Benzothiazine 1,1-dioxide compounds that inhibit HDAC6 enzyme, their preparation methods and applications

Abstract

This invention provides a benzothiadiazine 1,1-dioxide compound, its preparation method, and its applications. The general structural formula of the benzothiadiazine 1,1-dioxide compound is shown in Formula (I), or its isomers, or pharmaceutically acceptable salts, esters, or prodrugs thereof. The benzothiadiazine 1,1-dioxide compound of this invention has a novel structure, can selectively inhibit HDAC6 enzyme, has a strong protective effect on nerve cells, low toxicity, and low potential cardiotoxicity, and is expected to be used as a neuroprotective agent for the treatment of neurodegenerative diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to benzothiadiazine 1,1-dioxide compounds that inhibit HDAC6 enzyme, their preparation methods, and applications. Background Technology

[0002] Histone deacetylases (HDACs) and histone acetyltransferases (HATs) work together to regulate intracellular acetylation levels, thereby regulating gene expression. HDACs are key regulators of gene expression, and to date, 18 HDAC subtypes have been identified in mammals. Based on their homology with yeast proteins, they are divided into four classes: Class I (HDAC1, HDAC2, HDAC3, HDAC8) are usually located in the cell nucleus and are universally expressed in various cell lines and tissues; Class II is further divided into two subfamilies, IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6, HDAC10), which share homology with yeast proteins and mainly shuttle between the cell nucleus and cytoplasm; Class IV (HDAC11), as its only member, exists in both the cell nucleus and cytoplasm, and its catalytic site is similar to that of Class I and II enzymes. These three classes represent Zn2+-dependent deacetylases. Class III (Sirt1–Sirt7) NAD+-dependent deacetylases require the activity and homologs of the yeast protein SiR2, which contains NAD+.

[0003] Currently, there are five marketed histone deacetylase inhibitors (HDACi): vorinostat, belinostat, panobinostat, romidepsin, and chidamide. The first three are broad-spectrum inhibitors, while the latter two selectively target class I subtypes. Vorinostat and romidepsin are used to treat cutaneous T-cell lymphoma (CTCL), belinostat and chidamide are used to treat relapsed and refractory peripheral T-cell lymphoma (PTCL), and panobinostat is used in combination with bortezomib and dexamethasone to treat multiple myeloma (MM).

[0004] Although the aforementioned HDAC inhibitors have achieved good clinical efficacy, broad-spectrum HDAC inhibitors generally have the following drawbacks:

[0005] (1) Strong toxic side effects, such as nausea, vomiting, and bone marrow suppression;

[0006] (2) Genotoxicity;

[0007] (3) Poor pharmacokinetic characteristics, low bioavailability, short half-life, etc.

[0008] The above-mentioned drawbacks not only cause inconvenience to cancer patients, but also hinder the application of broad-spectrum HDAC inhibitors in areas other than cancer treatment.

[0009] Currently, HDAC subtype selective inhibitors have become a research hotspot in this field, and HDAC6, due to its unique structure and function, has become a new hotspot in tumor treatment.

[0010] HDAC6 is a widely expressed cytoplasmic protein deacetylase whose main targets include α-tubulin and HSP90. Through post-translational modification of these substrates and other cytoplasmic targets, it is involved in several key cellular processes, including primary cell cilia, intracellular signaling, and DNA damage responses. Inhibition of HDAC6 leads to the restoration of cell cilia and attenuation of malignant phenotypes, consistent with its role in cellular regulation. Simultaneously, inhibition of HDAC6 has been shown to reduce the oncogenic Hedgehog signaling pathway (which controls cell fate, proliferation, and differentiation; aberrant activation of this pathway leads to tumorigenesis and development). HDAC6 is an important intracellular chaperone, interacting with signaling mediators or directly modulating HSP90 to influence intracellular signaling. In summary, these studies link HDAC6 to multiple oncogenic processes and highlight the potential of HDAC6 inhibitors to induce cellular and immune-mediated antitumor activity.

[0011] One of the well-known substrates of HDAC6 is α-tubulin, a major component of microtubules. Acetylation of α-tubulin at lysine 40 is a common process in microtubules. The stability of microtubule function strongly depends on the acetylation state of α-tubulin. Impaired microtubule-based transport can disrupt mitochondrial transport between the neuronal cell body and axon / dendries, further leading to mitochondrial dysfunction and subsequent cell death. Mitochondria are prominent organelles for microtubule-based axonal transport; enhancing α-tubulin acetylation by inhibiting HDAC6 can improve microtubule-based transport, thereby improving mitochondrial transport defects. Existing research suggests that HDAC6 inhibition may slow or reverse Aβ-related neuronal damage, thus representing a potential therapeutic target for AD. Summary of the Invention

[0012] This invention provides a novel benzothiadiazine 1,1-dioxide compound that can selectively inhibit HDAC6 enzyme, has a strong protective effect on nerve cells, low toxicity and low potential cardiotoxicity, and is expected to be used as a neuroprotective agent for the treatment of neurodegenerative diseases.

[0013] In order to achieve the above-mentioned objectives, the first aspect of the present invention provides a benzothiadiazine 1,1-dioxide compound with the general structural formula shown in formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;

[0014]

[0015] in,

[0016] R1 and R2 are independently selected from hydrogen, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkane, acyl, sulfonyl or aminoalkyl, which may optionally be substituted;

[0017] When there is an N=C double bond between the 2-N and 3-C on the 1,1-dioxybenzothiadiazine ring, the compound of formula (Ⅰ) does not contain R3;

[0018] When the 2-N and 3-C bond on the 1,1-dioxybenzothiadiazine ring is an NC single bond, R3 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl, or -(CH m )n-R5, which may be optionally substituted; R5 is selected from cycloalkyl, aryl, heteroaryl or hydroxyl; m is an integer from 0 to 2, and n is a positive integer;

[0019] R4 is selected from hydrogen, hydroxyl, oxygen, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl or sulfonyl, which may optionally be substituted.

[0020] Preferably, the benzothiadiazine 1,1-dioxide compounds of this invention include compound (I-1) or compound (I-2):

[0021]

[0022] In the compound of formula (Ⅰ-1),

[0023] R1 and R2 are independently selected from hydrogen, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkane, acyl, sulfonyl or aminoalkyl, which may optionally be substituted;

[0024] R4 is selected from hydrogen, hydroxyl, oxy, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl or sulfonyl, which may optionally be substituted;

[0025]

[0026] In the compound of formula (Ⅰ-2),

[0027] R1 and R2 are independently selected from hydrogen, deuterium, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, benzyl, heterocycloalkyl, aryl, heteroaryl, cyano, haloalkane, acyl, sulfonyl or aminoalkyl, which may optionally be substituted;

[0028] R3 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl, or -(CH m )n-R5, which may be optionally substituted; R5 is selected from cycloalkyl, aryl, heteroaryl or hydroxyl; m is an integer from 0 to 2, and n is a positive integer;

[0029] R4 is selected from hydrogen, hydroxyl, oxygen, alkyl, cycloalkyl, benzyl, aryl, heteroaryl, heterocycloalkyl, acyl or sulfonyl, which may optionally be substituted.

[0030] Preferably, the alkyl group is an alkyl group containing 1 to 4 carbon atoms, which may optionally be substituted with 0 to 3 halogens;

[0031] Preferably, the cycloalkyl group is a cycloalkyl group containing 3 to 6 carbon atoms, which may optionally be substituted with 0 to 3 halogens;

[0032] Preferably, the heterocyclic alkyl group is selected from pyrroleyl, morpholinyl, piperidinyl, piperazine ring, tetrahydroquinolinyl, tetrahydrotriazolylpyrazineyl, diazacycloheptyl or piperazineyl, and may optionally be substituted.

