CN109942505B

CN109942505B - Isothiazolinone compounds and corresponding use

Info

Publication number: CN109942505B
Application number: CN201910288659.4A
Authority: CN
Inventors: 王卫; 陈晓蓓; 沈祖源; 钱彭飞; 耿慧慧
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2019-04-11
Filing date: 2019-04-11
Publication date: 2021-08-27
Anticipated expiration: 2039-04-11
Also published as: CN109942505A

Abstract

The invention provides an isothiazolinone compound with IDO inhibitory activity, a preparation method and a pharmaceutical application thereof. In particular to a compound shown as a formula (I), and pharmaceutically acceptable salts, isomers and prodrugs thereof, wherein the definition of each group is described in the specification. The invention also relates to a pharmaceutical preparation and a pharmaceutical composition of the compounds and application thereof in treating, relieving and/or preventing various related diseases caused by immunosuppression, such as tumors, viral infection or autoimmune diseases. The isothiazolinone compound has better IDO inhibitory activity.

Description

Isothiazolinone compounds and corresponding use

Technical Field

The invention relates to the technical field of medicines, in particular to the field of pharmaceutical chemistry synthesis, and specifically relates to an isothiazolinone compound and a corresponding application thereof.

Background

Indoleamine 2,3-dioxygenase (indoamine 2,3-dioxygenase, hereinafter referred to as "IDO") was first found in the intestinal tissues of rabbits in 1967, and is a heme-containing enzyme. The human IDO gene locus is positioned on chromosome 8 and consists of 403 amino acids, and IDO is the only enzyme which can catalyze the epoxidation and cleavage of indole in tryptophan molecules except liver, so that IDO is the rate-limiting enzyme for catabolism of tryptophan along the canine uric acid pathway.

The disease of cancer is caused by the escape of anti-tumor immunity of human body, the unlimited proliferation of tumor cells and the destruction of normal cells. In recent years, the popular tumor immunotherapy is to enhance the anti-tumor immunity of the tumor microenvironment by mobilizing the immune system of the organism, so as to control and kill the tumor cells. The tumor immunotherapy currently available in clinical development and market is mainly macromolecular biological agents such as antibodies, and small-molecule immunomodulators are gradually developed into an important research field in tumor immunotherapy due to relatively simple administration modes and low research and development costs.

The kynurenic acid pathway, which is thought to play a major role in tumor immune escape, is tryptophan metabolism, which results in the consumption of tryptophan responsible for local immunosuppression and the production of immune-suppressive harmful metabolites such as kynurenic acid. The kynurenine pathway thus plays an important role in immune regulation, while IDO, as a key enzyme for oxidative cleavage of L-tryptophan along the kynurenine pathway, is considered as a potential small molecule target for hot tumor immunotherapy. Numerous studies have shown that abnormal expression of IDO is associated with tumor cells evading the immune system, and therefore inhibition of IDO is expected to be a novel tumor treatment strategy. Five small molecule drugs are currently in clinical research phase, and in addition, several inhibitors are in biological activity testing phase.

A large amount of experimental data show that the IDO inhibitor can inhibit tumor immunity to treat cancers, enhance T cell activity, and treat and prevent IDO-related diseases, such as HIV virus infection, autoimmune diseases and the like. In view of the importance of IDO in immunosuppression, the development of novel IDO inhibitors has been the focus of extensive attention of leading researchers in the field, and is of great significance.

Disclosure of Invention

The present invention has been made to overcome the above-mentioned drawbacks of the prior art and an object of the present invention is to provide isothiazolinone compounds having excellent IDO inhibitory activity and having preventive or therapeutic effects against various diseases related to immunosuppression.

In order to achieve the above object, the invention provides an isothiazolinone compound, the structural formula of which is shown in general formula (I),

wherein, ring A is no or phenyl, five-membered or six-membered monocyclic heteroaryl, 8-12 membered fused ring heteroaryl;

R¹is hydrogen, substituted or unsubstituted C_1-6Alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, C_3-18One or more of cycloalkyl, heterocycloalkyl, substituted or unsubstituted phenyl, five-or six-membered monocyclic heteroaryl, and substituted or unsubstituted 8-12-membered fused-ring heteroaryl, and the substituent for the substituted aryl or heteroaryl is selected from 1 to 3 of halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, or heteroaryl;

R²is hydrogen, substituted or unsubstituted C_1-6Alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, C_3-18Cycloalkyl, heterocycloalkyl, substituted or unsubstituted phenylOne or more of five-membered or six-membered monocyclic heteroaryl, substituted or unsubstituted 8-12-membered fused-ring heteroaryl, and the substituent for substituting aryl or heteroaryl is selected from 1 to 3 of halogen, amino, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl or heteroaryl;

or, R¹And R²Substituted or unsubstituted 5-8 membered saturated, partially unsaturated, aromatic ring, the substituent used for substituting the 5-8 membered saturated, partially unsaturated, aromatic ring is selected from 1 to 3 of halogen, amino, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, substituted or unsubstituted aryl or heteroaryl, and the substituent used for substituting the aryl or heteroaryl is selected from 1 to 3 of halogen, amino, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy;

R³at any reasonable position of the valence bond on the A ring, R³Selected from the group consisting of hydrogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, -NHR^aOne or more of cycloalkyl, heterocycloalkyl, substituted or unsubstituted phenyl, five-or six-membered monocyclic heteroaryl, and substituted or unsubstituted 8-12 membered fused-ring heteroaryl, wherein the substituent for the substituted aryl or heteroaryl is selected from 1 to 3 of halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, and haloalkoxy;

wherein the selected halogen is selected from F, Cl, Br, I;

R^ais-S (O)₂NH₂One or more of substituted or unsubstituted phenyl, five-or six-membered monocyclic heteroaryl, and substituted or unsubstituted 8-12 membered fused-ring heteroaryl.

L is selected from a linking group C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Acylaminoalkyl, C_1-6Alkylamide group, C_1-6Sulfonylalkyl, C_1-6Alkylsulfonyl radical, C_1-6Sulfonamidoalkyl, C_1-6Alkylsulfonamide group, C_1-6Alkyl sulfanyl radical, C_1-6Thio groupAcylaminoalkyl, C_1-6Alkyl thioamide group, C_1-6Carbonylalkyl, C_1-6Alkylcarbonyl group, C_1-6Thiocarbonylalkyl radical, C_1-6Any one of alkylthiocarbonyl groups.

Preferably, the compound isothiazolinone comprises the following compounds:

the invention provides application of the isothiazolinone compound in preparation of IDO inhibitor drugs.

The invention provides application of the isothiazolinone compound in preparation of a medicament for treating IDO (insulin dependent diabetes) mediated diseases.

Preferably, the IDO-mediated disease comprises an infection, a cancer, or an autoimmune disease.

Preferably, the cancer is one or more of bone cancer, lung cancer, stomach cancer, colon cancer, membrane adenocarcinoma, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, innocent pill cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and skin cancer;

the infection is skin infection, gastrointestinal tract infection, urogenital system infection, systemic infection, or virus infection caused by one or more of influenza, hepatitis C virus, human papilloma virus, cytomegalovirus, Epstein Barr virus, poliovirus, hydrozymato-type cross-sectional virus, coxsackie virus and human immunodeficiency virus;

the autoimmune disease is one or more of rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic scleroderma, dermatomyositis, nodular vasculitis, nephropathy, endocrine related diseases, liver disease, psoriasis and autoimmune reaction caused by infection.

