CN117285484A - Benzothiadiazine 1, 1-dioxide compounds inhibiting HDAC6 enzyme, preparation method and application thereof - Google Patents

Abstract

The invention provides a benzothiadiazine 1, 1-dioxide compound, a preparation method and application thereofThe structural general formula of the benzothiadiazine 1, 1-dioxide compound is shown as a formula (I), or an isomer thereof, or pharmaceutically acceptable salt, ester or prodrug thereof. The benzothiadiazine 1, 1-dioxide compound disclosed by the invention has a novel structure, can selectively inhibit HDAC6 enzyme, has a relatively strong protective effect on nerve cells, is low in toxicity and potential cardiac toxicity, and is expected to be used as a neuroprotectant for treating neurodegenerative diseases.

Description

Benzothiadiazine 1, 1-dioxide compounds inhibiting HDAC6 enzyme, preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a benzothiadiazine 1, 1-dioxide compound for inhibiting HDAC6 enzyme, a preparation method and application thereof.

Background

Histone deacetylases (histone deacetylases, HDACs) and histone acetyltransferases (histone acetyltransferases, HATs) together regulate intracellular levels of acetylation, thereby regulating gene expression. HDACs are key regulators of gene expression, and 18HDAC subtypes have been identified in mammals to date, and are classified into four classes based on their homology to yeast proteins: class I (HDAC 1, HDAC2, HDAC3, HDAC 8) is usually present in the nucleus and has ubiquitous expression in various cell lines and tissues; class II is further divided into two subfamilies of IIa (HDAC 4, HDAC5, HDAC7, HDAC 9) and IIb (HDAC 6, HDAC 10) with homology to yeast proteins, mainly shuttling between the nucleus and cytoplasm; class IV (HDAC 11) exists as its sole member in the nucleus and cytoplasm, similar to the catalytic sites of class I and class II enzymes. These three classes represent zn2+ -dependent deacetylases. Class III (Sirt 1-Sirt 7) NAD+ -dependent deacetylases require the activity and homolog of the NAD+ yeast protein SiR 2.

There are a total of 5 histone deacetylase inhibitors (HDACi) currently on the market, vorinostat (vorinostat), belinostat (belinostat), panobinostat (panobinostat), romidepsin (romidepsin) and cidamide (chidamide), respectively, the first three being broad-spectrum inhibitors, the latter two selectively acting on class I subtypes. Vorinostat and romidepsin are used to treat Cutaneous T Cell Lymphomas (CTCL), belinostat and sidamine are used to treat recurrent and refractory Peripheral T Cell Lymphomas (PTCL), and panobinostat is used in combination with bortezomib and dexamethasone to treat Multiple Myeloma (MM).

Although the HDAC inhibitors described above have achieved good clinical efficacy, the following drawbacks are common to the broad-spectrum HDAC inhibitors:

(1) Stronger toxic and side effects, such as nausea, vomiting, bone marrow suppression and the like;

(2) Genotoxicity;

(3) Poor pharmacokinetic properties, low bioavailability, short half-life, etc.

The above disadvantages both cause inconvenience to the tumor patient and prevent the use of broad-spectrum HDAC inhibitors in fields other than tumor therapy.

Currently, HDACs subtype selective inhibitors are a research hotspot in this field, and HDAC6 is a new hotspot for tumor therapy due to its unique structure and function.

HDAC6 is a widely expressed cytoplasmic protein deacetylase, and major targets include a-tubulin and HSP90. Through post-translational modification of these substrates and other cytoplasmic targets, involvement in several critical cellular processes, including primary cell cilia, intracellular signaling, and DNA damage responses, inhibition of HDAC6 results in restoration of cell cilia and attenuation of malignant phenotypes, consistent with its role in cell regulation. At the same time, inhibition of HDAC6 has been shown to reduce the oncogenic Hedgehog signaling pathway (Hedgehog signaling pathway controls cell fate, proliferation and differentiation, which when abnormally activated, causes tumor development and progression.) HDAC6 is an important intracellular chaperone through interactions with signaling mediators or through modulation of HSP90 direct and intracellular signaling. Overall, these studies link HDAC6 with various oncogenic processes and underscores the potential of HDAC6 inhibitors to induce cellular and immune-mediated antitumor activity.

One of the well-known substrates for HDAC6 is α -tubulin, which is the major component of microtubules. Acetylation of α -tubulin at lysine 40 is a common process in microtubules. The stability of microtubule function is strongly dependent on the acetylation status of α -tubulin. Microtubule-based transport disorders can disrupt mitochondrial transport between neuronal cell bodies and axons/dendrites and further lead to mitochondrial dysfunction and subsequent cell death. Mitochondria are prominent microtubule-based axon transport organelles, and increasing the acetylation of α -tubulin by inhibiting HDAC6 can improve microtubule-based transport, thereby improving mitochondrial transport defects. Prior studies have shown that HDAC6 inhibition may slow or reverse aβ -related neuronal damage, thus representing a viable drug target for the treatment of AD.

Disclosure of Invention

The benzothiadiazine 1, 1-dioxide compound provided by the invention has the advantages of novel structure, capability of selectively inhibiting HDAC6 enzyme, strong protection effect on nerve cells, low toxicity and low potential cardiac toxicity, and is expected to be used as a neuroprotectant for treating neurodegenerative diseases.

In order to achieve the above object, the first aspect of the present invention provides a benzothiadiazine 1, 1-dioxide compound, the structural general formula of which is shown in formula (i), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;

wherein,

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

when there is an n=c double bond between 2-N and 3-C on the 1, 1-dioxybenzothiadiazine ring, the compounds of formula (i) do not contain R ₃ ；

When N-C single bond is between 2-N and 3-C on 1, 1-dioxybenzothiadiazine ring, R ₃ Selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl or- (CH) _m )n-R ₅ Which may be optionally substituted; r is R ₅ Selected from cycloalkyl, aryl, heteroaryl or hydroxy; m is an integer of 0 to 2, and n is a positive integer;

R ₄ Selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, arylA group, heteroaryl, heterocycloalkyl, acyl, or sulfonyl group, which may be optionally substituted.

Preferred benzothiadiazine 1, 1-dioxide compounds of the invention include the compound (I-1) or the compound (I-2):

in the compounds of formula (I-1),

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

R ₄ selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl, or sulfonyl, which may be optionally substituted;

in the compounds of formula (I-2),

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

R ₃ selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl or- (CH) _m )n-R ₅ Which may be optionally substituted; r is R ₅ Selected from cycloalkyl, aryl, heteroaryl or hydroxy; m is an integer of 0 to 2, and n is a positive integer;

R ₄ Selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl, or sulfonyl, which may be optionally substituted.

Preferably, the alkyl is an alkyl group having 1 to 4 carbon atoms, which may be optionally substituted with 0 to 3 halogens;

preferably, the cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, which may be optionally substituted with 0 to 3 halogens;

preferably, the heterocycloalkyl group is selected from pyrrolyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroquinolinyl, tetrahydrotriazolopyrazinyl, diazepanyl or piperazinyl, which may be optionally substituted;

preferably, the aryl or heteroaryl is selected from phenyl, naphthyl, anthracenyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl or 5,6,7, 8-tetrahydroisoquinolinyl; which may be optionally substituted;

preferably, the acyl group is selected from acetyl, propionyl, isobutyryl or aryl acyl groups, which may be optionally substituted;

Preferably, the sulfonyl group is selected from the group consisting of methanesulfonyl and arylsulfonyl, which may be optionally substituted;

preferably, the aminoalkyl group is selected from dimethylaminoalkyl, methylaminoalkyl, piperazinoalkyl, or piperidoalkyl, which may be optionally substituted;

preferably, the halogen is selected from fluorine or chlorine;

preferably, the alkoxy group is selected from alkoxy groups containing 1 to 4 carbon atoms;

preferably, the R ₅ Selected from aryl, cycloalkyl or hydroxy;

preferably, n is an integer from 0 to 4.

