HK1111998B - Process for preparing substituted benzothiazinoindoles - Google Patents

Description

Process for preparing substituted benzothiazinoindoles

Technical Field

The invention provides a method for preparing substituted benzothiazinoindole, which is characterized in that a compound shown in a formula (I) is obtained by cyclization of a substituted 7-bromoindole derivative shown in the formula (I) by using a proper catalyst and a proper solvent.

Formula (II) formula (I)

route-I (inventive step)

In a preferred embodiment, the invention comprises treating a compound of formula (II) with a suitable palladium (0) or (II) catalyst complex dissolved/suspended in a solvent in the presence of a suitable base under inert atmosphere/degassing conditions at a suitable temperature range.

Background

The Heck-reaction was first reported by Moritani, Fujiwara and Heck at the end of the 60's 20 th century (see reference). Several reports have been directed to the preparation of polycyclic systems, some of which are novel scaffolds (scaffold), by intramolecular heck reaction, which further explores their potential applications in the medical field. Our aim was to synthesize compounds having the structure shown in general formula (I) which are useful as pharmaceutical agents. The first strategy is shown in scheme (II) below, which employs the well-known heck reaction to cyclize a substituted 1- (2' -bromobenzenesulfonyl) indole.

Formula (I)

Route (II)

The synthetic route shown in scheme (II) above has several disadvantages:

1. only a few compounds with the desired tetracyclic ring system are available.

2. The conversion of reactants to products is low. This problem becomes particularly acute when the final product is synthesized and the reaction involves a catalyst such as palladium. This is particularly true when the substituents on the ring have varying electronic or steric effects.

3. Sometimes the resulting product needs further purification.

4. The average yield of each reaction step is usually at the lower end.

5. A large number of differently substituted 2-bromoarylsulfonyl chlorides were required to prepare the compound libraries. Further, when such a polysubstituted arylsulfonyl chloride is used, the reaction sometimes cannot occur due to the influence of steric and/or electronic effects of the respective substituents. It should be noted that mono/di-substituted aryl sulfonyl chlorides are not general chemical reagents, are not only expensive, but are also difficult to synthesize.

6. When R is₃A special case occurs when hydrogen is present; it is possible in this case to obtain a mixture of two isomeric compounds (see scheme IIa below, where R₃＝H)；

[ possibility A: formula III [ possibility B: formula I

Undesired products desired products ]

route-IIa

The major product is often an unwanted tetracyclic system, i.e. the system obtained by cyclization of C2 on indole (formula III), which is favored by steric and thermodynamic factors, and the reactions leading to this product can be expected to occur more in turn (see WO2004/000849a2, WO2004/055026a 1). Moreover, the separation, purification and even identification of these two isomeric compounds is an extremely difficult task. Further variation of the substitution pattern in the reactants results in a variation of the ratio of the two isomers obtained.

Thus, the number of compounds available is limited by the particular substituted 2' -bromoarylsulfonyl chlorides available. In view of this, in order to increase the diversity of the substitutions in this ring system, we have begun to search for new chemical methods for the synthesis of the ring system defined by the compounds of formula (I). We have found in their studies that route (I), which will be described in detail below, has undoubtedly a better potential solution to the problems of increasing synthesis diversity, purity, yield and economics. The key point is the use of substituted 7-bromoindoles which can participate in the heck reaction. The use of 7-bromoindole helps to eliminate the aforementioned limitations and increase the diversity of the targeted tetracyclic systems.

This result may be attributed to the following: the distribution of electrons, reactants which readily form complexes with the palladium catalyst, are more readily converted to products due to the steric chemical advantage, and increase yield due to other general principles that result in a more shifted equilibrium of the reaction towards the products formed. The reaction is beneficial to only one product, so that the purity of the obtained product is good. Once the starting 7-bromoindole is obtained, it may be further subjected to appropriate derivatization reactions. These derivatives are then treated with the commonly available off-the-shelf mono/di-substituted arylsulfonyl chlorides. This allows a significant expansion of the size and diversity of the compound library to achieve our primary goal.

Formula (II) formula (I)

route-I (inventive step)

Summary of The Invention

The present invention provides a process for the preparation of substituted benzothiazinoindoles of general formula (I) which comprises cyclisation of a starting material, i.e. a compound of general formula (II) (i.e. a substituted 1-benzenesulfonyl-7-bromo-1H-indole), using a suitable catalyst and solvent.

Formula (II) formula (I)

route-I (inventive step)

Suitable catalysts preferably comprise palladium (0) or (II) catalyst complexes dissolved/suspended in a suitable solvent in the presence of a suitable base under inert atmosphere/degassing conditions in a suitable temperature range.

Preferred substituents R in the compounds of the formulae (I) and (II)₁、R₂、R₃And R₄The definition is as follows: r₁、R₂And R₄Each independently hydrogen, chlorine, fluorine, amino, nitro, cyano, CHO, (C)₁-C₃) Alkyl, perhalogenated (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, aryl, aralkyl, aralkyloxy, (C)₅-C₇) Heterocyclic group, (C)₅-C₇) Heterocycloalkyl group, (C)₅-C₇) Heterocyclyloxy, acyl, acetyl, alkylamino, aminoalkyl, amide, hydroxyalkyl, carboxylic acid and derivatives thereof. R₃Independently hydrogen, (C)₁-C₃) Alkyl, aryl and carboxylic acids and derivatives thereof.