[0033] Preferably, the aryl or heteroaryl group is selected from phenyl, naphthyl, anthracene, pyridyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, benzoxazolyl, benzofuranyl, benzothiophene, benzothiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrroleyl, pyrazolyl, or 5,6,7,8-tetrahydroisoquinoline; it may optionally be substituted.

[0034] Preferably, the acyl group is selected from acetyl, propionyl, isobutyryl, or aryl acyl, and may optionally be substituted.

[0035] Preferably, the sulfonyl group is selected from methanesulfonyl or arylsulfonyl, and may optionally be substituted.

[0036] Preferably, the aminoalkyl group is selected from dimethylaminoalkyl, methylaminoalkyl, piperazinealkyl, or piperidinealkyl, and may optionally be substituted.

[0037] Preferably, the halogen is selected from fluorine or chlorine;

[0038] Preferably, the alkoxy group is selected from alkoxy groups containing 1 to 4 carbon atoms;

[0039] Preferably, in this invention, R5 is selected from aryl, cycloalkyl, or hydroxyl groups;

[0040] Preferably, in this invention, n is selected from an integer from 0 to 4.

[0041] Preferred from the present invention, pharmaceutically acceptable salts of the compound of formula (I) include anionic salts formed by reacting 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 cationic salts formed by reacting the compound of formula (I) with sodium ion solution or potassium ion solution.

[0042] In a further preferred embodiment of the present invention, R1 and R2 are independently selected from hydrogen, methyl, F, or Cl;

[0043] In a further preferred embodiment of the present invention, the N atom connected to R3 forms an N=C double bond with the adjacent C atom, and the compound of formula (I) does not contain R3; or, the N atom connected to R3 forms an NC single bond with the adjacent C atom, and R3 is selected from hydrogen or -(CH m )n-R5, where R5 is selected from phenyl, cyclopropane, cyclohexane or hydroxy; m is 1 or 2, and n is 1, 2 or 3;

[0044] In a further preferred embodiment of the present invention, R4 is selected from hydrogen, oxygen, or methyl.

[0045] In some specific embodiments of the present invention, benzothiadiazine 1,1-dioxide compounds include the compounds shown in Table 1 or isomers thereof, or pharmaceutically acceptable salts, esters or prodrugs thereof:

[0046] Table 1

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] A second aspect of the present invention provides a method for preparing the benzothiadiazine 1,1-dioxide compound described in the above-described technical solution, comprising one or more of the following methods:

[0054] If the compound of formula (Ⅰ) does not contain R3, it shall be prepared by method a;

[0055] Method a includes the following steps:

[0056] A1, Compound (II) reacts with methyl 4-bromomethylbenzoate under heating conditions to give compound (III);

[0057]

[0058] R1, R2, and R4 are as shown in the above technical solution;

[0059] Preferably, in this invention, the heating temperature in step A1 is 60℃~80℃, and the heating reaction time is 3~4h;

[0060] A2, the compound of formula (III) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-1);

[0061]

[0062] R1, R2, and R4 are as shown in the above technical solution;

[0063] In a preferred embodiment of the present invention, in step A2, the compound of formula (III) reacts with hydroxylamine in a sodium methoxide methanol solution;

[0064] In a preferred embodiment of the present invention, in step A2, the reaction temperature is -5℃ to 5℃, and the reaction time is 4 to 6 hours.

[0065] If the compound of formula (Ⅰ) contains R3, and R3 is hydrogen and R4 is non-oxygen, it can be prepared by method b:

[0066] Method b includes the following steps:

[0067] B1, Compound (III) is reduced to Compound (IV) by sodium borohydride;

[0068]

[0069] Wherein, R1 and R2 are as shown in the above technical solution; R4 is selected from the non-oxygen groups shown in the above technical solution;

[0070] In a preferred embodiment of the present invention, in step B1, sodium hydride is added to a solution of compound (III) to carry out a reduction reaction to generate compound (IV);

[0071] B2, the compound of formula (IV) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-2-1);

[0072]

[0073] Wherein, R1 and R2 are as shown in the above technical solution; R4 is selected from the non-oxygen groups shown in the above technical solution;

[0074] In a preferred embodiment of the present invention, in step B2, the compound of formula (Ⅳ) reacts with hydroxylamine in a sodium methoxide methanol solution;

[0075] In a preferred embodiment of the present invention, in step B2, the reaction temperature is -5℃ to 5℃, and the reaction time is 4 to 6 hours.

[0076] If the compound of formula (Ⅰ) contains R3, where R3 is hydrogen and R4 is an oxygen group, it is prepared using method c:

[0077] Method c includes the following steps:

[0078] C1, Compound (V) reacts with methyl 4-bromomethylbenzoate under alkaline conditions to give Compound (VI);

[0079]

[0080] R1 and R2 are as shown in the above technical solution;

[0081] In a preferred embodiment of the present invention, in step C1, compound (V) and sodium carbonate are dissolved in N,N-dimethylformamide, and methyl 4-bromomethylbenzoate is added dropwise to the above solution to react and obtain compound (VI);

[0082] In a preferred embodiment of the present invention, the reaction time in step C1 is 3 to 5 hours;

[0083] C2, the compound of formula (VI) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-2-2);

[0084]

[0085] R1 and R2 are as shown in the above technical solution;

[0086] If the compound of formula (Ⅰ) contains R3 and R3 is non-hydrogen, it is prepared using method d:

[0087] In a preferred embodiment of the present invention, in step C2, the compound of formula (VI) reacts with hydroxylamine in a sodium methoxide methanol solution;

[0088] In a preferred embodiment of the present invention, in step C2, the reaction temperature is -5℃ to 5℃, and the reaction time is 4 to 6 hours.

[0089] Method d includes the following steps:

[0090] D1, Compound (IV) reacts with compound (VII) under heating conditions to give compound (VIII);

[0091]

[0092] in,

[0093] Compound (Ⅳ) can be prepared according to the method shown in step B1;

[0094] R1, R2, and R4 are as shown in the above technical solution; R3 is selected from the non-hydrogen groups shown in the above technical solution.

[0095] X is a halogen;

[0096] Preferably, in step D1 of this invention, the heating temperature is 60°C to 80°C, and the reaction time is 1.5 to 3 hours.

[0097] D2, Compound (VIII) reacts with hydroxylamine under alkaline conditions to give compound (I-2-3);

[0098]

[0099] in,

[0100] R1, R2, and R4 are as shown in the above technical solution; R3 is selected from the non-hydrogen groups shown in the above technical solution.

[0101] Preferably, in step D2 of this invention, the compound of formula (VIII) reacts with hydroxylamine in a sodium methoxide methanol solution;

[0102] In a preferred embodiment of the present invention, in step D2, the reaction temperature is -5℃ to 5℃, and the reaction time is 4 to 6 hours.

[0103] Preferably, the method for preparing the compound of formula (V) of the present invention includes the following steps:

[0104] Compound (IX) was reacted with chlorosulfonyl isocyanate at -50℃ to 100℃, and then reacted with aluminum chloride at 30℃ to 120℃ to obtain compound (V).