Preferably, the pharmaceutically acceptable salts of the compounds of formula (I) of the present invention include anionic salts of the compounds of formula (I) formed by the reaction of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, malic acid, p-toluenesulfonic acid or oxalic acid; or a cationic salt formed by reacting the compound of formula (I) with a sodium ion solution and a potassium ion solution.

Further preferred in the present invention is R ₁ And R is ₂ Independently selected from hydrogen, methyl, F or Cl;

further preferred in the present invention is R ₃ The N atom being linked to adjacent C atoms by a N=C double bond, the compounds of formula (I) not containing R ₃ The method comprises the steps of carrying out a first treatment on the surface of the Or, R ₃ The N atom being bound to adjacent C atoms by N-C single bonds, R ₃ Selected from hydrogen or- (CH) _m )n-R ₅ ，R ₅ Selected from phenyl, cyclopropyl, cyclohexenyl or hydroxy; m is 1 or 2, n is 1, 2 or 3;

further preferred in the present invention is R ₄ Selected from hydrogen, oxygen or methyl.

In some embodiments of the present invention, the benzothiadiazine 1, 1-dioxide compound comprises a compound shown in table 1 or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof:

TABLE 1

The second aspect of the present invention provides a preparation method of the benzothiadiazine 1, 1-dioxide compound according to the technical scheme, which comprises one or more of the following methods:

if the compound of formula (I) does not contain R ₃ The preparation method a is adopted;

the method a comprises the following steps:

a1, reacting a compound shown in a formula (II) with methyl 4-bromomethylbenzoate under a heating condition to obtain a compound shown in a formula (III);

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme;

in the invention, preferably, the heating temperature in the step A1 is 60-80 ℃, and the heating reaction time is 3-4 hours;

a2, reacting the compound shown in the formula (III) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-1);

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme;

In a preferred embodiment of the invention, in step A2, the compound of formula (III) is reacted with hydroxylamine in sodium methoxide in methanol;

in the preferred embodiment of the invention, in the step A2, the reaction temperature is between-5 ℃ and the reaction temperature is between 4 and 6 hours;

if the compound of formula (I) comprises R ₃ And R is ₃ Is hydrogen, R ₄ For non-oxo, can be prepared using method b:

the method b comprises the following steps:

b1, reducing the compound of formula (III) into the compound of formula (IV) through sodium borohydride;

wherein R is ₁ 、R ₂ As shown in the technical scheme; r is R ₄ A non-oxo group selected from the group consisting of those set forth in the above schemes;

in the preferred embodiment of the present invention, in step B1, sodium hydride is added to a solution of the compound of formula (III) to perform a reduction reaction to produce the compound of formula (IV);

b2, reacting the compound shown in the formula (IV) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-2-1);

wherein R is ₁ 、R ₂ As shown in the technical scheme; r is R ₄ A non-oxo group selected from the group consisting of those set forth in the above schemes;

in a preferred embodiment of the invention, in step B2, the compound of formula (IV) is reacted with hydroxylamine in sodium methoxide in methanol;

in the preferred step B2, the reaction temperature is-5 ℃ and the reaction temperature is 4-6 h;

if the compound of formula (I) comprises R ₃ And R is ₃ Is hydrogen, R ₄ As oxo, prepared using method c:

The method c comprises the following steps:

c1, reacting a compound shown in a formula (V) with methyl 4-bromomethylbenzoate under alkaline conditions to obtain a compound shown in a formula (VI);

wherein R is ₁ 、R ₂ As shown in the technical scheme;

preferably, in the step C1, the compound of formula (V) and sodium carbonate are dissolved in N, N-dimethylformamide, methyl 4-bromomethylbenzoate is added into the solution dropwise, and the compound of formula (VI) is obtained by reaction;

in the preferred embodiment of the invention, in the step C1, the reaction time is 3-5 hours;

c2, reacting the compound shown in the formula (VI) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-2-2);

wherein R is ₁ 、R ₂ As shown in the technical scheme;

if the compound of formula (I) comprises R ₃ And R is ₃ Is non-hydrogen, prepared using method d:

in a preferred embodiment of the invention, in step C2, the compound of formula (VI) is reacted with hydroxylamine in sodium methoxide in methanol;

in the preferred step C2, the reaction temperature is-5 ℃ and the reaction temperature is 4-6 h;

the method d comprises the following steps:

d1, reacting the compound shown in the formula (IV) with the compound shown in the formula (VII) under heating condition to obtain a compound shown in the formula (VIII);

wherein,

the compound of formula (IV) can be prepared according to the method shown in the step B1;

R ₁ 、R ₂ 、R ₄ as shown in the technical scheme; r is R ₃ A non-hydrogen group selected from the group consisting of those described in the above schemes;

x is halogen;

in the invention, preferably, the heating temperature in the step D1 is 60-80 ℃ and the reaction time is 1.5-3 h;

d2, reacting a compound of formula (VIII) with hydroxylamine under alkaline conditions to obtain a compound of formula (I-2-3);

wherein,

R ₁ 、R ₂ 、R ₄ as shown in the technical scheme; r is R ₃ Selected from the non-hydrogen groups shown in the above technical scheme.

Preferably, in step D2, the compound of formula (VIII) is reacted with hydroxylamine in sodium methoxide in methanol;

in the preferred step D2, the reaction temperature is-5 ℃ and the reaction temperature is 4-6 h.

Preferably, the preparation method of the compound of the formula (V) comprises the following steps:

reacting a compound of formula (IX) with chlorosulfonyl isocyanate at-50-100 ℃, and then reacting with aluminum chloride at 30-120 ℃ to obtain a compound of formula (V);

wherein R is ₁ 、R ₂ As shown in the technical scheme;

in a further preferred process according to the invention, the reaction time of the compound of formula (IX) with chlorosulfonyl isocyanate is from 20 to 60 minutes;

in a further preferred process according to the invention, the reaction time of intermediate 1 with aluminium chloride is from 0.5 to 2 hours;

Preferably, the preparation method of the compound of the formula (II) comprises the following steps:

e1, reacting a compound of formula (V) with dilute sulfuric acid at 130-150 ℃ to obtain a compound of formula (X);

/>

wherein R is ₁ 、R ₂ As the technical proposalShowing;

in a further preferred aspect of the present invention, the dilute sulfuric acid in step E1 is an aqueous solution of sulfuric acid with a volume concentration of 45-60%;

in a further preferred embodiment of the invention, in step E1, the reaction time is from 6 to 10 hours;

e2, heating and reacting the compound of formula (X) with the compound of formula (XI) to obtain the compound of formula (II);

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme.

In a further preferred embodiment of the invention, in step E2, the heating temperature is from 90℃to 110℃and the reaction time is from 1.5 to 3 hours.

A third aspect of the present invention provides an intermediate compound for preparing a benzothiadiazine 1, 1-dioxide compound according to the preceding technical scheme, comprising one or more of the following compounds:

a compound of formula (ii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme;

and/or a compound of formula (iii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme;

And/or a compound of formula (iv) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in the technical scheme; r is R ₄ A non-oxy group selected from the group consisting of those set forth in the preceding claims;

and/or, a compound of formula (v):

wherein R is ₁ 、R ₂ As shown in the technical scheme;

and/or a compound of formula (vi) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in the technical scheme;

and/or a compound of formula (viii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in the technical scheme; r is R ₃ A non-hydrogen group selected from the group consisting of those set forth in the preceding claims;

and/or a compound of formula (ix) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in the technical scheme;

and/or a compound of formula (x) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in the technical scheme.

The fourth aspect of the invention provides an application of the benzothiadiazine 1, 1-dioxide compound in the technical scheme, the benzothiadiazine 1, 1-dioxide compound obtained by the preparation method in the technical scheme or the intermediate compound in the technical scheme in preparing histone deacetylase inhibitor or neurodegenerative disease treatment medicine.

