Benzothiazine derivatives, production and use thereof as medical drugs

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

 

The aim of the present invention are derived benzothiazines, the method of obtaining these derivatives, pharmaceutical compositions containing these compounds, and their use as medicaments for the treatment and/or prevention of type 2 diabetes, obesity, dyslipidemia, hypertension and atherosclerosis. These compounds may also find use in the treatment and/or prevention of hyperglycemia, intolerance to glucose, insulin resistance, hypertriglyceridemia, hypercholesterinemia, restenosis, pancreatitis, retinopathy, nephropathy, neuropathies (Reichard et al., N. Engl. J. Med. 1993, 329: 304-309), some types of cancer (Strickler et al., Diabetes Technology &Therapeutics 2001, 3(2): 263-274) or glaucoma (Pascale et al., Ophtalmology 2006, 113(7): 1081-86).

The present invention also relates to combinations of the described compounds and other agents used in the treatment of these pathologies. Indeed, the treatment of many pathologies such as type 2 diabetes, often requires the use of several classes of compounds in order to achieve recommended glycemic and to maintain the balance of glucose (Nathan et al., Diabetes Care 2009 32:193-203). These combinations can also be used in combined treatment of obesity and diabetes type 2 (Grundy et al., Circulation 2005, 112: 2735-2752).

Metabolic syndrome is an early stage the number of the x serious cardiovascular pathologies. It develops as a consequence of insulin resistance and is characterized by visceral obesity (Després et al., Nature 2006 444(14): 881-87), associated with some risk factors, such as intolerance to glucose and some types of dyslipidemia, which may be associated with arterial hypertension (Grundy, Nat. Rev. Drug Discov. 2006, 5: 295-309).

Type 2 diabetes is documented pathology, as glycemic disorders can be explained by three main mechanisms: by failure of function of β-cells of the islets of Langerhans of the pancreas, decrease of glucose utilization in peripheral tissues and excess glucose production in the liver (Monnier et al., Diabetes & Metabolism 2008, 34: 207-216). However, existing methods of treatment can not achieve recommended targets of blood glucose (especially HbA1c) many patients suffering from type 2 diabetes. Therefore, there is always high demand for methods of treatment of this pathology, based on new mechanisms.

Obesity is a disease that affects more and more people around the world. This disease is often associated with an increased risk of developing type 2 diabetes, cardiovascular disease, cerebrovascular stroke, and some types of cancer. Therefore, obesity is a major facto the Ohm risk for pathologies, associated with high morbidity or mortality.

Glucocorticoids (cortisol in humans, corticosterone in rodents) are ubiquitous hormones, which play a dominant role in the regulation of energy metabolism. They induce gluconeogenesis and inhibit insulin secretion by beta cells of the pancreas, as well as peripheral glucose uptake (Dallman ef al., Front Neuroendocrinol. 1993, 14: 303-347).

Recently found that 11β-hydroxysteroid-dehydrogenase (11β-HSD) regulate the level of glucocorticoids in some target tissues (liver, adipose tissue, kidney, brain etc). In humans, this mechanism may cause a local increase in the level of cortisol. The increased levels of cortisol in adipose tissue may lead to an increase in the mass of visceral adipose tissue due to the impact of glucocorticoids on the differentiation of preadipocytes in adipocytes and lipogenesis; in some cases, glucocorticoids induce lipolysis and the harmful effects of free fatty acids in plasma, liver, pancreas, skeletal muscle (lipotoxicity). The increased levels of cortisol in the liver may cause an increase in blood glucose that can lead to the development of type 2 diabetes.

There are two isoforms of 11β-HSD type 1 and type 2. 11β-HSD2 is localized mainly in the kidneys. This enzyme catalyzes p is avramania active glucocorticoids to inactive glucocorticoids (in humans the conversion of cortisol to cortisone) and therefore, essentially involved in the protection of mineralocorticoid receptor (MR) activation by cortisol (Edwars et al., Lancet, 1988, 2: 986-989). Conversely, 11β-HSD1 basically acts like 11-keto-reductase and turns inactive glucocorticoids in active glucocorticoids in the tissues where the enzyme has a high level of expression in liver and adipose tissue). Therefore, inhibition of this enzyme at the level of the liver and adipocytes should be reflected in the reduction of the above-described effects. A number of studies have used simulation obesity and/or diabetes in animals confirmed the involvement of 11β-HSD1 in these diseases. Thus, the level of expression of 11β-HSD1 is increased in diabetic rats Zucker, and this increase correlates with the progression of disease, modeled in these rats (Duplomb et al., Biochem. Biophys. Res. Commun., 2004, 313: 594-599). It is proved that mice with a null mutation in the gene encoding 11β-HSD1 (knockout mice)are resistant to hyperglycemia caused by obesity or stress (Kotelevtsev Y. et al. PNAS 1997, 94: 14924-14929). Conversely, transgenic mice with selective overexpression of 11β-HSD1 in adipose tissue develop visceral obesity, insulin-resistant diabetes, and hyperlipidemia (Masuzika et al., Science, 2001, 294: 2166-2170). Experimental data suggest the benefit of inhibition of 11β-HSD1 as a therapist who achieved target (Wamil et al., Drug Discovery Today, 2007, 12: 504-520).

Compounds of the present invention have the ability to selectively inhibit 11β-HSD1 in comparison with 11β-HSD2, man this should have a beneficial effect on type 2 diabetes, obesity, hyperlipidemia, hypertension, atherosclerosis and all abnormalities that are associated with this, such as coronary thrombosis, cerebrovascular strokes or Takayasu lower extremities (Wilcox et al., Stroke, 2007, 38: 865-873; Wilcox et al., Am. Heart J. 2008, 155:712-7).

These compounds differ from the compounds known in the art, their chemical structure and exceptional biological properties.

The aim of the present invention are derived benzothiazine with the ability to inhibit 11β-HSD1 not only on enzyme level, but also at the cellular level.

Compounds of the present invention are compounds of General Formula (I):

,

where

R1represents a hydrogen atom; C1-C6alkyl; COR5; SO2R5; CO(CH2)mR6; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10;

m has a value from 1 to 6;

n has the t is from 2 to 6;

R2represents phenyl having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, IT, CF3, OCF3, SMe, COMe, CMe(OH)CF3CH(OH)CF3, COOR7, CONR7R11; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenyl, pyridine or a heterocycle other than indole, in the case when R1, R4and R'4represent a hydrogen atom, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN, OH, CF3, OCF3, OMe, SMe; cycloalkyl, unsubstituted or having as substituents OH, CONH2, SO2Me, SO2NH2; C1-C6alkyl aryl or cycloalkyl aryl,

provided that R2always linked through the carbonyl carbon atom, and when R2represents phenyl, Deputy COOR7is never in position 4 relative to the carbonyl;

R3represents methyl or ethyl;

R4and R'4are the same or different and represent a hydrogen atom; a halogen atom; C1-C6alkyl; CN; CF3; OCF3; SMe; OMe; NR7R8; SO2Me;

R5represents a C1-C6alkyl; phenyl, unsubstituted or having as substituents one and more than one group, selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; naphthyl, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; cycloalkyl, unsubstituted or having as substituents CONH2, SO2Me, SO2NH2heteroaryl, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, IT, CF3, OCF3, SMe;

R6represents a hydrogen atom; C1-C6alkyl; phenyl, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; naphthyl or heterocycle, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN, IT, CF3, OCF3, SMe; cycloalkyl, unsubstituted or having as substituents CONH2, SO2Me, SO2NH2;

R7represents a hydrogen atom, a C1-C6alkyl;

R8represents a hydrogen atom, a C1-C6alkyl, phenyl, unsubstituted or having as substituents one or more than one group selected Isotoma halogen, C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; naphthyl or heterocycle, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; cycloalkyl, unsubstituted or having as substituents CONH2, SO2Me, SO2NH2;

R7and R8together with the nitrogen atom to which they are attached, may form a 4-6-membered ring which may contain one or more than one heteroatom selected from N, S or O and may be unsubstituted or may have as substituents one or more than one group selected from C1-C6of alkyl, C1-C6the alkyl aryl or aryl;

R9is a COOMe, COOEt;

R10represents a halogen atom, COOH, COOR7;

R11represents a hydrogen atom, a C1-C6alkyl, C1-C6alkyl cycloalkyl, cycloalkyl, aryl, C1-C6alkyl aryl;

and stereoisomers, salts and solvate of such compounds acceptable for therapeutic use.

In the above definitions all possible combinations of substituents or variables, provided that they give stable compounds; terms used in the definitions have the following meanings.

The term "halogen" refers to the fact fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to saturated or unsaturated, normal or branched aliphatic hydrocarbon chain containing the specified number of carbon atoms.

The term "cycloalkyl" refers to a cyclic or polycyclic hydrocarbon chain containing 3 to 12 carbon atoms. As an example of substituted, cyclohexyl.

The term "aryl" refers to any monocyclic or bicyclic carbon ring that may contain up to 7 ring atoms, where at least one of the rings is an aromatic ring. As an example, phenyl, biphenyl, naphthyl.

The term "heteroaryl" refers to a stable monocycle containing 5-7 atoms, or to a stable Bicycle containing 8-11 atoms, unsaturated, and which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S. as an example, furan, thiophene, pyridine, benzothiophene.

The term "heterocycle" refers to a stable monocycle containing 5-7 atoms, or to a stable Bicycle containing 8-11 atoms which may be saturated or unsaturated and may consist of carbon atoms and 1-4 heteroatoms selected from N, O or S. the Definition of Bicycle also includes monocyclic heterocycles condensed with a benzene ring, except the Ndola, when in Formula I, the radicals R1, R4and R'4represent a hydrogen atom. As an example, furan, pyrrole, thiophene, thiazole, isothiazol, oxadiazole, imidazole, oxazole, isoxazol, pyridine, pyrimidine, hinzelin, quinoline, cinoxacin, benzofuran, benzothiophene, indolin, indolizine, benzothiazole, benzothiazyl, benzopyran, benzoxazole, benzo[1,3]dioxol, benzisoxazol, benzimidazole, chroman, chrome, dihydrobenzofuran, dihydrobenzofuranyl, dihydroisoxazole, isoquinoline, dihydrobenzo[1,4]dioxin, imidazo[1,2-a]pyridine, furo[2,3-C]pyridine, 2,3-dihydro-1H-inden, [1,3]dioxolo[4,5-C]pyridine, pyrrolo[1,2-C]pyrimidine, pyrrolo[1,2-a]pyrimidine, tetrahydronaphthalen, benzo[b][1,4]oxazin.

OR1in the context of the present invention means a complex or a simple ester, where R1represents a C1-C6alkyl, or COR5or CO(CH2)mR6or CO(CH2)mOR6or (CH2)mR6or (CH2)mCONR7R8or (CH2)nNR7R8or (CH2)nOR6or CHR7OR9or (CH2)mR10such as defined above.

Salts of the compounds of the present invention, acceptable for therapeutic use, include the conventional non-toxic salts of the compounds according to the invention, for example salt, obrazovan the e with organic or inorganic acids or with organic or inorganic bases. As an example, salts formed with inorganic acids such as hydrochloric, Hydrobromic, phosphoric, sulfuric acid, and salts formed with organic acids such as acetic, triperoxonane, propionic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluensulfonate, methanesulfonate, stearic, lactic acid. As an example, salts formed with inorganic bases such as sodium carbonate, potassium or calcium hydroxide, and salts formed with organic bases such as lysine or arginine.

These salts can be synthesized from compounds according to the invention contains a basic or acidic group, and the corresponding acids or bases in accordance with standard chemical methods.

The solvate of the compounds of the present invention, acceptable for therapeutic use include standard solvate, for example the solvate formed at the last stage of preparing compounds according to the invention due to the presence of solvents. As an example the solvate formed due to the presence of water or ethanol.

In the scope of the present invention include all stereoisomers including in the e optical isomers of compounds of General Formula (I), as well as their racemic mixture.

In accordance with one of the features of the invention compounds of General Formula (I) are compounds in which

R2represents phenyl having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, or a heterocycle other than indole, in the case when R1, R4and R'4represent a hydrogen atom, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN, OH, CF3, OCF3, OMe, SMe; cycloalkyl, unsubstituted or having as substituents CONH2, SO2Me, SO2NH2,

provided that R2always linked through the carbonyl carbon atom;

R4and R'4are the same or different and represent a hydrogen atom; a halogen atom; C1-C6alkyl; CN; CF3; OCF3; SMe; OMe; NR7R8;

R8represents a hydrogen atom, a C1-C6alkyl, phenyl, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; naphthyl or heterocycle, unsubstituted Il is having as substituents one or more than one group, selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, SMe; cycloalkyl, unsubstituted or having as substituents CONH2, SO2Me, SO2NH2;

R7and R8together with the nitrogen atom to which they are attached, may form a 4-6-membered ring which may contain one or more than one heteroatom selected from N, S or O, and may be unsubstituted or may have as substituents one or more than one group selected from C1-C6the alkyl or aryl,

R1is the same as defined above, or as defined in the description below.

According to one variant embodiment of the invention compounds of General Formula (I) are compounds in which R1represents a hydrogen atom.

According to other variant embodiments of the invention compounds of General Formula (I) are compounds that have OR1is a complex or a simple ester, where R1represents a C1-C6alkyl, or COR5or CO(CH2)mR6or CO(CH2)mOR6or (CH2)mR6or (CH2)mCONR7R8or (CH2)nNR7R8or (CH2)nOR6or CHR7OR9or (CH2)mR10.

According to one the mu variant embodiment of the invention OR 1is an ester, where R1is a COR5or CO(CH2)mR6or(CH2)mOR6.

The aim of the present invention are also compounds of General Formula (I)in which R2represents naphthyl or 1,2,3,4-tetrahydro-naphthalene, or biphenyl, or phenyl pyridine, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, OH, CF3, OCF3, OMe, SMe, or phenyl, having as substituents one or more than one halogen atom, CN, CF3or C1-C6alkyl.

According to one variant embodiment of the invention compounds of General Formula (I) are compounds in which R4and R'4represent a hydrogen atom.

Among the compounds of General Formula (I) according to the present invention a preferred class of compounds consists of compounds of General Formula (I), where R1represents a hydrogen atom and R2represents naphthyl or 1,2,3,4-tetrahydro-naphthalene.

The present invention also relates to compounds of General Formula (I), where OR1is a complex or a simple ester and R2represents naphthyl or 1,2,3,4-tetrahydro-naphthalene.

Another preferred class of compounds of sostavlyayuscyeye General Formula (I), where R1represents a hydrogen atom and R2represents phenyl having as substituents one or more than one halogen atom, CN, CF3or C1-C6alkyl.

Another preferred class of compounds consists of compounds of General Formula (I), where R1represents a hydrogen atom and R2is a biphenyl or phenyl pyridine, unsubstituted or having substituents, such as defined in the description of General Formula (I).

The present invention also relates to compounds of General Formula (I), where OR1is a complex or a simple ester and R2represents phenyl having as substituents one or more than one halogen atom, CN, CF3or C1-C6alkyl.

Another preferred class of compounds consists of compounds of General Formula (I), where OR1is a complex or a simple ester and R2is a biphenyl or phenyl pyridine, unsubstituted or having substituents, such as defined in the description of General Formula (I).

The present invention also relates to the production of compounds of General Formula (I) using the General methods described in schemes of synthesis and, if necessary, supplemented by other standard procedures described in the literature or well-known special is the aliste in the art, or further illustrated in the experimental part.

Figure 1 summarizes the first General method that can be used to obtain compounds of General Formula (Ia). In the General formulas above, R2, R3, R4and R'4are as defined in the foregoing description of General Formula (I), and R1represents a hydrogen atom. X can be a leaving group such as, for example, Cl, Br, I, OSO2CH3, OSO2CF3or O-tosyl. In this case, the reaction involving compounds of General Formula (II) is performed in the presence of inorganic bases, such as NaH, in a polar anhydrous solvent such as THF (tetrahydrofuran) or DMF (N,N-dimethylformamide)at a temperature in the range from -20° to 100°C. the Intermediate compound of General Formula (III) is transformed into an intermediate compound of General Formula (IV) by rearrangement in the presence of a base, such as, for example, MeONa, EtONa, in a polar anhydrous solvent such as Meon or EtOH (possibly mixed with a nonpolar solvent such as toluene)at a temperature in the range from 25° to 100°C. the Intermediate compound of General Formula (IV) is converted into a product of General Formula (Ia) as a result of interaction with R3Y, where Y may represent sobo is a leaving group, such as, for example, Cl, Br, I, OSO2CH3, OSO2CF3or O-tosyl, and R3is the same as defined above. In this case, the conversion of compounds of General Formula (IV) is performed in the presence of inorganic bases, such as NaH, in a polar anhydrous solvent such as THF or DMF, at a temperature in the range from 20° to 100°C.

Scheme 2 shows a General method that can be used to obtain compounds of General Formula (Ib). In General the following formulas, R1, R2, R3, R4and R'4are as defined in the foregoing description of General Formula (I), except that R1is not a hydrogen atom.

