0277] 1 H NMR(600MHz,DMSO-d6)δ10.02(s,1H),8.42(s,1H),8.00(s,1H),7.88-7.85(m ,1H),7.73(d,J=8.2Hz,1H),7.49(d,J=1.8Hz,1H),7.34(d,J=1.5Hz,1H),7.2 9(dd,J=8.2,1.5Hz,1H),6.83(s,1H),6.74(s,1H),6.29(t,J=2.1Hz,1H),5.4 3(s,2H),3.84(s,3H),3.84(s,3H),3.78-3.72(m,1H),1.10-1.05(m,2H),1.05 -0.96(m,2H).

[0278] Example 12: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(azacyclobutane-1-yl))pyridin-3-yl)-2-methoxybenzenesulfonamide (12)

[0279] Step 1: Synthesis of compound 2-(azacyclobutane-1-yl)-5-bromopyridine (12-1)

[0280] 2-Fluoro-5-bromopyridine (300 mg, 1.0 eq), aziridine hydrochloride (117 mg, 1.2 eq), and DIPEA (592 μL, 2.0 eq) were dissolved in DMF and heated overnight at 100 °C. The reaction was detected by LC-MS. The reaction was quenched with a small amount of water, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then rapidly passed through a Flash column at medium pressure (0–5% EA) to give 182 mg of a white solid.

[0281] MS (m / z): 214.8 [M+H] + .

[0282] Step 2: Synthesis of 2-azacyclobutane-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxoboronyl-2-yl)pyridine (12-2) Compound 12-1 (182 mg, 1.0 eq), pinacol diboronate (434 mg, 2.0 eq), AcOK (167 mg, 2.0 eq), Pd2(dba)3 (78 mg, 0.1 eq), and X-phos (81 mg, 0.2 eq) were dissolved in 1,4-dioxane and reacted at 80 °C for 4 h. The reaction was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was compound 12-2.

[0283] Step 3: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(azacyclobutane-1-yl))pyridin-3-yl)-2-methoxybenzenesulfonamide (12)

[0284] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "compound 12-2", and the rest of the method was the same. Compound 12 (7.6 mg) was prepared from intermediate A (40 mg, 1.0 eq) with a yield of 17%.

[0285] MS (m / z): 547.1 [M+H] + .

[0286] 1 H NMR(600MHz,DMSO-d6)δ10.10(s,1H),8.50(d,J=2.5Hz,1H),7.93(dd,J=8.8,2 .5Hz,1H),7.87(d,J=2.3Hz,1H),7.80(d,J=8.0Hz,1H),7.51-7.46(m,1H),7.34 -7.29(m,2H),6.83(s,1H),6.74(s,1H),6.44(d,J=8.7Hz,1H),6.29(t,J=2.1Hz ,1H),5.43(s,2H),4.00(t,J=7.4Hz,4H),3.88-3.83(m,6H),2.38-2.31(m,2H).

[0287] Example 13: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxyisoxazole[4,5-c]pyridin-3-yl)-4-(2-(cyclopropyl-1-yl))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (13)

[0288] Referring to the synthesis of compound 1 in step 1 of Example 1, "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-cyclobutylamine-5-pyrimidinyl-boronic acid", and the rest of the method was the same. Compound 13 (8.06 mg) was prepared from common intermediate B (70 mg, 1.0 eq) with a yield of 10%.

[0289] MS (m / z): 549.2 [M+H] + .

[0290] 1 H NMR (600MHz, DMSO-d6) δ10.86(s,1H),8.76(s,2H),7.89(d,J=2.2Hz,1H),7.81(d,J=8.2Hz,1H),7.51(d,J=1.8Hz,1H),7 .43-7.02(m,3H),6.32(t,J=2.1Hz,1H),5.42(s,2H),4.10(t,J=7.5Hz,4H),3.95(s,3H),3.85(s,3H),2.38-2.30(m,2H).

[0291] Example 14: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(1-isopropyl-1H-pyrazol-4-yl)-2-methoxybenzenesulfonamide (14)

[0292] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "1-isopropylpyrazole-4-boronic acid", and the rest of the method was the same. Compound 14 (12.9 mg) was prepared from intermediate A (40 mg, 1.0 eq) with a yield of 30%.

[0293] MS (m / z): 523.1 [M+H] + .

[0294] 1H NMR (600MHz, DMSO-d6) δ10.01(s,1H),8.41(s,1H),8.01(s,1H),7.87(d,J=2.3Hz,1H),7.73(d,J=8.2Hz,1H),7.49(d,J=1.8Hz,1H),7.34(d,J=1.5H z,1H),7.32-7.28(m,1H),6.83(s,1H),6.74(s,1H),6.29(t,J=2.1Hz,1H) ,5.44(s,2H),4.55-4.46(m,1H),3.86-3.83(m,6H),1.45(d,J=6.7Hz,6H).

[0295] Example 15: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxybenzenesulfonamide (15)

[0296] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "N-cyclobutyl-pyrazole-4-pinacol diborate", and the rest of the method was the same. Compound 15 (18.1 mg) was prepared from intermediate A (80 mg, 1.0 eq) with a yield of 21%.

[0297] MS (m / z): 535.1 [M+H] + .

[0298] 1 H NMR (600MHz, DMSO-d6) δ10.03(s,1H),8.45(s,1H),8.02(s,1H),7.86(d,J=2.3Hz,1H),7.73(d,J=8.2Hz,1H),7.49(d,J=1.8Hz,1H),7.34-7. 24(m,2H),6.84-6.66(m,2H),6.29(t,J=2.0Hz,1H),5.42(s,2H),4.88 -4.79(m,1H),3.85-3.81(m,6H),2.49-2.38(m,4H),1.86-1.76(m,2H).

[0299] Example 16: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide (16)

[0300] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "1-methyl-1H-pyrazole-4-boronic acid", and the rest of the method was the same. Compound 16 (7.5 mg) was prepared from intermediate A (40 mg, 1.0 eq) with a yield of 18%.

[0301] MS (m / z): 495.2 [M+H] + .

[0302] 1 H NMR (600MHz, DMSO-d6) δ10.03(s,1H),8.31(s,1H),8.01(s,1H),7.87(d,J=2.3Hz,1H),7.74(d,J=8.2Hz,1H),7.3 2(s,1H),7.27(d,J=8.0Hz,1H),6.83(s,1H),6.74(s,1H),6.29(t,J=2.1Hz,1H),5.44(s,2H),3.89-3.82(m,9H).

[0303] Example 17: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazo-3-yl)-2-methoxy-4-(1H-pyrazol-4-yl)benzenesulfonamide (17)

[0304] Step 1: Synthesis of compound tert-butyl 3-(4-(N-(6-(((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)aminosulfonyl)-3-methoxyphenyl)-1H-pyrazol-1-carboxylic acid (17-1)

[0305] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "1-Boc-1H-pyrazole-4-boronic acid ester", and the rest of the method was the same. Compound 17-1 (35.0 mg) was prepared from intermediate A (100 mg, 1.0 eq).

[0306] MS (m / z): 581.1 [M+H] + .

[0307] Step 2: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4-(1H-pyrazol-4-yl)benzenesulfonamide (17)

[0308] Compound 17-1 was dissolved in 0.5 mL of trifluoroacetic acid and stirred at room temperature for half an hour. The reaction was monitored by TLC. After the raw materials had completely reacted, the trifluoroacetic acid was removed by direct vacuum concentration. Acetonitrile and water of HPLC grade were added, and the mixture was freeze-dried to obtain 19.9 mg of white powder solid, which was compound 17. The total yield was 17%.

[0309] MS (m / z): 481.1 [M+H] + .

[0310] 1 H NMR (600MHz, DMSO-d6) δ10.01(s,1H),8.22(s,2H),7.87(d,J=2.2Hz,1H),7.76-7.72(m,1H),7.49(d ,J=1.8Hz,1H),7.38-7.31(m,2H),6.83(s,1H),6.75(s,1H),6.29(t,J=2.1Hz,1H),5.44(s,2H),3.86 -3.83(m,6H).

[0311] Example 18: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)thiazolyl-5-yl)-2-methoxybenzenesulfonamide (18)

[0312] Step 1: Synthesis of compound N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)thiazole-2-amine (18-1)

[0313] At -78°C under nitrogen protection, 2 mL (2.5 M) of n-butyllithium was added dropwise to tetrahydrofuran containing 5-bromo-N,N-dimethylthioazole-2-amine (200 mg, 1.0 eq) and isopropanol pinacol borate (220 mg, 2.0 eq), and the mixture was stirred at this temperature for 1 hour. The temperature was then raised to 30°C and stirred for 1.5 hours. The mixture was quenched with methanol, and the solvent was evaporated to dryness to obtain compound 18-1, which was directly added to the next step.

[0314] Step 2: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)thiazo-5-yl)-2-methoxybenzenesulfonamide (18)

[0315] Referring to the synthesis of compound 1 in step 1 of Example 1, "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "compound 18-1", and the rest of the method was the same. Compound 18 (18.1 mg) was prepared from intermediate A (60 mg, 1.0 eq) with a yield of 27.5%.

[0316] MS (m / z): 541.1 [M+H] + .

[0317] 1 H NMR (600MHz, DMSO-d6) δ10.10(s,1H),7.89-7.85(m,2H),7.73(d,J=8.3Hz,1H),7.49(d,J=1.8Hz,1H),7.20(d,J=1.6Hz,1H) ,7.12(dd,J=8.3,1.6Hz,1H),6.83(s,1H),6.75(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.86-3.83(m,6H),3.11(s,6H).

[0318] Example 19: Preparation of compound 4-(2-(azacyclobutane-1-yl))pyrimidin-5-yl)-2-methoxy-N-(4-methoxy-6-(thiazolyl-2-yl))methoxybenzo[d]isoxazol-3-yl)benzenesulfonamide (19)

[0319] Referring to the synthesis of compound 1 in step 1 of Example 1, "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(azacyclobutane-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentane-2-yl)pyrimidine", and the rest of the method was the same. Compound 19 (25.0 mg) was prepared from intermediate C (35 mg, 1.0 eq) with a yield of 64.6%.

[0320] MS (m / z): 567.1 [M+H] + .