[0105]

[0106] R1 and R2 are as shown in the above technical solution;

[0107] In a further preferred embodiment of the present invention, in the method for preparing compound (V), the reaction time of compound (IX) with chlorosulfonyl isocyanate is 20–60 min;

[0108] In a further preferred embodiment of the present invention, in the method for preparing compound (V), the reaction time of intermediate 1 with aluminum chloride is 0.5 to 2 hours;

[0109] Preferably, the method for preparing the compound of formula (II) of the present invention includes the following steps:

[0110] E1, Compound (V) reacts with dilute sulfuric acid at 130℃~150℃ to give compound (X);

[0111]

[0112] R1 and R2 are as shown in the above technical solution;

[0113] In a further preferred embodiment of the present invention, the dilute sulfuric acid in step E1 is an aqueous sulfuric acid solution with a volume concentration of 45-60%.

[0114] In a further preferred embodiment of the present invention, the reaction time in step E1 is 6 to 10 hours;

[0115] E2, the compound of formula (X) reacts with the compound of formula (XI) upon heating to give the compound of formula (II);

[0116]

[0117] R1, R2, and R4 are as shown in the above technical solution.

[0118] In a further preferred embodiment of the present invention, in step E2, the heating temperature is 90℃~110℃ and the reaction time is 1.5~3h.

[0119] A third aspect of the present invention provides an intermediate compound for preparing the benzothiadiazine 1,1-dioxide compounds described in the foregoing technical solutions, comprising one or more of the following compounds:

[0120] Compound of formula (II) or its isomers, pharmaceutically acceptable salts, esters or prodrugs:

[0121]

[0122] R1, R2, and R4 are as shown in the aforementioned technical solution;

[0123] And / or, compounds of formula (III) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0124]

[0125] R1, R2, and R4 are as shown in the aforementioned technical solution;

[0126] And / or, compounds of formula (IV) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0127]

[0128] Wherein, R1 and R2 are as shown in the aforementioned technical solution; R4 is selected from the non-oxygen groups shown in the aforementioned technical solution;

[0129] And / or, compounds of formula (V) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0130]

[0131] R1 and R2 are as shown in the aforementioned technical solution;

[0132] And / or, compounds of formula (VI) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0133]

[0134] R1 and R2 are as shown in the aforementioned technical solution;

[0135] And / or, compounds of formula (VIII) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0136]

[0137] Wherein, R1, R2, and R4 are as shown in the aforementioned technical solution; R3 is selected from the non-hydrogen groups shown in the aforementioned technical solution;

[0138] And / or, compounds of formula (IX) or their isomers, pharmaceutically acceptable salts, esters, or prodrugs:

[0139]

[0140] R1 and R2 are as shown in the aforementioned technical solution;

[0141] And / or, a compound of formula (X) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug:

[0142]

[0143] R1 and R2 are as shown in the aforementioned technical solution.

[0144] The fourth aspect of the present invention provides the use of the benzothiadiazine 1,1-dioxide compounds described in the foregoing technical solutions, the benzothiadiazine 1,1-dioxide compounds obtained by the preparation methods described in the foregoing technical solutions, or the intermediate compounds described in the above technical solutions in the preparation of histone deacetylase inhibitors or drugs for the treatment of neurodegenerative diseases.

[0145] Preferably, the histone deacetylase inhibitor of the present invention is an HDAC6 and / or HDAC1 inhibitor.

[0146] Preferably, the neurodegenerative disease treatment drugs of this invention include drugs for treating acute and chronic neurodegenerative diseases. Acute neurodegenerative diseases mainly include 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, etc.

[0147] A fifth aspect of the present invention provides a pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; said active ingredient comprising benzothiadiazine 1,1-dioxide compounds as described in the foregoing technical solutions or benzothiadiazine 1,1-dioxide compounds prepared by the preparation methods described in the foregoing technical solutions.

[0148] Preferably, the pharmaceutically acceptable excipients of this invention include one or more of the following: diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorbent carriers, lubricants, flavorings, and sweeteners.

[0149] The pharmaceutical composition of this invention can be formulated into various forms such as tablets, powders, granules, capsules, oral liquids, and injectable drugs. All of these dosage forms can be prepared using conventional methods in the pharmaceutical field. The active component in the pharmaceutical composition of this invention can also be combined with other effective ingredients that have therapeutic effects or enhance therapeutic effects, reduce toxic side effects, or prolong metabolic time to form a pharmaceutical composition.

[0150] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0151] 1) The benzothiadiazine 1,1-dioxide compounds of the present invention have inhibitory activity against both HDAC6 and HDAC1, and show strong inhibitory activity against HDAC6; most compounds have better inhibitory activity against HDAC6 than against HDAC1, showing a certain degree of selectivity (compared to HDAC1);

[0152] 2) The benzothiadiazine 1,1-dioxide compounds described in this invention can improve cell viability in the SH-SY5Y cell injury model, showing a good protective effect against cell damage.

[0153] 3) The benzothiadiazine 1,1-dioxide compounds described in this invention generally have weak anti-proliferative effects on human neuroblastoma cells (SH-SY5Y) and human normal embryonic lung fibroblasts (MRC-5), and are weaker than existing drugs SW-100 and ACY-1215, and have less cytotoxicity.

[0154] 3) The benzothiadiazine 1,1-dioxide compounds described in this invention have weak inhibitory activity against hERG and low potential cardiotoxicity. Detailed Implementation

[0155] In this invention, the term "isomer" includes, but is not limited to, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, tautomers, mixtures of racemic mixtures and diastereomers, and their pharmaceutically acceptable salts. Unless otherwise stated, when an isomer component is not specifically specified, all possible isomers are included.

[0156] In this invention, "pharmaceutically acceptable salt" refers to a compound modified by forming an acidic or basic salt of the benzothiadiazine compound described in this invention, including but not limited to salts of inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromic acids, sulfates, sulfites, and nitrates; and salts of organic salts selected from, for example, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoates such as acetates, and salts of HOOC-(CH2)p-COOH, where p can be any integer from 0 to 4. If the compound is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acidic salt. Conversely, if the product is a free base, the 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 acid, consistent with the conventional process for preparing acid addition salts from basic compounds. Those skilled in the art will understand the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation. Similarly, "pharmaceutically acceptable ester" refers to an ester derivative formed by the formation of the small molecule inhibitors of the present invention, and "pharmaceuticalally acceptable prodrugs" include precursor compounds having the ability to form the small molecule inhibitors of the present invention in vitro and in vivo.

[0157] In this invention, the term "aromatic ring" or "aryl" refers to a monocyclic or fused polycyclic group with 5-12 carbon atoms, possessing a fully conjugated π-electron system. Non-limiting examples of aromatic rings include benzene rings, biphenyl rings, naphthyl rings, and anthracene rings. Aromatic rings can be unsubstituted or substituted. Substituents in aromatic rings can be selected from halogens, nitro groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkyl groups, halo-C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, and halo-C3-C6 cycloalkyl groups.

[0158] In this invention, "heteroaryl" refers to an unsaturated carbon ring with 5-12 ring atoms, wherein one or more carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. The heteroaryl ring can be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Specific heterocyclic aryl groups can be: pyrrole, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrrole, morpholinyl, piperidinyl or piperazinyl, thiophene, benzothiophene, pyrazolyl, benzopyrazolyl, indolyl, dioxopentyl, benzo[1,3]dioxopentyl, oxazolyl, benzooxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, etc. Heterocyclic aryl groups can be unsubstituted or substituted. The substituents of the heterocyclic aryl group can be selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, and halogenated C3-C6 cycloalkyl.