The intermediate compound of General Formula (Ia) is converted into a compound of General Formula (Ib) as a result of interaction with R1-Z. When R1represents a C1-C6alkyl, (CH2)mR6, (CH2)mCONR7R8, (CH2)nNR7R8, (CH2)nOR6, CHR7OR9or (CH2)mR10where R6, R7, R8, R9, R10type are as defined in the foregoing description of General Formula (I), except that R10are not acid, and Z is a leaving g the PPU, such as, for example, Cl, Br, I, OSO2CH3, OSO2CF3or O-tosyl, the conversion of the enol General Formula (Ia) can be performed in the presence of organic or inorganic bases, such as, for example, Et3N iPr2NEt, NaH, pyridine, Cs2CO3, K2CO3in a polar anhydrous solvent such as THF, DMF, DMSO (dimethylsulfoxide), acetone, at a temperature in the range from -20° to 140°C using, as catalyst, a salt that can be selected from KI, Bu4NI, LiI, AgBF4, AgClO4Ag2CO3, KF, Bu4NF or CsF, or without the use of such salt. This reaction can also be carried out in a test tube, sealed or closed by a screw cap, at a temperature in the range from 80 to 180°C using heating heat or microwave energy. Z may also be an alcohol. In this case, the conversion of intermediate compounds (Ia) can be carried out using reaction type reaction of Mitsunobu, which can be performed in the presence of diethylazodicarboxylate (DEAD) and triphenylphosphine in a polar anhydrous solvent such as THF, at a temperature in the range from 0 to 60°C. When R1is a COR5, SO2R5or CO(CH2)mR6where R5, R6and m are as defined in precede the eat the description of General Formula (I), Z can represent a chlorine atom. In this case, the conversion of the enol General Formula (Ia) is reduced to the interaction of the acid chloride and sulphonylchloride with alcohol. This interaction can be carried out in the presence of organic or inorganic bases, such as, for example, Et3N iPr2NEt, NaH, pyridine, Cs2CO3, K2CO3in a polar anhydrous solvent such as THF, DMF, DMSO, dichloromethane, at a temperature in the range from -20° to 140°C. When R1is a COR5, CO(CH2)mR6or(CH2)mOR6where R5, R6and m are as defined in the foregoing description of General Formula (I), Z may also represent hydroxyl. In this case, the conversion of the enol General Formula (Ia) is reduced to the interaction of the acid with the alcohol. This interaction can be carried out using methods and techniques well known to the person skilled in the art. Especially preferred is a technique, which involves a condensation reaction in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), 3-hydroxy-1,2,3-benzotriazin-4(3H)-she tertiary amine, such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane, at a temperature in the range of the -15°C to 40°C.

Scheme 3 shows a General method that can be used to obtain compounds of General Formula (Ic), where R1represents (CH2)nNR7R8or (CH2)nOR6and R6, R7, R8n and R2, R3, R4and R'4are as defined in the foregoing description of General Formula (I). The intermediate compound of General Formula (Ia) is transformed into an intermediate compound of General Formula (V) as a result of interaction with a reagent of General Formula X(CH2)nX', where X and X' are the same or different leaving group, such as, for example, Cl, Br, I, OSO2CH3, OSO2CF3or O-tosyl, and n has such a value as defined above.

The interaction of this reagent and enol General Formula (Ia), leading to the intermediate compounds of General Formula (V)may be carried out in the presence of organic or inorganic bases, such as, for example, Et3N iPr2NEt, NaH, pyridine, Cs2CO3, K2CO3in a polar anhydrous solvent such as THF, DMF, DMSO, acetone, at a temperature in the range from -20° to 140°C using, as catalyst, a salt that can be selected from KI, Bu4NI, LiI, AgBF4, AgClO4Ag2CO3,KF, Bu4NF, or CsF, or without the use of such salt. This interaction can also be carried out without solvent using a large excess of reagent X(CH2)nX'. This reaction can also be carried out in a test tube, sealed or closed by a screw cap, at a temperature in the range from 80 to 180°C using heating heat or microwave energy. X or X' may also be an alcohol. In this case, to obtain the intermediate compound (V) can be used with reaction type reaction of Mitsunobu, which can be performed in the presence of diethylazodicarboxylate (DEAD) and triphenylphosphine in a polar anhydrous solvent such as THF, at a temperature in the range from 0 to 60°C.

The intermediate compound of General Formula (V) into a product of General Formula (Ic) as a result of interaction with HNR7R8or HOR6where R6, R7and R8are as defined in the foregoing description of General Formula (I). This transformation can be carried out in the presence of organic or inorganic bases, such as, for example, Et3N iPr2NEt, NaH, pyridine, Cs2CO3, K2CO3in a polar anhydrous solvent such as THF, DMF, DMSO, acetone, at a temperature in the range from -20° to 140°C using, the quality is solid fuel catalyst the solvent which may be selected from KI, Bu4NI, LiI, AgBF4, AgCl4Ag2CO3, KF, Bu4NF or CsF, or without its use. The choice of experimental conditions and reagents necessary for carrying out this reaction, of course, depends on the nature of the substituents R6, R7and R8and executed in accordance with the procedures and techniques well known to the person skilled in the technical field.

Scheme 4 shows a General method that can be used to obtain compounds of General Formula (Id), where R1represents (CH2)mCONR7R8and R7, R8, m and R2, R3, R4and R'4are as defined in the foregoing description of General Formula (I).

The intermediate compound of General Formula (Ia) is transformed into an intermediate compound of General Formula (VI) as a result of interaction with a reagent of General Formula Y - (CH2)mCOOY', where Y is a leaving group such as, for example, Cl, Br, I, OSO2CH3, OSO2CF3or O-tosyl, m has the meaning as defined above, and Y' represents a C1-C4alkyl radical. This transformation can be carried out in the presence of organic or inorganic bases, such as, for example, Et3N iPr 2NEt, NaH, pyridine, Cs2CO3, K2CO3in a polar anhydrous solvent such as THF, DMF, DMSO, acetone, at a temperature in the range from -20° to 140°C, using, as catalyst, a salt that can be selected from KI, Bu4NI, LiI, AgBF4, AgClO4Ag2CO3, KF, Bu4NF or CsF, or without the use of such salt. This reaction can also be carried out in a test tube, sealed or closed by a screw cap, at a temperature in the range from 80 to 180°C using heating heat or microwave energy. The intermediate compound of General Formula (VI) is transformed into an intermediate compound of General Formula (VII) as a result of interaction with an inorganic base, such as NaOH, KOH, LiOH, in a polar solvent such as methanol, ethanol, THF and water, at a temperature in the range from 20° to 80°C. the Obtained carboxylic acid (VII) may be subjected to interaction with the amine of obtaining compounds of General Formula (Id). This interaction can be carried out using methods and techniques well known to the person skilled in the art. Especially preferred is a method, according to which the condensation reaction of these two compounds perform in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), 3-hydroxy-1,2,3-benzotriazin is -4(3H)-it, tertiary amine, such as, diisopropylethylamine, in a polar aprotic solvent such as dichloromethane or DMF, at a temperature in the range from -15°C to 50°C, or, for example, using benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexaflurophosphate (THIEF) in the presence of 1-hydroxybenzotriazole, tertiary amine, such as diisopropylethylamine, in a polar solvent such as DMF, CH2Cl2or DMSO, at a temperature in the range from 10° to 50°C. Another particularly preferred technique is the conversion of carboxylic acid to the acid chloride as a result of interaction with oxalylamino or thionyl chloride in the presence of a base such as pyridine or triethylamine, or without the use of a base, in a solvent such as toluene or dichloromethane, or without solvent, at a temperature in the range from 20 to 100°C. Then the obtained acid chloride may be subjected to interaction with the amine HNR7R8in the presence of a base such as pyridine or triethylamine, in a solvent such as dichloromethane, at a temperature in the range from 0 to 100°C.

Scheme 5 shows a General method that can be used for the conversion of compounds of General Formula (Ie), where R4represents a fluorine atom, and R2, R3and R'4are as defined is but in the foregoing description of General Formula (I), in compounds of General Formula (If), where R4represents NR7R8and R7, R8and R2, R3and R'4are as defined in the foregoing description of General Formula (I).

Compounds of General Formula (Ie) can be converted into compounds of General Formula (If) as a result of interaction with the amine of General Formula HNR7R8in the presence of organic or inorganic bases, such as, for example, Et3N iPr2NEt, NaH, Cs2CO3, K2CO3in a polar anhydrous solvent such as DMF, DMSO, at a temperature in the range from 20° to 140°C.

Scheme 6 shows a General method that can be used for the conversion of compounds of General Formula (Ig), where R3, R4and R'4are as defined in the foregoing description of General Formula (I) and where R2represents phenyl having as a substituent group, X represents a bromine atom, a chlorine atom or an OTf, in compounds of General Formula (Ih), where R2is a biphenyl or phenyl pyridine, substituted or unsubstituted, and where R3, R4and R'4are as defined in the foregoing description of General Formula (I).

Compounds of General Formula (Ig) can be PR is vrasene in compounds of General Formula (Ih) as a result of interaction with Bronevoy acid using a reaction type of reaction, Suzuki, in the presence of organic or inorganic bases, such as, for example, Et3N, NMP, iPr2NEt, NaH, Cs2CO3K2CO3, K3PO4in the presence of a catalyst, such as palladium acetate, tetranitroaniline palladium, Tris(dibenzylideneacetone)dipalladium, in a polar solvent such as, for example, acetone, methyl ethyl ketone, ethanol, DME (dimethoxyethane), water, dioxane, and possibly in the presence of a phosphine, such as triphenylphosphine or tricyclohexylphosphine, at a temperature in the range from 20° to 140°C.

Scheme 7 shows a General method that can be used for the conversion of compounds of General Formula (Ii), where R3, R4and R'4are as defined in the foregoing description of General Formula (I), and where Rg represents a phenyl having as a substituent group CN in ortho-or meta-position in compounds of General Formula (Ij), where R2represents phenyl having as a substituent carboxylic acid ortho - or meta-position, and then in the compounds of General Formula (Ik), where R2represents phenyl having as a substituent amide of the Formula CONR7R11and where R3, R4, R7, R11and R'4are as defined in the foregoing description of General Formula (I).

Compounds of General Formula (Ii) can be converted into compounds of General Formula (Ij) by treatment with an inorganic base, such as NaOH, KOH, LiOH, in a polar solvent such as ethanol, methanol, THF, water, at a temperature in the range from 20° to 140°C and subsequent oxidation by treatment with acid, such as HCl, H2SO4, HCOOH. Compounds of General Formula (Ij) can be converted into compounds of General Formula (Ik) as a result of interaction with the amine of the Formula HNR7R11. This interaction can be carried out using methods and techniques well known to the person skilled in the art. Especially preferred is a method, according to which the condensation reaction of these two compounds perform in the presence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), 3-hydroxy-1,2,3-benzotriazin-4(3H)-she tertiary amine, such as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane or DMF, at a temperature in the range from -15°C to 50°C, or, for example, using benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexaflurophosphate (THIEF) the presence of 1-hydroxybenzotriazole, tertiary amine, such as diisopropylethylamine, in a polar solvent such as DMF, CH2Cl2or DMSO, at a temperature in the range from 10° to 5°C. Another particularly preferred method is the conversion of carboxylic acid to the acid chloride as a result of interaction with oxalylamino or thionyl chloride in the presence of a base such as pyridine or triethylamine, or without the use of a base, in a solvent such as toluene or dichloromethane, or without solvent, at a temperature in the range from 20 to 100°C. Then the obtained acid chloride may be subjected to interaction with the amine HNR7R11in the presence of a base such as pyridine or triethylamine, in a solvent such as dichloromethane, at a temperature in the range from 0 to 100°C.

When it is desirable to provide a compound of General Formula (I)containing at least one acidic or basic functional group, in the form of a salt by adding a base or acid, the desired salt can be obtained by treating the free base or acid of General Formula (I) (which contains at least one acidic or basic functional group) with a suitable base or acid, preferably an equivalent amount of base or acid.

The following examples illustrate the invention without limiting its scope.

Note: the purity of all compounds (except as noted) was determined by Ehud using the following in the conditions:

column: Waters XTerra MS C18, a 4.6×50 mm, 5 µm; λ=220 nm; gradient 100% H2O (+0.05% of TFU) - 100% CH3CN (+0.05% of TFU) for 6 min and then 100% CH3CN (+0.05% of TFU) for 1 min; pump: Waters 600E; flow rate: 3 ml/min

Example 1

(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Example 1A - 2-(2-(Naphthalene-2-yl)-2-oxoethyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide

In a three-neck flask equipped with a thermometer and a fridge, made saccharin (25 g, 136 mmol) and DMF (350 ml). This mixture was washed with an inert gas by successive evacuation and filling with nitrogen (3x). Was slowly added sodium hydride (6 g, 150 mmol) and then 2-bromo-1-(naphthalene-2-yl)alanon time (37.4 g, 150 mmol). This reaction mixture was heated to 65°C for 4 h and then cooled to room temperature. The precipitate was separated by filtration, washed with water and dried to constant weight to obtain 37 g of the product 1A as a pale-being solids (ghvd: RT=equal to 4.97 min, 100%). The second portion of the product was obtained by adding to the filtrate water. The precipitate was separated by filtration, washed with water and then a minimal amount of ethanol and dried to obtain 10 g of the product (ghvd: RT=equal to 4.97 min, 93%). The overall yield of the reaction was 96%.

1H NMR, DMSO-d6, δ (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-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

In a two-neck flask, equipped with a fridge, in an atmosphere of inert gas was injected ethanol (165 ml) and then slowly added sodium, sliced into thin layers and washed with heptane (8 g, 347 mmol). After adding sodium the reaction mixture was heated to 70°C until the reaction involving sodium was not completed. Then the reaction mixture was cooled to room temperature and was quickly added to the compound 1A (47 g, 131 mmol). The mixture was reacted first at the intense crimson-red color, then red, and fell abundant precipitate. The reaction mixture was rapidly heated to 60°C, at this temperature the mixture zahustovali. Then the mixture was cooled to room temperature and diluted with ethyl acetate ohms (500 ml). Then added 1 N. aqueous solution of HCl until then, until he received a suspension Canary color. The precipitate was separated by filtration, washed with water and the minimum amount of the mixture of water/EtOH (50/50). Then the precipitate was dried under vacuum to constant weight to obtain product 1B in the form of solids Canary color (of 40.9 g, 88%). Jhud: RT=5,15 min, 100%.

1H NMR, DMSO-d6, δ (ppm): 7.66 (t, 1H); 7.72 (t, 1H); 7.95 (broadened s, 3H); 8.05 (d, 2H); 8.11 (broadened s, 2H); 8.22 (broadened 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-Dioxo-4-hydroxy-2-methyl-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 1B (of 40.9 g, 116 mmol) was dissolved in DMF (409 ml) in a two-neck flask in an atmosphere of inert gas. Added NaH (6,05 g, 151 mmol). During the reaction was allocated a small amount of heat and the reaction mixture had been intense scarlet color. Added itmean (10,8 ml, 174 mmol) and this reaction mixture was stirred for 2 h at room temperature. Was added water (10 ml) and the reaction mixture was concentrated. The residue was transferred into ethyl acetate and the precipitate was separated by filtration, washed with water and a minimal amount of ethyl acetate (the first portion of solids). The obtained filtrate is washed twice polysystem aqueous solution of NaCl, and then concentrated to half volume and filtered. The precipitate (the second portion of solids) were washed a minimum amount of the mixture of EtOAc/Et2O (50/50). The obtained filtrate was concentrated. The residue was filtered on silica gel (eluent: heptane/CH2Cl2(50/50) and then heptane/CH2Cl2(25/75)) to give after evaporation of the solvent a yellow powder (the third portion of the solids). All 3 servings solids were combined with obtaining the product 1 in the form of a solid substance is unreached color (40,1 g, 89%). Jhud: RT=5,65 min, 99%.

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

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

Obtaining the sodium salt of 4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]-thiazin-3-yl) - (naphthalene-2-yl)methanone

Fractions containing compound 1, was dissolved in methanol and treated at room temperature 1 N. aqueous solution of sodium carbonate (to 1.05 EQ.). This reaction mixture was concentrated and the resulting residue solid was washed with a mixture of dichloromethane and diethyl ether. The resulting solid Canary color was dried under vacuum for several days.

Jhud: RT=11,73 min, 99,71% (column: XBridge C8, 5 μm, a 4.6×250 mm (Waters); eluent: CH3CN/H2O/KH2PO4(600/400/6,8 g), pH 4, 25°C; 1 ml/min; 220 nm).

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

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

Examples 2-12

Connections 2-12 synthesized in accordance with the methodology of deriving 1, using the first stage of saccharin and various 2-bromo-1-(alkyl or aryl)atenonol and in the third stage, methyl iodide or ethyl iodide. The Protocol rearrangements used in the second stage, did not modify the.

Example**RThe name of the connectionEhudOutput (stage 3)Weight of MN+
2adamantane-1-yl(4-hydroxy-2-methyl-2H-1,1-loxo-benzo[e][1,2]thiazin-3-yl)(adamantane-1-yl)methane6,11' 98,9%30%374
34-were(4-hydroxy-2-methyl-2H-1,1-dioxo-benzo[e][1,2]thiazin-3-yl)(4-were)metano5,33' 99%49%330
44-chlorophenyl(4-hydroxy-2-methyl-2H-1,1-dioxo-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)metano5,43' 99%38%350
54-cyanophenyl(4-hydroxy-2-methyl-2H-1,1-dioxo-benzo[e][1,2]thiazin-3-yl)(4-cyanophenyl)metano4,7' 99% 82%339*
6biphenyl-4-ylbiphenyl-4-yl-(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)methanon5,86' 98%57%392
72,4-dichlorophenyl(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(2,4-dichlorophenyl)metano5,52' 98%14%384
* ESI (elektrorazpredelenie) in the negative ion mode (M-N)
**1H NMR, DMSO-d6Example 2: 1.72 (broadened s, 6H); 2.05 (broadened s, 3H); 2.10 (broadened s, 6H); 2.83 (s, 3H); 7.91 (broadened s, 3H); 8.10 (t, 1H); 16.1 (s, 1H). Example 5: 2.63 (s, 3H); 7.99 (s, 3H); 8.11 (s, 4H); 8.19 (broadened s, 1H); 14.5-15.5 (m, 1H, exchange). Example 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 (broadened s, 1H, exchange). Example 7: 2.67 (s, 3H); 7.54-7.64 (m, 2H); 7.83 (s, 1H); 7.93 (broadened s, 3H); 8.11 (broadened s, 1H); 13.5-14.5 (broadened s, 1H).