Preferably, the histone deacetylase inhibitor is an HDAC6 and/or HDAC1 inhibitor.

Preferably, the neurodegenerative disease treatment drug comprises a treatment drug for treating neurodegenerative diseases including acute neurodegenerative diseases and chronic neurodegenerative diseases, wherein the acute neurodegenerative diseases mainly comprise Cerebral Ischemia (CI), brain Injury (BI) and epilepsy; chronic neurodegenerative diseases include Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's Disease (HD), amyotrophic Lateral Sclerosis (ALS), different types of spinocerebellar ataxia (SCA), pick's disease, and the like.

In a fifth aspect, the invention provides a pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; the active component comprises the benzothiadiazine 1, 1-dioxide compound of the technical scheme or the benzothiadiazine 1, 1-dioxide compound obtained by the preparation method of the technical scheme.

Preferably, the pharmaceutically acceptable auxiliary materials comprise one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, flavoring agents and sweeteners.

The pharmaceutical composition can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicaments of the various forms can be prepared according to a conventional method in the pharmaceutical field. The active components in the pharmaceutical composition can also be combined with other active components with therapeutic effects or effective components for enhancing therapeutic effects, reducing toxic and side effects and prolonging metabolism time to form the pharmaceutical composition.

Compared with the prior art, the invention has the beneficial effects that:

1) The benzothiadiazine 1, 1-dioxide compound has inhibiting activity on HDAC6 and HDAC1, and has stronger inhibiting activity on HDAC 6; most compounds have better HDAC6 inhibitory activity than HDAC1, showing some selectivity (compared to HDAC 1);

2) The benzothiadiazine 1, 1-dioxide compound can improve the cell activity of an SH-SY5Y cell damage model, and shows better cell damage protection effect;

3) The benzothiadiazine 1, 1-dioxide compound has generally weaker antiproliferative effect on human neuroblastoma cells (SH-SY 5Y) and human normal embryo lung fibroblasts (MRC-5), is weaker than the prior medicines SW-100 and ACY-1215, and has smaller cytotoxicity;

3) The benzothiadiazine 1, 1-dioxide compound has weak hERG inhibition activity and low potential cardiotoxicity.

Detailed Description

In the present invention, the term "isomer" includes, but is not limited to, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, tautomers, racemic mixtures, and mixtures of diastereomers, and pharmaceutically acceptable salts thereof. Unless otherwise indicated, when an isomer component is not specifically indicated, all possible isomers are included.

In the present invention, the "pharmaceutically acceptable salt" refers to a compound modified by forming an acid or basic salt of the benzothiadiazine compound of the present invention, including but not limited to salts of inorganic acids selected from, for example, hydrochloride, phosphate, hydrogen phosphate, hydrobromide, sulfate, sulfite, and nitrate; and salts of organic salts selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and HOOC- (CH) ₂ ) Salts of p-COOH, wherein p can be any integer from 0 to 4. If the compound is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, consistent with conventional procedures for preparing acid addition salts from basic compounds. Those of skill in the art will appreciate the variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation. Similarly, the "pharmaceutically acceptable esters" refer to ester derivatives of the small molecule inhibitors of the present invention, and the "pharmaceutically acceptable prodrugs" include precursor compounds of the small molecule inhibitors of the present invention having an in vivo profile.

In the present invention, the "aromatic ring" or "aryl" refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a fully conjugated pi-electron system. Non-limiting examples of aromatic rings are: benzene rings, biphenyls, naphthalene rings, and anthracene rings. The aromatic ring may be unsubstituted or substituted. The substituents of the aromatic ring may be selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl.

In the present invention, 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. The heteroaromatic ring may be a single ring or may be a double ring, i.e., fused together through two rings. Specific heteroaryl groups may be: pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolyl, benzo [1,3] dioxolyl, oxazolyl, benzoxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, and the like. The heteroaryl group may be unsubstituted or substituted. The substituents of the heteroaryl groups may be selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl.

In the present invention, the term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy, which can be unsubstituted or substituted.

In the present invention, the "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

In the present invention, the pharmaceutically acceptable auxiliary materials include, but are not limited to, conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field, and flavoring agents, sweeteners and the like may be added as necessary. The pharmaceutical composition can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicaments of the various forms can be prepared according to a conventional method in the pharmaceutical field.

The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. All raw materials were analytically pure and purchased from manufacturers such as exploration platform, allatin, sigma-Aldrich, etc. without any indication of the synthetic method.

EXAMPLE 1 preparation of 4- (1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-1)

T-1 was prepared according to procedure a. The operation is as follows:

1) Aniline (270 mmol) was dissolved in 100mL nitromethane at-40 ℃ and then added dropwise to a solution of chlorosulfonyl isocyanate (26 mL,300 mmol) in 200mL nitromethane using a dropper funnel. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes and aluminum chloride (39 g,300 mmol) was added. The mixture was then heated to 110 ℃ with stirring and maintained for 1 hour. Then pouring the crude material into ice, filtering, collecting precipitate, washing with cold water and absolute ethyl ether, and pulping with absolute ethyl alcohol to obtain an intermediate a1.

2) Intermediate a1 was added to 320ml of 50% aqueous sulfuric acid and heated to 140 ℃ for 8 hours. The solution was then poured onto ice and neutralized with saturated aqueous sodium hydroxide at 0 ℃. The precipitate was collected by suction filtration, washed with cold water and dried in vacuo to afford intermediate a2.

3) The appropriate 2-aminobenzenesulfonamide a2 (100 mmol) was heated to reflux in triethyl orthoformate/triethyl orthoacetate (150 mL) for 2 hours. After the mixture was cooled to room temperature, the desired compound was collected by filtration, washed with diethyl ether, slurried with dichloromethane and dried in vacuo to give intermediate 4H-1,2, 4-benzothiadiazine 1, 1-dioxide (a 3). Yield 89%; mp 226-228 ℃;1H NMR (400 MHz, DMSO-d 6): delta 7.28 (m, 1H), 7.43 (m, 1H), 7.65 (m, 1H), 7.78 (m, 1H), 7.96 (s, 1H), 12.28 (s, 1H).

4) The appropriate amount of 4H-1,2, 4-benzothiadiazine 1, 1-dioxide a3 (10 mmol), potassium carbonate (30 mmol) and 40mL acetonitrile were warmed to 50℃and stirred for about 1 hour. An acetonitrile solution (10.5 mmol/20 mL) of methyl 4-bromomethylbenzoate was added dropwise thereto, and the mixture was stirred at 70℃for about 3-4 hours. After evaporation of the solvent under reduced pressure, the crude solid was washed with water, dried and then recrystallized from ethyl acetate to give intermediate methyl 4- ((1, 1-dioxido-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate (a 4). LC-MS (ESI) (M/z): 331.00 (M+). 1H NMR (400 MHz, DMSO-d 6) delta 8.39 (s, 1H), 7.99-7.94 (m, 2H), 7.91 (dd, J=7.8, 1.6Hz, 1H), 7.64 (ddd, J=8.7, 7.3,1.6Hz, 1H), 7.52-7.42 (m, 3H), 7.31 (dd, J=8.6, 1.0Hz, 1H), 5.49 (s, 2H), 3.82 (s, 3H).