The invention provides a pharmaceutical composition, which comprises an active component with a therapeutically effective amount and pharmaceutically acceptable auxiliary materials; the active ingredient comprises the isothiazolinone compound, isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2.

Preferably, the active ingredient further comprises a therapeutic agent for cancer, viral infection or autoimmune disease.

The compounds of formula (I), isomers, prodrugs, stable isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, are used in combination with one or more other therapeutic agents and/or methods for treating cancer; the other class of therapeutic agents and/or methods of treatment for cancer are one or more of tubulin inhibitors, alkylating agents, topoisomerase i/ii inhibitors, platinum-based compounds, antimetabolites, hormones and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies, immunotherapeutic agents, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiation therapies.

Preferably, the pharmaceutical composition is in the form of capsule, microcapsule, tablet, granule, pill, dispersion powder, liquid, soft extract, suspension, syrup, gel, aerosol, patch, liposome, oral liquid, intravenous injection or intramuscular injection.

Preferably, the dosage of the isothiazolinone compound, the isomer, the prodrug, the stable isotope derivative or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.05 mg/kg-90 mg/kg.

By adopting the isothiazolinone compound and the corresponding application, experimental results show that the isothiazolinone compound has the effect of inhibiting IDO enzyme, and the isoxazolinone compound provided by the invention can treat, relieve and/or prevent IDO-mediated related diseases and comprises the following components: cancer, viral or other infections or autoimmune diseases.

Detailed Description

For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.

In order to further illustrate the present invention, the following examples are provided to illustrate the preparation and application of an isoxazolinone compound provided by the present invention, and the scope of the present invention is not limited by the following examples.

Example 1

Synthesis of N- (substituted benzisothiazole) -2(3H) -formamide (I-1-I-5)

Weighing 4-substituted aniline (3mmol) into a dry double-neck bottle, adding 5mL of anhydrous dichloromethane for dissolving, slowly adding a dichloromethane solution (3mL) of triphosgene (445mg,1.5mmol) at 0 ℃ under the protection of nitrogen, then dropwise adding a dichloromethane solution (3mL) of triethylamine (460 mu L,3.3mmol), heating to room temperature after the addition is finished, stirring for 30 minutes, and then removing the reaction liquid in a rotating manner to obtain a crude product of the 4-substituted phenyl isocyanate.

6mL of methylene chloride was added thereto, 6mL of a tetrahydrofuran solution of 1, 2-benzisothiazol-3-one (BIT) (272mg, 1.8mmol) was added thereto, and the reaction system was heated to 45 ℃ for reaction for 8 hours. Stopping heating, cooling, removing the solvent by spinning, adding about 10mL of acetone and 10mL of water, ultrasonically mixing, standing, precipitating, filtering, washing a filter cake with (acetone: water: 1) to obtain a yellow solid crude product, dissolving the yellow solid crude product with a small amount of dichloromethane, and recrystallizing n-hexane to obtain the product.

N- (4-morpholino) -3-oxobenzisothiazole-2 (3H) -carboxamide (I-1) as a pale yellow solid in 13% yield.

¹H NMR(400MHz,CDCl₃)δppm 10.95(s,1H),8.06(d,J＝7.9Hz,1H),7.76-7.69(m,1H),7.61(d,J＝8.1Hz,1H),7.47(dd,J＝16.4,8.0Hz,3H),7.17(d,J＝8.3Hz,2H),2.34(s,3H)；¹³C NMR(100MHz,CDCl₃)δppm 165.3,148.5,140.8,134.6,134.3,134.2,129.8(2C),127.5,126.1,125.0,120.7,120.4(2C),21.0；HRMS(ESI)m/z calcd for C₁₅H₁₂N₂O₂S(M+Na)⁺337.1,found 337.1.

3-oxo-N- (p-tolyl) benzisothiazole-2 (3H) -carboxamide (I-2) as a white solid in 75% yield.

¹H NMR(400MHz,CDCl₃)δppm 10.88(s,1H),8.06(d,J＝7.9Hz,1H),7.78-7.69(m,1H),7.61(d,J＝8.1Hz,1H),7.51(d,J＝9.0Hz,2H),7.46(t,J＝7.5Hz,1H),6.93(d,J＝8.7Hz,2H),3.91-3.84(m,4H),3.22-3.09(m,4H)；¹³C NMR(100MHz,CDCl₃)δppm 165.34(2C),148.59,140.87,134.2(2C),127.5(2C),126.1(2C),125.1,121.70(2C),120.7(2C),116.53,66.99,49.82；HRMS(ESI)m/z calcd for C₁₈H₁₇N₃O₃S(M+H)⁺356.1069,found 356.1066.

N- (4- (1-isobutyl-1H-pyrazol-4-yl) phenyl) -3-oxobenzisothiazole-2 (3H) -carboxamide (I-3) as a yellow solid in 26% yield.

¹H NMR(400MHz,DMSO)δppm 7.90(s,1H),7.58(s,1H),7.17-7.05(m,4H),6.57-6.47(m,4H),3.91(d,J＝7.2Hz,2H),2.11-2.06(m,1H),0.80(d,J＝6.7Hz,6H)；HRMS(ESI)m/z calcd for C₂₁H₂₀N₄O₂S(M+H)⁺393.1,found 393.1.

N- (4- (2-methyl-2H-indazol-4-yl) phenyl) -3-oxobenzisothiazole-2 (3H) -carboxamide (i-4) as a yellow solid in 63% yield.

¹H NMR(400MHz,DMSO)δppm 11.17(s,1H),8.10(d,J＝8.7Hz,2H),7.79-7.62(m,7H),7.52-7.45(m,1H),7.40(dd,J＝8.7,7.0Hz,1H),7.19(d,J＝6.6Hz,1H),4.29(s,3H)；HRMS(ESI)m/z calcd for C₂₂H₁₆N₄O₂S(M+H)⁺401.1072,found 401.1071.

N- (3- (1H-tetrazol-5-yl) phenyl) -3-oxobenzisothiazole-2 (3H) -carboxamide (I-5) as a white solid in 48% yield.

HRMS(ESI)m/z calcd for C₁₅H₁₀N₆O₂S(M-H)^-337.0508,found 337.0509.

Example 2

Synthesis of N- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3-oxobenzisothiazole-2 (3H) -carboxamide (I-6)

Step 1

Synthesis of 1-azido-4-fluorobenzene (6.1)

4-fluoroaniline (1.11g,10mmol) was dissolved in 20mL acetonitrile, tert-butyl nitrite (1.55g, 15mmol) was added with stirring in an ice bath, then trimethylsilyl azide (1.73g,15mmol) was added dropwise, and the reaction was allowed to warm to room temperature for 1 hour after the addition (note that the reaction was largely exothermic and open to the atmosphere). Adding dichloromethane, washing the organic layer with water, washing with saturated salt water, drying with anhydrous sodium sulfate, removing solvent at low temperature to about 5mL (incomplete drying, low boiling point of product, easy removal), performing column chromatography with dichloromethane as eluent without pressurization, collecting and concentrating pure product to about 5mL, and directly feeding into next step with yield of about 80%.

Step 2

Synthesis of 3-oxo-N- (prop-2-yn-1-yl) benzisothiazole-2 (3H) -carboxamide (6.2)

Referring to method I-1, white solid 6.2 is obtained, and the yield is about 80%.

¹H NMR(400MHz,CDCl₃)δppm 9.11(s,1H),8.04(d,J＝8.0Hz,1H),7.75-7.67(m,1H),7.58(d,J＝8.1Hz,1H),7.49-7.39(m,1H),4.24(dd,J＝5.5,2.5Hz,2H),2.30(t,J＝2.5Hz,1H).