Example*RThe name of the connection EhudOutput (stage 3)Mass (M+N)+
8adamantane-1-yl(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(adamantane-1-yl)methanon6,24' 99%32%388
9naphthalene-2-yl(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon5,72' 99%55%380
104-were(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-were)metano5,49' 99%40%344
114-chlorophenyl(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)metano5,58' 99%35%364
12biphenyl-4-ylbiphenyl-4-yl-(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]t is Azin-3-yl)methanon 6,06' 99%61%406
*1H NMR, DMSO-d6Example 8: 0.68 (t, 3H); 1.71 (broadened s, 6H); 2.05 (broadened s, 3H); 2.09 (broadened s, 6H); 3.44 (q, 2H); 7.89 (broadened s, 3H); 8.05 (broadened s, 1H); 15.00 (s, 1H, exchange). Example 9: 0.51 (t, 3H); 3.13 (q, 2H); 7.66 (t, 1H); 7.72 (t, 1H); 7.99 (broadened s, 3H); 8.05 (d, 1H); 8.12 (broadened s, 3H); 8.22 (broadened s, 1H); 8.64 (s, 1H); 15.39 (s, 1H, exchange). Example 11: 0.53 (t, 3H); 3.13 (q, 2H); 7.71 (d, 2H); 7.98 (broadened s, 3H); 8.03 (d, 1H); 8.19 (broadened s, 1H). Example 12: 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-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Example 13A - 2-Chloro-6-sulfamoylbenzoic acid

In a three-neck flask equipped with a fridge, was administered 3-chloro-2-methylbenzenesulfonamide (of 13.27 g of 64.5 mmol) in the presence of 5% aqueous solution of sodium carbonate (385 ml). Was slowly added potassium permanganate (25,5 g, 161 mmol) and then the reaction mixture was heated to 100°C for 4 h the Temperature of the reaction mixture was brought to room temperature, the mixture was filtered, acidified to pH 1 and 3 times were extracted with ethyl acetate. The organic phases were combined, washed once with saturated aqueous NaCl and then dried sulfate is Agnes, was filtered and concentrated to obtain the product 13A as a white solid (12,87 g, 83%).

Jhud: RT=1,55 min, 98%.

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

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

Example 13B - 4-Hariharan

Into a flask were introduced compound 13A (12,87 g of 54.6 mmol) and then to 38.8 ml of concentrated sulfuric acid. This reaction mixture was stirred for 1.5 h at room temperature and then was poured into a mixture of ice water. The precipitate was separated by filtration, washed with water and dried to constant weight to obtain compound 13B as a white solid (9,16 g, 77%).

Jhud: RT=2.57 m min, 100%.

1H NMR, DMSO-d6, δ (ppm): 7.91 (broadened s, 2H); 8.08 (broadened s, 1H).

Example 13C - 4-Chloro-2-(2-(naphthalene-2-yl)-2-oxoethyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide

Compound 13 was synthesized from compound 13B (2.2 g, 10 mmol) in accordance with the methodology used for deriving 1A, compound 13C was obtained as a pale beige solid (3.3 g, 84%).

Jhud: RT=5,11 min, 99%.

1H NMR, DMSO-d6, δ (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/z 386 (MH+, 100%).

Example 13D - (5-Chloro-1,1-dioxo-4-hydroxy-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 13D synthesized is made from a compound 13C (3.3 grams, 8.5 mmol) in accordance with the methodology used for deriving 1B, compound 13D was obtained in the form of a Golden-yellow solid (1.7 g, 51%).

Jhud: RT=5,3 min, 99%.

1H NMR, AMCO-d6, δ (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/z 386 (MH+, 100%).

Example 13

Compound 13 was synthesized from compound 13D (3 g, 7.7 mmol) in accordance with the methodology used to obtain the derivative 1. Compound 13 was obtained as a yellow solid (2.3 g, 70%).

Jhud: RT=5,75 min, 95%.

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

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

Example 14

(5-Chloro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 14 was synthesized from compound 13D (1 g, 2.6 mmol) and 25 ionatana in accordance with the methodology used for deriving 1, with the release of 805 mg (60%) of the desired product.

Jhud: RT=5,77 min, 81%.

The fraction containing the product (200 mg)was purified on a column with spherical silica gel (12 g) (flow rate: 12 ml/min; 100% heptane (2 min), 30 gradient 0-50% EtOAc/heptane (30 min), 50% EtOAc/heptane (5 min), to obtain 64 mg of the desired product as a yellow solid.

Jhud: RT=5,77 min, 97%.

1 H NMR, DMSO-d6, δ (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-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Example 15A - (6-Fluoro-4-hydroxy-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 15A was synthesized from 4-fluoro-2-methylbenzenesulfonamide using the sequence of stages described in the method for obtaining compounds 13D. The desired product was obtained as yellow solid with a total yield of 79%.

Jhud: RT=5,26 min, 96%.

1H NMR, DMSO-d6, δ (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 (broadened s, 1H, exchange).

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

Example 15 - (6-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 15 was synthesized from compound 15A (1.5 g, 4 mmol) in accordance with the methodology used for deriving 1, with the yield of the desired product (1.47 g, 89%) as a yellow solid.

Jhud: RT=5,6 min, 93%.

The fraction containing the product was recrystallized from ethanol to obtain 186 mg of compound 15 higher purity (ghvd: RT=5,6 min, 99.4 per cent).

1H NMR, DMSO-d6, δ (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 (, 1H); 15.22 (broadened s, 1H, exchange).

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

Example 16

(6-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 16 was synthesized from compound 15A (1.5 g, 4 mmol) and iodata in accordance with the methodology used for deriving 1, with the yield of the desired product (520 mg, 29%) as a yellow solid.

Jhud: CT=5,8 min, 91%.

The fraction containing the product was recrystallized from ethanol to obtain 71 mg of compound 16 higher purity.

Jhud: RT=5,8 min, 97%.

1H NMR, DMSO-d6, δ (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 (broadened s, 1H).

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

Example 17

(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Example 17A - 5-fluoro-2-methylbenzenesulfonamide

To concentrated ammonia solution (23 ml) was slowly added at 0°C 5-fluoro-2-methylbenzenesulfonyl chloride (5,00 g of 23.9 mmol). Then this reaction mixture was heated to 100°C for 1 h and then cooled to room temperature. The precipitate was separated by filtration, washed with water and dried to constant weight. Compound 17A was obtained as a white powder (4,55 g, 100%).

Jhud: RT=3,10 min, 96%.

1H NMR, DMSO-d6, δ (ppm): 2.54 (s, 3H); 7.35-7.45 (m, 2H); 7.53 (broadened s, 2H, exchangeable); 7.58 (de, 1H).

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

Example 17B - (7-Fluoro-4-hydroxy-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 17B was synthesized from compound 17A, using the sequence of stages described in the method for obtaining compounds 13D. The desired product was obtained as yellow solid with an overall yield of 73%.

Jhud: RT=5,18 min, 98%.

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

Mass spectrum (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-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 17 was synthesized from compound 17B (4,00 g to 10.8 mmol) in accordance with the methodology used for deriving 1, received two portions of the desired product different purity.

The first portion: 3,79 g, pale-brown solid; Ehud: RT=5,65 min, 94%.

Second dose: 320 mg, yellow solid; Ehud: RT=5,65 min, 99%.

The yield of the reaction was 93%.

1H NMR, DMSO-d6, δ (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); at 8.62 (s, 1H); 15.62 (broadened s, 1H, exchange).

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

Example 18

(7-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 18 was synthesized from compound 17A (1.0 g, 2.7 mmol) and iodata in accordance with the methodology used for deriving 1, received two portions of the desired product different purity.

The first portion: 716 mg, pale-brown solid; Ehud: RT=5,78 min, 89%.

Second portion: 68 mg, yellow solid; Ehud: RT=5,78 min, 99%.

The yield of the reaction was 65%.

1H NMR, DMSO-d6, δ (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 (broadened s, 1H, exchange).

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

Example 19

Benzoic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Connection 1 (86 mg, 0.18 mmol) was dissolved in dichloromethane (0.5 ml) and pyridine (0.5 ml) in an atmosphere of inert gas. This reaction mixture was cooled to 0°C and then was added benzoyl chloride (33 μl, 0.27 mmol). The cooling bath was removed and the reaction mixture was stirred for 4 h at room temperature. Since the reaction was not completed, was added another portion of benzoyl chloride (16 μl, 0.14 mmol), the reaction mixture was stirred at room temperature for more the sory for 20 h and then concentrated. The residue was transferred into ethyl acetate, washed once with water and once with saturated aqueous NaCl, dried with sodium sulfate, filtered and concentrated. The obtained residue was evaporated three times with toluene to remove the remaining pyridine. The resulting yellow syrup was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient: 20-100% CH2Cl2/heptane (30 min)to yield compound 19 as a yellow foam (38 mg, 44%).

Jhud: RT=5,65 min, 96%.

1H NMR, DMSO-d6, δ (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

Cyclohexanecarbonyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Connection 1 (86 mg, 0.18 mmol) was dissolved in 0.5 ml of pyridine in an atmosphere of inert gas. This reaction mixture was cooled to 0°C and then added cyclohexanecarbonyl chloride (62 μl, 0.46 mmol). The cooling bath was removed and the reaction mixture was stirred for 18 h at room temperature and then was heated to 60°C for 8 hours and Then the reaction mixture was concentrated, and three times was evaporated with toluene. The resulting residue was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient: 20-100% CH2Cl2/heptane (20 min) to yield compound 20 as a yellow n is HN (65 mg, 28%).

Jhud: RT=5,99 min, 95%.

1H NMR, DMSO-d6, δ (ppm): 0.85-1.00 (m, 6N); 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 (MNH4+, 100%).

Example 21

tert-Butylcarbamoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Connection 1 (86 mg, 0.18 mmol) was dissolved in pyridine (0.5 ml) in an atmosphere of inert gas. This reaction mixture was cooled to 0°C and then added tert-butylcarbamoyl chloride (57 μl, 0.46 mmol). The cooling bath was removed and the reaction mixture was stirred for 18 h at room temperature. Then the reaction mixture was concentrated, and three times was evaporated with toluene. The resulting residue was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient: 20-100% CH2Cl2/heptane (20 min)output connection 21, in the form of a yellow foam (47 mg, 53%).

Jhud: RT=5,71 min, 98%.

1H NMR, DMSO-d6, δ (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 (MNH4+, 100%).

Example 22

4-Methylbenzoic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Compound 22 was synthesized from compound 1 (mg, 0.18 mmol) and 4-methylbenzoyl chloride (62 μl, 0.46 mmol) according to the methodology used to obtain compound 21. The desired product was obtained as a yellow foam (27 mg, 31%).

Jhud: RT=of 5.82 min, 95%.

1H NMR, DMSO-d6, δ (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 (MNH4+, 100%).

Example 23

4 Chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

4-Chlorbenzoyl acid (87 mg, 0.55 mmol) was dissolved in toluene (2 ml) in an atmosphere of inert gas. Was added at room temperature oxalicacid (100 μl, 1.1 mmol). This reaction mixture was heated for 2 h to 80°C and then concentrated, and three times was evaporated with toluene. The residue was again placed in an atmosphere of inert gas and cooled to 0°C. was Added compound 1 (86 mg, 0.18 mmol), previously dissolved in pyridine (0.5 ml) in an atmosphere of inert gas and cooled to 0°C. the Cooling bath was removed and the reaction mixture was stirred for 2 h at room temperature. Then the reaction mixture was concentrated, and three times was evaporated with toluene. The resulting residue was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient: 20-100% CH2Cl2/GE is tan (20 min) to yield compound 23 as a yellow foam (51 mg, 42%).

Jhud: RT=of 5.92 min, 97%.

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

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

Examples 24-27

Connection 24-27 synthesized from compound 15 and various acid chlorides in accordance with the above described method for obtaining compounds of 21.

Example*RThe name of the connectionEhudOutputWeight MNH4+
24tert-butyltert-butylcarbamoyl acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-loxo-2H-benzo[e][1,2]thiazin-4-silt etherof 5.82' 98%61%485
25cyclohexanecyclohexanecarboxylic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,09' 90%36%511

26phenylbenzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,73' 96%64%505
274-were4-methylbenzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,91' 95%56%519
*1H NMR, DMSO-d6, Example 24: 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). Example 25: 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). Example 26: 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). Example 27: 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 28-31

Compounds 28-31 synthesized from compound 16 and various acid chlorides in accordance with the above described method for obtaining compounds of 21.

Example*R The name of the connectionEhudOutputWeight MNH4+

28tert-butyltert-butylcarbamoyl acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,00' 98%53%499
29cyclohexanecyclohexanecarboxylic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,26' 95%42%525
30phenylbenzoic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,90' 99%40%519
314-were4-methylbenzoic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherbetween 6.08' 95% 59%533
*1H NMR, DMSO-d6, Example 28: 0.92 (broadened 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). Example 29: 0.80-1.10 (m, 8H); 1.38 (broadened s, 3H); 1.53 (de, 2H); 2.45 (te, 1H); 3.55 (q, 2H); 7.56 (d, 1H); 7.65-7.70 (m, 2H); 7.76 (t, 1H); 7.95-8.15 (m, 5H); 8.67 (s, 1H). Example 30: 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). Example 31: 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

Compounds 32 and 33 was synthesized from 4-chlorbenzoyl acid and compounds 15 and 16, respectively, using the above-described methods for obtaining compounds of 23.

Example*RThe name of the connectionEhudOutputWeight MNH4+
32methyl4 chlorbenzoyl acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,00' 95%18%539
33 ethyl4 chlorbenzoyl acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,16' 95%19%553
*1H NMR, DMSO-d6, Example 32: 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). Example 33: 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

Naphthalene-1-icarbonell acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Compound 3 (150 mg, 0,455 mmol) was dissolved in tetrahydrofuran (3 ml) in an atmosphere of inert gas. Was added sodium hydride (27 mg, of 0.68 mmol) and then, after 30 minutes, naphthalene-2-ylcarbonyl chloride (105 μl, of 0.68 mmol). This reaction mixture was stirred for 4 hours at room temperature. Then the reaction mixture was neutralized by adding water and the aqueous phase was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient of 0-45% EtOAc in heptane (20 min). The desired product was obtained as yellow solid (134 mg, 61%).

Jhud: RT=6.5 minutes, 98%.

1H NMR, DMSO-d6, δ (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 (MNH4+, 100%).

Examples 35-45

Connection 35-45 synthesized from compound 3 or compound 5 and various acid chlorides in accordance with the above-described method of obtaining connection 34.

The acid chlorides, required for the synthesis of compounds in the Examples 40-45, received in two stages from the corresponding aromatic alcohols. Receiving (naphthalene-2-yloxy)acetyl chloride is given as an example.

2-Naphthol (3.0 g, 20 mmol) was dissolved in 95 ml of methyl ethyl ketone (MEK) in the presence of sodium carbonate (40 g, 93 mmol) in a two-neck flask, equipped with a fridge, in an atmosphere of inert gas and then heated to 50°C for 30 minutes In the preheated mixture was added dropwise 2-bromatology acid (USD 5.76 g, 41 mmol)dissolved in MEK (23 ml). Heating was continued for another 4 h and Then the reaction mixture was cooled to room temperature and filtered. The solid is collected by filtration, transferred to a mixture of ethyl acetate and 1 N. aqueous HCl. The two phases were separated and the aqueous phase once were extracted with ethyl acetate. The organic phase was collected, dried with magnesium sulfate, filtered and concentrated until the appearance of the first crystals. Add recipients who do heptane (approximately 20% of the remaining volume and the precipitate was separated, washed with heptane and dried to constant weight to obtain (naphthalene-2-yloxy)acetic acid (3.04 from g, 72%) as a white solid.

Jhud: RT=4,10 min, 99%.

1H NMR, DMSO-d6, δ (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 (broadened s, 1H, exchange).

Macc-specr (ESI+): m/z 203 (MN+, 100%).

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

The acid obtained in the previous phase (totaling 3.04 g, 15 mmol)was partially dissolved in dichloromethane (34 ml) in an atmosphere of inert gas at room temperature. Added oxalicacid (1.35 ml, 15.7 mmol) and then DMF (100 μl). Note: when adding a DMF is a rapid reaction. The reaction mixture was stirred for 1 h, then concentrated, twice evaporated with toluene and dried to constant weight to obtain (naphthalene-2-yloxy)acetyl chloride (3.4 g, 100%) as an orange solid. The resulting acid chloride was used as is for the synthesis of compounds 40 and 41.

