HK1165802B - Derivatives of benzothiazines, preparation thereof and application thereof as drugs - Google Patents

Description

Benzothiazine derivatives, process for their preparation and their use as medicaments

Technical Field

The present invention relates to benzothiazine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia, arterial hypertension and atherosclerosis. The compounds may also be used for the treatment and/or prophylaxis of hyperglycemia, lactose intolerance, insulin resistance, hypertriglyceridemia, hypercholesterolemia, restenosis, pancreatitis, retinopathy, nephropathy, neuropathy (Reichard et al, N.Engl. J.Med.1993, 329: 304-.

The invention also relates to the combination of said compounds and other medicaments for the treatment of the above mentioned diseases. Indeed, the treatment of diseases such as type II Diabetes typically requires the combined use of multiple compounds in order to bring blood glucose to recommended values and maintain its balance (Nathan et al, Diabetes Care 200932: 193-203). The above associations also relate to the combined treatment of obesity and type II diabetes (Grundy et al, Circulation 2005, 112: 2735-2752).

Background

Metabolic syndrome is an early stage of a number of serious cardiovascular disorders. Develops from insulin resistance and is characterized by visceral obesity (despires et al, Nature 2006444 (14): 881-87), associated with certain risk factors such as glucose intolerance and certain dyslipidemia associated with arterial hypertension (Grundy, Nat. Rev. drug Discov.2006, 5: 295-.

Type II diabetes is a well-documented disease, as blood glucose disorders can be explained by three main mechanisms: pancreatic Langerhans beta island functional deficiency, decreased glucose use by peripheral tissues and overproduction of glucose by the liver (Monnier et al, Diabetes)&Metabolism 2008, 34: 207-216). However, many patients with type II diabetes do not reach the recommended glycemic target value (significantly HbA) regardless of the existing treatments_1c). Thus, there remains a strong need for new mechanism-based treatments for such diseases.

Obesity is a disease that is growing in the number of patients worldwide. It is often associated with increased risk of type II diabetes, cardiovascular disease, cerebrovascular stroke, and certain types of cancer. Thus, obesity represents a major risk factor for diseases associated with high levels of morbidity or mortality.

Glucocorticoids (cortisol in humans, corticosterone in rodents) are ubiquitous hormones that play a major role in the regulation of energy metabolism. It promotes gluconeogenesis and inhibits insulin secretion and peripheral recapture of glucose by pancreatic beta cells (Dallman et al, Front neuroendicolin.1993, 14: 303-347).

The latest evidence is that: in humans, this mechanism leads to a local increase in cortisol, in adipose tissue, which can lead to an increase in visceral fat mass due to the effects of glucocorticoids on differentiation from preadipocytes to adipocytes and lipogenesis, in some cases, glucocorticoids promote lipolysis and the deleterious effects of free plasma fatty acids (lipotoxicity) in, for example, the liver, pancreas, skeletal muscle, in the liver, this production of cortisol leads to an increase in blood glucose, which can progress to type II diabetes.

Two subtypes of 11 β -HSD are known: form I and form II. 11 β -HSD2 was primarily concentrated in the kidney. It catalyzes the conversion of active glucocorticoids into inactive glucocorticoids (the conversion of cortisol into corticosterone in humans) and, thus, essentially, participates in the protection of the Mineralocorticoid Receptor (MR) which contributes to cortisol activation (Edwards et al, Lancet, 1988, 2: 986-. In contrast, 11 β -HSD1 mainly behaves as a 11-keto-reductase and when strongly expressed (liver and adipose tissue), inactive glucocorticoids are converted to active glucocorticoids. Thus, inhibition of this enzyme at the liver and adipocyte levels should be expressed as a reduction in the aforementioned effects. Multiple animal studies have demonstrated the significance of 11 β -HSD1 in models of obesity and/or diabetes. Thus, increased expression of 11 β -HSD1 in diabetic Zucker rats was associated with pathological progression (Duplomb et al, biochem. Biophys. Res. Commun., 2004, 313: 594-599). Mice (KO mice) without any 11 β -HSD1 gene encoding have been shown to be resistant to hyperglycemia due to obesity or stress (Kotelevtsev Y.et al, PNAS 1997, 94: 14924-. In contrast, transgenic mice selectively overexpressing 11 β -HSD1 in adipose tissue developed visceral obesity, insulin-resistant diabetes and hyperlipidemia (Masuzika et al, Science, 2001, 294: 2166-2170). The above experimental data highlight the advantage of inhibition of 11 β -HSD1 as a therapeutic target (Wamil et al, Drug Discovery Today, 2007, 12: 504-520).

The compounds of the invention have the ability to selectively inhibit 11 β -HSD1 relative to 11 β -HSD2, which should manifest beneficial effects in humans on type II diabetes, obesity, hyperlipidemia, arterial hypertension, atherosclerosis, and all diseases associated with, for example, coronary Stroke, cerebrovascular Stroke, or lower limb arteritis (Wilcox et al, Stroke, 2007, 38: 865-.

The compounds are distinguished from the prior art by their different chemical structures and remarkable biological properties.

Disclosure of Invention

The object of the present invention is a benzothiazine derivative having the ability to inhibit 11 beta-hydroxysteroid dehydrogenase 1(11 beta-HSD 1) not only at the enzyme level but also at the cellular level.

The compounds of the invention correspond to general formula (I):

wherein:

R₁represents:

hydrogen; c₁-C₆An alkyl group; COR (continuous operating reference)₅；SO₂R₅；CO(CH₂)_mR₆；CO(CH₂)_mOR₆；(CH₂)_mR₆；(CH₂)_mCONR₇R₈；(CH₂)_nNR₇R₈；(CH₂)_nOR₆；CHR₇OR₉；(CH₂)_mR₁₀，

m represents:

1 to 6 of the total weight of the composition,

n represents:

2 to 6 of the total weight of the composition,

R₂represents:

from one or more groups selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃、SMe、COMe、CMe(OH)CF₃、CH(OH)CF₃、COOR₇、CONR₇R₁₁Phenyl substituted with the group of (a);unsubstituted or substituted by one or more radicals selected from halogen or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Naphthyl, 1,2,3, 4-tetrahydronaphthalene, biphenyl, phenylpyridine or substituted in R by OMe, SMe groups₁、R₄And R'₄A heterocycle other than indole when representing hydrogen; unsubstituted or substituted by OH, CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group; c₁-C₆An alkylaryl group or a cycloalkylaryl group,

with the following conditions:

-R₂the group is typically attached to the carbonyl group through a carbon atom,

when R is₂When phenyl, COOR for carbonyl₇The substituent is not in the 4-position,

R₃represents:

a methyl group or an ethyl group, and a salt thereof,

R₄or R'₄Or the same or different, represent:

hydrogen; halogen; c₁-C₆An alkyl group; CN; CF (compact flash)₃；OCF₃；SMe；OMe；NR₇R₈；SO₂Me，

R₅Represents:

C₁-C₆an alkyl group; unsubstituted or substituted by one or more members selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Phenyl substituted with groups of SMe; unsubstituted or substituted by one or more radicals selected from halogen or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Naphthyl substituted with groups of SMe; unsubstituted or substituted by CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group; unsubstituted or substituted by one or more members selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Group substituted hetero of SMeAn aryl group, a heteroaryl group,

R₆represents:

hydrogen; c₁-C₆An alkyl group; unsubstituted or substituted by one or more members selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Phenyl substituted with groups of SMe; unsubstituted or substituted by one or more radicals selected from halogen or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Naphthyl or heterocycle substituted with groups of SMe; unsubstituted or substituted by CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group, which is substituted,

R₇represents:

hydrogen, C₁-C₆An alkyl group, a carboxyl group,

R₈represents:

hydrogen; c₁-C₆An alkyl group; unsubstituted or substituted by one or more members selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Phenyl substituted with groups of SMe; unsubstituted or substituted by one or more radicals selected from halogen or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Naphthyl or heterocycle substituted with groups of SMe; unsubstituted or substituted by CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group, which is substituted,

R₇and R₈The ring may be 4 to 6 membered by a nitrogen atom and may contain one or more heteroatoms selected from N, S or O and be unsubstituted or substituted by one or more heteroatoms selected from C₁-C₆Alkyl radical, C₁-C₆Alkyl aryl or a radical of aryl,

R₉represents:

COOMe，COOEt，

R₁₀represents:

halogen, COOH, COOR₇，

R₁₁Represents:

hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkylcycloalkyl, cycloalkyl, aryl, C₁-C₆Alkylaryl, and stereoisomers, salts and solvates thereof, for use in therapy.

In the definition set forth above:

all combinations of substituents or parameters constitute stable compounds within reasonable ranges.

The term "halogen" represents fluorine, chlorine, bromine or iodine.

The term "alkyl" represents an aliphatic hydrocarbon chain which is saturated or unsaturated, linear or branched, and which comprises the specified number of carbon atoms.

The term "cycloalkyl" represents a cyclic or polycyclic hydrocarbon chain containing from 3 to 12 carbon atoms. For example adamantyl, cyclohexyl are mentioned.

The term "aryl" represents any monocyclic or bicyclic carbocyclic ring containing up to 7 atoms per ring system and in which at least one ring is aromatic. For example, mention may be made of phenyl, biphenyl, naphthyl.

The term "heteroaryl" represents a stable monocyclic ring comprising 5 to 7 atoms or represents a stable bicyclic ring comprising 8 to 11 atoms, unsaturated and consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S. Mention may be made, for example, of furan, thiophene, pyridine, benzothiophene.

The term "heterocycle" represents a stable monocyclic ring comprising 5 to 7 atoms or represents a stable bicyclic ring comprising 8 to 11 atoms, which is either saturated or unsaturated and consists of carbon atoms and 1 to 4 heteroatoms selected from N, O or S. Monocyclic heterocycles condensed with a benzene ring are likewise encompassed by the definition of bicyclic rings, except when R is in formula I₁、R₄And R'₄Indole when the group represents hydrogen.Mention may be made, for example, of furan, pyrrole, thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine, pyrimidine, quinazoline, quinoline, quinoxaline, benzofuran, benzothiophene, indoline, indolizine, benzothiazole, benzothiophenyl, benzopyran, benzoxazole, benzo [1, 3 ] benzo]Dioxoles, benzisoxazoles, benzimidazoles, chromanes, chromenes, dihydrobenzofurans, dihydrobenzothiophenes, dihydroisoxazoles, isoquinolines, dihydrobenzo [1, 4 ] s]Dioxins, imidazo [1, 2-a ]]Pyridine, furo [2, 3-c ]]Pyridine, 2, 3-dihydro-1H-indene, [1, 3 ]]Dioxacyclopenteno [4, 5-c]Pyridine, pyrrolo [1, 2-c ]]Pyrimidine, pyrrole [1, 2-a ]]Pyrimidines, tetrahydronaphthalenes, benzols [ b ]][1，4]Oxazines.

According to OR₁Is an ester or ether, R in the present invention₁It is meant to represent C as previously described₁-C₆Alkyl or COR₅Or CO (CH)₂)_mR₆Or CO (CH)₂)_mOR₆Or (CH)₂)_mR₆Or (CH)₂)_mCONR₇R₈Or (CH)₂)_nNR₇R₈Or (CH)₂)_nOR₆Or CHR₇OR₉Or (CH)₂)_mR₁₀。

Salts acceptable for therapeutic use of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention, such as those salts composed of organic or inorganic acids or of organic or inorganic bases. Mention may be made, for example, of the salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, salicylic acid, p-toluenesulfonic acid, methanesulfonic acid, stearic acid, lactic acid. Mention may be made, for example, of salts derived from inorganic bases such as soda, potassium carbonate or calcium hydroxide and salts derived from organic bases such as lysine or arginine.

The above salts can be synthesized from the compounds of the present invention containing a base or acidic moiety and the corresponding acid or base according to conventional chemical methods.

Solvates acceptable for therapeutic use of the compounds of the invention include conventional solvates such as those constituted in the last step of the preparation of the compounds of the invention due to the presence of a solvent. For example solvates mentioned as being due to the presence of water or ethanol.

All stereoisomers including all optical isomers of the compounds of formula (I) together with mixtures thereof in racemic form are part of the present invention.

According to a particular feature of the invention, the compounds of general formula (I) are those:

-R₂represents: from one or more groups selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Phenyl substituted with groups of SMe; naphthyl, 1,2,3, 4-tetrahydronaphthalene, biphenyl or in R₁、R₄And R'₄In the case of representing a hydrogen atom, unsubstituted or substituted by one or more groups selected from halogen or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃OMe, SMe, and other heterocyclic rings other than indole; unsubstituted or substituted by CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group;

with the following conditions: r₂The group is typically attached to the carbonyl group through a carbon atom.

-R₄And R'₄Identical or different, represents: hydrogen; halogen; c₁-C₆An alkyl group; CN; CF (compact flash)₃；OCF₃；SMe；OMe；NR₇R₈；

-R₈Represents: hydrogen; c₁-C₆An alkyl group; unsubstituted or substituted by one or more members selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Phenyl substituted with groups of SMe; unsubstituted or substituted by one or more radicals selected from halogenElement or C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Naphthyl or heterocycle substituted with groups of SMe; unsubstituted or substituted by CONH₂、SO₂Me、SO₂NH₂A substituted cycloalkyl group.

R₇And R₈The ring may be 4 to 6 membered by a nitrogen atom and may contain one or more heteroatoms selected from N, S or O and be unsubstituted or substituted by one or more heteroatoms selected from C₁-C₆Alkyl or aryl groups.

Wherein R1 is as previously defined or as hereinafter defined.

According to an embodiment of the invention, the compounds of general formula (I) are those R₁A compound representing hydrogen.

According to another embodiment of the invention, the compounds of general formula (I) are those OR₁Represents an ester or ether wherein R₁Represents C₁-C₆Alkyl or COR₅Or CO (CH)₂)_mR₆Or CO (CH)₂)_mOR₆Or (CH)₂)_mR₆Or (CH)₂)_mCONR₇R₈Or (CH)₂)_nNR₇R₈Or (CH)₂)_nOR₆Or CHR₇OR₉Or (CH)₂)_mR₁₀The compound of (1).

According to a particular embodiment of the invention, OR₁Represents an ester wherein R₁Representative of COR₅Or CO (CH)₂)_mR₆Or CO (CH)₂)_mOR₆。

Objects of the present invention are also compounds of the general formula (I) wherein R₂Represents naphthyl or 1,2,3, 4-tetrahydronaphthalene or is unsubstituted or substituted by one or more groups selected from halogen, C₁-C₆Alkyl, CN, OH, CF₃、OCF₃Biphenyl or phenylpyridine substituted with groups of OMe, SMe; or from one or more halogens、CN、CF₃Or C₁-C₆Alkyl-substituted phenyl.

According to an embodiment of the invention, the compound of general formula (I) is R₄And R'₄A compound representing hydrogen.

Among the compounds of the general formula (I) according to the invention, a suitable class of compounds corresponds to the compounds of the general formula (I) in which R is₁Is hydrogen and R₂Is naphthyl or 1,2,3, 4-tetrahydronaphthalene.

In addition, the invention relates to compounds of the general formula (I), in which OR₁Represents an ester or an ether and R₂Is naphthyl or 1,2,3, 4-tetrahydronaphthalene.

Another suitable class of compounds corresponds to the general formula (I), wherein R₁Is hydrogen and R₂Is made of one or more halogens, CN, CF₃Or C₁-C₆Alkyl-substituted phenyl.

Another suitable class of compounds corresponds to the general formula (I), wherein R₁Is hydrogen and R₂Is biphenyl or phenylpyridine, unsubstituted or substituted according to the definition described for formula (I).

Furthermore, the invention relates to compounds of the general formula (I), in which OR₁Represents an ester or an ether and R₂Is made of one or more halogens, CN, CF₃Or C₁-C₆Alkyl-substituted phenyl.

Another suitable class of compounds corresponds to the general formula (I), in which OR₁Represents an ester or an ether and R₂Is biphenyl or phenylpyridine, unsubstituted or substituted according to the definition described for formula (I).

The present invention also relates to the preparation of compounds of general formula (I) by conventional methods as described in the following synthetic schemes, if desired by all standard procedures described in the literature or well known to the skilled person or exemplified in the experimental part.

Scheme 1

Scheme 1 illustrates a first general procedure that can be used to prepare compounds of general formula (Ia). In the above formula R₂、 R₃、R₄And R'₄Defined as described previously for formula (I) and R₁Equal to hydrogen. X may represent a leaving group such as Cl, Br, I, OSO₂CH₃、OSO₂CF₃Or p-toluenesulfonyloxy. In this case, the reaction of the compound of formula (II) will be carried out in an anhydrous polar solvent such as THF or DMF containing an inorganic base such as for example NaH at a temperature between-20 ℃ and 100 ℃. The intermediates of formula (III) are converted to intermediates of formula (IV) by a rearrangement reaction in an anhydrous polar solvent such as methanol or ethanol (non-polar solvents miscible with toluene) containing a base such as, for example, MeONa, EtONa at a temperature between 25 ℃ and 100 ℃. Intermediates of the general formula (IV) by reaction with R₃Y is converted into a product of formula (Ia) wherein Y may represent a leaving group such as Cl, Br, I, OSO₂CH₃、OSO₂CF₃Or p-toluenesulfonyloxy and R₃As previously defined. In this case, the reaction of the compound of formula (IV) will be carried out in an anhydrous polar solvent such as THF or DMF containing an inorganic base such as NaH at a temperature of between-20 ℃ and 100 ℃.

Scheme 2 illustrates a general procedure that can be used to prepare compounds of general formula (Ib). In the general formula R₁、R₂、R₃、R₄And R'₄Defined as described previously for formula (I) but R₁Is not hydrogen.

Scheme 2

Intermediates of the general formula (Ia) by reaction with R₁-Z is converted into a compound of formula (Ib).When R is₁Represents C₁-C₆Alkyl group, (CH)₂)_mR₆、(CH₂)_mCONR₇R₈、(CH₂)_nNR₇R₈、(CH₂)_nOR₆、CHR₇OR₉Or (CH)₂)_mR₁₀Wherein R is₆、R₇、R₈、R₉、R₁₀M and n are defined as described previously for formula (I), except that R₁₀Not representing an acid, and Z is a leaving group such as Cl, Br, I, OSO₂CH₃、OSO₂CF₃Or p-toluenesulfonyloxy, the reaction of the alkenols of formula (Ia) can be carried out in the presence of an organic or inorganic base such as, for example, Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、K₂CO₃In an anhydrous polar solvent such as THF, DMF, DMSO, acetone, at a temperature of-20 deg.C to 140 deg.C, with or without a salt (which may be KI, Bu) as a catalyst₄NI、LiI、AgBF₄、AgClO₄、Ag₂CO₃、KF、Bu₄NF or CsF). The reaction can also be carried out in "sealed or threaded tubes" heated by thermal or microwave energy at temperatures between 80 and 180 ℃. Z may also represent an alcohol. In this case, the reaction of intermediate (Ia) is a "Mitsunobu" reaction and is carried out in an anhydrous polar solvent such as THF containing diethyl azodicarboxylate (DEAD) and triphenylphosphine at a temperature between 0 and 60 ℃. When R is₁Representative of COR₅、SO₂R₅Or CO (CH)₂)_mR₆Wherein R is₅、R₆And m is as previously defined for formula (I), Z may represent chlorine. In this case, the reaction of the alkenols of the formula (Ia) is ascribed to the reaction of the acid chlorides and sulfonyl chlorides with the alcohol. The reaction may be carried out in the presence of an organic or inorganic base such as, for example, Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、K₂CO₃In anhydrous solvents such as THF, DMF, DMSO, dichloromethane at temperatures between-20 deg.C and 140 deg.C. When R is₁Representative of COR₅、CO(CH₂)_mR₆Or CO (CH)₂)_mOR₆Wherein R is₅、R₆And m is as previously defined for formula (I), Z may also represent hydroxy. In this case, the reaction of the alkenols of the general formula (Ia) is ascribed to the reaction of the acid with the alcohol. The reaction can be carried out by methods and techniques well known to those skilled in the art. A particularly suitable process consists of producing the condensate in a polar aprotic solvent such as dichloromethane at a temperature between-15 ℃ and 40 ℃ and containing 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), 3-hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, a tertiary amine such as diisopropylethylamine.