Step 3

Synthesis of Compound I-6

6.2(232mg,1mmol) and 6.1(1.5mmol) are added into a single-mouth bottle, 10mL of methanol is added for dissolution, a mixed aqueous solution (0.8mL) of copper sulfate (11.2mg,0.07mmol) and sodium ascorbate (27.7mg,0.14mmol) is added under the protection of nitrogen, the reaction system is subjected to nitrogen protection reaction at room temperature for 12 hours after the addition is finished, TLC monitors the disappearance of raw materials, and the reaction is finished. The solvent was removed by rotation, extracted with ethyl acetate, washed with 10% aqueous ammonia (2 × 5mL), washed with water, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine: 1:0.02), and a small amount of ethyl acetate and a large amount of n-hexane were recrystallized to give i-6277 mg of a yellow solid in 75% yield.

¹H NMR(400MHz,CDCl₃)δppm 9.42(s,1H),8.02(d,J＝7.2Hz,2H),7.75-7.66(m,3H),7.58(d,J＝8.1Hz,1H),7.47-7.38(m,1H),4.81(d,J＝5.9Hz,2H)；¹³C NMR(100MHz,CDCl₃)δppm 165.6,161.7,151.9,145.7,141.2,134.5,127.9,126.4,125.2,123.1(d,J＝8.6Hz,2C),121.5,120.9,117.2(d,J＝23.2Hz,2C),100.4,36.5；HRMS(ESI)m/z calcd for C₁₇H₁₂FN₅O₂S(M+H)⁺370.08,found 369.99.

Example 3

Synthesis of N- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3-oxobenzisothiazole-2 (3H) carbothioamide (I-7)

Step 1

Synthesis of propargyl isothiocyanate (7.1)

Propargylamine (3.2mL,50mmol) and Et₃Dissolving N (6.9mL,50mmol) in 150mL tetrahydrofuran, dropwise adding carbon disulfide (3mL,50mmol) under ice-bath stirring, reacting at the temperature for 30 minutes until the reaction turns turbid, then dropwise adding 30% hydrogen peroxide, and finishing the additionThe reaction became clear. The solvent was removed by rotation, extracted with dichloromethane, washed with water, the organic layer was dried, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 8:1) to give 7.1777 mg of an off-white semisolid with a yield of 16%.

Step 2

Synthesis of 3-oxo-N- (prop-2-yn-1-yl) benzisothiazole-2 (3H) carbothioamide (7.2)

7.1(750mg,3.02mmol) and BIT (365mg,2.42mmol) were dissolved in 4mL of dichloromethane and 4mL of tetrahydrofuran, and the reaction was heated to 65 ℃ and refluxed for 8 hours. Cooling, removing the solvent by rotation, adding about 3mL of acetone and 3mL of water, mixing by ultrasonic waves, standing, precipitating, filtering, washing a filter cake with (acetone: water: 1), and drying the filter cake to obtain an off-white solid 7.2120 mg, wherein the yield is 13%.

¹H NMR(400MHz,CDCl₃)δppm 11.33(s,1H),8.00(d,J＝8.0Hz,1H),7.74-7.65(m,1H),7.53(d,J＝8.1Hz,1H),7.45-7.38(m,1H),4.53(dd,J＝4.9,2.6Hz,2H),2.37(t,J＝2.6Hz,1H).

Step 3

Synthesis of Compound I-7

Referring to method I-6, dimethyl sulfoxide is used as a solvent to replace methanol, so that a tan solid I-7 is obtained, and the yield is 21%.

¹H NMR(400MHz,CDCl₃)δppm 11.70(s,1H),8.14(s,1H),7.98(d,J＝10.1Hz,2H),7.77-7.65(m,5H),7.52(d,J＝8.1Hz,1H),7.44-7.33(m,2H),7.25-7.18(m,4H),5.15(d,J＝5.6Hz,2H),4.94(s,2H)；¹³C NMR(100MHz,CDCl₃)δ177.3,163.4,146.2(d,J＝62.4Hz,1C),142.0(d,J＝112.0Hz,1C),133.3,126.6,125.0,124.6,122.8(d,J＝28.3Hz,1C),121.7(d,J＝2.7Hz,1C),121.6(d,J＝2.7Hz,1C),120.3,119.3,118.9,115.8(dd,J＝23.3,15.2Hz,2C),44.8；HRMS(ESI)m/z calcd for C₁₇H₁₂FN₅OS₂(M+H)⁺386.0546,found 386.0545.

Example 4

Synthesis of N- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3-oxoisothiazolo [5,4-A ] pyridine-2 (3H) -carboxamide (I-8)

Step 1

Synthesis of 2-mercapto-3-pyridinecarboxamide (8.1)

2-Mercaptonicotinic acid (5.9g,38mmol) was dissolved in 60mL of toluene, thionyl chloride (13.8mL,190mmol) was added, and the reaction was refluxed for 3 hours. After cooling and concentration, adding 20mL of toluene, performing reduced pressure rotary evaporation twice to remove redundant thionyl chloride; to the residue were added ammonium chloride (7g,130mmol), aqueous ammonia (50mL), and water (17mL), and the mixture was stirred at room temperature for 18 hours; then, sodium borohydride was stirred at room temperature for 1 hour to terminate the reaction. The reaction solution was adjusted to pH 4 with about 100mL of 3M hydrochloric acid, and a precipitate precipitated out, filtered, and the filter cake was washed with water to obtain 8.14.3 g of a yellow solid, representing 74% yield.

¹H NMR(400MHz,DMSO)δppm 14.00(s,1H),10.06(s,1H),8.48(dd,J＝7.6,1.9Hz,1H),7.94(td,J＝6.2,1.8Hz,2H),7.05-6.95(m,1H).

Step 2

Synthesis of isothiazolo [5,4-b ] pyridin-3 (2H) -one (8.2)

8.1(4.3g,27.9mmol) was dissolved in 28mL of concentrated sulfuric acid and reacted at 100 ℃ for 2 hours. Cooling, adding 70mL of ice water, adjusting the pH value to 11 by adding 70mL of ammonia water into a constant pressure dropping hole, filtering insoluble solids, heating the filtrate at 100 ℃ to slightly boil, adjusting the pH value to 4 by adding 20mL of acetic acid into a constant pressure dropping funnel under heating, cooling, freezing, precipitating a large amount of precipitates, filtering, washing a filter cake with water, drying, and adding dichloromethane: methanol (1:1) was ultrasonically filtered and the filter cake was collected as a yellow solid 8.22.56 g with a yield of 60%.

¹H NMR(400MHz,DMSO)δppm 8.81(dd,J＝4.6,1.6Hz,1H),8.31(dd,J＝8.0,1.6Hz,1H),7.50(dd,J＝8.0,4.6Hz,1H).

Step 3

Synthesis of 3-oxo-N- (prop-2-yn-1-yl) isothiazolo [5,4-A ] pyridine-2 (3H) -carboxamide (8.3)

Referring to method I-1, a yellow solid 8.3 was obtained in 50% yield.

¹H NMR(400MHz,DMSO)δppm 9.00(t,J＝5.5Hz,1H),8.94(dd,J＝4.7,1.6Hz,1H),8.40(dd,J＝8.0,1.6Hz,1H),7.58(dd,J＝8.0,4.7Hz,1H),4.14(dd,J＝5.7,2.4Hz,2H),3.24(t,J＝2.4Hz,1H).