[0321] 1 H NMR (600MHz, DMSO-d6) δ10.36(s,1H),8.80(s,2H),7.84(d,J=8.2Hz,1H),7.42(s,1H),7.38(d,J=8.5Hz,1H),7.36– 7.31(m,2H),7.28–7.25(m,1H),6.89(d,J=1.9Hz,1H),4.11(t,J=7.5Hz,4H),3.90–3.86(m,6H),2.39–2.31(m,2H).

[0322] Example 20: Preparation of compound N-(5-((1H-pyrazol-1-yl))methyl)-3,4-2H-benzodihydropyran[8,7-d]benzisoxazol-9-yl)-4-(2-(azacyclobutane-1-yl))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (20)

[0323] Step 1: Synthesis of compound 2-(azacyclobutane-1-yl)-5-(4-(benzylthio)-3-methoxyphenyl)pyrimidine (20-11)

[0324] Intermediate Int9 (100 mg, 1.0 eq), 2-cyclobutane-5-pyrimidine-boronic acid (350 mg, 1.5 eq), Pd(dppf)Cl2 (95 mg, 0.1 eq), and K2CO3 (138 mg, 4.0 eq) were placed in a pressure-resistant flask. Approximately 1 mL of a mixed solution of 1,4-dioxane:water = 5:1 was added. The flask was then purged with nitrogen and heated at 100°C with stirring for at least 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the filtrate was collected, concentrated under reduced pressure, and purified using 0–45% EA Flash to obtain 400 mg of a pale yellow oily liquid, which was compound 20-11.

[0325] MS (m / z): 364.0 [M+H] + .

[0326] Step 2: Synthesis of compound 4-(2-(azacyclobutane-1-yl))pyrimidin-5-yl)-2-methoxybenzenesulfonyl chloride (20-12)

[0327] Compound 20-11 (400 mg, 1.0 eq) was dissolved in 5 mL of a mixed solvent of acetonitrile:water:glacial acetic acid = 20:1:0.5 and cooled in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (260 mg, 1.5 eq) was added in small batches. The reaction was monitored by TLC. When the reactants were fully reacted, a small amount of water was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then rapidly passed through a Flash column at medium pressure (0–10% MeOH) to obtain 170 mg of a pale yellow solid, which was compound 20-12.

[0328] MS (m / z): 340.0 [M+H] + .

[0329] Step 3: Synthesis of compound 4-bromo-2-fluoro-6-hydroxybenzonitrile (20-1)

[0330] 4-Bromo-2,6-difluorobenzonitrile (20.00 g, 1.0 eq) was dissolved in 1,4-dioxane (200.00 mL) and water (200.00 mL), and NaOH (22.00 g, 6.0 eq) was added in portions at 0 °C. The mixture was stirred at 60 °C for 6 hours. TLC analysis showed that the starting material had been consumed. The mixture was adjusted to acidity with 6N hydrochloric acid, 500 mL was added, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (750 g SiO2, 10% EA / PE) to give 20-1 (16.1 g), in 80.2% yield, as a white solid.

[0331] MS (m / z): 430.7 [M+H] + .

[0332] Step 4: Synthesis of compound 2-(allyloxy)-4-bromo-6-4-fluorobenzonitrile (20-2)

[0333] Compound 20-1 (16.1 g, 1.0 eq) was dissolved in THF (400 mL), and 3-bromopropene (14.4 g, 1.5 eq) and cesium carbonate (36.5 g, 1.5 eq) were added. The reaction was carried out at room temperature for 16 hours. The mixture was extracted with ethyl acetate and water, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (3% EA / PE) to give product 20-2 (16.5 g), with a yield of 87.3%.

[0334] 1 H NMR (600MHz, DMSO-d6) δ7.51-7.47(m,1H),7.41(s,1H),6.09-6.00(m,1H),5.49-5.43(m,1H),5.37-5.32(m,1H),4.82(d,J=5.3Hz,2H).

[0335] Step 5: Synthesis of compound 3-allyl-4-bromo-6-fluoro-2-cyanophenol (20-3)

[0336] Compound 20-2 (16.5 g, 1.0 eq) was dissolved in 50 mL of o-dichlorobenzene, and the reaction solution was stirred at 180 °C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure in an oil bath at 120 °C until no solvent dripped out. It was then diluted with DCM and mixed with 30 g of 300-400 mesh silica gel. The crude product was purified by column chromatography (40% EA / PE) to obtain product 20-3 (14.2 g), with a yield of 86.1%, as a white solid.

[0337] 1H NMR (600MHz, DMSO-d6) δ11.47(s,1H),7.38(d,J=8.9Hz,1H),5.87-5.78(m,1H),5.06-5.01(m,1H),4.93-4.88(m,1H),3.52(d,J=5.9Hz,2H).

[0338] Step 6: Synthesis of compound 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile (20-4)

[0339] Compound 20-3 (14.2 g, 1.0 eq) was dissolved in THF (200 mL), cooled to 0 °C, and a tetrahydrofuran solution of borane (1.0 M) (65 mL) was added. The reaction was continued for 2 hours, followed by the addition of an aqueous solution of sodium hydroxide (3.0 M) (40 mL) and an aqueous solution of hydrogen peroxide (30%) (10 mL). The reaction was allowed to proceed overnight. The pH was adjusted to approximately 2 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (30% EA / PE) to obtain product 20-4 (6.23 g), with a yield of 41.17%, as a white solid.

[0340] 1 H NMR (600MHz, DMSO-d6) δ7.35 (d, J = 8.9 Hz, 1H), 3.44 (t, J = 6.5 Hz, 2H), 2.78-2.73 (m, 2H), 1.64-1.56 (m, 2H).

[0341] Step 7: Synthesis of compound 5-bromo-7-fluorobenzodihydropyran-8-onitrile (20-5)

[0342] Compound 20-4 (6.23 mg, 1.0 eq) and triphenylphosphine (6.82 g, 1.2 eq) were dissolved in THF (60 mL), and DEAD (4.41 g, 1.2 eq) was added dropwise under ice bath conditions, maintaining the system temperature below 5 °C. Nitrogen gas was purged, and the mixture was stirred at room temperature for 2 h. LCMS analysis showed that the starting material was exhausted. Ethyl acetate and water were added for extraction. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (10% EA / PE) to give product 20-5 (3.81 g), with a yield of 57.3%, as a pink solid.

[0343] 1 H NMR (600MHz, Chloroform-d) δ7.00 (d, J = 8.2Hz, 1H), 4.30 (t, J = 5.3Hz, 2H), 2.76-2.70 (m, 2H), 2.11-2.02 (m, 2H).

[0344] Step 8: Synthesis of compound 7-fluoro-5-vinylbenzodihydropyranbenzopyran-8-onitrile (20-6)

[0345] Compound 20-5 (1.5 g, 1.0 eq) was dissolved in a mixed solvent of water and N,N-dimethylformamide (V:V = 1:6), and potassium vinyltrifluoroborate (941 mg, 1.2 eq), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (428 mg, 0.1 eq), and cesium carbonate (5.7 g, 3.0 eq) were added sequentially. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0–23% EA / PE) to give 968 mg of a white solid.

[0346] 1 H NMR(600MHz,DMSO-d6)δ7.23(d,J=10.8Hz,1H),6.96-6.88(m,1H),6.03-5.97(m,1 H),5.62-5.57(m,1H),4.35-4.27(m,2H),2.72(t,J=6.8Hz,2H),2.01-1.92(m,2H).

[0347] Step 9: Synthesis of compound 7-fluoro-5-formylbenzodihydropyran-8-onitrile (20-7)

[0348] Compound 20-6 (968 mg, 1.0 eq) was dissolved in tetrahydrofuran, cooled to 0 °C, and an aqueous solution of potassium osmium tetroxide dihydrate (31 mg, 0.02 eq) was added. The mixture was stirred for 30 minutes, followed by the addition of an aqueous solution of sodium periodate (2.64 g, 2.5 eq). The reaction was carried out at 20 °C for 0.5 hours. The mixture was extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0–25% EA / PE) to obtain product 20-7 (781 mg).

[0349] Step 10: Synthesis of compound 7-fluoro-5-hydroxymethylbenzodihydropyran-8-carboxynitrile (20-8)

[0350] Compound 20-7 (600 mg, 1.0 eq) was dissolved in methanol, cooled to 0 °C, and sodium borohydride (422 mg, 3.0 eq) was added. The reaction was continued for 1 hour, quenched with water, concentrated, and the pH was adjusted to about 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by 0–55% EA Flash to give a white solid 20-8 (540 mg).

[0351] 1 H NMR(600MHz,DMSO-d6)δ6.99(d,J=10.4Hz,1H),5.52(t,J=5.4Hz,1H),4.50( d,J=5.3Hz,2H),4.31-4.26(m,2H),2.56(t,J=6.5Hz,2H),1.99-1.92(m,2H).

[0352] Step 11: Synthesis of compound 5-((1H-pyrazol-1-yl)methyl)-7-fluorobenzodihydropyran-8-carboxynitrile (20-9)

[0353] A CH3CN solution of compound 20-8 (540 mg, 1.0 eq) and 1-(methanesulfonyl)-1H-pyrazole (493 mg, 1.1 eq) was mixed with Cs2CO3 (2.0 g, 2.0 eq) and stirred at 70 °C for 2 h. LCMS analysis showed that the starting material was exhausted. The mixture was extracted with ethyl acetate and water, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by 0–45% EA Flash to give a yellow solid 20-9 (560 mg).

[0354] 1 H NMR(600MHz,DMSO-d6)δ7.78(d,J=2.3Hz,1H),7.51(d,J=1.8Hz,1H),6.33-6.30(m,2H) ,5.86(s,2H),5.38(s,2H),4.25-4.21(m,2H),2.67(t,J=6.4Hz,2H),2.03-1.97(m,2H).

[0355] Step 12: Synthesis of compound 5-((1H-pyrazol-1-yl)methyl)-3,4-2H-benzodihydropyran[8,7-d]benzisoxazole-9-amine (20-10)

[0356] Compound 20-8 (560 mg, 1.0 eq) and N-hydroxyacetamide (0.7 mL, 5.0 eq) were added to a solution of acetonitrile and water, followed by the addition of K₂CO₃ (1.5 g, 5.0 eq). The mixture was heated at 60 °C for 16 h. Extraction was performed with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified using 0–65% EA–10% MeOH Flash to give 386 mg of a white solid, which was compound 20-10.