Scheme 3 illustrates a conventional process that can be used to prepare compounds of general formula (Ic) wherein R₁Is represented by (CH)₂)_nNR₇R₈Or (CH)₂)_nOR₆，R₆、R₇、R₈N and R₂、R₃、R₄And R'₄As defined previously for formula (I). Intermediates of formula (Ia) can be prepared by reaction with an intermediate of formula X (CH)₂) The nX 'reagent is converted into an intermediate of the general formula (V), wherein X and X' represent the same or different leaving groups such as Cl, Br, I, OSO₂CH₃、OSO₂CF₃Or p-toluenesulfonyloxy and n is as previously defined.

Scheme 3

The reaction between said reagent and the enol of formula (Ia) to obtain the intermediate of formula (V) can be carried out in the presence of an organic or inorganic base such as, for example, Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、K₂CO₃In an anhydrous polar solvent such as THF, DMF, DMSO, acetone, at a temperature of-20 deg.C to 140 deg.C, with or without a salt (which may be KI, Bu) as a catalyst₄NI、LiI、AgBF₄、AgClO₄、Ag₂CO₃、KF、Bu₄NF or CsF). The reaction can also be carried out in the absence of any solvent, with an excess of X (CH)₂) nX' reagent. The reaction can also be carried out in "sealed or threaded tubes" heated by thermal or microwave energy at temperatures between 80 and 180 ℃. X and X' may also represent an alcohol. In this case, the reaction of the intermediate (V) is a "Mitsunobu" reaction and is carried out in an anhydrous polar solvent such as THF containing diethyl azodicarboxylate (DEAD) and triphenylphosphine at a temperature between 0 and 60 ℃.

Intermediate of formula (V) is reacted with HNR₇R₈Or HOR₆The reaction is converted to a product of the general formula (Ic) in which R₆、R₇And R₈As defined previously for formula (I). The reaction may be carried out in the presence of an organic or inorganic base such as, for example, Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、K₂CO₃In an anhydrous polar solvent such as THF, DMF, DMSO, acetone, at a temperature of-20 deg.C to 140 deg.C, with or without a salt (which may be KI, Bu) as a catalyst₄NI、LiI、AgBF₄、AgClO₄、Ag₂CO₃、KF、Bu₄NF or CsF). The experimental conditions and the choice of the reagents to carry out the reaction naturally depend on the substituent R₆、R₇And R₈And may be performed according to methods and techniques well known to those skilled in the art.

Scheme 4 illustrates a general procedure useful for preparing compounds of general formula (Id) wherein R₁Is represented by (CH)₂)_mCONR₇R₈，R₇、R₈M and R₂、R₃、R₄And R'₄As defined previously for formula (I).

Scheme 4

Intermediates of formula (Ia) can be prepared by reaction with a compound of formula Y (CH)₂)_mCOOY' reagent is converted into an intermediate of general formula (VI) in which Y represents a leaving group such as, for example, Cl, Br, I, OSO₂CH₃、OSO₂CF₃Or p-toluenesulfonyloxy, m is as previously defined and Y' represents C₁-C₄An alkyl group. The reaction may be carried out in the presence of an organic or inorganic base such as, for example, Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、K₂CO₃In an anhydrous polar solvent such as THF, DMF, DMSO, acetone, at a temperature of-20 deg.C to 140 deg.C, with or without a salt (which may be KI, Bu) as a catalyst₄NI、LiI、AgBF₄、AgClO₄、Ag₂CO₃、KF、Bu₄NF or CsF). The reaction can also be carried out in "sealed or threaded tubes" heated by thermal or microwave energy at temperatures between 80 and 180 ℃. Intermediates of formula (VI) can be converted to intermediates of formula (VII) by reaction with an inorganic base such as, for example, NaOH, KOH, LiOH in a polar solvent such as methanol, ethanol, THF and water at a temperature between 20 ℃ and 80 ℃. The carboxylic acid (VII) obtained can be reacted with an amine to obtain a compound of general formula (Id). The reaction may be carried out by methods and techniques well known to those skilled in the art. A particularly suitable process consists of condensing the two entities in the presence of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDC), 3-hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, a polar aprotic solvent such as dichloromethane or DMF, and a tertiary amine such as diisopropylethylamine at a temperature of between-15 ℃ and 50 ℃. Or further, for example, in the presence of 1-hydroxybenzotriazole, a polar solvent such as DMF, CH of a tertiary amine such as diisopropylethylamine₂Cl₂Or DMSO at a temperature of between 10 ℃ and 50 ℃ using benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). Another particularly suitable process consists in converting the carboxylic acid by reaction with oxalyl chloride or thionyl chloride in the absence or presence of a base such as pyridine or triethylamine, with or without a solvent such as toluene or dichloromethane, at a temperature of between 20 and 100 ℃Is composed of acyl chloride. The acid chloride may then be reacted with an amine HNR₇R₈In a solvent containing a base such as pyridine or triethylamine, such as dichloromethane, at a temperature of between 0 and 100 ℃.

Scheme 5 illustrates that compounds of formula (Ie) (wherein R is₄Represents fluorine and R₂、R₃And R'₄As defined previously for formula (I)) to a compound of formula (If) (wherein R is₄Represents NR₇R₈，R₇、R₈And R₂、R₃And R'₄As defined previously for formula (I).

Scheme 5

The compounds of formula (Ie) can be prepared by reaction with a compound of formula HNR₇R₈In the presence of an organic or inorganic base, e.g. Et₃N、iPr₂NEt、NaH、Cs₂CO₃、K₂CO₃In an anhydrous polar solvent such as DMF or DMSO at a temperature of between 20 ℃ and 140 ℃ to convert the compound of the general formula (If).

Scheme 6 illustrates that compounds of general formula (Ig) (wherein R is₃、R₄And R'₄Defined as described previously for formula (I) and R₂Represents phenyl substituted by an X group representing bromine, chlorine or trifluoromethanesulfonic acid) to a compound of general formula (Ih) in which R is₂Represents a substituted or unsubstituted biphenyl or phenylpyridine and wherein R₃、R₄And R'₄As defined previously for formula (I).

Scheme 6

By the Suzuki reaction, the compounds of the general formula (Ig) are prepared by reaction with boric acid, organic or inorganic bases such as, for example, Et₃N、NMP、iPr₂NEt、NaH、Cs₂CO₃、K₂CO₃、K₃PO₄Catalysts such as palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium in polar solvents such as, for example, acetone, methyl ethyl ketone, ethanol, DME, water, dioxane, and optionally phosphines such as triphenylphosphine or tricyclohexylphosphine at temperatures between 20 ℃ and 140 ℃ are converted into compounds of the general formula (Ih).

Scheme 7 illustrates that compounds of formula (Ii) (wherein R is₃、R₄And R'₄Defined as described previously for formula (I) and R₂Representing phenyl substituted by cyano in ortho-or meta-position) to a compound of general formula (Ij) (wherein R is₂Represents phenyl substituted by a carboxylic acid in ortho-or meta-position) and is converted into a compound of the general formula (Ik)

(wherein R is₂Represents a structural formula shown as CONR₇R₁₁And wherein R is phenyl substituted with an amide of₃、R₄、R₇、R₁₁And R'₄As defined previously for formula (I).

Scheme 7

The compound of formula (Ii) can be prepared by treating with a polar solvent such as ethanol, methanol, THF, water, and an inorganic base such as NaOH, KOH, LiOH at a temperature of 20 deg.C to 140 deg.C, and then with an acid such as HCl, H₂SO₄HCOOH is converted into a compound of the general formula (Ij). The compound of the general formula (Ij) can be prepared by reacting with a structural formula HNR₇R₁₁Is converted into a compound of the general formula (Ik). The reaction may be carried out by methods and techniques well known to those skilled in the art. A particularly suitable process consists in reacting a compound of formula (I) with a compound of formula (I) in the presence of 1- (3-dimethylamino)Propyl) -3-ethyl-carbodiimide (EDC), 3-hydroxy-1, 2, 3-benzotriazin-4 (3H) -one, a polar aprotic solvent such as dichloromethane or DMF, and a tertiary amine such as diisopropylethylamine at a temperature of-15 deg.C to 50 deg.C. Or further, for example, in the presence of 1-hydroxybenzotriazole, a polar solvent such as DMF, CH of a tertiary amine such as diisopropylethylamine₂Cl₂Or DMSO at a temperature of between 10 ℃ and 50 ℃ using benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). Another particularly suitable process consists of converting the carboxylic acid into the acid chloride by reaction with oxalyl chloride or thionyl chloride in the absence or presence of a base such as pyridine or triethylamine, with or without a solvent such as toluene or dichloromethane, at a temperature between 20 and 100 ℃. The acid chloride may then be reacted with an amine HNR₇R₁₁In a solvent containing a base such as pyridine or triethylamine, such as dichloromethane, at a temperature of between 0 and 100 ℃.

When it is desired to isolate a compound of formula (I) in the form of a salt comprising at least one acidic or basic functional group, obtained by addition of a base or acid, this can be done by treating the free base or acid of formula (I), which contains at least one acidic or basic functional group, with a suitable base or acid, preferably in an equivalent amount.

The examples which follow illustrate the invention without limiting its scope.

Note: HPLC purity measurements were performed on the following total compounds (unless otherwise noted) using the following conditions:

chromatographic column Waters XTerra MS C₁₈4.6X 50mm, 5 μm,. lambda.220 nm, gradient elution 100% H in 6min₂O (+ 0.05% TFA) with 100% CH₃CN (+ 0.05% TFA), 100% CH within 1 minute thereafter₃CN (+ 0.05% TFA), pump Waters 600E at a flow rate of 3 ml/min.

Detailed Description

Example 1

(4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

Example 1A-2- (2- (naphthalen-2-yl) -2-oxoethyl) benzo [ d]Isothiazol-3 (2H) -one-1, 1-dioxides

Saccharin (25g, 136mmol) and DMF (350mL) were added to a three-necked flask equipped with a thermometer and condenser. The medium was inerted by successive exchanges of vacuum/nitrogen (3 times). Sodium hydride (6g, 150mmol) was added slowly followed by 2-bromo-1- (naphthalen-2-yl) ethanone (37.4g, 150 mmol). The reaction medium is heated to 65 ℃ and held for 4 hours and subsequently cooled to room temperature. Filtering the precipitate, rinsing with water, and drying to constant weight to obtain product1A37g of milky white solid (HPLC: RT 4.97min, 100%). A second crop of product was obtained by adding water to the filtrate. The resulting precipitate was filtered, rinsed with water and then a minimum amount of ethyl to obtain 10g of product after drying (HPLC: RT ═ 4.97min, 93%). The overall yield of the reaction was 96%.

¹H NMR，dmso-d₆，(ppm)：5.62(s，2H)；7.68(t，1H)；7.73(t，1H)；8.00-8.25(m，7H)；8.39(d，1H)；8.92(s，1H).

Mass spectrum (ESI +): m/z 352 (MH)⁺，100％)；369(MNH₄ ⁺，24％).

Example 1B- (4-hydroxy-1, 1-dioxido-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

Ethanol (165mL) was added to the flask under an inert atmosphere with coolingIn a two-necked flask of a coagulation tube, sodium, sliced and rinsed with heptane (8g, 347mmol), was then slowly added. After the addition is complete, the reaction medium is heated to 70 ℃ until the sodium has reacted completely. The reaction was then cooled to room temperature and the compound was added rapidly1A(47g, 131 mmol). In addition to the dense precipitate, a strong vermillion and subsequent reddish-bloody coloration occurred. The reaction medium is briefly heated to its solidification temperature of 60 ℃. It was then cooled to room temperature and diluted with 500mL of ethyl acetate. 1N aqueous HCl was then added until a pale yellow suspension was obtained. The precipitate was filtered and rinsed with water and a minimum amount of 50/50 water/ethanol mixture. Followed by vacuum drying to constant weight to obtain the product as a pale yellow solid1B(40.9g；88％)。HPLC：RT＝5.15min，100％。

¹H NMR，dmso-d₆(ppm): 7.66(t, 1H); 7.72(t, 1H); 7.95 (width s, 3H); 8.05(d, 2H); 8.11 (width s, 2H); 8.22 (width s, 1H); 8.64(s, 1H); 9.99(s, 1H); 15.59(s, 1H).

Mass spectrum (ESI +): m/z 352 (MH)⁺，100％)；369(MNH₄ ⁺，31％).

Example 1- (1, 1-dioxido-4-hydroxy-2-methyl-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

In an inert atmosphere, the compound is put in a double-neck flask1B(40.9g, 116mmol) was dissolved in DMF (409 mL). NaH (6.05g, 151mmol) was added. The reaction was slightly exothermic and the reaction medium exhibited a strong blood-red color. Methyl iodide (10.8mL, 174mmol) was added and the reaction medium was stirred at room temperature for 2 hours. Water (10mL) was added and the reaction medium was concentrated. The residue was treated with ethyl acetate and the precipitate was filtered, washed with water and minimal amount of ethyl acetate (solid 1). The filtrate was washed twice with half-saturated aqueous NaCl solution and then concentrated to half the volume and filtered. The precipitate (solid 2) was rinsed with a minimum of 50/50 ethyl acetate/ether. The filtrate was concentrated. The residue is filtered over silica (eluent: hept from 50/50)Alkane/dichloromethane followed by 25/75 heptane/dichloromethane) to obtain a yellow powder (solid 3) after evaporation of the solvent. The 3 solids were combined in order to obtain the product as a pale yellow solid1(40.1g；89％)。HPLC：RT＝5.65min，99％。

¹H NMR，dmso-d₆(ppm): 2.65(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 8.00 (width s, 3H); 8.02(d, 1H); 8.12 (width s, 3H); 8.22 (width s, 1H); 8.67(s, 1H).

Mass spectrum (ESI +): m/z 366 (MH)⁺，100％).

Preparation of sodium salt of (4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

Compound (I)1A portion of which was dissolved in methanol and treated with 1.05 equivalents of 1N soda aqueous solution at room temperature. The reaction medium is concentrated and the solid residue is rinsed with a mixture of dichloromethane and diethyl ether. The pale yellow solid thus obtained was dried in vacuo for several days.

HPLC: RT 11.73min, 99.71% (column: Xbridge C8, 5. mu.M, 4.6X 250mm (Waters); eluent: CH)₃CN/H₂O/KH₂PO₄ 600/400/6.8g，pH 4，25℃；1mL/min；220nm)

1H NMR，dmso-d₆(ppm): 2.61(s, 3H); 7.50 (width s, 2H); 7.62 (width s, 2H); 7.65-7.72(m, 2H); 7.80(d, 1H); 7.89 (width s, 2H); 7.93-7.98(m, 2H).

Mass spectrum (ESI +): m/z 366 (MH)⁺，100％).

Examples 2 to 12

According to the use for the preparation of derivatives1From saccharin and the various 2-bromo-1- (alkyl or aryl) ethanones of the first step and methyl iodide or ethyl iodide of the third step2To12. The rearrangement reaction in the second step is not carried outAnd (5) changing.

Negative ions ESI (M-H).

**¹H NMR，dmso-d₆Examples of the invention2: 1.72 (width s, 6H); 2.05 (width s, 3H); 2.10 (width s, 6H); 2.83(s, 3H); 7.91 (width s, 3H); 8.10(t, 1H); 16.1(s, 1H) examples5: 2.63(s, 3H); 7.99(s, 3H); 8.11(s, 4H); 8.19 (width s, 1H); 14.5-15.5(m, 1H, exchange)6: 2.70(s, 3H); 7.46(t, 1H); 7.54(t, 2H); 7.82(d, 2H); 7.95-8.00(m, 5H); 8.18-8.23(m, 3H); 15.65 (width s, 1H, exchange). EXAMPLE7: 2.67(s, 3H); 7.54-7.64(m, 2H); 7.83(s, 1H); 7.93 (width s, 3H); 8.11 (width s, 1H); 13.5-14.5 (width s, 1H).

*¹H NMR，dmso-d₆Examples of the invention8: 0.68(t, 3H); 1.71 (width s, 6H); 2.05 (width s, 3H); 2.09 (width s, 6H); 3.44(q, 2H); 7.89 (width s, 3H); 8.05 (width s, 1H); 15.00(s, 1H, exchange). EXAMPLE9: 0.51(t, 3H); 3.13(q, 2H); 7.66(t, 1H); 7.72(t, 1H); 7.99 (width s, 3H); 8.05(d, 1H); 8.12 (width s, 3H); 8.22 (width s, 1H); 8.64(s, 1H); 15.39(s, 1H, exchange.) example11: 0.53(t, 3H); 3.13(q, 2H); 7.71(d, 2H); 7.98 (width s, 3H); 8.03(d, 1H); 8.19 (Width s, 1H.) examples12: 0.56(t, 3H); 3.18(q, 2H); 7.45(t, 1H); 7.53(t, 2H); 7.82(d, 2H); 7.94-7.98(m, 5H); 8.16(d, 2H); 8.20-8.21(m, 1H); 15.46(s, 1H, exchange)

Example 13

(5-chloro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

Example 13A-2-chloro-6-sulfonylbenzoic acid

3-chloro-2-methylbenzenesulfonamide (13.27g, 64.5mmol) was added to a three-necked flask equipped with a condenser tube in the presence of 5% soda water (385 mL). Potassium permanganate (25.5g, 161mmol) is slowly added and the reaction medium is subsequently heated to 100 ℃ for 4 hours. The reaction was returned to room temperature, filtered, acidified to pH 1 and extracted 3 times with ethyl acetate. The organic phases were combined, washed once with saturated aqueous NaCl solution, dried over magnesium sulfate, filtered and concentrated to obtain the product as a white solid13A(12.87g；83％)。

HPLC：RT＝1.55min，98％

¹H NMR，dmso-d₆(ppm): 7.48(s, 2H, exchange); 7.62(t, 1H); 7.75(d, 1H); 7.87(d, 1H); 11-15(mL, 1H, exchange).