Suitable catalysts may be any catalyst known in the literature to be useful for carrying out cyclization reactions. Preferred catalysts include catalysts containing palladium metal in the appropriate valence state. More preferred catalysts are palladium (0) or (II) in the form of a catalyst complex with a ligand/base. Intramolecular cyclization is known to proceed with Pd (0). Thus, a suitable catalyst system preferably comprises a Pd compound in combination with a support and, in some cases, a base, which system provides in situ activated Pd (0), which activated Pd (0) is sufficiently stable to allow the reaction to proceed in the forward direction. Some examples of such Pd complexes described in the literature are as follows:

pd (II) compounds, ligands bound thereto such as phosphines, phosphites, heterocyclic carbene ligands, literature [6 ]]Reported as Li. Pd (II) compounds such as Pd (OAc)₂、PdCl₂、Pd(0)(PPh₃)₄、PdCl₂(PPh₃)₂、Pd₂(dba)₃CHCl₃、(η³-allyl-PdCl)₂Or Pd on carbon without phosphine ligands. Pd (OAc)₂And PdCl₂As precursor for the Pd (0) catalyst, a reducing agent such as a phosphine ligand may or may not be added. For example, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride and [ bis (tri-o-tolylphosphine)]Palladium (II). Document [6]Incorporated herein.

2. Colloidal Pd particles protected with tetraalkylammonium salt.

3. Polymer supported active Pd catalyst.

4. No Pd on phosphine carbon.

Both types of Pd compounds can be used, i.e. Pd (0) complex and Pd (ii) salt. It has been established in the literature that the catalytic activity of Pd (0) generated in situ from these Pd compounds is not all the same, and it is recommended to test them one by one to achieve an efficient catalytic reaction.

The ratio of Pd catalyst to ligand is very important. It is known that the presence of excess ligand reduces the concentration of active catalytic species, thereby inhibiting the catalytic process. Some Pd-catalyzed reactions are carried out in the absence of phosphine ligands, and a phosphine-free catalyst is a desirable catalyst because phosphines are expensive, difficult to recover, and such coordinated phosphines do not directly participate in the catalytic reaction. Since Pd is an expensive metal, it is very important to maximize the utilization efficiency thereof by recovery.

The suitable base selected should be at least capable of activating the Pd catalyst complex and may also serve some minor role. Such suitable bases include CH₃COOK, TEA, and the like. These bases are preferably used in an amount of 1 to 5 molar equivalents based on the compound represented by the formula (II), the reaction solvent and the reaction temperature.

Suitable solvents for the reaction are preferably inert, non-toxic and have a high boiling point under the reaction conditions. Some examples of suitable solvents include polar aprotic solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dimethylacetamide (DMA), and the like. The boiling point of the solvent is generally preferably higher than 80 deg.C, and examples thereof include dimethylacetamide, dimethylformamide and the like. The solvent is suitably used in an amount of about 5 to about 20 volumes per volume.

The inert atmosphere may be with an inert gas, such as N₂Ar or He. The reaction mixture may be further degassed, if desired.

Depending on the solvent chosen, the reaction temperature may be between 0 and 200 ℃ and preferably between 80 and 140 ℃.

The most preferred reaction conditions are summarized below:

PREFERRED EMBODIMENTS FOR CARRYING OUT THE INVENTION

The following text sets forth the preparation of various substituted compounds of the general formula (I). These are provided for illustrative purposes only and should not be mistaken for limitations on the scope of the invention.

Commercial reagents were used without further purification. The room temperature is 25-30 ℃. The melting point was not corrected. IR spectra were measured using solid KBr and the absorption wavelength expressed in wavenumber in centimeters^-1. Unless otherwise stated, all mass spectra were determined using ESI conditions.¹H NMR spectra were recorded on a Bruker instrument at 400 MHz. Deuterated chloroform (99.8% D) was used as solvent. TMS was used as a reference internal standard. The chemical shift values reported here are expressed in parts per million (δ ppm). The following abbreviations are used to indicate the multiplicity of NMR signals: s ═ singlet, bs ═ broad singlet, d ═ doublet, t ═ triplet, q ═ quartet, qui ═ quintet, h ═ heptat, dd ═ 2 doublets, dt ═ 2 triplets, tt ═ 3 triplets, and m ═ multiplet. The NMR spectrum and mass spectrum corrected for background peaks. Chromatography refers to column chromatography, performed with 60-120 mesh silica gel under nitrogen pressure (flash column chromatography).