[0159] In this invention, "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. Examples of "alkoxy" as used in this invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy, and the alkoxy group may be unsubstituted or substituted.

[0160] In this invention, "halogen" or "halogenated" means fluorine, chlorine, bromine or iodine.

[0161] In this invention, the pharmaceutically acceptable excipients include, but are not limited to, conventional pharmaceutical diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, etc., and flavoring agents, sweeteners, etc., may be added if necessary. The pharmaceutical compositions of this invention can be formulated into various forms such as tablets, powders, granules, capsules, oral liquids, and injectable drugs, and all of the above dosage forms can be prepared according to conventional pharmaceutical methods.

[0162] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention. Experimental methods in the following embodiments without specific conditions are generally performed under conventional conditions or according to the manufacturer's recommendations. All raw materials without specified synthesis methods were purchased from manufacturers such as Exploration Platform, Aladdin, and Sigma-Aldrich, and were of analytical grade.

[0163] Example 1: Preparation of 4-(1,1-dioxy-4H-benzo[e][1,2,4]thiadiazine-4-yl)methyl)-N-hydroxybenzamide (T-1)

[0164]

[0165] T-1 was prepared according to method a. The procedure was as follows:

[0166] 1) At -40°C, aniline (270 mmol) was dissolved in 100 mL of nitromethane, and then added dropwise to a 200 mL solution of chlorosulfonyl isocyanate (26 mL, 300 mmol) in nitromethane using a dropper funnel. After the addition was complete, the reaction mixture was stirred for another 30 minutes and aluminum chloride (39 g, 300 mmol) was added. The mixture was then heated to 110°C with stirring and maintained for 1 hour. The crude material was then poured into ice, the precipitate was collected by vacuum filtration, washed with cold water and anhydrous diethyl ether, and slurried with anhydrous ethanol to obtain intermediate a1.

[0167] 2) Add intermediate a1 to 320 mL of 50% sulfuric acid aqueous solution and heat to 140 °C for 8 hours. Then pour the solution onto ice and neutralize with saturated sodium hydroxide aqueous solution at 0 °C. Collect the precipitate by suction filtration, wash with cold water, and dry under vacuum to obtain intermediate a2.

[0168] 3) A suitable amount of 2-aminobenzenesulfonamide a2 (100 mmol) was heated to reflux for 2 hours in triethyl orthoformate / triethyl orthoacetate (150 mL). After cooling the mixture to room temperature, the desired compound was collected by filtration, washed with diethyl ether, slurried with dichloromethane, and dried under vacuum to give intermediate 4H-1,2,4-benzothiadiazine 1,1-dioxide (a3). Yield 89%; mp 226-228℃; 1H NMR (400 MHz, DMSO-d6): δ 7.28 (m, 1H), 7.43 (m, 1H), 7.65 (m, 1H), 7.78 (m, 1H), 7.96 (s, 1H), 12.28 (s, 1H).

[0169] 4) Add appropriate amounts of 4H-1,2,4-benzothiadiazine 1,1-dioxide a3 (10 mmol), potassium carbonate (30 mmol), and 40 mL of acetonitrile to a temperature of 50 °C and stir for about 1 hour. Add dropwise a solution of methyl 4-bromomethylbenzoate in acetonitrile (10.5 mmol / 20 mL). After the addition is complete, raise the temperature to 70 °C and stir for about 3-4 hours. After evaporating the solvent under reduced pressure, wash the crude solid with water, dry it, and then recrystallize it in ethyl acetate to obtain the intermediate methyl 4-((1,1-dioxide-4H-1,2,4-benzothiadiazine-4-yl)methyl)benzoate (a4). LC-MS (ESI) (m / z): 331.00 (M+). 1H NMR(400MHz, DMSO-d6)δ8.39(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).

[0170] 5) Add an appropriate amount of methyl 4-((1,1-dioxy-4H-1,2,4-benzothiadiazin-4-yl)methyl)benzoate a4 (2 mmol) to a methanol solution of hydroxylamine / sodium methoxide (20 mmol). Under ice-water bath conditions, add 10 mmol of methanol solution of sodium methoxide dropwise and react for 4-6 hours. After the reaction is complete, add twice the volume of water and adjust the pH to 7-8 with 2M HCl aqueous solution. A solid precipitates out; filter and slurry with methanol to obtain 4-(1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-1). mp 220.7-222.7℃. LC-MS (ESI) (m / z): 365.00 [M+CH3OH+H]+. 1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),9.05(s,1H),8.41(s,1H),7.91(dd,J=7.9,1.5Hz,1H),7.77–7.7 3(m,2H),7.66(ddd,J=8.7,7.3,1.6Hz,1H),7.51(t,J=7.6Hz,1H),7.38(t,J=8.6Hz,3H),5.46(s,2H).

[0171] Example 2: Preparation of 4-(1,1-dioxide-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazine-4-yl)methyl)-N-hydroxybenzamide (T-2)

[0172]

[0173] T-2 was prepared according to method b. The procedure was as follows:

[0174] 1) An appropriate amount of methyl 4-((1,1-dioxane-4H-1,2,4-benzothiadiazin-4-yl)methyl)benzoate (5 mmol) was added to 40 mL of methanol and stirred at room temperature. Sodium borohydride (20 mmol) was added in portions, and the mixture was stirred for 30 min. After the reaction was complete, the solvent was evaporated under reduced pressure, water was added and stirred, and the pH was adjusted to acidic (pH = 2-3) with 2 M HCl aqueous solution. A large amount of solid precipitated out; this solid was filtered, dried, and the intermediate methyl 4-((1,1-dioxane-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl)methyl)benzoate (b1) was obtained. LC-MS (ESI) (m / z): 333.10 (M+). 1HNMR(400MHz,DMSO-d6)δ8.22(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(d dd,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).

[0175] 2) An appropriate amount of methyl 4-((1,1-dioxide-2,3-dihydro-4H-1,2,4-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzoate b1 (2 mmol) was added to a methanol solution of hydroxylamine / sodium methoxide (20 mmol). Sodium methoxide methanol solution (10 mmol) was added dropwise under ice-water bath conditions, and the reaction was allowed to proceed for 4-6 hours. After the reaction was complete, twice the volume of water was added, and the pH was adjusted to 7-8 with 2M HCl aqueous solution. A solid precipitated out; this was filtered, slurried in methanol, to obtain 4-(1,1-dioxide-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-2). mp 180.2-181.8℃. LC-MS (ESI) (m / z): 334.00 (M+). 1HNMR(400MHz,DMSO-d6)δ7.71(d,J=7.9Hz,2H),7.55(dd,J=7.8,1.6Hz,1H),7.37(d,J=7.9Hz, 2H),7.30–7.25(m,1H),6.76(t,J=7.5Hz,1H),6.63(d,J=8.6Hz,1H),4.88(s,2H),4.64(s,2H).

[0176] Example 3: Preparation of 4-(7-chloro-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-3)

[0177]

[0178] T-3 was prepared according to method a. mp 175.9-176.1℃. LC-MS (ESI) (m / z): 399.00 [M+CH3OH+H]+. 1H NMR (600MHz, DMSO-d6) δ 11.14 (s, 1H), 8.99 (s, 1H), 7.69 (d, J = 8.2Hz, 2H), 7.59 (d, J = 2.7Hz, 1H), 7.40 (d, J = 8.0Hz, 2H), 7.31 (dd, J = 9.0, 2.7Hz, 1H), 6.77 (s, 1H), 6.63 (d, J = 9.0Hz, 1H), 4.54 (d, J = 6.0Hz, 2H).

