CN114671827B

CN114671827B - O-benzoyl-sulfonyl imide derivative and application thereof

Info

Publication number: CN114671827B
Application number: CN202111605327.8A
Authority: CN
Inventors: 盛荣; 刘瑶; 张冯敏
Original assignee: Hangzhou Hundred New Bio Pharmaceutical Technology Co ltd; Zhejiang University ZJU
Current assignee: Hangzhou Hundred New Bio Pharmaceutical Technology Co ltd; Zhejiang University ZJU
Priority date: 2020-12-24
Filing date: 2021-12-24
Publication date: 2024-09-20
Anticipated expiration: 2041-12-24
Also published as: CN114671827A

Abstract

The invention relates to an o-benzoyl-sulfonyl imide derivative and application thereof, in particular to a HIF-2 inhibitor, wherein the derivative also comprises pharmaceutically acceptable salts, chiral isomers and the like. The HIF-2 inhibitor provided by the invention has the application of treating cancers, inflammations and metabolic diseases, and has a huge clinical application prospect.

Description

O-benzoyl-sulfonyl imide derivative and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to an o-benzoyl-sulfonyl imide derivative and application thereof. Specifically, the derivative also comprises pharmaceutically acceptable salts, chiral isomers and the like, is a HIF-2 inhibitor, has the application of treating cancers, inflammations, hypoxia tolerance and metabolic diseases, and has a huge clinical application prospect.

Background

Renal Cell Carcinoma (RCC), abbreviated as renal carcinoma, is a malignancy that originates in the renal parenchymal urinary tubular epithelial system. In recent years, the incidence of renal cell carcinoma has continued to increase, with about 134000 patients dying annually worldwide. The pathological types of renal cell carcinoma mainly include renal clear cell carcinoma (CLEAR CELL RENAL CELL carcinoma, ccRCC), papillary renal cell carcinoma (PAPILLARY RENAL CELL carcinoma, pRCC), chromophobe renal cell carcinoma (chromophobe RENAL CELL carcinoma, chRCC), and the like. Among them, ccRCC is the most common form of kidney cancer (85%) that is the inactivation of tumor suppressor (von Hippel-Lindau, VHL) due to genetic susceptibility, somatic mutation or methylation, whereas VHL acts as a substrate recognition subunit of the E3 ubiquitin ligase complex, targeting degradation of hypoxia inducible factor (Hypoxia induced factors, HIF), regulating stress of cells to hypoxia. Loss of VHL function causes HIF to accumulate and transduce in cancer cells activating downstream target genes, promoting tumor proliferation and metastasis.

At present, targeted therapeutic drugs for advanced ccRCC are mainly VEGFR inhibitors represented by sorafenib and sunitinib, but the drugs are mainly factors acting on downstream angiogenesis promotion, have stronger cardiotoxicity and are easy to generate drug resistance. Studies have shown that HIF-2 regulates a variety of physiological processes, such as cell proliferation, metabolism, angiogenesis, tumor metastasis, etc., associated with poor prognosis for a variety of cancers. In particular, in the renal clear cell carcinoma ccRCC of VHL, HIF-2 is considered as a key driver of tumor growth, and therefore, HIF-2 has become a new target for the treatment of renal clear cell carcinoma.

Currently, drugs targeting HIF-2 pathway can be broadly classified into 4 classes according to mechanism of action: (1) Agents that modulate HIF-2 alpha expression, such as the chemotherapeutic agent topotecan; (2) Agents that modulate HIF-2 protein synthesis, such as 2-methoxyestradiol (2 ME 2); (3) Drugs that regulate HIF-2 alpha accumulation and degradation, such as the HSP90 inhibitors tamsulosin and azithromycin; (4) Small molecule inhibitors that target HIF-2 a/ARNT dimerization, such as PT-2385(J.Med.Chem.2018,61,9691)、MK-6482(PT-2977)(J.Med.Chem.2019,62,6876)、THS-044(J.Am.Chem.Soc.2009,131,17647)、0X3(J.Med.Chem.2013,56,1739) and tetrazolohydropyrimidine derivatives (S, R) -37 (j.med. Chem.2015,58,5930), and the like. Although the medicines with the first three action mechanisms can generate the inhibition effect of HIF-2, the medicines have the inhibition effect on HIF-1 and have no selectivity, but researches show that HIF-1 alpha and HIF-2 alpha show different or even opposite effects on the growth of different cancer cells, and tens of downstream proteins regulated by HIF-1 are easy to generate toxic and side effects. Whereas inhibitors of HIF-2α/ARNT dimerization, which are a fourth class of mechanism of action, are capable of specifically binding to the unique cavity of the PAS-B domain of HIF-2α, with a high degree of HIF-2 selectivity. Among them, MK-6482 (PT-2977) has been studied in clinical stage III as a selective HIF-2. Alpha./ARNT dimerization inhibitor for treating recurrent glioblastoma, hipperling channel syndrome-related renal clear cell carcinoma, etc.

In conclusion, the HIF-2 alpha/ARNT dimerization small molecule inhibitor has shown good prospect, but the structure type of the inhibitor is still scarce, so that the novel skeleton HIF-2 inhibitor is searched and found, and has important clinical significance in treating tumors such as renal clear cell carcinoma and the like. The invention designs brand-new o-benzoyl sulfimide and analogues thereof by adopting the bioisostere and skeleton migration principles of medicinal chemistry, and the o-benzoyl sulfimide and analogues thereof show excellent HIF-2 inhibition activity, and in vivo experiments show that the representative compound shows better pharmacokinetic properties than PT-2385 and has low toxicity, thus having the potential of being used as a novel HIF-2 inhibitor.

Disclosure of Invention

The technical problem to be solved by the invention is to provide the o-benzoyl sulfimide derivative, or the pharmaceutically acceptable salt and chiral isomer thereof, which is a novel HIF-2 inhibitor and has obvious renal clear cell carcinoma resisting activity and hypoxia resisting effect.

In order to solve the technical problems, the invention adopts the following technical scheme:

an o-benzoyl-sulfonyl imide derivative is a compound with the following structural general formula a or pharmaceutically acceptable salt thereof:

Wherein:

R ₁ is selected from C _3-8 cycloalkyl substituted by R _a, a 5-14 membered aryl or a 5-14 membered heteroaryl; wherein R _a is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, halogen, or cyano;

R ₂ is selected from hydrogen, nitro, halogen, cyano, aldehyde, carboxyl, ester, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _2-6 unsaturated aliphatic hydrocarbon group;

m is 0 or 1;

y is selected from O or NR _b, wherein R _b is selected from hydrogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl or C _2-6 unsaturated aliphatic hydrocarbon;

R ₃ is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 unsaturated aliphatic hydrocarbon or halogenated C _1-6 alkyl;

R ₄ and R ₅ are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, aldehyde, carboxyl, ester, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _2-6 unsaturated aliphatic hydrocarbon; or R ₄ and R ₅ together form a carbonyl group or thiocarbonyl group.

Preferably, in the structural general formula a, R ₁ is phenyl, pyridyl or cyclobutyl substituted by R _a; r _a is halogen or cyano; r ₂ is C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, fluoro, chloro, bromo, cyano or nitro; y is O; r ₃ is hydrogen, C _1-6 alkyl, C _2-6 unsaturated aliphatic hydrocarbon or C _3-8 cycloalkyl; r ₄ and R ₅ are each independently hydrogen, hydroxy, fluoro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or C _2-6 unsaturated aliphatic hydrocarbon; or R ₄ and R ₅ together form a carbonyl group or thiocarbonyl group.

More preferred are compounds having the following structural formula b:

Wherein:

r ₃ is selected from hydrogen or C _1-6 alkyl;

R ₄ and R ₅ are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, aldehyde, carboxyl, ester, C _1-6 alkyl, C _1-6 alkoxy or C _2-6 unsaturated aliphatic hydrocarbon; or R ₄ and R ₅ together form a carbonyl group or thiocarbonyl group.

An o-benzoylsulfonyl imide derivative is a compound having the following structure or its pharmaceutically acceptable salt:

Preferably, a compound having the following isomerism or a pharmaceutically acceptable salt thereof:

The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.

The "compounds" described herein may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The term "compound" as used herein also includes tautomeric forms. Tautomers originate from the exchange of one single bond with an adjacent double bond and accompany the migration of one proton.

The "compound" of the present invention, the solvent compound of which is selected from the group consisting of hydrate, ethanol, methanol, acetone, ethyl ether and isopropyl alcohol.

The invention also includes all isotopically-substituted atoms, whether in intermediate or final compounds. The atoms of the isotope include atoms having the same atomic number but different mass numbers. Isotopes of hydrogen include deuterium and tritium, for example.

Compounds containing the foregoing general structure, the terms used herein have the following meanings:

The term "alkyl", unless a different number of atoms is indicated, refers to a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, tert-butyl, and the like. "alkyl" also includes substituted alkyl groups, which may be optionally substituted one or more times with halogen, hydroxy, or amino. Thus, the term "alkyl" may include: trifluoromethyl and other haloalkyl groups, aminomethyl and other aminated alkyl groups as indicated, hydroxymethyl and other hydroxylated alkyl groups as indicated.

The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like. "alkoxy" also includes substituted alkoxy groups, which may be optionally substituted one or more times with halogen, hydroxy or amino.

The term "unsaturated aliphatic hydrocarbon group" means a straight-chain or branched alkenyl or alkynyl group having 2 to 6 carbon atoms containing a double bond or a triple bond. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, ethynyl, and the like.

The term "aryl" refers to an all-carbon monocyclic or fused multicyclic group of 5 to 12 carbon atoms having a fully conjugated pi-electron system. Examples include, but are not limited to, benzene rings, naphthalene rings, anthracene rings, and the like.

The term "heteroaryl" refers to an unsaturated carbocyclic ring of 5 to 12 ring atoms in which one or more carbons are replaced by heteroatoms such as oxygen, nitrogen, sulfur, and the like, having a fully conjugated pi-electron system. The heteroaromatic ring may be a single ring or may be a fused polycyclic ring. Examples include, but are not limited to, pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, imidazolyl, indazolyl, benzothiophene, and the like.

The term "cycloalkyl" refers to a saturated carbocyclic ring of 3 to 8 ring atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

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

The invention also provides a preparation method of the o-benzoyl-sulfonyl imide derivative, which comprises the following steps:

The synthesis method of IA series compounds comprises the following steps:

(1) The aniline compound Ia and chloral hydrate and hydroxylamine hydrochloride are subjected to addition reaction to prepare an iso-nitroso-acetamides intermediate Ib;

(2) The intermediate Ib is dehydrated and cyclized in concentrated sulfuric acid in sequence and oxidized under alkaline condition to prepare an anthranilic acid intermediate Id, wherein the used alkali comprises NaOH, KOH and the like;

(3) The intermediate Id is subjected to esterification reaction with methanol under the catalysis of concentrated sulfuric acid to prepare an intermediate Ie;

(4) The intermediate Ie reacts with sodium nitrite and concentrated hydrochloric acid to prepare diazonium salt, and the diazonium salt reacts with sodium bisulphite under the catalysis of copper sulfate pentahydrate to prepare a benzenesulfonyl chloride intermediate If which is directly used for the next reaction;

(5) The intermediate If is cyclized with ammonia water in THF to prepare an o-benzoyl-sulfonyl imide intermediate Ig;

(6) Intermediate Ig and p-methoxybenzyl chloride are subjected to nucleophilic substitution reaction under alkaline conditions to prepare intermediate Ih, wherein the used alkali comprises NaH, naOH, KOH and the like;

(7) Carrying out nucleophilic substitution reaction on the intermediate Ih and a phenolic compound (or a fatty alcohol compound) under an alkaline condition to obtain an intermediate Ii, wherein the used alkali comprises K ₂CO₃、Na₂CO₃, naH and the like;

(8) And removing PMB protecting groups from the intermediate Ii in a CH ₃CN/H₂ O mixed solvent by using cerinamine nitrate to obtain target compounds IA-1 to IA-3.

The synthesis method of IB series compounds comprises the following steps:

The intermediate Ig reacts with iodinated hydrocarbon (or bromohydrocarbon) in turn under alkaline condition to obtain Ij, and then nucleophilic substitution reaction is carried out with phenolic compound (or aliphatic alcohol compound) to obtain target compounds IB-1-IB-21, wherein the used alkali comprises K ₂CO₃、Na₂CO₃, naH and the like.

The synthesis method of II, III and IV series compounds comprises the following steps:

The specific reaction process can be as follows:

Reducing the IB series compound in a THF/MeOH mixed solvent by sodium borohydride to obtain a II series target compound;

Nucleophilic substitution reaction is carried out on the II series compound and diethylaminosulfur trifluoride in anhydrous DCM to obtain III series target compound.

And carrying out nucleophilic substitution reaction on the II-series compound and trimethylcyano silane under the catalysis of boron trifluoride diethyl ether to obtain IV-series target compounds.

4.V, VI series compound synthesis method:

The specific reaction process can be as follows:

reacting the intermediate Ij with Lawson's reagent in toluene to produce thioamide intermediate Va;

and carrying out nucleophilic substitution reaction on the intermediate Va and a phenolic compound (or a fatty alcohol compound) under an alkaline condition to obtain a V-series target compound, wherein the used alkali comprises K ₂CO₃、Na₂CO₃, naH and the like.

The V series compound reacts with tetrabutylammonium dihydrotrifluoride and N-bromosuccinimide in anhydrous DCM to obtain the VI series target compound.

The synthesis method of VII series compound (without CN group and unsaturated carbon double and triple bond) comprises the following steps:

The specific reaction process can be as follows:

And carrying out nucleophilic addition reaction on the I series of compounds and Grignard reagent in anhydrous THF to obtain VII series of target compounds.

The synthesis of the VIII series compound (R ₄＝CF₃、CF₂H、CF₂CF₃):

The specific reaction process can be as follows:

reacting aniline compound Ia with sodium nitrite and concentrated hydrochloric acid to obtain diazonium salt, and reacting the diazonium salt with sodium bisulphite under the catalysis of cupric sulfate pentahydrate to obtain a benzenesulfonyl chloride intermediate VIIIa;

Nucleophilic substitution reaction is carried out on the intermediate VIIIa and primary amine compounds under alkaline conditions, thus obtaining a benzenesulfonamide intermediate VIIIb, wherein the used alkali comprises TEA, pyridine and the like;

The intermediate VIIIb reacts with fluoroethyl (propyl) acid ethyl ester compound in an electrophilic substitution way under the participation of n-butyllithium to prepare an intermediate VIIIc;

Intermediate VIIIc is reacted with trifluoroacetic acid in PhMe to produce intermediate VIIId;

And carrying out nucleophilic substitution reaction on the intermediate VIIID and a phenolic compound (or a fatty alcohol compound) under alkaline conditions to obtain VIII series target compounds, wherein the used alkali comprises K ₂CO₃、Na₂CO₃, naH and the like.

Synthesis of the ix series of compounds (no CN group and R ₄＝R₅ +.h):

The specific reaction process can be as follows:

Dehydrating the IA series compound in thionyl chloride to prepare an intermediate IXa;

the intermediate IXa and Grignard reagent are subjected to substitution reaction in anhydrous THF to prepare IXA series target compounds;

nucleophilic substitution reaction is carried out on the compound IXA and iodinated hydrocarbon (or bromohydrocarbon) under alkaline condition to obtain IXB series target compounds, wherein the used alkali comprises K ₂CO₃、Na₂CO₃ and the like.