5) An appropriate amount of methyl 4- ((1, 1-dioxido-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate a4 (2 mmol) was added to a methanolic solution of hydroxylamine/sodium methoxide (20 mmol). And under the ice water bath condition, dropwise adding sodium methoxide methanol solution (10 mmol) for 4-6 hours. After the reaction was completed, 2 volumes of water was added and the pH was adjusted to 7-8 with 2M aqueous HCI, and a solid was precipitated, filtered and slurried with methanol to give 4- (1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-1). mp 220.7-222.7 ℃. LC-MS (ESI) (m/z) 365.00[ M+CH3OH+H ] + ]. 1H NMR (600 MHz, DMSO-d 6) δ11.21 (s, 1H), 9.05 (s, 1H), 8.41 (s, 1H), 7.91 (dd, J=7.9, 1.5Hz, 1H), 7.77-7.73 (m, 2H), 7.66 (ddd, J=8.7, 7.3,1.6Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.38 (t, J=8.6 Hz, 3H), 5.46 (s, 2H).

EXAMPLE 2 preparation of 4- (1, 1-dioxide-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-2)

T-2 was prepared according to procedure b. The operation is as follows:

1) An appropriate amount of methyl 4- ((1, 1-dioxido-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate (5 mmol) was added to 40mL of methanol, stirred at room temperature, sodium borohydride (20 mmol) was added in portions, and stirred for 30min. After the reaction was completed, the solvent was evaporated under reduced pressure, water was added and stirred, and the PH was adjusted to be acidic (ph=2-3) with a 2M aqueous HCI solution. A large amount of solid is separated out, filtered and dried to obtain the intermediate 4- ((1, 1-dioxide-2, 3-dihydro-4H-1, 2, 4-benzothiadiazin-4-yl) methyl benzoate (b 1). LC-MS (ESI) (M/z): 333.10 (M+). 1HNMR (400 MHz, DMSO-d 6) delta 8.22 (s, 1H), 7.99-7.88 (m, 2H), 7.56 (dd, J=7.8, 1.7Hz, 1H), 7.53-7.44 (m, 2H), 7.28 (ddd, J=8.7, 7.2,1.7Hz, 1H), 6.81-6.74 (m, 1H), 6.60 (dd, J=8.7, 1.0Hz, 1H), 4.89 (s, 2H), 4.71 (s, 2H), 3.84 (s, 3H).

2) An appropriate amount of methyl 4- ((1, 1-dihydro-2, 3-dihydro-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate b1 (2 mmol) was added to a methanolic solution of hydroxylamine/sodium methoxide (20 mmol). And under the ice water bath condition, dropwise adding sodium methoxide methanol solution (10 mmol) for 4-6 hours. After the reaction was completed, 2 volumes of water were added and the pH was adjusted to 7-8 with a 2M aqueous HCI solution, and a solid was precipitated, filtered and slurried with methanol to give 4- (1, 1-dioxide-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-2). mp 180.2-181.8 ℃. LC-MS (ESI) (M/z): 334.00 (M+). 1HNMR (400 MHz, DMSO-d 6) delta 7.71 (d, J=7.9 Hz, 2H), 7.55 (dd, J=7.8, 1.6Hz, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.30-7.25 (m, 1H), 6.76 (t, J=7.5 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 4.88 (s, 2H), 4.64 (s, 2H).

EXAMPLE 3 preparation of 4- (7-chloro-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-3)

T-3 was prepared according to procedure a. mp 175.9-176.1 ℃. LC-MS (ESI) (m/z): 399.00[ M+CH3OH+H ] + ]. 1H NMR (600 MHz, DMSO-d 6) δ11.14 (s, 1H), 8.99 (s, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.59 (d, J=2.7 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.31 (dd, J=9.0, 2.7Hz, 1H), 6.77 (s, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.54 (d, J=6.0 Hz, 2H).

Example 4: preparation of 4- ((7-chloro-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-4)

T-4 was prepared according to procedure b. mp 172.3-175.9 ℃. LC-MS (ESI) (M/z): 368.40 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(s,1H),7.72(d,J＝7.8Hz,2H),7.52(s,1H),7.32(t,J＝10.1Hz,3H),6.64(d,J＝9.1Hz,1H),4.88(s,2H),4.64(s,2H).

Example 5: preparation of 4- (7-fluoro-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-5)

T-5 was prepared according to procedure a. mp 155.3-158.3 ℃. LC-MS (ESI) (M/z): 349.90 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.14(d,J＝7.0Hz,1H),8.98(s,1H),7.68(d,J＝8.1Hz,2H),7.41(dd,J＝8.4,3.9Hz,3H),7.18(td,J＝8.6,3.4Hz,1H),6.59(ddd,J＝14.8,10.4,5.0Hz,2H),4.51(d,J＝5.9Hz,2H).

Example 6: preparation of 4- ((7-fluoro-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-6)

T-6.Mp 181.4-182.6℃was prepared according to procedure b. LC-MS (ESI) (M/z): 352.00 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.20(s,1H),9.04(s,1H),8.36(s,1H),7.72(d,J＝8.0Hz,2H),7.48–7.37(m,3H),7.23(td,J＝8.9,3.2Hz,1H),6.65(dd,J＝9.4,4.2Hz,1H),4.87(s,2H),4.66(s,2H).

Example 7: preparation of N-hydroxy-4- (7-methyl-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-7)

T-7 was prepared according to procedure a. mp 179.9-181.8 ℃. LC-MS (ESI) (M/z): 346.00 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ11.19(s,1H),9.05(s,1H),8.34(s,1H),7.76–7.67(m,3H),7.46(dd,J＝8.7,2.1Hz,1H),7.36(d,J＝7.9Hz,2H),7.26(d,J＝8.7Hz,1H),5.43(s,2H),2.36(s,3H).

Example 8: preparation of N-hydroxy-4- (7-methyl-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-8)

T-8.Mp 175.9-176.4℃was prepared according to procedure b. LC-MS (ESI) (M/z): 348.50 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.73–10.65(m,1H),9.08(s,1H),7.73–7.67(m,2H),7.47–7.40(m,3H),7.07(dd,J＝8.5,2.2Hz,1H),6.52(d,J＝8.4Hz,1H),6.37(t,J＝6.0Hz,1H),4.49(d,J＝5.9Hz,2H),2.16(s,3H).

Example 9: preparation of N-hydroxy-4- (7-methoxy-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-9)

T-9 was prepared according to procedure a. mp 186.3-188.8 ℃. LC-MS (ESI) (M/z): 361.40 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ11.14(s,1H),9.15(s,1H),8.32(s,1H),7.74(d,J＝8.2Hz,2H),7.36–7.31(m,4H),7.25(dd,J＝9.4,3.1Hz,1H),5.43(s,2H),3.82(s,3H).

Example 10: preparation of N-hydroxy-4- (7-methoxy-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-10)

T-10 was prepared according to procedure b. mp 165.1-166.9 ℃. LC-MS (ESI) (M/z): 364.60 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ9.37(s,1H),7.72(d,J＝8.0Hz,2H),7.38(d,J＝7.9Hz,2H),7.08(d,J＝3.0Hz,1H),6.98(dd,J＝9.2,3.1Hz,1H),6.64(d,J＝9.3Hz,1H),4.81(s,2H),4.61(s,2H),3.71(s,3H).

EXAMPLE 11 4- (1, 1-dioxide-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-11)

T-11 was prepared according to procedure c. The specific operation is as follows:

1) Intermediate a1 (10 mmol) and potassium carbonate (12 mmol) were added to 30mL of N, N-dimethylformamide, and an acetonitrile solution of methyl 4-bromomethylbenzoate (10 mmol/20 mL) was added dropwise, followed by stirring at room temperature for 4 hours. After the completion of the reaction, the reaction solution was poured into 200mL of water, and solids were precipitated and the obtained solids were isolated by filtration. The filter cake was washed with water and dried in vacuo to yield a mixture of regioisomerised alkylation products which was purified by column chromatography (petroleum ether: ethyl acetate system) to give intermediate methyl 4- ((1, 1-dioxo-3-oxo-2, 3-dihydro-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate (c 1). LC-MS (ESI) (M/z): 346.90 (M+). 1H NMR (600 MHz, DMSO-d 6) δ12.30 (s, 1H), 8.05-8.00 (m, 2H), 7.80 (dd, J=8.0, 1.4Hz, 1H), 7.65 (dd, J=7.6, 4.2Hz, 3H), 7.40-7.37 (m, 1H), 7.28 (d, J=8.2 Hz, 1H), 5.47 (s, 2H), 3.87 (s, 3H).