Example 1: 8-methyl-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

A mixture of 1- (4-methylbenzenesulfonyl) -3- (4-methylpiperazin-1-yl-methyl) -7-bromoindole (170 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 ml) was heated to 90-100 ℃ under a nitrogen atmosphere. The reaction was monitored by TLC to determine if the reaction was complete. After completion of the reaction (3-4 h, TLC), the reaction mixture was cooled to 25 ℃ and filtered through Hyflow. The filtrate was diluted with an ice-water mixture under vigorous stirring. After basification with aqueous KOH to pH 9-10, the product was extracted with ethyl acetate (2 × 10 ml). The combined ethyl acetate extracts were washed with brine and water, dried over magnesium sulfate, and distilled under reduced pressure to removeThe crude residue was purified by column chromatography (silica gel, ethyl acetate: triethylamine ═ 99.5: 0.5). The pure compound was obtained as a slightly brown oil (60 mg, 46%) which turned into a solid upon standing. IR Spectrum (in centimeters)^-1): 799, 1145, 1322, 1455; mass Spectrometry (m/z): 382(M + H)⁺；¹H-NMR：2.30(3H，s)，2.39-2.58(8H，m)，2.60(3H，s)，3.75(2H，s)，7.42-7.48(2H，m)，7.64(1H，s)，7.88-7.90(1H，dd)，7.95-7.98(2H，m)，8.10-8.12(1H，d)。

Example 2: 8-fluoro-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

A mixture of 1- (4-fluorobenzenesulfonyl) -3- (4-methylpiperazin-1-yl-methyl) -7-bromoindole (171 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 130-140 ℃ under a nitrogen atmosphere. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. IR Spectrum (in centimeters)^-1): 801, 1102, 1262, 1323; mass Spectrometry (m/z): 386 (M + H)⁺；¹H-NMR：2.30(3H，s)，2.37-2.60(8H，m)，3.57(2H，s)，7.30-7.32(1H，m)，7.47-7.51(1H，t)，7.64(1H，s)，7.82-7.85(1H，dd)，7.89-7.91(1H，d)，7.94-7.96(1H，d)，8.22-8.26(1H，dd)。

Example 3: 3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

A mixture of 1- (benzenesulfonyl) -3- (4-methylpiperazin-1-ylmethyl) -7-bromoindole (165 mg, 0.368 mmol), dichlorobis (triphenylphosphine) palladium (II) (8.0 mg, 0.11 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 110 and 120 ℃ under a nitrogen atmosphere. The reaction was monitored by TLC to determine if the reaction was complete. Isolated, pure in principle according to the method described in example 1 aboveThe resulting compounds were combined and characterized. Mass Spectrometry (m/z): 368(M + H)⁺。

Example 4: 8-isopropyl-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

A mixture of 1- (4-isopropylbenzenesulfonyl) -3- (4-methylpiperazin-1-yl-methyl) -7-bromoindole (180 mg, 0.368 mmol), dichlorobis (triphenylphosphine) palladium (II) (8.0 mg, 0.011 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 110-. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. IR Spectrum (in centimeters)^-1): 804, 1172, 1322, 1454; mass Spectrometry (m/z): 410(M + H)⁺；¹H-NMR：1.35-1.37(6H，d)，2.29(3H，s)，2.31-2.60(8H，m)，3.09-3.13(1H，sep.)，3.75(2H，s)，7.45-7.50(2H，m)，7.64(1H，s)，7.88-7.90(1H，dd)，7.98-8.01(2H，m)，8.14-8.16(1H，d)。

Example 5: 1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxides

A mixture of 1- (benzenesulfonyl) -7-bromoindole (124 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (21.0 mg, 0.018 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 ml) was heated to 90-110 ℃ under a nitrogen atmosphere. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 256(M + H)⁺。

Example 6: 1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide-3-carbaldehyde

Under a nitrogen atmosphere, 1-benzenesulfonyl-3-formyl-7-bromoindole (134 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol), and potassium acetate (54.0 mg, 0.55 mmol)The mixture in dimethylacetamide (4.0 ml) was heated to 130-140 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 284(M + H)⁺。

Example 7: 3-acetyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

A mixture of 1-benzenesulfonyl-3-acetyl-7-bromoindole (140 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 130 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 298(M + H)⁺。

Example 8: 3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen atmosphere, [2- (1-benzenesulfonyl-7-bromo-1H-indol-3-yl) ethyl]A mixture of dimethylamine (150 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylformamide (4.0 mL) was heated to 120-140 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. IR Spectrum (KBr, cm)_-1): 2982, 1594, 1328, 1173, 1128, 756; mass Spectrometry (m/z): 327.2(M + H)⁺；¹H-NMR：2.35(6H，s)，2.69-2.72(2H，m)，2.97-3.01(2H，m)，7.46-7.5(1H，m)，7.59-7.64(2H，m)，7.71-7.73(1H，d，J＝7.72)，7.779(1H，bm)，7.95-7.97(1H，d，J＝7.68)，8.17-8.19(1H，d，J＝7.92)，8.22-8.24(1H，dd，J＝8.0，0.96)。

Example 9: 8-methyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen atmosphere, {2- [ 7-bromo-1- (4-methylbenzenesulfonyl) -1H-indol-3-yl]A mixture of ethyl } dimethylamine (155 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (13.0 mg, 0.011 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 110-. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 341.2(M + H)⁺；¹H-NMR：2.36(6H，s)，2.56(3H，s)，2.69-2.73(2H，t)，2.97-3.018(2H，t)，7.41-7.49(2H，m)，7.585(1H，s)，7.7-7.72(d，1H，J＝7.8)，7.94-7.96(d，1H，J＝7.68)，7.981(1H，s)，8.1-8.12(d，1H，J＝8.12)。