[0357] 1H NMR(600MHz,DMSO-d6)δ7.78(d,J=2.3Hz,1H),7.51(d,J=1.8Hz,1H),6.34-6.30(m,2H) ,5.86(s,2H),5.38(s,2H),4.25-4.21(m,2H),2.67(t,J=6.4Hz,2H),2.03-1.94(m,2H).

[0358] Step 13: Synthesis of compound N-(5-((1H-pyrazol-1-yl))methyl)-3,4-2H-benzodihydropyran[8,7-d]benzisoxazol-9-yl)-4-(2-(azacyclobutane-1-yl))pyrimidin-5-yl)-2-methoxybenzenesulfonamide (20)

[0359] Compound 20-10 (55 mg, 1.0 eq) was placed in a three-necked flask, purged with N2, and then anhydrous THF was added. The flask was pre-cooled in a -60°C cold well, and NaHMDS (133 μl, 2 M) was slowly added dropwise, ensuring the temperature did not exceed -40°C. After the addition was complete, the flask was stirred at -60°C for 30 min. Then, compound 20-12 (100 mg, 1.2 eq, dissolved in THF) was slowly added dropwise. The mixture was stirred at -60°C for 1 h, then slowly raised to room temperature and allowed to react overnight at room temperature. After the reaction was detected by LC-MS, saturated NH4Cl solution was added to quench the reaction. The mixture was extracted three times with EA, backwashed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to prepare compound 20 (6.4 mg), with a yield of 5.5%.

[0360] MS (m / z): 574.1 [M+H] + .

[0361] 1 H NMR(600MHz,DMSO-d6)δ9.98(s,1H),8.77(s,2H),7.82-7.79(m,1H),7.79-7. 77(m,1H),7.52-7.49(m,1H),7.41-7.38(m,1H),7.37-7.33(m,1H),6.45(s,1H ),6.31(t,J=2.0Hz,1H),5.41(s,2H),4.21(t,J=5.1Hz,2H),4.10(t,J=7.5Hz, 4H),3.90(s,3H),2.68(t,J=6.5Hz,2H),2.38-2.30(m,2H),2.00-1.96(m,2H).

[0362] Example 21: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazole)-4-(2-cyclobutylpyrimidin-5-yl)-2-methoxybenzenesulfonamide (21)

[0363] Step 1: Synthesis of compound cyclobutane carboimide methyl ester (21-1)

[0364] 30 mL of methyl tert-butyl ether and 8.4 g of methanol (1.0 eq) were added to a reaction flask. Under nitrogen protection, acetyl chloride (18.8 g, 1.0 eq) solution was slowly added dropwise at 0 °C for 1 h. Then, 5 mL of methyl tert-butyl ether solution containing 2.8 g of cyclobutyronitrile (0.1 eq) was slowly added, and the reaction was continued at 0 °C for 5 h. The solvent was removed by rotary evaporation to obtain 3.8 g of yellow solid (21-1), which was used directly in the next reaction without purification.

[0365] Step 2: Synthesis of compound cyclobutanecarbamate (21-2)

[0366] Compound 21-1 (3.8 g, 1.0 eq) was dissolved in methanol (40 mL), and a methanol solution of 7N ammonia (8.8 mL) was added at 0 °C. The reaction was carried out at 0 °C for 3.5 h. The solvent was removed by rotary evaporation, and the crude product was slurried with petroleum ether to give 3.4 g of yellow solid (21-2), which was used directly in the next reaction without purification.

[0367] Step 3: Synthesis of compound 5-chloro-2-cyclobutylpyrimidine (21-3)

[0368] Compound 21-2 (2 g, 1.0 eq) was dissolved in DMA (20 mL), and hexafluorophosphate (4.3 g, 1.2 eq) and NMM (3 g, 2.5 eq) were added. The mixture was reacted at 80 °C for 1 h. The reaction solution was extracted twice with DCM / H2O, and the organic phase was washed with 10% citric acid aqueous solution. The combined organic phases were dried over anhydrous Na2SO4 and purified by Flash column chromatography to obtain the target compound 21-3 (0.65 g), with a yield of 23%.

[0369] Step 4: Synthesis of compound 2-cyclobutyl-5-(4,4,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidine (21-4)

[0370] Compound 21-3 (0.64 g, 1.0 eq, 3.0 mmol), B2Pin (0.85 g, 1.3 eq), AcOK (0.5 g, 2.0 eq), Pd2(dba)3 (0.12 g, 0.05 eq), and Xphos (0.12 g, 0.1 eq) were dissolved in 1,4-dioxane (10 mL). The reaction was carried out at 80 °C for 2 h under nitrogen protection. The reaction was then cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the solvent was removed under vacuum to obtain crude product 21-4, which was used directly in the next reaction without purification.

[0371] MS (m / z): 297.1 [M+H] + .

[0372] Step 5: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazole)-4-(2-cyclobutylpyrimidin-5-yl)-2-methoxybenzenesulfonamide (21)

[0373] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "compound 21-4", and the rest of the method was the same. Compound 21 (3.2 mg) was prepared from common intermediate A (60 mg, 1.0 eq) with a yield of 4.7%.

[0374] MS (m / z): 547.1 [M+H] +

[0375] 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),9.14(s,2H),7.92-7.85(m,2H),7.59-7.41(m,3H),6.89 -6.68(m,2H),6.30(s,1H),5.44(s,2H),3.90(s,3H),3.85-3.79(m,4H),2.47-2.29(m,4H),2.12-1.86(m,2H).

[0376] Example 22: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(dimethylamino)pyrimidin-4-yl)-2-methoxybenzenesulfonamide (22)

[0377] Step 1: Synthesis of compound 2-(4-(benzylthio)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22-1)

[0378] Compound Int9 (400 mg, 1.0 eq), pinacol diboronic acid ester (361 mg, 1.1 eq), Pd(dppf)Cl2 (94.7 mg, 0.1 eq), and KOAc (381 mg, 3.0 eq) were placed in a pressure-resistant flask, DMF (4 mL) was added, and the mixture was purged with nitrogen for protection. The mixture was heated and stirred at 105 °C for 3 hours. After the reaction was complete, the filtrate was collected, evaporated to dryness under reduced pressure, and the crude product was purified by column chromatography to obtain product 22-1 (230 mg), with a yield of 50%, as a yellow solid.

[0379] 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.56(s,1H),7.89–7.84(m,2H),7.75(s,2H),7.48(d,J=1.8Hz,1H),7 .17(s,1H),6.63(d,J=32.6Hz,2H),6.28(t,J=2.0Hz,1H),5.39(s,2H),3.84(d,J=10.7Hz,6H),3.14(s,6H).

[0380] Step 2: Synthesis of compound 6-(4-(benzylthio)-3-methoxyphenyl)-N,N-dimethylpyrimidin-4-amine (22-2)

[0381] Compound 22-1 (207 mg, 1.0 eq), 6-chloro-N,N-dimethylpyrimidin-4-amine (110 mg, 1.2 eq), Pd(dppf)Cl2 (43 mg, 0.1 eq), and K2CO3 (201 mg, 2.5 eq) were placed in a pressure-resistant flask. Approximately 1 mL of a 5:1 mixture of 1,4-dioxane and water was added. The flask was purged with nitrogen and heated at 100 °C with stirring for 3 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to obtain product 22-2 (90 mg), with a yield of 44%, as a yellow solid.

[0382] 1 H NMR(600MHz,DMSO-d6)δ8.53(d,J=1.1Hz,1H),7.73-7.69(m,2H),7.44-7.39(m,2H),7.36-7 .29(m,3H),7.27-7.22(m,1H),7.11(d,J=1.2Hz,1H),4.25(s,2H),3.91(s,3H),3.14(s,6H).

[0383] Step 3: Synthesis of compound 4-(6-(dimethylamino)pyrimidin-4-yl)-2-methoxybenzenesulfonyl chloride (22-3)

[0384] Compound 22-3 (100 mg, 1.0 eq) was dissolved in a mixed solvent of acetonitrile:water:glacial acetic acid = 20:1:0.5 and cooled in an ice bath. 1,3-dichloro-5,5-dimethylhydantoin (84 mg, 1.5 eq) was added in small batches. The reaction was monitored by TLC. When the starting material had completely reacted, a small amount of water was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was rapidly passed through a Flash column at medium pressure to give 90 mg of a yellow solid, with a yield of 97%.

[0385] Step 4: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(dimethylamino)pyrimidin-4-yl)-2-methoxybenzenesulfonamide (22)

[0386] Referring to the synthesis of compound A in step 7 of the common intermediate A, replace "compound Int10" with "compound 22-3" and follow the same procedure. Compound 22 (33 mg) was prepared from intermediate Int6 (70 mg, 1.0 eq) with a yield of 22%.

[0387] MS (m / z): 536.1 [M+H] + .

[0388] 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.56(s,1H),7.90-7.83(m,2H),7.75(s,2H),7.48(d,J=1.8Hz,1 H),7.17(s,1H),6.73-6.54(m,2H),6.28(t,J=2.0Hz,1H),5.39(s,2H),3.86-3.81(m,6H),3.14(s,6H).

[0389] Example 23: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(dimethylamino)pyrazin-2-yl)-2-methoxybenzenesulfonamide (23)

[0390] Step 1: Synthesis of compound 6-(4-(benzylthio)-3-methoxyphenyl)-N,N-dimethylpyrazine-2-amine (23-2)

[0391] Referring to the synthesis of compound 22-2 in step 2 of Example 22, "6-chloro-N,N-dimethylpyrimidin-4-amine" was replaced with "2-dimethylamino-6-chloropyrazine", and the rest of the method was the same. Compound 23-2 (670 mg) was synthesized from compound 23-1 (700 mg, 1.0 eq) with a yield of 97%.

[0392] Step 2: Synthesis of compound 4-(6-(dimethylamino)pyrazin-2-yl)-2-methoxybenzenesulfonyl chloride (23-3)

[0393] Referring to the synthesis of compound 22-3 in step 3 of Example 22, "compound 22-2" was replaced with "compound 23-2", and the rest of the method was the same. Compound 23-3 (102 mg) was synthesized from compound 23-2 (200 mg, 1.0 eq) with a yield of 55%.