Step 4

Synthesis of Compound I-8

Referring to method I-6, the solvent was replaced with dimethyl sulfoxide to give a tan solid I-8 in 8% yield.

¹H NMR(400MHz,DMSO)δppm 10.87(s,1H),8.74(t,J＝63.9Hz,2H),8.19(t,J＝47.5Hz,2H),7.72(d,J＝75.5Hz,1H),7.41(s,1H),7.10(s,1H),6.77(s,1H),4.01(d,J＝20.9Hz,2H).

Example 5

Synthesis of N- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3-oxo-4-phenylbenzoisothiazole-2 (3H) -carboxamide (I-9)

Step 1

Synthesis of 2-bromo-6-iodobenzoic acid (9.1)

2-Bromobenzoic acid (8.04g,40mmol), iodobenzene diacetic acid (19.3g,60mmol), palladium acetate (449mg,2mmol) and iodine particles (15.2g,60mmol) were dissolved in 80mL of anhydrous N, N-dimethylformamide and reacted at 100 ℃ for 24 hours, thus completing the reaction. Cooling, extracting with ethyl acetate, washing with 0.5M hydrochloric acid, washing with water, drying the organic layer, concentrating, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain 9.17.32 g of reddish brown liquid with a yield of 46%.

¹H NMR(400MHz,DMSO)δppm 7.79(dd,J＝8.0,0.8Hz,1H),7.58(dd,J＝8.1,0.8Hz,1H),6.97(t,J＝8.0Hz,1H).

Step 2

Synthesis of 2-bromo-6-iodobenzamide (9.2)

9.1(7.32g,22mmol) is dissolved in 40mL of tetrahydrofuran, 4mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide are added, the reaction solution is removed after 3 hours of reflux reaction under nitrogen protection, 40mL of tetrahydrofuran is added to the residue, and 33mL of ammonia water is added dropwise under stirring in an ice bath at room temperature for 3 hours. Ethyl acetate was added for extraction, washed with saturated sodium bicarbonate, and the organic layer was dried, concentrated, and purified by recrystallization from a small amount of methylene chloride and a large amount of n-hexane to obtain 9.26.09 g of a white solid with a yield of 85%.

¹H NMR(400MHz,DMSO)δppm 7.97(s,1H),7.84(dd,J＝7.9,0.9Hz,1H),7.70(s,1H),7.64(dd,J＝8.0,0.9Hz,1H),7.02(t,J＝8.0Hz,1H).

Step 3

Synthesis of 2-bromo-6-iodobenzonitrile (9.3)

9.2(6g,18.4mmol) was dissolved in 20mL of tetrahydrofuran, and trifluoroacetic anhydride (2.8mL,20.2mmol) and triethylamine (3.3mL,23.9mmol) were added and reacted at room temperature for 2 hours. And adding 21mL of water for quenching reaction, removing tetrahydrofuran by spinning, separating out a large amount of solid, filtering, washing and drying a filter cake to obtain 9.35.38 g of white solid, wherein the yield is 95%.

¹H NMR(400MHz,DMSO)δppm 7.88(d,J＝8.0Hz,1H),7.67(d,J＝8.1Hz,1H),7.12(t,J＝8.1Hz,1H).

Step 4

Synthesis of 3-bromo- [1,1' -biphenyl ] -2-carbonitrile (9.4)

9.3(5.3g,17.2mmol), phenylboronic acid (2.3g,18.9mmol) and sodium carbonate (3.65g,34.4mmol) were dissolved in 126mL of toluene: ethanol: in a mixed solvent of water (5:1:1), after being aerated for 5 minutes by nitrogen, tetrakistriphenylphosphine palladium (994mg,0.86mmol) is added, and the reaction is finished after 6 hours of reaction at 90 ℃ under the protection of the whole nitrogen. Cooling, removing the solvent by rotation, extracting with ethyl acetate, washing with water, drying the organic layer, concentrating, and purifying by silica gel column chromatography (petroleum ether: dichloromethane 15:1) to obtain 9.41.77g of a white solid with a yield of 40%.

¹H NMR(400MHz,CDCl3)δppm 7.68(dd,J＝7.8,1.3Hz,1H),7.58-7.38(m,7H).

Step 5

Synthesis of 3- (ethylthio) - [1,1' -biphenyl ] -2-carbonitrile (9.5)

Adding 9.4(1.03g,4mmol), bromoethane (298 mu L,4mmol), potassium thiocyanate (389mg,4mmol), cuprous bromide (57mg,0.4mmol), phenanthroline (72mg,0.4mmol), tetrabutylammonium bromide (258mg,0.8mmol), sodium hydroxide (320mg,8mmol) and 16mL of water into a sealed tube in sequence, and reacting for 48 hours at 130 ℃. Cooled to room temperature, extracted with a larger amount of ethyl acetate, washed with water, the organic layer dried, concentrated and purified by silica gel column chromatography (petroleum ether: dichloromethane 20:1) to give 9.5335 mg of a yellow oil in 40% yield.

¹H NMR(400MHz,DMSO)δppm 7.59-7.43(m,6H),7.37(d,J＝8.0Hz,1H),7.26(d,J＝7.7Hz,1H),3.10(q,J＝7.4Hz,2H),1.41(t,J＝7.4Hz,3H).

Step 6

Synthesis of 3- (ethylthio) - [1,1' -biphenyl ] -2-carbonitrile (9.6)

9.5(201mg,0.84mmol) was dissolved in 0.8mL of chlorobenzene, water (18. mu.L, 1mmol) and sulfuryl chloride (74. mu.L, 0.92mmol) were added, and the reaction was allowed to proceed to 75 ℃ for 1 hour. A white solid precipitated, which was cooled and filtered, and the filter cake was washed with chlorobenzene and dried to obtain 9.6153 mg of a white solid with a yield of 81%.

¹H NMR(400MHz,DMSO)δppm 7.98(d,J＝8.1Hz,2H),7.65-7.61(m,1H),7.48-7.35(m,5H),7.23(dd,J＝7.2,0.7Hz,1H).

Step 7

Synthesis of 3-oxo-4-phenyl-N- (prop-2-yn-1-yl) benzisothiazole-2 (3H) -carboxamide (9.7)

Referring to method I-1, 9.7 was obtained as a yellow solid in 75% yield.

¹H NMR(400MHz,CDCl₃)δppm 9.06(s,1H),7.71(t,J＝7.7Hz,1H),7.57(dd,J＝8.1,0.6Hz,1H),7.48-7.42(m,5H),7.28(d,J＝8.2Hz,1H),4.16(dd,J＝5.5,2.5Hz,2H),2.22(t,J＝2.5Hz,1H).

Step 8

Synthesis of Compound I-9

Referring to method I-6, the solvent was replaced with dimethyl sulfoxide to give a tan solid I-9 in 70% yield.

¹H NMR(400MHz,DMSO)δppm 9.35(t,J＝5.8Hz,1H),7.96(s,1H),7.73-7.65(m,3H),7.57(d,J＝8.1Hz,1H),7.48-7.43(m,3H),7.40(dd,J＝6.7,3.0Hz,2H),7.28(s,1H),7.23-7.17(m,2H),4.72(d,J＝6.0Hz,2H)；¹³C NMR(100MHz,CDCl₃)δppm 164.7,163.8,161.3,151.7,145.3,144.9,142.1,137.2,133.4,129.4(2C),128.5(d,J＝7.9Hz,2C),127.9(2C),122.7(d,J＝8.6Hz,2C),121.2,120.8,119.7,116.9,116.7,36.0；HRMS(ESI)m/z calcd for C₂₃H₁₆FN₅O₂S(M+H)⁺446.1087,found 446.1088.