Example 10: 8-isopropyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen atmosphere, [2- (1- (4-isopropylbenzenesulfonyl) -7-bromo-1H-indol-3-yl) ethyl]A mixture of dimethylamine (165 mg, 0.368 mmol), bis (triphenylphosphine) palladium (II) dichloride (13.0 mg, 0.018 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 110-. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 369.4(M + H)⁺；¹H-NMR：1.355-1.372(6H，d，J＝6.96)，2.35(6H，s)，2.69-2.73(2H，m)，2.97-3.01(2H，m)，3.09-3.12(1H，septet，J＝6.92)，7.459-7.498(2H，m)，7.586(1H，s)，7.7-7.72(dd，1H，J＝7.8)，7.98-7.99(1H，d，J＝7.64)，8.00-8.01(1H，d，J＝1.52)，8.13-8.16(1H，d，J＝8.24)。

Example 11: 8-chloro-3- (N.N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen gasUnder the atmosphere, adding [2- (1- (4-chlorobenzenesulfonyl) -7-bromo-1H-indol-3-yl) ethyl]A mixture of dimethylamine (162 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 140-. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Mass Spectrometry (m/z): 361.6(M + H)⁺；¹H-NMR：2.35(6H，s)，2.68-2.72(2H，t)，2.97-3.01(2H，t)，7.48-7.6(2H，m)，7.75-7.77(1H，d，J＝7.8)，8.14-8.175(2H，m)，7.92-7.94(1H，d，J＝7.68)。

Example 12: 8-fluoro-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen atmosphere, [2- (1- (4-fluorobenzenesulfonyl) -7-bromo-1H-indol-3-yl) ethyl]A mixture of dimethylamine (156 mg, 0.368 mmol), bis (triphenylphosphine) palladium (II) dichloride (16.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 mL) was heated to 140-160 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. IR Spectrum (KBr, cm)^-1): 2930, 1602, 1463, 1323, 1173, 633; mass Spectrometry (m/z): 345.3(M + H)⁺；¹H-NMR：2.38(6H，s)，2.6-2.72(2H，t)，3.0-3.04(2H，t)，7.31-7.32(1H，m)，7.485-7.523(1H，t，J＝7.8)，7.596(1H，s)，7.76-7.78(d，1H，J＝7.72)，7.81-7.84(1H，dd，J＝9.64，2.48)，7.89-7.91(1H，d，J＝7.68)，8.226-8.261(1H，dd，J＝8.8，5.28)。

Example 13: 5-fluoro-8-methyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under a nitrogen atmosphere, [2- (1- (4-methylbenzenesulfonyl) -5-fluoro-7-bromo-1H-indol-3-yl) ethyl]Dimethylamine (162 mg, 0.368 mmol)A mixture of tetrakis (triphenylphosphine) palladium (0) (13.0 mg, 0.011 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethylacetamide (4.0 ml) was heated to 110 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. Melting point: 215 ℃ and 218 ℃; IR Spectrum (KBr, cm)^-1): 2921, 1602, 1473, 1316, 1171, 1136, 533; mass Spectrometry (m/z): 359.2(M + H)⁺；¹H-NMR：2.43(6H，s)，2.56(3H，s)，2.76-2.8(2H，m)，2.99-3.03(2H，m)，7.41-7.47(3H，m)，7.62-7.72(2H，m)，7.87(1H，s)，8.09-8.11(1H，d，J＝7.88)。

Example 14: 5-chloro-8-fluoro-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Under nitrogen atmosphere, [2- (1- (4-fluorobenzenesulfonyl) -5-chloro-7-bromo-1H-indol-3-yl) ethyl]A mixture of dimethylamine (169 mg, 0.368 mmol), tetrakis (triphenylphosphine) palladium (0) (26.0 mg, 0.022 mmol) and potassium acetate (54.0 mg, 0.55 mmol) in dimethyl sulfoxide (4.0 mL) was heated to 160-180 ℃. The reaction was monitored by TLC to determine if the reaction was complete. The resulting compound was isolated, purified and characterized in principle according to the method described above in example 1. IR Spectrum (KBr, cm)^-1): 2763, 1603, 1330, 1174, 1126, 865, 551; mass Spectrometry (m/z): 379.2(M + H)⁺；¹H-NMR：2.34(6H，s)，2.66-2.7(2H，t)，2.93-2.96(2H，m)，7.34-7.38(1H，m)，7.63(1H，s)，7.723-7.727(1H，d，J＝1.52)，7.77-7.8(1H，dd，J＝9.4)，7.863-7.866(1H，d，J＝1.28)，8.22-8.26(1H，dd，J＝8.6)。