[0394] Step 3: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(6-(dimethylamino)pyrazin-2-yl)-2-methoxybenzenesulfonamide (23)

[0395] Referring to the synthesis of compound A in step 7 of intermediate A, replace "compound Int10" with "compound 23-3" and follow the same procedure. Compound 23 (26.9 mg) was prepared from intermediate Int6 (75 mg, 1.0 eq) with a yield of 16.2%.

[0396] MS (m / z): 536.1 [M+H] + .

[0397] 1 H NMR (600MHz, DMSO-d6) δ10.32(s,1H),8.50(s,1H),8.20(s,1H),7.94-7.85(m,2H),7.82-7.76(m,2H),7.49(d,J= 1.8Hz,1H),6.84(s,1H),6.75(s,1H),6.29(t,J=2.1Hz,1H),5.44(s,2H),3.89(s,3H),3.83(s,3H),3.16(s,6H).

[0398] Example 24: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(4-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonamide (24)

[0399] Step 1: Synthesis of compound 2-(4-(benzylthio)-3-methoxyphenyl)-N,N-dimethylpyrimidin-4-amine (24-2)

[0400] Referring to the synthesis of compound 22-2 in step 2 of Example 22, "6-chloro-N,N-dimethylpyrimidin-4-amine" was replaced with "2-dimethylamino-4-chloropyrazine", and the rest of the method was the same. Compound 24-2 (750 mg) was synthesized from compound 24-1 (1.0 g, 1.0 eq) with a yield of 76%.

[0401] Step 2: Synthesis of compound 4-(4-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonyl chloride (24-3)

[0402] Referring to the synthesis of compound 22-3 in step 3 of Example 22, "compound 22-2" was replaced with "compound 24-2", and the rest of the method was the same. Compound 24-3 (204 mg) was synthesized from compound 24-2 (500 mg, 1.0 eq) with a yield of 44%.

[0403] Step 3: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(4-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonamide (24)

[0404] Referring to the synthesis of compound A in step 7 of intermediate A, replace "compound Int10" with "compound 24-3" and follow the same procedure. Compound 24 (24.0 mg) was prepared from intermediate Int6 (150 mg, 1.0 eq) with a yield of 7.2%.

[0405] MS (m / z): 536.1 [M+H] +

[0406] 1 H NMR (600MHz, DMSO-d6) δ10.32(s,1H),8.50(s,1H),8.20(s,1H),7.94-7.85(m,2H),7.82-7.76(m,2H),7.49(d,J= 1.8Hz,1H),6.84(s,1H),6.75(s,1H),6.29(t,J=2.1Hz,1H),5.44(s,2H),3.89(s,3H),3.83(s,3H),3.16(s,6H).

[0407] Example 25: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(5-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonamide (25)

[0408] Step 1: Synthesis of compound 2-(4-(benzylthio)-3-methoxyphenyl)-N,N-dimethylpyrimidin-5-amine (25-2)

[0409] In step 2 of Example 22, the synthesis of compound 22-2 was carried out by replacing "6-chloro-N,N-dimethylpyrimidin-4-amine" with "2-chloro-N,N-dimethylpyrimidin-5-amine" in the same manner. Compound 25-2 (182.0 mg) was synthesized from compound 25-1 (248.7 mg, 1.0 eq) with a yield of 82%.

[0410] Step 2: Synthesis of compound 4-(5-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonyl chloride (25-3)

[0411] In step 3 of Example 22, the synthesis of compound 22-3 was carried out by replacing "compound 22-2" with "compound 25-2" and the rest of the method was the same. Compound 25-3 (96.0 mg) was synthesized from compound 25-2 (150 mg, 1.0 eq) with a yield of 69%.

[0412] Step 3: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(5-(dimethylamino)pyrimidin-2-yl)-2-methoxybenzenesulfonamide (25)

[0413] Referring to the synthesis of compound A in step 7 of intermediate A, replace "compound Int10" with "compound 25-3" and follow the same procedure. Compound 25 (4.8 mg) was prepared from intermediate Int6 (64.1 mg, 1.0 eq) with a yield of 3.4%.

[0414] MS (m / z): 536.1 [M+H] + .

[0415] 1H NMR (600MHz, DMSO-d6) δ10.21(s,1H),8.41(s,2H),7.96-7.93(m,2H),7.89-7.85(m,2H),7.49(d,J=1. 8Hz,1H),6.85-6.71(m,2H),6.29(t,J=2.1Hz,1H),5.43(s,2H),3.85(s,3H),3.82(s,3H),3.04(s,6H).

[0416] Example 26: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-aminopyrimidin-5-yl)-2-methoxybenzenesulfonamide (26)

[0417] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-aminopyrimidinyl-5-boronic acid pinacol ester", and the rest of the method was the same. Compound 26 (12.6 mg) was prepared from intermediate A (50 mg, 1.0 eq) with a yield of 24.5%.

[0418] MS (m / z): 508.1 [M+H] + .

[0419] 1 H NMR (600MHz, DMSO-d6) δ10.13(s,1H),8.68(s,2H),7.86(d,J=2.3Hz,1H),7.80(d,J=8.2Hz,1H),7.49(d,J=1.8H z,1H),7.35-7.29(m,2H),6.95(s,2H),6.83-6.66(m,2H),6.29(t,J=2.1Hz,1H),5.42(s,2H),3.87-3.83(m,6H).

[0420] Example 27: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4-(2-(methylamino)pyrimidin-5-yl)benzenesulfonamide (27)

[0421] Referring to the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(methyl)amino-5-boronic acid ester", and the rest of the method was the same. Compound 27 (50.7 mg) was prepared from intermediate A (100 mg, 1.0 eq) with a yield of 48%.

[0422] MS (m / z): 522.0 [M+H] + .

[0423] 1 H NMR (600MHz, DMSO-d6) δ10.15(s,1H),8.76(s,2H),7.87(d,J=2.3Hz,1H),7.81(d,J=8.2Hz,1H),7.53(s,1H),7.49(d,J=1.8Hz,1H),7.40(d,J =1.6Hz,1H),7.36(dd,J=8.2,1.6Hz,1H),6.84(s,1H),6.75(s,1H),6.3 0(t,J=2.1Hz,1H),5.44(s,2H),3.88(s,3H),3.85(s,3H),2.86(s,3H).

[0424] Example 28: Preparation of compound 4-(2-cyclopropylpyrimidin-5-yl)-2-methoxy-N-(4-methoxy-6-(thiazol-2-yl)oxy)methoxybenzo[d]isoxazol-3-yl)benzenesulfonamide (28)

[0425] Referring to the synthesis of compound 1 in step 1 of Example 1, compound 28 (10.3 mg) was prepared from intermediate C (40 mg, 1.0 eq) in a yield of 23%.

[0426] MS (m / z): 552.0 [M+H] + .

[0427] 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),9.06(s,2H),7.91(d,J=8.2Hz,1H),7.55(s,1H),7.48(d,J=8.2Hz,1H),7.36-7.3 1(m,2H),7.27(s,1H),6.89(s,1H),3.90(s,3H),3.86(s,3H),2.31-2.24(m,1H),1.14-1.08(m,2H),1.08-1.03(m,2H).

[0428] Example 29: Preparation of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxyisoxazole[4,5-c]pyridin-3-yl)-4-(6-(dimethylamino)pyridin-3-yl)-2-methoxybenzenesulfonamide (29)

[0429] Following the synthesis of compound 1 in step 1 of Example 1, only "(2-cyclopropyl-5-pyrimidinyl)boronic acid" was replaced with "2-(dimethylamino)pyridine-5-boronic acid", and the rest of the method was the same. Compound 29 (1.5 mg) was prepared from intermediate B (50 mg, 1.0 eq) with a yield of 2.7%.

[0430] MS (m / z): 536.6 [M+H] + .

[0431] 1 H NMR (600MHz, DMSO-d6) δ8.50 (s, 1H), 7.90-7.87 (m, 2H), 7.77 (d, J = 8.0Hz, 1H), 7.52-7.49 (m, 1H), 7.33 -7.02(m,3H),6.72(d,J=8.9Hz,1H),6.31(s,1H),5.39(s,2H),3.95(s,3H),3.82(s,3H),3.07(s,6H).

[0432] Example 30: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (30)

[0433] Referring to the synthesis of compound 1 in step 1 of Example 1, "common intermediate A" was replaced with "common intermediate F", and compound 30 (44.9 mg) was prepared from F (100 mg, 1.0 eq).

[0434] MS (m / z): 566.1 [M+H] + .

[0435] 1 H NMR (400MHz, DMSO-d6) δ9.56(s,1H),8.83(s,2H),7.88(d,J=2.3Hz,1H),7.50(d,J=1.9Hz,1H),6.99(s,2 H),6.83(s,1H),6.77(s,1H),6.30(t,J=2.1Hz,1H),5.45(s,2H),3.91(s,3H),3.86(s,6H),3.19(s,6H).

[0436] Example 31: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)4-(5-(dimethylamino)pyrimidin-2-yl)-2,6-dimethoxybenzenesulfonamide (31)

[0437] Step 1: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazo-3-yl)-4-bromo-2,6-dimethoxy-N-(4-methoxybenzyl)benzenesulfonamide (31-1)

[0438] Compound F (500 mg, 1.0 eq), PMB-Cl (225 mg, 1.5 eq), and K₂CO₃ (400 mg, 3.0 eq) were dissolved in 5 mL of DMF under nitrogen protection and heated at 85 °C for 3 hours. The reaction was monitored by TLC. The mixture was extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by 0–20% EA / PE Flash to give 430 mg of a brown oily liquid.

[0439] Step 2: Synthesis of compound (4-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-N-(4-methoxybenzyl)aminosulfonamide)-3,5-dimethoxyphenyl)boronic acid (31-2)

[0440] Compound 31-1 (430 mg, 1.0 eq), pinacol diboronate (697 mg, 2.0 eq), Pd(dppf)Cl2 (49 mg, 0.1 eq), and KOAc (198 mg, 3.0 eq) were placed in a pressure-resistant flask, and approximately 3 mL of DMF was added. The flask was then purged with nitrogen and heated at 90 °C with stirring for at least 2 hours. The reaction was monitored by LC-MS. The mixture was extracted with ethyl acetate and water, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography to give 75 mg of a white solid.