ExampleRR'The name of the connectionEhudOutputWeight MNH4+

35naphthalene-2-carbonylCH3naphthalene-2-icarbonell acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherof 5.89' 99%81%501
36naphthalene-1-carbonylCNnaphthalene-1-icarbonell acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,59' 98%85%512
37naphthalene-2-carbonylCNnaphthalene-2-icarbonell acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,58' 93%30%512
384-chloro benzoylCH34 chlorbenzoyl acid 2-methyl-3-(4-methylbenzoyl)-1,1-loxo-2H-benzo[e][1,2]thiazin-4-silt etherof 5.82' 96%24%85
394-chloro benzoylCN4 chlorbenzoyl acid 2-methyl-3-(4-cyanobenzoyl)-1,1-loxo-2H-benzo[e][1,2]thiazin-4-silt ether5,48' 91%19%496
40naphthalene-2-yloxy)acetylCH3(naphthalene-2-yloxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherby 5.87' 98%85%531
41naphthalene-2-yloxy)acetylCN(naphthalene-2-yloxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,59' 98%21%542

42naphthalene-1-yloxy)acetylCH3(naphthalene-1-yloxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether of 5.89' 98%60%531
43naphthalene-1-yloxy)acetylCN(naphthalene-1-yloxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,64' 97%29%542
44(4-chloro, phenoxy)acetylCH3(4 chlorophenoxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,76' 99%64%515
454-chloro, phenoxy)acetylCN(4 chlorophenoxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,50' 90%31%526
*1H NMR, DMSO-d6, Example 35: 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). Example 36: 3.07 (s, 3H); 7.58 (t, 1H); 7.61-7.68 (m, 2H); 7.89 (broadened s, 3H); 7.98 (d, 2H); 8.00-8.10 (m, 5H); 8.31 (d, 1H); 8.60 (dd, 1H). Example 3: 3.08 (s, 3H); 7.67 (t, 1H); 7.71-7.79 (m, 2H); 7.90 (broadened s, 3H); 7.99-8.11 (m, 8H); 8.40 (s, 1H). Example 38: 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 (broadened s, 1H). Example 39: 3.04 (s, 3H); 7.59 (d, 2H); 7.79 (d, 2H); 7.83-7.90 (m, 3H); 7.99-8.07 (m, 5H). Example 40: 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 (broadened s, 1H). Example 41: 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). Example 42: 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).). Example 43: 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, 1 H); 8.05-8.11 (m, 5H). Example 44: 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). Example 45: 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-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Compound 1 (100 mg, 0,274 mmol) was dissolved in dichloromethane (2 ml) in an atmosphere of inert gas. Was added at 0°C triethylamine (230 μl, of 1.64 mmol) and then acetylchloride (78 μl, of 1.09 mmol). This reaction mixture was stirred for 18 h at room temperature and then concentrated. The resulting residue was purified on a column with spherical silica gel (12 g) with output connection 46 (21 mg, 30%).

Jhud: RT=5,34 min, 97%.

1H NMR, DMSO-d6, δ (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 (MNH4+, 100%).

Examples 47-54

Connection 47-54 synthesized from compound 1 and various acid chlorides in accordance with the above-described method of obtaining connection 46.

ExampleRThe name of the connectionEhudOutputWeight MNH4+
472,4-chlorphenyl2,4-dichlorobenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,05' 98%47%555
484-forfinal4-fermenting acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,86' 98%69%505
49cyclopentylcyclopentane acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e[1,2]thiazin-4-silt ether 5,99' 91%48%479
50furan-2-yl2-furan acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-loxo-2H-benzo[e][1,2]thiazin-4-silt ether5,33' 97%68%477
51thiophene-2-ylthiophene-2-carboxylic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,68' 99%61%493
523-chlorophenyl3 chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherby 5.87' 98%45%521

532-chlorophenyl2 chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,74' 96%63%521
54phenoxymethylphenoxyalkanoic acid 2-methyl-3-(naphthalene-2-ylcarbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,63' 97%71%517
*1H NMR, DMSO-d6, Example 47: 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). Example 48: 3.10 (s, 3H); 7.15 (t, 2H); 7.63-8.08 (m, 12H); 8.67(s, 1H). Example 49: 1.20-1.31 (m, 6H); 1.50-1.58 (m, 2H); 2.75 (quintet, 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). Example 50: 3.08 (s, 3H); 6.60 (d, 1H); 7.19 (d, 1H); 7.65 (t, 1H); 7.72-7.77 (m, 2H); 7.88 (broadened s, 2H); 7.95-8.08 (m, 6H); 8.69 (s, 1H). Example 51: 3.09 (s, 3H); 7.09 (dd, 1H); 7.62-8.04 (m, 12H); 8.20 (s, 1H). Example 52: 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). Example 53: 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). Example 54: 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-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Connection 1 (159 mg, 0,435 mmol) was dissolved in DMF (2 ml) in an atmosphere of inert gas. Was added sodium hydride (26 mg, of 0.65 mmol) and then, after 30 minutes, itmean (30 μl, 0.48 mmol). This reaction mixture was stirred for 2 h at room te is the temperature and then for 26 h at 60°C. At this stage, the reaction was not completed. Added cesium carbonate (213 mg, of 0.65 mmol) and itmean (150 μl, 2.1 mmol). This reaction mixture was stirred for 24 h at room temperature and then neutralized by addition of water, the aqueous phase was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column with spherical silica gel (12 g; flow rate: 12 ml/min; gradient 20-60% dichloromethane in heptane) to yield compound 55 as a yellow foam (70 mg, 38%).

Jhud: RT=5,27 min, 90%.

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

Examples 56-58

Connection 56-58 received in accordance with the following method. Compound 1 (150 mg, 0.42 mmol) was dissolved in DMF (0.3 ml) in an atmosphere of inert gas. Added cesium carbonate (201 mg, 0.61 mmol) and the desired alkylated (4 mmol). This reaction mixture was stirred for 18 h at room temperature, for 4 h at 50°C and then neutralized by addition of water, the aqueous phase was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on columns with spherical silica gel (12 g; flow rate: 12 ml/min; gradient 20-0% dichloromethane in heptane) to yield the desired products.

ExampleRThe name of the connectionEhudOutputWeight of MN+
56ethyl(4 ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon5,43' 99%66%394
57n-propyl4 propyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon5,61' 99%65%408
58n-butyl4 Butylochka-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon5,81' 97%24%422
*1H NMR, DMSO-d6, Example 56: 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). Example 7: 0.49 (t, 3H): 1.28 (sextet, 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). Example 58: 0.50 (t, 3H): 0.89 (sextet, 2H); 1.23 (quintet, 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-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metano

Compound 3 (100 mg, 0.3 mmol) was dissolved in THF (3 ml) in an atmosphere of inert gas in the presence of 2-chloroethanol (100 μl, 1.5 mmol). This reaction mixture was cooled to 0°C, was then added dropwise successively triphenylphosphine (318 mg, 1.2 mmol) and dieseldiesel-1,2, in primary forms (DEAD, 211 mg, 1.2 mmol). Stirring was continued for 20 h at room temperature and then the reaction mixture was neutralized by adding saturated aqueous solution of ammonium chloride. The resulting aqueous phase was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (35 g; flow rate: 20 ml/min; gradient 0-100% ethyl acetate in heptane) to yield compound 59 (70 mg, 58%).

Jhud: RT=5,28 min, 99%.

1H NMR, DMSO-d6, δ (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-(Naphthalene-2-yloxy)ethoxy]-2-methyl-1,1-dioxo-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metano

Compound 59 (70 mg, 0,17 mmol) was dissolved in DMF (2 ml) in an atmosphere of inert gas in the presence of potassium carbonate (64 mg, of 0.53 mmol), potassium iodide (31 mg, 0,19 mmol) and 2-naphthol (38 mg, 0.27 mmol). This reaction mixture was heated to 65°C for 22 h, then neutralized by addition of water and was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on column Waters Sunfire (19×100 mm, 5 μm) by prepreparation ghvd (flow rate: 20 ml/min; gradient of 10-100% acetonitrile in water (0.1% of TFU-buffer) for 15 min) output connection 60 (30 mg, 29%).

Jhud: RT=5,95 min, 99%.

1H NMR, DMSO-d6, δ (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-Phenoxy-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 1 (100 mg, 0,274 mmol) was dissolved in DMF (0.5 ml) in the presence of potassium carbonate (90 mg, 0.55 mmol) and 2-phenoxyethyl bromide (110 mg, 0.55 mmol). This reaction mixture was heated in a sealed tube to 80°C for 16 hours the Mixture was transferred into ethyl acetate and then washed with water and saturated NaCl solution. Organic f the s United, dried sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 20 ml/min; gradient 0-10% dichloromethane in heptane) to yield compound 61 as a yellow syrup (45 mg, 34%).

Jhud: RT=5,88 min, 98%.

1H NMR, DMSO-d6, δ (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); at 8.62 (s, 1H).

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

Example 62

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

Compound 62 was synthesized from compound 3 (300 mg, of 0.91 mmol) and methylglucose (350 μl, 4.5 mmol) in accordance with the methodology used to obtain the connection 59, the desired product was obtained as a yellow syrup (300 mg, 79%).

Jhud: RT=equal to 4.97 min, 97%.

1H NMR, DMSO-d6, δ (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-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetic acid

Compound 62 (75 mg, 0.18 mmol) was dissolved in THF (1 ml) was added lithium hydroxide (1M/H2O, and 0.37 mmol). This reaction mixture was stirred for 2 h at room temperature and then was diluted with water and two the water was extracted with dichloromethane. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated to obtain 22 mg of the desired product (ghvd: RT=4,55 min, 97%). The yield of the reaction was 30%.

1H NMR, DMSO-d6, δ (ppm) 2.41 (s, 3H); 2.88 (s, 3H); 4.28 (s, 2H); 7.39 (d, 2H); 7.81 (t, 1H); 7.85-7.95 (m, 5H); 12.96 (se, 1H, exchange).

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

Examples 64-66

Compound 63 (110 mg, 0.28 mmol) was dissolved in DMF (3 ml). Added various amines (0.23 mmol), DIEA (N,N-diisopropylethylamine) (82 μl, 0,472 mmol), HOOBT (3-hydroxy-1,2,3-benzotriazin-4-one) (35 mg, 0.26 mmol), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride) (50 mg, 0.26 mmol). This reaction mixture was stirred for 18 h at room temperature. The mixture was transferred into dichloromethane and then washed with 1 N. solution of sodium carbonate, water and saturated NaCl solution. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residues were purified on columns with spherical silica gel (12 g; flow rate: 12 ml/min; 0-50% AcOEt in heptane) to yield the desired products.

ExampleR1R2NThe name of the connectionEhud OutputWeight MNH4+
64naphthalene-1-yl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(naphthalene-1-yl)ndimethylacetamidethe 5.45' 95%40%530
65adamantane-1-yl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantane-1-yl)ndimethylacetamide5,90' 99%72%538
66adamantane-2-yl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantane-2-yl)ndimethylacetamideof 5.83' 99%85%538
*1H NMR, DMSO-d6, Example 64: 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-shall ethylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetate

Compound 1 (1.0 g, to 2.74 mmol) was dissolved in DMF (2 ml) in the presence of potassium carbonate (682 mg, 4.1 mmol) and bromoxynil acid methyl ester (1.26 in ml, 13,68 mmol). This reaction mixture was stirred for 5 h at room temperature and then added another portion bromoxynil acid methyl ester. The mixture was left overnight at room temperature, then transferred to the ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (90 g; flow rate: 32 ml/min; gradient 40-100% dichloromethane in heptane) to yield compound 67 as a yellow syrup (486 mg, 41%).

Jhud: RT=5,23 min, 86%.

1H NMR, DMSO-d6, δ (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-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetic acid

Compound 67 (480 mg, 1.1 mmol) was dissolved in a mixture of THF/water (5:1) (6 ml) and then was treated with LiOH (103 mg, 4,39 mmol) for 15 min at room temperature. The mixture was transferred into ethyl acetate and then washed with 1 N. HCl, water and saturated NaCl solution. Organization the practical phases were combined, dried sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (30 g; eluent: dichloromethane/methanol/acetic acid (95/4,5/0)output connection 68 as a yellow foam (321 mg, 69%).

Jhud: RT=a 4.86 min, 99%.

1H NMR, DMSO-d6, δ (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 69-71

Connection 69-71, received in accordance with the following method. Compound 1 (100 mg, 0.23 mmol) was dissolved in dichloromethane (1.5 ml). Added various amines (0.23 mmol), DIEA (82 μl, 0,472 mmol), HOOBT (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). This reaction mixture was stirred for 24 h at room temperature, then added an excess of amine (0.07 mmol) and the resulting mixture was stirred for 5 hours the Mixture was transferred into dichloromethane and washed with 1 N. solution of sodium carbonate, water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residues were purified on columns with spherical silica gel (12 g; flow rate: 12 ml/min; the mixture of 1% methanol/ammonia (9:1) in dichloromethane) to yield the desired products.

Example NR1R2The name of the connectionEhudOutputWeight of MN+
692-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidine-1-yl-alanon5,26' 98%49%491

702-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazine-1-yl)-alanon3,93' 98%47%506
711-(4-benzyl-piperazine-1-yl)-2-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-alanon4,28' 98%20%582
*1H NMR, DMSO-d6, Example 69: 1.08-1.31 (m, 6H): 2.87 (t, 2H); 2.95 (s, 3H); 3.04 (t, 2H); 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, H). Example 70: 1.85 (t, 2H): 1.92 (t, 2H); 1.95 (s, 3H); 2.94 (broadened s, 5H); 3.04 (broadened 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). Example 71: 1.88 (broadened s, 2H); 1.96 (broadened s, 2H); 2.92 (m, 5H); 3.08 (broadened 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 72-74

Connection 72-74 synthesized from compound 1 and various acid chlorides in accordance with the above-described method of obtaining connection 46.

ExampleRThe name of the connectionEhudOutputWeight MNH4+
724-chlorophenyl hydroxy-acetyl(4-chloro-phenoxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,02' 94%77%551

73naphthalene-1-yloxy-acetyl(naphthalene-1-yloxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo is[e][1,2]thiazin-4-silt ether 6,16' 98%84%567
74naphthalene-2-yloxy-acetyl(naphthalene-2-yloxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,11' 96%83%567
*1H NMR, DMSO-d6, Example 72: 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). Example 73: 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). Example 74: 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

Connections 75 and 76 was synthesized from compound 59 and various alcohols in accordance with the above described method for obtaining compounds of 60.

ExampleRThe name of the connectionEhudOutputWeight of MN+
75 naphthalene-1-yl(4-[2-(naphthalene-1-yloxy)ethoxy]-2-methyl-1,1-loxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metano6,00' 97%38%500

764-chlorophenyl(4-[2-(4-chlorphenoxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metanoby 5.87' 98%48%484
*1H NMR, DMSO-d6, Example 75: 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). Example 76: 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

Connections 77 and 78 was synthesized from compound 3 and acetylchloride and propanol chloride, respectively, using the above-described methods for obtaining compounds of 34.

ExampleRThe name of the connectionEhudOutputWeight MNH4+
77methylacetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherof 5.05' 99%81%389
78ethylpropanoic acid, 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherthe 5.25' 99%88%403
*1H NMR, DMSO-d6, Example 77: 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). Example 78: 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

Connections 79 and 80 was synthesized from compound 3 and from methanol and ethanol, respectively, using the above-described methods for obtaining compounds of 59.

ExampleRThe name of the connectionEhudOutputWeight of MN+
79methyl (4 metiloksi-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metano5,13' 98%58%344
80ethyl(4 acyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)metanoof 5.29' 99%63%358
*1H NMR, DMSO-d6, Example 79: 2.42 (s, 3H); 2.91 (s, 3H); 3.50 (s, 3H); 7.41 (d, 2H); 7.78-7.95 (m, 6H). Example 80: 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-Bromo-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalene-2-yl-metano

Compound 1 (150 mg, 0.41 mmol) was dissolved in methyl ethyl ketone (3 ml) and then treated with dibromoethane (71 μl, 0.82 mmol) in the presence of K2CO3(170 mg, of 1.02 mmol). This reaction mixture was heated in the microwave in a sealed tube for 4 h 30 min at 130°C. the Mixture was transferred into ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residue (brown syrup, 197 mg) as is used in the next reaction.

Example 82

{4-[2-(4-X is the PR-phenoxy)-ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl}-naphthalene-2-yl-metano

Compound 81 (197 mg, 0.41 mmol) was dissolved in methyl ethyl ketone (1.5 ml) and then was treated with 4-chlorophenol (107 μl, 0.82 mmol) in the presence of K2CO3(173 mg, 1.04 mmol). This reaction mixture was heated in the microwave in a sealed tube for 2 h at 130°C. the Mixture was transferred into ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 12 ml/min; gradient-10-100% dichloromethane in heptane) to yield compound 82 as a yellow syrup (21 mg, 14%).

Jhud: RT=6,10 min, 89%.

1H NMR, DMSO-d6, δ (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+, 66%).

Example 83

Carbonic acid ethyl 1-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethyl ester

Compound 1 (100 mg, 0.27 mmol) was dissolved in DMF (1 ml) and then was treated with ethyl 2-chlorpropamide (110 μl, 0.82 mmol) in the presence of K2CO3(91 mg, 0.55 mmol). This reaction mixture was heated in a sealed vessel to 60°C over night and then added another portion of ethyl 2-chloropropane the a and the reaction mixture was stirred additionally for 24 hours The mixture was transferred into ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 12 ml/min; gradient 25-80% dichloromethane in heptane) to yield compound 83 as a yellow syrup (100 mg, 76%).

Jhud: RT=5,55 min, 97%.

1H NMR, DMSO-d6, δ (ppm) 0.94 (t, 3H); 1.25 (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-dioxo-4-(2-piperidine-1-yl-ethoxy)-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl]-naphthalene-2-yl-metano

Compound 1 (100 mg, 0.27 mmol) was dissolved in methyl ethyl ketone (0.5 ml) and then treated with 1-(2-chloroethyl)piperidine (252 mg, 1.37 mmol) in the presence of K2CO3(159 mg, 0.96 mmol). This reaction mixture was heated up to 80°C during the night. Then the mixture was treated with ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 12 ml/min; dichloromethane/MeOH/NH4OH 99/09/01)output connection 84 in the form of a yellow syrup (50 mg, 43%).

Jhud: RT=4,17 m is h, 92%.