Example 6

Synthesis of N- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3-oxoisothiazole-2 (3H) -carboxamide (I-10)

Step 1

Synthesis of 3-oxo-N- (prop-2-yn-1-yl) isothiazole-2 (3H) -carboxamide (10.1)

Referring to method I-1, a yellow solid 10.1 was obtained in 45% yield.

Step 2

Synthesis of Compound I-10

Referring to method I-6, the solvent was replaced with isopropanol to give I-10 as a yellow solid in 17% yield.

¹H NMR(400MHz,CDCl₃)δppm 9.45(s,1H),8.22(d,J＝6.4Hz,1H),7.99(s,1H),7.73-7.67(m,2H),7.25-7.18(m,2H),6.26(d,J＝6.4Hz,1H),4.77(d,J＝5.9Hz,2H)；¹³C NMR(100MHz,DMSO)δppm 167.9,162.9,150.7,147.6,145.4,133.2(d,J＝2.9Hz,2C),122.4(d,J＝8.8Hz,2C),121.5,116.7(d,J＝23.2Hz,2C),114.6,35.3；HRMS(ESI)m/z calcd for C₁₃H₁₀FN₅O₂S(M+NA0)⁺342.0437,found 342.0435.

Example 7

Synthesis of 3-oxo-N- ((3-phenyl-1, 2, 4-oxadiazol-5-yl) methyl) benzisothiazole-2 (3H) -carboxamide (I-11)

Step 1

Synthesis of 5- (chloromethyl) -3-phenyl-1, 2, 4-oxadiazole (11.1)

Hydroxylamine hydrochloride (4.17g,60mmol) and sodium carbonate (4.07g,38.4mmol) were dissolved in 50mL of water, 25mL of an ethanol solution of benzonitrile (2.47g,24mmol) was added thereto, and the reaction was refluxed at 105 ℃ for 10 hours. Cooling to room temperature, extracting with a large amount of ethyl acetate, washing with water, drying an organic layer, and concentrating to obtain a crude product of (E) -2-amino-2-phenylacetaldehyde oxime. 40mL of dichloromethane was added thereto and dissolved, N-diisopropylethylamine (5.58g,43.2mmol) was added with stirring in an ice bath, chloroacetyl chloride (2.44g,21.6mmol) was added dropwise, and the reaction was refluxed for 18 hours. Cooling, ethyl acetate extraction, water washing, organic layer drying, concentration, silica gel column chromatography (petroleum ether: ethyl acetate 20:1) purification to obtain 11.13.13 g of light yellow liquid, two-step yield 67%.

¹H NMR(400MHz,CDCl3)δppm 8.09(dd,J＝8.0,1.6Hz,2H),7.54-7.45(m,3H),4.75(s,2H).

Step 2

Synthesis of 2- ((3-phenyl-1, 2, 4-oxadiazol-5-yl) methyl) isoindoline-1, 3-dione (11.2)

11.1(2.92g,15mmol) was dissolved in 25mL of N, N-dimethylformamide, and potassium phthalimide (2.78g,15mmol) was added in portions and reacted at 60 ℃ for 4 hours. Cooling, adding 100mL of water, performing ultrasonic treatment, generating a large amount of precipitate, filtering, washing and drying a filter cake to obtain 11.22.84 g of white-yellow solid with the yield of 62%.

¹H NMR(400MHz,CDCl3)δppm 8.04-8.00(m,2H),7.95(dd,J＝5.5,3.1Hz,2H),7.80(dd,J＝5.5,3.1Hz,2H),7.49-7.41(m,3H),5.18(s,2H).

Step 3

Synthesis of (3-phenyl-1, 2, 4-oxadiazol-5-yl) methylamine (11.3)

11.2(2.74g,9mmol) was dissolved in 40mL of ethanol, and 80% hydrazine hydrate (675mg,10.8mmol) was added thereto, followed by refluxing for 4 hours to terminate the reaction. Cooling, removing solvent, adding water, adjusting to alkalinity, extracting with ethyl acetate, drying, and concentrating to obtain 11.31.45 g of white solid with a yield of 92%.

¹H NMR(400MHz,CDCl₃)δppm 8.11-8.03(m,2H),7.51-7.41(m,3H),4.14(s,2H).

Step 4

Synthesis of Compound I-11

Referring to method I-1, the isocyanate preparation was extended to 8 hours to provide I-11 as a white solid in 73% yield.

¹H NMR(400MHz,DMSO)δppm 9.56(t,J＝5.7Hz,1H),8.01(dd,J＝17.2,8.1Hz,4H),7.81(t,J＝8.2Hz,1H),7.61-7.48(m,4H),4.96(d,J＝5.8Hz,2H)；¹³C NMR(100MHz,DMSO)δppm 177.2,167.7,164.4,151.2,140.9,134.2,131.7,129.3(2C),127.0(2C),126.7,126.2,126.0,124.4,122.2,37.0；HRMS(ESI)m/z calcd for C₁₇H₁₂N₄O₃S(M+NA0)⁺375.0528,found375.0530.

Example 8

Synthesis of N- (1- ((3-fluorophenyl) sulfonyl) piperidin-4-yl) -3-oxobenzisothiazole-2 (3H) -carboxamide (I-12)

Step 1

Synthesis of tert-butyl 1- ((3-fluorophenyl) sulfonyl) piperidin-4-yl) carbamate (12.1)

4-Boc-aminopiperidine (2.5g,12.5mmol) and triethylamine (5.2mL,37.5mmol) were dissolved in 20mL of dichloromethane, and 10mL of a solution of 3-fluorobenzenesulfonyl chloride (1.74mL,13.1mmol) in dichloromethane was added dropwise with stirring in an ice bath, after which the temperature was raised to room temperature and the reaction was carried out for 5 hours. Extraction with ethyl acetate, 1M hydrochloric acid washing, saturated sodium bicarbonate, water washing, drying of the organic layer, concentration, and purification by silica gel column chromatography (petroleum ether: ethyl acetate 8:1) gave 12.14.1 g of a white solid with a yield of 92%.

¹H NMR(400MHz,CDCl₃)δppm 7.55-7.49(m,2H),7.44(d,J＝7.7Hz,1H),7.34-7.27(m,1H),4.46(s,1H),3.69(d,J＝10.8Hz,2H),3.39(d,J＝5.7Hz,1H),2.47(t,J＝11.3Hz,2H),1.97(d,J＝15.5Hz,2H),1.48(ddd,J＝24.1,11.6,4.0Hz,2H),1.40(s,9H).

Step 2

Synthesis of 1- ((3-fluorophenyl) sulfonyl) piperidin-4-amine (12.2)

12.1(3g,8.37mmol) was dissolved in 6mL of methylene chloride, and 6mL of trifluoroacetic acid was added thereto to carry out a reaction at room temperature for 3 hours, thereby terminating the reaction. The solvent was removed by evaporation, water was added, made basic, extracted with dichloromethane, dried and concentrated to give 12.22.22 g of a white solid with a yield of 93%.

¹H NMR(400MHz,CDCl₃)δppm 8.50(t,J＝5.5Hz,1H),8.33(d,J＝7.7Hz,1H),8.04(t,J＝7.4Hz,1H),7.78(d,J＝5.8Hz,1H),7.69(d,J＝5.1Hz,2H),4.08(dd,J＝5.7,2.4Hz,2H).