The method for synthesizing 8.X series of compounds comprises the following steps:

The specific reaction process can be as follows:

Dehydrating the VIIA series compound in p-toluenesulfonic acid to prepare an intermediate Xa;

reducing the intermediate Xa in a THF/MeOH mixed solvent by sodium borohydride to obtain a target compound XA series of target compounds;

Nucleophilic substitution reaction is carried out on the compound XA and an iodo compound (or bromo compound) under alkaline condition to obtain the XB series target compound, wherein the used alkali comprises K ₂CO₃、Na₂CO₃ and the like.

The synthesis of the XI series of compounds:

The specific reaction process can be as follows:

Ring-opening the intermediate Ig under the catalysis of concentrated sulfuric acid to prepare an o-sulfonamide benzoate intermediate XIa;

The intermediate XIa is respectively substituted and added with tert-butyl dimethyl chlorosilane and triphenylphosphine dichloride in sequence to prepare an intermediate XIb which is directly used for the next reaction;

performing nucleophilic substitution reaction on the intermediate XIb and primary amine compounds to prepare an intermediate XIc;

Performing nucleophilic substitution reaction on the intermediate XIc and a phenolic compound (or fatty alcohol compound) under alkaline conditions to obtain an intermediate XId, wherein the used base comprises K ₂CO₃、Na₂CO₃, naH and the like;

Intermediate XId is deprotected by hydrochloric acid in MeOH/H ₂ O mixed solvent to afford the target compound of XI series.

A method for synthesizing a compound of the xii series:

The specific reaction process can be as follows:

The intermediate Id reacts with sodium nitrite and concentrated hydrochloric acid to prepare diazonium salt, and the diazonium salt reacts with temporarily prepared sodium polysulfide solution in a coupling way to prepare an intermediate XIIa;

the intermediate XIIa and methanol are subjected to esterification reaction under the catalysis of concentrated sulfuric acid to prepare an intermediate XIIb;

The intermediate XIIB sequentially performs substitution and cyclization reaction with bromine water and primary amine compounds to prepare a benzisothiazole-3-ketone intermediate XIIB, wherein the used base comprises TEA, pyridine and the like;

the intermediate XIIC is oxidized by hydrogen peroxide under the catalysis of acetic acid to prepare a sulfinyl benzoyl imine intermediate XIId;

And carrying out nucleophilic substitution reaction on the intermediate XIId and a phenolic compound (or a fatty alcohol compound) under an alkaline condition to obtain XII series target compounds, wherein the used alkali comprises K ₂CO₃、Na₂CO₃, naH and the like.

The invention also provides a pharmaceutical composition comprising at least one active ingredient as described above and at least one pharmaceutically acceptable carrier or excipient.

The "pharmaceutically acceptable carrier" refers to a pharmaceutical carrier which is conventional in the pharmaceutical field, and includes diluents, excipients such as water and the like, fillers such as starch and the like, binders such as cellulose derivatives, gelatin and the like, wetting agents such as glycerin, disintegrants such as agar-agar, calcium carbonate and the like, absorption promoters such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and soap clay, lubricants such as talc and the like, and flavoring agents, sweeteners and the like may be added as necessary.

The pharmaceutical formulation is suitable for administration by any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. These formulations may be prepared by any method known in the art of pharmacy. For example by mixing the active ingredient with carriers or excipients.

The "pharmaceutically acceptable salts" in the present invention include, but are not limited to, alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts, and the like.

The invention also provides the use of a compound or pharmaceutical composition as described above for treating a drug associated with mediating aberrant expression of HIF-2 signaling pathways.

Preferably, the medicament is for the prevention or treatment of a tumor or inflammation.

More preferably, the tumor is selected from solid tumors including renal cancer, liver cancer, colorectal cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer, cervical cancer, skin cancer, glioma, lymphoma or neuroblastoma, etc.; the inflammation is selected from nephritis, pneumonia, enteritis, arthritis or traumatic infection.

Antitumor agents which may be used in combination with the compounds provided herein or pharmaceutically acceptable salts thereof include, but are not limited to, at least one of the following classes: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine); tubulin degradation inhibitors (e.g. taxol); alkylating agents (such as cisplatin, carboplatin, and cyclophosphamide); antimetabolites (e.g., 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea); antibiotics (such as alexin, mitomycin, and bleomycin) may be inserted; enzymes (e.g., asparaginase); topoisomerase inhibitors (e.g. etoposide and camptothecins); biological response modifiers (e.g., interferons); proteasome inhibitors (e.g., bortezomib).

Compared with the prior art, the o-benzoyl-sulfonyl imide derivative developed by the invention designs the structure of the compound scientifically and reasonably based on the target, and a series of compounds with novel structures are obtained through the substitution and modification of the groups; and a series of compounds with anti-tumor activity are optimally screened by combining in-vitro and in-vivo experiment evaluation, so that the method has great clinical application value and considerable market potential for preventing or treating cancers.

Detailed Description

The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.

EXAMPLE 1 Compound IA

Step 1: (E) Synthesis of-N- (2-bromo-3-fluorophenyl) -2- (hydroxyimino) acetamide (Ib-1)

To an aqueous solution (150.00 mL) of 2-bromo-3-fluoroaniline (5.00 g,26.30 mmol) was added 2N HCl (12.00 mL), and the solution was stirred at room temperature until it became clear, anhydrous sodium sulfate (24.60 g,0.17 mol), hydroxylamine hydrochloride (6.40 g,92.10 mmol) and chloral hydrate (5.70 g,34.20 mmol) were added in this order, and the reaction was allowed to proceed at 55℃for about 5 hours until the starting material was completely converted. The reaction system was cooled to room temperature, extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 63.0%;

¹H NMR(500MHz,DMSO-d₆)：δ12.51(d,J＝2.0Hz,1H),9.58(s,1H),7.75(d,J＝8.5Hz,1H),7.68(d,J＝2.0Hz,1H),7.48-7.42(m,1H),7.25-7.20(m,1H)

ESI-MS:m/z＝261/263[M+H]⁺。

(E) Synthesis of-N- (3-fluoro-2-methylphenyl) -2- (hydroxyimino) acetamide (Ib-2)

Preparation of intermediate Ib-2 reference was made to the synthesis of intermediate Ib-1. 2-bromo-3-fluoroaniline was replaced with 3-fluoro-2-methylaniline to give a white solid. The yield thereof was found to be 59%;

¹HNMR(500MHz,DMSO-d₆)：δ12.26(s,1H),9.78(s,1H),7.71(s,1H),7.31(d,J＝8.5Hz,1H),7.24-7.20(m,1H),7.04(t,J＝8.5Hz,1H),2.10(d,J＝2.0Hz,3H);

ESI-MS:m/z＝197[M+H]⁺。

(E) Synthesis of-N- (2-chloro-3-fluorophenyl) -2- (hydroxyimino) acetamide (Ib-3)

Preparation of intermediate Ib-3 reference was made to the synthesis of intermediate Ib-1. 2-bromo-3-fluoroaniline is replaced by 2-chloro-3-fluoroaniline to obtain white solid. The yield thereof was found to be 67%;

¹HNMR(500MHz,DMSO-d₆)：δ12.48(s,1H),9.68(s,1H),7.77(d,J＝8.5Hz,1H),7.71(s,1H),7.41-7.39(m,1H),7.28(td,J＝8.5,1.5Hz,1H);

ESI-MS:m/z＝217[M+H]⁺。

(E) Synthesis of-N- (3-fluoro-2-methoxyphenyl) -2- (hydroxyimino) acetamide (Ib-4)

Preparation of intermediate Ib-4 reference was made to the synthesis of intermediate Ib-1. 2-bromo-3-fluoroaniline is replaced by 3-fluoro-2-methoxyaniline to obtain white solid. The yield was 86%;

¹HNMR(500MHz,DMSO-d₆)：δ12.45(s,1H),9.40(s,1H),7.93(d,J＝8.5Hz,1H),7.74(s,1H),7.12-7.07(m,1H),7.07-7.02(m,1H),3.89(d,J＝1.5Hz,3H);

ESI-MS:m/z＝213[M+H]⁺。

(E) Synthesis of-N- (3-fluoro-2-trifluoromethylphenyl) -2- (hydroxyimino) acetamide (Ib-5)

Preparation of intermediate Ib-5 reference was made to the synthesis of intermediate Ib-1. 2-bromo-3-fluoroaniline is replaced by 3-fluoro-2-trifluoromethylaniline to obtain white solid. The yield thereof was found to be 49%;

ESI-MS:m/z＝251[M+H]⁺。

(E) Synthesis of-N- (3-fluoro-2-nitrophenyl) -2- (hydroxyimino) acetamide (Ib-6)

Preparation of intermediate Ib-6 reference was made to the synthesis of intermediate Ib-1. 2-bromo-3-fluoroaniline is replaced by 3-fluoro-2-nitroaniline to obtain white solid. The yield was 70%;

ESI-MS:m/z＝228[M+H]⁺。

Step 2: synthesis of 7-bromo-6-fluoroindole-2, 3-dione (Ic-1)

Concentrated sulfuric acid (8.78 mL) was added to the double flask and heated to 50℃and intermediate Ib-1 (3.2 g,12.3 mmol) was added in portions to maintain the temperature at 60-70℃and stirring was continued after the reaction system had been heated to 80℃for 1 hour. Cooling to room temperature, pouring into ice water (25 mL) to precipitate solid, filtering, washing filter cake with water to neutrality, and vacuum drying to obtain yellow solid. The yield was 98%;

¹H NMR(500MHz,CDCl₃)：δ8.27(s,1H),7.63(dd,J＝8.5,5.0Hz,1H),6.91(t,J＝8.5Hz,1H)；

ESI-MS:m/z＝244/246[M+H]⁺。

synthesis of 6-fluoro-7-methylindole-2, 3-dione (Ic-2)

Preparation of intermediate Ic-2 reference was made to the synthesis of intermediate Ic-1. Intermediate Ib-1 is replaced by intermediate Ib-2 to obtain a yellow solid. The yield thereof was found to be 97%;

¹HNMR(500MHz,DMSO-d₆)：δ11.30(s,1H),7.45(dd,J＝8.5,5.0Hz,1H),6.85(dd,J＝10.0,8.5Hz,1H),2.10(d,J＝1.5Hz,3H);

ESI-MS:m/z＝180[M+H]⁺。

synthesis of 7-chloro-6-fluoroindole-2, 3-dione (Ic-3)

Preparation of intermediate Ic-3 reference was made to the synthesis of intermediate Ic-1. Intermediate Ib-1 is replaced by intermediate Ib-3 to obtain a yellow solid. The yield thereof was found to be 87%;

¹HNMR(500MHz,DMSO-d₆)：δ11.71(s,1H),7.59(dd,J＝8.5,5.0Hz,1H),7.08(dd,J＝10.0,8.5Hz,1H);

ESI-MS:m/z＝200[M+H]⁺。

synthesis of 6-fluoro-7-methoxyindole-2, 3-dione (Ic-4)

Preparation of intermediate Ic-4 reference was made to the synthesis of intermediate Ic-1. Intermediate Ib-1 is replaced by intermediate Ib-4 to obtain a yellow solid. The yield thereof was found to be 92%;

ESI-MS:m/z＝196[M+H]⁺。

Synthesis of 6-fluoro-7-trifluoromethylindole-2, 3-dione (Ic-5)

Preparation of intermediate Ic-5 reference was made to the synthesis of intermediate Ic-1. Intermediate Ib-1 is replaced by intermediate Ib-5 to obtain a yellow solid. The yield was 90%;

ESI-MS:m/z＝234[M+H]⁺。

synthesis of 6-fluoro-7-nitroindole-2, 3-dione (Ic-6)

Preparation of intermediate Ic-6 reference was made to the synthesis of intermediate Ic-1. Intermediate Ib-1 is replaced by intermediate Ib-6 to give a yellow solid. The yield was 95%;

ESI-MS:m/z＝211[M+H]⁺。

Step 3: synthesis of 2-amino-3-bromo-4-fluorobenzoic acid (Id-1)

To an aqueous solution (50 mL) of NaOH (3.2 g,80.5 mmol) was added intermediate Ic-1 (2.8 g,11.5 mmol), and a 30% H ₂O₂ solution (0.9 mL) was added dropwise under ice-bath and stirred at room temperature for 1.5 hours until the starting material was completely converted. And regulating the pH to 3-4 by using 2N HCl, precipitating a solid, filtering, and drying in vacuum to obtain a white solid. The yield thereof was found to be 87%;

¹HNMR(500MHz,DMSO-d₆)：δ13.11(s,1H),7.88(dd,J＝9.0,6.5Hz,1H),6.79(s,2H),6.62(t,J＝9.0Hz,1H);

ESI-MS:m/z＝234/236[M+H]⁺。

synthesis of 2-amino-4-fluoro-3-methylbenzoic acid (Id-2)

Preparation of intermediate Id-2 reference was made to the synthesis of intermediate Id-1. Intermediate Ic-1 was replaced with intermediate Ic-2 to give a white solid. The yield thereof was found to be 82%;

¹HNMR(500MHz,DMSO-d₆)：δ7.66(dd,J＝9.0,6.5Hz,1H),6.86(s,2H),6.36(t,J＝9.0Hz,1H),1.99(d,J＝2.0Hz,3H);

ESI-MS:m/z＝170[M+H]⁺。

synthesis of 2-amino-3-chloro-4-fluorobenzoic acid (Id-3)

Preparation of intermediate Id-3 reference was made to the synthesis of intermediate Id-1. Intermediate Ic-1 was replaced with intermediate Ic-3 to give a white solid. The yield thereof was found to be 79%;

ESI-MS:m/z＝190[M+H]⁺。

synthesis of 2-amino-4-fluoro-3-methoxybenzoic acid (Id-4)

Preparation of intermediate Id-4 reference was made to the synthesis of intermediate Id-1. Intermediate Ic-1 was replaced with intermediate Ic-4 to give a white solid. The yield thereof was found to be 77%;

¹HNMR(500MHz,DMSO-d₆)：δ12.78(s,1H),7.50(dd,J＝9.0,6.0Hz,1H),6.81(s,2H),6.41(dd,J＝10.5,9.0Hz,1H),3.77(d,J＝1.0Hz,3H);

ESI-MS:m/z＝186[M+H]⁺。

Synthesis of 2-amino-4-fluoro-3-trifluoromethylbenzoic acid (Id-5)

Preparation of intermediate Id-5 reference was made to the synthesis of intermediate Id-1. Intermediate Ic-1 was replaced with intermediate Ic-5 to give a white solid. The yield was 85%;

ESI-MS:m/z＝224[M+H]⁺。

Synthesis of 2-amino-4-fluoro-3-nitrobenzoic acid (Id-6)

Preparation of intermediate Id-6 reference was made to the synthesis of intermediate Id-1. Intermediate Ic-1 was replaced with intermediate Ic-6 to give a white solid. The yield was 90%;

ESI-MS:m/z＝201[M+H]⁺。

step 4: synthesis of methyl 2-amino-3-bromo-4-fluorobenzoate (Ie-1)