1H NMR, DMSO-d6, δ (ppm): 1.21 (broadened s, 6H); 1.99 (broadened 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/z 477 (MH+, 100%).

Examples 85-96

Connection 85-96 synthesized in accordance with the following method. The connection 13, 15 or 17 (100 mg) was dissolved in dichloromethane (2 ml) in an atmosphere of inert gas in the presence of triethylamine (6 EQ.) and then was treated with various acid chlorides (4 equiv.) at 0°C. the Reaction mixture was stirred for 2 h at 0°C and then for 20 h at room temperature. The mixture was transferred into ethyl acetate and then washed with water and saturated NaCl solution. The organic phases were combined, dried with sodium sulfate, filtered and concentrated. The resulting residues were purified on a column of silica gel (12 g; flow rate: 12 ml/min; gradient of 0-20% ethyl acetate in heptane) to yield the desired compounds.

ExampleR1R2The name of the connectionEhudOutputMass MH+/MNa+
85 4-chlorophenyl5-Cl4-chloro-benzoic acid 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherto 6.43' 96%29%555

86cyclohexyl5-Clcyclohexanecarbonyl acid 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,50' 98%26%527
87phenyl5-C1benzoic acid, 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,11' 92%65%521
884-chlorophenyl6-F4-chloro-benzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,30' 99%40%539
89cyclohexyl6-Fcyclohexanecarboxylic acid 6-fluoro-2-methyl-3-naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,30' 97%55%511
90phenyl6-Fbenzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,90' 94%50%505
914-chlorophenyl7-F4-chloro-benzoic acid 7-fluoro-2-methyl-3-naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,20' 98%60%539

92cyclohexyl7-Fcyclohexanecarbonyl acid 7-fluoro-2-methyl-3-naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,37' 98%19% 511
93phenyl7-Fbenzoic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,91' 93%69%505
94methyl7-Facetic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,46' 97%62%448
95phenoxymethyl7-Fphenoxy-acetic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt etherof 5.89' 92%50%540
964-Cl-phenoxymethyl7-F(4-chloro-phenoxy)-acetic acid 7-fluoro-2-methyl-3-naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether6,10' 93%18%574

P is emery 97-104

Connection 97-104 synthesized from compound 13, 15 or 17 and the corresponding alkyl iodides or sulfates in accordance with the methodology used to obtain the compounds in Examples 56-58.

ExampleR1R2The name of the connectionEhudOutputWeight of MN+/MNH4+
97ethyl5-Cl(5-chloro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,61' 97%11%428
98cut5-Cl(5-chloro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano6,02' 96%44%442
99methyl6-F(6-fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][,2]thiazin-3-yl)-naphthalene-2-yl-metano 5,65' 93%34%398
100ethyl6-F(6-fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,72' 97%52%429
101cut6-F(6-fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metanoof 5.92' 97%56%426
102methyl7-F(7-fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,56' 97%20%398
103ethyl7-F(7-fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,77' 95%47%412
104 cut7-F(7-fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,90' 98%52%426

Example 105

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

Compound 105 was synthesized from compound 17 (1 g, 2,61 mmol) in accordance with the methodology used to obtain the compound in Example 67. The desired product was obtained as a yellow syrup (810 mg, 68%).

Jhud: RT=lower than the 5.37 min, 95%.

1H NMR, DMSO-d6, δ (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-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-acetic acid methyl ester

Compound 106 was synthesized from compound 105 (598 mg, 1,31 mmol) in accordance with the methodology used to obtain the compound in Example 68. The desired product was obtained as a beige powder (262 mg, 45%).

Jhud: RT=4,92 min, 97%.

Mass spectrum (ESI+): m/z 442 (MH+, 100%).

Examples 107-109

Connection 107-109 synthesized from compound 106 and the corresponding amines in accordance with the tvii with methods used to obtain the compounds in Examples 69-71.

ExampleNR1R2The name of the connectionEhudOutputWeight of MN+
1072-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidine-1-yl-alanon5,40' 91%64%509
1082-[7-fluoro-2-methyl-3-naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazine-1-yl)-alanon3,99' 99%67%524
1091-(4-benzyl-piperazine-1-yl)-2-7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-alanon4,35' 98%69%600
*1H NMR, DMSO-d6, Example 107: 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). Example 108: 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). Example 109: 1.90 (broadened s, 2H); 1.97 (broadened s, 2H); 2.92 (broadened s, 2H); 2.95 (s, 3H); 3.09 (broadened 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

Benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether

Compound 17 (200 mg, 0.52 mmol) was dissolved in dichloromethane (2 ml) and then treated at 0°C benzosulfimide acid acid chloride (67 μl, 0.52 mmol) in the presence of Et3N (145 μl, 1.04 mmol). This reaction mixture was stirred for 4 h (until the temperature of the reaction mixture did not rise from 0°C to room temperature) and then the mixture was transferred into dichloromethane and washed with water and saturated NaCl solution. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 12 ml/min; gradient 20 to 50% dichloromethane in heptane) to yield compound 110 in the form of a cream-colored powder (177 mg, 6%).

Jhud: RT=5,72 min, 94%.

1H NMR, DMSO-d6, δ (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 (MNH4+, 100%).

Examples 111-117

Connection 111-117 synthesized from compound 1 or 17 and the corresponding sulphonylchloride in accordance with the methodology used to obtain the compound in Example 110.

ExampleR1R2The name of the connectionEhudOutputMass MH+/MNa+

of 5.84' 99%
111HNbenzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,59' 99%71%506
112HCl4-chloro-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether94%540
113HMe4-methyl-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,74' 99%93%520
114HCN4-cyano-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,50' 99%89%531
115FCl4-chloro-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,96' 96%55%558
580
116FMe4-methyl-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,88' 97% 59%538
560
117FCN4-cyano-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ether5,59' 97%56%549
571

Example 118

(4-Hydroxy-2-methyl-7-piperidine-1-yl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Compound 17 (200 mg, 0.52 mmol) was dissolved in DMSO (2 ml) in the presence of K2CO3(144 mg, 1.04 mmol) and then treated at room temperature with piperidine (154 μl, 1.56 mmol). This reaction mixture was stirred for 20 h at 100°C and the mixture is then transferred into ethyl acetate and washed with water and saturated NaCl solution. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g; flow rate: 12 ml/min; gradient 0-50% ethyl acetate in heptane) to yield compound 118 as a yellow powder (22 mg, 9.5 per cent).

Jhud: RT=6,39 min, 96%.

1H NMR, DMSO-d6, δ (ppm): 1.64 (broadened s, 6H); 2.63 (s, 3H); 3.57 (broadened s, 4H); 7.22 (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); at 8.62 (s, 1H).

Mass spectrum (ESI+): m/z 449 (MH+ , 100%).

Examples 119-121

Connection 119-121 synthesized from compound 17 and the corresponding amines in accordance with the methodology used to obtain the compound in Example 118.

ExampleNR1R2The name of the connectionEhudOutputWeight of MN+/M-N-
119NMe2(7-dimethylamino-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano5,86' 100%35%409

120(4-hydroxy-2-methyl-7-pyrrolidin-1-yl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano6,18' 100%13%435
121[4-hydroxy-2-methyl-7-(4-phenyl-piperazine-1-yl)-1,1-dioxo-2H-benzo[e][12]thiazin-3-yl]-naphthalene-2-yl-metano 6,18' 94%93%524

Example 122

(7-tert-Butyl-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanon

Compound 122 was synthesized from 2-methyl-5-tert-butylbenzenesulfonyl chloride, using the sequence of stages described in the method for obtaining compounds of 17. The compound was obtained as yellow solid with an overall yield of 10%.

Jhud: RT=6,33 min, 95%.

1H NMR, DMSO-d6, δ (ppm): 1.38 (s, N); 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 123-130

Connection 123-130 synthesized from saccharin and the corresponding 2-bromo-1-arelation using the sequence of stages described in the method for obtaining compounds 1 (123, 125, 127 and 128), compound 8 (124 and 126) and compound 17 (129 and 130).

ExampleR1R2ArThe name of the connectionEhudOutput1Mass MH+/M-H-
123MeH3,4-dichlorophenyl(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)metano5,88' 99%60%382 and 384
124EtH3,4-dichlorophenyl(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)metano6,07' 99%64%396 and 398
125MeHbenzofuran-2-yl(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanon5,31' 99%68%356
126EtHbenzofuran-2-yl(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanon5,54' 99%63%370
127MeH5,6,7,8-tetrahydro-naphthalene-2-yl(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro-naphthalene-2-yl)-methanon6,04' 100%60%370
128MeH5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-methanon6,66' 100%70%426

129MeF5,6,7,8-tetrahydro-naphthalene-2-yl(7-fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-5,6,7,8-tetrahydro-naphthalene-2-yl)-methanon6,14' 95%68%386
130MeF5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl (7-fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-methanon6,75' 93%80%442
1The total yield after 3 stages
*1H NMR, DMSO-d6, Example 123: 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). Example 124: 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). Example 125: 2.98 (s, 3H); 7.43 (t, 1H); 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). Example 126: 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). Example 127: 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). Example 128: 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). Example 129: 1.77 (broadened s, 4H); 2.67 (s, 3H); 2.80 (broadened s, 4H); 7.23 (broadened s, 1H); 7.60-7.85 (m, 4H); 8.21 (m, 1H); 15.85 (s, 1H). Example 130: 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 (broadened s, 1H); 8.21 (q, 1H); 15.65 (s,1H).

Examples 131-143

Connection 131-143 synthesized from saccharin and the corresponding 2-bromo-1-arelation using the sequence of stages described in the method for obtaining compounds 1 (R2=Me) or compound 8 (R2=Et).

tr>
Example*R1R2The name of the connectionEhudOutput1MN+
131Me(2,3-dihydro-benzofuran-5-yl)-(4-hydroxy-2-methyl-1,1-loxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,59' 98%24%358
132Et(2,3-dihydro-benzofuran-5-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,75' 98%23%372
133Mebenzo[1,3]dioxol-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,50' 99%34%360
134 Etbenzo[1,3]dioxol-5-yl-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,66' 97%34%374
135Me(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanonof 5.53' 96%45%374
136Et(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,68' 99%42%388

137Mebenzo[b]thiophene-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,56' 99%31% 372
138Mebenzofuran-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,34' 99%36%356
139Me(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-methyl-1H-benzoimidazol-5-yl)-methanon3,72' 99%5%370
140Mebenzo[b]thiophene-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanonof 5.89' 99%48%372
141Me(4-tert-butyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,97' 99%**32% 372
142Me(3-bromo-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,47' 99%**57%394/3 96
143Me3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzonitrileof 5.84' 93%**37%358
1The total yield after 3 stages

*1H NMR, DMSO-d6, Example 131: 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). Example 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). Example 133: 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). Example 134: 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). Example 135: 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). Example 136: 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). Example 137: 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). Example 138: 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). Example 139: 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). Example 140: 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). Example 141: 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). Example 142: 2.65 (s, 3H); 7.60 (t, 1H); 7.90 (d, 1H); 7.95-8.05 (m, 4H); 8.11 (s, 1H); 8.19 (broadened s, 1H); 15.06 (s, 1H, exchange). Example 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); at 14.86 (broadened s, 1H, exchange).
** XBridge column

Examples 144-146

Connection 144-146 synthesized from saccharin and the corresponding 2-bromo-1-arelation using the sequence of stages described in the method for obtaining compounds 1.

2-Bromo-1-arelation received by the synthesized relevant arelation in accordance with the above-described method of obtaining connection 144A. 1-(3,4-Dimetilfenil)alanon (2.5 g, about 16.9 mmol) was dissolved in THF (42 ml) at room temperature under nitrogen atmosphere. Added triperoxonane acid (1.5 ml and 16.9 mmol) and then t is Bromid pyridinium (6.5 g, a 20.2 mmol). The solution was crimson red, and gradually formed a white precipitate. The reaction mixture was stirred for three hours at room temperature, then neutralized by addition of water (50 ml) and then extracted with ethyl acetate (100 ml). The organic phase was washed with saturated solution of CuSO4(40 ml), saturated NaCl solution (40 ml) and then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a column of silica gel (130) with a gradient of 0%-5% ethyl acetate in heptane with getting two servings of 2-bromo-1-(3,4-dimethyl-phenyl)-ethanone (144A. 57%).

Portion 1: 1,25 g, Ehud: RT=4,90 min, 90%.

Portion 2: 1,90 g, Ehud: RT=4,90 min, 70%.

Example*R1The name of the connectionEhudOutput1MH+
144(3,4-dimethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon5,62' 99%27%344
145 (4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-trifluoromethyl-phenyl)-methanon6,56' 99%**23%384
146(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4-trifluoromethyl-phenyl)-methanon6,64' 99%**17%384
1The total yield after 4 stages
*1H NMR, DMSO-D6, Example 144: 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 (m, 3H); 8.18-8.21 (m, 1H); 15.73 (s, 1H, exchange). Example 145: 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 (broadened s, 2H), 15.00 (broadened s, 1H, exchange). Example 146: 2.64 (s, 3H); 8.00-8.03 (m, 5H); 8.17-8.21 (m, 3H); 15.06 (broadened s, 1H, exchange).
** XBridge column.

Example 147

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

Example A - Adamantane-2-carbonitrile

Adamantane (2.5 g, of 16.6 mmol) was dissolved in 1,2-dimethoxyethane (DME) (58 ml) in the presence of ethanol (1.7 ml) and TosMIC (4,22 g, 21.6 mmol) under nitrogen atmosphere. This reaction mixture was cooled with an ice bath. Was slowly added Tr is t-butyl potassium (5,72 g, 51 mmol), maintaining the temperature of the reaction mixture in the range from 2 to 11°C. the Reaction mixture was stirred for 30 min, keeping the temperature of the reaction mixture in the range from 5 to 12°C, then heated to room temperature and continued stirring for 2 h Then the reaction mixture was filtered, the filtered white precipitate was washed with DME. The filtrate was concentrated. The resulting residue was purified on silica gel (5% ethyl acetate in heptane) to yield compounds A in the form of a white solid (2.38 g, 88%).

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

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

Example V - 1-Adamantane-2-yl-alanon

Connection A (4,63 g, 28.7 mmol) was dissolved in diethyl ether (61 ml) under nitrogen atmosphere and then cooled using an ice bath. Was added dropwise motility (27 ml of 1.6 M/Et2O, 43 mmol), maintaining the temperature of the reaction mixture in the range from 5°C to 12°C. Immediately after completion of the addition the cold bath was removed and stirring continued for 30 min at room temperature. Then the reaction mixture was neutralized by adding water (46 ml). Selected organic phase, which was dried by magnesium sulfate, dried and concentrated under reduced pressure. The residue was transferred into a mixture of Aceto is a (28 ml) and 6 N. HCl (28 ml) and then heated at the temperature of reflux distilled for 80 minutes Then evaporated acetone and the remaining aqueous phase was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (90 g; 32 ml/min; 6% ethyl acetate in heptane) to yield compounds V in the form of a yellow solid (3,66 g, 71%).

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

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

Example C - 1-Adamantane-2-yl-2-bromo-alanon

Connection V (500 mg, 2.8 mmol) was dissolved in methanol (8.6 ml) in nitrogen atmosphere, and then cooled to 0°C. was Slowly added bromine (151 μl, to 2.94 mmol). This reaction mixture was stirred for 1 h 40 min at 0°C and then neutralized by addition of water and was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (35 g; 20 ml/min; gradient 0%-15% ethyl acetate in heptane over 25 min) to yield compounds S (of 1.37 g, 85%).

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

Example 147 - Adamantane-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihyd the on-2H-benzo[e][1,2]thiazin-3-yl)-methanon

Compound 147 was synthesized from saccharin and connections S using the sequence of stages described in the method of obtaining compound 1 (yield after three stages: 11%).

White solid.

Jhud: RT=6,28 min, 97%.

1H NMR, DMSO-d6, δ (ppm): 1.54-1.61 (m, 2H); 1.68-1.93 (m, 8H); 2.05-2.25 (m, 2H); 2.36 (broadened 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 spectrum (ESI-): m/z 372 (M-H-, 100%).

Example 148

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

Example A - Chroman

4-Chromanone (5.0 g, or 33.7 mmol) was dissolved in THF (102 ml) in nitrogen atmosphere. Was added at room temperature BF3.OEt2(of 12.8 ml, 101 mmol) and slowly added cyanoborohydride sodium (4,33 g of 67.4 mmol) of (violent reaction). The resulting white suspension was heated to 65°C for 18 h and then neutralized with water. The reaction mixture was twice extracted with ethyl acetate. The organic phases were combined, washed sequentially with saturated solution of NaHCO3and saturated NaCl solution and then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel (gradient 0%to 50% dichloromethane in heptane and then with 10% ethyl acetate in heptane) to yield partially purified compound 148A (3,34g, 61%).

Jhud: RT=4,56 min, 83%.

1H NMR, DMSO-d6, δ (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 V - 1-Chroman-6-yl-alanon

Chroman (with 4.64 g, 29.4 mmol) was dissolved in 30 ml of anhydrous dichloromethane (DHM) in nitrogen atmosphere. This reaction mixture was cooled to -30°C and then for 5 min was added to a cold (-10°C) solution of ethanoyl chloride and 4.75 ml, 67 mmol) in anhydrous DHM (20 ml). This mixture was stirred for 45 min at -15°C and then poured into a mixture of ice (100 g) and concentrated HCl (50 ml) and three times were extracted DHM. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on a column of silica gel (120 g; gradient 0%-20% EtOAc in heptane for 60 min) to obtain the two portions of the connection V (70%).

Portion 1: 2.25 g, Ehud: RT=4.09 to min, 96,6%.