Mass Spectrometry (ESI-): m/z 234 (M-H)^-，55％).

Example 13B-4-chlorosaccharin

The compound13A(12.87g, 54.6mmol) was added to the flask followed by 38.8mL of concentrated sulfuric acid. The reaction mixture was stirred at room temperature for 1.5 hours and then poured into an ice-water mixture. The resulting precipitate was filtered, rinsed with water and dried to constant weight to obtain the compound as a white solid13B(9.16g；77％)。

HPLC：RT＝2.57min，100％

¹H NMR，dmso-d₆(ppm): 7.91 (width s, 2H); 8.08 (width s, 1H).

Example 13C-4-chloro-2- (2- (naphthalen-2-yl) -2-oxoethyl) benzo [ d]Isothiazol-3 (2H) -one-1, 1-dioxides

According to the use for the preparation of derivatives1AFrom a compound of13B(2.2g, 10mmol) of the synthesized Compound13CIn order to obtain compounds which appear as milky white solids13C(3.3g；84％)。

HPLC：RT＝5.11min，99％

¹H NMR，dmso-d₆，(ppm)：5.62(s，2H)；7.69(t，1H)，7.74(t，1H)；7.95-8.20(m，6H)；8.38(d，1H)；8.92(s，1H).

Mass spectrum (ESI +): m/z386 (MH)⁺，100％).

Example 13D- (5-chloro-1, 1-dioxido-4-hydroxy-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

According to the use for the preparation of derivatives1BFrom a compound of13C(3.3g, 8.5mmol) Synthesis of Compound13DIn order to obtain compounds which behave as golden yellow solids13D(1.7g；51％)。

HPLC：RT＝5.3min，99％

1H NMR，dmso-d₆，(ppm)：7.68(t，1H)，7.72(t，1H)；7.85-8.15(m，8H)；8.59(s，1H)；10.11(s，1H).

Mass spectrum (ESI +): m/z386 (MH)⁺，100％).

Example 13According to the use for the preparation of derivatives1From a compound of13D(3g, 7.7mmol) Synthesis of Compound13To obtain a watchCompound as yellow solid13(2.3g；70％)。

HPLC：RT＝5.75min，95％

¹H NMR，dmso-d₆(ppm): 2.69(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 7.9-8.2(m, 7H); 8.60 (width s, 1H); 16.15 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 400 (MH)⁺，100％).

Example 14

(5-chloro-4-hydroxy-2-ethyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

According to the use for the preparation of derivatives1From a compound of13D(1g, 2.6mmol) and iodoethane Synthesis of Compounds14To obtain 805mg (60%) of the desired product.

HPLC：RT＝5.77min，81％

A portion of the product (200mg) was purified over a 12g spherical silica column (flow rate 12mL/min, 100% heptane (2 min), ethyl acetate/heptane gradient from 0 to 50% (30 min), 50% ethyl acetate/heptane (5 min)) to obtain 64mg of the desired product as a yellow solid.

HPLC：RT＝5.77min，97％

¹H NMR，dmso-d₆(ppm): 0.51(t, 3H); 3.11(q, 2H); 7.66(t, 1H); 7.72(t, 1H); 7.85-8.2(m, 7H); 8.60(s, 1H); 15.9(s, 1H, exchange).

Mass spectrum (ESI +): m/z 414 (MH)⁺，100％).

Example 15

(6-fluoro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

Example 15A- (6-fluoro-4-hydroxy-1, 1-dioxido-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

According to the preparation of the compounds13DThe same sequence of steps of (1), synthesizing a compound from the compound 4-fluoro-2-methylbenzenesulfonamide15A. The product was obtained as a yellow solid in 79% overall yield.

HPLC：RT＝5.26min，96％

1H NMR，dmso-d₆(ppm): 7.66(t, 1H); 7.72(t, 1H); 7.80(t, 1H); 7.94-8.11(m, 6H); 8.64(s, 1H); 10.18(s, 1H, exchange); 15.2 (width s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 368 (M-H)^-，100％).

Example 15- (6-fluoro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

According to the use for the preparation of derivatives1From a compound of15A(1.5g, 4mmol) Synthesis of Compound15，

In order to obtain 1.47g (89%) of the desired product, which behaves as a yellow solid.

HPLC：RT＝5.6min，93％

A part of the product is recrystallized by ethanol so as to obtain the product with higher purity186mg Compound15(HPLC：RT＝5.6min，99.4％)。

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 7.84(t, 1H); 7.97(d, 1H); 8.02-8.15(m, 5H); 8.66(s, 1H); 15.22 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 384 (MH)⁺，100％).

Example 16

(6-fluoro-4-hydroxy-2-ethyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

According to the use for the preparation of derivatives1From a compound of15A(1.5g, 4mmol) and iodoethane Synthesis of Compounds16To obtain 520mg of the desired product (29%) as a yellow solid.

HPLC：RT＝5.8min，91％

A portion of the product was recrystallized from ethanol to yield 71mg of the compound in higher purity16。

HPLC：RT＝5.8min，97％

¹H NMR，dmso-d₆(ppm): 0.56(t, 3H); 3.15(q, 2H); 7.66(t, 1H); 7.72(t, 1H); 7.82(t, 1H); 7.97(d, 1H); 8.00-8.2(m, 5H); 8.63(s, 1H); 14.95 (width s, 1H).

Mass spectrum (ESI +): m/z 398 (MH)⁺，100％).

Example 17

(7-fluoro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

Example 17A-5-fluoro-2-methylbenzenesulfonamide

5-fluoro-2-methylbenzenesulfonyl chloride (5.00g, 23.9mmol) was slowly added to 23mL of concentrated ammonia at 0 ℃. The reaction medium is heated to 100 ℃ for 1 hour and subsequently cooled to room temperature. The resulting precipitate was filtered, rinsed with water and dried to constant weight. The compound is obtained as a white solid17A(4.55g；100％)。

HPLC：RT＝3.10min，96％

¹H NMR，dmso-d₆(ppm): 2.54(s, 3H); 7.35-7.45(m, 2H); 7.53 (width s, 2H, exchange); 7.58(de, 1H).

Mass Spectrometry (ESI-): m/z 188 (M-H)^-，100％).

Example 17B- (7-fluoro-4-hydroxy-1, 1-dioxido-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

According to the preparation of the compounds13DBy the same sequence of steps as in (A) for the preparation of (B)17ASynthesis of compounds17B. The product was obtained as a yellow solid in an overall yield of 73%.

HPLC：RT＝5.18min，98％

¹H NMR，dmso-d₆(ppm): 7.66(t, 1H); 7.72(t, 1H); 7.81(t, 1H); 7.90(d, 1H); 8.04(d, 2H); 8.11 (width s, 2H); 8.30(dd, 1H); 8.63(s, 1H); 10.19 (width s, 1H); 15.63 (width s, 1H).

Mass Spectrometry (ESI-): m/z 368(M-H^-，100％).

Mass spectrum (ESI +): m/z 370 (MH)⁺，100％).

Example 17- (7-fluoro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e)][1，2]Thiazin-3-yl) (naphthalen-2-yl) methanones

According to the use for the preparation of derivatives1From a compound of17B(4.00g, 10.8mmol) Synthesis of Compound17In order to obtain two batches of the desired product of different purity.

First batch: 3.79 g; a light brown solid; HPLC: RT 5.65min, 94%.

And (2) second batch: 320 mg; a yellow solid; HPLC: RT 5.65min, 99%.

The yield of the reaction was 93%.

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 7.83(t, 1H); 7.92(d, 1H); 8.02-8.15(m, 4H); 8.28(dd, 1H); 8.62(s, 1H); 15.62 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 384 (MH)⁺，100％).

Example 18

(7-fluoro-4-hydroxy-2-ethyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

According to the use for the preparation of derivatives1From a compound of17A(1.0g, 2.7mmol) and iodoethane to synthesize Compound18In order to obtain two batches of the desired product of different purity.

First batch: 716 mg; a light brown solid; HPLC: RT 5.78min, 89%.

And (2) second batch: 68 mg; a yellow solid; HPLC: RT 5.78min, 99%.

The yield of the reaction was 65%.

¹H NMR，dmso-d₆(ppm): 0.54(t, 3H); 3.14(q, 2H); 7.66(t, 1H); 7.71(t, 1H); 7.82(t, 1H); 7.92(d, 1H); 8.00-8.15(m, 4H); 8.29(dd, 1H); 8.60(s, 1H); 15.45 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 398 (MH)⁺，100％).

Example 19

Benzoic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

In an inert atmosphere, the compound1(86mg, 0.18mmol) was dissolved in 0.5mL of dichloromethane and 0.5mL of pyridine. The reaction medium is cooled to 0 ℃ and benzoyl chloride (33. mu.l, 0.27mmol) is then added. The cold bath was removed and the reaction stirred at room temperature for 4 hours. As the reaction was not complete, 16. mu.l (0.14mmol) of benzoyl chloride were added and the reaction medium was stirred at warm before concentration for 20 h. The residue was treated with ethyl acetate, washed once with water and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated. The second residue was co-evaporated three times with toluene to remove remaining pyridine. The yellow syrup thus obtained was purified through a column of 12g of spherical silica (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 100% (30 min)) so as to obtain a compound which appeared as a yellow foam19(38mg；44％)。

HPLC：RT＝5.65min，96％

¹H NMR，dmso-d₆，(ppm)：3.10(s，3H)；7.32(t，2H)；7.55-7.30(m，6H)；7.86(dd，2H)；7.90-8.05(m，5H)；8.70(s，1H).

Example 20

Cyclohexanecarboxylic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

In an inert atmosphere, the compound1(86mg, 0.18mmol) was dissolved in 0.5mL of pyridine. The reaction medium is cooled to 0 ℃ and cyclohexanecarbonyl chloride (62. mu.l, 0.46mmol) is then added. The cold bath was removed and the reaction stirred at room temperature for 18 hours and then heated to 60 ℃ for 8 hours. The reaction mixture was concentrated and co-evaporated with toluene three times. The residue thus obtained was purified on a 12g spherical silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 100% (20 min)) in order to obtain the compound which appeared as a yellow foam20(65mg；28％)。

HPLC：RT＝5.99min，95％

¹H NMR，dmso-d₆，(ppm)：0.85-1.00(m，6H)；1.38(de，2H)；1.49(de，2H)；2.28(tt，1H)；3.06(s，3H)；7.66(t，2H)；7.75(t，1H)；7.83(t，1H)；7.88(t，1H)；7.95-8.15(m，5H)；8.66(s，1H).

Mass spectrum (ESI +): m/z 493 (MNH)₄ ⁺，100％).

Example 21

tert-Butylbenzoic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

In an inert atmosphere, the compound1(86mg, 0.18mmol) was dissolved in 0.5mL of pyridine. The reaction medium is cooled to 0 ℃ and tert-butylcarbonyl chloride (57. mu.l, 0.46mmol) is subsequently added. The cold bath was removed and the reaction stirred at room temperature for 18 hours. The reaction medium is concentrated and co-evaporated three times with toluene. The residue thus obtained was purified on a 12g spherical silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 100% (20 min)) in order to obtain the compound which appeared as a yellow foam21(47mg；53％)。

HPLC：RT＝5.71min，98％

¹H NMR，dmso-d₆，(ppm)：0.88(s，9H)；3.07(s，3H)；7.59(d，1H)；7.66(t，1H)；7.75(t，1H)；7.84(t，1H)；7.89(t，1H)；8.00-8.09(m，4H)；8.12(d，1H)；8.69(s，1H).

Mass spectrum (ESI +): m/z 467 (MNH)₄ ⁺，100％).

Example 22

4-Methylbenzoic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

According to the application for the compound21From the same step of1Synthesis of a Compound (86mg, 0.18mmol) and 4-methylbenzoyl chloride (62. mu.l, 0.46mmol)22. The product was obtained as a yellow foam (27mg, 31%).

HPLC：RT＝5.82min，95％

¹H NMR，dmso-d₆，(ppm)：2.28(s，3H)；3.10(s，3H)；7.11(d，2H)；7.54(d，2H)；7.65(t，1H)；7.73(te，2H)；7.86(dd，2H)；7.95(d，1H)；7.97-8.05(m，4H)；8.69(s，1H).

Mass spectrum (ESI +): m/z 501 (MNH)₄ ⁺，100％).

Example 23

4-Chlorobenzoic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

4-chlorobenzoic acid (87mg, 0.55mmol) was dissolved in 2mL of toluene under an inert atmosphere. Oxalyl chloride (100. mu.l, 1.1mmol) was added at room temperature. The reaction mixture was heated to 80 ℃ for 2 hours, then concentrated and co-evaporated with toluene three times. The residue was placed back in an inert atmosphere and cooled to 0 ℃. Under an inert atmosphere, a compound dissolved in 0.5mL of pyridine and cooled to 0 ℃ is added1(86mg, 0.18 mmol). The cold bath was removed and the reaction stirred at room temperature for 2 hours. The reaction medium is concentrated and co-evaporated three times with toluene. The residue thus obtained was purified on a 12g spherical silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 100% (20 min)) in order to obtain the compound which appeared as a yellow foam23(51mg；42％)。

HPLC：RT＝5.92min，97％

¹H NMR，dmso-d₆(ppm): 3.10(s, 3H); 7.37(d, 2H); 7.63-7.67(m, 3H); 7.72(t, 1H); 7.79 (width s, 1H); 7.86 (width s, 2H); 7.94(d, 1H); 7.95-8.07(m, 4H); 8.66(s, 1H).

Mass spectrum (ESI +): m/z 521 (MNH)₄ ⁺，100％)；523(MNH₄ ⁺，37％).

Examples 24 to 27

According to the use for preparing compounds21From a compound of15And various acyl chloride synthetic compounds24To27。

*¹H NMR，dmso-d₆Examples of the invention24: 0.87(s, 9H); 3.08(s, 3H); 7.32(d, 1H); 7.63-7.80(m, 3H); 7.95-8.15(m, 5H); 8.69(s, 1H). examples25: 0.80-1.10(m, 5H); 1.15-1.55(m, 5H); 2.39(te, 1H); 3.08(s, 3H); 7.56(d, 1H); 7.65-7.70(m, 2H); 7.76(t, 1H); 7.95-8.15(m, 5H); 8.67(s, 1H) examples26: 3.12(s, 3H); 7.29(t, 2H); 7.55-7.75(m, 7H); 7.94(d, 1H); 7.98-8.15(m, 3H); 8.15(dd, 1H); 8.69(s, 1H). examples27：2.28(s，3H)；3.11(s，3H)；7.09(d，2H)；7.51(d，2H)；7.60-7.76(m，4H)；7.94(d，1H)；7.99-8.08(m，3H)；8.13(dd，1H)；8.69(s，1H).

Examples 28 to 31

According to the use for preparing compounds21From a compound of16And various acyl chloride synthetic compounds28To31。

*¹H NMR，dmso-d₆Examples of the invention28: 0.92 (width s, 12H); 3.56(q, 2H); 7.34(d, 1H); 7.63-7.80(m, 3H); 8.00-8.15(m, 5H); 8.68(s, 1H) examples29: 0.80-1.10(m, 8H); 1.38 (width s, 3H); 1.53(de, 2H); 2.45(te, 1H); 3.55(q,2H) (ii) a 7.56(d, 1H); 7.65-7.70(m, 2H); 7.76(t, 1H); 7.95-8.15(m, 5H); 8.67(s, 1H) examples30: 0.95(t, 3H); 3.58(q, 2H); 7.35(t, 2H); 7.55-7.75(m, 7H); 7.96(d, 1H); 7.98-8.10(m, 3H); 8.14(dd, 1H); 8.69(s, 1H). examples31：0.95(t，3H)；2.30(s，3H)；3.57(q，2H)；7.15(d，2H)；7.60-7.76(m，6H)；7.95(d，1H)；7.99-8.08(m，3H)；8.14(dd，1H)；8.68(s，1H).

Examples 32 and 33

According to the use for preparing compounds23Respectively reacting 4-chlorobenzoic acid with a compound15And16synthesis of compounds32And33。

*¹H NMR，dmso-d₆examples of the invention32: 3.12(s, 3H); 7.34(d, 2H); 7.55-7.76(m, 6H); 7.92(d, 1H); 7.95-8.05(m, 3H); 8.14(dd, 1H); 8.65(s, 1H) examples33：0.95(t，3H)；3.58(q，2H)；7.40(d，2H)；7.60-7.80(m，6H)；7.94(d，1H)；7.00-8.05(m，3H)；8.14(dd，1H)；8.65(s，1H).

Example 34

1-Naphthoic acid 2-methyl-3- (4-methylbenzoyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

In an inert atmosphere, the compound3(150mg, 0.455mmol) was dissolved in 3mL of tetrahydrofuran. Sodium hydride (27mg, 0.68mmol) was added and after 30 minutes 2-naphthoyl chloride (105. mu.l) was added0.68 mmol). The reaction was stirred at room temperature for 4 hours. The reaction medium is neutralized with water and the aqueous phase is extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g spherical silica column (flow rate 12mL/min, ethyl acetate/heptane gradient from 0 to 45% (20 min)). The product was obtained as a yellow solid (134 mg; 61%).

HPLC：RT＝6.59min，98％

¹H NMR，dmso-d₆，(ppm)：2.35(s，3H)；3.08(s，3H)；7.36(d，2H)；7.54(t，1H)；7.58-7.63(m，2H)；7.79-7.87(m，3H)；7.92(d，2H)；8.00(d，1H)；8.04-8.07(m，2H)；8.27(d，1H)；8.50-8.55(m，1H).

Mass spectrum (ESI +): m/z 501 (MNH)₄ ⁺，100％).

Examples 35 to 45

According to the use for preparing compounds34From a compound of3Or5And various acyl chloride synthetic compounds35To45。

In the examples40To45In the process, the acid chloride required for the reaction is prepared in two steps from the corresponding aromatic alcohol. Preparation of (naphthalen-2-yloxy) acetyl chloride as an example:

in a two-necked flask equipped with a condenser and under an inert atmosphere, 2-naphthol (3.0g, 20mmol) was dissolved in 95mL of Methyl Ethyl Ketone (MEK) containing soda (40g, 93mmol), and then heated to 50 ℃ for 30 minutes. 2-Bromoacetic acid (5.76g, 41mmol) dissolved in 23mL MEK was added dropwise under heat. The heating state was maintained for another 4 hours. The reaction medium is cooled to room temperature and filtered. The combined solids were filtered and treated with a mixture of ethyl acetate and 1N aqueous HCl. The two phases were separated and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated until the first crystallization occurred. Heptane (about 20% of the remaining volume) was added and the resulting precipitate was recovered, rinsed with heptane and dried to constant weight to obtain 3.04g (naphthalene-2-yloxy) acetic acid as a white solid (72%).

HPLC：RT＝4.10min，99％

¹H NMR，dmso-d₆(ppm): 4.80(s, 2H); 7.20(dd, 1H); 7.26(d, 1H); 7.35(td, 1H); 7.45(td, 1H); 7.79(d, 1H); 7.80-7.86(m, 2H); 13.07 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 203 (MH)⁺，100％).

Mass Spectrometry (ESI-): m/z 201 (M-H)^-，100％).