Example 15: 3- (N, N-dimethylaminoethyl) -5-chloro-8-methyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range: 155 ℃ and 160 ℃; IR Spectrum (KBr, cm)^-1)：29231332, 1166, 1136, 810.67; mass Spectrometry (m/z): 375.1(M + H)⁺；¹H-NMR：2.46(3H，s)，2.57(6H，s)，3.03(2H，bm)，3.049(2H，bm)，7.46-7.48(1H，bd，J＝7.72)，7.61(1H，s)，7.71-7.73(1H，bm)，7.92-7.94(2H，bm)，8.1-8.12(1H，d，J＝8.16)。

Example 16: 3- (N, N-dimethylaminoethyl) -5, 8-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 150-152.5; IR Spectrum (KBr, cm)^-1): 2976, 1602, 1474, 1336, 1173, 1134, 860, 662, 539; mass Spectrometry (m/z): 363.3(M + H)⁺；¹H-NMR：2.34(6H，s)，2.66-2.7(2H，m)，2.92-2.96(2H，m)，7.358(1H，m)，7.43-7.45(1H，dd，J＝8.52)，7.59-7.62(1H，dd，J＝9.6)，7.64(1H，s)，7.72-7.75(1H，dd，J＝9.4)，8.22-8.26(dd，1H，J＝8.8)。

Example 17: 3- (N, N-dimethylaminoethyl) -5-fluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 126-129; IR Spectrum (KBr, cm)^-1): 2953, 1461, 1333, 1173, 1138, 765, 561; mass Spectrometry (m/z): 345.3(M + H)⁺；¹H-NMR：2.35(6H，s)，2.67-2.71(2H，m)，2.92-2.96(2H，m)，7.38-7.41(1H，dd，J＝8.56，2.08)，7.64-7.69(3H，m)，7.78-7.8(1H，m)，8.09-8.11(1H，d，J＝7.92)，8.22-8.25(1H，dd，J＝7.92，1.00)。

Example 18: 3- (N, N-dimethylaminoethyl) -8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 154-158; IR Spectrum (KBr, cm)^-1)：2933, 1595, 1468, 1318, 1166, 1132, 858; mass Spectrometry (m/z): 357.1(M + H)⁺；¹H-NMR：2.35(6H，s)，2.68-2.72(2H，m)，2.96-3.00(2H，m)，7.1-7.13(1H，m)，7.44-7.48(1H，t)，7.58(1H，s)，7.6-7.606(1H，d，J＝2.44)，7.7-7.72(1H，d，J＝7.84)，7.9-7.92(1H，d，J＝7.64)，8.14-8.16(d，1H，J＝8.92)。

Example 19: 3- (N, N-dimethylaminoethyl) -5-fluoro-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 186-187.5 ℃; IR Spectrum (KBr, cm)^-1): 2946, 1597, 1411, 1327, 1168, 1126, 857, 501; mass Spectrometry (m/z): 375.3(M + H)⁺；¹H-NMR：2.34(6H，s)，2.66-2.7(2H，m)，2.91-2.95(2H，m)，7.13-7.16(1H，dd，J＝8.88，2.44)，7.38-7.4(1H，dd，J＝8.56)，7.5-7.506(1H，d，J＝2.4)，7.6-7.63(2H，m)，8.14-8.16(d，1H，J＝8.88)。

Example 20: 3- (N, N-dimethylaminoethyl) -5-fluoro-8-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 152-153.4; IR Spectrum (KBr, cm)^-1): 2948, 1333, 1175, 1132, 894, 627; mass Spectrometry (m/z): 379.1(M + H)⁺；¹H-NMR：2.348(6H，s)，2.66-2.7(2H，m)，2.92-2.96(2H，m)，7.42-7.45(1H，dd)，7.616-7.659(3H，m，J＝8.48)，8.05-8.06(d，1H，J＝1.96)，8.15-8.176(1H，d，J＝8.48)。

Example 21: 3- (N, N-dimethylaminoethyl) -5-methyl-8-fluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1)：2921, 1327, 1176, 786, 762; mass Spectrometry (m/z): 359.4(M + H)⁺；¹H-NMR：2.35(6H，s)，2.68-2.72(2H，m)，2.96-3.00(2H，m)，7.1-7.13(1H，m )，7.44-7.48(1H，t)，7.58(1H，s)，7.60-7.606(1H，d，J＝2.44)，7.7-7.72(1H，d，J＝7.84)，7.9-7.92(1H，d，J＝7.64)，8.14-8.16(1H，d，J＝8.92)。

Example 22: 3- (N, N-dimethylaminoethyl) -5-methyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2919, 1338, 1175, 1127, 786, 763; mass Spectrometry (m/z): 341.4(M + H)⁺；¹H-NMR：2.4(6H，s)，2.6(3H，s)，2.75-2.77(2H，m)，2.99(2H，m)，7.52(1H，s)，7.53(1H，s)，7.59-7.63(1H，m)，7.75-7.79(2H，m)，8.16-8.18(1H，d，J＝7.88)，8.21-8.23(1H，dd，J＝9.08)。

Example 23: 3- (N, N-dimethylaminoethyl) -5, 8-dimethyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2918, 1463, 1327, 1174, 1139, 807, 607, 527; mass Spectrometry (m/z): 355.5(M + H)⁺：¹H-NMR：2.4(6H，s)，2.56(3H，s)，2.59(3H，s)，2.73-2.77(2H，m)，2.98-3.02(2H，m)，7.4-7.42(1H，m)，7.51-7.52(2H，m)，7.77(1H，s)，7.96(1H，s)，8.09-8.11(d，1H，J＝8.16)。