[0441] MS (m / z): 609.1 [M+H] + .

[0442] Step 3: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(5-(dimethylamino)pyrimidin-2-yl)-2,6-dimethoxy-N-(4-methoxybenzyl)benzenesulfonamide (31-3)

[0443] Compound 31-2 (75 mg, 1.0 eq), 2-chloro-N,N-dimethylpyrimidin-5-amine (23 mg, 1.2 eq), Pd(dppf)Cl2 (9 mg, 0.1 eq), and K2CO3 (51 mg, 3.0 eq) were placed in a pressure-resistant flask, and approximately 1 mL of a mixed solution of 1,4-dioxane:water = 8:1 was added. The mixture was then purged with nitrogen for protection and heated at 90°C with stirring for at least 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure and passed through a 0–70% EA / DCM Flash column to obtain 45 mg of a yellow oily liquid.

[0444] MS (m / z): 686.2 [M+H] + .

[0445] Step 4: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)4-(5-(dimethylamino)pyrimidin-2-yl)-2,6-dimethoxybenzenesulfonamide (31)

[0446] Compound 31-3 (45 mg) was dissolved in 1 mL of a DCM:TFA = 1:1 mixed solution, stirred overnight at room temperature, concentrated under reduced pressure to remove the solvent, and separated by pre-liquid phase to obtain 21.7 mg of white solid.

[0447] MS (m / z): 566.1 [M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),8.41(s,2H),7.88(d,J=2.3Hz,1H),7.60(s,2H),7.50(d,J=1.9H z,1H),6.83(s,1H),6.77(s,1H),6.30(t,J=2.1Hz,1H),5.45(s,2H),3.91–3.84(m,9H),3.04(s,6H).

[0449] Example 32: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl-4-(1-cyclopropyl-1H-pyrazol-4-yl)-2,6-dimethoxybenzenesulfonamide (32)

[0450] Referring to the synthesis of compound 1 in step 1 of Example 1, "common intermediate A" was replaced with "common intermediate F", and compound 32 was prepared from F (100 mg, 1.0 eq) at a dose of 57.0 mg.

[0451] MS (m / z): 551.1 [M+H]+ .

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.02(s,1H),7.87(d,J=2.3Hz,1H),7.49(d,J=1.8Hz,1H),6.92(s,2H),6.79(s, 1H), 6.74 (s, 1H), 6.30 (t, J = 2.1Hz, 1H), 5.43 (s, 2H), 3.89 (s, 3H), 3.80 (s, 6H), 3.77–3.70 (m, 1H), 1.08–0.96 (m, 4H).

[0453] Example 33: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2-methoxybenzenesulfonamide (33)

[0454] Step 1: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-bromo-2-methoxybenzenesulfonamide (33-1)

[0455] Compound E (200 mg, 1.0 eq) was dissolved in THF and placed in an ice bath at 0°C. 280 mg of potassium tert-butoxide was added and stirred for 5 minutes. Then, a THF solution of compound Int10 was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for half an hour. The reaction was confirmed by TLC. The pH was adjusted to about 5 by adding 10% citric acid aqueous solution. Extraction was performed by adding EA / H2O, followed by backwashing with brine and drying with anhydrous sodium sulfate. The EA was then slurryed and purified to give 224 mg of white solid.

[0456] MS (m / z): 492.89 [M+H] + .

[0457] Step 2: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2-methoxybenzenesulfonamide (33)

[0458] Compound 33-1 (100 mg, 1.0 eq), 2-dimethylaminopyrimidine-5-boronic acid (50 mg, 1.5 eq), Pd(dppf)Cl2 (14 mg, 0.1 eq), and K2CO3 (80 mg, 3.0 eq) were placed in a pressure-resistant flask, and approximately 3 mL of a mixed solution of 1,4-dioxane:water = 5:1 was added. The flask was then purged with nitrogen and heated at 100°C with stirring for at least 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the filtrate was collected, concentrated under reduced pressure, and filtered through a column at 0–60% EA Flash to obtain 135 mg of crude product. This crude product was purified using preparative HPLC and then freeze-dried to obtain 6.2 mg of compound 33-1.

[0459] MS (m / z): 536.1 [M+H] + .

[0460] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.79(s,2H),7.88(d,J=8.2Hz,1H),7.80(d,J=2.3Hz,1H),7.61(s,1H),7.49( d,J=1.8Hz,1H),7.40–7.34(m,2H),6.82(s,1H),6.29(t,J=2.1Hz,1H),5.39(s,2H),3.92–3.86(m,6H),3.18(s,6H).

[0461] Example 34: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (34)

[0462] Step 1: Synthesis of compound N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-bromo-2,6-dimethoxybenzenesulfonamide (34-1)

[0463] Compound E (200 mg, 1.0 eq) was dissolved in THF and placed in an ice bath at 0°C. 280 mg of potassium tert-butoxide was added, and the mixture was stirred for 5 minutes. Then, a THF solution of 4-bromo-2,6-dimethoxybenzenesulfonyl chloride was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for half an hour. The reaction was confirmed by TLC. The pH was adjusted to approximately 5 by adding 10% citric acid aqueous solution. Extraction was performed by adding EA / H2O, followed by backwashing with brine and drying with anhydrous sodium sulfate. The mixture was then purified by slurrying with EA to obtain 212 mg of a white solid.

[0464] MS (m / z): 522.9 [M+H] + .

[0465] Step 2: Synthesis of N-(6-((1H-pyrazol-1-yl))methyl)-5-methoxybenzo[d]isoxazol-3-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (34)

[0466] Compound 34-1 (50 mg, 1.0 eq), 2-dimethylaminopyrimidine-5-boronic acid (32 mg, 1.5 eq), Pd(dppf)Cl2 (7 mg, 0.1 eq), and Cs2CO3 (90 mg, 3.0 eq) were placed in a pressure-resistant flask, and approximately 3 mL of DMF was added. The flask was then purged with nitrogen for protection and heated at 100 °C with stirring for at least 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the filtrate was collected, concentrated under reduced pressure, and filtered through a 0–60% EA Flash column to obtain 30 mg of crude product. This crude product was purified using preparative HPLC and then freeze-dried to obtain 20.3 mg of compound 34-1.

[0467] MS (m / z): 566.0 [M+H] + .

[0468] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.81(s,2H),7.81(d,J=2.3Hz,1H),7.65(s,1H),7.49(d,J=1.9 Hz,1H),6.96(s,2H),6.80(s,1H),6.30(t,J=2.1Hz,1H),5.39(s,2H),3.89–3.80(m,9H),3.17(s,6H).

[0469] Example 35: Preparation of N-(5-((1H-pyrazol-1-yl))methyl)-3,4-dihydro-2H-benzodihydropyran[8,7-d]benzoisoxazo-9-yl)-3,5-dimethoxy-[1,1′-biphenyl]-4-sulfonamide (35)

[0470] Step 1: Synthesis of compound N-(5-((1H-pyrazol-1-yl))methyl)-3,4-dihydro-2H-benzodihydropyran[8,7-d]benzisoxazol-9-yl)-4-bromo-2,6-dimethoxybenzenesulfonamide (35-1)

[0471] Compound 20-10 (200 mg, 1.0 eq) was dissolved in THF and placed in an ice bath at 0°C. 280 mg of potassium tert-butoxide was added, and the mixture was stirred for 5 minutes. Then, a THF solution of compound 4-bromo-2,6-dimethoxybenzenesulfonyl chloride was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for half an hour. The reaction was confirmed by TLC. The pH was adjusted to about 5 by adding 10% citric acid aqueous solution. Extraction was performed by adding EA / H2O, followed by backwashing with brine and drying with anhydrous sodium sulfate. The mixture was then purified by EA slurry to give 224 mg of white solid.

[0472] Step 2: Synthesis of compound N-(5-((1H-pyrazol-1-yl))methyl)-3,4-dihydro-2H-benzodihydropyran[8,7-d]benzisoxazol-9-yl)-3,5-dimethoxy-[1,1′-biphenyl]-4-sulfonamide (35)

[0473] To a solution of 35-1 (30.00 mg, 1.0 eq, 54.61 μmol), phenylboronic acid (10.00 mg, 1.5 eq, 81.91 μmol), and 1,4-dioxane (4 mL), an aqueous solution of potassium carbonate (30.00 mg, 4.0 eq, 0.22 mmol) (1 mL) was added, followed by the addition of (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (4 mg, 0.1 eq, 5.46 μmol). After purging with nitrogen, the mixture was stirred at 120 °C for 1 h. Extraction was performed with ethyl acetate (100 mL) and water (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the final product (10.00 mg, yield: 33.50%).

[0474] MS (m / z): 547.1 [M+H] + .

[0475] 1 H NMR(600MHz,Methanol-d4)δ7.69–7.62(m,3H),7.55(s,1H),7.47–7.42(m,2H),7.41–7.38(m,1H),6.92(s,2H), 6.41(s,1H),6.37(s,1H),5.42(s,2H),4.42–4.36(m,2H),3.94(s,6H),2.70(t,J=6.5Hz,2H),2.16–2.10(m,2H).

[0476] Example 36: Preparation of N-(5-((1H-pyrazol-1-yl))methyl)-3,4-dihydro-2H-benzodihydropyran[8,7-d]benzoisoxazo-9-yl)-4-(2-cyclopropylpyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (36)

[0477] Referring to the synthesis of compound 1 in step 1 of Example 1, "common intermediate A" was replaced with "compound 35-1", and the rest of the method was the same. Compound 36 was prepared from compound 35-1 (50 mg, 1.0 eq) at a dose of 8 mg.

[0478] 1 H NMR (600MHz, DMSO-d6) δ9.53(s,1H),9.06(s,2H),7.78(d,J=2.3Hz,1H),7.51(d,J=1.8Hz,1H),7.10(s,2H),6.44(s,1H),6.35–6.27(m ,1H),5.41(s,2H),4.26(t,J=4.9Hz,2H),3.88(s,6H),2.70(t,J=6.5Hz,2H),2.30–2.24(m,1H),2.07–1.96(m,2H),1.20–0.93(m,4H).