The previously formed acid (3.04g, 15mmol) was partially dissolved in 34mL of dichloromethane under an inert atmosphere at room temperature. Oxalyl chloride (1.35mL, 15.7mmol) was added followed by 100. mu.l of DMF. Note that a strong reaction occurred after the addition of DMF. The reaction mixture was stirred for 1 hour and then concentrated, co-evaporated twice with toluene and dried to constant weight to obtain 3.4g (naphthalen-2-yloxy) acetyl chloride (100%) as an orange solid. The acid chlorides thus obtained are used, for example, for the preparation of compounds40And41。

*¹H NMR，dmso-d₆examples of the invention35: 2.34(s, 3H); 3.07(s, 3H); 7.35(d, 2H); 7.65(t, 1H); 7.72(t, 1H); 7.75-7.92(m, 6H); 7.95-8.06(m, 4H); 8.39(s, 1H) examples36: 3.07(s, 3H); 7.58(t, 1H); 7.61-7.68(m, 2H); 7.89 (width s, 3H); 7.98(d, 2H); 8.00-8.10(m, 5H); 8.31(d, 1H); 8.60(dd, 1H) examples37: 3.08 (s.3h); 7.67(t, 1H); 7.71-7.79(m, 2H); 7.90 (width s, 3H); 7.99-8.11(m, 8H); 8.40(s, 1H) examples38: 2.38(s, 3H); 3.04(s, 3H); 7.35(d, 2H); 7.58(d, 2H); 7.70-7.80(m, 3H); 7.83-8.88(m, 4H); 8.02 (Wide)s, 1H) examples39: 3.04(s, 3H); 7.59(d, 2H); 7.79(d, 2H); 7.83-7.90(m, 3H); 7.99-8.07(m, 5H). examples40: 2.38(s, 3H); 2.97(s, 3H); 5.10(s, 2H); 7.13(dd, 1H); 7.20(d, 1H); 7.36-7.41(m, 3H); 7.48(t, 1H); 7.67(d, 1H); 7.80-7.99(m, 7H); 8.00 (Width s, 1H.) examples41: 2.94(s, 3H); 5.14(s, 2H); 7.15(dd, 1H); 7.25(d, 1H); 7.38(t, 1H); 7.47(t, 1H); 7.69(d, 1H); 7.81-7.94(m, 5H); 7.99-8.10(m, 5H). examples42: 2.38(s, 3H); 2.99(s, 3H); 5.14(s, 2H); 6.70(d, 1H); 7.28(t, 1H); 7.40(d, 2H); 7.47-7.55(m, 3H); 7.81-7.88(m, 4H); 7.92(d, 2H); 8.00(d, 1H); 8.08(d, 1H).) examples43: 2.96(s, 3H); 5.20(s, 2H); 6.82(d, 1H); 7.34(t, 1H); 7.49-7.56(m, 3H); 7.88-7.56(m, 4H); 8.00-8.02(m, 1H); 8.05-8.11(m, 5H). examples44: 2.42(s, 3H); 2.97(s, 3H); 4.98(s, 2H); 6.81(d, 2H); 7.23(d, 2H); 7.42(d, 2H); 7.81-7.92(m, 5H); 7.99(d, 1H) examples45：2.95(s，3H)；5.01(s，2H)；6.90(d，2H)；7.28(d，2H)；7.85-8.15(m，8H).

Example 46

Acetic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

In an inert atmosphere, the compound1(100mg, 0.274mmol) was dissolved in 2mL of dichloromethane. Triethylamine (230. mu.l, 1.64mmol) was added at 0 ℃ followed by acetyl chloride (78. mu.l, 1.09 mmol). The reaction medium is stirred at room temperature for 18 hours and then concentrated. The residue thus obtained was purified by means of a 12g spherical silica column to obtain a compound46(21mg；30％)。

HPLC：RT＝5.34min，97％

¹H NMR，dmso-d₆，(ppm)：1.96(s，3H)；3.03(s，3H)；7.66(t，1H)；7.75(t，1H)；7.80-7.91(m，3H)；7.99-8.08(m，4H)；8.12(d，1H)；8.67(s，1H).

Mass spectrum (ESI +): m/z 425 (MNH)₄ ⁺，100％).

Examples 47 to 54

According to the use for preparing compounds46From a compound of1And various acyl chloride synthetic compounds47To54。

*¹H NMR，dmso-d₆Examples of the invention47: 3.11(s, 3H); 7.29(d, 1H); 7.58(d, 1H); 7.62-7.68(m, 2H); 7.72(t, 1H); 7.82-7.92(m, 3H); 7.95-8.09(m, 5H); 8.66(s, 1H). examples48: 3.10(s, 3H); 7.15(t, 2H); 7.63-8.08(m, 12H); 8.67(s, 1H) examples49: 1.20-1.31(m, 6H); 1.50-1.58(m, 2H); 2.75 (quintuple, 1H); 3.07(s, 3H); 7.64-7.70(m, 2H); 7.74(t, 1H); 7.84(t, 1H); 7.89(t, 1H); 7.99-8.08(m, 4H); 8.12(d, 1H); 8.67(s, 1H) examples50: 3.08(s, 3H); 6.60(d, 1H); 7.19(d, 1H); 7.65(t, 1H); 7.72-7.77(m, 2H); 7.88 (width s, 2H); 7.95-8.08(m, 6H); 8.69(s, 1H). examples51: 3.09(s, 3H); 7.09(dd, 1H); 7.62-8.04(m, 12H); 8.20(s, 1H) examples52: 3.12(s, 3H); 7.6(t, 1H); 7.41(s, 1H); 7.60-7.67(m, 3H); 7.72(t, 1H); 7.82-8.08(m, 8H); 8.69(s, 1H). examples53: 3.11(s, 3H); 7.20(t, 1H); 7.49-7.57(m, 3H); 7.65(t, 1H); 7.73(t, 1H); 7.80(d, 1H); 7.85-7.93(m, 2H); 7.98-8.09(m, 5H); 8.71(s, 1H) examples51：3.04(s，3H)；4.89(s，2H)；6.66(d，2H)；6.86(t，1H)；7.09(t，2H)；7.65(t，1H)；7.76(t，1H)；7.83-7.92(m，3H)；8.03-8.09(m，4H)；8.14(d，1H)；8.71(s，1H).

Example 55

(4-methoxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

In an inert atmosphere, the compound1(159mg, 0.435mmol) was dissolved in 2mL of DMF. Sodium hydride (26mg, 0.65mmol) was added for 30 minutes and then methyl iodide (30. mu.l, 0.48mmol) was added. The reaction was stirred at room temperature for 2 hours and then held at 60 ℃ for 26 hours. At this stage, the reaction is still incomplete. Cesium carbonate (213mg, 0.65mmol) and iodomethane (150. mu.l, 2.1mmol) were added. The reaction medium is stirred for 24 hours at room temperature, neutralized with water and the aqueous phase is extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g column of spherical silica (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 60%) in order to obtain the compound which appeared as a yellow foam55(70mg；38％)。

HPLC：RT＝5.27min，90％

Mass spectrum (ESI +): m/z 380 (MH)⁺，100％).

Examples 56 to 58

The compound was prepared according to the following procedure56To58：

Compound 1(150mg, 0.42mmol) was dissolved in 0.3mL DMF under an inert atmosphere. Cesium carbonate (201mg, 0,61mmol) and the desired iodoalkane (4mmol) were added. The reaction medium is stirred at room temperature for 18 hours, after being held at 50 ℃ for 4 hours is neutralized with water and the aqueous phase is extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g column of spherical silica (flow rate 12mL/min, dichloromethane/heptane gradient 20 to 60%) in order to obtain the desired product.

*¹H NMR，dmso-d₆Examples of the invention56: 0.87(t, 3H): 2.98(s, 3H); 3.74(q, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.80-7.93(m, 3H); 7.95-8.15(m, 5H); 8.67(s, 1H) examples57: 0.49(t, 3H): 1.28 (hexameric, 2H); 2.97(s, 3H); 3.63(t, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.80-7.93(m, 3H); 7.95-8.15(m, 5H); 8.68(s, 1H) examples58: 0.50(t, 3H): 0.89 (sextuplex, 2H); 1.23 (quintuple, 2H); 2.97(s, 3H); 3.66(t, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.80-7.93(m, 3H); 7.95-8.15(m, 5H); 8.67(s, 1H).

Example 59

(4- (2-chloroethoxy) -2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (p-tolyl) methanone

In an inert atmosphere, the compound3(100mg, 0.3mmol) was dissolved in 3mL of THF containing 2-chloroethanol (100. mu.L, 1.5 mmol). After the reaction mixture was cooled to 0 ℃ triphenylphosphine (318mg, 1.2mmol) and diethyl azo-1, 2-dicarboxylate (DEAD, 211mg, 1.2mmol) were successively added dropwise. Stirring was continued for 20 hours at room temperature, followed by saturated ammonium chlorideAnd (4) neutralizing the reaction by using an aqueous solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a 35g silica column (flow rate 20mL/min, ethyl acetate/heptane gradient from 0 to 100%) so as to obtain the compound59(70mg；58％)。

HPLC：RT＝5.28min，99％

¹H NMR，dmso-d₆，(ppm)：2.41(s，3H)；2.91(s，3H)；3.57(t，2H)；3.92(t，2H)；7.40(d，2H，)；7.75-7.98(m，6H).

Mass spectrum (ESI +): m/z 392 (MH)⁺，100％)；394(MH⁺，42％).

Example 60

(4- [2- (naphthalen-2-yloxy) ethoxy ] -2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (p-tolyl) methanone)

In an inert atmosphere, the compound59(70mg, 0.17mmol) was dissolved in 2mL of DMF containing potassium carbonate (64mg, 0.53mmol), potassium iodide (31mg, 0.19mmol) and 2-naphthol (38mg, 0.27 mmol). The reaction medium is heated to 65 ℃ for 22 hours, then neutralized with water and extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a Waters Sunfire semi-preparative HPLC column (19X 100mm, 5 μm) at a flow rate of 20mL/min and a gradient of acetonitrile/water (0.1% TFA buffer) from 10 to 100% in 15 minutes, so as to obtain the compound60(30mg；29％)。

HPLC：RT＝5.95min，99％

¹H NMR，dmso-d₆，(ppm)2.26(s，3H)；2.90(s，3H)；4.03(d，2H)；4.10(d，2H)； 6.92(dd，1H)；7.06(d，1H)；7.24(d，2H)；7.33(t，1H)；7.44(t，1H)；7.70-7.90(m，7H)；7.94-7.98(m，2H).

Mass spectrum (ESI +): m/z 500 (MH)⁺，100％).

Example 61

(4- (2-Phenoxyethoxy) -2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

In an inert atmosphere, the compound1(100mg, 0.274mmol) was dissolved in 0.5mL of DMF containing potassium carbonate (90mg, 0.55mmol) and 2-phenoxybromoethane (110mg, 0.55 mmol). The reaction medium is heated to 80 ℃ in a sealed tube and held for 16 hours. The medium is treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a 12g silica column (flow rate 20mL/min, dichloromethane/heptane gradient 0 to 10%) in order to obtain the compound which appeared as a yellow syrup61(45mg；34％)。

HPLC：RT＝5.88min，98％

¹H NMR，dmso-d₆，(ppm)2.97(s，3H)；3.85-3.87(m，2H)；4.01-4.05(m，2H)；6.59(d，2H)；6.82(t，1H)；7.11(t，2H)；7.62(t，1H)；7.71(t，1H)；7.83(t，1H)；7.88(t，1H)；7.91-8.04(m，6H)；8.62(s，1H).

Mass spectrum (ESI +): m/z 486 (MH)⁺，100％).

Example 62

Methyl 2- (2-methyl-3- (4-methylbenzoyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy) acetate

According to the application for the compound59From the same step of3Synthesis of Compound (300mg, 0.91mmol) and methyl glycolate (350. mu.l, 4.5mmol)62In order to obtain 300mg of the desired product (79%) appearing as yellow syrup.

HPLC：RT＝4.97min，97％

¹H NMR，dmso-d₆，(ppm)：2.42(s，3H)；2.88(s，3H)；3.47(s，3H)；4.42(s，2H)；7.40(d，2H，)；7.75-7.98(m，6H).

Mass spectrum (ESI +): m/z 402 (MH)⁺，100％)；419(MNH₄ ⁺，42％).

Example 63

(2-methyl-3- (4-methylbenzoyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy) acetic acid

The compound62(75mg, 0.18mmol) was dissolved in 1mL THF, and lithium hydroxide (1M/H) was added₂O, 0.37 mmol). The reaction medium is stirred for 2 hours at room temperature, then diluted with water and extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to obtain 22mg of the desired product (HPLC: RT ═ 4.55min, 97%). The yield of this operation was 30%.

¹H NMR，dmso-d₆，(ppm)2.41(s，3H)；2.88(s，3H)；4.28(s，2H)；7.39(d，2H)；7.81(t，1H)；7.85-795(m, 5H); 12.96(se, 1H, exchange).

Mass spectrum (ESI +): m/z 388 (MH)⁺，100％)；405(MNH₄ ⁺，54％).

Examples 64 to 66

The compound63(110mg, 0.28mmol) was dissolved in 3mL DMF. Different amines (0.23mmol), DIEA (82. mu.l, 0.472mmol), HOOBT (35mg, 0.26mmol) and EDCI (50mg, 0.26mmol) were added. The reaction medium is stirred at room temperature for 18 hours. The medium is treated with dichloromethane and subsequently washed with 1N soda, water and saturated NaCl solution. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g column of spherical silica (flow rate 12mL/min, ethyl acetate/heptane gradient from 0 to 50%) in order to obtain the desired product.

*¹H NMR，dmso-d₆Examples of the invention64: 2.33(s, 3H); 2.93(s, 3H); 4.55(s, 2H); 7.35(d, 2H); 7.43-7.55(m, 4H); 7.76(d, 1H); 7.82-7.85(m, 2H); 7.91-7.99(m, 5H); 8.12(d, 1H); 7.76(s, 1H, exchange).65：1.51-1.59(m，6H)；1.71(s，6H)；1.94(s，3H)；2.41(s，3H)； 2.88(s，3H)；4.05(s，2H)；6.78(s，1H)；7.42(d，2H)；7.81(t，1H)；7.87-7.95(m，4H)；7.99(d，1H).66：1.39-1.41(m，2H)；1.64-1.77(m，12H)；2.41(s，3H)；2.88(s，3H)；3.65-3.75(m，1H)；4.21(s，2H)；7.39(d，3H)；7.81(t，1H)；7.87-7.95(m，4H)；8.0(d，1H).

Example 67

Methyl 2- (2-methyl-3- (4-methylbenzoyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy) acetate

The compound1(1.0g, 2.74mmol) was dissolved in 2mL of DMF containing potassium carbonate (682mg, 4.1mmol) and methyl bromoacetate (1.26mL, 13.68 mmol). The reaction medium is stirred at room temperature for 5 hours and an equal amount of methyl bromoacetate is added again. At room temperature overnight, the mixture was treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified over a 90g silica column (flow rate 32mL/min, dichloromethane/heptane gradient from 40 to 100%) in order to obtain the compound which appeared to be a yellow syrup67(486mg；41％)。

HPLC：RT＝5.23min，86％

¹H NMR，dmso-d₆，(ppm)2.95(s，3H)；3.39(s，3H)；4.45(s，2H)；7.64(t，1H)；7.72(t，1H)；7.81-7.89(m，1H)；7.93(d，2H)；7.97(d，1H)；7.99-8.11(m，4H)；8.66(s，1H).

Mass spectrum (ESI +): m/z 438 (MH)⁺，100％).

Example 68

2- (2-methyl-3- (4-methylbenzoyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy) acetic acid

The compound67(480mg, 1.1mmol) was dissolved in a 5: 1 THF/water mixture (6mL) and subsequently treated with LiOH (103mg, 4.39mmol) for 15 minutes at room temperature. The medium is treated with ethyl acetate and then washed with 1N HCl, water and saturated NaCl solution. The organic phases are combined, dried over sodium sulfate,filtered and concentrated. The residue thus obtained is purified by means of a 30g silica column (eluent dichloromethane/methanol/acetic acid 95/4.5/0) in order to obtain a compound which behaves as a yellow foam68(321mg；69％)。

HPLC：RT＝4.86min，99％

¹H NMR，dmso-d₆，(ppm)2.93(s，3H)；4.29(s，2H)；7.64(t，1H)；7.72(t，1H)；7.83(t，1H)；7.89-8.09(m，7H)；8.66(s，1H).

Mass spectrum (ESI +): m/z 424 (MH)⁺，100％).

Examples 69 to 71

The compound was prepared according to the following procedure69To71：

The compound1(100mg, 0.23mmol) was dissolved in 1.5mL of dichloromethane. Different amines (0.23mmol), DIEA (82. mu.l, 0.472mmol), HOOBT (35mg, 0.26mmol) and EDCI (50mg, 0.26mmol) were added. The reaction mixture is stirred at room temperature for 24 hours, an excess of amine (0.07mmol) is added and the medium is stirred for a further 5 hours. The medium is treated with dichloromethane and washed with 1N soda, water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a 12g spherical silica column (flow rate 12mL/min, 1% dichloromethane solution of a 9: 1 methanol/ammonia mixture) to obtain the desired product.

*¹H NMR，dmso-d₆Examples of the invention69：1.08-1.31(m，6H)：2.87(t，2H)；2.95(s，3H)；3.04(t，2H) (ii) a 4.41(s, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.84(m, 1H); 7.92(d, 2H); 7.97-8.10(m, 5H); 8.65(s, 1H) examples70: 1.85(t, 2H): 1.92(t, 2H); 1.95(s, 3H); 2.94 (width s, 5H); 3.04 (width s, 2H); 4.44(s, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.84(m, 1H); 7.92(m, 2H); 7.97-8.10(m, 5H); 8.65(s, 1H) examples71: 1.88 (width s, 2H); 1.96 (width s, 2H); 2.92(m, 5H); 3.08 (width s, 2H); 3.22(s, 2H); 4.42(s, 2H); 7.16(d, 2H); 7.21-7.31(m, 3H); 7.63(t, 1H); 7.72(t, 1H); 7.82(m, 1H); 7.78(m, 2H); 7.97-8.09(m, 5H); 8.65(s, 1H).

Examples 72 to 74

According to the use for preparing compounds46From a compound of1And various acyl chloride synthetic compounds72To74。

*¹H NMR，dmso-d₆Examples of the invention72: 3.04(s, 3H); 4.94(s, 2H); 6.67(d, 2H); 7.07(d, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.84-7.93(m, 3H); 8.02(m, 3H); 8.08(d, 1H); 8.14(d, 1H); 8.69(s, 1H). examples73: 3.05(s, 3H); 5.10(s, 2H); 6.59(d, 1H); 7.12(t, 1H); 7.38-7.41(m, 2H); 7.49(t, 1H); 7.66(t, 1H); 7.75(t, 1H); 7.81-7.90(m, 4H); 7.98(d, 1H); 8.02-8.08(m, 4H); 8.13(d, 1H); 8.72(s, 1H) examples74：3.02(s，3H)；5.07(s，2H)；7.01(dd，1H)；7.12(d，1H)；7.32-7.41(m，2H)；7.57(d，1H)；7.63(t，1H)；7.70-7.79(m，3H)；7.85-7.94(m，3H)；8.02-8.12(m，5H)；8.71(s，1H).