Example 24: 3- (N, N-dimethylaminoethyl) -5-methyl-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2918, 1596, 1323, 1303, 1240, 1169, 811, 533; mass Spectrometry (m/z): 370.7 (M)+H)⁺；¹H-NMR：2.41(6H，s)，2.75-2.79(2H，m)，2.98-3.29(2H，m)，3.99(3H，s)，7.09-7.12(1H，dd，J＝8.84，2.44)，7.51-7.52(2H，m)，7.57-7.58(1H，d，J＝2.4)，7.72(1H，s)，8.12-8.15(1H，d，J＝8.8)。

Example 25: 3- (N, N-dimethylaminoethyl) -5, 8-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 101-108; IR Spectrum (KBr, cm)^-1): 2982, 2769, 1329, 1178, 1150, 851, 791, 619, 529; mass Spectrometry (m/z): 395, 397, 399(M + H)⁺；¹H-NMR：2.35(6H，s)，2.67-2.71(2H，m)，2.93-2.97(2H，m)，7.61-7.64(2H，m)，7.72-7.727(2H，d，J＝1.64)，7.89-7.90(1H，d，J＝1.52)，8.09-8.10(1H，d，J＝1.56)8.15-8.17(1H，d，J＝8.56)。

Example 26: 3- (N, N-dimethylaminoethyl) -5-fluoro-9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 207-210; IR Spectrum (KBr, cm)^-1): 2918, 1454, 1340, 1175, 1163, 838, 581; mass Spectrometry (m/z): 413.2, 415.2(M + H)⁺；¹H-NMR：2.35(6H，s)，2.66-2.70(2H，m)，2.92-2.96(2H，m)，7.41-7.44(1H，dd，J＝8.4，2.12)，7.59-7.62(1H，dd，J＝9.98，2.0)，7.68(1H，s)，7.83-7.85(1H，d，J＝8.78)，7.97-7.99(1H，d，J＝8.78)。

Example 27: 3- (N, N-dimethylaminoethyl) -5, 9, 10-trichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 210.4-214.9; IR Spectrum (KBr, cm)^-1)：2946，1445, 1339, 1163, 838, 594, 568; mass Spectrometry (m/z): 429.1, 431.1, 432.9(M + H)⁺；¹H-NMR：2.35(6H，s)，2.67-2.71(2H，m)，2.93-2.97(2H，m)，7.66(1H，s)，7.70-7.71(1H，d，J＝1.48)，7.83-7.86(2H，m)，8.01-8.03(1H，d，J＝8.76)。

Example 28: 3- (N, N-dimethylaminoethyl) -5-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 133-136.3; IR Spectrum (KBr, cm)^-1): 2962, 1331, 1169, 1124, 826, 766, 749; mass Spectrometry (m/z): 361, 363(M + H)⁺；¹H-NMR：2.35(6H，s)，2.67-2.71(2H，m)，2.93-2.97(2H，m)，7.62-7.69(3H，m)，7.78-7.80(1H，m)，7.92-7.93(1H，d，J＝1.56)，8.12-8.14(1H，d)，8.22-8.24(1H，dd，J＝8.0，1.08)。

Example 29: 3- (N, N-dimethylaminoethyl) -9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): is more than 240; IR Spectrum (KBr, cm)^-1): 2940, 1448, 1329, 1165, 793, 600; mass Spectrometry (m/z): 394.9, 397(M + H)⁺；¹H-NMR：2.37(6H，s)，2.71-2.75(2H，m)，3.00-3.03(2H，m)，7.45-7.49(1H，t)，7.74-7.76(1H，d，J＝7.72)，7.81-7.83(1H，d，J＝8.76)，7.89-7.91(1H，d，J＝7.76)，8.08-8.10(1H，d，J＝8.72)。

Example 30: 3- (N, N-dimethylaminoethyl) -5-chloro-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 176.6-183; IR Spectrum (KBr, cm)^-1)：2980，1596，1311，1167，850，573，534(ii) a Mass Spectrometry (m/z): 391.1(M + H)⁺；¹H-NMR：2.36(6H，s)，2.67-2.71(2H，m)，2.93-2.97(2H，m)，4.0(3H，s)，7.13-7.16(1H，dd，J＝8.84，2.36)，7.52-7.53(1H，d，J＝2.36)，7.61(1H，s)，7.68-7.687(1H，d，J＝1.56)，7.86-7.87(1H，d，J＝1.56)，8.13-8.16(1H，d，J＝8.84)。

Example 31: 3- (N, N-dimethylaminoethyl) -5-methyl-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivative was prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 86.5-93.5; IR Spectrum (KBr, cm)^-1): 2957, 1599, 1458, 1322, 1174; mass Spectrometry (m/z): 383(M + H)⁺；¹H-NMR：1.35-1.38(6H，d)，2.36(6H，s)，2.61(3H，s)，2.68-2.72(2H，m)，2.94-2.98(2H，m)，3.09-3.12(1H，sep.)，7.46-7.48(1H，dd，J＝8.24，1.32)，7.49(1H，s)，7.53(1H，s)，7.79(1H，s)，7.98-7.99(1H，d，J＝1.61)，8.12-8.14(1H，d，J＝8.28)。