[0479] Example 37: Preparation of N-(5-((3-cyclopropyl-1H-pyrazole-5-yl))amino)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzoisoxazo-1-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (37)

[0480] Step 1: Synthesis of compound 8-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-3-yl)amino)-6-fluoro-5-nitrile (37-1)

[0481] Intermediate D (1.0 g, 1.0 eq), intermediate 37-8 (1.61 g, 2.0 eq), tBuBrettphos Pd G3 (334 mg, 0.1 eq), and Cs₂CO₃ (3.8 g, 3.0 eq) were dissolved in 20 mL of anhydrous 1,4-dioxane. The mixture was heated overnight at 100 °C under N₂ protection. The reaction was detected by LC-MS. The solvent was removed by concentration under reduced pressure, and the sample was mixed and passed through a 0–35% EA / PE Flash column to obtain 1.36 g of a pale yellow solid.

[0482] MS (m / z): 383.1 [M+H] + .

[0483] Step 2: Synthesis of tert-butyl(5-cyano-6-fluoro-8-yl)(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-3-yl)carbamate (37-2)

[0484] Dissolve 37-1 (1.36 g, 1.0 eq), (Boc)2O (7.4 g, 10.0 eq), DMAP (207 mg, 0.5 eq), and TEA (4.7 mL, 10.0 eq) in 20 mL of DCM, under N2 protection, and heat at 50 °C overnight. The reaction was detected by LC-MS. The solvent was removed by concentration under reduced pressure, and the sample was mixed and passed through a 0–20% EA / PE Flash column to obtain 1.5 g of a pale yellow oily liquid.

[0485] MS (m / z): 483.2 [M+H] + .

[0486] Step 3: Synthesis of tert-butyl(1-amino-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazol-1-yl)(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-3-yl)carbamate (37-3)

[0487] 37-2 (1.5 g, 1.0 eq), acetyloxyoxime acid (4.66 g, 20.0 eq), and K2CO3 (8.58 g, 20.0 eq) were dissolved in 15 mL of DMF, heated overnight at 100 °C under N2 protection. The reaction was detected by LC-MS, extracted with EA / H2O, extracted with saturated NaCl solution, dried over anhydrous NaSO4, concentrated under reduced pressure to remove solvent, mixed, and then passed through a 0–60% EA / PE Flash column to obtain 1.0 g of pale yellow solid.

[0488] MS (m / z): 496.2 [M+H] + .

[0489] Step 4: Synthesis of tert-butyl(1-((4-bromo-2,6-dimethoxyphenyl))sulfonamido)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazol-1-yl)(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-5-yl)carbamate (37-4)

[0490] Dissolve 37-3 (300 mg, 1.0 eq) in anhydrous THF, protect with N2, and in an ice bath at 0°C. Add potassium tert-butoxide (210 mg, 3.0 eq), and react at 0°C for 30 min. Then, add 4-bromo-2,6-dimethoxybenzenesulfonyl chloride (130 mg, 1.0 eq) every 20 min for a total of 3 additions. After the additions are complete, turn to room temperature and react overnight. LC-MS was used to detect the reaction. Extraction was performed with EA / H2O, followed by extraction with saturated NaCl solution. The sample was dried over anhydrous NaSO4, concentrated under reduced pressure to remove the solvent, mixed, and then passed through a 0–40% EA / PE Flash column to obtain 106 mg of a pale yellow solid.

[0491] MS (m / z): 772.0 [MH] + .

[0492] Step 5: Synthesis of compound tert-butyl(3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazole-5-yl)(1-((4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxyphenyl)sulfinylamino)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazol-5-yl)carbamate (37-5)

[0493] 37-4 (100 mg, 1.0 eq), 2-dimethylaminopyrimidine-5-boric acid (40 mg, 2.0 eq), Pd(dppf)Cl2 (9 mg, 0.1 eq), and K2CO3 (47.7 mg, 3.0 eq) were dissolved in 1 mL of solvent (1,4-dioxane:H2O = 8:1). The mixture was reacted under N2 protection at 100 °C for 2 hours. The reaction was monitored by LC-MS. The solvent was removed by concentration under reduced pressure. After mixing, the sample was passed through a 0–5% MeOH / DCM Flash column to obtain 133 mg of a brown oily solid.

[0494] MS (m / z): 817.2 [M+H] + .

[0495] Step 6: Synthesis of compound 2-(5-cyclopropyl-1H-pyrazol-3-yl)isoindoline-1,3-dione (37-6)

[0496] 38-0 (25 g, 1.0 eq, 203 mmol) and phthalic anhydride (30.07 g, 1.0 eq, 203 mmol) were added to acetic acid (250 mL), stirred at 100 °C for 2 hours, stirred at 120 °C for 14 hours, cooled to room temperature, evaporated to dryness, slurried with water, filtered, and the filter cake was dried to obtain 37-6 (46 g, yield: 89%), which was a yellow solid.

[0497] Step 7: Synthesis of compound 2-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-3-yl)isoindoline-1,3-dione (37-7)

[0498] 37-6 (23 g, 1.0 eq, 90.3 mmol), DHP (15.3 g, 3.0 eq, 182 mmol), and PPTS (3.43 g, 13.67 mmol) were added to acetonitrile (500 mL) and stirred at 60 °C for 16 hours. After cooling to room temperature, the mixture was evaporated to dryness, slurried with ethyl acetate, filtered, and the filter cake was dried to give 37-7 (22 g, yield: 72%) as a yellow solid.

[0499] Step 8: Synthesis of compound 5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-amine (37-8)

[0500] Add 22 g of 37-7 and 15 mL of 98% hydrazine hydrate to 350 mL of tetrahydrofuran and stir at 70 °C for 4 hours. Cool to room temperature and filter. Reverse dryness of the filtrate, add water, extract with ethyl acetate, dry the resulting organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and reverse dryness to give 12 g of 37-8 (yield: 96%) as a yellow liquid.

[0501] Step 9: Synthesis of compound N-(5-((3-cyclopropyl-1H-pyrazol-5-yl))amino)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazol-1-yl)-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (37)

[0502] Dissolve 37-5 (133 mg, 1.0 eq) in 2 mL of 2 M HCl-1,4-dioxane solution and stir overnight at room temperature. Monitor the reaction by LC-MS. Once all protecting groups have been removed, evaporate the solvent at low temperature, separate by preparative liquid chromatography, and lyophilize to obtain 40 mg of a white solid.

[0503] MS (m / z): 633.0 [M+H] + .

[0504] 1 H NMR (600MHz, DMSO-d6) δ11.93(s,1H),9.81(s,1H),8.88(s,2H),8.03–7.98(m,2H),7.02(s,2H),5.80(s,1H),4.29(t,J=5.0Hz,2 H),3.87(s,6H),3.20(s,6H),3.13(t,J=6.5Hz,2H),2.04–1.99(m,2H),1.92–1.82(m,1H),0.95–0.83(m,2H),0.72–0.64(m,2H).

[0505] Example 38: Preparation of N-(5-((1H-pyrazol-1-yl))methyl)-8,9-dihydrobenzodihydropyran[5,6-d]benzisoxazole-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (38)

[0506] Step 1: Synthesis of compound 6-fluoro-8-vinylbenzene-5-carboxynitrile (38-1)

[0507] Intermediate D (2.0 g, 1.0 eq) was dissolved in a mixed solvent of water and 1,4-dioxane (V / V = 1 / 8), and potassium vinyltrifluoroborate (1.25 mg, 1.2 eq), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (570 mg, 0.1 eq), and cesium carbonate (7.6 g, 3.0 eq) were added sequentially. The reaction mixture was stirred at 90 °C for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0–8% EtOAc / petroleum ether) to obtain the product (1.26 mg) as a white solid.

[0508] Step 2: Synthesis of compound 6-fluoro-8-formylbenzene-5-carboxynitrile (38-2)

[0509] Dissolve 1.2 g (1.0 eq) of 38-1 in tetrahydrofuran, cool to 0 °C, add an aqueous solution of potassium osmium tetroxide dihydrate (37 mg, 0.02 eq), stir for 30 minutes, and then add an aqueous solution of sodium periodate (3.18 g, 2.5 eq). React at 20 °C for 0.5 hours. Extract with ethyl acetate and water, dry the resulting organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by column chromatography (0–25% EtOAc / petroleum ether) to obtain the product (565 mg) as a white solid.

[0510] Step 3: Synthesis of compound 6-fluoro-8-(hydroxymethyl)benzene-5-carboxynitrile (38-3)

[0511] Dissolve 38-2 (560 mg, 1.0 eq) in methanol, cool to 0 °C, add sodium borohydride (207 mg, 2.0 eq), continue the reaction for 1 hour, quench with water, concentrate, adjust pH to about 2 with dilute hydrochloric acid, extract with ethyl acetate and water, dry the resulting organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify with 0–30% EA / PE Flash to give 500 mg of white solid.

[0512] Step 4: Synthesis of compound 8-((1H-pyrazol-1-yl)methyl)-6-fluorobenzene-5-carboxynitrile (38-4)

[0513] Cs₂CO₃ (1.57 g, 2.0 eq) was added to a CH₃CN solution of 38-3 (500 mg, 1.0 eq) and 1-(methanesulfonyl)-1H-pyrazole (388 mg, 1.1 eq), and the mixture was stirred at 70 °C for 2 h. LCMS analysis showed that the starting material was exhausted. The mixture was extracted with ethyl acetate and water, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by 0–30% EA / PE Flash to give 616 mg of a pale yellow solid.

[0514] Step 5: Synthesis of compound 5-((1H-pyrazol-1-yl)methyl)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazole-1-amine (38-5)

[0515] K₂CO₃ (5.9 g, 20.0 eq) was added to a solution of 38-4 (550 mg, 1.0 eq) and N-hydroxyacetamide (3.2 g, 20.0 eq) in N,N-dimethylformamide. Under nitrogen protection, the mixture was heated at 100 °C for 24 h. Extraction was performed with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by 0–100% EA / PE Flash to give 400 mg of a white solid.