Intermediate Id-1 (2.5 g,10.7 mmol) was dissolved in methanol (50 mL), concentrated sulfuric acid (1.3 mL) was added dropwise under ice, and the mixture was warmed to reflux and stirred overnight. Cooling to room temperature, decompressing, evaporating the solvent, adding 50mL of water, adjusting the pH to 3 by 2N NaOH, precipitating solid, filtering, and vacuum drying to obtain white solid. The yield thereof was found to be 83%;

¹HNMR(500MHz,DMSO-d₆)：δ7.86(dd,J＝9.0,6.5Hz,1H),7.03(s,2H),6.61(t,J＝9.0Hz,1H),3.82(s,3H);

ESI-MS:m/z＝248/250[M+H]⁺。

Synthesis of methyl 2-amino-4-fluoro-3-methyl-benzoate (Ie-2)

Preparation of intermediate Ie-2 reference was made to the synthesis of intermediate Ie-1. Intermediate Id-1 was replaced with intermediate Id-2 to give a white solid. The yield thereof was found to be 89%;

¹HNMR(500MHz,DMSO-d₆)：δ7.71(dd,J＝9.0,6.5Hz,1H),6.81(s,2H),6.40(t,J＝9.0Hz,1H),3.78(s,3H),2.00(d,J＝2.0Hz,3H);

ESI-MS:m/z＝184[M+H]⁺。

Synthesis of methyl 2-amino-3-chloro-4-fluorobenzoate (Ie-3)

Preparation of intermediate Ie-3 reference was made to the synthesis of intermediate Ie-1. Intermediate Id-1 was replaced with intermediate Id-3 to give a white solid. The yield thereof was found to be 72%;

¹HNMR(500MHz,DMSO-d₆)：δ7.80(dd,J＝9.0,6.5Hz,1H),7.07(s,2H),6.63(t,J＝9.0Hz,1H),3.82(s,3H);

ESI-MS:m/z＝204[M+H]⁺。

synthesis of methyl 2-amino-4-fluoro-3-methoxybenzoate (Ie-4)

Preparation of intermediate Ie-4 reference was made to the synthesis of intermediate Ie-1. Intermediate Id-1 was replaced with intermediate Id-4 to give a white solid. The yield thereof was found to be 88%;

¹HNMR(500MHz,DMSO-d₆)：δ7.52(dd,J＝8.5,6.0Hz,1H),6.67(s,2H),6.45(t,J＝8.5Hz,1H),3.79(s,3H),3.78(d,J＝1.0Hz,3H);

ESI-MS:m/z＝200[M+H]⁺。

Synthesis of methyl 2-amino-4-fluoro-3-trifluoromethylbenzoate (Ie-5)

Preparation of intermediate Ie-5 reference was made to the synthesis of intermediate Ie-1. Intermediate Id-1 was replaced with intermediate Id-5 to give a white solid. The yield thereof was found to be 79%;

ESI-MS:m/z＝238[M+H]⁺。

synthesis of methyl 2-amino-4-fluoro-3-nitrobenzoate (Ie-6)

Preparation of intermediate Ie-6 reference was made to the synthesis of intermediate Ie-1. Intermediate Id-1 was replaced with intermediate Id-6 to give a white solid. The yield thereof was found to be 76%;

ESI-MS:m/z＝215[M+H]⁺。

Step 5: synthesis of methyl 3-bromo-2- (chlorosulfonyl) -4-fluorobenzoate (If-1)

Intermediate Ie-1 (1.5 g,6.1 mmol) was added to a 9N HCl (3.0 mL) solution, and a 40% NaNO ₂ solution (1.0 mL,7.9 mmol) was added dropwise with ice bath stirring, maintaining the temperature at 0-10deg.C, and stirring was continued for 0.5 hours to obtain a diazonium salt solution for use.

NaHSO ₃ (1.3 g,12.2 mmol) was dissolved in an aqueous solution (5 mL) and divided equally into A, B portions, copper sulfate pentahydrate (151.8 mg,0.6 mmol) and concentrated hydrochloric acid (8 mL) were added to A, and B was added dropwise to A simultaneously with diazonium salt solution under ice bath, and stirred at room temperature for 3 hours. Extraction with ethyl acetate (15 ml×3), combining the organic layers, washing with water, washing with saturated NaCl, drying over anhydrous Na ₂SO₄, concentrating to a yellow solid, the crude product was used in the next step without further purification. The yield thereof was found to be 78%;

ESI-MS:m/z＝331/333[M+H]⁺。

Synthesis of methyl 2- (chlorosulfonyl) -4-fluoro-3-methylbenzoate (If-2)

Preparation of intermediate If-2 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with intermediate Ie-2 to give a yellow solid. The yield thereof was found to be 69%;

ESI-MS:m/z＝267[M+H]⁺。

Synthesis of methyl 3-chloro-2- (chlorosulfonyl) -4-fluorobenzoate (If-3)

Preparation of intermediate If-3 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with intermediate Ie-3 to give an orange solid. The yield thereof was found to be 73%;

ESI-MS:m/z＝287[M+H]⁺。

synthesis of methyl 2- (chlorosulfonyl) -4-fluoro-3-methoxybenzoate (If-4)

Preparation of intermediate If-4 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with intermediate Ie-4 to give a yellow solid. The yield thereof was found to be 57%;

ESI-MS:m/z＝283[M+H]⁺。

Synthesis of methyl 2- (chlorosulfonyl) -4-fluoro-3-trifluoromethylbenzoate (If-5)

Preparation of intermediate If-5 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with intermediate Ie-5 to give a yellow solid. The yield thereof was found to be 49%;

ESI-MS:m/z＝321[M+H]⁺。

Synthesis of methyl 2- (chlorosulfonyl) -4-fluoro-3-nitrobenzoate (If-6)

Preparation of intermediate If-6 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with intermediate Ie-6 to give an orange solid. The yield thereof was found to be 37%;

ESI-MS:m/z＝298[M+H]⁺。

step 6: synthesis of 7-bromo-6-fluorobenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-1)

To a solution of intermediate If-1 (1.5 g,4.5 mmol) in tetrahydrofuran (20 mL) was added aqueous ammonia (8 mL), and the mixture was stirred at room temperature for 1.5 hours until the starting materials were completely reacted. The pH was adjusted to 2 with 2N HCl, the organic solvent was distilled off under reduced pressure, extracted with dichloromethane (10 mL. Times.3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 63%;

¹HNMR(500MHz,DMSO-d₆)：δ7.59(dd,J＝8.5,4.5Hz,1H),7.53(t,J＝8.5Hz,1H)；

ESI-MS:m/z＝280/282[M+H]⁺。

Synthesis of 6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-2)

Preparation of intermediate Ig-2 reference was made to synthesis of intermediate Ig-1. Intermediate If-1 is replaced by intermediate If-2 to give a white solid. The yield thereof was found to be 54%;

¹HNMR(500MHz,DMSO-d₆)：δ7.41(dd,J＝8.5,4.5Hz,1H),7.34(t,J＝8.5Hz,1H),2.38(d,J＝1.5Hz,3H);

ESI-MS:m/z＝216[M+H]⁺。

synthesis of 7-chloro-6-fluorobenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-3)

Preparation of intermediate Ig-3 reference was made to synthesis of intermediate Ig-1. Intermediate If-1 is replaced by intermediate If-3 to give a white solid. The yield thereof was found to be 71%;

¹HNMR(500MHz,DMSO-d₆)：δ7.62(t,J＝8.5Hz,1H),7.58(dd,J＝8.5,4.5Hz,1H)；

ESI-MS:m/z＝236[M+H]⁺。

Synthesis of 6-fluoro-7-methoxybenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-4)

Preparation of intermediate Ig-4 reference was made to synthesis of intermediate Ig-1. Intermediate If-1 is replaced by intermediate If-4 to give a white solid. The yield was 70%;

ESI-MS:m/z＝232[M+H]⁺。

synthesis of 6-fluoro-7-trifluoromethyl-benzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-5)

Preparation of intermediate Ig-5 reference was made to synthesis of intermediate Ig-1. Intermediate If-1 is replaced by intermediate If-5 to give a white solid. The yield thereof was found to be 58%;

ESI-MS:m/z＝270[M+H]⁺。

Synthesis of 6-fluoro-7-nitrobenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ig-6)

Preparation of intermediate Ig-6 reference was made to synthesis of intermediate Ig-1. Intermediate If-1 is replaced by intermediate If-6 to give a white solid. The yield thereof was found to be 63%;

ESI-MS:m/z＝247[M+H]⁺。

step 7: synthesis of 7-bromo-6-fluoro-2- (4-methoxybenzyl) benzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ih-1)

NaH (62.4 mg,2.6 mmol) was dissolved in DMF (8 mL), intermediate Ig-1 (500.0 mg,2.3 mmol) was added under ice-bath, stirred at room temperature under N ₂ for 0.5 h, PMBCl (282.9 mg,2.8 mmol) was added dropwise, and the temperature was raised to 80℃for reaction overnight. Cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (30 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 88%;

¹HNMR(500MHz,CDCl₃)：δ7.97(dd,J＝8.5,4.0Hz,1H),7.50(t,J＝8.5Hz,1H),7.46-7.42(m,2H),6.90-6.86(m,2H),4.86(s,2H),3.79(s,3H);

ESI-MS:m/z＝400[M+H]⁺。

synthesis of 6-fluoro-2- (4-methoxybenzyl) -7-methylbenzo [ d ] isothiazol-3 (2H) one-1, 1-dioxide (Ih-2)

Preparation of intermediate Ih-2 reference synthesis of intermediate Ih-1. Intermediate Ig-1 was replaced with intermediate Ig-2 to give a white solid. The yield thereof was found to be 82%;

¹HNMR(500MHz,CDCl₃)：δ7.86(dd,J＝8.5,4.0Hz,1H),7.46-7.42(m,2H),7.40(t,J＝8.5Hz,1H),6.90-6.85(m,2H),4.84(s,2H),3.79(s,3H),2.59(d,J＝1.5Hz,3H);

ESI-MS:m/z＝336[M+H]⁺。

step 8: synthesis of 3- ((7-bromo-2- (4-methoxybenzyl) -1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (Ii-1)

Intermediate Ih-1 (150 mg,0.38 mmol) and 3-fluoro-5-hydroxybenzonitrile (56.2 mg,0.41 mmol) were dissolved in DMF (1.0 mL) and K ₂CO₃ (131.3 mg,0.95 mmol) was added and the temperature was raised to 80℃and stirred for about 4 hours until complete conversion of the starting material. Cooled to room temperature, water (5 mL) was added, extracted with ethyl acetate (5 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 90%;

¹HNMR(500MHz,CDCl₃)：δ7.97(dd,J＝8.5,4.0Hz,1H),7.73-7.71(m,1H),7.60-7.59(m,1H),7.56(dt,J＝10.0,2.5Hz,1H),7.50(t,J＝8.5Hz,1H),7.46-7.42(m,2H),6.90-6.86(m,2H),4.86(s,2H),3.79(s,3H);

ESI-MS:m/z＝517/519[M+H]⁺。

synthesis of 3- ((7-methyl-2- (4-methoxybenzyl) -1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (Ii-2)

Preparation of intermediate Ii-2 reference was made to the synthesis of intermediate Ii-1. Intermediate Ih-1 was replaced with intermediate Ih-2 to give a white solid. The yield thereof was found to be 79%; ESI-MS: m/z=453 [ M+H ] ⁺.

Synthesis of 6- (3, 5-difluorophenoxy) -2- (4-methoxybenzyl) -7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ii-3)

Preparation of intermediate Ii-3 reference was made to the synthesis of intermediate Ii-1. Replacing Ih-1 with Ih-2, 3-fluoro-5-hydroxybenzonitrile with 3, 5-difluorophenol to obtain white solid. The yield thereof was found to be 63%; ESI-MS: m/z=446 [ M+H ] ⁺.

Step 9: synthesis of 3- ((7-bromo-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IA-1)

Intermediate Ii-1 (100 mg,0.19 mmol) was dissolved in acetonitrile (2.0 mL), and an aqueous solution (0.5 mL) of cerinamine nitrate (416.7 mg,0.76 mmol) was added and stirred at room temperature for 2.5 hours until the starting material was completely converted. The organic solvent was distilled off under reduced pressure, extracted with ethyl acetate (1 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 35%;

¹H NMR(500MHz,DMSO-d₆):δ7.71-7.68(m,1H),7.59(d,J＝8.5Hz,1H),7.51-7.50(m,1H),7.43(dt,J＝10.0,2.5Hz,1H),7.35(d,J＝8.5Hz,1H);

ESI-MS:m/z＝397[M+H]⁺。

Synthesis of 3- ((7-methyl-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IA-2)

Preparation of target Compound IA-2 reference compound IA-1 was synthesized. Intermediate Ii-1 was replaced with intermediate Ii-2 to give a white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,DMSO-d₆)：δ7.79(d,J＝8.5Hz,1H),7.76-7.74(m,1H),7.60-7.59(m,1H),7.56(dt,J＝10.0,2.5Hz,1H),7.38(d,J＝8.5Hz,1H),2.46(s,3H);

ESI-MS:m/z＝333[M+H]⁺。

synthesis of 6- (3, 5-difluorophenoxy) -7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (IA-3)

Preparation of target Compound IA-3 reference Compound IA-1 was synthesized. Intermediate Ii-1 was replaced with intermediate Ii-3 to give a white solid. The yield was 32%;

¹H NMR(500MHz,DMSO-d₆)：δ7.73(d,J＝8.5Hz,1H),7.60-7.59(m,2H),7.52(dt,J＝10.0,2.5Hz,1H),7.35(d,J＝8.5Hz,1H),2.46(s,3H);

ESI-MS:m/z＝326[M+H]⁺。

EXAMPLE 2 Compound IB series

Step 1: synthesis of 7-bromo-6-fluoro-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-1)

Intermediate Ig-1 (200 mg,0.72 mmol) and K ₂CO₃ (247.7 mg,1.79 mmol) were dissolved in DMF (2.0 mL) and CH ₃ I (71. Mu.L, 1.08 mmol) was added dropwise and the temperature was raised to 40℃to react until complete conversion of starting material. Cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 56%;

¹HNMR(500MHz,DMSO-d₆)：δ8.15(dd,J＝8.5,4.0Hz,1H),7.96(t,J＝8.5Hz,1H),3.19(s,3H)；

ESI-MS:m/z＝294/296[M+H]⁺。

synthesis of 6-fluoro-2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-2)

Preparation of intermediate Ij-2 reference was made to the synthesis of intermediate Ij-1. Intermediate Ig-1 was replaced with intermediate Ig-2 to give a white solid. The yield thereof was found to be 77%;

¹H NMR(500MHz,DMSO-d₆)：δ8.00(dd,J＝8.5,4.0Hz,1H),7.80(dd,J＝9.5,8.5Hz,1H),3.17(s,3H),2.53(d,J＝2.0Hz,3H);

ESI-MS:m/z＝230[M+H]⁺。

synthesis of 7-chloro-6-fluoro-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-3)

Preparation of intermediate Ij-3 reference was made to the synthesis of intermediate Ij-1. Intermediate Ig-1 was replaced with intermediate Ig-3 to give a white solid. The yield was 80%;

ESI-MS:m/z＝250[M+H]⁺。

Synthesis of 6-fluoro-7-methoxy-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-4)

Preparation of intermediate Ij-4 reference was made to the synthesis of intermediate Ij-1. Intermediate Ig-1 was replaced with intermediate Ig-4 to give a white solid. The yield thereof was found to be 66%;

¹HNMR(500MHz,CDCl₃)：δ7.65(dd,J＝8.5,3.5Hz,1H),7.48(dd,J＝12.0,8.5Hz,1H),4.29(d,J＝3.5Hz,3H),3.24(s,3H);

ESI-MS:m/z＝246[M+H]⁺。

Synthesis of 6-fluoro-7-trifluoromethyl-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-5)

Preparation of intermediate Ij-5 reference synthesis of intermediate Ij-1. Intermediate Ig-1 was replaced with intermediate Ig-5 to give a white solid. The yield thereof was found to be 78%; ESI-MS: m/z=284 [ M+H ] ⁺.