Example 32: 3- (N, N-dimethylaminoethyl) -5-fluoro-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 117-124; IR Spectrum (KBr, cm)^-1): 2917, 1598, 1344, 1178, 1128, 796, 661; mass Spectrometry (m/z): 387(M + H)⁺；¹H-NMR：1.35-1.37(6H，d)，2.36(6H，s)，2.68-2.72(2H，m)，2.93-2.97(2H，m)，3.1-3.13(1H，sep.)，7.38-7.4(1H，dd，J＝8.56，2.1)，7.51-7.53(1H，dd，J＝8.28，1.56)，7.63(1H，s)，7.68-7.71(1H，dd，J＝9.9，2.08)，7.914-7.918(1H，d，J＝1.48)，8.14-8.16(1H，d，J＝8.28)。

Example 33: 3- (N, N-dimethylaminoethyl) -8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 155-; IR Spectrum (KBr, cm)^-1): 2963, 1612, 1331, 1261, 1173, 1111, 855, 797, 512; mass Spectrometry (m/z): 363.1(M + H)⁺；¹H-NMR：2.41(6H，s)，2.74-2.78(2H，m)，3.02-3.06(2H，m)，7.04-7.1(1H，m)，7.47-7.53(1H，t)，7.62(1H，s)，7.67-7.71(1H，m)，7.8-7.82(1H，d，J＝7.76)，7.87-7.89(1H，d，J＝7.72)。

Example 34: 3- (N, N-dimethylaminoethyl) -5, 8, 10-trifluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. Melting point range (. degree. C.): 140-144; IR Spectrum (KBr, cm)^-1): 2917, 1579, 1462, 1339, 1173, 1094, 857, 799, 529; mass Spectrometry (m/z): 380.7(M + H)⁺；¹H-NMR：2.38(6H，s)，2.7-2.74(2H，m)，2.95-2.99(2H，m)，7.08-7.14(1H，m)，7.47-7.5(1H，dd，J＝8.4，2.04)，7.58-7.61(2H，dd，J＝9.84)，7.67(1H，s)。

Example 35: 3- (N, N-dimethylaminoethyl) -5-methyl-9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2936, 1460, 1333, 1175, 1132, 816, 609, 594; mass Spectrometry (m/z): 409, 411(M + H)⁺；¹H-NMR：2.37(6H，s)，2.70-2.74(2H，m)，2.96-3.00(2H，m)，7.53(1H，s)，7.58(1H，s)，7.70(1H，s)，7.79-7.81(1H，d，J＝8.8)，8.06-8.08(1H，d，J＝8.82)。

Example 36: 3- (N, N-dimethylaminoethyl) -5-chloro-8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

Using phases substantially as described in example 1The same procedure was used to prepare the above derivatives. IR Spectrum (KBr, cm)^-1): 2917, 1339, 1172, 1123, 757; mass Spectrometry (m/z): 397.1, 399(M + H)⁺；¹H-NMR：2.42(6H，s)，2.74-2.78(2H，m)，2.99-3.03(2H，m)，7.08-7.14(1H，m)，7.63-7.66(2H，m)，7.78-7.784(1H，d，J＝1.32)，7.85-7.854(1H，d，J＝1.32)。

Example 37: 3- (N, N-dimethylaminoethyl) -5-methyl-8-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2918, 2762, 1330, 1177, 1096, 790; mass Spectrometry (m/z): 375, 376.9(M + H)⁺；¹H-NMR：2.37(6H，s)，2.60(3H，s)，2.69-2.73(2H，m)，2.96-3.00(2H，m)，7.53-7.5 8(3H，m)，7.74(1H，s)，8.12-8.15(2H，m)。

Example 38: 3- (N, N-dimethylaminoethyl) -5-chloro-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2963, 1457, 1406, 1336, 1178, 1126, 827; mass Spectrometry (m/z): 403.2, 405.2(M + H)⁺；¹H-NMR：1.382-1.399(6H，d，J＝6.8)，2.37(6H，s)，2.65-2.73(2H，m)，2.94-2.98(2H，m)，3.12-3.15(1H，sep.)，7.53-7.56(1H，dd，J-8.28)，7.63(1H，s)，7.694-7.699(1H，d，J＝1.68)，7.96-7.967(2H，m)，8.15-8.17(1H，d，J＝8.24)。

Example 39: 3- (N, N-dimethylaminoethyl) -5-methyl-8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2918, 2849, 1619, 1332, 1170, 853, 802; mass spectrum (m)/z)：377.1(M+H)⁺；¹H-NMR：2.45(6H，s)，2.60(3H，s)，2.75-2.83(2H，m)，3.10-3.60(2H，m)，7.02-7.08(1H，m)，7.56-7.70(4H，m)。