[0516] Step 6: Synthesis of compound N-(5-((1H-pyrazol-1-yl))methyl)-8,9-dihydro-7H-benzodihydropyran[5,6-d]benzisoxazol-1-yl)-4-bromo-2,6-dimethoxybenzenesulfonamide (38-6)

[0517] Compound 38-5 (160 mg, 1.0 eq) was placed in a three-necked flask, purged with N2, and anhydrous THF was added. The flask was then pre-cooled in a -60°C cold well. NaHMDS (333 μl, 2 M) was slowly added dropwise. After the addition was complete, the mixture was stirred at -60°C for 60 min. Subsequently, A (280 mg, 1.5 eq, dissolved in THF) was slowly added dropwise. The mixture was stirred at -60°C for 1 h and then slowly raised to room temperature. The reaction was allowed to proceed overnight at room temperature. After the reaction was detected by LC-MS, saturated NH4Cl solution was added to quench the reaction. The mixture was extracted three times with EA, backwashed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography. After lyophilization, 36 mg of a white solid was obtained.

[0518] Step 7: Synthesis of compound N-(5-((1H-pyrazol-1-yl))methyl)-8,9-dihydrobenzodihydropyran[5,6-d]benzisoxazol-4-(2-(dimethylamino)pyrimidin-5-yl)-2,6-dimethoxybenzenesulfonamide (38)

[0519] 38-6 (36 mg, 1.0 eq), 2-dimethylaminopyrimidine-5-boronic acid (18 mg, 2.0 eq), Pd(dppf)Cl2 (4 mg, 0.1 eq), and K2CO3 (24 mg, 3.0 eq) were dissolved in 1 mL of diox / H2O (8 / 1) N2 under N2 protection and reacted at 100 °C for 2 hours. The reaction was monitored by LC-MS. The solvent was removed by concentration under reduced pressure, and the solution was purified by preparative liquid chromatography. After lyophilization, 25.0 mg of a white solid was obtained.

[0520] MS (m / z): 592.1 [M+H]+ .

[0521] 1 H NMR (600MHz, DMSO-d6) δ10.09(s,1H),8.87(s,2H),7.81(d,J=2.2Hz,1H),7.50(d,J=1.8Hz,1H),7.02(s,2H),6.69 (s,1H),6.30(t,J=2.1Hz,1H),5.36(s,2H),4.29–4.24(m,2H),3.85(s,6H),3.21–3.15(m,8H),2.03–1.96(m,2H).

[0522] Example 39: Preparation of N-(6-((1H-pyrazol-1-yl))methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(3-(dimethylamino)azacyclobutane-1-yl)-2,6-dimethoxybenzenesulfonamide (39)

[0523] Referring to the synthesis of compound 1 in step 1 of Example 1, "common intermediate A" was replaced with "common intermediate F", and compound 39 was prepared from F (80 mg, 1.0 eq) at a dose of 34.4 mg.

[0524] MS (m / z): 543.2 [M+H] + .

[0525] 1 H NMR(600MHz,Chloroform-d)δ8.13(s,1H),7.58(d,J=1.9Hz,1H),7.47(d,J=2.3Hz,1H),6.74(s,1H),6.44(s,1H),6.33(t,J=2.1Hz ,1H),5.47(s,2H),5.39(s,2H),4.32–4.27(m,2H),4.18(t,J=8.4Hz,2H),4.12–4.06(m,1H),3.95(s,3H),3.72(s,6H),2.85(s,6H).

[0526] Example 40: Preparation of 1-(4-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]oxazol-3-yl)sulfonyl)-3,5-dimethoxyphenyl)-N-cyclopropyl-3-fluorozahexacyclobutane-3-carboxamide (40)

[0527] Step 1: Synthesis of compound 3-(cyclopropylcarbamoyl)-3-fluorozacriane-1-carboxylic acid tert-butyl ester (40-1)

[0528] 500 mg (1.0 eq) of 1-(tert-butoxycarbonyl)-3-fluorozabutane-3-carboxylic acid, 1.1 g (1.2 eq) of HATU, and 2.5 mL of DIPEA were dissolved in 10 mL of DMF and stirred at 0 °C for 0.5 h. Cyclopropylamine was added, and the reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until completion. EA was added, and the mixture was extracted with water and flash purified to obtain 480 mg of the product, with a yield of 62%.

[0529] Step 2: Synthesis of compound N-cyclopropyl-3-fluorozacriane-3-carboxamide (40-2)

[0530] Dissolve 100 mg of 40-1 in 2 mL of DCM, add 1 mL of trifluoroacetic acid, react at room temperature for 1 hour, monitor the reaction for completion by TLC, concentrate under reduced pressure to remove the solvent, and use directly for the next step.

[0531] Step 3: Synthesis of compound 1-(4-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]oxazol-3-yl)sulfonyl)-3,5-dimethoxyphenyl)-N-cyclopropyl-3-fluorozahexacyclobutane-3-carboxamide (40)

[0532] 40-2 (67 mg, 5.0 eq) was dissolved in anhydrous DMA, and Cs2CO3 (432 mg, 20.0 eq) and F (70 mg, 1.0 eq) were added. Under nitrogen protection, Pd2(dba)3 (36 mg, 0.3 eq) and Ruphos (36 mg, 0.6 eq) were added. Under nitrogen protection, the reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LC-MS until it was completed. The mixture was filtered, concentrated, and sent to prepare compound 40 in 25.0 mg.

[0533] MS (m / z): 601.1 [M+H] + .

[0534] 1 H NMR(600MHz,DMSO-d6)δ8.90(s,1H),8.51–8.46(m,1H),7.88(s,1H),7.50(s,1H),6.81(s,1H),6.77(s,1H),6.30(t,J=2.1Hz,1H),5.69(s, 2H),5.44(s,2H),4.39–4.26(m,2H),4.19–4.08(m,2H),3.95(s,3H), 3.74(s,6H),2.79–2.68(m,1H),0.67–0.59(m,2H),0.59–0.50(m,2H).

[0535] Example 41: Preparation of 1-(4-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)aminosulfonyl)-3-methoxyphenyl)-N-cyclopropyl-3-fluorozahexacyclobutane-3-carboxamide (41)

[0536] 40-2 (67 mg, 5.0 eq) was dissolved in anhydrous DMA, and Cs2CO3 (432 mg, 20.0 eq) and A (70 mg, 1.0 eq) were added. Under nitrogen protection, Pd2(dba)3 (36 mg, 0.3 eq) and Ruphos (36 mg, 0.6 eq) were added. Under nitrogen protection, the mixture was reacted at 100 °C for 3 hours. The reaction was monitored by LC-MS until it was complete. The mixture was filtered, concentrated, and sent to prepare compound 41 (33.4 mg).

[0537] MS (m / z): 571.2 [M+H] + .

[0538] 1 H NMR (600MHz, DMSO-d6) δ9.39(s,1H),8.50(d,J=4.6Hz,1H),7.87(d,J=2.2Hz,1H),7.59(d ,J=8.6Hz,1H),7.51–7.45(m,1H),6.81(s,1H),6.75(s,1H),6.30(d,J=2.1Hz,1H),6.10( dd,J=8.6,2.0Hz,1H),6.06(d,J=2.1Hz,1H),5.44(s,2H),4.36–4.28(m,2H),4.19–4.11( m,2H),3.90(s,3H),3.75(s,3H),2.77–2.71(m,1H),0.67–0.61(m,2H),0.58–0.52(m,2H).

[0539] Biological evaluation

[0540] Test Example 1: KAT6A Enzyme Inhibitory Activity Test

[0541] 1. Experimental materials and consumables:

[0542] Centrifuge (TDZ5-WS); Echo (BECKMAN, 655system); Plate reader (BMG, PHERAstar FSX); KAT6A (Active motif, 81223); AcCOA (Sigma, A2056-25MG); Bio-H3 (GenScript); Eu-Ab (Perkin Elmer, TRF0412-M); Ulight-SA (Perkin Elmer, TRF0102-M); 96-well polypropylene plate (CLY96001); 384reaction plate (Greiner, 784075).

[0543] 2. Experimental Procedure

[0544] The compound was prepared to 10 mM using DMSO as a stock solution. The stock solutions of the compound and positive control were diluted to multiple concentrations. Using an ECHO instrument, 50 nL of the compound was transferred to a 384-well plate, with each compound concentration in duplicate, and centrifuged at 1000 rpm. The final compound concentration was tested. 2.5 μL of KAT6A protein was added to each well and incubated at 25°C for 10 min. 2.5 μL of Bio-H3 & AcCOA was added to each well and incubated at 25°C for 90 min. 5 μL of Eu-Ab & Ulight-SA working solution was added to each well and centrifuged at 1000 rpm. The 384-well plate was incubated at 25°C for 60 min. The HTRF signal values ​​at 665 nm and 620 nm were read using a microplate reader, and the 665 nm / 620 nm ratio was calculated.

[0545] 3. Data Analysis

[0546] Compound inhibition rate (%) = (negative control signal - compound signal) / (negative control signal - positive control signal) * 100%; negative control signal is the signal reading of the well without compound (iso-concentration DMSO group); positive control signal is the signal reading of the positive compound.

[0547] 4. Test Results

[0548] Table 1. Inhibitory activity of the compounds of the present invention against KAT6A

[0549] [Note] "++++" ≤ 1nM; 1nM < "+++" ≤ 5nM; 5nM < "++" ≤ 10nM; 10nM < "+" ≤ 50nM;

[0550] Test Example 2: ZR-75-1 Cell Proliferation Assay

[0551] 1. Experimental materials and consumables

[0552] RPMI 1640 medium (Gibco, C22400500BT); penicillin-streptomycin solution (DT15140); PBS (Cytiva, SH30256.01); FBS (Gibco A5669701); TrypLE Express (Gibco, 12605-010); CellCounting-Lite 2.0 (Vazyme DD1101-02); 75cm 2 Cell culture flasks (Thermo Scientific, 156499); 96-well cell culture plates (SPL, 30196); ZR-75-1 cells (Zhejiang Meisen).

[0553] 2. Experimental Procedure

[0554] 2.1 Cell Plating

[0555] Complete culture medium preparation: RPMI 1640 + 10% FBS + 1% P / S; wash the culture flask with PBS 3 times, digest the monolayer of cells with trypsin, add culture medium and mix well by pipetting, centrifuge at 1000 rpm for 5 min to collect cells; resuspend the cells in complete culture medium, add trypan blue to the cell suspension in equal proportion and count the cells with a cell counter; use a pipette to add 95 μL / well of the diluted cells to a 96-well plate to ensure 2000 cells per well, and incubate in a 37℃, 5% CO2, saturated humidity incubator for 24 h.