Synthesis of 6-fluoro-2-methyl-7-difluoromethyl benzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-6)

A) Synthesis of 7- (dibromomethyl) -6-fluoro-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-6 a)

Intermediate Ij-2 (460 mg,2.0 mmol) was dissolved in carbon tetrachloride (5.0 mL), NBS (889.8 mg,5.0 mmol) and benzoyl peroxide (4.9 mg,0.02 mmol) were added, and the reaction was warmed to reflux overnight. The system is cooled to room temperature, solid is separated out, suction filtration is carried out, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain white solid. The yield was 90%;

¹HNMR(500MHz,CDCl₃)：δ8.19(dd,J＝8.5,4.0Hz,1H),7.76(t,J＝8.5Hz,1H),7.38(s,1H),2.45(s,3H);

ESI-MS:m/z＝386/388[M+H]⁺。

B) Synthesis of 6-fluoro-2-methyl-3-oxo-2, 3-dihydrobenzo [ d ] isothiazole-7-carbaldehyde-1, 1-dioxide (Ij-6 b)

Intermediate Ij-6a (600 mg,1.56 mmol) was taken up in saturated sodium bicarbonate solution (5.5 mL) and warmed to reflux overnight. The system was cooled to room temperature, extracted with dichloromethane (10 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 82%;

¹HNMR(500MHz,DMSO-d₆)：δ10.36(s,1H),8.50(dd,J＝8.5,4.0Hz,1H),7.92(t,J＝8.5Hz,1H),3.06(s,3H);

ESI-MS:m/z＝244[M+H]⁺。

C) Synthesis of 7- (difluoromethyl)) -6-fluoro-2-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-6)

Intermediate Ij-6b (250 mg,1.03 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), diethylaminosulfur trifluoride (408.6. Mu.L, 3.09 mmol) was added dropwise under ice-bath, and stirred at room temperature overnight. Dropwise adding water under ice bath to make no bubbles emerge, evaporating under reduced pressure to remove organic solvent, extracting with ethyl acetate (5 mL×3), mixing organic layers, washing with saturated NaCl, drying with anhydrous Na ₂SO₄, concentrating, and purifying by silica gel column chromatography to obtain white solid. The yield thereof was found to be 63%;

¹H NMR(500MHz,DMSO-d₆)：δ8.25(dd,J＝9.0,6.5Hz,1H),7.76(t,J＝9.0Hz,1H),6.44(t,J＝76.0Hz,1H),3.23(s,3H);

ESI-MS:m/z＝266[M+H]⁺。

Synthesis of 6-fluoro-2-methyl-7-cyanobenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-7)

Intermediate Ij-1 (150 mg,0.51 mmol) was dissolved in NMP (2.0 mL) and cuprous cyanide (54.9 mg,0.61 mmol) was added and the system was heated to 160℃with microwaves to effect complete conversion of the starting material. The system was taken up in water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the organic layers were combined, washed successively with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by column chromatography on silica gel to give a white solid. The yield was 18%;

¹H NMR(500MHz,DMSO-d₆)：δ8.54(dd,J＝9.0,6.5Hz,1H),7.97(t,J＝9.0Hz,1H),2.88(s,3H)；

ESI-MS:m/z＝241[M+H]⁺。

synthesis of 6-fluoro-2-methyl-7-nitrobenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-8)

Preparation of intermediate Ij-8 reference was made to the synthesis of intermediate Ij-1. Intermediate Ig-1 was replaced with intermediate Ig-6 to give a white solid. The yield thereof was found to be 83%;

ESI-MS:m/z＝261[M+H]⁺。

synthesis of 7-bromo-2-ethyl-6-fluorobenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-9)

Preparation of intermediate Ij-9 reference was made to the synthesis of intermediate Ij-1. The methyl iodide is replaced by ethyl iodide to obtain white solid. The yield thereof was found to be 72%;

¹HNMR(500MHz,CDCl₃)：δ7.99(dd,J＝8.5,4.0Hz,1H),7.51(t,J＝8.5Hz,1H),3.87(q,J＝7.0Hz,2H),1.45(t,J＝7.0Hz,3H);

ESI-MS:m/z＝308/310[M+H]⁺。

synthesis of 2-ethyl-6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-10)

Preparation of intermediate Ij-10 reference was made to the synthesis of intermediate Ij-2. The methyl iodide is replaced by ethyl iodide to obtain white solid. The yield was 65%;

¹HNMR(500MHz,CDCl₃)：δ7.83(dd,J＝8.5,4.0Hz,1H),7.46(t,J＝8.5Hz,1H),3.75(q,J＝7.0Hz,2H),3.43(s,3H),1.73(t,J＝7.0Hz,3H);

ESI-MS:m/z＝244[M+H]⁺。

Synthesis of 2-ethyl-6-fluoro-7-difluoromethyl benzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-11)

Preparation of intermediate Ij-11 reference was made to the synthesis of intermediate Ij-6. Ij-2 was replaced with Ij-10 to give a white solid. The yield thereof was found to be 46%;

ESI-MS:m/z＝280[M+H]⁺。

synthesis of 2-isopropyl-6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-12)

Preparation of intermediate Ij-12 reference was made to the synthesis of intermediate Ij-2. The methyl iodide was replaced with 2-iodopropane to give a white solid. The yield thereof was found to be 47%;

¹HNMR(500MHz,DMSO-d₆)：δ7.76(dd,J＝8.0,4.0Hz,1H),7.68(t,J＝8.0Hz,1H),5.31-5.26(m,1H),2.48(d,J＝1.5Hz,3H),1.45(d,J＝6.0Hz,6H);

ESI-MS:m/z＝258[M+H]⁺。

Synthesis of 2- (sec-butyl) -6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-13)

Preparation of intermediate Ij-13 reference was made to the synthesis of intermediate Ij-2. The methyl iodide was replaced with 2-bromobutyl to give a white solid. The yield thereof was found to be 68%;

¹HNMR(500MHz,CDCl₃)：δ8.12(dd,J＝8.5,4.0Hz,1H),7.68(t,J＝8.5Hz,1H),3.63-3.58(m,1H),2.72(m,3H),1.68-1.62(m,2H),2.48(d,J＝1.5Hz,3H),0.87(t,J＝7.0Hz,3H);

ESI-MS:m/z＝272[M+H]⁺。

synthesis of 2- (cyclopropylmethyl) -6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-14)

Preparation of intermediate Ij-14 reference synthesis of intermediate Ij-2. Methyl iodide is replaced by bromomethyl cyclopropane to obtain white solid. The yield thereof was found to be 73%;

¹HNMR(500MHz,CDCl₃)：δ7.87(dd,J＝8.5,4.0Hz,1H),7.42(t,J＝8.5Hz,1H),3.64(d,J＝7.0Hz,2H),2.62(d,J＝1.5Hz,3H),1.36-1.30(m,1H),0.67-0.62(m,2H),0.48-0.44(m,2H);

ESI-MS:m/z＝270[M+H]⁺。

Synthesis of 2- (propenyl) -6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-15)

Preparation of intermediate Ij-15 reference was made to the synthesis of intermediate Ij-2. The methyl iodide is replaced by 3-bromoprop-1-ene to obtain white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,CDCl₃)：δ7.94(dd,J＝8.5,4.0Hz,1H),7.56(t,J＝8.5Hz,1H),5.88-5.86(m,1H),5.20-5.17(m,2H),3.65(dd,J＝7.0,2.5Hz,2H),2.72(s,3H);

ESI-MS:m/z＝256[M+H]⁺。

Synthesis of 2- (but-2-yn-1-yl) -6-fluoro-7-methylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (Ij-16)

Preparation of intermediate Ij-16 reference was made to the synthesis of intermediate Ij-2. The methyl iodide is replaced by 1-bromobut-2-yne to obtain white solid. The yield thereof was found to be 78%;

ESI-MS:m/z＝268[M+H]⁺。

Step 2: synthesis of 3- ((7-bromo-2-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-1)

Intermediate Ij-1 (150 mg,0.51 mmol) and 3-fluoro-5-hydroxybenzonitrile (76.8 mg,0.56 mmol) were dissolved in DMF (2.0 mL), K ₂CO₃ (174.4 mg,1.27 mmol) was added, and the temperature was raised to 80℃and stirred until complete conversion of the starting material. Cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (15 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 57%;

¹H NMR(500MHz,CDCl₃)：δ8.01(d,J＝8.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.28-7.26(m,1H),7.14-7.13(m,1H),7.04(dt,J＝8.5,2.5Hz,1H),3.31(s,3H);

ESI-MS:m/z＝411/413[M+H]⁺。

synthesis of 3- ((2, 7-dimethyl-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-2)

Preparation of the target Compound IB-2 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-2 to give a white solid. The yield was 60%;

¹H NMR(500MHz,DMSO-d₆)δ7.93(dd,J＝8.5,1.0Hz,1H),7.79(ddd,J＝8.5,2.5,1.5Hz,1H),7.66–7.63(m,1H),7.61(dt,J＝10.0,2.5Hz,1H),7.45(d,J＝8.5Hz,1H),3.18(s,3H),2.53(s,3H);

ESI-MS:m/z＝347[M+H]⁺。

synthesis of 3- ((7-chloro-2-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-3)

Preparation of the target Compound IB-3 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-3 to give a white solid. The yield thereof was found to be 67%;

¹H NMR(500MHz,DMSO-d₆)：δ8.04(d,J＝8.5Hz,1H),7.84-7.82(m,1H),7.74-7.73(m,1H),7.71(dt,J＝9.5,2.5Hz,1H),7.66(d,J＝8.5Hz,1H),3.20(s,3H);

ESI-MS:m/z＝367[M+H]⁺。

synthesis of 3-fluoro-5- ((7-methoxy-2-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-4)

Preparation of the target Compound IB-4 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-4 to give a white solid. The yield thereof was found to be 77%;

¹H NMR(500MHz,CDCl₃)：δ7.88(d,J＝8.5Hz,1H),7.74(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.31-7.28(m,1H),6.94(dt,J＝9.0,2.5Hz,1H),3.83(s,3H),2.35(s,3H);

ESI-MS:m/z＝363[M+H]⁺。

Synthesis of 3-fluoro-5- ((2-methyl-1, 1-dioxo-3-oxo-7- (trifluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-5)

Preparation of the target Compound IB-5 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-5 to give a white solid. The yield thereof was found to be 59%;

¹H NMR(500MHz,CDCl₃)：δ8.20(d,J＝8.5Hz,1H),7.94-7.92(m,1H),7.53-7.52(m,1H),7.46(d,J＝8.5Hz,1H),6.94(dt,J＝9.5,2.5Hz,1H),2.74(s,3H);

ESI-MS:m/z＝401[M+H]⁺。

synthesis of 3-fluoro-5- ((2-methyl-1, 1-dioxo-3-oxo-7- (difluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-6)

Preparation of the target Compound IB-6 reference was made to the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-6 to give a white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,CDCl₃)：δ8.23(d,J＝8.5Hz,1H),7.84-7.82(m,1H),7.56-7.51(m,2H),6.98(dt,J＝9.5,2.5Hz,1H),6.44(t,J＝76.0Hz,1H),3.15(s,3H);

ESI-MS:m/z＝383[M+H]⁺。

synthesis of 3-fluoro-5- ((2-methyl-7-cyano-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-7)

Preparation of the target Compound IB-7 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-7 to give a white solid. The yield was 50%;

¹H NMR(500MHz,CDCl₃)：δ8.48(d,J＝8.0Hz,1H),8.05-8.02(m,1H),7.71(d,J＝8.0Hz,1H),7.48-7.47(m,1H),7.22(dt,J＝9.0,2.5Hz,1H),2.89(s,3H);

ESI-MS:m/z＝358[M+H]⁺。

Synthesis of 3-fluoro-5- ((2-methyl-7-nitro-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-8)

Preparation of the target Compound IB-8 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-8 to give a white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,CDCl₃)：δ8.59(d,J＝8.5Hz,1H),7.95-7.94(m,1H),7.79(d,J＝8.5Hz,1H),7.53-7.52(m,1H),6.92(dt,J＝9.0,2.5Hz,1H),3.08(s,3H);

ESI-MS:m/z＝378[M+H]⁺。

Synthesis of 3- ((7-bromo-2-ethyl-1, 1-dioxo-3-oxo-2, 3 dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-9)

Preparation of the target compound IB-9 reference IB-1 synthesis. Intermediate Ij-1 was replaced with intermediate Ij-9 to give a white solid. The yield thereof was found to be 53%;

¹H NMR(500MHz,CDCl₃)：δ8.00(d,J＝8.5Hz,1H),7.31(d,J＝8.5Hz,1H),7.27-7.25(m,1H),7.13-7.12(m,1H),7.02(dt,J＝9.0,2.5Hz,1H),3.89(q,J＝7.5Hz,2H),1.47(t,J＝6.0Hz,3H);

ESI-MS:m/z＝425/427[M+H]⁺。

Synthesis of 3- ((2-ethyl-7-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-10)

Preparation of the target compound IB-10 reference IB-1 synthesis. Intermediate Ij-1 was replaced with intermediate Ij-10 to give a white solid. The yield thereof was found to be 82%;

¹H NMR(500MHz,DMSO-d₆)：δ7.92(d,J＝8.5Hz,1H),7.79-7.77(m,1H),7.64-7.63(m,1H),7.60(dt,J＝9.5,2.5Hz,1H),7.45(d,J＝8.5Hz,1H),3.77(q,J＝7.0Hz,2H),2.51(s,3H),1.32(t,J＝7.0Hz,3H);

ESI-MS:m/z＝361[M+H]⁺。

Synthesis of 3- ((2-ethyl-7-difluoromethyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-11)

Preparation of the target Compound IB-11 reference the synthesis of IB-1. Intermediate Ij-1 was replaced with intermediate Ij-11 to give a white solid. The yield thereof was found to be 67%;

¹H NMR(500MHz,DMSO-d₆)：δ8.23(d,J＝8.5Hz,1H),7.96-7.95(m,1H),7.56(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.32(dt,J＝10.0,2.5Hz,1H),6.76(t,J＝76.0Hz,1H),3.20(q,J＝7.0Hz,2H),1.28(t,J＝7.0Hz,3H);

ESI-MS:m/z＝397[M+H]⁺。

synthesis of 3-fluoro-5- ((2-isopropyl-7-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-12)

Preparation of the target Compound IB-12 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-12 to give a white solid. The yield was 55%;

¹H NMR(500MHz,CDCl₃)：δ7.86(d,J＝8.5Hz,1H),7.23(d,J＝8.5Hz,1H),7.22-7.19(m,1H),7.08-7.06(m,1H),6.96(dt,J＝9.0,2.5Hz,1H),4.57-4.48(m,1H),2.57(s,3H),1.63(d,J＝7.0Hz,6H);