Example 40: 3- (N, N-dimethylaminoethyl) -7-trifluoromethyl-10-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2917, 1348, 1297, 1170, 1142, 753; mass Spectrometry (m/z): 429.1, 431(M + H)⁺；¹H-NMR：2.37(6H，s)，2.72-2.76(2H，m)，2.99-3.04(2H，m)，7.48-7.58(2H，m)，7.72-7.82(2H，m)，8.20-8.60(2H，m)。

Example 41: 3- (N, N-dimethylaminoethyl) -5-fluoro-7-trifluoromethyl-10-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2943, 1435, 1349, 1298, 1170, 868; mass Spectrometry (m/z): 447.2, 449.2(M + H)⁺；¹H-NMR：2.36(6H，s)，2.69-2.73(2H，m)，2.94-2.98(2H，m)，7.46-7.49(1H，dd，J＝8.0，2.1)，7.54(1H，s)，7.76-7.78(1H，d，J＝8.72)，7.79-7.82(1H，dd)，8.04-8.07(1H，d，J＝8.60)。

Example 42: 3- (N, N-dimethylaminoethyl) -5, 10-dichloro-7-trifluoromethyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide

The above derivatives were prepared using essentially the same procedure as described in example 1. IR Spectrum (KBr, cm)^-1): 2926, 1356, 1297, 1173, 1130, 795; mass Spectrometry (m/z): 463, 465(M + H)⁺；¹H-NMR：2.45(6H，s)，2.79-2.83(2H，m)，3.03-3.10(2H，m)，7.53 8-7.549(1H，s)，7.76-7.78(1H，d，J＝8.64)，7.80-7.804(1H，d，J＝1.4)，8.03(1H，bs)，8.05-8.07(1H，d，J＝8.60)。

Reference to the literature

1.Moritani，I.，Fujiwara，Y.；Tetrahedron Lett.；1967 1119-1122.

2.Fujiwara，Y.，Moritani，I.，Mastuda，M.；Tetrahedron Lett.；1968，24，4819-4824.

3.Heck，R.F.；J.Am.Chem.Soc.；1968，90，5518-5526.

4.Heck，R.F.；J.Am.Chem.Soc.；1969，91，6707-6714.

5.Braese，S.，Gil，C.，Knepper，K.；Bioorg.Med.Chem.；2002，10：8，2415-2438.

6.Amos，P.C.，Whiting，D.A.；J.Chem.Soc.Chem.Commun.；1987，510-511.

Claims (10)

1. A process for the preparation of a compound selected from the group consisting of,

8-methyl-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-fluoro-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-isopropyl-3- (4-methylpiperazin-1-ylmethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide-3-carbaldehyde;

3-acetyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-methyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-isopropyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-chloro-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

8-fluoro-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

5-fluoro-8-methyl-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

5-chloro-8-fluoro-3- (N, N-dimethylaminoethyl) -1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-chloro-8-methyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 8-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-8-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-8-fluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 8-dimethyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 8-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 9, 10-trichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-chloro-8-methoxy-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 8, 10-trifluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-9, 10-dichloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-chloro-8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-8-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-chloro-8-isopropyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-methyl-8, 10-difluoro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -7-trifluoromethyl-10-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5-fluoro-7-trifluoromethyl-10-chloro-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

3- (N, N-dimethylaminoethyl) -5, 10-dichloro-7-trifluoromethyl-1, 2-benzothiazinyl [2, 3, 4-ab ] indole-S, S-dioxide;

the process comprises cyclisation of a compound of formula (II) to give the aforementioned compound using a suitable palladium (0) or (II) catalyst complex system in the presence of a suitable base and solvent at a temperature between 0 and 200 ℃

Wherein R is₁、R₂、R₃And R₄Corresponding to the corresponding radicals in the above-mentioned compounds.

2. The process of claim 1, wherein the suitable palladium (0) or (II) catalyst complex system is selected from one or more of the following systems: pd (0) (PPh)₃)₄、Pd(0)(P(o-CH₃)Ph₃)₄、PdCl₂(PPh₃)₂、Pd₂(dba)₃CHCl₃Or (η)³-allyl-PdCl)₂。

3. The process according to claim 1, wherein the molar ratio of the palladium catalyst used in the reaction is between 0.01 and 0.10 molar equivalent (1 and 10 mol%) based on the compound of formula (II).

4. The process according to claim 3, wherein the molar ratio of the palladium catalyst used in the reaction is more preferably between 0.03 and 0.05 molar equivalents (3 and 5 mol%) based on the compound of formula (II).

5. The method of claim 1, wherein the suitable base is CH₃COOK or TEA.

6. The process according to claim 5, wherein the molar ratio of the base used in the reaction is in the range of 0 to 5 molar equivalents based on the compound of the formula (II).

7. The method according to claim 5 or 6, wherein the suitable base is dissolved or suspended in a polar aprotic solvent.

8. The method of claim 7, wherein the polar aprotic solvent is Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dimethylacetamide (DMA), and mixtures thereof in various ratios.

9. The method as set forth in claim 1, wherein the temperature range is 120-160 ℃.

10. The process of claim 1, wherein said cyclization is carried out under inert atmosphereUnder an atmosphere of a neutral gas, the inert gas being N₂Ar or He.