[0179] Example 4: Preparation of 4-((7-chloro-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-4)

[0180]

[0181] T-4 was prepared according to method b. mp 172.3-175.9℃. LC-MS (ESI) (m / z): 368.40 (M + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0182] Example 5: Preparation of 4-(7-fluoro-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-5)

[0183]

[0184] T-5 was prepared according to method a. mp 155.3-158.3℃. LC-MS (ESI) (m / z): 349.90 (M + ). 1H NMR (400MHz, DMSO-d6) 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).

[0185] Example 6: Preparation of 4-((7-fluoro-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-6)

[0186]

[0187] T-6 was prepared according to method b. The temperature range was 181.4–182.6 °C. LC-MS (ESI) (m / z): 352.00 (M). + ). 1 H NMR(400MHz,DMSO-d6)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).

[0188] Example 7: Preparation of N-hydroxy-4-(7-methyl-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-7)

[0189]

[0190] T-7 was prepared according to method a. mp 179.9-181.8℃. LC-MS (ESI) (m / z): 346.00 (M + ). 1 H NMR(600MHz,DMSO-d6)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).

[0191] Example 8: Preparation of N-hydroxy-4-(7-methyl-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-8)

[0192]

[0193] T-8 was prepared according to method b. The chromatogram was 175.9-176.4℃. LC-MS (ESI) (m / z): 348.50 (M). + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0194] Example 9: Preparation of N-hydroxy-4-(7-methoxy-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-9)

[0195]

[0196] T-9 was prepared according to method a. mp 186.3-188.8℃. LC-MS (ESI) (m / z): 361.40 (M + ). 1 H NMR (600MHz, DMSO-d6) δ11.14(s,1H),9.15(s,1H),8.32(s,1H),7.74(d,J=8.2H z,2H),7.36–7.31(m,4H),7.25(dd,J=9.4,3.1Hz,1H),5.43(s,2H),3.82(s,3H).

[0197] Example 10: Preparation of N-hydroxy-4-(7-methoxy-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-10)

[0198]

[0199] T-10 was prepared according to method b. mp 165.1-166.9℃. LC-MS (ESI) (m / z): 364.60 (M + ).1 H NMR (600MHz, DMSO-d6) δ9.37(s,1H),7.72(d,J=8.0Hz,2H),7.38(d,J=7.9Hz,2H),7.08(d,J=3.0H z,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).

[0200] Example 11: 4-(1,1-dioxide-3-oxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-11)

[0201]

[0202] T-11 was prepared according to method c. The specific procedures are as follows:

[0203] 1) Intermediate a1 (10 mmol) and potassium carbonate (12 mmol) were added to 30 mL of N,N-dimethylformamide, and a solution of methyl 4-bromomethylbenzoate in acetonitrile (10 mmol / 20 mL) was added dropwise. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was poured into 200 mL of water, and a solid precipitated. The solid was separated by filtration. The filter cake was washed with water and dried under vacuum to produce a mixture of regioisoalkylated products. The mixture was then subjected to 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 (c1). LC-MS (ESI) (m / z): 346.90 (M+). 1H NMR(600MHz,DMSO-d6)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=8.2Hz,1H),5.47(s,2H),3.87(s,3H).

[0204] 2) Add 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) to a methanol solution of hydroxylamine / sodium methoxide (20 mmol). Under ice-water bath conditions, add 10 mmol of methanol solution of sodium methoxide dropwise and react for 4-6 hours. After the reaction is complete, add twice the volume of water and adjust the pH to 7-8 with 2M HCl aqueous solution. A solid precipitates; filter, slurry with methanol, to obtain T-1. mp 219.6-219.8℃. LC-MS (ESI) (m / z): 348.50 (M+). 1H NMR(400MHz,DMSO-d6)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=7.6Hz,1H),7.24(d,J=8.2Hz,1H),5.40(s,2H).

[0205] Example 12: 4-((7-fluoro-1,1-dioxy-3-oxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-12)

[0206]

[0207] T-12 was prepared according to method c. mp 216.2-217.0℃. LC-MS (ESI) (m / z): 366.50 (M + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0208] Example 13: N-hydroxy-4-(7-methoxy-1,1-dioxy-3-oxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-13)

[0209]

[0210] T-13 was prepared according to method c. mp 211.9-212.7℃. LC-MS (ESI) (m / z): 378.60 (M + ).1 H NMR (400MHz, DMSO-d6) 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).

[0211] Example 14: 4-((7-bromo-1,1-dioxy-3-oxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-14)

[0212]

[0213] T-14 was prepared according to method c. mp 222.6-223.3℃. LC-MS (ESI) (m / z): 427.80 (M + ). 1 H NMR (600MHz, DMSO-d6) 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).

[0214] Example 15: 4-((7-chloro-1,1-dioxy-3-oxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-15)

[0215]

[0216] T-15 was prepared according to method c. mp 216.2-217.1℃. LC-MS (ESI) (m / z): 381.90 (M + ). 1 H NMR (600MHz, DMSO-d6) 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).

[0217] Example 16: N-hydroxy-4-(7-methyl-1,1-dioxy-3-oxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)benzamide (T-16)

[0218]

[0219] T-16 was prepared according to method c. mp 214.5-217.8℃. LC-MS (ESI) (m / z): 362.70 (M + ). 1 H NMR(400MHz,DMSO-d6)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).

[0220] Example 17: 4-((7-chloro-3-methyl-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-17)

[0221]

[0222] T-17 was prepared according to method a. Calcium content: 174.6-175.6 °C. LC-MS (ESI) (m / z): 380.60 (M). + ). 1 H NMR (600MHz, DMSO-d6) 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).

[0223] Example 18: 4-((2-benzyl-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-18)

[0224]

[0225] T-18 was prepared according to method d. The procedure is as follows:

[0226] 1) Intermediate b1 (1.5 mmol), potassium carbonate (3.26 mmol), and 10 mL of acetonitrile were heated to 70 °C, and RBr (1.65 mmol) was added. The reaction was allowed to proceed for approximately 2 hours. After evaporating the solvent under reduced pressure, the crude solid was washed with water, dried, and then recrystallized in ethyl acetate to give intermediate methyl 4-methyl(2-benzyl-1,1-dioxy-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl)benzoate (d1). LC-MS (ESI) (m / z): 423.80 (M + ). 1 H NMR(600MHz,DMSO-d6)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,5 H),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).

[0227] 2) Intermediate d1 (1.5 mmol) was added to a methanol solution of hydroxylamine / sodium methoxide (15 mmol). Sodium methoxide methanol solution (7.5 mmol) was added dropwise under ice-water bath conditions, and the reaction was allowed to proceed for 4-6 hours. After the reaction was complete, twice the volume of water was added, and the pH was adjusted to 7-8 with 2M HCl aqueous solution. A solid precipitated out; this was filtered, slurried in methanol, and T-18 was obtained. mp 128.1-129.9℃. LC-MS (ESI) (m / z): 424.80 (M + ). 1 HNMR (600MHz, DMSO-d6) 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).