ESI-MS:m/z＝375[M+H]⁺。

Synthesis of 3-fluoro-5- ((2- (sec-butyl) -7-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-13)

Preparation of the target compound IB-13 reference IB-1 synthesis. Intermediate Ij-1 was replaced with intermediate Ij-13 to give a white solid. The yield thereof was found to be 78%;

¹H NMR(500MHz,CDCl₃)：δ7.90(d,J＝8.5Hz,1H),7.24-7.23(m,1H),7.21-7.19(m,1H),7.17(d,J＝8.5Hz,1H),6.89(dt,J＝9.0,2.5Hz,1H),3.62-3.54(m,1H),3.28(s,3H),1.68-1.56(m,2H),1.26(d,J＝7.0Hz,3H),0.87(t,J＝7.0Hz,3H);

ESI-MS:m/z＝389[M+H]⁺。

Synthesis of 3-fluoro-5- ((2- (cyclopropylmethyl) -7-methyl-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (IB-14)

Preparation of the target Compound IB-14 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-14 to give a white solid. The yield thereof was found to be 69%;

¹H NMR(500MHz,CDCl₃)：δ7.89(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),7.23-7.21(m,1H),7.09-7.08(m,1H),6.97(dt,J＝9.5,2.5Hz,1H),3.66(d,J＝7.0Hz,2H),2.60(s,3H),1.35-1.31(m,1H),0.67-0.63(m,2H),0.49-0.45(m,2H);

ESI-MS:m/z＝387[M+H]⁺。

Synthesis of 3- ((2-allyl-7-methyl-1, 1-dioxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-15)

Preparation of the target compound IB-15 reference IB-1 synthesis. Intermediate Ij-1 was replaced with intermediate Ij-15 to give a white solid. The yield thereof was found to be 44%;

¹H NMR(500MHz,CDCl₃)：δ7.90(d,J＝8.5Hz,1H),7.54-7.52(m,1H),7.37(d,J＝8.5Hz,1H),7.36-7.35(m,1H),6.99(dt,J＝9.5,2.5Hz,1H),5.86-5.84(m,1H),5.19-5.17(m,2H),3.83(dd,J＝7.0,2.5Hz,2H),2.76(s,3H);

ESI-MS:m/z＝373[M+H]⁺。

synthesis of 3- ((2- (but-2-yn-1-yl) -7-methyl-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IB-16)

Preparation of the target Compound IB-16 reference the synthesis of intermediate IB-1. Intermediate Ij-1 was replaced with intermediate Ij-16 to give a white solid. The yield thereof was found to be 48%;

¹H NMR(500MHz,CDCl₃)：δ8.02(d,J＝8.5Hz,1H),7.74-7.72(m,1H),7.43(dt,J＝9.5,2.5Hz,1H),7.39-7.37(m,1H),7.36(d,J＝8.5Hz,1H),3.85(q,J＝7.0Hz,2H),2.76(s,3H),1.83(t,J＝7.0Hz,3H);

ESI-MS:m/z＝385[M+H]⁺。

synthesis of 6- (3-chloro-5-fluorophenoxy) -2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-17)

Preparation of the target Compound IB-17 reference Compound IB-2 was synthesized. 3-fluoro-5-hydroxybenzonitrile was replaced with 3-chloro-5-fluorophenol to give a white solid. The yield thereof was found to be 72%;

¹H NMR(500MHz,CDCl₃)：δ8.10(d,J＝8.5Hz,1H),7.54-7.52(m,1H),7.50(d,J＝8.5Hz,1H),7.48-7.47(m,1H),7.11(dt,J＝9.5,2.5Hz,1H),3.48(s,3H),2.72(s,3H);

ESI-MS:m/z＝356[M+H]⁺。

synthesis of 6- (3, 5-difluorophenoxy) -2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-18)

Preparation of the target Compound IB-18 reference the synthesis of intermediate IB-2. 3-fluoro-5-hydroxybenzonitrile is replaced by 3, 5-difluorophenol to obtain a white solid. The yield was 64%;

¹H NMR(500MHz,CDCl₃)：δ7.93(d,J＝8.5Hz,1H),7.80-7.69(m,2H),7.65(d,J＝8.5Hz,1H),7.12(dt,J＝10.0,2.5Hz,1H),3.28(s,3H),2.82(s,3H);

ESI-MS:m/z＝340[M+H]⁺。

synthesis of 6- (3-chloro-4-fluorophenoxy) -2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-19)

Preparation of the target Compound IB-19 reference the synthesis of intermediate IB-2. 3-fluoro-5-hydroxybenzonitrile was replaced with 3-chloro-4-fluorophenol to give a white solid. The yield thereof was found to be 56%;

¹H NMR(500MHz,CDCl₃)：δ8.10(d,J＝8.5Hz,1H),7.48(d,J＝8.5Hz,1H),7.33-7.31(m,2H),7.13(dt,J＝9.5,2.5Hz,1H),2.98(s,3H),2.86(s,3H);

ESI-MS:m/z＝356[M+H]⁺。

synthesis of 5- ((2, 7-dimethyl-1, 1-dioxido-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) nicotinonitrile (IB-20)

Preparation of the target Compound IB-20 reference the synthesis of intermediate IB-2. 3-fluoro-5-hydroxybenzonitrile was replaced with 3-cyano-5-hydroxypyridine to give a white solid. The yield was 70%;

¹H NMR(500MHz,CDCl₃)：δ8.98(s,1H),8.79(s,1H),8.11-8.09(m,1H),7.97(d,J＝10.0Hz,1H),7.29(d,J＝10.0Hz,1H),3.38(s,3H),2.74(s,3H);

ESI-MS:m/z＝330[M+H]⁺。

synthesis of 6- (3, 3-difluorocyclobutoxy) -2, 7-dimethylpheno [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-21)

Intermediate Ij-2 (100 mg,0.44 mmol) and 3, 3-difluorocyclobutanol (51.9 mg,0.48 mmol) were dissolved in tetrahydrofuran (2.0 mL), naH (11.8 mg,0.49 mmol) was added under ice-bath and stirred at room temperature under N ₂ protection for 2 hours until complete conversion of the starting material. The system was quenched slowly with water, extracted with ethyl acetate (5 ml×3), the combined organic layers were washed sequentially with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 87%;

¹H NMR(500MHz,CDCl₃)：δ8.14(d,J＝8.5Hz,1H),7.44(d,J＝8.5Hz,1H),6.55-6.39(m,1H),3.38(s,3H),2.74(s,3H),2.64-2.62(m,2H),2.38-2.36(m,2H);

ESI-MS:m/z＝318[M+H]⁺。

Synthesis of 6- (3, 4-difluorophenoxy) -2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-22)

Preparation of the target Compound IB-22 reference the synthesis of intermediate IB-2. 3-fluoro-5-hydroxybenzonitrile was replaced with 3, 4-difluorophenol to give a white solid. The yield was 42%;

ESI-MS:m/z＝340[M+H]⁺。

synthesis of 6- ((5-chloropyridin-3-yl) oxy-2, 7-dimethylpheno [ d ] isothiazol-3 (2H) -1, 1-dioxide (IB-23)

Preparation of the target Compound IB-23 reference the synthesis of intermediate IB-2. 3-fluoro-5-hydroxybenzonitrile was replaced with 3-chloro-5-hydroxypyridine to give a white solid. The yield was 64%;

ESI-MS:m/z＝339[M+H]⁺。

EXAMPLE 3 Compound II series

3- ((7-Bromo-3-hydroxy-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-1)

Compound IB-1 (82 mg,0.2 mmol) was dissolved in methanol/tetrahydrofuran (1 mL:2 mL) and NaBH ₄ (22.7 mg,0.6 mmol) was added slowly in portions at 0deg.C and stirred at room temperature for about 3.5 hours until complete conversion of the starting material. Dropwise adding water under ice bath to make no bubbles emerge, evaporating under reduced pressure to remove organic solvent, extracting with ethyl acetate (2 mL×3), mixing organic layers, washing with saturated NaCl, drying with anhydrous Na ₂SO₄, concentrating, and purifying by silica gel column chromatography to obtain white solid. The yield thereof was found to be 88%;

¹H NMR(500MHz,DMSO-d₆)：δ7.74-7.73(m,1H),7.69(d,J＝8.5Hz,1H),7.58(d,J＝8.5Hz,1H),7.49-7.48(m,1H),7.46(dt,J＝10.0,2.5Hz,1H),7.34(d,J＝8.0Hz,1H),5.68(d,J＝8.0Hz,1H),2.85(s,3H);

ESI-MS:m/z＝413/415[M+H]⁺。

3- ((2, 7-dimethyl-3-hydroxy-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-2)

Preparation of the target Compound II-2 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-2 to give a white solid. The yield thereof was found to be 72%;

¹H NMR(500MHz,DMSO-d₆)：δ7.68(ddd,J＝8.5,2.5,1.0Hz,1H),7.52(d,J＝8.5Hz,1H),7.41(d,J＝8.5Hz,1H),7.40–7.38(m,1H),7.36(dt,J＝10.0,2.5Hz,1H),7.15(d,J＝8.0Hz,1H),5.65(d,J＝8.0Hz,1H),2.83(s,3H),2.39(s,3H);

ESI-MS:m/z＝349[M+H]⁺。

Resolving the compound II-2 by chiral column to obtain chiral isomer S-II-2 And R-II-2

3- ((7-Chloro-3-hydroxy-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-3)

Preparation of the target Compound II-3 Synthesis of the reference Compound II-1. The compound IB-1 was replaced with the compound IB-3 to give a white solid. The yield was 95%;

¹H NMR(500MHz,DMSO-d₆)：δ7.75-7.73(m,1H),7.66(d,J＝8.5Hz,1H),7.61(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.50(dt,J＝10.0,2.5Hz,1H),7.30(d,J＝8.0Hz,1H),5.71(d,J＝8.0Hz,1H),2.85(s,3H);

ESI-MS:m/z＝369[M+H]⁺。

3-fluoro-5- ((3-hydroxy-7-methoxy-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-4)

Preparation of the target Compound II-4 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-4 to give a white solid. The yield thereof was found to be 67%;

¹H NMR(500MHz,DMSO-d₆)：δ7.97(d,J＝8.5Hz,1H),7.74(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.31-7.28(m,1H),7.27(d,J＝8.0Hz,1H),6.94(dt,J＝9.0,2.5Hz,1H),5.70(d,J＝8.0Hz,1H),3.83(s,3H),2.35(s,3H);

ESI-MS:m/z＝365[M+H]⁺。

3-fluoro-5- ((3-hydroxy-2-methyl-1, 1-dioxo-7- (trifluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-5)

Preparation of the target Compound II-5 Synthesis of the reference Compound II-1. The compound IB-1 was replaced with the compound IB-5 to give a white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,DMSO-d₆)：δ8.20(d,J＝8.5Hz,1H),7.94-7.92(m,1H),7.53-7.52(m,1H),7.46(d,J＝8.5Hz,1H),7.33(dt,J＝9.5,2.5Hz,1H),7.29(d,J＝8.0Hz,1H),5.66(d,J＝8.0Hz,1H),2.74(s,3H);

ESI-MS:m/z＝403[M+H]⁺。

3-fluoro-5- ((3-hydroxy-2-methyl-1, 1-dioxo-7- (difluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-6)

Preparation of the target Compound II-6 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-6 to give a white solid. The yield thereof was found to be 37%;

¹H NMR(500MHz,DMSO-d₆)：δ8.03-8.02(m,1H),7.79(d,J＝8.5Hz,1H),7.53-7.52(m,2H),7.46(dt,J＝10.0,2.5Hz,1H),7.28(d,J＝8.0Hz,1H),6.58(t,J＝75.5Hz,1H),6.01(d,J＝8.0Hz,1H),2.68(s,3H);

ESI-MS:m/z＝385[M+H]⁺。

the compound II-6 is resolved by chiral column to obtain chiral isomer S-II-6 And R-II-6

3-Fluoro-5- (93-hydroxy-2-methyl-7-cyano-1, 1-dioxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-7)

Preparation of the target Compound II-7 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-7 to give a white solid. The yield thereof was found to be 67%;

¹H NMR(500MHz,DMSO-d₆)：δ8.10-8.08(m,1H)7.94(d,J＝8.5Hz,1H),7.68-7.67(m,1H),7.63(d,J＝8.5Hz,1H),7.24(dt,J＝9.5,2.5Hz,1H),7.06(d,J＝8.0Hz,1H),5.86(d,J＝8.0Hz,1H),2.75(s,3H);

ESI-MS:m/z＝360[M+H]⁺。

3-fluoro-5- ((3-hydroxy-2-methyl-7-nitro-1, 1-dioxido-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-8)

Preparation of the target Compound II-8 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-8 to give a white solid. The yield thereof was found to be 37%;

¹H NMR(500MHz,DMSO-d₆)：δ8.12(d,J＝8.5Hz,1H),7.74-7.72(m,1H),7.56(d,J＝8.5Hz,1H),7.51-7.50(m,1H),7.33(d,J＝8.0Hz,1H),7.29(dt,J＝9.5,2.5Hz,1H),5.71(d,J＝8.0Hz,1H),2.74(s,3H);

ESI-MS:m/z＝380[M+H]⁺。

3- ((7-bromo-2-ethyl-3-hydroxy-1, 1-dioxido-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-9)

Preparation of the target Compound II-9 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-9 to give a white solid. The yield thereof was found to be 88%;

¹H NMR(500MHz,DMSO-d₆)：δ7.84-7.83(m,1H),7.79(d,J＝8.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.59-7.58(m,1H),7.49(dt,J＝10.0,2.5Hz,1H),7.32(d,J＝8.0Hz,1H),5.68(d,J＝8.0Hz,1H),3.43(q,J＝7.0Hz,2H),2.85(t,J＝7.0Hz,3H);

ESI-MS:m/z＝427/429[M+H]⁺。

3- ((2-ethyl-3-hydroxy-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-10)

Preparation of the target Compound II-10 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-10 to give a white solid. The yield thereof was found to be 92%;

¹H NMR(500MHz,DMSO-d₆)：δ7.69-7.66(m,1H),7.52(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.38-7.37(m,1H),7.34(dt,J＝10.0,2.5Hz,1H),7.18(d,J＝7.5Hz,1H),5.81(d,J＝7.5Hz,1H),3.36(q,J＝7.5Hz,2H),2.37(s,3H),1.29(t,J＝7.5Hz,3H);

ESI-MS:m/z＝363[M+H]⁺。

The compound II-10 is resolved by chiral column to obtain chiral isomer S-II-10 And R-II-10

3- ((2-Ethyl-3-hydroxy-7-difluoromethyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-11)

Preparation of the target Compound II-11 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-11 to give a white solid. The yield thereof was found to be 29%;

¹H NMR(500MHz,DMSO-d₆)：δ8.21-8.19(m,1H),8.05(d,J＝8.5Hz,1H),7.72-7.71(m,1H),7.71(d,J＝8.5Hz,1H),7.36(dt,J＝9.0,2.5Hz,1H),7.18(d,J＝8.0Hz,1H),6.78(t,J＝76.0Hz,1H),6.03(d,J＝8.0Hz,1H),3.36(q,J＝7.5Hz,2H),1.29(t,J＝7.5Hz,3H);