2) An appropriate amount of methyl 4- ((1, 1-dioxo-3-oxo-2, 3-dihydro-4H-1, 2, 4-benzothiadiazin-4-yl) methyl) benzoate c1 (2 mmol) was added to a methanolic solution of hydroxylamine/sodium methoxide (20 mmol). And under the ice water bath condition, dropwise adding sodium methoxide methanol solution (10 mmol) for 4-6 hours. After the reaction was completed, 2 volumes of water was added and the pH was adjusted to 7-8 with 2M aqueous HCI, and a solid was precipitated, filtered, and slurried with methanol to give T-1.mp 219.6-219.8 ℃. LC-MS (ESI) (M/z): 348.50 (M+). 1H NMR (400 MHz, DMSO-d 6) δ12.25 (s, 1H), 11.25 (s, 1H), 9.06 (s, 1H), 7.83-7.74 (m, 3H), 7.58 (dd, J=15.6, 7.6Hz, 3H), 7.34 (t, J=7.6 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 5.40 (s, 2H).

Example 12:4- ((7-fluoro-1, 1-dioxo-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-12)

T-12 was prepared according to procedure c. mp 216.2-217.0 ℃. LC-MS (ESI) (M/z): 366.50 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.34–11.14(m,1H),9.06(s,1H),7.82–7.75(m,2H),7.64(dd,J＝7.6,2.9Hz,1H),7.59–7.47(m,3H),7.29(dd,J＝9.1,4.5Hz,1H),5.40(s,2H).

Example 13: n-hydroxy-4- (7-methoxy-1, 1-dioxo-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-13)

T-13 was prepared according to procedure c. mp 211.9-212.7 ℃. LC-MS (ESI) (M/z): 378.60 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.26(s,1H),9.07(s,1H),7.82–7.76(m,2H),7.55(d,J＝8.2Hz,2H),7.25–7.16(m,3H),5.38(s,2H),3.81(s,3H).

Example 14:4- ((7-bromo-1, 1-dioxo-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-14)

T-14 was prepared according to procedure c. mp 222.6-223.3 ℃. LC-MS (ESI) (M/z): 427.80 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ12.52(d,J＝192.4Hz,1H),11.27(s,1H),9.08(s,1H),7.94(d,J＝2.2Hz,1H),7.84–7.78(m,3H),7.58(d,J＝8.0Hz,2H),7.22(d,J＝8.8Hz,1H),5.43(s,2H).

Example 15:4- ((7-chloro-1, 1-dioxo-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-15)

T-15 was prepared according to procedure c. mp 216.2-217.1 ℃. LC-MS (ESI) (m/z):381.90(M ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ12.44(s,1H),11.27(s,1H),9.07(s,1H),7.85(d,J＝2.4Hz,1H),7.83–7.78(m,2H),7.72(dd,J＝8.8,2.4Hz,1H),7.58(d,J＝8.1Hz,2H),7.29(d,J＝8.8Hz,1H),5.43(s,2H).

Example 16: n-hydroxy-4- (7-methyl-1, 1-dioxo-3-oxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) benzamide (T-16)

T-16 was prepared according to procedure c. mp 214.5-217.8 ℃. LC-MS (ESI) (M/z): 362.70 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.26(s,1H),9.06(s,1H),7.81–7.77(m,2H),7.60–7.55(m,3H),7.45(dd,J＝8.4,2.0Hz,1H),7.15(d,J＝8.4Hz,1H),5.40(s,2H),2.36(s,3H).

Example 17:4- ((7-chloro-3-methyl-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-17)

T-17.Mp 174.6-175.6℃was prepared according to procedure a. LC-MS (ESI) (M/z): 380.60 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ11.16(s,1H),9.01(s,1H),7.71(d,J＝7.9Hz,2H),7.61(d,J＝2.8Hz,3H),7.43(d,J＝7.9Hz,2H),7.31(dd,J＝9.0,2.6Hz,1H),6.65–6.59(m,2H),4.54(d,J＝6.0Hz,2H).

Example 18:4- ((2-benzyl-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-18)

T-18 was prepared according to method d. The procedure was as follows:

1) Intermediate b1 (1.5 mmol), potassium carbonate (3.26 mmol) and10mL of acetonitrile was warmed to 70℃and RBr (1.65 mmol) was added and reacted for about 2 hours. After evaporation of the solvent under reduced pressure, the crude solid was washed with water, dried and then recrystallized from ethyl acetate to give intermediate methyl 4-methyl (2-benzyl-1, 1-dioxo-2, 3-dihydro-4H-1, 2, 4-benzothiadiazin-4-yl) benzoate (d 1). LC-MS (ESI) (M/z): 423.80 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ7.96–7.93(m,2H),7.66(dd,J＝7.9,1.6Hz,1H),7.43–7.39(m,3H),7.34–7.27(m,5H),6.90–6.87(m,1H),6.83(d,J＝8.6Hz,1H),4.95(s,2H),4.71(d,J＝1.8Hz,2H),4.21(s,2H),3.85(s,3H).

2) Intermediate d1 (1.5 mmol) was added to a methanolic solution of hydroxylamine/sodium methoxide (15 mmol). Sodium methoxide methanol solution (7.5 mmol) was added dropwise thereto under ice-water bath conditions, followed by reaction for 4 to 6 hours. After the reaction was completed, 2 volumes of water was added and the pH was adjusted to 7-8 with 2M aqueous HCI, and a solid was precipitated, filtered, and slurried with methanol to give T-18.mp 128.1-129.9 ℃. LC-MS (ESI) (M/z): 424.80 (M) ⁺ )。 ¹ HNMR(600MHz,DMSO-d ₆ )δ7.76–7.70(m,2H),7.65(dd,J＝8.0,1.7Hz,1H),7.41(ddd,J＝8.8,7.2,1.7Hz,1H),7.34(dd,J＝8.0,6.2Hz,2H),7.31(dd,J＝7.6,3.3Hz,3H),7.28–7.25(m,2H),6.90–6.85(m,2H),4.94(s,2H),4.66(s,2H),4.19(s,2H).

Example 19:4- (7-bromo-1, 1-dioxo-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) -N-hydroxybenzoamide (T-19)

T-19.Mp 164.3-165.0deg.C was prepared according to procedure a. LC-MS (ESI) (M/z): 401.80 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),7.73–7.67(m,3H),7.40(dd,J＝8.9,2.1Hz,3H),6.62(t,J＝6.0Hz,1H),6.58(d,J＝9.0Hz,1H),4.52(d,J＝5.9Hz,2H).

Example 20:4- ((2-benzyl-7-chloro-1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-20)

T-20.Mp 128.4-132.5℃was prepared according to method d. LC-MS (ESI) (M/z): 458.50 (M+). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.79(s,1H),7.74–7.72(m,2H),7.66(d,J＝2.6Hz,1H),7.46(dd,J＝9.2,2.6Hz,1H),7.34–7.30(m,3H),7.26–7.24(m,4H),6.92(d,J＝9.2Hz,1H),4.95(s,2H),4.65(s,2H),4.18(s,2H).

Example 21:4- (7-chloro-2- (cyclopropylmethyl) -1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-21)

T-21.Mp 126.5-128.2℃was prepared according to method d. LC-MS (ESI) (M/z): 421.90 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ9.67(s,1H),7.55(d,J＝8.2Hz,2H),7.39(d,J＝2.6Hz,1H),7.22(dd,J＝9.2,2.6Hz,1H),7.08(d,J＝8.0Hz,2H),6.66(d,J＝9.2Hz,1H),5.01(s,2H),4.57(s,2H),2.71(d,J＝7.0Hz,2H),0.85–0.80(m,1H),0.31–0.28(m,2H).