Examples 75 and 76

According to the use for preparationCompound (I)60From a compound of59And various alcohol synthesis compounds75And76。

*¹H NMR，dmso-d₆examples of the invention75: 2.31(s, 3H); 2.90(s, 3H); 4.10-4.20(m, 4H); 6.75(d, 1H); 7.21(d, 2H); 7.33(t, 1H); 7.40-7.44(m, 2H); 7.51(t, 1H); 7.78-7.85(m, 6H); 7.97(t, 2H). examples76：2.37(s，3H)；2.89(s，3H)；3.85-3.95(m，2H)；4.00-4.05(m，2H)；6.69(d，2H)；7.23(d，2H)；7.29(d，2H)；7.78-7.96(m，6H).

Examples 77 and 78

According to the use for preparing compounds34From a compound of3Synthesis of compounds with acetyl chloride and propionyl chloride respectively77And78。

*¹H NMR，dmso-d₆examples of the invention77: 2.04(s, 3H); 2.42(s, 3H); 2.98(s, 3H); 7.42(d, 2H); 7.76-7.90(m, 5H); 7.98(d, 1H) examples78：0.86(t，3H)；2.33(q，2H)；2.42(s，3H)；2.99(s，3H)；7.41(d，2H)；7.73(d，1H)；7.79-7.89(m，4H)；7.98(d，1H).

Examples 79 and 80

According to the use for preparing compounds59From a compound of3Synthesis of Compounds with methanol and ethanol, respectively79And80。

*¹H NMR，dmso-d₆examples of the invention79: 2.42(s, 3H); 2.91(s, 3H); 3.50(s, 3H); 7.41(d, 2H); 7.78-7.95(m, 6H). examples80：0.93(t，3H)；2.41(s，3H)；2.90(s，3H)；3.73(q，2H)；7.40(d，2H)；7.78-7.94(m，6H).

Example 81

[4- (2-Bromoethoxy) -2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl ] -naphthalen-2-yl-methanone

The compound1(150mg, 0.41mmol) was dissolved in methyl ethyl ketone (3mL) and then dissolved with a solution containing K₂CO₃(170mg, 1.02mmol) of dibromoethane (71. mu.l, 0.82 mmol). The reaction was heated to 130 ℃ with microwave energy in a sealed tube and held for 4 hours and 30 minutes. The medium is treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained (brown syrup, 197mg) was used directly in the next reaction.

Example 82

{4- [2- (4-chlorophenoxy) ethoxy ] -2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl } -naphthalen-2-yl-methanone

The compound81(197mg, 0.41mmol) was dissolved in methyl ethyl ketone(1.5mL) and then with a solution containing K₂CO₃(173mg, 1.04mmol) of 4-chlorophenol (107. mu.l, 0.82 mmol). The reaction was heated to 130 ℃ in a sealed tube with microwave energy and held for 2 hours. The medium is treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 10 to 100%) in order to obtain the compound appearing as yellow syrup82(21mg；14％)。

HPLC：RT＝6.10min，89％

¹H NMR，dmso-d₆，(ppm)2.96(s，3H)；3.85(m，2H)；3.97(m，2H)；6.57(d，2H)；7.08(d，2H)；7.61(t，1H)；7.70(t，1H)；7.83(t，1H)；7.89-8.02(m，7H)；8.60(s，1H).

Mass spectrum (ESI +): m/z 520 (MH)⁺，100％).

Example 83

Ethyl carbonate 1- [ 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy ] -ethyl ester

The compound1(100mg, 0.27mmol) was dissolved in DMF (13mL) and then washed with a solution containing K₂CO₃(91mg, 0.55mmol) of ethyl 2-chloropropionate (110. mu.l, 0.82 mmol). The reaction was heated to 60 ℃ with microwave energy in a sealed tube overnight, then an equal amount of ethyl 2-chloropropionate was added and the reaction was stirred for an additional 24 hours. The medium is treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 25 to 80%) so as to obtainCompounds appearing as yellow syrups83(100mg；76％)。

HPLC：RT＝5.55min，97％

¹H NMR，dmso-d₆，(ppm)0.94(t，3H)；1.25(d，3H)；2.94(s，3H)；3.80-3.93(m，2H)；5.99(q，1H)；7.65(t，1H)；7.73(t，1H)；7.85(m，1H)；7.90(d，2H)；7.97(d，1H)；8.01-8.11(m，4H)；8.69(s，1H).

Mass spectrum (ESI +): m/z 504 (MNa)⁺，100％).

Example 84

[ 2-methyl-1, 1-dioxido-4- (2-piperidin-1-yl-ethoxy) -1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl ] -naphthalen-2-yl-methanone

The compound1(100mg, 0.27mmol) was dissolved in methyl ethyl ketone (0.5mL) and then dissolved with a solution containing K₂CO₃(159mg, 0.96mmol) of 1- (2-chloroethyl) piperidine (252mg, 1.37 mmol). The reaction was heated to 80 ℃ overnight. The medium is then treated with ethyl acetate and subsequently washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a 12g silica column (flow rate 12mL/min, dichloromethane/methanol/ammonium hydroxide 99/09/01) so as to obtain a compound which appeared to be a yellow syrup84(50mg；43％)。

HPLC：RT＝4.17min，92％

¹H NMR，dmso-d₆(ppm)1.21 (width s, 6H); 1.99 (width s, 4H); 2.19(t, 2H); 2.98(s, 3H); 3.72(t, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.83(t, 1H); 7.90(t, 1H); 7.97(d, 1H); 8.01-8.11(m, 5H); 8.66(s, 1H).

Mass spectrum (ESI +): m/z477(MH +, 100%).

Examples 85 to 96

The compound was synthesized according to the following procedure85To96：

In an inert atmosphere, compound 13, 15, or 17 was dissolved in 2mL of dichloromethane containing triethylamine (6 equivalents) and treated with various acid chlorides (4 equivalents) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours, followed by stirring at room temperature for 20 hours. The medium is treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (flow rate 12mL/min, ethyl acetate/heptane gradient from 0 to 20%) in order to obtain the expected compound.

Examples 97 to 104

According to the preparation examples56To58From a compound of13，15Or is or17And corresponding alkyl iodide or sulfate synthetic compound97To104。

Example 105

[ 7-fluoro-2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy ] acetic acid methyl ester

According to the preparation examples67From a compound of17(1g, 2.61mmol) Synthesis of Compound105. The product was obtained as a yellow syrup (810 mg; 68%).

HPLC：RT＝5.37min，95％

¹H NMR，dmso-d₆，(ppm)2.95(s，3H)；3.40(s，3H)；4.45(s，2H)；7.64(t，1H)；7.70(t，1H)；7.80(dt，1H)；7.91(dd，1H)；7.99-8.10(m，5H)；8.65(s，1H).

Mass spectrum (ESI +): m/z 456 (MH)⁺，100％).

Example 106

[ 7-fluoro-2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yloxy ] acetic acid methyl ester

According to the preparation examples68From a compound of105(598mg, 1.31mmol) preparation of the Compound106. The compound was obtained as a light brown powder (262 mg; 45%).

HPLC：RT＝4.92min，97％

Mass spectrum (ESI +): m/z442(MH⁺，100％).

Examples 107 to 109

According to the preparation examples69To71From a compound of106And corresponding amine synthesis compounds107To109。

*¹H NMR，dmso-d₆Examples of the invention107: 1.09-1.14(m, 4H); 1.31(m, 2H); 2.87(t, 2H); 2.95(s, 3H); 3.05(t, 2H); 4.41(s, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.79(dt, 1H); 7.89(dd, 1H); 7.99-8.10(m, 5H); 8.64(s, 1H) examples108: 1.86(t, 2H); 1.92(t, 2H); 1.96(s, 3H); 2.92-2.95(m, 5H); 3.05(t, 2H); 4.44(s, 2H); 7.64(t, 1H); 7.72(t, 1H); 7.79(dt, 1H); 7.90(dd, 1H); 7.98-8.10(m, 5H); 8.64(s, 1H) examples109: 1.90 (width s, 2H); 1.97 (width s, 2H); 2.92 (width s, 2H); 2.95(s, 3H); 3.09 (width s, 2H); 3.22(s, 2H); 4.43(s, 2H); 7.16(d, 2H); 7.21-7.31(m, 3H); 7.64(t, 1H); 7.72(t, 1H); 7.80(dt, 1H); 7.90(dd, 1H); 7.98-8.09(m, 5H); 8.64(s, 1H).

Example 110

Benzenesulfonic acid 7-fluoro-2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester

The compound17(200mg, 0.52mmol) was dissolved in dichloromethane (2mL) and treated with Et-containing solution at 0 deg.C₃N (145. mu.l, 1.04mmol) was treated with benzenesulfonyl chloride (67. mu.l, 0.52 mmol). The reaction is stirred for 4 hours from 0 ℃ to room temperature, the medium is treated with dichloromethane and washed with water and saturated NaCl solution. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (flow rate 12mL/min, dichloromethane/heptane gradient from 20 to 50%) in order to obtain the compound as a cream-colored powder110(177mg；65％)。

HPLC：RT＝5.72min，94％

¹H NMR，dmso-d₆，(ppm)2.98(s，3H)；7.40(t，2H)；7.54-7.61(m，4H)；7.66(t，1H)；7.75(m，2H)；7.84-7.90(m，2H)；8.04-8.09(m，3H)；8.57(s，1H).

Mass spectrum (ESI +): m/z 541 (MNH)₄ ⁺，100％).

Examples 111 to 117

According to the preparation examples110From a compound of1Or17And corresponding sulfonyl chloride synthesis compounds111To117。

Example 118

(4-hydroxy-2-methyl-7-piperidin-1-yl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) -naphthalen-2-yl-methanone

The compound17(200mg, 0.52mmol) was dissolved in a solution containing K₂CO₃(144mg, 1.04mmol) in DMSO (2mL) and treated with piperidine (154. mu.l, 1.56mmol) at room temperature. The reaction is stirred for 20 hours at 100 ℃ and the medium is subsequently treated with ethyl acetate and washed with water and saturated NaCl solution. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (flow rate 12mL/min, ethyl acetate/heptane gradient from 0 to 50%) in order to obtain the compound which appeared as a yellow powder118(22mg；9.5％)。

HPLC：RT＝6.39min，96％

¹H NMR，dmso-d₆(ppm)1.64 (width s, 6H); 2.63(s, 3H); 3.57 (width s, 4H); 7.22(d, 1H); 7.34(dd, 1H); 7.65-7.70(m, 2H); 7.96(d, 1H); 8.03(d, 1H); 8.09-8.11(m, 3H); 8.62(s, 1H). Mass Spectrometry (ESI +): m/z 449 (MH)⁺，100％).

Examples 119 to 121

According to the preparation examples118From a compound of17And corresponding amine synthesis compounds119To121。

Example 122

(7-tert-butyl-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone

According to the preparation of the compounds17The same sequence of steps of (1), Synthesis of Compound from 2-methyl-5-tert-butylbenzenesulfonyl chloride122. The compound was obtained as a yellow solid in a total yield of 10%.

HPLC：RT＝6.33min，95％

¹H NMR，dmso-d₆(ppm)1.38(s, 9H); 2.65(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 7.88(s, 1H); 8.05(d, 2H); 8.12-8.17(m, 4H); 8.65(s, 1H); 15.69(s, 1H, exchange).

Mass spectrum (ESI +): m/z 422 (MH)⁺，100％).

Examples 123 to 130

According to the use for preparing compounds1From the corresponding 2-bromo-1-arylethanones (suitably123， 125，127And128) Of a compound8(is suitable for124And126) And compounds17(is suitable for129And130) Synthesis of compounds123To130。

¹Three-step total yield

*¹H NMR，dmso-d₆Examples of the invention123: 2.68(s, 3H); 7.95(d, 1H); 7.98-8.00(m, 4H); 8.16(d, 1H); 8.19-8.21(m, 1H); 14.93(s, 1H, exchange). EXAMPLE124: 0.55(t, 3H); 3.16(q, 2H); 7.92(d, 1H); 7.97-7.98(m, 4H); 8.16(d, 1H); 8.19-8.20(m, 1H); 14.77(s, 1H, exchange). EXAMPLE125：2.98(s，3H)；7.43(t，1H)(ii) a 7.62(dt, 1H); 7.80(d, 1H); 7.99-8.04(m, 4H); 8.20(se, 1H); 8.34(s, 1H); 15.56(se, exchange, 1H). examples126: 0.67(t, 3H); 3.57(q, 2H); 7.43(t, 1H); 7.63(dt, 1H); 7.80(d, 1H); 7.96-8.18(m, 4H); 8.20(se, 1H); 8.31(s, 1H); 15.33(se, exchange, 1H) examples127: 1.78(s, 4H); 2.64(s, 3H); 2.81(s, 4H); 7.30(d, 1H); 7.45(s, 1H); 7.86(d, 1H); 7.98(m, 3H); 8.18-8.21(m, 1H); 15.75(s, 1H) examples128: 1.30(d, 12H); 1.70(s, 4H); 2.64(s, 3H); 7.58(d, 1H); 7.78(d, 1H); 7.98(m, 3H); 8.18-8.21(m, 1H); 8.25(d, 1H); 15.62(s, 1H) examples129: 1.77 (width s, 4H); 2.67(s, 3H); 2.80 (width s, 4H); 7.23 (width s, 1H); 7.60-7.85(m, 4H); 8.21(m, 1H); 15.85(s, 1H) examples130: 1.28(d, 12H); 1.69(s, 4H); 2.65(s, 3H); 7.51(d, 1H); 7.66(d, 1H); 7.88(m, 2H); 8.08 (width s, 1H); 8.21(q, 1H); 15.65(s, 1H).

Examples 131 to 143

According to the use for preparing compounds1(R2 ═ Me) or compound8(R2 ═ Et) from saccharin and the corresponding 2-bromo-1-arylethanone131To143。

¹Three-step total yield

*¹H NMR，dmso-d₆Examples of the invention131: 2.68(s, 3H); 3.33(m, 2H); 4.69(t, 2H); 7.02(d, 1H); 7.97-7.98(m, 3H); 8.03(s, 1H); 8.08(dd, 1H), 8.18-8.20(m, 1H); 16.03(s, 1H, exchange) implementationExample (b)132: 0.55(t, 3H); 3.18(q, 2H); 3.28-3.34(m, 2H); 4.69(t, 2H); 7.00(d, 1H); 7.94-7.98(m, 4H); 8.03(d, 1H); 8.17-8.19(m, 1H); 15.77(s, 1H, exchange). EXAMPLE133: 2.69(s, 3H); 6.21(s, 2H); 7.19(d, 1H); 7.56(d, 1H); 7.82(dd, 1H); 7.96-7.99(m, 3H); 8.18-8.20(m, 1H); 15.66(s, 1H, exchange). EXAMPLE134: 0.56(t, 3H); 3.18(q, 2H); 6.20(s, 2H); 7.18(d, 1H); 7.53(d, 1H); 7.77(dd, 1H); 7.94-7.96(m, 3H); 8.17-8.19(m, 1H); 15.39(s, 1H, exchange.) example135: 0.55(t, 3H); 3.18(q, 2H); 4.33(t, 2H); 4.37(t, 2H); 7.09(d, 1H); 7.64(d, 1H); 7.67(dd, 1H); 7.94-7.96(m, 3H); 8.17-8.19(m, 1H); 15.55(s, 1H, exchange.) example136: 0.55(t, 3H); 3.18(q, 2H); 4.33(t, 2H); 4.37(t, 2H); 7.09(d, 1H); 7.64(d, 1H); 7.67(dd, 1H); 7.94-7.96(m, 3H); 8.17-8.19(m, 1H); 15.55(s, 1H, exchange.) example137: 2.65(s, 3H); 7.69(d, 1H); 7.96(d, 1H); 7.98-8.00(m, 3H); 8.07(d, 1H); 8.21-8.23(m, 1H); 8.28(d, 1H); 8.60(s, 1H); 15.69(s, 1H, exchange). EXAMPLE138: 2.64(s, 3H); 7.22(d, 1H); 7.86(d, 1H); 7.98-8.00(m, 3H); 8.09(dd, 1H); 8.19(d, 1H); 8.21-8.45(m, 1H); 8.45(s, 1H); 15.71(s, 1H, exchange). EXAMPLE139: 2.63(s, 3H); 3.92(s, 3H); 7.81(d, 1H); 7.98-8.05(m, 4H); 8.20-8.23(m, 1H); 8.52(s, 1H); 8.52(s, 1H); 15.87(s, 1H, exchange). EXAMPLE140: 2.97(s, 3H); 7.53(t, 1H); 7.61(t, 1H); 8.00-8.02(m, 3H); 8.17-8.22(m, 3H); 8.67(s, 1H); 15.70(s, 1H, exchange.) example141: 1.34(s, 9H), 2.66(s, 3H); 7.66(d, 2H); 7.98-8.00(m, 3H); 8.06(d, 2H); 8.18-8.21(m, 1H); 15.71(s, 1H, exchange). EXAMPLE142: 2.65(s, 3H); 7.60(t, 1H); 7.90(d, 1H); 7.95-8.05(m, 4H); 8.11(s, 1H); 8.19 (width s, 1H); 15.06(s, 1H, exchange)143: 2.65(s, 3H); 7.84(t, 1H); 7.95-8.00(m, 3H); 8.15-8.21(m, 2H); 8.28-8.31(m, 2H); 14.86 (width s, 1H, exchange).

XBridge chromatography column

Examples 144 to 146

According to the use for preparing compounds1The same sequence of steps of (a) from saccharin and the corresponding 2-bromo-1-arylethanone144To146。

According to the use for preparing compounds144APreparing 2-bromo-1-arylethanones by bromination of the corresponding arylethanones: 1- (3, 4-dimethylphenyl) ethanone (2.5g, 16.9mmol) was dissolved in 42mL of THF at room temperature under a nitrogen atmosphere. Trifluoroacetic acid (1.5mL, 16.9mmol) was added followed by the addition of the tribromopyridinium salt (6.5g, 20.2 mmol). The solution turned vermillion and a white precipitate gradually appeared. After stirring at room temperature for 3 hours, the reaction was neutralized by adding 50mL of water and then extracted with 100mL of ethyl acetate. The organic phase was saturated with 40mL of CuSO₄The solution was washed with 40mL of saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified over a 130g silica column with an ethyl acetate/heptane gradient from 0% to 5% in order to obtain two batches of 2-bromo-1- (3, 4-dimethylphenyl) -ethanone (E)144A，57％)。

First batch: 1.25 g; HPLC: RT 4.90min, 90%.

And (2) second batch: 1.90 g; HPLC: RT 4.90min, 70%.