ESI-MS:m/z＝399[M+H]⁺。

The compound II-11 is resolved by chiral column to obtain chiral isomer S-II-11 And R-II-11

3-Fluoro-5- ((3-hydroxy-2-isopropyl-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (II-12)

Preparation of the target Compound II-12 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-12 to give a white solid. The yield was 33%;

¹H NMR(500MHz,DMSO-d₆)：δ7.68-7.65(m,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.36-7.35(m,1H),7.32(dt,J＝10.0,2.5Hz,1H),7.12(d,J＝8.0Hz,1H),5.95(d,J＝8.0Hz,1H),3.99-3.94(m,1H),2.35(s,3H),1.41(d,J＝7.0Hz,6H);

ESI-MS:m/z＝377[M+H]⁺。

Resolving the compound II-12 by chiral column to obtain chiral isomer S-II-12 And R-II-12

3- ((2- (Sec-butyl) -3-hydroxy-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-13)

Preparation of the target Compound II-13 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-13 to give a white solid. The yield thereof was found to be 43%;

¹H NMR(500MHz,DMSO-d₆)：δ8.01-7.98(m,1H),7.74(d,J＝8.5Hz,1H),7.43-7.42(m,1H),7.38(d,J＝8.5Hz,1H),7.20(dt,J＝10.0,2.5Hz,1H),7.09(d,J＝8.0Hz,1H),5.95(d,J＝8.0Hz,1H),2.72(s,3H),2.63-2.57(m,1H),1.48-1.42(m,2H),1.06(d,J＝1.5Hz,3H),0.94(t,J＝7.0Hz,3H);

ESI-MS:m/z＝391[M+H]⁺。

3- ((2- (cyclopropylmethyl) -3-hydroxy-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-14)

Preparation of the target Compound II-14 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-14 to give a white solid. The yield thereof was found to be 51%;

¹H NMR(500MHz,DMSO-d₆)：δ7.69-7.67(m,1H),7.54(d,J＝8.5Hz,1H),7.42(d,J＝8.5Hz,1H),7.38-7.37(m,1H),7.35(dt,J＝10.0,2.5Hz,1H),7.19(d,J＝8.0Hz,1H),5.91(d,J＝8.0Hz,1H),3.27(d,J＝7.0Hz,2H),2.38(s,3H),1.17-1.11(m,1H),0.62-0.54(m,2H),0.44-0.40(m,2H);

ESI-MS:m/z＝389[M+H]⁺。

3- ((2-allyl-3-hydroxy-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-15)

Preparation of the target Compound II-15 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-15 to give a white solid. The yield thereof was found to be 51%;

¹H NMR(500MHz,DMSO-d₆)：δ7.90(d,J＝8.5Hz,1H),7.64-7.63(m,1H),7.57-7.55(m,1H),7.47(d,J＝8.5Hz,1H),7.29(dt,J＝9.0,2.5Hz,1H),7.23(d,J＝8.0Hz,1H),5.71(d,J＝8.0Hz,1H),5.66-5.64(m,1H),5.09-5.07(m,2H),3.63-3.61(m,2H),2.28(s,3H);

ESI-MS:m/z＝375[M+H]⁺。

3- ((2- (but-2-yn-1-yl) -3-hydroxy-7-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (II-16)

Preparation of the target Compound II-16 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-16 to give a white solid. The yield thereof was found to be 29%;

¹H NMR(500MHz,DMSO-d₆)：δ8.02(d,J＝8.5Hz,1H),7.74-7.72(m,1H),7.43(dt,J＝9.5,2.5Hz,1H),7.39-7.37(m,1H),7.36(d,J＝8.5Hz,1H),7.13(d,J＝8.0Hz,1H),5.81(d,J＝8.0Hz,1H),3.85(q,J＝7.0Hz,2H),2.76(s,3H),1.83(t,J＝7.0Hz,3H);

ESI-MS:m/z＝387[M+H]⁺。

6- (3-chloro-5-fluorophenoxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-17)

Preparation of the target Compound II-17 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-17 to give a white solid. The yield thereof was found to be 89%;

¹H NMR(500MHz,DMSO-d₆)：δ8.20(d,J＝8.5Hz,1H),7.74-7.72(m,1H),7.70(d,J＝8.5Hz,1H),7.58-7.57(m,1H),7.21(dt,J＝9.5,2.5Hz,1H),7.18(d,J＝7.5Hz,1H),5.69(d,J＝7.5Hz,1H),3.48(s,3H),2.72(s,3H);

ESI-MS:m/z＝358[M+H]⁺。

resolving the compound II-17 by chiral column to obtain chiral isomer S-II-17 And R-II-17

6- (3, 5-Difluorophenoxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-18)

Preparation of the target Compound II-18 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-18 to give a white solid. The yield thereof was found to be 77%;

¹H NMR(500MHz,DMSO-d₆)：δ7.98(d,J＝8.5Hz,1H),7.75(d,J＝8.5Hz,1H),7.73-7.64(m,2H),7.20(d,J＝7.5Hz,1H),7.12(dt,J＝10.0,2.5Hz,1H),5.92(d,J＝7.5Hz,1H),3.28(s,3H),2.82(s,3H);

ESI-MS:m/z＝342[M+H]⁺。

Resolving the compound II-18 by chiral column to obtain chiral isomer S-II-18 And R-II-18

6- (3-Chloro-4-fluorophenoxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-19)

Preparation of the target Compound II-19 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-19 to give a white solid. The yield thereof was found to be 82%;

¹H NMR(500MHz,DMSO-d₆)：δ8.10(d,J＝8.5Hz,1H),7.58(d,J＝8.5Hz,1H),7.33-7.31(m,2H),7.13(dt,J＝9.5,2.5Hz,1H),7.11(d,J＝10.0Hz,1H),5.72(d,J＝10.0Hz,1H),2.98(s,3H),2.86(s,3H);

ESI-MS:m/z＝358[M+H]⁺。

5- ((3-hydroxy-2, 7-dimethyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) nicotinonitrile (II-20)

Preparation of the target Compound II-20 Synthesis of the reference Compound II-1. The compound IB-1 was replaced with the compound IB-20 to give a white solid. The yield was 64%;

¹H NMR(500MHz,DMSO-d₆)：δ8.98(s,1H),8.71-8.69(m,1H),8.59(s,1H),7.97(d,J＝10.0Hz,1H),7.29(d,J＝10.0Hz,1H),7.21(d,J＝8.5Hz,1H),5.92(d,J＝8.5Hz,1H),3.38(s,3H),2.74(s,3H);

ESI-MS:m/z＝332[M+H]⁺。

6- (3, 3-Difluorocyclobutoxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-21)

Preparation of the target Compound II-21 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-21 to give a white solid. The yield was 42%;

¹H NMR(500MHz,DMSO-d₆)：δ8.14(d,J＝8.5Hz,1H),7.64(d,J＝8.5Hz,1H),7.21(d,J＝9.5Hz,1H),6.75-6.69(m,1H),5.92(d,J＝9.5Hz,1H),3.38(s,3H),2.74(s,3H),2.64-2.62(m,2H),2.38-2.36(m,2H);

ESI-MS:m/z＝320[M+H]⁺。

6- (3, 4-difluorophenoxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-22)

Preparation of the target Compound II-22 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-22 to give a white solid. The yield thereof was found to be 71%;

¹H NMR(500MHz,CDCl₃)δ7.41(d,J＝8.5Hz,1H),7.18–7.12(m,1H),7.11(d,J＝8.5Hz,1H),6.78-6.82(m,1H),6.64-6.68(m,1H),5.51(s,1H),3.01(s,3H),2.53(s,3H).

ESI-MS:m/z＝342[M+H]⁺。

6- ((5-chloropyridin-3-yl) oxy) -3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (II-23)

Preparation of the target Compound II-23 reference Synthesis of Compound II-1. The compound IB-1 was replaced with the compound IB-23 to give a white solid. The yield thereof was found to be 63%;

¹H NMR(500MHz,CDCl₃)δ8.36(d,J＝2.0Hz,1H),8.24(d,J＝2.5Hz,1H),7.48(d,J＝8.5Hz,1H),7.22(t,J＝2.5Hz,1H),7.19(d,J＝8.5Hz,1H),5.55(s,1H),3.04(s,3H),2.55(s,3H).

ESI-MS:m/z＝341[M+H]⁺。

EXAMPLE 4 Compound III series

3- ((7-Bromo-3-fluoro-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (III-1)

Compound II-1 (50 mg,0.12 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), diethylaminosulfur trifluoride (47.6. Mu.L, 0.36 mmol) was added dropwise under ice-bath, and stirred at room temperature overnight. Dropwise adding water under ice bath to make no bubbles emerge, evaporating under reduced pressure to remove organic solvent, extracting with ethyl acetate (2 mL×3), mixing organic layers, washing with saturated NaCl, drying with anhydrous Na ₂SO₄, concentrating, and purifying by silica gel column chromatography to obtain white solid. The yield thereof was found to be 51%;

¹H NMR(500MHz,DMSO-d₆)：δ7.73-7.71(m,1H),7.58(d,J＝8.5,1H),7.54(d,J＝8.5,1H),7.53-7.52(m,1H),7.48(dt,J＝10.0,2.5Hz,1H),5.45(d,J＝46.5Hz,1H),2.86(s,3H);

ESI-MS:m/z＝415/417[M+H]⁺。

3-fluoro-5- ((3-fluoro-2, 7-dimethyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (III-2)

Preparation of the target Compound III-2 Synthesis of the reference Compound III-1. The compound II-1 was replaced with the compound II-2 to give a white solid. The yield was 64%;

¹H NMR(500MHz,DMSO-d₆)：δ7.98(d,J＝8.5,1H),7.53-7.51(m,1H),7.44(d,J＝8.5,1H),7.43-7.42(m,1H),7.28(dt,J＝9.5,2.5Hz,1H),5.75(d,J＝46.5Hz,1H),3.43(s,3H),2.86(s,3H);

ESI-MS:m/z＝351[M+H]⁺。

resolving the compound III-2 by chiral column to obtain chiral isomer S-III-2 And R-III-2

3- ((7-Chloro-3-fluoro-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (III-3)

Preparation of the target Compound III-3 Synthesis of the reference Compound III-1. The compound II-1 was replaced with the compound II-3 to give a white solid. The yield thereof was found to be 44%;

¹H NMR(500MHz,DMSO-d₆)：δ7.93-7.91(m,1H),7.54-7.53(m,1H),7.37(d,J＝8.5Hz,1H),7.32(d,J＝8.5Hz,1H),7.22(dt,J＝9.5,2.5Hz,1H),5.83(d,J＝46.5Hz,1H),3.43(s,3H);

ESI-MS:m/z＝371[M+H]⁺。

3-fluoro-5- ((3-fluoro-7-methoxy-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (III-4)

Preparation of the target Compound III-4 Synthesis of the reference Compound III-1. The compound II-1 was replaced with the compound II-4 to give a white solid. The yield thereof was found to be 52%;

¹H NMR(500MHz,DMSO-d₆)：δ8.03-8.01(m,1H),7.83-7.82(m,1H),7.38(d,J＝8.5Hz,1H),7.17(d,J＝8.5Hz,1H),7.28(dt,J＝9.5,2.5Hz,1H),5.74(d,J＝46.5Hz,1H),3.93(s,3H),3.24(s,3H);

ESI-MS:m/z＝367[M+H]⁺。

3- ((7- (difluoromethyl) -3-fluoro-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (III-5)

Preparation of the target Compound III-5 Synthesis of the reference Compound III-1. The compound II-1 was replaced with the compound II-6 to give a white solid. The yield thereof was found to be 38%;

¹H NMR(500MHz,DMSO-d₆)：δ7.88(d,J＝8.5,1H),7.63-7.61(m,1H),7.37-7.32(m,2H),7.28(dt,J＝9.5,2.5Hz,1H),6.47(t,J＝76.0Hz,1H),5.88(d,J＝46.5Hz,1H),3.32(s,3H);

ESI-MS:m/z＝387[M+H]⁺。

Resolving the compound III-5 by chiral column to obtain chiral isomer S-III-5 And R-III-5

EXAMPLE 5 Compound IV series

3- ((7-Bromo-3-cyano-2-methyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (IV-1)

Compound II-1 (50 mg,0.12 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), BF ₃·Et₂ O (14.8. Mu.L, 0.12 mmol) and TMSCN (23.8 mg,0.24 mmol) were added at-78deg.C under N ₂ and stirring continued for 1 hour until complete conversion of the starting material. The reaction system was quenched with aqueous NaHCO ₃, extracted with dichloromethane (2 ml×3), the organic layers were combined, washed sequentially with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 90%;

¹H NMR(500MHz,DMSO-d₆)：δ8.08-8.06(m,1H),7.55-7.54(m,1H),7.43(d,J＝8.5Hz,1H),7.27(d,J＝8.5Hz,1H),7.21(dt,J＝9.5,2.5Hz,1H),4.91(s,1H),2.66(s,3H);

ESI-MS:m/z＝422/424[M+H]⁺。

6- (3-cyano-5-fluorophenoxy) -2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-3-carbonitrile-1, 1-dioxide (IV-2)

Preparation of the target Compound IV-2 Synthesis of the reference Compound IV-1. The compound II-1 was replaced with the compound II-2 to give a white solid. The yield thereof was found to be 79%;

¹H NMR(500MHz,DMSO-d₆)：δ7.98-7.96(m,1H),7.71(d,J＝8.5Hz,1H),7.53-7.52(m,1H),7.49(d,J＝8.5Hz,1H),7.28(dt,J＝9.0,2.5Hz,1H),4.87(s,1H),3.24(s,3H),2.66(s,3H);

ESI-MS:m/z＝358[M+H]⁺。

Resolving the compound IV-2 by chiral column to obtain chiral isomer S-IV-2 And R-IV-2

6- (3-Cyano-5-fluorophenoxy) -7- (difluoromethyl) -2-methyl-2, 3-dihydrobenzo [ d ] isothiazole-3-carbonitrile-1, 1-dioxide (IV-3)

Preparation of the target Compound IV-3 Synthesis of the reference Compound IV-1. The compound II-1 was replaced with the compound II-6 to give a white solid. The yield was 85%;

¹H NMR(500MHz,DMSO-d₆)：δ8.01-7.98(m,1H),7.79(d,J＝8.5Hz,1H),7.55-7.51(m,2H),7.18(dt,J＝9.0,2.5Hz,1H),6.55(t,J＝75.5Hz,1H),4.91(s,1H),3.45(s,3H);

ESI-MS:m/z＝394[M+H]⁺。

EXAMPLE 6 Compound V series

Step 1: synthesis of 7-bromo-6-fluoro-2-methylbenzo [ d ] isothiazol-3 (2H) -thione 1, 1-dioxide (Va-1)

Intermediate Ij-1 (50 mg,0.17 mmol) and lawson reagent (56.6 mg,0.14 mmol) were dissolved in anhydrous toluene (1.0 mL) and warmed to reflux under N ₂ protection for about 2 hours until complete conversion of starting material. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow solid. Yield is as follows 67％;¹HNMR(500MHz,CDCl₃)：δ8.22(dd,J＝8.5,4.0Hz,1H),7.50(t,J＝8.5Hz,1H),3.55(s,3H);ESI-MS:m/z＝310/312[M+H]⁺.