[0228] Example 19: 4-(7-bromo-1,1-dioxy-4H-benzo[e][1,2,4]thiadiazin-4-yl)-N-hydroxybenzamide (T-19)

[0229]

[0230] T-19 was prepared according to method a. The temperature range was 164.3-165.0℃. LC-MS (ESI) (m / z): 401.80 (M). + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0231] Example 20: 4-((2-benzyl-7-chloro-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-20)

[0232]

[0233] T-20 was prepared according to method d. The temperature range was 128.4–132.5 °C. LC-MS (ESI) (m / z): 458.50 (M+). 1 H NMR(600MHz,DMSO-d6)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,1 H),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).

[0234] Example 21: 4-(7-chloro-2-(cyclopropylmethyl)-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-21)

[0235]

[0236] T-21 was prepared according to method d. The temperature range was 126.5-128.2℃. LC-MS (ESI) (m / z): 421.90 (M). + ). 1H NMR (600MHz, DMSO-d6) 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).

[0237] Example 22: 4-(7-chloro-2-(2-hydroxyethyl)-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-22)

[0238]

[0239] T-22 was prepared according to method d. The temperature range was 130.7-132.3℃. LC-MS (ESI) (m / z): 411.90 (M). + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0240] Example 23: 4-(7-chloro-2-(cyclohexylmethyl)-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-23)

[0241]

[0242] T-23 was prepared according to method d. The temperature range was 127.1-129.4℃. LC-MS (ESI) (m / z): 464.00 (M). + ). 1H NMR(400MHz, DMSO-d6)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,1 H),5.04(s,2H),4.72(s,2H),2.74(d,J=7.2Hz,2H),1.67–1.59(m,5H),1.4 8(ddd,J=11.4,7.8,3.4Hz,1H),1.18–1.09(m,3H),0.85(t,J=11.1Hz,2H).

[0243] Example 24: 4-(7-chloro-2-(3-hydroxypropyl)-1,1-dioxy-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-24)

[0244]

[0245] T-24 was prepared according to method d. The temperature range was 136.4-138.8℃. LC-MS (ESI) (m / z): 426.00 (M). + ). 1 H NMR (400MHz, DMSO-d6) 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).

[0246] Example 25: 4-((7-chloro-1,1-dioxy-2-phenethyl-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-N-hydroxybenzamide (T-25)

[0247]

[0248] T-25 was prepared according to method d. The temperature range was 141.6-144.0℃. LC-MS (ESI) (m / z): 472.00 (M). + ). 1H NMR (600MHz, DMSO-d6) 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).

[0249] Example 26: HDAC Inhibition Activity of Compound

[0250] The inhibitory effects of the compounds on HDAC6 and HDAC1 targets were detected using the established experimental platform and testing conditions, with HDAC6 inhibitors Rocilinostat (ACY-1215) and SW-100 as positive control compounds.

[0251] 1) Reagents and consumables

[0252] Table 2

[0253]

[0254] 2) Instruments

[0255] Table 3

[0256]

[0257] 3) HDAC enzyme preparation

[0258] HDAC6 enzyme inhibition assay: Prepare a 40mM DMSO solution from the sample and store it in the dark for later use.

[0259] HDAC1 enzyme inhibition experiment: The compounds were prepared as 20 mM DMSO solutions and stored in the dark for later use.

[0260] 4) HDAC6 enzymatic reaction process

[0261] a. Prepare a 1× reaction solution.

[0262] b. Preparation of compound concentration gradients: The final concentration of the analyte was initially 80 nM, diluted 4-fold, resulting in 5 concentrations, and a single-well assay was performed. The final concentration of the positive compound was initially 3 μM, diluted 3-fold, resulting in 10 concentrations, and a replicate assay was performed. Solutions were serially diluted to the corresponding 100-fold final concentrations in a 384-well Source plate, and then 250 nL was transferred to the 384-well reaction plate using an Echo 550. 250 nL of 100% DMSO was transferred to both the Max and Min wells.

[0263] c. Prepare a 1.67× enzyme solution using a 1× reaction solution.

[0264] Add 15 μL of 1.67× enzyme solution to each well; add 15 μL of 1.6× reaction solution to each Min well. Incubate at room temperature for 15 minutes.

[0265] e. Prepare a 2.5× substrate mixture using 1× reaction solution.

[0266] Add 10 μL of a 2.5× substrate mixture to each well of the reaction plate to initiate the reaction.

[0267] g uses Synergy to continuously read fluorescence signals.

[0268] 5) HDAC1 enzymatic reaction process

[0269] a. Prepare a 1× reaction solution.

[0270] b. Preparation of compound concentration gradients: The final concentration of the analyte was initially 2 μM, diluted 10-fold, and four concentrations were set up for single-well detection; the positive control concentration was initially 3 μM, diluted 3-fold, and ten concentrations were set up for replicate detection. Solutions were serially diluted to the corresponding 100-fold final concentrations in a 384-well Source plate, and then 250 nmol was transferred to the 384-well reaction plate using an Echo 550. 250 nmol of 100% DMSO was transferred to both the Max and Min wells.

[0271] c. Prepare a 1.67× enzyme solution using a 1× reaction solution.

[0272] Add 15 μL of 1.67× enzyme solution to each well; add 15 μL of 1.6× reaction solution to each Min well. Incubate at room temperature for 15 minutes.

[0273] e. Prepare a 2.5× substrate mixture using 1× reaction solution.

[0274] Add 10 μL of a 2.5× substrate mixture to each well of the reaction plate to initiate the reaction.

[0275] g uses Synergy to continuously read fluorescence signals.

[0276] 5) Data Analysis

[0277] The slope is obtained by selecting the linear response segment. The percentage inhibition rate is then calculated using the following formula:

[0278]

[0279] Where: Mean(Max) is the mean slope value of each Max well (containing DMSO and enzyme); Mean(Min) is the mean slope value of each Min well (without enzyme); Sample Signal is the slope value of the compound well.

[0280] Fitting dose-response curves: Using the log value of compound concentration as the X-axis and the corresponding percentage inhibition rate as the Y-axis, the dose-response curves were fitted using the log(inhibitor) vs. response-variable slope function of GraphPad Prism 5 to obtain the IC50 of each compound inhibiting enzyme activity. 50 value.

[0281] The experimental results are shown in Table 4:

[0282] Table 4

[0283]

[0284]

[0285] Experimental results show that the compounds of this invention exhibit strong inhibitory activity against HDAC6. Compared with HDAC1, the compounds show stronger inhibitory activity against HDAC6 and exhibit a certain degree of selectivity.

[0286] Example 27 Compound's Anti-cell Proliferation Activity

[0287] Using the CCK-8 assay, with SW-100 and ACY-1215 as positive controls, a subset of the compounds of this invention were selected to test their antiproliferative activity against SH-SY5Y cells (human neuroblastoma cell line) and MRC-5 human normal embryonic lung fibroblasts at a concentration of 20 μM (replicas). The experimental data are shown in the table.

[0288] The results of the anti-cell proliferation experiment are shown in Table 5 (unit: Inh%in 20μM):

[0289] Table 5

[0290]

[0291]

[0292] A:>90%; B:80~90%; C:70~80%; D:50~70%E:<50%

[0293] Experimental results showed that at a test concentration of 20 μM, the compound of the present invention generally had a weak antiproliferative effect on SH-SY5Y cells and MRC-5 human normal embryonic lung fibroblasts, and was weaker than the positive control drugs SW-100 and ACY-1215, indicating that it has low cytotoxicity.

[0294] Example 28: Protective effect of compound against L-glutamate-induced SH-SY5Y cell damage model

[0295] Using SW-100 and ACY-1215 as positive control drugs, some compounds of this invention were selected to test their protective effect on an L-glutamate-induced SH-SY5Y cell damage model.