1H NMR, DMSO-d6, δ (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%).

Portion 2: 1,79 g, Ehud: RT=4.09 to min, 81%.

Example S - 2-Bromo-1-chroman-6-yl-alanon

Connection IS synthesized from compound V in accordance with the method of obtaining compounds 144A (yield: 65%).

Jhud: RT=4,59 min, 74%.

1H NMR, DMSO-d6, δ (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-dioxo-1,2-Digi the ro-2H-benzo[e][1,2]thiazin-3-yl)-methanon

Compound 148 was synthesized from saccharin and connections S using the sequence of stages described in the method for obtaining compounds 1, with a total yield of 36%.

Jhud: RT=the 5.45 min, 98%.

1H NMR, DMSO-d6, δ (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 (MN+, 100%).

Example 149

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

Example A - 1-(4-Chloro-3-trifluoromethyl-phenyl)-ethanol

4-Chloro-3-trifluoromethyl-benzaldehyde (to 6.19 g, 29.7 mmol) was dissolved in THF (124 ml) in nitrogen atmosphere. This reaction mixture was cooled to -78°C, then was added dropwise MeMgBr (13 ml, 3M/Et2O, and 38.6 mmol) and then was stirred for 2 h at low temperature (-78°C), finally neutralized by adding a saturated solution of NH4Cl (60 ml). Then the reaction mixture was twice extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl solution and then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on a column of silica gel (120 g; 92 ml/min; gradient 0%-35% ethyl acetate in heptane over 40 min) to yield compounds A (5,71 g, 62%).

Jhud: RT=5,71 min, 98% (XBridge column).

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

Example V - 1-(4-Chloro-3-trifluoromethyl-phenyl)-alanon

Connection A (2,62 g, 11.7 mmol) was dissolved in DHM (53 ml) in the presence of celite (3.8 g). Was added at room temperature RCC (chlorproma pyridinium) (3.77 g, 17.5 mmol) and this reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified on a column of silica gel (80 g; 32 ml/min; gradient 0%-30% EtOAc in heptane over 26 min) output connection V of 2.27 g, 87%).

Jhud: RT=of 5.84 min, 97% (XBridge column).

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

Example S - 2-Bromo-1-(4-chloro-3-trifluoromethyl-phenyl)-alanon

Connection IS synthesized from compound V in accordance with the method of obtaining compounds 144A (yield: 66%).

Jhud: RT=6,18 min, 89% (XBridge column).

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

Example 149 - (4-Chloro-3-trifluoromethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon

Compound 149 was synthesized from saccharin and connections S using the sequence of stages described in the method for obtaining compounds 1, with an overall yield of 20%.

Jhud: RT=of 6.71 min, 99% (XBridge column).

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

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

Example 150

(7-Bromo-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

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

5-Bromo-2-methyl-benzosulfimide (2.5 g, of 9.99 mmol) was dissolved in 5% aqueous sodium carbonate solution (62 ml). This reaction mixture was heated to 100°C, and gradually, over 15 min, was added KMPO4(to 6.43 g, 25 mmol). Heating was continued for 140 minutes, the Reaction mixture was cooled to room temperature and then filtered. the pH of the filtrate is brought to 1.2 with concentrated HCl and then filtered. The precipitate was washed with ethyl acetate. Two phases of the filtrate were separated and the resulting aqueous phase once were extracted with ethyl acetate. The organic phase was collected, dried with magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 150A (1.64 g, 58%).

Jhud: RT=0,29 min, 99.5 per cent.

1H NMR, DMSO-d6, δ (ppm): 7.35 (s, 2H, exchangeable); 7.67 (d, 1H); 7.91 (d, 1H); 8.08 (s, 1H); 13.83 (broadened s, 1H, exchange).

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

Example 150V - 6-Bromo-1,1-dioxo-1,2-dihydro-2H-benzo[d]isothiazol-3-one

Connection 150A (1,59 g, to 5.56 mmol) was dissolved in concentrated sulfuric acid (6 ml) at the room for the Noah temperature and this reaction mixture was stirred for 3 h, then poured into ice. The resulting suspension was filtered. The precipitate was washed three times with water and then dried for 24 h at 50°C under vacuum. Connection 150V (1,33 g, 89%) was obtained as a white solid.

Jhud: RT=3,16 min, 96%.

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

Mass spectrum (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)-naphthalene-2-yl-metano

Compound 150 was synthesized from compound 150V and 2-bromo-1-(naphthalene-2-yl)ethanone using the sequence of stages described in the method for obtaining compounds 1, with a total yield of 55%.

Jhud: RT=6,14 min, 97%.

1H NMR, DMSO-d6, δ (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-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Example A - 6-Chloro-1,1-dioxo-1,2-dihydro-2H-benzo[d]isothiazol-3-one

Methyl 2-amino-4-chlorobenzoate (5 g, 26.9 mmol) was heated in 20% aqueous HCl (18 ml) until complete dissolution and then cooled to 0°C. was Added dropwise a solution of NaNO2(1.85 g, 26.9 mmol) in water (4.5 ml), maintaining the temperature in the range from 2°C to 6°C. Then the reaction mixture was stirred during the 1 h at room temperature. In another flask a mixture of acetic acid (22 ml) and water (2.3 ml) at 0°C was barbotirovany gaseous SO2(approximately 15 g). Then was added CuCl (666 mg, 6.7 mmol). Then to the resulting blue-green solution at a temperature in the range from 1°C to 3°C was added to the reaction mixture in the first flask. Observed gas; mixing at low temperature was continued for 45 min, then the cooling bath was removed and the reaction mixture was poured into ice (100 g) and three times were extracted with ethyl acetate. The organic phase was collected, washed with saturated solution of NaHCO3, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was transferred to a THF (5 ml) at 0°C and slowly added concentrated ammonia solution (2.8 ml). The cooling bath was removed and stirring was continued for 1 h Then the reaction mixture was concentrated, treated with saturated solution of NaHCO3once washed with diethyl ether and then the pH was brought back to 1 with concentrated HCl solution. The precipitate was separated by filtration, washed with water and dried under reduced pressure at 50°C with connection A (896 mg, 15%).

Jhud: RT=3,07 min, 99%.

1H NMR, DMSO-d6, δ (ppm): 7.94 (broadened d, 2H); 8.38 (s, 1H).

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

Example 151 - (7-Chloro-4-guide is hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Compound 151 was synthesized from compound A and 2-bromo-1-(naphthalene-2-yl)ethanone using the sequence of stages described in the method for obtaining compounds 1, with a total yield of 39%.

Jhud: RT=6,13 min, 95%.

1H NMR, DMSO-d6, δ (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 spectrum (ESI-): m/z 398 (M-H-, 100%); 400 (M-H-, 32%).

Example 152

(4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Example 152A - 2-Cyano-5-methyl-benzosulfimide

2-Amino-4-methyl-benzonitrile (2.5 g, to 18.9 mmol) was heated in 20% aqueous HCl (12 ml) until complete dissolution and then cooled to 0°C. was Added dropwise a solution of NaNO2(1.3 g, to 18.9 mmol) in water (3.2 ml), maintaining the temperature in the range from 2°C to 6°C. Then the reaction mixture was stirred for 1 h at room temperature. In another flask a mixture of acetic acid (15 ml) and water (1.6 ml) at 0°C was barbotirovany gaseous SO2(approximately 15 g). Then was added CuCl (468 mg, 4.7 mmol). Then to the resulting blue-green solution at a temperature in the range from 1°C to 3°C was added to the reaction mixture in the first flask. Mixing at low temperature was continued for 45 min, then remove the cooling bath and then the reaction mixture was poured into ice (70 g) and three RA is and was extracted with a mixture of 20% methanol/DHM. The organic phase was collected, washed with saturated solution of NaHCO3, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was transferred to a THF (5 ml) at 0°C and slowly added concentrated ammonia solution (2.8 ml). The cooling bath was removed and stirring was continued for 1 h Then the reaction mixture was concentrated, treated with saturated solution of NaHCO3once washed with diethyl ether and then the pH was brought back to 1 with concentrated HCl solution. The precipitate was separated by filtration, washed with water and dried under reduced pressure at 50°C with connection 152A (800 mg, 21%).

Jhud: RT=3,67 min, 99% (XBridge column).

1H NMR, DMSO-d6, δ (ppm): 7.61 (d, 1H); 7.77 (s, 1H); 7.99 (d, 1H); 8.77 (broadened s, 2H).

Macc-specr (ESI+): m/z 197 (MH+, 100%).

Example V - 4-Methyl-2-sulfamoyl-benzoic acid

Connection 152A (620 mg, 3,15 mmol) was dissolved in 30% aqueous KOH solution (7.5 ml), hydrogen peroxide (530 μl of 30% aqueous solution). This reaction mixture was heated at the temperature of reflux distilled for 4 h and then cooled to room temperature, the pH is brought back to 1 with concentrated HCl and three times were extracted with a mixture of 20% methanol/DHM. The organic phase was collected, dried with magnesium sulfate, filtered and concentrated under decreased the pressure obtaining connection V (428 g, 60%).

Jhud: RT=4,11 min, 95% (XBridge column).

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

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

Example S - 6-Methyl-1,1-dioxo-1,2-dihydro-2H-benzo[d]isothiazol-3-one

Connection V (428 mg, 1.94 mmol) was dissolved in concentrated sulfuric acid (3 ml) at room temperature. This reaction mixture was stirred for 2 h and then poured into ice and filtered. The precipitate was washed with plenty of water and then dried to obtain compound C (359 mg, 93%) as a pink solid.

Jhud: RT=4,00 min, 96% (XBridge column).

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

Mass spectrum (ESI-): m/z 196 (M-N-, 100%).

Example 152 - (4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanon.

Compound 152 was synthesized from compound C and 2-bromo-1-(naphthalene-2-yl)ethanone using the sequence of stages described in the method for obtaining compounds J., with a total yield of 21%.

Jhud: RT=6,87 min, 98% (XBridge column).

1H NMR, DMSO-d6, δ (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+(chemical ionization at atmospheric pressure)): m/z 380(MH+, 24%).

Example 153

Bifani the-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon

Example 153 - Biphenyl-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon

Compound 142 (200 mg, 0.5 mmol) was dissolved in acetone (1.1 ml) and water (1.2 ml) in the presence of phenylboronic acid (68 mg, 0.55 mmol), potassium carbonate (175 mg, of 1.27 mmol) and palladium acetate (5 mg, 0.02 mmol) in an atmosphere of inert gas. This reaction mixture was heated to 85°C for 1 h and 30 min and then cooled to room temperature, diluted with water and three times were extracted DHM. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on a column of silica gel (12 g)using elution DHM, with output connections 153 (141 mg, 68%).

Jhud: RT=7,07 min, 96% (XBridge column).

1H NMR, DMSO-d6, δ (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 (broadened s, 1H); 8.31 (s, 1H); 15.36 (broadened s, 1H, exchange).

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

Examples 154-169

Connection 154-169 synthesized from compound 142 and various Baranovich acids in accordance with the above-described method of obtaining connection 153.

Example*RThe name is connected is th Jhud**OutputM-N-(MH+)
154(2'-fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,80' 95,9%27%404

155(3'-fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,93' of 98.2%66%408
156(4'-fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,92' 98,7%64%408
157(2'-chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,99 is 94,8% 11%(426)
158(3'-chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon7,19' 98%58%(426)
159(4'-chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon7,22' 97,9%67%(426)
160(2'-methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon7,08' 98,4%61%404
161(3'-methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon7,15' 99,6%60%404

162(4'-methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon7,16' 99,5%70%404
163(2'-methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,85' 100%69%420
164(3'-methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,86' 98,5%53%420
165(4'-methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,83' 99,5%72%420
166 (4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3'-trifluoromethyl-biphenyl-3-yl)-methanon7,17'
97,5%
45%458
167(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4'-trifluoromethyl-biphenyl-3-yl)-methanon7,22' 98,3%44%458
168(3'-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-biphenyl-3-carbonitril6,57' 99,5%50%415

1693'-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-biphenyl-4-carbonitrile6,57' to 97.1%61%415
*1H NMR, DMSO-d6, Example 154: 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 (broadened s, exchangeable, 1H). Example 155: 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 (broadened s, exchangeable, 1H). Example 156: 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 (broadened s, exchangeable, 1H). Example 157: 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 (broadened s, exchangeable, 1H). Example 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 (broadened s, exchangeable, 1H). Example 159: 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 (broadened s, exchangeable, 1H). Example 160: 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 (broadened s, exchangeable, 1H). Example 161: 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 (broadened s, 1H, exchange). Example 162: 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 (broadened s, 1H, exchange). Example 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 (broadened s, 1H, exchange). Example 164: 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 (broadened s, 1H, exchange). Example 165: 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 (broadened s, 1H, exchange). Example 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 (broadened s, 1H, exchange rate the config). Example 167: 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 (broadened s, 1H, exchange). Example 168: 2.67 (s, 3H); 7.73 (d, 1H); 7.78 (d, 1H); 7.91 (d, 1H); 8.00 (broadened s, 3H); 8.07-8.10 (m, 3H); 8.19-8.25 (m, 2H); 8.32 (s, 1H); 15.23 (broadened s, 1H, exchange). Example 169: 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 (broadened s, 1H, exchange).
** XBridge column

Example 170

(4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Example 170 - (4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-metano

Compound 170 was synthesized from 5-methanesulfonyl-2-methyl-benzazolyl chloride, using the sequence of stages described in the method for obtaining compounds of 17, with a total yield of 7%.

Jhud: RT=5,43 min, 97%.

1H NMR, DMSO-d6, δ (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-2W-benzo[e][1,2]thiazin-3-yl)-(1-phenyl-cyclopropyl)-methanon

Example A - 1-(1-Phenyl-cyclopropyl)-alanon

Connection A was synthesized from 1-phenyl-cyclopropanecarbonitrile in accordance with the above described method for obtaining compounds of V (yield: 40%).

Jhud: RT4,30 min, 96% (XBridge column).

1H NMR, DMSO-d6, δ (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-phenyl-cyclopropyl)-methanon

Compound 171 was synthesized from compound A using the sequence of stages described in the method for obtaining compounds of 144, with a total yield of 6%.

Jhud: RT=6,40 min, 96% (XBridge column).

1H NMR, DMSO-d6, δ (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]thiazin-3-carbonyl)-phenyl]-alanon

Example 172 - 1-[3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-phenyl]-alanon

Compound 172 was synthesized from 1-(3-acetyl-phenyl)-ethanone using the sequence of stages described in the method for obtaining compounds of 144, with a total yield of 21%.

Jhud: RT=6,25 min, 97% (XBridge column).

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

Mass spectrum (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-Cryptor-1-hydroxy-1-methyl-ethyl)-phenyl]-Manon

Example A - 1-[3-(2,2,2-Cryptor-1-hydroxy-1-methyl-ethyl)-phenyl]-alanon

1-(3-Acetyl-phenyl)-Etalon (2.5 g, to 15.4 mmol) was dissolved in THF (120 ml) under nitrogen atmosphere at 0°C in the presence of TMS-CF3(2.7 ml, 18.4 mmol). Within 20 min by means of a piston pump was added TBAF (tetrabutylammonium fluoride) (MLTF, an 18.4 ml, 18.4 mmol). The cooling bath was removed and the reaction mixture was stirred additionally for 18 h, then neutralized by adding a saturated solution of NaHCO3and finally 3 times were extracted with ethyl acetate. The organic phases were combined, washed with water and then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel (gradient of 0%-50% ethyl acetate in heptane over 20 min) to yield partially purified compounds A (2,87 g), which was used as is in the next stage.

Example W - 2-Bromo-1-[3-(2,2,2-Cryptor-1-hydroxy-1-methyl-ethyl)-phenyl]-alanon

Connection W synthesized from compound A in accordance with the method of obtaining compounds 144A (yield: 57%).

Jhud: RT=5,50 min, 74% (XBridge column).

1H NMR, DMSO-d6, δ (ppm): 1.73 (s, 3H); 4.96 (s, 2H); 6.81 (broadened 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-Cryptor-1-g is droxy-1-methyl-ethyl)-phenyl]-methanon

Compound 173 was synthesized from saccharin and connections V using the sequence of stages described in the method for obtaining compounds 1, with a total yield of 52%.

Jhud: RT=6,05 min, 95% (XBridge column).

1H NMR, DMSO-d6, δ (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 (broadened s, 1H, exchange).

Mass spectrum (ESI+): m/z 445 (MNH4+, 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-Cryptor-1-hydroxy-ethyl)-phenyl]-methanon

Example A - 1-[3-(2,2,2-Cryptor-1 trimethylsilyloxy-ethyl)-phenyl]-alanon

3-Acetilsalicilic (1.27 g, to 8.57 mmol) was dissolved in DMF (30 ml) under nitrogen atmosphere in the presence of potassium carbonate (59 mg, 0.42 mmol) and S-CF3(of 1.52 ml of 10.3 mmol). This reaction mixture was stirred for 30 min at room temperature, then neutralized by adding a saturated solution of NH4Cl (1 ml) and concentrated under reduced pressure. The residue was transferred into ethyl acetate and then washed with 1 N. HCl solution in water, dried with magnesium sulfate, filtered and concentrated under reduced pressure to obtain partially purified compounds A (2.55 g), which was used as is in the next stage.

Jhud: RT=5,15 min, 42% (HE) within 6,91 min, 40% (OTMS) (XBridge column, partially the removal of the protective groups on the column).

1H NMR, DMSO-d6, δ (ppm): 0.09 (s, N); 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 W - 2-Bromo-1-[3-(2,2,2-Cryptor-1-hydroxy-ethyl)-phenyl]-alanon

Connection W synthesized from compound A in accordance with the method of obtaining compounds 144A (yield: 60%).