Synthesis of 6-fluoro-2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -thione 1, 1-dioxide (Va-2)

Preparation of intermediate Va-2 reference was made to the synthesis of intermediate Va-1. Intermediate Ij-1 was replaced with intermediate Ij-2 to give a yellow solid. The yield thereof was found to be 88%;

¹HNMR(500MHz,CDCl₃)：δ8.10(dd,J＝8.5,4.5Hz,1H),7.40(t,J＝8.5Hz,1H),3.52(s,3H),2.62(d,J＝1.5Hz,3H);

ESI-MS:m/z＝246[M+H]⁺。

step 2: synthesis of 3- ((7-bromo-2-methyl-1, 1-dioxo-3-thioxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (V-1)

Intermediate Va-1 (31 mg,0.10 mmol) and 3-fluoro-5-hydroxybenzonitrile (15.1 mg,0.11 mmol) were dissolved in DMF (1.0 mL) and K ₂CO₃ (34.6 mg,0.25 mmol) was added and the temperature was raised to 80℃and stirred until complete conversion of the starting material. Cooled to room temperature, water (5 mL) was added, extracted with ethyl acetate (5 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a yellow solid. The yield thereof was found to be 57%;

¹H NMR(500MHz,CDCl₃)：δ8.22(d,J＝8.5Hz,1H),7.30(d,J＝8.5Hz,1H),7.27-7.24(m,1H),7.13-7.12(m,1H),7.02(dt,J＝9.0,2.5Hz,1H),3.57(s,3H);

ESI-MS:m/z＝427/429[M+H]⁺。

Synthesis of 3- ((2, 7-dimethyl-1, 1-dioxido-3-thioxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (V-2)

Preparation of the target Compound V-2 Synthesis of the reference Compound V-1. Intermediate Va-1 was replaced with intermediate Va-2 to give a yellow solid. The yield thereof was found to be 73%;

¹H NMR(500MHz,CDCl₃)：δ8.12(d,J＝8.5Hz,1H),7.23(d,J＝8.5Hz,1H),7.22-7.21(m,1H),7.10-7.09(m,1H),6.97(dt,J＝9.51,2.5Hz,1H),3.55(s,3H),2.61(s,3H);

ESI-MS:m/z＝363[M+H]⁺。

EXAMPLE 7 Compound VI series

3- ((7-Bromo-3, 3-difluoro-2-methyl-1, 1-dioxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (VI-1)

Compound V-1 (30 mg,0.07 mmol) and tetrabutylammonium bifluoride (67. Mu.L, 0.21 mmol) were dissolved in anhydrous dichloromethane (0.5 mL), NBS (28.6 mg,0.16 mmol) was added under ice-bath, and stirred at room temperature overnight. The system was added with a mixed solution (1.5 mL) of NaHCO ₃-NaHSO₃ (0.1M-0.1M), extracted with dichloromethane (2 mL. Times.3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 53%;

¹HNMR(500MHz,CDCl₃):δ8.01(d,J＝8.5Hz,1H),7.31(d,J＝8.5Hz,1H),7.28-7.26(m,1H),7.14-7.13(m,1H),7.04(dt,J＝9.0,2.5Hz,1H),3.31(s,3H);

ESI-MS:m/z＝433/435[M+H]⁺。

3- ((3, 3-difluoro-2, 7-dimethyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (VI-2)

Preparation of the target Compound VI-2 Synthesis of the reference Compound VI-1. Intermediate V-1 was replaced with intermediate V-2 to give a white solid. The yield was 65%;

¹HNMR(500MHz,DMSO-d₆)：δ7.93(d,J＝8.5Hz,1H),7.80-7.78(m,1H),7.67-7.64(m,1H),7.62(dt,J＝10.0,2.5Hz,1H),7.44(d,J＝8.5Hz,1H),3.18(s,3H),2.53(s,3H);

ESI-MS:m/z＝369[M+H]⁺。

EXAMPLE 8 Compound VII series (without CN group and unsaturated carbon double and triple bond)

6- (3, 5-Difluorophenoxy) -3-hydroxy-3, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (VII-1)

Compound IA-3 (33 mg,0.11 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL), and a tetrahydrofuran solution of methyl magnesium bromide (80. Mu.L, 0.24 mmol) was added dropwise under the protection of N ₂, and stirred overnight at room temperature. The system was quenched by dropwise addition of saturated NH ₄ Cl solution, extracted with dichloromethane (2 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by column chromatography on silica gel to give a white solid. The yield thereof was found to be 78%;

¹HNMR(500MHz,DMSO-d₆)：δ7.82(d,J＝8.0Hz,1H),7.52-7.47(m,3H),7.11-7.04(m,1H),5.12(s,1H),3.31(s,3H),1.63(s,3H);

ESI-MS:m/z＝342[M+H]⁺。

6- (3, 5-difluorophenoxy) -3-hydroxy-2, 3, 7-trimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (VII-2)

Preparation of the target Compound VII-2 reference Compound VII-1 was synthesized. Replacement of compound IA-3 with compound IB-18 gives a white solid. The yield thereof was found to be 67%;

¹HNMR(500MHz,DMSO-d₆)：δ7.72(d,J＝8.5Hz,1H),7.58-7.53(m,3H),7.31(dt,J＝9.5,2.5Hz,1H),6.12(s,1H),3.31(s,3H),2.56(s,3H),1.53(s,3H);

ESI-MS:m/z＝356[M+H]⁺。

Resolving the compound VII-2 by chiral column to obtain chiral isomer S-VII-2 And R-VII-2

6- (3, 5-Difluorophenoxy) -3-ethyl-3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (VII-3)

Preparation of the target Compound VII-3 reference Synthesis of Compound VII-2. Methyl magnesium bromide was replaced with ethyl magnesium bromide to give a white solid. The yield thereof was found to be 52%;

¹HNMR(500MHz,DMSO-d₆)：δ7.95(d,J＝8.5Hz,1H),7.67-7.61(m,3H),7.28-7.23(m,1H),5.28(s,1H),3.38(s,3H),2.26(s,3H),1.89(q,J＝7.0Hz,2H),0.89(t,J＝7.0Hz,3H);

ESI-MS:m/z＝370[M+H]⁺。

EXAMPLE 9 Compound VIII series (R ₄＝CF₃、CF₂H、CF₂CF₃)

Step 1: synthesis of 3-fluoro-2-methylbenzenesulfonyl chloride (VIIIa-1)

Preparation of intermediate VIIIa-1 reference was made to the synthesis of intermediate If-1. Intermediate Ie-1 was replaced with 3-fluoro-2-methylaniline to give a yellow oil which was used in the next step without further purification. The yield was 80%; ESI-MS: m/z=209 [ M+H ] ⁺.

Step 2: synthesis of 3-fluoro-N, 2-dimethylbenzenesulfonamide (VIIIb-1)

Intermediate VIIIa-1 (2.0 g,9.61 mmol) was dissolved in dichloromethane (30 mL), aqueous methylamine (562.2. Mu.L, 11.53 mmol) and triethylamine (2.67 mL,19.22 mmol) were added and stirred at room temperature for 4 hours. The pH was adjusted to neutrality with 2N HCl, the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate (2 mL. Times.3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated, and purified by silica gel column chromatography to give a white solid. The yield was 85%;

ESI-MS:m/z＝204[M+H]⁺。

Step 3: synthesis of 3-fluoro-N, 2-dimethyl-6- (2, 2-trifluoroacetyl) benzenesulfonamide (VIIIc-1)

Intermediate VIIIb-1 (1.5 g,7.39 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), N-BuLi (1.74 mL,18.48 mmol) was slowly added dropwise at-78 ℃ under N ₂ protection, after stirring for 0.5 hours CF ₃ COOEt (2.64 mL,22.17 mmol) was slowly added dropwise, and the reaction was gradually warmed to room temperature for about 6 hours. The reaction was quenched with 5% hcl solution, the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate (2 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated to give a white solid, and the crude product was further purified without further purification.

ESI-MS:m/z＝300[M+H]⁺。

Synthesis of 6- (2, 2-difluoroacetyl) -3-fluoro-N, 2-dimethylbenzenesulfonamide (VIIIc-2)

The preparation of intermediate VIIIc-2 refers to the synthesis of VIIIc-1. The CF ₃ COOEt was replaced with CF ₂ HCOOEt to give a white solid, the crude product was further purified;

ESI-MS:m/z＝282[M+H]⁺。

Synthesis of 3-fluoro-N, 2-dimethyl-6- (2, 3-pentafluoropropionyl) benzenesulfonamide (VIIIc-3)

Preparation of intermediate VIIIc-3 refers to the synthesis of VIIIc-1. The CF ₃ COOEt was replaced with CF ₃CF₂ COOEt to give a white solid, the crude product was further purified;

ESI-MS:m/z＝350[M+H]⁺。

step 4: synthesis of 6-fluoro-3-hydroxy-2, 7-dimethyl-3- (trifluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (VIIId-1)

Intermediate VIIIc-1 (1.0 g,4.93 mmol) was dissolved in toluene (15 mL), a solution of trifluoroacetic acid (1.83 mL,24.65 mmol) in toluene (10 mL) was added and the temperature was raised to reflux for about 3 hours until complete conversion of the starting material. The system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, extracted with dichloromethane (15 ml×3), the organic layers were combined, washed successively with saturated NaHCO ₃, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 54%;

ESI-MS:m/z＝300[M+H]⁺。

Synthesis of 3- (difluoromethyl) -6-fluoro-3-hydroxy-2, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole 1, 1-dioxide (VIIId-2)

Preparation of intermediate VIIID-2 refers to the synthesis of VIIID-1. Intermediate VIIIc-1 was replaced with intermediate VIIIc-2 to give a white solid. The yield was 45%;

ESI-MS:m/z＝282[M+H]⁺。

Synthesis of 6-fluoro-3-hydroxy-2, 7-dimethyl-3- (perfluoroethyl) -2, 3-dihydrobenzo [ d ] isothiazole 1, 1-dioxide (VIIId-3)

Preparation of intermediate VIIID-3 refers to the synthesis of VIIID-1. Intermediate VIIIc-1 was replaced with intermediate VIIIc-3 to give a white solid. The yield thereof was found to be 63%;

ESI-MS:m/z＝350[M+H]⁺。

Step 5: synthesis of 3-fluoro-5- ((3-hydroxy-2, 7-dimethyl-1, 1-dioxido-3- (trifluoromethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (VIII-1)

Intermediate VIIId-1 (600 mg,2.01 mmol) and 3-fluoro-5-hydroxybenzonitrile (302.6 mg,2.21 mmol) were dissolved in DMF (10 mL), K ₂CO₃ (694.5 mg,5.03 mmol) was added, and the temperature was raised to 60 ℃ and stirred until complete conversion of the starting material. Cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (50 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 38%;

¹HNMR(500MHz,DMSO-d₆)：δ7.93-7.91(m,1H),7.71(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.39(d,J＝8.5Hz,1H),7.24(dt,J＝9.0,2.5Hz,1H),5.31(s,1H),3.31(s,3H),2.35(s,3H);

ESI-MS:m/z＝417[M+H]⁺。

Synthesis of 3- ((3- (difluoromethyl) -3-hydroxy-2, 7-dimethyl-1, 1-dioxide-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (VIII-2)

Preparation of target Compound VIII-2 reference compound VIII-1 synthesis. Intermediate VIIID-1 was replaced with intermediate VIIID-2 to give a white solid. The yield thereof was found to be 38%;

¹HNMR(500MHz,DMSO-d₆)：δ7.98(d,J＝8.5Hz,1H),7.93-7.91(m,1H),7.64-7.63(m,1H),7.29(d,J＝8.5Hz,1H),7.26(dt,J＝9.0,2.5Hz,1H),5.49(t,J＝76.0Hz,1H),5.29(s,1H),3.48(s,3H),2.44(s,3H);

ESI-MS:m/z＝399[M+H]⁺。

resolving the compound VIII-2 by chiral column to obtain chiral isomer S-VIII-2 And R-VIII-2

Synthesis of 3-fluoro-5- ((3-hydroxy-2, 7-dimethyl-1, 1-dioxido-3- (perfluoroethyl) -2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) benzonitrile (VIII-3)

Preparation of target Compound VIII-3 reference Synthesis of Compound VIII-1. Intermediate VIIID-1 was replaced with intermediate VIIID-3 to give a white solid. The yield thereof was found to be 38%;

¹HNMR(500MHz,DMSO-d₆)：δ8.11(d,J＝8.5Hz,1H),7.71-7.69(m,1H),7.59(d,J＝8.5Hz,1H),7.54-7.53(m,1H),7.34(dt,J＝9.0,2.5Hz,1H),5.19(s,1H),3.54(s,3H),2.67(s,3H);

ESI-MS:m/z＝467[M+H]⁺。

EXAMPLE 10 Compound IX series (without CN group and R ₄＝R₅. Noteq.H)

Step 1: synthesis of 3-chloro-6- (3, 5-difluorophenoxy) -7-methylbenzo [ d ] isothiazole-1, 1-dioxide (IXa-1)

Compound IA-3 (200 mg,0.62 mmol), thionyl chloride (66.9. Mu.L, 0.94 mmol) and catalytic amount of DMF (8.3. Mu.L) were dissolved in dioxane (3.0 mL) and warmed to reflux and stirred for 48 hours. Cooling to room temperature, evaporating the organic solvent under reduced pressure, and recrystallizing the residue with toluene to obtain yellow solid. The yield was 85%;

ESI-MS:m/z＝344[M+H]⁺。

Step 2: synthesis of 6- (3, 5-difluorophenoxy) -3,3,7-trimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (IXA-1)

Compound IXa-1 (150 mg,0.44 mmol) was dissolved in anhydrous tetrahydrofuran (2.0 mL), and a tetrahydrofuran solution of methyl magnesium bromide (587.4. Mu.L, 1.76 mmol) was added dropwise under N ₂ protection, and the mixture was stirred at 40℃for about 3 hours until the starting material was completely converted. The system was quenched by dropwise addition of saturated NH ₄ Cl solution in ice bath, extracted with diethyl ether (5 ml×3), combined with the organic layer, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 82%;

¹HNMR(500MHz,DMSO-d₆)：δ7.95(d,J＝8.5Hz,1H),7.45-7.39(m,3H),7.28-7.25(m,1H),3.38(s,3H),1.25(s,6H);

ESI-MS:m/z＝340[M+H]⁺。

Step 3: synthesis of 6- (3, 5-difluorophenoxy) -2,3,3,7-tetramethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (IXB-1)

Intermediate IXA-1 (100 mg,0.29 mmol) and K ₂CO₃ (100.2 mg,0.73 mmol) were dissolved in DMF (2.0 mL) and CH ₃ I (28.6. Mu.L, 0.44 mmol) was added dropwise and the reaction was warmed to 60℃until complete conversion of starting material. Cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 32%;

¹HNMR(500MHz,CDCl₃)：δ8.05(d,J＝8.5Hz,1H),7.65-7.59(m,3H),7.38-7.35(m,1H),3.34(s,3H),2.66(s,3H),1.28(s,6H);

ESI-MS:m/z＝354[M+H]⁺。

EXAMPLE 11 Compound X series

Step 1: synthesis of 6- (3, 5-difluorophenoxy) -3, 7-dimethylbenzo [ d ] isothiazole-1, 1-dioxide (Xa-1)