¹Four-step total yield

*¹H NMR，dmso-d₆(ppm) examples144：2.33(s，3H)；2.34(s，3H)；2.63(s，3H)；7.40(d，1H)；7.82(s，1H)；7.90(d，1H)；7.98-8.00(m3H); 8.18-8.21(m, 1H); 15.73(s, 1H, exchange.) example145: 2.65(s, 3H); 7.89(t, 1H); 8.00-8.01(m, 3H); 8.08(d, 1H); 8.20-8.22(m, 1H); 8.30 (width s, 2H), 15.00 (width s, 1H, exchange)146: 2.64(s, 3H); 8.00-8.03(m, 5H); 8.17-8.21(m, 3H); 15.06 (width s, 1H, exchange).

XBridge chromatography column

Example 147

Adamantan-2-yl- (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -methanone

Example 147AAdamantane-2-carbonitriles

Adamantanone (2.5g, 16.6mmol) was dissolved in 58mL 1, 2-Dimethoxyethane (DME) containing ethanol (1.7mL) and p-toluenesulfonylmethylisonitrile (TosMIC, 4.22g, 21.6mmol) under a nitrogen atmosphere. The reaction medium is cooled in an ice bath. Potassium tert-butoxide (5.72g, 51mmol) was added slowly while maintaining the reaction medium temperature between 2 ℃ and 11 ℃. The reaction was stirred between 5 ℃ and 12 ℃ for 30 minutes and then returned to room temperature and stirring was continued for 2 hours. The reaction medium was filtered and the white precipitate rinsed with DME. The filtrate was concentrated. The residue thus obtained is purified over silica (5% ethyl acetate/heptane) in order to obtain the compound which appears as a white solid147A(2.38g，88％)。

¹H NMR，dmso-d₆(ppm): 1.65-1.95(m, 12H); 2.07 (width s, 2H); 3.14 (width s, 1H).

Mass spectrum (ESI +): m/z 162 (MH)⁺，20％)；194(MH⁺.MeOH，100％).

Example 147B-1-adamantan-2-yl-ethanone

In a nitrogen atmosphere, the compound147A(4.63g, 28.7mmol) was dissolved in 61mL of diethyl ether, followed by cooling in an ice bath. Methyllithium (27mL, 1.6M/Et) was added dropwise₂O, 43mmol) while maintaining the reaction medium temperature between 5 ℃ and 12 ℃. Once the addition was complete, the ice bath was removed and stirring continued at room temperature for 30 minutes. The reaction medium is neutralized with 46mL of water. The organic phases are combined, dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was treated with 28mL of acetone and 28mL of 6N HCl, and then heated at reflux for 80 minutes. The acetone was evaporated to dryness and the residual aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 90g silica column (32mL/min, 6% ethyl acetate/heptane) in order to obtain the compound which appeared to be a yellow solid147B(3.66g，71％)。

¹H NMR，dmso-d₆(ppm): 1.45-1.55(m, 2H); 1.65-1.90(m, 10H); 2.09(s, 3H); 2.29 (width s, 2H); 2.54 (width s, 1H).

Mass spectrum (ESI +): m/z 179 (MH)⁺，100％).

Example 147C-1-adamantan-2-yl-2-bromo-ethanone

In a nitrogen atmosphere, the compound147B(500mg, 2.8mmol) was dissolved in 8.6mL of methanol and then cooled to 0 ℃. Bromine (151. mu.l, 2.94mmol) was added slowly. The reaction medium is stirred for 1 hour 40 minutes at 0 ℃ and is subsequently neutralized with water and extracted twice with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified by means of a 35g silica column (20mL/min, gradient from 0% to 15% ethyl acetate/heptane over 25 min) so as to obtain the compound147C(1.37g，85％)。

¹H NMR，dmso-d₆(ppm): 1.5-1.6(m, 2H); 1.65-1.90(m, 10H); 2.38 (width s, 2H); 2.86 (width s, 1H); 4.45(s, 2H).

Example 147-adamantan-2-yl- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ]][1，2]Thiazin-3-yl) -methanones

According to the use for preparing compounds1By the same sequence of steps as for the preparation of the compound147CSynthesis of compounds147The yield of the three steps is 11 percent.

White solid

HPLC：RT＝6.28min，97％.

¹H NMR，dmso-d₆(ppm): 1.54-1.61(m, 2H); 1.68-1.93(m, 8H); 2.05-2.25(m, 2H); 2.36 (width s, 2H); 2.89(s, 3H); 3.27(s, 1H); 7.93-7.96(m, 3H); 8.08-8.11(m, 1H); 15.22(s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 372 (M-H)^-，100％).

Example 148

Chroman-6-yl- (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -methanone

Example 148A-chromane

4-chromone (5.0g, 33.7mmol) was dissolved in 102mL THF under a nitrogen atmosphere. Adding BF at room temperature₃.OEt₂(12.8mL, 101mmol) and sodium cyanoborohydride (4.33g, 67.4mmol) was added slowly (vigorous reaction). White color obtained therebyThe color suspension was heated to 65 ℃ for 18 hours and then neutralized with water. The reaction mixture was extracted twice with ethyl acetate. The organic phases were combined and successively saturated NaHCO₃The solution was washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained is purified over silica (dichloromethane/heptane gradient from 0% to 50%, followed by 10% ethyl acetate/heptane) in order to obtain a partially purified compound148A(3.34g，61％)。

HPLC：RT＝4.56min，83％.

¹H NMR，dmso-d₆，(ppm)：1.91(q，2H)；2.72(t，2H)；4.11(t，2H)；6.70(d，1H)；6.80(t，1H)；7.0-7.05(m，2H).

Example 148B-1-chroman-6-yl-ethanones

Chromane (4.64g, 29.4mmol) is dissolved in 30mL of anhydrous Dichloromethane (DCM) under a nitrogen atmosphere. The reaction medium was cooled to-30 ℃ and then a cold solution (-10 ℃) of acetyl chloride (4.75mL, 67mmol) dissolved in 20mL of anhydrous DCM was added over 5 minutes. The mixture was stirred at-15 ℃ for 45 minutes, then poured into a mixture of 100g ice and 50mL concentrated HCl and extracted three times with DCM. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified over a 120g silica column (ethyl acetate/heptane gradient from 0% to 20% in 60 min) in order to obtain two batches of the compound148B(70％)。

First batch: 2.25 g; HPLC: RT ═ 4.09min, 96.6%.

¹H NMR，dmso-d₆，(ppm)：1.93(q，2H)；2.49(s，3H)；2.79(t，2H)；4.21(t，2H)；6.81(d，1H)；7.65-7.75(m，2H).

Mass spectrum (ESI +): m/z 177 (MH)⁺，100％).

And (2) second batch: 1.79 g; HPLC: RT 4.09min, 81%.

Example 148C-2-bromo-1-chroman-6-yl-ethanone

According to the use for preparing compounds144AFrom a compound of148BSynthesis of compounds148CThe yield thereof was found to be 65%.

HPLC：RT＝4.59min，74％.

¹H NMR，dmso-d₆，(ppm)：1.95(q，2H)；2.80(t，2H)；4.20(t，2H)；4.80(s，2H)；6.85(d，1H)；7.70-7.85(m，2H).

Example 148-chroman-6-yl- (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -methanones

According to the use for preparing compounds1By the same sequence of steps as for the preparation of the compound148CSynthesis of compounds148The total yield was 36%.

HPLC：RT＝5.45min，98％.

¹H NMR，dmso-d₆(ppm): 1.98(t, 2H); 2.69(s, 3H); 2.84(t, 2H); 4.27(t, 2H); 6.96(d, 1H); 7.89(s, 1H); 7.97-8.02(m, 4H); 8.17-8.18(m, 1H); 16.02(s, 1H, exchange).

Mass spectrum (ESI +): m/z 372 (MH)⁺，100％).

Example 149

(4-chloro-3-trifluoromethylphenyl) - (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -methanone

Example 149A-1- (4-chloro-3-trifluoromethylphenyl) -ethanol

4-chloro-3-trifluoromethylbenzaldehyde (6.19g, 29.7mmol) was dissolved in 124mL under a nitrogen atmosphere

In THF. The reaction medium was cooled to-78 ℃ and MeMgBr (13mL, 3M/Et) was added dropwise₂O, 38.6mmol), stirred at this low temperature for a further 2 hours, finally by addition of 60mL of saturated NH₄And (4) neutralizing with a Cl solution. The reaction medium is extracted twice with ethyl acetate. The organic phases are combined, washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by means of a 120g silica column (92mL/min, gradient from 0% to 35% ethyl acetate/heptane over 40 min) so as to obtain the compound149A(5.71g，62％)。

HPLC：RT＝5.71min，98％(colonne XBridge).

¹H NMR，dmso-d₆(ppm): 1.33(d, 3H); 4.81 (quintuple, 1H); 5.46(d, 1H, exchange); 7.60-7.69(m, 2H); 7.81(s, 1H).

Example 149B-1- (4-chloro-3-trifluoromethylphenyl) -ethanone

The compound149A(2.62g, 11.7mmol) was dissolved in 53mL of DCM containing 3.8g of diatomaceous earth. PCC (3.77g, 17.5mmol) is added at room temperature, and the reaction medium is filtered after stirring overnight at room temperature. The filtrate was concentrated under reduced pressure. The residue thus obtained was purified by means of an 80g silica column (32mL/min, gradient from 0% to 30% ethyl acetate/heptane over 26 min) so as to obtain the compound149B(2.27g，87％)。

HPLC：RT＝5.84min，97％(colonne XBridge).

¹H NMR，dmso-d₆，(ppm)：2.65(s，3H)；7.92(d，1H)；8.22-8.27(m，2H).

Example 149C-2-bromo-1- (4-chloro-3-trifluoromethylphenyl) -ethanone

According to the use for preparing compounds144AFrom a compound of149BSynthesis of compounds149CThe yield thereof was found to be 66%.

HPLC：RT＝6.18min，89％(colonne XBridge).

¹H NMR，dmso-d₆，(ppm)：5.05(s，2H)；7.96(d，1H)；8.28(d，1H)；8.34(s，1H).

Example 149- (4-chloro-3-trifluoromethylphenyl) - (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -methanones

According to the use for preparing compounds1By the same sequence of steps as for the preparation of the compound149CSynthesis of compounds149The total yield was 20%.

HPLC: RT ═ 6.71min, 99% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.98-8.04(m, 4H); 8.18-8.21(m, 1H); 8.29(d, 1H); 8.40(s, 1H); 14.82(s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 416 (M-H)^-，100％)；418(M-H^-，25％).

Example 150

(7-bromo-4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -naphthalen-2-yl-methanone

Example 150A-4-bromo-2-sulfamoyl-benzoic acid

5-bromo-2-methyl-benzenesulfonamide (2.5g, 9.99mmol) was dissolved in 62mL of soda (5% aqueous solution). The reaction was heated to 100 ℃ and KMnO was added gradually over 15 minutes₄(6.43g, 25 mmol). Heating was continued for 140 minutes. The reaction medium is cooled to room temperature and filtered. The filtrate was adjusted to pH 1.2 with concentrated HCl solution and filtered. The precipitate was rinsed with ethyl acetate. The two phases of the filtrate were separated and the aqueous phase was extracted once with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure in order to obtain the compound150A(1.64g，58％)。

HPLC：RT＝0.29min，99.5％.

¹H NMR，dmso-d₆(ppm): 7.35(s, 2H, exchange); 7.67(d, 1H); 7.91(d, 1H); 8.08(s, 1H); 13.83 (width s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 278 (M-H)^-，100％)；280(M-H^-，87％).

Example 150B-6-bromo-1, 1-dioxo-1, 2-dihydro-2H-benzo [ d]Isothiazol-3-ones

The compound150A(1.59g, 5.56mmol) are dissolved in 6mL of concentrated sulfuric acid at room temperature, the reaction medium is stirred for 3 hours and poured onto ice. The suspension was filtered. The precipitate was rinsed three times with water and subsequently dried under vacuum at 50 ℃ for 24 hours. The compound is obtained as a white solid150B(1.33g，89％)。

HPLC：RT＝3.16min，96％.

¹H NMR，dmso-d₆，(ppm)：7.85(d，1H)；8.08(d，1H)；8.48(s，1H).

Mass Spectrometry (ESI-): m/z 260 (M-H)^-，100％)；262(M-H^-，94％).

Example 150- (7-bromo-4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -naphthalen-2-yl-methanones

According to the use for preparing compounds1By the same sequence of steps as in (A) for the preparation of (B)150BAnd 2-bromo-1- (naphthalen-2-yl) ethanone synthesis of compounds150The total yield was 55%.

HPLC：RT＝6.14min，97％.

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.66(t, 1H); 7.73(t, 1H); 8.04-8.15(m, 5H); 8.19-8.22(m, 2H); 8.65(s, 1H); 15.38(s, 1H, exchange).

Mass spectrum (ESI +): m/z 444 (MH)⁺，100％)；446(MH⁺，99％).

Example 151

(7-chloro-4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -naphthalen-2-yl-methanone

Example 151A-6-chloro-1, 1-dioxo-1, 2-dihydro-2H-benzo [ d]Isothiazol-3-ones

Methyl 2-amino-4-chlorobenzoate (5g, 26.9mmol) was heated in 18mL HCl (20% aq) until complete dissolution, then cooled to 0 ℃. NaNO is dripped₂(1.85g, 26.9mmol) of 4.5mL of aqueous solution while maintaining the temperature between 2 ℃ and 6 ℃. The reaction medium is subsequently stirred at room temperature for 1 hour. In a second flask, about 15g SO₂The gas was flooded with 22mL of acetic acid and 2.3mL of water at 0 ℃. CuCl (666mg, 6.7mmol) was then added. The first reaction medium is added to the blue-green solution at a temperature between 1 ℃ and 3 ℃. Observing the change of the gas; after stirring for 45 minutes at low temperature, the cold bath is removed and the reaction medium is subsequently poured into 100g of ice and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated NaHCO₃The solution was washed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was treated with 5mL THF at 0 deg.C and 2.8mL concentrated ammonia solution was added slowly. The cold bath was removed and stirring was continued for 1 hour. The reaction medium is concentrated and saturated NaHCO₃The solution was worked up, washed once with ether and adjusted to pH 1 with concentrated HCl solution. The resulting precipitate was filtered, rinsed with water and dried under reduced pressure at 50 ℃ to obtain the compound151A(896mg，15％)。

HPLC：RT＝3.07min，99％.

¹H NMR，dmso-d₆(ppm): 7.94 (width d, 2H); 8.38(s, 1H).

Mass Spectrometry (ESI-): m/z 216 (M-H)^-，100％)；218(M-H^-，32％).

Example 151- (7-chloro-4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -naphthalen-2-yl-methanones

According to the use for preparing compounds1By the same sequence of steps as in (A) for the preparation of (B)151AAnd 2-bromo-1- (naphthalen-2-yl) ethanone synthesis of compounds151The total yield was 39%.

HPLC：RT＝6.13min，95％.

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.66(t, 1H); 7.74(t, 1H); 8.03-8.16(m, 6H); 8.21(d, 1H); 8.65(s, 1H); 15.41(se, 1H, exchange).

Mass Spectrometry (ESI-): m/z 398 (M-H)^-，100％)；400(M-H^-，32％).

Example 152

(4-hydroxy-2, 7-dimethyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] H, 2] thiazin-3-yl) -naphthalen-2-yl-methanone

Example 152A-2-cyano-5-methyl-benzenesulfonamide

2-amino-4-methylbenzonitrile (2.5g, 18.9mmol) was heated in 12mL HCl (20% aq.) until complete dissolution, then cooled to 0 ℃. NaNO is dripped₂(1.3g, 18.9mmol) of 3.2mL of aqueous solution while maintaining the temperature between 2 ℃ and 6 ℃. The reaction medium is subsequently stirred at room temperature for 1 hour. In a second flask, about 15.7g SO₂The gas was flooded with 15mL of acetic acid and 1.6mL of water at 0 ℃. CuCl (468mg, 4.7mmol) was then added. The first reaction medium is added to the blue-green solution at a temperature between 1 ℃ and 3 ℃. Observing the change of the gas; after stirring for 45 minutes at low temperature the cold bath was removed and the reaction mixture was subsequently poured into 70g of ice and extracted three times with a 20% methanol/DCM mixture. The organic phases were combined and washed with saturated NaHCO₃The solution was washed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was treated with 5mL THF at 0 deg.C and 2.8mL concentrated ammonia solution was added slowly. The cold bath was removed and stirring was continued for 1 hour. The reaction medium is concentrated and saturated NaHCO₃The solution was worked up, washed once with ether and adjusted to pH 1 with concentrated HCl solution. The resulting precipitate was filtered, rinsed with water and dried under reduced pressure at 50 ℃ to obtain the compound152A(800mg，21％)。

HPLC：RT＝3.67min，99％(colonne XBridge).

¹H NMR，dmso-d₆，(ppm)：7.61(d，1H)；7.77(s，1H)；799(d, 1H); 8.77 (width s, 2H).

Mass spectrum (ESI +): m/z 197 (MH)⁺，100％).

Example 152B-4-methyl-2-aminosulfonylbenzoic acid

The compound152A(620mg, 3.15mmol) was dissolved in 7.5mL KOH (30% aq) and 530. mu.l hydrogen peroxide (30% aq). The reaction medium is heated to reflux for 4 hours, cooled to room temperature, adjusted to pH 1 with concentrated HCl solution and extracted three times with a 20% methanol/DCM mixture. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure in order to obtain the compound152B(428g，60％)。

HPLC：RT＝4.11min，95％(colonne XBridge).

¹H NMR，dmso-d₆(ppm): 2.41(s, 3H); 7.19 (width s, 2H, exchange); 7.48(d, 1H); 7.65(d, 1H); 7.77(s, 1H); 12.5-14.5 (width s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 214 (M-H)^-，100％).

Example 152C-6-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ d]Isothiazol-3-ones

The compound152B(428mg, 1.94mmol) was dissolved in 3mL of concentrated sulfuric acid at room temperature. The reaction mixture was stirred for 2 hours, poured onto ice and filtered. The precipitate was rinsed thoroughly with water and dried to obtain the compound as a pink solid152C(359mg，93％)。

HPLC: RT 4.00min, 96% (XBridge column).

¹H NMR，dmso-d₆，(ppm)：7.74(d，1H)；7.89(d，1H)；8.00(s，1H).

Mass Spectrometry (ESI-): m/z 196 (M-H)^-，100％).

Example 152- (4-hydroxy-2, 7-dimethyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -naphthalen-2-yl-methanones

According to the use for preparing compounds1By the same sequence of steps as in (A) for the preparation of (B)152CAnd 2-bromo-1- (naphthalen-2-yl) ethanone synthesis of compounds152The total yield thereof was 21%.

HPLC: RT 6.87min, 98% (XBridge column).

¹H NMR，dmso-d₆(ppm): 2.55(s, 3H); 2.64(s, 3H); 7.66(t, 1H); 7.72(t, 1H); 7.80(d, 1H); 7.84(s, 1H); 8.05(d, 1H); 8.11-8.11(m, 4H); 8.67(s, 1H); 15.75(s, 1H, exchange).

Mass spectrum (APCI +): m/z 380 (MH)⁺，24％).