Step 3

Synthesis of Compound I-12

Referring to method I-1, white solid I-12 was obtained in 20% yield.

¹H NMR(400MHz,CDCl₃)δ8.92(d,J＝7.4Hz,1H),7.99(d,J＝7.9Hz,1H),7.74-7.66(m,1H),7.56(dd,J＝10.7,8.7Hz,3H),7.48(dd,J＝9.6,1.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.35-7.30(m,1H),3.88-3.77(m,1H),3.75-3.70(m,2H),2.62(td,J＝12.1,2.6Hz,2H),2.12(dd,J＝13.1,3.5Hz,2H),1.74(ddd,J＝24.1,10.9,4.0Hz,2H)；¹³C NMR(100MHz,CDCl₃)δppm 165.3,162.6(d,J＝252Hz,1C),150.5,140.8,138.4(d,J＝6.5Hz,1C),134.1,131.1(d,J＝7.8Hz,1C),127.3,126.0,124.9,123.4(d,J＝3.3Hz,1C),120.6,120.2(d,J＝21.2Hz,1C),115.0(d,J＝24.1Hz,1C),47.2,45.0(2C),31.4(2C)；HRMS(ESI)m/z calcd for C₁₉H₁₈FN₃O₄S₂(M+Na)⁺458.1,found 458.1.

Example 9

Synthesis of 3-oxo-N- (2- (sulfamoylamino) ethyl) benzisothiazole-2 (3H) -carboxamide (I-13)

Step 1

Synthesis of tert-butyl 1- ((3-fluorophenyl) sulfonyl) piperidin-4-yl) carbamate (13.1)

The synthesis method is the same as I-1, and saturated sodium bicarbonate is used as the alkali to replace triethylamine, so that 411mg of 13.1 of white solid is obtained, and the yield is 90%.

¹H NMR(400MHz,DMSO)δppm 9.03(s,1H),8.02(d,J＝7.9Hz,1H),7.70(t,J＝7.7Hz,1H),7.58(d,J＝8.1Hz,1H),7.43(t,J＝7.3Hz,1H),4.91(s,1H),3.57(dd,J＝11.6,5.8Hz,2H),3.38(dd,J＝11.2,5.5Hz,2H),1.43(s,9H).

Step 2

Synthesis of N- (2-aminoethyl) -3-oxobenzisothiazole-2 (3H) -carboxamide (13.2)

Weighing 13.1(337mg,1mmol) add trifluoroacetic acid under ice bath: the reaction was terminated by adding 4mL of a mixed solution of water (9:1) and then allowing the mixture to react at room temperature for 2 hours. The reaction mixture was removed by rotation, extracted with dichloromethane, washed with saturated sodium bicarbonate, washed with water, dried, concentrated, and purified by silica gel plate separation (dichloromethane: methanol: aqueous ammonia: 10:1:0.1) to obtain 13.2221 mg of a white solid with a yield of 93%.

Step 3

Synthesis of tert-butyl (N- (2- (3-oxo-2, 3-dihydrobenzo [ d ] isothiazole-2-carboxamido) ethyl) sulfamoyl) carbamate (13.3)

Chlorosulfonyl isocyanate (78 mu L,0.88mmol) is dissolved in 3mL dichloromethane, a dichloromethane solution of tert-butyl alcohol (85 mu L,0.88mmol) is added dropwise under stirring in an ice bath, and after the addition, the temperature is raised to room temperature for reaction for 1.5 hours, thus obtaining the N-Aoc sulfonyl chloride solution. 13.2(190mg,0.8mmol) in 3mL dichloromethane at-15 ℃ slowly adding the prepared N-Aoc sulfonyl chloride solution, stirring for 10 minutes to generate solid, adding triethylamine (945 uL, 4mmol) dropwise, heating to room temperature after adding for 10 minutes, reacting for 10 minutes, dissolving the precipitate, clarifying the solution, and completing the reaction. The pH was adjusted to 7 with 1M hydrochloric acid, extracted with ethyl acetate, washed with water, dried, concentrated and purified by silica gel plate separation (dichloromethane: methanol: aqueous ammonia: 20:1:0.2) to give 13.3117mg of a white solid in 35% yield.

¹H NMR(400MHz,DMSO)δppm 7.57(d,J＝8.0Hz,1H),7.31(q,J＝7.7Hz,2H),7.03(t,J＝8.0Hz,1H),3.22-3.17(m,2H),2.84(t,J＝6.0Hz,2H),1.03(s,9H).

Step 4

Synthesis of Compound I-13

Referring to procedure 13.2, white solid I-13 was obtained in 15% yield.

¹H NMR(400MHz,DMSO)δppm 9.00-8.89(m,1H),7.99(dd,J＝26.5,8.0Hz,2H),7.80(t,J＝8.3Hz,1H),7.50(t,J＝7.6Hz,1H),7.46(s,1H),6.75(t,J＝5.9Hz,1H),6.59(s,2H),3.47(q,J＝6.1Hz,2H),3.08(dd,J＝11.7,5.7Hz,2H)；¹³C NMR(100MHz,DMSO)δppm 164.2,150.9,140.7,133.9,126.4,126.0,124.7,122.0,54.9,41.9；HRMS(ESI)m/z calcd for C₁₀H₁₂N₄O₄S₂(M+Na)⁺339.0198,found 339.0197.

Example 10

Synthesis of 2- ((1- (substituted phenyl) -1H-1,2, 3-triazole-4-yl) methyl (or ethyl) benzisothiazol-3 (2H) -one (I-14-I-16)

Step 1

Synthesis of 5- (chloromethyl) -3- (3-trifluoromethylphenyl) -1,2, 4-thiadiazole (14.1 and 15.1)

AIT (2.27g,15mmol) was dissolved in 150mL of acetonitrile, potassium carbonate (4.15g,30mmol) was added, and after 30 minutes at room temperature, bromoethyl (or propyl) alkyne (22.5mmol) was added and the reaction was terminated at room temperature for 4 hours. Extracting with ethyl acetate, washing with water, drying the organic layer, concentrating, and purifying by silica gel column chromatography (petroleum ether: dichloromethane: 1) to obtain product;

2- (prop-2-yn-1-yl) benzisothiazol-3 (2H) -one (14.1) as a white solid in 38% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.05-8.00(m,1H),7.64-7.60(m,1H),7.56(d,J＝8.1Hz,1H),7.42-7.38(m,1H),4.69(d,J＝2.6Hz,2H),2.44(t,J＝2.6Hz,1H).

2- (but-3-yn-1-yl) benzisothiazol-3 (2H) -one (15.1) as a yellow solid in 13% yield.

Step 2

Synthesis of Compounds I-14 to I-16

Reference method I-6

2- (2- (1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) benzisothiazol-3 (2H) -one (I-14) as a yellow solid in 79% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.08-8.00(m,2H),7.72-7.64(m,2H),7.64-7.58(m,1H),7.54(d,J＝8.1Hz,1H),7.44-7.38(m,1H),7.23-7.15(m,2H)；¹³C NMR(100MHz,CDCl₃)δppm 165.5,163.9,161.4,144.0,140.8,132.3,126.8,125.8,124.1,122.7(d,J＝8.7Hz,2C),121.8,120.7,116.9(d,J＝23.2Hz,2C),39.1；HRMS(ESI)m/z calcd for C₁₆H₁₁FN₄OS(M+H)⁺327.07,found 326.83.