Compound VII-1 (200 mg,0.59 mmol) was dissolved in toluene (2.0 mL), p-toluenesulfonic acid (101.6 mg,0.59 mmol) was added, and the temperature was raised to reflux overnight. The mixture was cooled to room temperature, the organic solvent was evaporated under reduced pressure, a saturated NH ₄ Cl solution (1.5 mL) was added to the residue, extracted with dichloromethane (3 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 70%;

ESI-MS:m/z＝324[M+H]⁺。

step 2: synthesis of 6- (3, 5-difluorophenoxy) -3, 7-dimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (XA-1)

Intermediate Xa-1 (100 mg,0.31 mmol) was dissolved in tetrahydrofuran (2.0 mL) and NaBH ₄ (46.9 mg,1.24 mmol) was added slowly in portions at 0deg.C and stirred at room temperature for 24 hours until complete conversion of the starting material. Dropwise adding water under ice bath to make no bubbles emerge, evaporating under reduced pressure to remove organic solvent, extracting with ethyl acetate (2 mL×3), mixing organic layers, washing with saturated NaCl, drying with anhydrous Na ₂SO₄, concentrating, and purifying by silica gel column chromatography to obtain white solid. The yield thereof was found to be 49%;

¹HNMR(500MHz,DMSO-d₆)：δ7.95(d,J＝8.5Hz,1H),7.55-7.49(m,3H),7.38-7.35(m,1H),4.05(q,J＝7.0Hz,1H),3.26(s,3H),1.27(d,J＝7.0Hz,3H);

ESI-MS:m/z＝326[M+H]⁺。

Step 3: synthesis of 6- (3, 5-difluorophenoxy) -2,3, 7-trimethyl-2, 3-dihydrobenzo [ d ] isothiazole-1, 1-dioxide (XB-1)

Compound XA-1 (33 mg,0.10 mmol) and K ₂CO₃ (35.1 mg,0.25 mmol) were dissolved in DMF (1.0 mL), CH ₃ I (9.8. Mu.L, 0.15 mmol) was added dropwise and the mixture was warmed to 60℃and reacted overnight. Cooled to room temperature, water (5 mL) was added, extracted with ethyl acetate (5 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 57%;

¹HNMR(500MHz,DMSO-d₆)：δ7.85(d,J＝8.5Hz,1H),7.35-7.29(m,3H),7.28-7.26(m,1H),4.17(q,J＝7.0Hz,1H),3.44(s,3H),2.43(s,3H),1.29(d,J＝7.0Hz,3H);

ESI-MS:m/z＝340[M+H]⁺。

EXAMPLE 12 Compound XI series

Step 1: synthesis of methyl 4-fluoro-3-methyl-2-sulfamoylbenzoate (XIa-1)

Intermediate Ig-2 (5.0 g,23.3 mmol) was dissolved in anhydrous methanol (25 mL), concentrated sulfuric acid (0.5 mL) was added dropwise, and the reaction was warmed to reflux overnight. Cooling to room temperature, precipitating solid, suction filtering, washing filter cake with water, and vacuum drying to obtain white solid. The yield was 65%;

ESI-MS:m/z＝248[M+H]⁺。

step 2: synthesis of methyl 2- (N- (t-butyldimethylsilyl) -S-chlorosulfonyl) -4-fluoro-3-methylbenzoate (XIb-1)

Intermediate XIa-1 (3.5 g,14.2 mmol), TBS-Cl (2.52 g,16.7 mmol) and TEA (5.94 mL,42.6 mmol) were dissolved in dichloromethane (50 mL) and stirred overnight at room temperature. Obtaining a system A, and cooling to 0 ℃; ph ₃ P (4.38 g,16.7 mmol) and hexachloroethane (3.95 g,16.7 mmol) were dissolved in chloroform (30 mL) and reacted for 6 hours at 85℃with N ₂. Thus, system B was obtained, which was cooled to 0 ℃.

Adding the system B into the system A in ice bath, heating to 35 ℃ for reaction for 10 hours until the raw materials are completely converted. Cooled to room temperature, the organic solvent was distilled off under reduced pressure, and the crude product was carried forward without further purification.

ESI-MS:m/z＝380[M+H]⁺。

Step 3: synthesis of 1- ((tert-butyldimethylsilyl) imino) -6-fluoro-2, 7-dimethyl-1, 2-dihydro-3H-1λ ⁴ -benzo [ d ] isothiazol-3-one 1-oxide (XIc-1)

Intermediate XIb-1 (400 mg,1.06 mmol) was dissolved in dichloromethane (4.0 mL), aqueous methylamine (62.0. Mu.L, 1.28 mmol) and triethylamine (294.6. Mu.L, 2.12 mmol) were added and stirred at room temperature until complete conversion of the starting material. The system was added with saturated NaCl solution, extracted with dichloromethane (4 mL. Times.3), the organic layers were combined, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 36%;

ESI-MS:m/z＝343[M+H]⁺。

Step 4: synthesis of 3- (((1- ((tert-butyldimethylsilyl) imino) -2, 7-dimethyl-1-oxo-3-oxo-2, 3-dihydro-1H-1λ ⁴ -benzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (XId-1)

Intermediate XIc-1 (120 mg,0.35 mmol) and 3-fluoro-5-hydroxybenzonitrile (52.9 mg,0.39 mmol) were dissolved in DMF (2.0 mL) and K ₂CO₃ (120.9 mg,0.88 mmol) was added and the temperature was raised to 80℃and stirred until complete conversion of the starting material. Cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (15 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 77%;

ESI-MS:m/z＝460[M+H]⁺。

Step 5: synthesis of 3-fluoro-5- (((1-imino-2, 7-dimethyl-1-oxo-3-oxo-2, 3-dihydro-1H-1λ ⁴ -benzo [ d ] isothiazol-6-yl) oxy) benzonitrile (XI-1)

To intermediate XId-1 (100 mg,0.22 mmol) was added a solution of 0.25M HCl in methanol/water (4:1) (1.0 mL) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow solid. The yield thereof was found to be 92%;

¹HNMR(500MHz,DMSO-d₆)：δ8.02(d,J＝8.5Hz,1H),7.53(d,J＝8.5Hz,1H),7.28-7.26(m,1H),7.14-7.13(m,1H),7.04(dt,J＝9.0,2.5Hz,1H),5.72(s,1H),3.31(s,3H),2.81(s,3H);

ESI-MS:m/z＝346[M+H]⁺。

EXAMPLE 13 Compound XII series

Step 1: synthesis of 2,2' -dithiodiylbis (4-fluoro-3-methylbenzoic acid) (XIIa-1)

Intermediate Id-2 (3.0 g,12.9 mmol) was added to a 9N HCl (6.2 mL) solution, and a 40% NaNO ₂ solution (2.2 mL,16.7 mmol) was added dropwise with ice bath stirring, keeping the temperature at 0-5℃and stirring continued for 0.5 hours to obtain a diazonium salt solution for use.

Sodium sulfide nonahydrate (3.4 g,14.1 mmol) and sublimed sulfur (451.2 mg,14.1 mmol) were dissolved in boiling water (5.0 mL), 10M NaOH solution (1.3 mL) was added, and the mixture was cooled to 0℃to obtain a sodium polysulfide solution for use.

Dropwise adding the diazonium salt solution into the sodium polysulfide solution in an ice bath, and reacting at room temperature until nitrogen is not generated any more. Adding concentrated hydrochloric acid for acidification, separating out solid, carrying out suction filtration, heating and refluxing a filter cake in 30% Na ₂CO₃ solution (25 mL), carrying out suction filtration, adding concentrated hydrochloric acid into filtrate for acidification, separating out solid, carrying out suction filtration, washing with water, and carrying out vacuum drying to obtain white solid. The yield was 86.0%;

ESI-MS:m/z＝371[M+H]⁺。

step 2: synthesis of dimethyl 2,2' -dithiodialkylbis (4-fluoro-3-methylbenzoate) (XIIb-1)

Compound XIIa-1 (3.50 g,9.46 mmol) was dissolved in anhydrous methanol (30.00 mL), concentrated sulfuric acid (4.13 mL) was added dropwise, and the mixture was warmed to reflux overnight. Cooled to room temperature, the system was poured into a K ₂CO₃/ice water mixture (15.00 g,30.00 mL), the organic solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane (30 mL. Times.3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, and concentrated to give a white solid. The yield thereof was found to be 92.0%;

ESI-MS:m/z＝399[M+H]⁺。

step 3: synthesis of 6-fluoro-2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -one (XIIC-1)

To a carbon tetrachloride solution (15.00 mL) of intermediate XIIB-1 (3.00 g,7.54 mmol) was added dropwise a carbon tetrachloride solution (6.00 mL) of Br ₂ (1.29 g,8.29 mmol), and after stirring at room temperature for 0.5 hours, the system was added dropwise to a carbon tetrachloride solution (6 mL) containing aqueous methylamine (438.40. Mu.l, 9.05 mmol) and triethylamine (1.26 mL,9.05 mmol), and the reaction mixture was stirred at room temperature for 1 hour and then heated at reflux to complete conversion of the starting material. Cooled to room temperature, the system was added with water (45 mL), extracted with dichloromethane (50 ml×3), the organic layers were combined, washed with saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield was 24.0%;

ESI-MS:m/z＝198[M+H]⁺。

step 4: synthesis of 6-fluoro-2, 7-dimethylbenzo [ d ] isothiazol-3 (2H) -one-1-oxide (XIId-1)

Intermediate XIIC-1 (300.00 mg,1.52 mmol) was dissolved in acetic acid (8.00 mL), 50% H ₂O₂ (0.54 mL) was added dropwise, and the temperature was raised to 50℃for reaction for 6 hours. Cooling to room temperature, separating out solid, suction filtering, sequentially washing with acetic acid (2 mL×2), water, vacuum drying, and recrystallizing the crude product with acetone-isopropanol to obtain yellow solid. The yield was 85.0%;

ESI-MS:m/z＝214[M+H]⁺。

Step 5: synthesis of 3- ((2, 7-dimethyl-1-oxo-3-oxo-2, 3-dihydrobenzo [ d ] isothiazol-6-yl) oxy) -5-fluorobenzonitrile (XII-1)

Intermediate XIId-1 (200.00 mg,0.94 mmol) and 3-fluoro-5-hydroxybenzonitrile (141.60 mg,1.03 mmol) were dissolved in DMF (3.00 mL) and K ₂CO₃ (324.80 mg,2.35 mmol) was added and the temperature was raised to 80℃and stirred until complete conversion of the starting material. Cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (15 ml×3), the organic layers were combined, washed with water, saturated NaCl, dried over anhydrous Na ₂SO₄, concentrated and purified by silica gel column chromatography to give a white solid. The yield thereof was found to be 27%;

¹HNMR(500MHz,DMSO-d₆)：δ8.03(d,J＝8.5Hz,1H),7.73-7.71(m,1H),7.69(d,J＝8.5Hz,1H),7.52-7.51(m,1H),7.33(dt,J＝9.5,2.5Hz,1H),2.74(s,3H),2,33(s,3H);

ESI-MS:m/z＝331[M+H]⁺。

EXAMPLE 14 VEGF ELISA Activity test of the Compounds of the invention

The VEGF protein inhibitory activity of some of the above compounds on human renal clear cell carcinoma cell line 786-O was evaluated using VEGF ELISA ASSAY, and other compounds of the present invention have similar beneficial effects to those listed below, but this should not be construed as compounds of the present invention having only the following beneficial effects.

786-O cells in the logarithmic growth phase were seeded in 96-well plates (FISHER SCIENTIFIC), 7500 cells per well (180. Mu.L/well), and after 4 hours of culture, 20. Mu.L of different concentration compound stock solutions were added to each well to give the final concentration as follows (. Mu.M): 20,6.67,2.22,0.74,0.25,0.082,0.027,0.009. After about 20 hours, the medium was removed by aspiration and 180 μl of growth medium was provided to each well. mu.L of freshly prepared 10 Xstock of test compound was added to each well. The cell culture medium was removed by culturing under hypoxic conditions (1% oxygen+5% carbon dioxide+94% nitrogen) for 24 hours. VEGF concentration was determined using ELISA kits purchased from R & D Systems. The reaction was stopped by adding 50. Mu. L CELLTITER Glo reagent to each well and gently shaking the ELISA plate to allow the stopping reaction to proceed well. Cell titer-Glo luminescent cell viability assay (Promega) was performed on the cell-inoculated plates, and then the light absorbance of each well was measured immediately using a microplate reader at a wavelength of 450 nm. EC ₅₀ values were calculated by GraphPadPrism analysis of the data using the formulation of dose-response-inhibition (four parameters) and the results are shown in table 1.

TABLE 1 VEGF protein inhibiting Activity of related Compounds

[ Note ] "+"; ++ "stands for: less than or equal to 10nM; "+". ++'s representing: less than or equal to 50nM, but >10nM; "++" represents ∈250nM, but >50nM; "+" represents ∈1000nM, but >250nM.

As shown in the results of Table 1, most of the compounds show strong VEGF protein expression inhibition activity on human kidney clear cell carcinoma cell line 786-O, and part of the compounds have better activity than PT-2385 and PT2977, so that the compounds have good application prospects.

EXAMPLE 15 Effect of the Compound II-2 of the invention on rat weight in hypoxic environmental conditions

9 Healthy Wistar rats (SPF grade, male, weight 180-200 g) are adaptively fed for 1 week, the weight is weighed and recorded, 3 groups are randomly divided, 3 groups are fed in normal environment, the rest 2 groups are fed into a low-pressure oxygen cabin for feeding, the high-primary living environment (the altitude is 5000m, the atmospheric pressure is 54kPa, the oxygen content is 11 percent) of human beings is simulated, each group is fed for 4 weeks, the weight is weighed, II-2 groups are fed with II-2, the feeding dose is 8 mg/kg/day, and the feeding is carried out twice in the morning and afternoon; the normal group and the model group are given with blank solvent with the same volume, and the administration mode is the same as that of the II-2 group. The body weight was weighed after 20 days of continuous gastric lavage for each group, and the results are shown in Table 2.

TABLE 2 body weight of rats at various times

As can be seen from the results of Table 2, the compound II-2 of the present invention is effective in improving the weight of rats under hypoxic conditions.

Claims

1. An o-benzoylsulfonyl imide derivative is a compound having the following structure or its pharmaceutically acceptable salt:

2. The phthalylsulfonimide derivative according to claim 1, which is a compound having the following configuration or a pharmaceutically acceptable salt thereof:

3. a pharmaceutical composition comprising at least one active ingredient according to any one of claims 1 to 2 and at least one pharmaceutically acceptable carrier or excipient.

4. Use of a compound according to any one of claims 1-2 or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for treating a condition associated with the mediation of aberrant expression of HIF-2 signaling pathways.

5. The use according to claim 4, wherein the medicament is for the prevention or treatment of a tumor or inflammation.

6. The use according to claim 5, wherein the tumor is selected from the group consisting of solid tumors including renal, liver, colorectal, lung, gastric, breast, ovarian, cervical, skin, glioma, lymphoma and neuroblastoma.

7. The use according to claim 5, wherein said tumor is selected from the group consisting of renal clear cell carcinoma.

8. The use according to claim 5, wherein the inflammation is selected from nephritis, pneumonia, enteritis, arthritis or traumatic infection.