Jhud: RT=5,23 min, 83% (XBridge column).

1H NMR, DMSO-d6, δ (ppm): 4.93 (s, 2H); 5.32 (q, 1H); 7.03 (broadened 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-Cryptor-1-hydroxy-ethyl)-phenyl]-methanon

Compound 174 was synthesized from saccharin and connections V using the sequence of stages described in the method for obtaining compounds 1, with a total yield of 33%.

Jhud: RT=of 5.92 min, 92% (XBridge column).

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

Mass spectrum (ESI+): m/z 431 (MNH4+, 100%).

Example 175

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

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

Compound 143 (100 mg, 0.29 mmol) was dissolved in 30% solution of KOH in water (1 ml) in the Pris is under ethanol (330 ml) and then was heated up to 70°C for 18 hours This reaction mixture was diluted with water (10 ml), washed twice with diethyl ether, the pH was brought again to 26 N. aqueous solution of HCl and finally the mixture three times was extracted with 20% solution of methanol in DHM. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated to obtain compound 175 in the form of a yellow solid (99 mg, 93%).

Jhud: RT=5,49 min, 98% (XBridge column).

1H NMR, DMSO-d6, δ (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, exchangeable, 1H); 15.32 (s, exchangeable, 1H).

Mass spectrum (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]thiazin-3-carbonyl)-N-methyl-benzamide

Example 176 - 3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N-methyl-benzamide

Compound 175 (150 mg, 0.41 mmol) was dissolved in DMF (3 ml) in the presence of (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (120 mg, of 0.62 mmol), 3-hydroxy-3H-benzo[d][1,2,3]triazine-4-it (102 mg, of 0.62 mmol) and iPr2NEt (162 mg, 1.25 mmol) in an atmosphere of inert gas, and then was stirred for 72 h at room temperature. Then the reaction mixture was concentrated under reduced pressure, diluted DHM (20 ml) and twice washed with 1 N. aqueous solution of HCl. The aqueous phase was collected and extracted DHM. The organic phases were combined, who left the house taking magnesium sulfate, was filtered and concentrated. The resulting residue was purified on a column of silica gel (12 g, 12 ml/min; gradient 0%to 25% acetone in DHM for 20 min) to yield compound 176 in the form of a yellow solid (101 mg, 64%).

Jhud: RT=total of 5.21 min, 97% (XBridge column).

1H NMR, DMSO-d6, δ (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 (broadened s, 1H, exchange).

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

Examples 177-183

Connection 177-183 synthesized from compound 175 and various amines in accordance with the above-described method of obtaining connection 176.

Example*RThe name of the connectionJhud**OutputMN+
1773-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N,N-dimethyl-benzamide5,33' 95,8%44%387
178N-ethyl-3-(4-hydroxy-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide 5,41' to 96.9%39%387
1793-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N,N-diethyl-benzamide5,71' to 96.9%34%415
180N-cyclopropyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide5,43' 96,6%33%399
181N-cyclopropylmethyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide5,71' 98,7%33%413

1823-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N-phenyl-benzamide6,09' 99,5% 67%435
183N-benzyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide5,96' 93,8%6%449
*1H NMR, DMSO-d6, Example 177: 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 (broadened s, exchangeable, 1H). Example 178: 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 (broadened s, exchangeable, 1H). Example 179: 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 (broadened s, exchangeable, 1H). Example 180: 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 (broadened s, exchangeable, 1H). Example 181: 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 (broadened s, exchangeable, 1H). Example 182: 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 (broadened s, exchangeable, 1H). Example 183: 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 (broadened s, exchangeable, 1H).
** XBridge column

Example 184

3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]tease the-3-carbonyl)-benzamide

Example 184 - 3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide

Compound 175 (150 mg, 0.42 mmol) was dissolved in THF (3 ml) in the presence of Rumor (239 mg, 0.46 mmol), ammonia (152 μl, 1.25 mmol) and DIEA (80 μl, 0.46 mmol) and was stirred for 4 h at room temperature. Then the reaction mixture was diluted DHM (20 ml) and washed with 1 N. aqueous solution of HCl. The aqueous phase is four times were extracted DHM. The organic phases were combined, dried with magnesium sulfate, filtered and concentrated to obtain compound 184 in the form of a yellow solid (71 mg, 46%).

Jhud: RT=5,06 min, 97,4% (XBridge column).

1H NMR, DMSO-d6, δ (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 (broadened s, exchangeable, 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]thiazin-3-carbonyl)-benzoic acid ethyl ester

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

Compound 175 (150 mg, 0.42 mmol) was dissolved in ethanol (6 ml) in the presence of pTsOH (8 mg, 0.04 mmol) and was heated at the temperature of reflux distilled for 18 h with stirring. Then the reaction mixture was concentrated under reduced pressure. The obtained results in the E. the residue was purified on a column of silica gel (12 g; 12 ml/min; DHM) connection output 185 in the form of a yellow solid (138 mg, 84%).

Jhud: RT=6,28 min, 95,8% (XBridge column).

1H NMR, DMSO-d6, δ (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 (broadened s, exchangeable, 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)-methanon

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)-methanon

Compound 142 (200 mg, 0.5 mmol) was dissolved in 1,4-dioxane (1.5 ml) in the presence of pyridine-3-Voronovo acid (104 mg, from 0.76 mmol), potassium orthophosphate (1,27 mol/l, 679 μl, 0.86 mmol), Tris(dibenzylideneacetone)diplegia (23 mg, of 0.025 mmol) and tricyclo-existsfile (21 mg, 0,076 mmol) in an atmosphere of inert gas. This reaction mixture was heated to 100°C for 18 h and then cooled to room temperature, diluted DHM and washed with saturated solution of NH4Cl. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on a column of silica gel (12 g; 16 ml/min; gradient 0%-5% methanol for 7 min) to yield compound 186 (128 mg, 62%).

Jhud: RT=5,07 min, 97,5% (XBridge column).

1H NMR, DMSO-d6, δ (ppm): 2.67 (s, 3H); 7.77-7.82 (m 3 is); 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 (broadened s, 1H, exchange).

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

Examples 187-195

Connection 187-195 synthesized from compound 144 and various Baranovich acids in accordance with the above-described method of obtaining connection 186.

Example*RThe name of the connectionJhud**OutputM-N-(MN+)
187(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-4-yl-phenyl)-methanon5,02' 97,5%62%393
188(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methyl-pyridin-3-yl)-phenyl]-methanon5,04' 93%49%407
189 (4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(5-methyl-pyridin-3-yl)-phenyl]-methanon5,09' 97,9%53%407
190(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methyl-pyridine-3-yl)-phenyl]-methanonof 5.05' 98,1%60%407
191(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methyl-pyridin-3-yl)-phenyl]-methanon5,02' 100%70%407
192(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methoxy-pyridine-3-yl)-phenyl]-methanon5,07' 100%21%423

193(4-hydroxy-2-methyl-,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-fluoro-pyridin-3-yl)-phenyl]-methanon 6,28' 97,3%37%411
194(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methoxy-pyridin-3-yl)-phenyl]-methanon6,41' to 96.9%63%423
195(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methoxy-pyridin-3-yl)-phenyl]-methanon6.35mm' 97,5%27%423
*1H NMR, DMSO-d6, Example 187: 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 (broadened s, 1H, exchange). Example 188: 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 (broadened s, 1H, exchange). Example 189: 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 (broadened s, 1H, exchange). Example 190: 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 (broadened s, 1H, exchange). Example 191: (CDCl3) 2.58 (s, 3H); 2.74 (s, 3H); 7.24 (dd, 1 H); 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). Example 192: 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 (broadened s, 1H, exchange). Example 193: 2.67 (s, 3H); 7.37 (dd, 1H); 7.77 (t, 1H); 8.00 (broadened 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 (broadened s, 1H, exchange). Example 194: 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 (broadened s, 1H, exchange). Example 195: 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 (broadened s, 1H); 8.28 (s, 1H); 8.55 (s, 1H); 15.30 (broadened s, 1H, exchange).
** XBridge column

Examples 196 and 197

Connection 196 and 197 was synthesized from saccharin and 2-bromo-1-(3-chlorophenyl)ethanone and 2-bromo-1-(3-forfinal)ethanone, respectively, using the above-described methods for obtaining compounds 1.

Example*RThe name of the connectionJhud**Output1M-N-
196Cl(3-chloro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanonto 6.43' 98,7%37%348/
350
197F(3-fluoro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanon6,14' 96,5%19%332
The total yield after 3 stages.
*1H NMR, DMSO-d6, Example 196: 2.66 (s, 3H); 7.67 (t, 1H); 7.78 (1H); 7.99 (s, 5H); 8.15 (broadened s, 1H); 15.07 (broadened s, 1H, exchange). Example 197: 2.65 (s, 3H); 7.58 (t, 1H); 7.70 (dd, 1H); 7.76 (d, 1H); 7.90 (d, 1H); 7.99 (broadened s, 3H); 8.20 (broadened s, 1H); 15.15 (broadened s, 1H, exchange).
** XBridge column

In model experiments, the results of which are given below, shows that the compounds of the present invention selectively inhibit 11β-HSD1 in comparison with 11β-HSD2.

1) the Enzymatic activity of 11β-HSD1 from the macro human liver after processing any abscopal compounds (% inhibition)

This enzymatic test is based on the conversion of cortisone to cortisol by using 11β-HSD1. The enzymatic reaction was started by adding to the wells of 96-well plates with half the volume of the wells containing 160 nmol of cortisone in 20 mm Tris buffer (pH 7.4)containing 5 mm EDTA, 200 μm NADP(H) (nicotinamide adenine dinucleotide phosphate, reduced) and an inhibitory compound or vehicle (1% DMSO), 1 μg of the preparation of human liver microsomes (Xenotech) (volume of the reaction mixture of 50 ál). Data to construct the calibration curve for known concentrations of cortisol were obtained simultaneously with the experimental data using the same conditions. The plates were incubated for 2 h at 37°C (enzyme phase). The enzymatic reaction can be stopped by adding 25 µl of conjugate cortisol-d2 and 25 μl of labeled Eu3+-Cryptocom antibodies against cortisol per well; after incubation for 2 h at room temperature, the resulting cortisol (registration phase) can be determined using HTRF®(CISBIO international, Keith 62CO2PEC). Measurement of fluorescence was performed using reader Fusion™ α (Perkin Elmer). The fluorescence of each well was measured at 620 nm and 665 nm. To calculate the ratio (λ665 nm/λ620 nm) and specific FRET signal, which can be determined the percentage of inhibition for each concentration of the analyzed inhibitory connections.

References (posters):

IC50determination 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 HTRF®acceptor, d2: M.Amoravain et al., SBS, 12thAnnual Conference, September 2006, Seatle (USA)

2) the Enzymatic activity of 11β-HSD1 from human liver microsomes after treatment any abscopal compounds (% inhibition or EC50)

the p enzymatic test is based on the conversion of [ 3H]-cortisone [3H]-cortisol with 11β-HSD1. The enzymatic reaction was started by adding to the wells of 96-well plates Optiplate™; containing 20 nmol [1,2-3H]-cortisol (specific activity 40-50 CI/mmol, Amersham-GE Healthcare) in 50 mm HEPES-buffer (pH 7.4)containing 100 mm KCl, 5 mm NaCl, 2 mm MgCl2, 1 mm NADP(H) and an inhibitory compound or vehicle (1% DMSO), 1 μg of the preparation of human liver microsomes (Xenotech) (standardized quantity of the drug, providing the transformation to a maximum of 80% of the substrate in the used experimental conditions) (volume of the reaction mixture of 50 ál). Hermetically sealed plates were centrifuged at low speed for mixing the components and then incubated for 2 h at 37°C (enzyme phase). The enzymatic reaction was stopped by adding to each well 70 μl of the complex (10 mg/ml)obtained by pre-incubation yttrium silicate SPA beads coated with A-protein (GE Healthcare), with a monoclonal antibody against cortisol (East Coast Biologies, ME)containing 10 µmol 18β-glycyrrhetinic acid. Tablets hermetically closed and then incubated with a weak orbital stirring for 2 h at room temperature (phase register). After centrifugation measured using a scintillation counter TopCount NXT (Perkin Elmer). For all the concentrations of the analyzed compounds was calculated percent inhibition of enzyme activity relative to the standard enzyme activity (vehicle: 1% DMSO); then, on the basis of these data determined the activity of each compound (value EU50(the concentration at which achieved a 50% effect), calculated using the program SigmaPlot v.11 using the 4-parametric logistic equation).

Links:

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) the Enzymatic activity of 11β-HSD2 of macro human kidney after processing any abscopal compounds (% inhibition)

This enzymatic test is based on the conversion of [3H]-cortisol [3N]-cortisone with 11β-HSD2. The enzymatic reaction was started by adding to the wells of 96-well plates Optiplate™, containing 8 nm [1,2,6,7-3H] cortisol (specific activity 70-75 CI/mmol, Amersham-GE Healthcare) in 50 mm HEPES-buffer (pH 7.4)containing 100 mm KCl, 5 mm NaCl, 2 mm MgCl2, 1 mm NAD+and inhibitory compound or vehicle (1% DMSO), 0.75 μg of microsomal human kidney (Xenotech) (standardized quantity of the drug, providing the transformation to a maximum of 80% of the substrate in the used experimental conditions) (volume of the reaction mixture of 50 ál). Hermetically sealed plates were centrifuged at n is scoi speed for mixing the components and then incubated for 2 h at 37°C (enzyme phase). The enzymatic reaction was stopped by adding to each well 70 μl of the complex (10 mg/ml)obtained by pre-incubation yttrium silicate SPA beads coated with A-protein (GE Healthcare), with a monoclonal antibody against cortisol (East Coast Biologies, ME)containing 10 µmol 18β-glycyrrhetinic acid. Tablets hermetically closed and then incubated with a weak orbital stirring for 2 h at room temperature (phase register). After centrifugation measured using a scintillation counter TopCount NXT (Perkin Elmer). For each concentration of the analyzed compounds was calculated percent inhibition of enzyme activity relative to the standard enzyme activity (vehicle: 1% DMSO).

Links:

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

Results

Some of the following examples, selected from the compounds of the present invention, illustrate the unexpected ability of these compounds to selectively inhibit 11β-HSD1 in comparison with 11β-HSD2.

[01874]

Examples11β-HSD1/HTRF11β-HSD1/SPA11β-HSD2/SPA
% inhibition (10-6M)% inhibition (10-6M)EU50(nm)% inhibition (10-5M)
199971642
399936433
99888605
17100991161
18100916925
46100917263
54100 972771
123100934331
1421008721-
1921009817-

The aim of the present invention are compounds of General Formula (I), or one of their stereoisomers, or one of their salts, are acceptable for pharmaceutical use, intended for use as a medicine.

The aim of the present invention are also pharmaceutical compositions containing as active ingredient a compound of General Formula (I), or one of its stereoisomers, or one of its salts that are acceptable for pharmaceutical use in combination with a pharmaceutically acceptable carrier, as medicines. These compositions can be in the form of, for example, solid and liquid compositions, emulsions, lotions or creams.

Pharmaceutical compositions containing as active ingredient a compound of General Formula (I), or one of his with whom eriosoma, or one of its salts that are acceptable for pharmaceutical use can be used for inhibiting 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1).

Pharmaceutical compositions containing as active ingredient a compound of General Formula (I), or one of its stereoisomers, or one of its salts that are acceptable for pharmaceutical use can be used in the treatment and prevention of type 2 diabetes.

Pharmaceutical compositions containing as active ingredient a compound of General Formula (I), or one of its stereoisomers, or one of its salts that are acceptable for pharmaceutical use can be used in the treatment and prevention of disorders associated with 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1); or obesity; or dyslipidemia; or hypertension; or atherosclerosis and clinical pathologies that result from this disease, such as coronary artery stroke, or cerebrovascular strokes, or Takayasu lower extremities; or hyperglycemia; or intolerance to glucose; or resistance to insulin; or hypertriglyceridemia; or hypercholesterinemia; or restenosis, or pancreatitis; or retinopathy; or nephropathy; or neuropathies; or some types of cancer or glaucoma.

Song data can be entered in combination protivodiabeticheskie means, such as biguanides (e.g. Metformin), various forms of insulin, sulfonylureas (such as carbutamide, glibornuride, glipizide, gliclazide, glibenclamide, glimepiride), meglitinide (for example, nateglinide, Repaglinide, mitiglinide), PPAR modulators (receptor peroxisome proliferator-activated) (e.g., pioglitazone), alpha-glucosidase inhibitors (e.g. acarbose, miglitol, voglibose), analogues of GLP-1 like peptide) (for example, exenatide, liraglutide), DPP-4 inhibitors (dipeptidylpeptidase 4) (e.g., sitagliptin, vildagliptin), Amylin analogues (for example, pramlintide).

Song data can also be introduced in combination with an agent that counteracts obesity, such as orlistat or sibutramine.

As solid compositions for oral administration can be used in tablets, pills, powders (gelatin capsules, tablets or granules. In these compositions, the active ingredient according to the invention are mixed in a flow of argon with one or more than one inert diluent such as starch, cellulose, sucrose, lactose or silica. Song data in addition to diluents may also contain other substances, for example one or more lubricating substance, such as magnesium stearate or talc, a coloring agent, a coating (coated tablets) or a varnish.

As the liquid compositions for oral administration can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. Song data in addition to diluents may contain other substances, for example wetting agents, sweeteners, thickeners, corrigentov or stabilizers.