[0556] 2.2 Drug dilution and cell dosing

[0557] Prepare the working stock solution for the test compound: For test compound 50000×, take 2 μL of compound 50000× and dilute it with 18 μL of DMSO to obtain compound 5000×; then take 4 μL of compound 5000× and dilute it with 16 μL of DMSO to obtain compound 1000×; finally, take 4 μL of compound 1000× and dilute it with 16 μL of DMSO to obtain compound 200×, and use DMSO... The compound was serially diluted 4-fold to obtain 8 concentrations. Then, 10 μL of each serially diluted compound in DMSO was added to 90 μL of complete culture medium to obtain the compound working stock solution 20×. 5 μL of the compound working stock solution (DMSO final concentration 0.5%) was added to each well of a 96-well plate inoculated with cells. The final concentrations of the compound were tested as follows: 200.00 nM, 50.00 nM, 12.50 nM, 3.125 nM, 0.781 nM, 0.195 nM, 0.049 nM, and 0.012 nM.

[0558] Control well settings: Solvent control: 0.5% DMSO; Blank control: Untreated culture medium. 96-well plates were used for reading and incubated at 37°C in a 5% CO2 incubator.

[0559] The medication was administered by changing the solution every 3 days, for a total of 3 administrations. CTG testing was performed on the 9th day after administration.

[0560] 2.3 CTG method detection

[0561] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 50 μL of reagent to each well, shake for 5 minutes to mix (protect from light), and incubate at room temperature for 10 minutes (protect from light). Read the light signal value using a multi-functional microplate reader.

[0562] 3. Data Analysis

[0563] Inhibition rate (%) = (DMSO solvent control well reading - test sample well reading) / (DMSO solvent control well reading - blank control well reading)

[0564] 4. Test Results

[0565] Table 2. Cell proliferation inhibitory activity of the compounds of the present invention

[0566] [Note] "++++" ≤ 5nM; 5nM < "+++" ≤ 10nM; 10nM < "++" ≤ 50nM; 50nM < "+" ≤ 200nM;

[0567] Test Example 3: Pharmacokinetic Study in Mice

[0568] Six female Balb / c mice were used as experimental animals and divided into two groups. The test substance was administered via gavage (ig) and intravenous injection (iv), respectively. The dosage for both gavage (ig) and intravenous injection (iv) was 1 mg / kg, with administration volumes of 10 mL / kg and 5 mL / kg, respectively. The administration solvents were 5% DMSO + 40% PEG300 + 55% PBS (1X) and 5% DMSO + 5% Kolliphor EL + 90% Saline, respectively. Blood samples were collected from the gavage group at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h after administration; blood samples were collected from the intravenous group at the same time points. The collected whole blood was immediately transferred to EDTA-2K coated centrifuge tubes, inverted at least 5 times to mix, placed in an ice bath, and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 2000g, 4℃ for 10 min). After protein precipitation with an organic solvent, the plasma samples were analyzed by HPLC-MS / MS to obtain the concentration of the analyte in the plasma at different time points. Relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.1, as shown in the table below.

[0569] Table 3. Pharmacokinetic parameters in mice

[0570] Test Example 4: Pharmacokinetic Study in Rats

[0571] Three SD rats were used as experimental animals and administered the analyte via gavage. The gavage dosage (ig) was referenced in Table 4, with a volume of 10 mL / kg. The solvent was 5% DMSO + 40% PEG300 + 55% PBS. Blood samples were collected from the gavage group at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h after administration. The whole blood samples were immediately transferred to EDTA-2K coated centrifuge tubes, inverted at least five times to mix, placed in an ice bath, and centrifuged within one hour to separate the plasma (centrifugation conditions: 2000 g, 4℃, 10 min). After protein precipitation with an organic solvent, the plasma samples were analyzed by HPLC-MS / MS to obtain the concentration of the analyte in the plasma at different time points. Relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.1, as shown in the table below.

[0572] Table 4. Pharmacokinetic parameters in rats

Claims

A sulfonamide derivative is a compound having the following general structural formula (I), stereoisomers, tautomers, deuterated analogs, or pharmaceutically acceptable salts thereof: in: R a selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy; m is selected from 0, 1, 2, 3 or 4; X is selected from -C(R1)(R2)-, -NR3-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-; Y 1 selected from CR4or N; Y 2 selected from CR5or N; Y 3 selected from CR6or N; It is an aromatic ring or a heterocyclic aromatic ring; X 1 Selected from CR7, NR7, N, O, or S; X 2 Selected from CR8, NR8, N, O, or S; X 3 Selected from CR9, NR9, N, O, or S; X 4 Selected from CR 10 NR 10 , N, O or S; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group; Alternatively, R4 and R5, along with the atoms they are attached to, together form a 6-10 membered heterocyclic group or a 5-14 membered heteroaryl group, which may optionally be further substituted by one or more groups selected from: deuterium, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group; R7, R8, R9, R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, C 6-14 Mixed aromatics, -OR 11 -SR 11 -SF5, -N(R) 11 (R) 12 -C(O)OR 11 -OC(O)-N(R) 11 (R) 12 ), -N(R 13 )C(O)N(R 11 (R) 12 ), -N(R 13 )C(O)OR 14 -N(R) 13 )S(O)2R 14 -C(O)R 14 -OC(O)R 14 -C(O)N(R) 11 (R) 12 ), -S(O)R 14 -C(O)C(O)N(R) 11 (R) 12 ), -N(R 13 )C(O)R 14 -S(O)2R 14 -S(O)2N(R) 11 (R) 12 )-、S(=O)(=NH)N(R 11 (R) 12 -CH2C(O)N(R) 11 (R) 12 ), -CH2N(R 13 )C(O)R 14 -CH2S(O)2R 14 or -CH2S(O)2N(R) 11 (R) 12 ), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics; R 11 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, C 6- 14 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics; R 12 , R 13 are each independently selected from hydrogen or C 1-6 alkyl; R 14 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, C 6-14 heteroaryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl and C 6-14 The heteroaryl group may optionally be further substituted by one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatics; Ring A is selected from C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups may optionally be further substituted with one or more groups selected from the following: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group; n is selected from 0 or 1. Sulfonamide derivatives according to claim 1, characterized in that Compounds having the following structural general formula (II) or (III), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: in: X is selected from -C(R1)(R2)-, -NR3-, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-; Y 1 selected from CR4or N; Y 2 selected from CR5or N; Y 3 selected from CR6or N; R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group; R a , m, X 1 , X 2 , X 3 , X 4 , ring A is as defined in claim 1. Sulfonamide derivatives according to claim 2, characterized in that Compounds of the following general structure (II-1), (II-2) or (III-1), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: wherein R b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; p is selected from 0, 1, or 2; R a , m, X, Y 2 , X 1 , X 2 , X 3 , X 4 , ring A, R4are as defined in claim 1. Sulfonamide derivatives according to claim 3, characterized in that Compounds of the following general structure (II-1-1) or (III-1-1), stereoisomers, tautomers, deuterated forms, or pharmaceutically acceptable salts thereof: wherein R a , R b , m, p, X, Y 2 , X 1 , X 2 , X 3 , X 4 , ring A, R4 are as defined in claim 3. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein X is selected from CH2 or O. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein: said Y 1 , Y 2 , Y 3 each independently is selected from -CH, -COCH3 or N. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein The R7, R8, R9, R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -OR 11 -N(R) 11 (R) 12 ), the C 1-6 Alkyl, C 3-8 The cycloalkyl or 3-10 membered heterocyclic group may optionally be further substituted with one or more groups selected from the following: halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 6-14 Mixed aromatic compounds. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein said R 11 each independently selected from hydrogen or C 1-6 alkyl. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein: The selected from the group consisting of The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein The ring A is selected from 5-14-membered heteroaryl groups, which may optionally be further substituted by one or more groups selected from: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl or C 1-6 Alkyl sulfone group. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein Ring A is selected from The sulfamide derivative according to any one of claims 1 to 11, wherein Compounds, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof having the general structure Formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), or (IV-9) of the following structures: Among them, R 8 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or -N(R) 11 (R) 12 ), the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups may optionally be further surrounded by one or more groups selected from hydrogen, halogen, or C. 1-6 Substituents of alkyl groups; R 11 , R 12 are each independently selected from hydrogen or C 1-6 alkyl; R a , R b are each independently selected from hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy; m and q are each independently selected from 0, 1, or 2. The sulfamide derivative according to any one of claims 1 to 12, characterized in that, Compounds, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof having the general structure of Formula (V-1), (V-2), or (V-3) below: Among them, R8 is selected from C 1-3 Alkoxy, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups or -N(R) 11 (R) 12 ), the C 1-3 Alkoxy, C 3-5 The cycloalkyl group and the 3-5 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, halogen, or C. 1-6 Substituents of alkyl groups; R 11 , R 12 are each independently selected from hydrogen or C 1-6 alkyl; R a , R b , m, q are as defined in claim 12. The compound, stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof of claim 12 or 13, characterized in that, said R8 is selected from the group consisting of H, -CH3, -OCH3, -NH2, -NHCH3, -N(CH3)2, The compound, stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof of any one of claims 12-14, wherein R a , R b is methoxy; m is selected from 1 or 2; p is 1. The compound, stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein: selected from the group consisting of: A pharmaceutical composition comprising, as an active ingredient, a compound, stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof as any one of claims 1-16, and at least one pharmaceutically acceptable carrier. The use of any compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable thereof as described in any one of claims 1-16, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating diseases or conditions mediated by KAT and related diseases or conditions. The use of any compound, stereoisomer, tautomer, deuterated compound or pharmaceutical composition thereof as described in any one of claims 1-16 for the treatment of diseases or conditions mediated by KAT and related diseases or conditions. A method of treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of any one of claims 1-16, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof, or a pharmaceutical composition of claim 17. The use according to claim 18 or 19 or the method according to claim 20, characterized in that The disease is cancer; the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, colorectal cancer, small bowel cancer, gastric cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, spinal cord tumor, glioma, brain glioma, pituitary adenoma, or squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer, or leukemia.

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