[0296] Experimental methods

[0297] Day 0: Cell inoculation

[0298] 1. Centrifuge the suspended cells and resuspend them in growth medium, then count them using a cell counter.

[0299] 2. Dilute the cell suspension in the growth medium to the required density.

[0300] 3. Seed 100 μL of cells into 96-well plates containing growth medium according to the plate diagram. Medium is used only as a background control (Min).

[0301] 4. Incubate overnight at 37°C and 5% CO2.

[0302] Day 1: Compound Processing

[0303] 1. Prepare a 200-fold compound solution in DMSO.

[0304] 2. The compound containing the growth medium was diluted to a final concentration by adding 3 μL of a 200-fold dilution of the compound solution to 197 μL of growth medium.

[0305] 3. Add 50 μL of the diluted compound solution to the cells and incubate at 37°C and 5% CO2 for 48 h.

[0306] 4. Remove the growth medium

[0307] 5. Add 150 μL of culture medium containing 1X cpds and 16 mM L-glutamate to the cells and incubate at 37°C and 5% CO2 for 24 hours.

[0308] Day 4: Measurement

[0309] 1. Equilibrate the test plate to room temperature before measurement.

[0310] 2. Add 40 μL of CellTiter to each well. Reagent.

[0311] 3. Mix the contents on an orbital oscillator for 2 minutes to induce cell lysis.

[0312] 4. Incubate at room temperature for 60 minutes to stabilize the luminescence signal.

[0313] 5. Record the luminescence on Envision.

[0314] Data Analysis

[0315] (1) Use GraphPadPrism 5.

[0316] (2)%Inh = (maximum signal - composite signal) / (maximum signal - minimum signal) × 100.

[0317] (3) The maximum signal comes from the effect of DMSO.

[0318] (4) The minimum signal is obtained solely by the action of the medium.

[0319] The experimental results are shown in Table 6.

[0320] Table 6

[0321]

[0322]

[0323] Discussion of results from an in vitro glutamate-induced neuronal injury model:

[0324] 1) Glutamate (15 nM) can significantly reduce the viability of neurons. SW-100 can improve the viability of SH-SY5Y cells damaged by L-glutamate, reduce the cytotoxic effect of L-glutamate, and has a certain neuroprotective effect, while ACY-1215 has a weaker neuroprotective effect and even shows some toxicity.

[0325] 2) The compound of the present invention can enhance the viability of SH-SY5Y cells and shows a protective effect against L-glutamate-induced damage to SH-SY5Y cells, which is superior to SW-100.

[0326] Example 29: Experiment on the effect of compounds on hERG potassium channels

[0327] The potential cardiotoxic side effects of some compounds of this invention were preliminarily investigated in vitro using the hERG potassium channel inhibition assay. The experimental procedure is as follows:

[0328] 1) Cell preparation

[0329] CHO-hERG cells were cultured at 175 cm⁻¹ 2 In the culture flask, when the cell density grows to 60-80%, remove the culture medium, wash once with 7 mL PBS, and then add 3 mL Detachin for digestion.

[0330] After complete digestion, add 7 mL of culture medium to neutralize, then centrifuge, aspirate the supernatant, and resuspend in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁻⁶ cells / mL. 6 / mL.

[0331] 2) Electrophysiological recording process

[0332] The entire process of single-cell high-impedance sealing and whole-cell pattern formation was automated by the Qpatch instrument. After obtaining the whole-cell recording pattern, the cells were clamped at -80 mV. Before applying a 5-second +20 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulus was applied every 15 seconds. After recording for 2 minutes, extracellular fluid was applied for another 2 minutes of recording, and then the drug administration process began. The compound concentration started from the lowest test concentration, and each test concentration was administered for 2 minutes. After all concentrations were administered, 10 μM Cisapride, a positive control compound, was administered. At least 3 cells (n≥3) were tested for each concentration.

[0333] 3) Compound preparation

[0334] The stock solution of the compound was diluted with extracellular fluid. 2 μL of the stock solution was added to 998 μL of extracellular fluid, and then the solution was serially diluted 5-fold in extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested. Experimental data were analyzed using XLFit software.

[0335] The experimental results are shown in Table 7 below:

[0336] Table 7

[0337]

[0338]

[0339] hERG experimental results showed that the compounds of this invention exhibited inhibitory activity against hERG potassium ion channels greater than 20 μM, suggesting that the compounds of this invention have low potential cardiotoxicity.

[0340] Example 30 Pharmaceutical Composition 1

[0341] 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 with compound T-3 as the active ingredient.

[0342] Example 31 Pharmaceutical Composition 2

[0343] The compound T-24 prepared in Example 24 was mixed with a solvent and a stabilizer, filtered, and packaged to obtain pharmaceutical composition 2 with compound T-24 as the active ingredient.

[0344] Example 32 Pharmaceutical Composition 3

[0345] Compound T-5 prepared in Example 5 and compound T-15 prepared in Example 15 were mixed with filler, disintegrant, and lubricant, granulated, and tableted to obtain pharmaceutical composition 3 with compounds T-5 and T-15 as active ingredients.

[0346] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A benzothiadiazine 1,1-dioxide compound having the general structural formula shown in formula (I), or a pharmaceutically acceptable salt thereof; ， in, R1 and R2 are independently selected from hydrogen, halogen, alkyl or alkoxy; When there is an N=C double bond between the 2-N and 3-C on the 1,1-dioxybenzothiadiazine ring, the compound of formula (Ⅰ) does not contain R3; R3is selected from hydrogen or -(CH2)n-R5; R5is selected from cycloalkyl, aryl or hydroxy; said cycloalkyl is a cycloalkyl group containing 3 to 6 carbon atoms, which is optionally substituted with 0 to 3 halogen; said aryl is selected from phenyl, naphthyl or anthryl; m is 2, n is a positive integer selected from 1 to 4; and m R3is selected from hydrogen or -(CH2)n-R5; R5is selected from cycloalkyl, aryl or hydroxy; said cycloalkyl is a cycloalkyl group containing 3 to 6 carbon atoms, which is optionally substituted with 0 to 3 halogen; said aryl is selected from phenyl, naphthyl or anthryl; m is 2, n is a positive integer selected from 1 to 4; and R4 is selected from hydrogen, oxo group or alkyl group; The alkyl group is an alkyl group containing 1 to 4 carbon atoms, which is optionally substituted with 0 to 3 halogens; The alkoxy group is selected from alkoxy groups containing 1 to 4 carbon atoms.

2. The benzothiadiazine 1,1-dioxide compound according to claim 1, characterized in that, Including compound (I-1) or compound (I-2): ， In the compound of formula (Ⅰ-1), R1 and R2 are independently selected from hydrogen, halogen, alkyl or alkoxy; R4 is selected from hydrogen or alkyl groups; The alkyl group is an alkyl group containing 1 to 4 carbon atoms, which is optionally substituted with 0 to 3 halogens; The alkoxy group is selected from alkoxy groups containing 1 to 4 carbon atoms; In the compound of formula (Ⅰ-2), R1 and R2 are independently selected from hydrogen, halogen, alkyl or alkoxy; R3 is selected from hydrogen or -(CH) m )n-R5; R5 is selected from cycloalkyl, aryl or hydroxyl; the cycloalkyl is a cycloalkyl containing 3 to 6 carbon atoms, which is optionally substituted by 0 to 3 halogens; the aryl is selected from phenyl, naphthyl or anthracene; m is 2, and n is selected from positive integers from 1 to 4; R4 is selected from hydrogen or oxo group; The alkyl group is an alkyl group containing 1 to 4 carbon atoms, which is optionally substituted with 0 to 3 halogens; The alkoxy group is selected from alkoxy groups containing 1 to 4 carbon atoms.