Example 22:4- (7-chloro-2- (2-hydroxyethyl) -1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-22)

T-22.Mp 130.7-132.3℃was prepared according to method d. LC-MS (ESI) (M/z): 411.90 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(s,1H),7.73(d,J＝8.0Hz,2H),7.58(d,J＝2.6Hz,1H),7.41(dd,J＝9.2,2.7Hz,1H),7.26(d,J＝7.9Hz,2H),6.83(d,J＝9.2Hz,1H),5.15(s,2H),4.92(s,1H),4.73(s,2H),3.59(t,J＝5.8Hz,2H),3.06(t,J＝5.8Hz,2H).

Example 23:4- (7-chloro-2- (cyclohexylmethyl) -1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-23)

T-23.Mp 127.1-129.4℃was prepared according to method d. LC-MS (ESI) (M/z): 464.00 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.91(s,1H),7.76–7.70(m,2H),7.56(d,J＝2.6Hz,1H),7.41(dd,J＝9.2,2.6Hz,1H),7.27(d,J＝8.1Hz,2H),6.90(d,J＝9.3Hz,1H),5.04(s,2H),4.72(s,2H),2.74(d,J＝7.2Hz,2H),1.67–1.59(m,5H),1.48(ddd,J＝11.4,7.8,3.4Hz,1H),1.18–1.09(m,3H),0.85(t,J＝11.1Hz,2H).

Example 24:4- (7-chloro-2- (3-hydroxypropyl) -1, 1-dioxo-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-24)

T-24.Mp 136.4-138.8℃was prepared according to method d. LC-MS (ESI) (M/z): 426.00 (M) ⁺ )。 ¹ H NMR(400MHz,DMSO-d ₆ )δ7.73(d,J＝8.0Hz,2H),7.58(d,J＝2.6Hz,1H),7.41(dd,J＝9.2,2.6Hz,1H),7.26(d,J＝7.9Hz,2H),6.84(d,J＝9.2Hz,1H),5.10(s,2H),4.72(s,2H),3.41(t,J＝6.0Hz,3H),3.04(dd,J＝8.2,6.4Hz,2H),1.72–1.66(m,2H).

Example 25:4- ((7-chloro-1, 1-dioxo-2-phenethyl-2, 3-dihydro-4H-benzo [ e ] [1,2,4] thiadiazin-4-yl) methyl) -N-hydroxybenzoamide (T-25)

T-25.Mp 141.6-144.0℃was prepared according to method d. LC-MS (ESI) (M/z): 472.00 (M) ⁺ )。 ¹ H NMR(600MHz,DMSO-d ₆ )δ7.95(d,J＝7.8Hz,1H),7.75(d,J＝7.8Hz,1H),7.62–7.56(m,1H),7.41(d,J＝7.6Hz,2H),7.30–7.16(m,6H),6.87(dd,J＝28.4,9.3Hz,1H),5.12(d,J＝19.6Hz,2H),4.76(d,J＝67.7Hz,2H),3.20(q,J＝9.8,8.9Hz,2H),2.87(q,J＝7.9Hz,2H).

Example 26: compounds having HDAC inhibitory Activity

The test conditions of the established experimental platform are used for detecting the inhibition effect of the compound on the HDAC6 and HDAC1 targets, and the HDAC6 inhibitor Rocilinostat (ACY-1215) and SW-100 are used as positive control compounds.

1) Reagent and consumable

TABLE 2

2) Instrument for measuring and controlling the intensity of light

TABLE 3 Table 3

3) HDAC enzyme configuration

HDAC6 enzyme inhibition assay: samples were prepared as DMSO solutions at stock concentration of 40mM and stored in the dark for use.

HDAC1 enzyme inhibition assay: the compound was prepared as a stock concentration of 20mM in DMSO and kept in the dark for further use.

4) HDAC6 enzymatic reaction process

a 1X reaction solution was prepared.

b, preparation of compound concentration gradient: the final concentration of test compound is 80nM, 4-fold dilution, 5 concentrations, single well test is set, the final concentration of test positive compound is 3 μM, 3-fold dilution, 10 concentrations, and multiple well test is set. The solution was diluted in a 384 well Source plate in a gradient to a corresponding 100-fold final concentration, and then transferred with Echo550 to a 384 well reaction plate for assay. 250nL of 100% DMSO was transferred in both Max wells and Min wells.

c 1.67 Xthe enzyme solution was prepared from the 1 Xreaction solution.

d adding 15. Mu.L of 1.67 Xenzyme solution to each well; 15. Mu.L of 1.6Xthe reaction solution was added to the Min well. Incubate for 15 minutes at room temperature.

e a 2.5 Xsubstrate mixed solution was prepared from the 1X reaction solution.

f reaction plate each well was charged with 10. Mu.L of 2.5 Xsubstrate mixed solution to initiate reaction.

g using Synergy to read the fluorescent signal continuously.

5) HDAC1 enzymatic reaction process

a 1X reaction solution was prepared.

b, preparation of compound concentration gradient: the final concentration of the compound to be tested is 2 mu M, 10 times of dilution and 4 concentrations, and single-hole detection is set; the positive drug test concentration was 3 μm initial, 3-fold diluted, 10 concentrations, and multiplex well assay was set. The solution was diluted in a 384 well Source plate in a gradient to a corresponding 100-fold final concentration, and then transferred with Echo550 to a 384 well reaction plate for assay. 250nL of 100% DMSO was transferred in both Max wells and Min wells.

c 1.67 Xthe enzyme solution was prepared from the 1 Xreaction solution.

d adding 15. Mu.L of 1.67 Xenzyme solution to each well; 15. Mu.L of 1.6Xthe reaction solution was added to the Min well. Incubate for 15 minutes at room temperature.

e a 2.5 Xsubstrate mixed solution was prepared from the 1X reaction solution.

f reaction plate each well was charged with 10. Mu.L of 2.5 Xsubstrate mixed solution to initiate reaction.

g using Synergy to read the fluorescent signal continuously.

5) Data analysis

The linear reaction section is selected to obtain a slope (slope). And further calculating the percentage inhibition rate, wherein the calculation formula is as follows:

wherein: mean (Max) is the average of the slope values of each Max well (containing DMSO and enzyme); mean (Min) is the Mean of the slope values of each Min well (no enzyme well); sample Signal is the slope value of the compound well.

Fitting dose-response curve: the log value of the compound concentration is taken as an X axis, the corresponding percentage inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit response curve of analysis software GraphPad Prism 5 is adopted to obtain eachIC for inhibiting enzyme activity by compound ₅₀ Values.

The experimental results are shown in table 4:

TABLE 4 Table 4

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Experimental results show that the compound of the invention has stronger inhibition activity on HDAC6, and compared with HDAC1, the compound has stronger inhibition activity on HDAC6 and shows certain selectivity.

Example 27 anti-cell proliferation Activity of Compounds

Using CCK-8 method, SW-100 and ACY-1215 are used as positive control drugs, and part of the compounds of the invention are selected to test the antiproliferative activity of the compounds on SH-SY5Y cells (human neuroblastoma cell line) and MRC-5 human normal embryo lung fibroblast cells at 20 mu M concentration (compound hole). Experimental data are shown in the table.

The results of the anti-cell proliferation assay are shown in Table 5 (unit: inh% in 20. Mu.M):

TABLE 5

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A:>90％；B:80～90％；C:70～80％；D:50～70％E:<50％

The experimental results show that: at a test concentration of 20. Mu.M, the compounds of the invention have generally weaker antiproliferative effects on SH-SY5Y cells and MRC-5 human normal embryo lung fibroblasts than positive control drugs SW-100 and ACY-1215, indicating less toxicity to cells.