Example 153

Biphenyl-3-yl- (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -methanone

Example 153-biphenyl-3-yl- (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -methanones

In an inert atmosphere, the compound142(200mg, 0.5mmol) was dissolved in 1.1mL of acetone and 1.2mL of water containing phenylboronic acid (68mg, 0.55mmol), potassium carbonate (175mg, 1.27mmol) and palladium acetate (5mg, 0.02 mmol). The reaction mixture was heated to 85 ℃ for 1 hour 30 minutes and then returned to room temperature, diluted with water and extracted with DCMTaking three times. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by means of a 12g silica column, so as to obtain a compound153(141mg，68％)。

HPLC：RT＝7.07min，96％(colonneXBridge).

¹H NMR，dmso-d₆(ppm): 2.68(s, 3H); 7.44(t, 1H); 7.53(t, 2H); 7.69-7.76(m, 3H); 7.97-8.04(m, 5H); 8.21 (width s, 1H); 8.31(s, 1H); 15.36 (width s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 390 (M-H)^-，100％).

Examples 154 to 169

According to the use for preparing compounds153By the same method as in (1), from compounds142And various boric acid synthesis compounds154To169。

*¹H NMR，dmso-d₆Examples of the invention154: 2.68(s, 3H); 7.35-7.41(m, 2H); 7.47-7.52(m, 1H); 7.62(t, 1H); 7.75(t, 1H); 7.89(d, 1H); 7.99-8.01(m, 3H); 8.08(d, 1H); 8.21-8.22(m, 1H); 8.26(s, 1H); 15.41 (Width s, exchange, 1H.) example155: 2.67(s, 3H); 7.28(t, 1H); 7.55-7.61(m, 3H); 7.74(t, 1H); 8.00-8.06(m, 5H); 8.21-8.23(m, 1H); 8.32(s, 1H); 15.26 (width s, exchange,1H) examples of the invention156: 2.67(s, 3H); 7.37(t, 2H); 7.72(t, 1H); 7.77-7.80(m, 2H); 7.99-8.05(m, 5H); 8.20-8.23(m, 1H); 8.27(s, 1H); 15.32 (width s, exchange, 1H.) examples157: 2.68(s, 3H); 7.45-7.50(m, 3H); 7.63-7.65(m, 1H); 7.71-7.74(m, 2H); 7.97-7.99(m, 3H); 8.03(d, 1H); 8.15(s, 1H); 8.19-8.20(m, 1H); 15.41 (width s, exchange, 1H).158: 2.67(s, 3H); 7.51(d, 1H); 7.57(t, 1H); 7.72-7.76(m, 2H); 7.81(d, 1H); 7.98-8.07(m, 5H); 8.21-8.23(m, 1H); 8.31(s, 1H); 15.26 (Width s, exchange, 1H.) example159: 2.67(s, 3H); 7.59(d, 2H); 7.72-7.78(m, 3H); 7.99-8.02(m, 4H); 8.06(d, 1H); 8.20-8.23(m, 1H); 8.28(s, 1H); 15.30 (Width s, exchange, 1H.) examples160: 2.32(s, 3H); 2.68(s, 3H); 7.27-7.38(m, 4H); 7.67-7.73(m, 2H); 7.98-8.04(m, 5H); 8.20-8.22(m, 1H); 15.45 (width s, exchange, 1H.) examples161: 2.41(s, 3H); 2.67(s, 3H); 7.25(d, 1H); 7.41(t, 1H); 7.53(d, 1H); 7.56(s, 1H); 7.71(t, 1H); 7.98-8.03(m, 5H); 8.21-8.23(m, 1H); 8.32(s, 1H); 15.35 (width s, 1H, exchange). EXAMPLE162: 2.37(s, 3H); 2.67(s, 3H); 7.34(d, 2H); 7.63(d, 2H); 7.70(t, 1H); 7.97-8.01(m, 5H); 8.20-8.21(m, 1H); 8.30(s, 1H); 15.37 (width s, 1H, exchange)163: 2.70(s, 3H); 3.83(s, 3H); 7.09(t, 1H); 7.18(d, 1H); 7.35-7.44(m, 2H); 7.67(t, 1H); 7.79(d, 1H); 7.97-8.01(m, 4H); 8.19-8.23(m, 1H); 8.29(s, 1H); 15.58 (width s, 1H, exchange). EXAMPLE164: 2.68(s, 3H); 3.86(s, 3H); 7.00(dd, 1H); 7.27(s, 1H); 7.31(d, 1H); 7.44(t, 1H); 7.72(t, 1H); 7.98-8.03(m, 5H); 8.19-8.24(m, 1H); 8.37(s, 1H); 15.32 (width s, 1H, exchange). EXAMPLE165: 2.67(s, 3H); 3.82(s, 3H); 7.09(d, 2H); 7.66-7.71(m, 3H); 7.94-8.02(m, 5H); 8.19-8.23(m, 1H); 8.28(s, 1H); 15.38 (width s, 1H, exchange)166: 2.66(s, 3H); 7.74-7.83(m, 3H); 7.97-8.12(m, 7H); 8.19-8.24(m, 1H); 8.37(s, 1H); 15.22 (width s, 1H, exchange). EXAMPLE167：2.68(s，3H)；7.78(t，1H)；7.89(d, 2H); 7.95-8.02(m, 5H); 8.08-8.13(m, 2H); 8.19-8.24(m, 1H); 8.34(s, 1H); 15.27 (width s, 1H, exchange). EXAMPLE168: 2.67(s, 3H); 7.73(d, 1H); 7.78(d, 1H); 7.91(d, 1H); 8.00 (width s, 3H); 8.07-8.10(m, 3H); 8.19-8.25(m, 2H); 8.32(s, 1H); 15.23 (width s, 1H, exchange). EXAMPLE169: 2.67(s, 3H); 7.78(t, 1H); 7.94-8.03(m, 7H); 8.08-8.12(m, 2H); 8.19-8.23(m, 1H); 8.33(s, 1H); 15.23 (width s, 1H, exchange).

XBridge chromatography column

Example 170

(4-hydroxy-7-methanesulfonyl-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) -naphthalen-2-yl-methanone

Example 170- (4-hydroxy-7-methanesulfonyl-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) -naphthalen-2-yl-methanones

According to the use for preparing compounds17The same sequence of steps of (1), synthesis of a compound from 5-methanesulfonyl-2-methyl-benzenesulfonyl chloride170The total yield was 7%.

HPLC：RT＝5.43min，97％.

¹H NMR，dmso-d₆(ppm): 2.71(s, 3H); 3.47(s, 3H); 7.67(t, 1H); 7.73(t, 1H); 8.05-8.15(m, 4H); 7.42-8.49(m, 3H); 8.67(s, 1H); 14.76(se, 1H, exchange).

Mass spectrum (ESI +): m/z 444 (MH)⁺，100％).

Example 171

(4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) - (1-phenylcyclopropyl) -methanone

Example 171A-1- (1-phenylcyclopropyl) -ethanone

According to the use for preparing compounds147BBy the same procedure as in (1-phenyl-cyclopropanecarbonitrile)171AThe yield thereof was found to be 40%.

HPLC: RT 4.30min, 96% (XBridge column).

¹H NMR，dmso-d₆，(ppm)：1.15(dd，2H)；1.47(dd，1H)；1.92(s，3H)；7.23-7.40(m，5H).

Mass spectrum (ESI +): m/z 161 (MH)⁺，100％).

Example 171- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) - (1-phenylcyclopropyl) -methanones

According to the use for preparing compounds144By the same sequence of steps as in (A) for the preparation of (B)171ASynthesis of compounds171The total yield was 6%.

HPLC: RT ═ 6.40min, 96% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 1.38-1.41(m, 2H); 1.65-1.68(m, 2H); 2.46(s, 3H); 7.25-7.37(m, 5H); 7.78-7.83(m, 1H); 7.86-7.91(m, 2H); 8.06-8.08(m, 1H); 15.31(s, 1H, exchange).

Mass spectrum (ESI +): m/z 356 (MH)⁺，100％).

Example 172

1- [3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -phenyl ] -ethanone

Example 172-1- [3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ]][1，2]Thiazine-3-carbonyl) -phenyl]-ethanones

According to the use for preparing compounds144The same sequence of steps of (1) from 1- (3-acetylphenyl) -ethanone172The total yield thereof was 21%.

HPLC: RT ═ 6.25min, 97% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 2.64(s, 3H); 2.66(s, 3H); 7.79(t, 1H); 8.00 (width s, 3H); 8.15-8.35(m, 3H); 8.58(s, 1H); 15.21 (width s, 1H, exchange).

Mass Spectrometry (ESI-): m/z 356 (M-H)^-，100％).

Example 173

(4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) - [3- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -phenyl ] -methanone

Example 173A-1- [3- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -phenyl]-ethanones

1- (3-Acetylphenyl) ethanone (2.5g, 15.4mmol) was dissolved in a solution containing TMS-CF at 0 ℃ under a nitrogen atmosphere₃(2.7mL, 18.4mmol) in 120mL THF. TBAF (1M/THF, 18.4mL, 18.4mmol) was added over 20 minutes using a syringe pump. The cold bath was removed and the reaction medium was stirred for a further 18 hours, then with saturated NaHCO₃The solution was neutralized and finally extracted three times with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained is purified over silica (ethyl acetate/heptane gradient from 0% to 50% in 20 min) in order to obtain a partially purified compound173A(2.87 g). The compound was used as such in the next step.

Example 173B-2-bromo-1- [3- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -phenyl]-ethanones

According to the use for preparing compounds144AFrom a compound of173ASynthesis of compounds173BThe yield thereof was found to be 57%.

HPLC: RT 5.50min, 74% (XBridge column).

¹H NMR，dmso-d₆(ppm): 1.73(s, 3H); 4.96(s, 2H); 6.81 (width s, 1H, exchange); 7.60(t, 1H); 7.89(d, 1H); 8.03(d, 1H); 8.17(s, 1H).

Example 173- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) - [3- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -phenyl]-methanones

According to the use for preparing compounds1By the same sequence of steps as for the preparation of the compound173BSynthesis of compounds173The total yield was 52%.

HPLC: RT 6.05min, 95% (XBridge column).

¹H NMR，dmso-d₆(ppm): 1.76(s, 3H); 2.61(s, 3H); 6.84(s, 1H, exchange); 7.67(t, 1H); 7.90-8.05(m, 5H); 8.17-8.23(m, 1H); 8.36(s, 1H); 15.47 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 445 (MNH)₄ ⁺，100％).

Example 174

(4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) - [3- (2, 2, 2-trifluoro-1-hydroxy-ethyl) -phenyl ] -methanone

Example 174A-1- [3- (2, 2, 2-trifluoro-1-trimethylsiloxy-ethyl) -phenyl]-ethanones

3-Acetylbenzaldehyde (1.27g, 8.57mmol) was dissolved in a solution containing potassium carbonate (59mg, 0.42mmol) and TMS-CF in a nitrogen atmosphere₃(1.52mL, 10.3mmol) in 30mL DMF. The reaction mixture was stirred at room temperature for 30 minutes, followed by 1mL of saturated NH₄The Cl solution was neutralized and concentrated under reduced pressure. The residue was treated with ethyl acetate and washed once with HCl (1N aqueous solution), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a partially purified compound174A(2.55 g). The compound was used as such in the next step.

HPLC: RT ═ 5.15min, 42% (OH) and 6.91min, 40% (OTMS) (XBridge column, shaft deprotected).

¹HNMR，dmso-d₆，(ppm)：0.09(s，9H)；2.60(s，3H)；5.60(q，1H)；7.60(t，1H)；7.76(d，1H)；8.02(d，1H)；8.08(s，1H).

Mass spectrum (ESI +): m/z 291 (MH)⁺，100％).

Example 174B-2-bromo-1- [3- (2, 2, 2-trifluoro-1-hydroxy-ethyl) -phenyl]-ethanones

According to the use for preparing compounds144AFrom a compound of174ASynthesis of compounds174BThe yield thereof was found to be 60%.

HPLC: RT 5.23min, 83% (XBridge column).

¹H NMR，dmso-d₆(ppm): 4.93(s, 2H); 5.32(q, 1H); 7.03 (width s, 1H, exchange); 7.61(t, 1H); 7.81(d, 1H); 8.05(d, 1H); 8.11(s, 1H).

Example 174- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e)][1，2]Thiazin-3-yl) - [3- (2, 2, 2-trifluoro-1-hydroxy-ethyl) -phenyl]-methanones

According to the use for preparing compounds1By the same sequence of steps as for the preparation of the compound174BSynthesis of compounds174The total yield was 33%.

HPLC: RT 5.92min, 92% (XBridge column).

¹H NMR，dmso-d₆(ppm): 2.60(s, 3H); 5.32 (width s, 1H); 7.05(d, 1H, exchange); 7.67(t, 1H); 7.80(d, 1H); 7.98 (width s, 3H); 8.08(d, 1H); 8.20 (width s, 2H); 15.45 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 431 (MNH)₄ ⁺，100％).

Example 175

3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -benzoic acid

Example 175-3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ]][1，2]Thiazine-3-carbonyl) -benzoic acid

The compound143(100mg, 0.29mmol) was dissolved in 1mL KOH (30% in water) containing 330. mu.l ethanol, followed by heating to 70 ℃ for 18 hours. The reaction medium is diluted with 10mL of water, washed twice with diethyl ether, adjusted to pH 2 with HCl (6N aqueous solution) and finally extracted three times with 20% methanol in DCM. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to obtain the compound as a yellow solid175(99mg，93％)。

HPLC: RT 5.49min, 98% (XBridge column).

¹H NMR，dmso-d₆(ppm): 2.64(s, 3H); 7.77(t, 1H); 7.99-8.00(m, 3H); 8.20-8.24(m, 2H); 8.28(d, 1H); 8.61(s, 1H); 13.33(s, exchange, 1H); 15.32(s, exchange, 1H).

Mass Spectrometry (ESI-): m/z 358 (M-H)^-，100％).

Example 176

3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -N-methyl-benzamide

Example 176-3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ]][1，2]Thiazine-3-carbonyl) -N-methyl-benzamides

In an inert atmosphere, the compound175(150mg, 0.41mmol) was dissolved in a solution containing (3-dimethylaminopropyl) -ethyl-carbodiimide hydrochloride (120mg, 0.62mmol), 3-hydroxy-3H-benzo [ d ]][1，2，3]Triazin-4-one (102mg, 0.62mmol) and iPr₂Net (162mg, 1.25mmol) in 3mL DMF followed by stirring at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure, diluted with 20mL of DCM and washed twice with HCl (1N aqueous solution). The aqueous phases were combined and extracted with DCM. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified over a 12g silica column (12mL/min, acetone/DCM gradient from 0% to 25% in 20 min) to obtain the compound as a yellow solid176(101mg，64％)。

HPLC: RT ═ 5.21min, 97% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 2.63(s, 3H); 2.82(d, 3H); 7.72(t, 1H), 7.99(d, 3H); 8.10(d, 1H); 8.20-8.22(m, 2H); 8.42(s, 1H); 8.66(d, 1H); 15.35 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 373 (MH)⁺，100％).

Examples 177 to 183

According to the use for preparing compounds176From the same step of175And various amines177To183。

*¹H NMR，dmso-d₆Examples of the invention177: 2.65(s, 3H); 2.98(s, 3H); 3.03(s, 3H); 7.68-7.75(m, 2H); 7.99-8.07(m, 4H); 8.08(d, 1H); 8.20-8.21(d, 1H); 15.28 (width s, exchange, 1H.) examples178: 1.15(t, 3H); 2.63(s, 3H); 3.29-3.36(m, 2H + H2O); 7.71(t, 1H); 7.99-8.00(m, 3H); 8.12(d, 1H); 8.21-8.22(m, 2H); 8.42(s, 1H); 8.68(t, 1H); 15.36 (Width s, exchange, 1H.) example179: 1.09-1.23(m, 6H); 2.64(s, 3H); 3.24-3.47(m, 4H + H2O); 7.66-7.72(m, 2H); 7.95-8.08(m, 5H); 8.20-8.21(m, 1H); 15.28 (width s, exchange, 1H.) examples180: 0.71-0.75(m, 2H); 0.8(m, 2H); 2.63(s, 3H); 2.86-2.91(m, 1H); 7.70(t, 1H); 7.99-8.00(m, 3H); 8.09(d, 1H); 8.20-5.21(m, 2H); 8.40(s, 1H); 8.66(d, 1H); 15.34 (Width s, exchange, 1H.) example181: 0.45-0.47(m, 2H); 0.6(m, 2H); 1.06(m, 1H); 2.64(s, 3H); 3.18(t, 2H); 7.72(t, 1H); 7.99-8.00(m, 3H); 8.13(d, 1H); 8.21(m, 2H); 8.43(s, 1H); 8.78(t, 1H); 15.35 (Width s, exchange, 1H.) examples182: 2.66(s, 3H); 7.13(t, 1H); 7.38(t, 2H); 7.78-7.81(m, 3H), 8.00(d, 3H); 8.21-8.28(m, 3H); 8.52(s, 1H); 10.47(s, 1H); 15.33 (Width s, exchange, 1H.) examples183: 2.63(s, 3H); 4.52(d, 2H); 7.25-7.28(m, 1H); 7.32-7.36(m, 4H); 7.73(t, 1H); 8.00(d, 3H); 8.17-8.25(m, 3H); 8.49(s, 1H); 9.26-9.27(m, 1H); 15.34 (width s, exchange, 1H).

XBridge chromatography column

Example 184

3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -benzamide

Example 184-3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ]][1，2]Thiazine-3-carbonyl) -benzamides

The compound175(150mg, 0.42mmol) was dissolved in 3mL THF containing PyBOP (239mg, 0.46mmol), aqueous ammonia (152. mu.L, 1.25mmol) and DIEA (80. mu.L, 0.46mmol) and stirred at room temperature for 4 h. The reaction medium is diluted with 20mL of DCM and washed with HCl (1N aqueous solution). The aqueous phase was extracted four times with DCM. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to obtain the compound as a yellow solid184(71mg，46％)。

HPLC: RT ═ 5.06min, 97.4% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 2.63(s, 3H); 7.57(s, 1H); 7.71(t, 1H); 7.99(d, 3H); 8.14-8.23(m, 4H); 8.46(s, 1H); 15.36 (width s, exchange, 1H).

Mass spectrum (ESI +): m/z 359 (MH)⁺，100％).

Example 185

3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -benzoic acid ethyl ester

Example 185-3- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazine-3-carbonyl) -benzoic acid ethyl ester

The compound175(150mg, 0.42mmol) was dissolved in 6mL of ethanol containing pTsOH (8mg, 0.04mmol)And stirred under reflux for 18 hours. The reaction medium is concentrated under reduced pressure. The residue thus obtained was purified over a 12g silica column (12mL/min, DCM) to obtain the compound as a yellow solid185(138mg，84％)。

HPLC: RT ═ 6.28min, 95.8% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 1.36(t, 3H); 2.64(s, 3H); 4.37(q, 2H); 7.79(t, 1H); 8.00(d, 3H); 8.20-8.30(m, 3H); 8.65(s, 1H), 15.23 (wide s, exchange, 1H).