3. The benzothiadiazine 1,1-dioxide compound according to claim 1 or 2, characterized in that, The halogen is selected from fluorine or chlorine.

4. The benzothiadiazine 1,1-dioxide compound according to claim 1 or 2, characterized in that, Pharmaceutically acceptable salts of compounds of formula (I) include anionic salts formed by the reaction of compounds 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 cationic salts formed by the reaction of compounds of formula (I) with sodium ion solution or potassium ion solution.

5. The benzothiadiazine 1,1-dioxide compound according to claim 1 or 2, characterized in that, R1 and R2 are independently selected from hydrogen, methyl, F or Cl; The N atom bonded by R3 forms an N=C double bond with the adjacent C atom, and the compound of formula (Ⅰ) does not contain R3; or, the N atom bonded by R3 forms an NC single bond with the adjacent C atom, and R3 is selected from hydrogen or -(CH) m )n-R5, where R5 is selected from phenyl, cyclopropane, cyclohexane or hydroxy; m is 2, and n is 1, 2 or 3; R4 is selected from hydrogen, oxo group or methyl.

6. The benzothiadiazine 1,1-dioxide compound according to claim 1, characterized in that, Including the following compounds, or pharmaceutically acceptable salts thereof: 。 7. A method for preparing the benzothiadiazine 1,1-dioxide compound according to any one of claims 1-6, characterized in that, Includes one or more of the following methods: If the compound of formula (Ⅰ) does not contain R3, it shall be prepared by method a; Method a includes the following steps: A1, Compound (II) reacts with methyl 4-bromomethylbenzoate under heating conditions to give compound (III); ， Wherein, R1, R2, and R4 are as described in any one of claims 1-6; A2, the compound of formula (III) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-1); ， Wherein, R1, R2, and R4 are as described in any one of claims 1-6; If the compound of formula (Ⅰ) contains R3, where R3 is hydrogen and R4 is a non-oxo group, it can be prepared using method b: Method b includes the following steps: B1, Compound (III) is reduced to Compound (IV) by sodium borohydride; ， Wherein, R1 and R2 are as described in any one of claims 1-6; R4 is selected from the non-oxo-substituted groups shown in any one of claims 1-6; B2, the compound of formula (IV) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-2-1); ， Wherein, R1 and R2 are as described in any one of claims 1-6; R4 is selected from the non-oxo-substituted groups shown in any one of claims 1-6; If the compound of formula (Ⅰ) contains R3, where R3 is hydrogen and R4 is an oxo group, it is prepared using method c: Method c includes the following steps: C1, Compound (V) reacts with methyl 4-bromomethylbenzoate under alkaline conditions to give Compound (VI); ， Wherein, R1 and R2 are as described in any one of claims 1-6; C2, the compound of formula (VI) reacts with hydroxylamine under alkaline conditions to give the compound of formula (Ⅰ-2-2); ， Wherein, R1 and R2 are as described in any one of claims 1-6; If the compound of formula (Ⅰ) contains R3 and R3 is non-hydrogen, it is prepared using method d: Method d includes the following steps: D1, Compound (IV) reacts with Compound (VII) under heating conditions to give Compound (VIII); ， in, Compound (Ⅳ) can be prepared according to the method shown in step B1; R1, R2, and R4 are as described in any one of claims 1-6; R3 is selected from the non-hydrogen groups shown in any one of claims 1-6; X is a halogen; D2, the compound of formula (VIII) reacts with hydroxylamine under alkaline conditions to give the compound of formula (I-2-3); ， in, R1, R2, and R4 are as described in any one of claims 1-6; R3 is selected from the non-hydrogen groups described in any one of claims 1-6.

8. The preparation method according to claim 7, characterized in that, It also includes one or more of the following methods: The method for preparing the compound of formula (V) includes the following steps: Compound (IX) was reacted with chlorosulfonyl isocyanate at -50℃ to 100℃, and then reacted with aluminum chloride at 30℃ to 120℃ to obtain compound (V). ， Wherein, R1 and R2 are as described in any one of claims 1-6; And / or, the method for preparing the compound of formula (II) includes the following steps: E1, compound of formula (V) reacts with dilute sulfuric acid at 130℃~150℃ to obtain compound of formula (X); ， Wherein, R1 and R2 are as described in any one of claims 1-6; E2, the compound of formula (X) reacts with the compound of formula (XI) upon heating to give the compound of formula (II); ， Wherein, R1, R2, and R4 are as described in any one of claims 1-6.

9. The preparation method according to claim 7, characterized in that, The heating temperature in step A1 is 60℃~80℃, and the heating reaction time is 3~4h; And / or, in step B1, sodium borohydride is added to a solution of compound (III) to carry out a reduction reaction to generate compound (IV); And / or, in step C1, compound (V) and sodium carbonate are dissolved in N,N-dimethylformamide, and methyl 4-bromomethylbenzoate is added dropwise to the above solution to react and obtain compound (VI); And / or, in step C1, the reaction time is 3~5 hours; And / or, the heating temperature in step D1 is 60℃~80℃, and the reaction time is 1.5~3h; And / or, in step A2, the compound of formula (III) reacts with hydroxylamine in a sodium methoxide methanol solution; And / or, in step B2, the compound of formula (IV) reacts with hydroxylamine in a sodium methoxide methanol solution; And / or, in step C2, the compound of formula (VI) reacts with hydroxylamine in a sodium methoxide methanol solution; And / or, in step D2, the compound of formula (VIII) reacts with hydroxylamine in a sodium methoxide methanol solution; And / or, in any one or more of steps A2, B2, C2 and D2, the reaction temperature is independently -5℃ to 5℃ and the reaction time is independently 4 to 6h.

10. The preparation method according to claim 8, characterized in that, In the preparation method of compound (V), the reaction time of compound (IX) with chlorosulfonyl isocyanate is 20~60 min; And / or, in the preparation method of compound (V), the reaction time of intermediate 1 with aluminum chloride is 0.5~2h; And / or, the dilute sulfuric acid mentioned in step E1 is an aqueous sulfuric acid solution with a volume concentration of 45-60%; And / or, in step E1, the reaction time is 6~10h; And / or, in step E2, the heating temperature is 90℃~110℃, and the reaction time is 1.5~3h.

11. The use of the benzothiadiazine 1,1-dioxide compound according to any one of claims 1-6, or the benzothiadiazine 1,1-dioxide compound obtained by the preparation method according to any one of claims 7-10, in the preparation of histone deacetylase inhibitors or drugs for the treatment of neurodegenerative diseases.

12. The application according to claim 11, characterized in that, The histone deacetylase inhibitor is an HDAC6 and / or HDAC1 inhibitor.

13. The application according to claim 11, characterized in that, The aforementioned medications for treating neurodegenerative diseases include those 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.

14. A pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; said active ingredient comprising a benzothiadiazine 1,1-dioxide compound as described in any one of claims 1-6 or a benzothiadiazine 1,1-dioxide compound prepared by any one of claims 7-10.

15. The pharmaceutical composition according to claim 14, characterized in that, Pharmaceutically acceptable excipients include one or more of the following: diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, flavorings, and sweeteners.

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