EXAMPLE 28 protection of L-glutamic acid-induced SH-SY5Y cell damage model by Compounds

SW-100 and ACY-1215 are used as positive control medicines, and partial compounds are selected to test the protection effect of the compounds on the L-glutamic acid induced SH-SY5Y cell damage model.

Experimental method

Day 0: cell seeding

1. The cells were suspended by centrifugation and resuspended in growth medium and then counted with a cell counter.

2. The cell suspension in the growth medium is diluted to the desired density.

3. 100. Mu.L of cells were seeded into 96-well plates in growth medium according to the plate diagram. Only the medium is used as background control (Min).

4. 37℃、5％CO ₂ Incubate overnight.

Day 1: treatment with a compound

1. Preparation of 200-fold Compound solutions in DMSO

2. By adding 3. Mu.L of a 200-fold compound solution to 197. Mu.L of growth medium, the compound containing the growth medium was diluted to a 3-fold final concentration

3. 50. Mu.L of diluted compound solution was added to the cells at 37℃with 5% CO ₂ Incubate for 48h.

4. Removal of growth medium

5. 150. Mu.L of a medium containing 1 Xcpds and 16mM L-glutamic acid, 37℃and 5% CO were added to the cells ₂ Incubate for 24 hours.

Day 4: measurement of

1. The assay plate was equilibrated to room temperature prior to measurement.

2. 40. Mu.L CellTiter-Reagent。/>

3. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis.

4. Incubate for 60 minutes at room temperature to stabilize the luminescent signal.

5. Luminescence was recorded on Envision.

Data analysis

(1) GraphPadPrism 5 was used.

(2) % inh= (maximum signal-composite signal)/(maximum signal-minimum signal) ×100.

(3) The maximum signal comes from the effect of DMSO.

(4) The minimum signal is only obtained by the medium effect.

The experimental results are shown in table 6.

TABLE 6

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Compound in vitro glutamate-induced neuronal injury model results discussion:

1) Glutamate (15 nM) significantly reduces neuronal cell viability. SW-100 can improve the activity of SH-SY5Y cells damaged by L-glutamic acid, reduce the cytotoxicity of the L-glutamic acid, has a certain neuroprotection effect, and has weaker neuroprotection effect of ACY-1215, even shows partial toxicity.

2) The compound can improve the activity of SH-SY5Y cells, and has a protective effect on the damage of the L-glutamic acid induced SH-SY5Y cells, which is superior to SW-100.

Example 29 Compounds on hERG potassium channel effect experiment

The potential toxic and side effects of the partial compounds of the invention in vitro are primarily examined by adopting an hERG potassium channel inhibition test. The experimental procedure was as follows:

1) Cell preparation

CHO-hERG cells were cultured in 175cm ² In the flask, after the cell density grows to 60 to 80%, the culture solution is removed, washed once with 7mL of LPBS, and then digested with 3mL of Detachin.

After digestion is completed, 7mL of culture solution is added for neutralization, and then centrifugation is carried out, supernatant is sucked away, and 5mL of culture solution is added for resuspension so as to ensureThe cell density is 2-5 multiplied by 10 ⁶ /mL。

2) Electrophysiological recording procedure

The single cell high impedance sealing and whole cell mode formation process is all completed automatically by Qpatch instrument, after obtaining whole cell record mode, the cell is clamped at-80 millivolts, before a depolarization stimulus of +20 millivolts for 5 seconds is given, a pre-voltage of-50 millivolts is given for 50 milliseconds, then repolarization is carried out to-50 millivolts for 5 seconds, and then return to-80 millivolts is carried out. This voltage stimulus was applied every 15 seconds, 2min after which the extracellular fluid was recorded, and then the dosing process was started, starting with the lowest test concentration, 2min for each test concentration, and after all concentrations were continuously administered, 10 μm Cisapride of positive control compound was administered. At least 3 cells were tested per concentration (n.gtoreq.3).

3) Preparation of Compounds

The compound mother liquor was diluted with extracellular fluid, 998. Mu.L of extracellular fluid was added to 2. Mu.L of the compound mother liquor, and then 5-fold serial dilutions were sequentially performed in extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested. Experimental data were analyzed by XLFit software.

The experimental results are shown in table 7 below:

TABLE 7

The hERG experimental results show that the inhibition activity of the compound of the invention on the hERG potassium ion channel is more than 20 mu M, which indicates that the compound of the invention has lower potential cardiotoxicity.

EXAMPLE 30 pharmaceutical composition 1

The compound T-3 prepared in example 3 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 1 containing the compound T-3 as an active ingredient.

EXAMPLE 31 pharmaceutical composition 2

The compound T-24 prepared in the example 24 is mixed with a solvent and a stabilizer, filtered and packaged to obtain the pharmaceutical composition 2 taking the compound T-24 as an active ingredient.

EXAMPLE 32 pharmaceutical composition 3

The compound T-5 prepared in example 5 and the compound T-15 prepared in example 15 are mixed with a filler, a disintegrant and a lubricant, granulated and tabletted to obtain a pharmaceutical composition 3 with the compounds T-5 and T-15 as active ingredients.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (16)

1. A benzothiadiazine 1, 1-dioxide compound, the structural general formula of which is shown as the formula (I), or an isomer thereof, or pharmaceutically acceptable salt, ester or prodrug thereof;

wherein,

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

when there is an n=c double bond between 2-N and 3-C on the 1, 1-dioxybenzothiadiazine ring, the compounds of formula (i) do not contain R ₃ ；

When N-C single bond is between 2-N and 3-C on 1, 1-dioxybenzothiadiazine ring, R ₃ Selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl or- (CH) _m )n-R ₅ Which may be optionally substituted; r is R ₅ Selected from cycloalkyl, aryl, heteroaryl or hydroxy;m is an integer of 0 to 2, and n is a positive integer;

R ₄ Selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl, or sulfonyl, which may be optionally substituted.

2. Benzothiadiazine 1, 1-dioxide compound according to claim 1, characterized in that it comprises compound (i-1) or compound (i-2):

in the compounds of formula (I-1),

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

R ₄ selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl, or sulfonyl, which may be optionally substituted;

in the compounds of formula (I-2),

R ₁ and R is ₂ Independently selected from hydrogen, deuterium, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkyl, acyl, sulfonyl, or aminoalkyl, which may be optionally substituted;

R ₃ selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl or- (CH) _m )n-R ₅ Which may be optionally substituted; r is R ₅ Selected from cycloalkyl, aryl, heteroaryl or hydroxy; m is an integer of 0 to 2, and n is a positive integer;

R ₄ selected from hydrogen, hydroxy, oxo, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl, or sulfonyl, which may be optionally substituted.

3. Benzothiadiazine 1, 1-dioxide compound according to claim 1 or 2, characterized in that said alkyl is an alkyl group containing 1 to 4 carbon atoms, optionally substituted by 0 to 3 halogens;

and/or said cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, optionally substituted with 0 to 3 halogens;

and/or said heterocycloalkyl is selected from pyrrolyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroquinolinyl, tetrahydrotriazolopyrazinyl, diazepanyl or piperazinyl, which may be optionally substituted;

and/or the aryl or heteroaryl is selected from phenyl, naphthyl, anthracenyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl or 5,6,7, 8-tetrahydroisoquinolinyl; which may be optionally substituted;

And/or said acyl is selected from acetyl, propionyl, isobutyryl or aryl acyl, which may be optionally substituted;

and/or said sulfonyl is selected from methanesulfonyl or arylsulfonyl, which may be optionally substituted;

and/or said aminoalkyl is selected from dimethylaminoalkyl, methylaminoalkyl, piperazinalkyl or piperidinoalkyl, which may be optionally substituted;

and/or, the halogen is selected from fluorine or chlorine;

and/or the alkoxy is selected from alkoxy groups containing 1 to 4 carbon atoms;

and/or, the R ₅ Selected from aryl, cycloalkyl or hydroxy;

and/or n is selected from integers of 0 to 4.