Mass spectrum (ESI +): m/z 405 (MH)⁺，100％).

Example 186

(4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) - (3-pyridin-3-yl-phenyl) -methanone

Example 186- (4-hydroxy-2-methyl-1, 1-dioxo-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) - (3-pyridin-3-yl-phenyl) -methanone

In an inert atmosphere, the compound142(200mg, 0.5mmol) was dissolved in 1.5mL 1, 4-dioxane containing pyridin-3-ylboronic acid (104mg, 0.76mmol), potassium phosphate (1.27mol/l, 679. mu.l, 0.86mmol), tris (dibenzylideneacetone) dipalladium (23mg, 0.025mmol) and tricyclohexylphosphine (21mg, 0.076 mmol). The reaction medium is heated to 100 ℃ and, after 18 hours, brought to room temperature, diluted with DCM and saturated NH₄And (5) washing with a Cl solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by means of a 12g silica column (16mL/min, methanol gradient from 0% to 5% in 7 min) to obtain the compound186(128mg，62％)。

HPLC: RT ═ 5.07min, 97.5% (XBridge chromatography column).

¹H NMR，dmso-d₆(ppm): 2.67(s, 3H); 7.77-7.82(m, 3H); 7.98-8.01(m, 3H); 8.11-8.15(m, 2H); 8.22(dd, 1H); 8.39(s, 1H); 8.71(d, 2H); 15.20 (width s, 1H, exchange).

Mass spectrum (ESI +): m/z 393 (MH)⁺，100％).

Examples 187 to 195

According to the use for preparing compounds186By the same method as in (1), from compounds144And various boric acid synthesis compounds187To195。

*¹H NMR，dmso-d₆Examples of the invention187: 2.67(s, 3H); 7.77-7.82(m, 3H); 7.98-8.01(m, 3H); 8.11-8.15(m, 2H); 8.22(dd, 1H); 8.39(s, 1H); 8.71(d, 2H); 15.20 (width s, 1H, exchange). EXAMPLE188: 2.54(s, 3H); 2.67(s, 3H); 7.41(d, 1H); 7.75(t, 1H); 7.98-8.07(m, 6H); 8.19-8.23(m, 1H); 8.31(s, 1H); 8.82(s, 1H); 15.28 (width s, 1H, exchange). EXAMPLE189: 2.40(s, 3H); 2.97(s, 3H); 7.76(t, 1H); 7.98-8.09(m, 6H); 8.19-8.24(m, 1H); 8.32(s, 1H); 8.48(s, 1H); 8.76(s, 1H); 15.25 (width s, 1H, exchange)Examples of the embodiments190: 2.35(s, 3H); 2.68(s, 3H); 7.42(d, 1H); 7.76(d, 2H); 7.97-8.07(m, 5H); 8.19-8.23(m, 1H); 8.46(s, 1H); 8.49(d, 1H); 15.35 (width s, 1H, exchange). EXAMPLE191：(CDCl₃)2.58(s, 3H); 2.74(s, 3H); 7.24(dd, 1H); 7.51-7.64(m, 3H); 7.78-7.84(m, 2H); 7.91-7.96(m, 1H); 8.10(s, 1H); 8.19-8.23(m, 2H); 8.56(dd, 1H); 15.75(s, 1H, exchange.) example192: 2.70(s, 3H); 3.93(s, 3H); 7.24(d, 1H); 7.69(t, 1H); 7.82(d, 1H); 7.96-8.00(m, 4H); 8.17-8.21(m, 1H); 8.27(s, 1H); 8.45(s, 1H); 8.51(d, 1H); 15.48 (width s, 1H, exchange)193: 2.67(s, 3H); 7.37(dd, 1H); 7.77(t, 1H); 8.00 (width s, 3H); 8.04-8.11(m, 2H); 8.19-8.23(m, 1H); 8.29(s, 1H); 8.32-8.39(td, 1H); 8.32(s, 1H); 15.24 (width s, 1H, exchange). EXAMPLE194: 2.70(s, 3H); 3.95(s, 3H); 7.16(dd, 1H); 7.70(t, 1H); 7.82-7.89(m, 2H); 7.98-8.03(m, 4H); 8.17-8.24(m, 2H); 8.37(s, 1H); 15.53 (width s, 1H, exchange). EXAMPLE195: 2.67(s, 3H); 3.92(s, 3H); 6.98(d, 1H); 7.73(t, 1H); 7.99-8.05(m, 5H); 8.09(dd, 1H); 8.21 (width s, 1H); 8.28(s, 1H); 8.55(s, 1H); 15.30 (width s, 1H, exchange).

XBridge chromatography column

Examples 196 and 197

According to the use for preparing compounds1The same method as that of (1) is to synthesize the compound by the saccharin and the 2-bromo-1- (3-chlorphenyl) ethanone and the 2-bromo-1- (3-fluorophenyl) ethanone respectively196And197。

¹three-step total yield

*¹H NMR，dmso-d₆Examples of the invention196: 2.66(s, 3H); 7.67(t, 1H); 7.78(d, 1H); 7.99(s, 5H); 8.15 (width s, 1H); 15.07 (Width s, 1H, exchange). EXAMPLE197: 2.65(s, 3H); 7.58(t, 1H); 7.70(dd, 1H); 7.76(d, 1H); 7.90(d, 1H); 7.99 (width s, 3H); 8.20 (width s, 1H); 15.15 (width s, 1H, exchange).

XBridge chromatography column

The derivatives of the invention are selective inhibitors of 11-HSD1 relative to 11-HSD2, as demonstrated by the model results set forth below:

1) inhibitor compound treatment results in the enzymatic activity of 11 β -HSD1 in human liver microsomes (percent inhibition).

Enzymatic assays were performed based on the conversion of corticosterone to cortisol by 11 β -HSD 1. The enzymatic reaction was initiated by adding 1. mu.g of human liver microsomes (Xenotech) to wells (half volume 96 well plate, reaction volume 50. mu.L) containing 20mM Tris buffer (pH 7.4) containing 160nM corticosterone, 5mM EDTA, 200. mu.M NADPH, and inhibitor compound or vehicle (1% DMSO). Calibration curves for cortisol of known concentration were also generated under the same experimental conditions. The plate was incubated at 37 ℃ for 2 hours (enzyme phase). By adding 25. mu.L of coupled deuterated cortisol (conjugate cortisol-d2) and 25. mu.L Eu to each well³⁺The anti-cortisol antibody labelled with cryptate stopped the enzymatic reaction. After 2 hours incubation at room temperature, the cortisol produced can be determined by HTRF(CIS bio international, reference 62CO2PEC) quantification (detection phase). By Fusion^TMFluorescence measurements were performed with an alpha reader (Perkin Elmer). The fluorescence of each well was measured at 620nm and 665 nm. The ratio (lambda) can be calculated_665nm/λ_620nm) And a specific FRET signal, thereby determining the percent inhibition of each concentration of inhibitor compound being evaluatedAnd (4) rate.

Reference (poster):

IC₅₀ determination of Carbenoxolone and Glycyrrhetinic acid on 11-beta hydroxysteroid dehydrogenase type 1 activity by HTRF：C.Tokuda et al.，Screentech，March 2004，San Diego(USA).

New Cortisol assay for 11-beta hydroxysteroid dehydrogenase type 1 activity using a new HTRFacceptor，d2：M.Amoravain et al.，SBS，12^th Annual Conference，September 2006，Seatle(USA).

2) enzymatic Activity of 11 β -HSD1 in human liver microsomes (percent inhibition or EC) following treatment with inhibitor Compounds₅₀)。

Based on the conversion of [ 2], [ 2] by 11 β -HSD1³H]Conversion of corticosterone to [ 2]³H]Cortisol was detected enzymatically. By adding 20nM [1, 2-³H]Cortisone (specific activity 40-50Ci/mmol, Amersham-GE Healthcare) in 50mM HEPES buffer (pH 7.4), 100mM KCl, 5mM NaCl, 2mM mgCl₂Wells (Optiplate) of 1mM NADPH and inhibitor compound or vehicle (1% DMSO)^TM96-well plates, reaction volume 50 μ L) to 1 μ g (dose normalized to obtain maximum 80% substrate conversion under experimental conditions) of human liver microsomes (Xenotech) to initiate the enzyme reaction. The contents were mixed by low speed centrifugation in a sealed plate and then incubated at 37 ℃ for 2 hours (enzyme stage). By adding 70 μ L of a complex containing 10 μ M18 β glycyrrhetinic acid [10mg/mL yttrium silicate SPA beads (GE Healthcare) pre-incubated with anti-cortisol monoclonal antibodies (ME) related to protein A ] to each well]The enzyme reaction was stopped. The plates were sealed and then incubated at room temperature for 2 hours with slow rotary stirring (detection phase). Separation deviceAfter the heart, the potency of each compound was determined by calculating the percentage inhibition of each concentration of the compound evaluated relative to the standard enzymatic activity (vector 1% DMSO) (EC50 available by SigmaPlot v.11 software, logistic equation with 4 parameters).

Reference to the literature

Development and application of a scintillation proximity assay(SPA)for identification of selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1：S.Mundt et al.，ASSAY and Drug Development Technologies，volume 3，number 4，367-375，2005.

High-throughput screening of 11β-hydroxysteroid dehydrogenase type 1 in scintillation proximity assay format：K.Solly et al.，ASSAY and Drug Development Technologies，volume 3，number 4，377-384，2005.

3) Inhibitor compound treatment results in the enzymatic activity of 11 β -HSD2 in human kidney microsomes (percent inhibition).

Based on the conversion of [ 2], [ 2] by 11 β -HSD21³H]Conversion of cortisol to [ 2]³H]Corticosterone was detected enzymatically. By adding 8nM [1,2, 6, 7-³H]Cortisol (specific activity 70-75Ci/mmol, Amersham-GE Healthcare) in 50mM HEPES buffer (pH 7.4), 100mM KCl, 5mM NaCl, 2mM mgCl₂、1mM NAD⁺And wells (Optiplate) of inhibitor compound or vehicle (1% DMSO)^TM96-well plates, reaction volume 50. mu.L) 0.75. mu.g (dose standardized to obtain a maximum of 80% substrate conversion under experimental conditions) of human kidney microsomes (Xenotech) was added to initiate the enzymatic reaction. The contents were mixed by low speed centrifugation in a sealed plate and then incubated at 37 ℃ for 2 hours (enzyme stage). By adding 70 μ L of a complex containing 10 μ M18 β glycyrrhetinic acid [10mg/mL yttrium silicate SPA beads (GE Healthcare) pre-incubated with anti-cortisol monoclonal antibodies (ME) related to protein A ] to each well]The enzyme reaction was stopped.The plates were sealed and then incubated at room temperature for 2 hours with slow rotary stirring (detection phase). After centrifugation, the measurement was carried out by means of a scintillation counter TopCount NXT (Perkin Elmer). The percent inhibition of each concentration of the compound evaluated can be calculated relative to the standard enzyme activity (vehicle 1% DMSO).

Reference documents:

Development and application of a scintillation proximity assay(SPA)for identification of selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1：S.Mundt et al.，ASSAY and Drug Development Technologies，volume 3，number 4， 367-375，2005.

High-throughput screening of 11β-hydroxysteroid dehydrogenase type 1 in scintillation proximity assay format：K.Solly et al.，ASSAY and Drug Development Technologies，volume 3，number 4，377-384，2005.

as a result:

the following few examples, selected from the compounds of the present invention, illustrate the highly surprising ability of these compounds to selectively inhibit 11 β -HSD1 relative to 11 β -HSD 2:

the object of the present invention is a compound of general formula (I) or one of its stereoisomers or one of its pharmaceutically acceptable salts for use as a medicine.

Pharmaceutical compositions comprising as active principle a compound of general formula (I) or one of its stereoisomers, or one of its pharmaceutically acceptable salts for pharmaceutical use, in association with a pharmaceutically acceptable carrier are also an object of the present invention. The above compositions may take the form of, for example, solids, liquid compositions, emulsions, lotions or creams.

The above pharmaceutical composition comprising as an active ingredient a compound of general formula (I) or one of its stereoisomers or one of its pharmaceutically acceptable salts may be used for inhibiting 11 β -hydroxysteroid dehydrogenase type I (11 β HSD 1).

The above pharmaceutical composition comprising as an active ingredient a compound of the general formula (I) or one of its stereoisomers or one of its pharmaceutically acceptable salts for use in the treatment and prevention of type II diabetes.

The above pharmaceutical composition comprising as an active ingredient a compound of the general formula (I) or one of its stereoisomers or one of its pharmaceutically acceptable salts for use in the treatment and prevention of diseases associated with 11 β -hydroxysteroid dehydrogenase type I (11 β HSD 1); or obesity; or dyslipidemia; or arterial hypertension; or atherosclerosis and clinical conditions caused by, for example, coronary stroke, or cerebrovascular stroke, or arteritis in the lower extremities; or hyperglycemia; or glucose intolerance; or insulin resistance; or hypertriglyceridemia; or hypercholesterolemia; or restenosis, or pancreatitis; or retinopathy; or renal disease; or a neuropathy; or some type of cancer or glaucoma.

The above compositions may be administered in combination with an antidiabetic agent such as a biguanide (e.g., metformin), a different form of insulin, a sulfonylurea (e.g., sulfabutamide, glibornuride, glipizide, gliclazide, glyburide, glimepiride), a meglitinide (e.g., nateglinide, repaglinide, mitiglinide), a PPAR modulator (e.g., pioglitazone), an alpha-glucosidase inhibitor (e.g., acarbose, miglitol, voglibose), a GLP-1 analog (e.g., exenatide, liraglutide), a DPP-4 inhibitor (e.g., sitagliptin, vildagliptin), a starch granule cellulose film analog (e.g., pramlintide).

The above compositions may also be administered in combination with anti-obesity drugs such as, for example, orlistat or sibutramine.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, tablets) or granules can be used. In the above compositions, the active substance according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silicon dioxide under argon flow. The above compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, colorants, coatings (dragees) or varnishes.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin may be used. The above compositions may include substances other than diluents, such as wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

Sterile compositions for non-oral administration are preferably aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters such as ethyl oleate or other suitable organic solvents may be used as solvents or carriers. The above compositions may also comprise adjuvants, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizers. Sterilization can be accomplished in a variety of ways, such as by sterile filtration, by combining the antimicrobial compositions, by irradiation, or by heating. It can also be prepared as a sterile solid composition which can be dissolved in sterile water or any other sterile vehicle for injection at the time of use.

Compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical application may be, for example, creams, lotions, collyrium, mouthwash, nasal drops or aerosols.

The dose depends on the sought effect (therapeutic effect), the tolerance of the treatment and the route of administration employed; the daily dose, preferably oral, preferably for adults is generally between 0.001g and 1g (preferably between 0.005g and 0.75g), with a unit dose of active substance ranging from 0.1mg to 500 mg. Generally, the physician will determine the appropriate dosage depending on the age, weight and all other specific factors of the subject to be treated.

Claims (14)

1. A compound having the general formula (I):

wherein:

R₁represents:

hydrogen; COR (continuous operating reference)₅；CO(CH₂)_mOR₆；

m represents:

1 to 6 of the total weight of the composition,

n represents:

2 to 6 of the total weight of the composition,

R₂represents:

by one or more radicals selected from halogen, C₁-C₆Phenyl substituted with alkyl groups;

-a naphthyl group;

with the following conditions:

-R₂the group is typically attached to the carbonyl group through a carbon atom,

R₃represents:

a methyl group or an ethyl group, and a salt thereof,

R₄or R'₄Identical or different, represents:

hydrogen; halogen;

R₅represents:

C₁-C₆an alkyl group;

R₆represents:

a phenyl group;

with the proviso that said compound is selected from:

(4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone;

(4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (4-methylphenyl) methanone;

(4-hydroxy-2-ethyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone;

(7-fluoro-4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone;

(7-fluoro-4-hydroxy-2-ethyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (naphthalen-2-yl) methanone;

acetic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester;

phenoxyacetic acid 2-methyl-3- (naphthalene-2-carbonyl) -1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-4-yl ester;

(4-hydroxy-2-methyl-1, 1-dioxido-2H-benzo [ e ] [1,2] thiazin-3-yl) (3, 4-dichlorophenyl) methanone;

(3-bromophenyl) - (4-hydroxy-2-methyl-1, 1-dioxido-1, 2-dihydro-2H-benzo [ e ] [1,2] thiazin-3-yl) methanone.

2. A process for the preparation of a compound having the general formula (Ia) corresponding to formula I as claimed in claim 1, wherein R₁Represents a hydrogen atom, characterized by condensing an intermediate of general formula (IV),

wherein R is₂、R₄And R'₄As defined in claim 1, and the formula R₃-intermediates of Y, wherein R₃As defined in claim 1 and Y represents a leaving group.

3. A process for preparing compounds of the general formula (Ib) corresponding to the general formula I as claimed in claim 1, wherein R₁Not a hydrogen atom, characterized in that an intermediate of the general formula (Ia),

wherein R is₂、R₃、R₄And R'₄As defined in claim 1, and the formula R₁-Z intermediates, wherein R₁As defined in claim 1, with the proviso that R₁Is not hydrogen; and Z represents a leaving group.

4. Use of a compound according to claim 1 for the preparation of a medicament for inhibiting 11 β -hydroxysteroid dehydrogenase type I or for the treatment and prevention of type II diabetes.

5. A pharmaceutical composition comprising as active ingredient at least one compound according to claim 1 in combination with a pharmaceutically acceptable carrier as a medicament.

6. Use of a pharmaceutical composition according to claim 5 in the manufacture of a medicament for use as an inhibitor of 11 β -hydroxysteroid dehydrogenase type I.

7. Use of the pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment and prevention of type II diabetes.

8. Use of a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment and prevention of a disease associated with 11 β -hydroxysteroid dehydrogenase type I, hyperglycemia, glucose intolerance, insulin resistance, hypertriglyceridemia, hypercholesterolemia, restenosis, pancreatitis, retinopathy, nephropathy, neuropathy, or glaucoma.

9. Use of a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment and prevention of obesity, dyslipidemia, arterial hypertension, atherosclerosis and clinical conditions caused thereby.

10. The use according to claim 9, wherein the clinical condition caused by atherosclerosis is coronary stroke, cerebrovascular stroke or lower limb arteritis.

11. Use of a pharmaceutical composition according to claim 5 in the manufacture of a medicament for administration in combination with a pharmaceutically acceptable carrier and in combination with an anti-diabetic agent.

12. Use of a pharmaceutical composition according to claim 5 in the manufacture of a medicament for administration in combination with a pharmaceutically acceptable carrier and in combination with an anti-obesity agent.

13. Use according to claim 11, characterized in that the antidiabetic agent is selected from the group consisting of biguanides, different forms of insulin, sulfonylureas, meglitinides, PPAR modulators, α -glucosidase inhibitors, GLP-1 analogues, DPP-4 inhibitors, amyloid-cellulose film analogues.

14. The use according to claim 12, characterized in that the anti-obesity drug is orlistat or sibutramine.