2- (2- (1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) ethyl) benzisothiazol-3 (2H) -one (I-15) as a yellow solid in 79% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.02(d,J＝7.9Hz,1H),7.84(s,1H),7.69-7.62(m,2H),7.62-7.56(m,1H),7.52(d,J＝8.1Hz,1H),7.39(dd,J＝11.4,4.4Hz,1H),7.22-7.15(m,2H),4.31(t,J＝7.0Hz,2H),3.29(t,J＝7.0Hz,2H)；¹³C NMR(100MHz,CDCl₃)δppm 165.7,162.5(d,J＝249Hz,1C),144.9,140.5,133.5(d,J＝3.1Hz,1C),132.0,126.7,125.7,124.5,122.5(d,J＝8.6Hz,2C),120.5,120.3,116.8(d,J＝23.2Hz,2C),43.2,26.0；HRMS(ESI)m/z calcd for C₁₇H₁₃FN₄OS(M+H)⁺341.0872,found 341.0871.

2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) benzisothiazol-3 (2H) -one (I-16) as a yellow solid in 84% yield.

¹H NMR(400MHz,DMSO)δppm 10.97(s,1H),8.58(s,1H),7.93(dd,J＝26.9,7.9Hz,2H),7.68(t,J＝7.2Hz,2H),7.53–7.26(m,2H),7.11(d,J＝8.0Hz,1H),5.19(s,2H)；HRMS(ESI)m/z calcd for C₁₆H₁₁ClN₄O₂S(M+H)⁺359.0369,found 359.0367.

Example 11

Synthesis of 2- ((5- (substituted phenyl) -1,2, 4-thiadiazol-3-yl) methyl) benzisothiazol-3 (2H) -one (I-17 and I-18)

Step 1

Synthesis of 5- (substituted phenyl) -1,3, 4-oxathiazol-2-one (17.1 and 18.1)

The substituted benzamide (10mmol) was dissolved in 80mL of toluene, and chlorocarbonyl methanesulfonyl chloride (1.57g,12mmol) was added thereto, followed by reflux reaction for 6 hours, to thereby complete the reaction. Removing the solvent by rotation, adding n-pentane: and (3) carrying out ultrasonic treatment on the ethyl ether at a ratio of 1:1, freezing and standing, filtering, recrystallizing the filtrate, and combining filter cakes to obtain the product.

5- (3-trifluoromethylphenyl) -1,3, 4-oxathiazol-2-one (17.1) as an off white solid in 70% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.25(s,1H),8.16(d,J＝7.9Hz,1H),7.83(d,J＝7.9Hz,1H),7.66(t,J＝7.9Hz,1H)。

5- (5-chloro-2-hydroxyphenyl) -1,3, 4-oxathiazol-2-one (18.1) as a white solid in 70% yield.

¹H NMR(400MHz,CDCl₃)δ9.74(s,1H),7.70(d,J＝2.6Hz,1H),7.43(s,1H),7.03(d,J＝8.9Hz,1H).

Step 2

Synthesis of 5- (chloromethyl) -3- (substituted phenyl) -1,2, 4-thiadiazole (17.2 and 18.2)

17.1 or 18.1(6.88mmol) was dissolved in 17mL of chloroacetonitrile (40 eq.) and reacted under reflux for 36 hours, then the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: dichloromethane ═ 10:1) to give the product.

5- (chloromethyl) -3- (3-trifluoromethylphenyl) -1,2, 4-thiadiazole (17.2) as a pale yellow solid in 53% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.56(s,1H),8.46(d,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.61(t,J＝7.8Hz,1H),5.00(s,2H).

5- (chloromethyl) -3- (5-chloro-2-hydroxyphenyl) phenyl) -1,2, 4-thiadiazole (18.2) as a yellow solid in 32% yield.

¹H NMR(400MHz,CDCl₃)δppm 10.73(s,1H),8.23(d,J＝2.6Hz,1H),7.33(d,J＝11.5Hz,1H),7.01(d,J＝8.8Hz,1H),5.01(s,2H).

Step 3

Synthesis of Compounds I-17 and I-18

17.2 or 18.2(3mmol) was dissolved in 10mL of acetone, sodium iodide (675mg,4.5mmol) was added, reflux reaction was carried out for 4 hours, then ethyl acetate was added for extraction, washing with water, drying of the organic layer, and concentration was carried out to obtain crude N- (2-iodoethyl) -3-oxobenzisothiazole-2 (3H) -carboxamide. BIT (378mg,2.5mmol) and potassium carbonate (518mg,3.75mmol) were dissolved in 4mL of DMF, and after 30 minutes of reaction at room temperature, the crude product was added thereto and reacted with 150W at 100 ℃ for 20 minutes by microwave to terminate the reaction. Extracting with ethyl acetate, washing with water, drying the organic layer, concentrating, and purifying by silica gel column chromatography (petroleum ether: dichloromethane: triethylamine: 1:0.02) to obtain the product.

2- ((5- (3-trifluoromethylphenyl) -1,2, 4-thiadiazol-3-yl) methyl) benzisothiazol-3 (2H) -one (I-17) as a pale yellow solid in 32% yield.

¹H NMR(400MHz,CDCl₃)δppm 8.56(s,1H),8.46(d,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.61(t,J＝7.8Hz,1H),5.00(s,2H)；¹³C NMR(100MHz,CDCl₃)δppm 187.6,171.7,161.3,152.5,133.4,131.6,131.5,131.3,129.4,129.3,127.1(q,J＝3.7Hz,1C),125.4(q,J＝3.8Hz,1C),125.1,124.6,123.1,120.5,66.4；HRMS(ESI)m/z calcd for C₁₇H₁₀F₃N₃OS₂(M+H)⁺394.0,found 394.0.

2- ((5- (5-chloro-2-hydroxyphenyl) -1,2, 4-thiadiazol-3-yl) methyl) benzisothiazol-3 (2H) -one (I-18) as a yellow solid in a yield of 10%.

¹H NMR(400MHz,CDCl₃)δppm 10.91(s,1H),8.30(s,1H),8.00(d,J＝8.6Hz,1H),7.84(d,J＝9.1Hz,1H),7.59(t,J＝7.8Hz,1H),7.51-7.42(m,1H),7.32(d,J＝8.5Hz,1H),7.02(d,J＝9.3Hz,1H),6.07(s,2H)；HRMS(ESI)m/z calcd for C₁₆H₁₀ClN₃O₂S₂(M+H)⁺376.0,found 376.0.

Example 12

Synthesis of N- (2- (3-cyclopropylisoxazol-5-yl) ethyl) -4- (naphthalen-1-yl) -3-oxoisothiazole-2 (3H) -sulfonamide (I-19)

Step 1

Synthesis of 3- (benzyloxy) -4-bromoisothiazole (19.1)

3-Benzyloxyiisothiazole (590mg, 3mmol) was dissolved in anhydrous MeCN (10mL) and NBS (588mg, 3.3mmol) was added. The mixture was stirred at room temperature for 7 days. The mixture was concentrated to about 50 ℃. Add 1mL and EtOAc. Subjecting the organic solution to H₂O washing, then brine washing and MgSO₄Drying, concentrating, and purifying by silica gel column chromatography (petroleum ether: toluene: 2: 1-1: 1) to obtain the product.

3- (benzyloxy) -4-bromoisothiazole (19.1) was obtained as a clear oil in 88% yield.

¹H NMR(400MHz,CDCl₃):δ5.40(s，2H)，7.27-7.43(m，5H)，8.20(s，1H).