4. Benzothiadiazine 1, 1-dioxide compound according to claim 1 or 2, characterized in that the pharmaceutically acceptable salts of the compound of formula (i) comprise anionic salts of the compound of formula (i) with hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, malic acid, p-toluenesulfonic acid or oxalic acid; or a cationic salt formed by reacting the compound of formula (I) with a sodium ion solution and a potassium ion solution.

5. Benzothiadiazine 1, 1-dioxide compound according to claim 1 or 2, characterized in that R ₁ And R is ₂ Independently selected from hydrogen, methyl, F or Cl;

R ₃ the N atom being linked to adjacent C atoms by a N=C double bond, the compounds of formula (I) not containing R ₃ The method comprises the steps of carrying out a first treatment on the surface of the Or, R ₃ The N atom being bound to adjacent C atoms by N-C single bonds, R ₃ Selected from hydrogen or- (CH) _m )n-R ₅ ，R ₅ Selected from phenyl, cyclopropyl, cyclohexenyl or hydroxy; m is 1 or 2, n is 1, 2 or 3;

R ₄ selected from hydrogen, oxygen or methyl.

6. Benzothiadiazine 1, 1-dioxide compound according to claim 1, characterized in that it comprises the following compounds or isomers thereof, or pharmaceutically acceptable salts, esters or prodrugs thereof:

7. a process for the preparation of a benzothiadiazine 1, 1-dioxide compound according to any of claims 1 to 6, comprising one or more of the following processes:

if the compound of formula (I) does not contain R ₃ The preparation method a is adopted;

the method a comprises the following steps:

a1, reacting a compound shown in a formula (II) with methyl 4-bromomethylbenzoate under a heating condition to obtain a compound shown in a formula (III);

wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6;

a2, reacting the compound shown in the formula (III) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-1);

wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6;

If the compound of formula (I) comprises R ₃ And R is ₃ Is hydrogen, R ₄ For non-oxo, can be prepared using method b:

the method b comprises the following steps:

b1, reducing the compound of formula (III) into the compound of formula (IV) through sodium borohydride;

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6; r is R ₄ A non-oxy group selected from those shown in any one of claims 1 to 6;

b2, reacting the compound shown in the formula (IV) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-2-1);

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6; r is R ₄ A non-oxy group selected from those shown in any one of claims 1 to 6;

if the compound of formula (I) comprises R ₃ And R is ₃ Is hydrogen, R ₄ As oxo, prepared using method c:

the method c comprises the following steps:

c1, reacting a compound shown in a formula (V) with methyl 4-bromomethylbenzoate under alkaline conditions to obtain a compound shown in a formula (VI);

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

c2, reacting the compound shown in the formula (VI) with hydroxylamine under alkaline conditions to obtain a compound shown in the formula (I-2-2);

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

if the compound of formula (I) comprises R ₃ And R is ₃ Is non-hydrogen, prepared using method d:

the method d comprises the following steps:

d1, reacting the compound shown in the formula (IV) with the compound shown in the formula (VII) under heating condition to obtain a compound shown in the formula (VIII);

Wherein,

the compound of formula (IV) can be prepared according to the method shown in the step B1;

R ₁ 、R ₂ 、R ₄ as shown in any one of claims 1-6; r is R ₃ A non-hydrogen group selected from those shown in any one of claims 1 to 6;

x is halogen;

d2, reacting a compound of formula (VIII) with hydroxylamine under alkaline conditions to obtain a compound of formula (I-2-3);

wherein,

R ₁ 、R ₂ 、R ₄ as shown in any one of claims 1-6; r is R ₃ Selected from the non-hydrogen groups as set forth in any one of claims 1 to 6.

8. The method of manufacturing of claim 7, further comprising one or more of the following:

the preparation method of the compound of the formula (V) comprises the following steps:

reacting a compound of formula (IX) with chlorosulfonyl isocyanate at-50-100 ℃, and then reacting with aluminum chloride at 30-120 ℃ to obtain a compound of formula (V);

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

and/or, the preparation method of the compound of the formula (II) comprises the following steps:

e1, reacting a compound of formula (V) with dilute sulfuric acid at 130-150 ℃ to obtain a compound of formula (X);

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

e2, heating and reacting the compound of formula (X) with the compound of formula (XI) to obtain the compound of formula (II);

Wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6.

9. The preparation method according to claim 7, wherein the heating temperature in the step A1 is 60-80 ℃ and the heating reaction time is 3-4 hours;

and/or, in the step B1, adding sodium hydride into the solution of the compound of the formula (III) to perform a reduction reaction to generate the compound of the formula (IV);

and/or, in the step C1, the compound of the formula (V) and sodium carbonate are dissolved in N, N-dimethylformamide, and 4-bromomethyl benzoate is added into the solution dropwise to react to obtain the compound of the formula (VI);

and/or, in the step C1, the reaction time is 3-5 h;

and/or the heating temperature in the step D1 is 60-80 ℃ and the reaction time is 1.5-3 h;

and/or, in step A2, the compound of formula (iii) is reacted with hydroxylamine in sodium methoxide methanol solution;

and/or, in step B2, reacting the compound of formula (IV) with hydroxylamine in sodium methoxide methanol solution;

and/or, in step C2, the compound of formula (VI) is reacted with hydroxylamine in sodium methoxide in methanol;

and/or, in step D2, the compound of formula (viii) is reacted with hydroxylamine in sodium methoxide methanol solution;

and/or in any one or more of the steps A2, B2, C2 and D2, the reaction temperature is independently-5 ℃ and the reaction temperature is independently 4-6 h.

10. The process according to claim 8, wherein the reaction time of the compound of formula (IX) with chlorosulfonyl isocyanate is 20 to 60 minutes;

and/or, in the preparation method of the compound of the formula (V), the reaction time of the intermediate 1 and aluminum chloride is 0.5-2 h;

and/or, the dilute sulfuric acid in the step E1 is a sulfuric acid aqueous solution with the volume concentration of 45-60%;

and/or, in the step E1, the reaction time is 6-10 h;

and/or in the step E2, the heating temperature is 90-110 ℃ and the reaction time is 1.5-3 h.

11. An intermediate compound for preparing the benzothiadiazine 1, 1-dioxide compound of any of claims 1 to 6, comprising one or more of the following compounds:

a compound of formula (ii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6;

and/or a compound of formula (iii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6;

and/or a compound of formula (iv) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6; r is R ₄ A non-oxy group selected from those shown in any one of claims 1 to 6;

and/or, a compound of formula (v):

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

and/or a compound of formula (vi) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

and/or a compound of formula (viii) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ 、R ₄ As shown in any one of claims 1-6; r is R ₃ A non-hydrogen group selected from those shown in any one of claims 1 to 6;

and/or a compound of formula (ix) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

(Ⅸ)

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6;

and/or a compound of formula (x) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is ₁ 、R ₂ As shown in any one of claims 1-6.

12. Use of a benzothiadiazine 1, 1-dioxide compound according to any one of claims 1 to 6, a benzothiadiazine 1, 1-dioxide compound obtained by the process according to any one of claims 7 to 10 or an intermediate compound according to claim 10 for the preparation of a histone deacetylase inhibitor or a medicament for the treatment of neurodegenerative diseases.

13. The use according to claim 12, wherein the histone deacetylase inhibitor is an HDAC6 and/or HDAC1 inhibitor.

14. The use according to claim 11, wherein said neurodegenerative disease treatment comprises a treatment for cerebral ischemia, brain injury, epilepsy, alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia or Pick's disease.

15. A pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; the active component comprises the benzothiadiazine 1, 1-dioxide compound according to any one of claims 1 to 6 or the benzothiadiazine 1, 1-dioxide compound obtained by the preparation method according to any one of claims 7 to 10.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, flavoring agents, and sweeteners.