Sterile compositions for parenteral administration preferably prepared in the form of aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or carrier can be used water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic esters for injection, for example etiloleat, or other suitable organic solvents. These compositions can also contain adjuvants, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, for example by aseptic filtration, by adding to the composition sterilizing agents, by irradiation or heating. These compositions can also be prepared in the form of sterile solid compositions which can be dissolved immediately before use in sterile water or any other sterile environment for injection.

Compositions for rectal the aqueous injection can be prepared in the form of suppositories or rectal capsules, which in addition to the active product contain excipients, such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for local injection can be prepared in the form of, for example, creams, lotions, eye drops, solutions for rinsing the mouth, nasal drops or aerosols.

The doses depend on the desired effect, the duration of treatment and the route of administration, the dose for an adult subject, preferably orally, usually from 0.001 g to 1 g, preferably from 0.005 g to 0.75 g) per day, the standard dose is in the range from 0.1 mg to 500 mg of active substance. Usually the attending physician determines the appropriate dose depending on the age, weight and all other factors specific to the particular subject in need of treatment.

1. Compounds of General Formula (I):

where
R1represents a hydrogen atom; C1-C6alkyl; COR5; SO2R5; CO(CH2)mOR6;
(CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10;
m has a value from 1 to 6;
n has a value from 2 to 6;
R2represents phenyl having as substituents one or more Comodo group, selected from a halogen atom, a C1-C6of alkyl, CN, CF3, Soma, CMe(OH)CF3CH(OH)CF3, COOR7, CONR7R11; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, vinylpyridine or benzolive ring condensed with a saturated or unsaturated monocyclic the heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, non-indole, in the case when R1, R4and R'4represent a hydrogen atom, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN, CF3, OMe; cyclic or polycyclic hydrocarbon ring containing 3-12 carbon atoms; C1-C6alkyl aryl or cycloalkyl aryl,
provided that R2always linked through the carbonyl carbon atom,
and, when R2represents phenyl, Deputy COOR7is never in position 4 relative to the carbonyl;
R3represents methyl or ethyl;
R4and R'4are the same or different and represent a hydrogen atom; a halogen atom; C1-C6alkyl; NR7R8; SO2Me;
R5represents a C1-C6alkyl; phenyl, unsubstituted or having as substituents one or is more than one group, selected from a halogen atom, a C1-C6of alkyl, CN; naphthyl, unsubstituted or having as substituents one or more than one group selected from a halogen atom or C1-C6of alkyl, CN; cyclic or polycyclic hydrocarbon ring containing 3-12 carbon atoms, unsubstituted monocyclic heteroaryl containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S;
R6represents a hydrogen atom; C1-C6alkyl; phenyl, unsubstituted or having as substituents one or more than one group selected from a halogen atom; a naphthyl;
R7represents a hydrogen atom, a C1-C6alkyl;
R8represents a hydrogen atom; or naphthyl, cyclic or polycyclic hydrocarbon ring containing 3-12 carbon atoms;
R7and R8together with the nitrogen atom to which they are attached, may form a 4-6-membered ring which may contain one or more than one heteroatom selected from N, S or O and may be unsubstituted or may have as substituents one or more than one group selected from C1-C6of alkyl, C1-C6the alkyl aryl or aryl;
R9represents the Sooma, COOEt;
R10represents a halogen atom, COOH, COOR7;
R11 represents a hydrogen atom, a C1-C6alkyl, C1-C6alkyl cycloalkyl,
cycloalkyl, aryl, C1-C6alkyl aryl;
as well as their stereoisomers, salts and solvate acceptable for therapeutic use.

2. Compounds according to claim 1, wherein R1represents a hydrogen atom.

3. Compounds according to claim 1, characterized in that the OR1is a complex or a simple ester.

4. Compounds according to any one of claims 1 to 3, wherein R2represents naphthyl or 1,2,3,4-tetrahydro-naphthalene, or biphenyl, or phenyl pyridine, unsubstituted or having as substituents one or more than one group selected from a halogen atom, a C1-C6of alkyl, CN, CF3, OME, or phenyl, having as substituents one or more than one halogen atom, CN, CF3or C1-C6alkyl.

5. Compounds according to any one of claims 1 to 3, wherein R4and R'4represent a hydrogen atom.

6. The compound according to claim 1, selected from
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(adamantane-1-yl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-were)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)methanone,
(4-Ki-the Roxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-cyanophenyl)methanone,
Biphenyl-4-yl-(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(2,4-dichlorophenyl)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(adamantane-1-yl)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-were)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)methanone,
Biphenyl-4-yl-(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)methanone,
(5-Chloro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(5-Chloro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(6-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(6-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(7-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
Benzoic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarbonyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
tert-Butylcarbamoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-and the new ester,
4-Methylbenzoic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4 Chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
tert-Butylcarbamoyl acid 16-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarboxylic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Methylbenzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
tert-Butylcarbamoyl acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarboxylic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzoic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Methylbenzoic acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4 Chlorbenzoyl acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4 Chlorbenzoyl acid 6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Naphthalene-1-icarbonell acid 2-METI the-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Naphthalene-2-icarbonell acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Naphthalene-1-icarbonell acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Naphthalene-2-icarbonell acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4 Chlorbenzoyl acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4 Chlorbenzoyl acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(Naphthalene-2-yloxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo [e][1,2]thiazin-4-silt ester,
(Naphthalene-2-yloxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(Naphthalene-1-yloxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(Naphthalene-1-yloxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4 Chlorophenoxy)acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4 Chlorophenoxy)acetic acid 2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
2,4-Dichlorobenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-ilobolo ester,
4-Fermenting acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclopentane acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
2-Furan acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Thiophene-2-carboxylic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
3 Chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
2 Chlorbenzoyl acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Phenoxyalkanoic acid 2-methyl-3-(naphthalene-2-ylcarbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4-Methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4 Ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4 Propyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4 Butylochka-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4-(2-Chloroethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)methanone,
(4-[2-(Naphthalene-2-yloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) (para-tolyl)methanone,
(4-(2-Phenoxy-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
Methyl 2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-BAA is zo[e][1,2]thiazin-4-yloxy)acetate,
2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetic acid,
2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(naphthalene-1-yl)acetamide", she
2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantane-1-yl)acetamide", she
2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantane-2-yl)acetamide", she
Methyl 2-(1,1-dioxo-2-methyl-3-(4-methylbenzoyl)-2H-benzo[e][1,2]thiazin-4-yloxy)acetate,
(1,1-Dioxo-2-methyl-3-(4-methylbenzoyl)-2H-benzo[e][1,2]thiazin-4-yloxy)acetic acid,
2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidine-1-yl-ethanone,
2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazine-1-yl)-ethanone,
1-(4-Benzyl-piperazine-1-yl)-2-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethanone,
(4-Chloro-phenoxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(Naphthalene-1-yloxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(Naphthalene-2-yloxy)-acetic acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4-[2-(Naphthalene-1-yloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)methanone,
(4-[2-(4-Chlorphenoxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-the l)(para-tolyl)methanone,
Acetic acid 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Propanoic acid, 2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4 Metiloksi-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)methanone,
(4 Acyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(para-tolyl)methanone, [4-(2-Bromo-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalene-2-yl-methanone,
{4-[2-(4-Chloro-phenoxy)-ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl}-naphthalene-2-yl-methanone,
Carbonic acid ethyl 1-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethyl ester,
[2-Methyl-4-(2-piperidine-1-yl-ethoxy)-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalene-2-yl-methanone,
4-Chloro-benzoic acid 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarbonyl acid 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzoic acid, 5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Chloro-benzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarboxylic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzoic acid 6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzoe][1,2]thiazin-4-silt ester,
4-Chloro-benzoic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Cyclohexanecarbonyl acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzoic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Acetic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Phenoxy-acetic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(4-Chloro-phenoxy)-acetic acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
(5-Chloro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(5-Chloro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(6-Fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(6-Fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(6-Fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(7-Fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(7-Fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(7-Fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
[7-fluoro-2-methyl-3-(NAF the Alin-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-acetic acid methyl ester,
[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-acetic acid methyl ester,
2-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidine-1-yl-ethanone,
2-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazine-1-yl)-ethanone,
1-(4-Benzyl-piperazine-1-yl)-2-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethanone,
Benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
Benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Chloro-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Methyl-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Cyano-benzosulfimide acid 2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Chloro-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Methyl-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-silt ester,
4-Cyano-benzosulfimide acid 7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ilovekeifer,
(4-Hydroxy-2-methyl-1,1-dioxo-7-piperidine-1-yl-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(7-Dimethylamino-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-7-pyrrol one-1-yl-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
[4-Hydroxy-2-methyl-1,1-dioxo-7-(4-phenyl-piperazine-1-yl)-2H-benzo[e][1,2]thiazin-3-yl]-naphthalene-2-yl-methanone,
(7-tert-Butyl-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl) - (naphthalene-2-yl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanone,
(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro-naphthalene-2-yl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-methanone,
(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro-naphthalene-2-yl)-methanone,
(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-methanone,
(2,3-Dihydro-benzofuran-5-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2,3-Dihydro-benzo is Uran-5-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
Benzo[1,3]dioxol-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
Benzo[1,3]dioxol-5-yl-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
Benzo[b]thiophene-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
Benzofuran-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-methyl-1H-benzoimidazol-5-yl)-methanone,
Benzo[b]thiophene-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4-tert-Butyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3-Bromo-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzonitrile,
(3,4-Dimethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-trifluoromethyl-phenyl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4-trifluoromethyl-phenyl)-meth is Nona,
Adamantane-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
Chroman-6-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4-Chloro-3-trifluoromethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(7-Bromo-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(7-Chloro-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
Biphenyl-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2'-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3'-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4'-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2'-Chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3'-Chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4'-Chloro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2'-Methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3'-Methyl-bi is enyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4'-Methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(2'-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3'-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4'-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3'-trifluoromethyl-biphenyl-3-yl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4'-trifluoromethyl-biphenyl-3-yl)-methanone,
3'-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-biphenyl-3-carbonitrile,
3'-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-biphenyl-4-carbonitrile,
(4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalene-2-yl-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-phenyl-cyclopropyl)-methanone,
1-[3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-phenyl]-ethanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-Cryptor-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-Cryptor-1-hydroxy-ethyl)-phenyl]-methanone,
3-(4-Hydro is si-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzoic acid,
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N-methyl-benzamide,
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N,N-dimethyl-benzamide,
N,N-Ethyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N,N-diethyl-benzamide,
N-Cyclopropyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide
N-Cyclopropylmethyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-N-phenyl-benzamide,
N-Benzyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamide
3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzoic acid ethyl ester,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-3-yl-phenyl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-4-yl-phenyl)-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methyl-pyridin-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(5-methyl-pyridin-3-yl)-phenyl]methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methyl-pyridine-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methyl-pyridin-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methoxy-pyridine-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-fluoro-pyridin-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methoxy-pyridin-3-yl)-phenyl]-methanone,
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methoxy-pyridin-3-yl)-phenyl]-methanone,
(3-Chloro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone,
(3-Fluoro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone.

7. The method of obtaining compounds of General Formula (Ia)corresponding to the Formula I according to any one of claims 1 to 6
,
where R1represents a hydrogen atom, characterized in that an intermediate compound of General Formula (IV)
,
where R2, R4and R'4are as defined in claim 1, condensed with an intermediate compound of General Formula R3-Y, where R3is such as defined in claim 1, and Y represents a leaving group.

8. The way recip is of compounds of General Formula (Ib), corresponding to the Formula I according to any one of claims 1 to 6
,
where R1is not a hydrogen atom, characterized in that an intermediate compound of General Formula (Ia)

where R2, R3, R4and R'4are as defined in claim 1, condensed with an intermediate compound of General Formula R1-Z, where R1is the same as defined above, and Z represents a leaving group.

9. The method of obtaining compounds of General Formula (Ic)corresponding to the Formula I according to any one of claims 1 to 6
,
where R1represents (CH2)nNR7R8or (CH2)nOR6, characterized in that an intermediate compound of General Formula (V)
,
where R2, R3, R4, R'4n are as defined in claim 1, and X' represents a leaving group, is condensed with an intermediate compound of General Formula R7R8NH or R8OH, where R7R8and R6are as defined in claim 1.

10. The method of obtaining compounds of General Formula (Id)corresponding to the Formula I according to any one of claims 1 to 6
,
where R1represents (CH2)nCONR7R8, characterized in that the intermediate connection General the th of Formula (VII)

where R2, R3, R4, R'4and m are as defined in claim 1, condensed with an intermediate compound of General Formula R7R8NH, where R7and R8are as defined in claim 1.

11. The method of obtaining compounds of General Formula (If)corresponding to the Formula I according to any one of claims 1 to 6
,
where R4represents NR7R8, characterized in that an intermediate compound of General Formula (Ie)

where R2R3and R'4are as defined in claim 1, condensed with an intermediate compound of General Formula R7R8NH, where R7and R8are as defined in claim 1.

12. The method of obtaining compounds of General Formula (Ih), corresponding to the Formula I according to any one of claims 1 to 6
,
where R2is a biphenyl or phenyl pyridine, substituted or unsubstituted, wherein the intermediate compound of General Formula (Ig)

where R3, R4, R'4are as defined in claim 1, and X represents a leaving group, condense with Bronevoy acid.

13. The method of obtaining compounds of General Formula (Ik)corresponding to the Formula I according to any one of claims 1 to 6
,
where R2represents phenyl having as a substituent amide in ortho - or meta-position, characterized in that an intermediate compound of General Formula (Ij)
,
where R3, R4, R'4are as defined in claim 1, condensed with an amine of General Formula R7R11NH, where R7and R11are as defined in claim 1.

14. Compounds according to any one of claims 1 to 6 for use as medicaments for the inhibition of 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1).

15. Pharmaceutical compositions containing as active ingredient at least one compound according to any one of claims 1 to 6 in combination with a pharmaceutically acceptable carrier, as an inhibitor of 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1).

16. The pharmaceutical compositions according to § 15 for the treatment and prevention of type 2 diabetes.

17. The pharmaceutical compositions according to § 15 for the treatment and prevention of disorders associated with 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1); or obesity; or dyslipidemia; or hypertension; or atherosclerosis and clinical pathologies that result from this disease, such as coronary artery stroke, or cerebrovascular strokes, or Takayasu lower extremities; or hyperglycemia; or intolerance to gluco is e; or insulin resistance; or hypertriglyceridemia; or hypercholesterinemia; or restenosis; or pancreatitis; or retinopathy; or nephropathy; or neuropathies; or some types of cancer or glaucoma.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1): where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the following: hydrazides of general formula RC(O)NHNH2 (R=mentioned above) undergo interaction with 1,4-butanedithiol, preliminarily mixed at 20°C with water formaldehyde solution, in presence of catalyst crystallohydrate of copper chloride CuCl2·2H2O with molar ration 1,4-butanedithiol: CH2O : RC(O)NHNH2 : CuCl2·2H2O = 10:20:10:(0.3-0.7) at 75-85°C and atmospheric pressure for 44-52 h.

EFFECT: elaborated is method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 3,3'-[oxa(thia)alkane-α,ω-diyl]-bis-1,5,3-dithiazepinanes of general formula (1) R=CH2CH2OCH2CH2, (CH2CH2O)2CH2CH2, (CH2CH2S)2 , which consists in the following: oxa(thia)alkane-α,ω-diamine (3-oxapentane-1,5-diamine, 3,6-dioxaoctane-1,8-diamine, 3,4-dithiahexane-1,6-diamine) undergoes interaction with 1-oxa-3,6-dithiacycloheptane in ethanol-chloroform system of solvents in argon medium in presence of catalyst SmCl3·6H2O with molar ratio oxa(thia)alkane-α,ω-diamine: 1-oxa-3,6-dithiacycloheptane: SmCl3·6H2O = 10 : 20 : (0.3-0.7) at room (~20°C) temperature for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds which can be applied as selective sorbents and extractants of precious metals, preparations for protection of leather, fur, fabrics against biodamage, biologically active substances with respect to various microorganisms and sulfate-reducing bacteria.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely, to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1) where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the fact, that N1,N1,N8,N8-tetramethyl-2.7-dithiaoctane-1.8-diamine is subjected to interaction with hydrazide of general formula RC(O)NHNH2 [R=upper said] in presence of catalyst samarium nitrate crystalhydrate Sm(NO3)3·6H2O, at molar ratio N1,N1,N8,N8-tetramethyl-2.7-dithiaoctane-1.8-diamine: RC(O)NHNH2 : Sm(NO3)3·6H2O = 10 : 10 : (0.3-0.7) at temperature 75-85°C and atmospheric pressure in mixture of solvents ethyl alcohol-chloroform for 20-28 h.

EFFECT: method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals, is developed.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing a salt of tetrazole methanesulphonic acid of formula (I) , which involves acylating a compound (II) with a compound (III) and then adding methanesulphonic acid. The invention also relates to an intermediate compound of formula (II) and a method for production thereof.

EFFECT: method according to the present invention can cut reaction time, improve safety and enables to obtain salts of tetrazole methanesulphonic acid of high purity with high output without using a column chromatography technique.

22 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-(1,2-phenylene)-bis-1,5,3-dithiazepinane and 3,3'-[methylene-bis-(1,4-phenylene)]-bis-1,5,3-dithiazepinane of general formula (1):

, R=1,2-C6H4; 4-C6H4-CH2C6H4-4, which lies in the following: α,ω-diamines (1,2-phenylenediamine or 4,4'-diaminodiphenylmethane) is subjected to interaction with 1,3,6-oxadithiapinane in presence of catalyst Sm(NO3)3·6H2O in mole ratio α,ω-diamine : 1,3,6-oxadithiapinane : Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) in chlorophorm and argon atmosphere for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds, which cam be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

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