Step 2

Synthesis of 3- (naphthalen-1-yl) isothiazol-3 (2H) -one (19.2)

19.1(297mg, 1.1mmol), 1-naphthylboronic acid (567mg, 3.3mmol, 3 equiv.) and powdered K are stirred₂CO₃(228mg, 1.65mmol, 1.5 equiv.). Pd (OAc) in dry and degassed DMF (2ml) under nitrogen₂(12mg, 5 mol%) was heated to about 100 ℃ until no starting material remained (TLC). The mixture was cooled to about 20 ℃. Dilute with DCM (15ml) and H₂O (4X 10ml) wash. Separating the organic layer, and purifying by column chromatography to obtain the product.

3- (Naphthalen-1-yl) isothiazol-3 (2H) -one (19.2) as a clear oil in 77% yield.

¹H NMR(400MHz,CDCl₃):δ7.98–7.90(m,3H),7.69–7.59(m,3H),7.48(s,1H),7.06(s,1H),6.88(s,1H).

Step 3

Synthesis of N- (but-3-yn-1-yl) -4- (naphthalen-1-yl) -3-oxoisothiazole-2 (3H) -sulfonamide (19.3)

A stirred solution of 19.2(102mg, 0.495mmol) and triethylamine (69 μ L, 0.495mmol, 1 eq.) in DCM (2ml) was cooled to about 0 ℃. 3-Propyn-1-ylaminosulfonyl chloride (165mg, 0.99mmol, 2 equivalents) was added to the reaction mixture. The reaction mixture was kept stirring at about 100 ℃ until no starting material remained (TLC). The product was purified by column chromatography (hexane-DCM ═ 5: 3).

N- (but-3-yn-1-yl) -4- (naphthalen-1-yl) -3-oxoisothiazol-2 (3H) -sulfonamide (19.3) as a pale yellow solid in 24% yield.

¹H NMR(400MHz,CDCl₃):δ7.98–7.86(m,3H),7.77–7.64(m,3H),7.46(m,1H),6.84(m,1H),6.32(s,1H),2.87(m,2H),2.46m,2H),1.99(m,1H).

Step 4

Synthesis of Compound I-19

To a solution of N-hydroxycyclopropanecarbonimide chloride (3mmol) in ethyl acetate (7mL) was added 19.3(6mmol) and solid sodium bicarbonate (840mg, 10 mmol). The mixture was stirred at room temperature until the halogenated oxime disappeared; the progress of the reaction was monitored by TLC. (eluent: 20% ethyl acetate/cyclohexane). The slurry was poured into water, the organic layer was separated and the aqueous phase was further extracted with ether (2X 20 mL). The organic extract was dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether: dichloromethane: triethylamine: 1:0.02) to obtain a product.

N- (2- (3-Cyclopropylisoxazol-5-yl) ethyl) -4- (naphthalen-1-yl) -3-oxoisothiazole-2 (3H) -sulfonamide (I-19) as a pale yellow solid in 51% yield.

¹H NMR(400MHz,CDCl₃):δ7.93–7.85(m,3H),7.73–7.62(m,3H),7.43(m,1H),6.85(m,1H),6.81(m,1H),4.74(m,1H),3.01(m,J＝2.7Hz,4H),2.21(m,1H),1.11(m,J＝124.7Hz,4H).

Example 13

The inhibitory activity of isothiazolinone compounds on IDO enzyme was studied.

The test methods are described in reference to Yue E W, Douty B, Wayland B, et al, discovery of content inhibition of induced 2,3-dioxygenase with in vivo pharmacological activity and efficacy in a mouse melanema model [ J ]. Journal of Medicinal Chemistry,2009,52(23): 7364-.

IDO catalyzes the indole epoxidation cleavage of tryptophan to produce N' -formylkynurenine. The assay was performed at room temperature using 20nM IDO and 2mM L-tryptophan in 50mM potassium phosphate buffer (pH6.5) to which 20mM ascorbate, 3.5. mu.M methylene blue and 0.2mg/mL catalase were added as described in the literature. The initial reaction rate was recorded by continuously tracking the increase in absorbance at 321nm due to the formation of N' -formylkynurenine. The test is divided into a blank control group, a sample group and a positive control group; simultaneously adding 10 mu M and 0.1 mu M of I-1-I-18 dimethyl sulfoxide solution into the sample group and the positive control group; the blank was added with the same volume of dimethyl sulfoxide. Two replicates of each group were run and the results are shown in table 1.

TABLE 1 inhibitory Activity of isothiazolinone Compounds on IDO enzyme

Compound	10 μ M inhibition (%)	0.1. mu.M inhibition (%)
			Ⅰ-1	It is preferable that	In general
Ⅰ-2	Good effect	In general
			Ⅰ-3	In general	In general
Ⅰ-4	In general	In general
			Ⅰ-5	Good effect	In general
Ⅰ-6	It is preferable that	In general
			Ⅰ-7	It is preferable that	In general
Ⅰ-8	In general	In general
			Ⅰ-9	Good effect	In general
Ⅰ-10	Good effect	In general
			Ⅰ-11	It is preferable that	In general
Ⅰ-12	In general	In general
			Ⅰ-13	Good effect	In general
Ⅰ-14	Good effect	In general
			Ⅰ-15	Good effect	In general
Ⅰ-16	Good effect	In general
			Ⅰ-17	Good effect	In general
Ⅰ-18	Good effect	In general
			Ⅰ-19	It is preferable that	In general

Preferably: the compound inhibition rate is between 76% and 100%, and is good: the inhibition rate of the compound is between 51% and 75%, and generally: the inhibition rate of the compound is between 0 and 50 percent.

As can be seen from the results in Table 1, most of the compounds of formula (I) exhibited good inhibitory activity against IDO enzyme at a concentration of 10. mu.M, and exhibited some inhibitory activity against IDO enzyme at a concentration of 0.1. mu.M, with 4 compounds being more effective in inhibiting IDO.

In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.

Claims

1. An isothiazolinone compound, which is characterized in that the structural formula of the isothiazolinone compound is as follows:

2. use of the isothiazolinone compound according to claim 1 for preparing IDO inhibitor.

3. The application of isothiazolinone compounds in preparing IDO inhibitor medicines is characterized in that the isothiazolinone compounds are selected from the following:

4. use of an isothiazolinone compound according to claim 1 for the preparation of a medicament for the treatment of IDO mediated diseases.

5. Use of an isothiazolinone compound for the manufacture of a medicament for the treatment of IDO mediated diseases, wherein the isothiazolinone compound is selected from the group consisting of:

6. the use according to claim 4 or 5, wherein the IDO mediated disease comprises an infection, cancer, or autoimmune disease.

7. The use according to claim 6, wherein the cancer is one or more of bone cancer, gastric cancer, colon cancer, membrane adenocarcinoma, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, cancer of the innocent pill, kidney cancer, head and neck cancer, lymphoma, leukemia and skin cancer;

8. A pharmaceutical composition is characterized by comprising a therapeutically effective amount of an active component and pharmaceutically acceptable excipients; the active ingredient comprising the isothiazolinone compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 8, wherein said active ingredient further comprises a therapeutic agent for cancer, infection, or autoimmune disease.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in the form of capsule, microcapsule, tablet, granule, pill, dispersed powder, liquid, soft extract, suspension, syrup, gel, aerosol, patch or liposome.

11. The pharmaceutical composition according to claim 8, wherein the isothiazolinone compound or pharmaceutically acceptable salt is present in the pharmaceutical composition in an amount of 0.05mg/kg to 90 mg/kg.